WO2014004676A1 - Use of faah inhibitors as neuroprotective agents in the cns - Google Patents

Abstract

The present disclosure relates to methods of using a fatty acid amide hydrolase (FAAH) inhibitor of Formula I alone or in combination with one or more additional therapeutic agents for the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

Description

USE OF FAAH INHIBITORS AS NEUROPROTECTIVE AGENTS IN THE CNS

PRIORITY CLAIM

[0001] This application claims priority to United States Provisional Application Serial No. 61/664,562, filed on June 26, 2012. The entire contents of the aforementioned application is herein incorporated by reference.

TECHNICAL FIELD

[0002] The present disclosure relates to methods of using fatty acid amide hydrolase (FAAH) inhibitors of Formula I and pharmaceutically acceptable salts thereof, alone or in combination with one or more additional therapeutic agents, for the treatment or prevention of neuronal injury or neurodegeneration in patients in need thereof. The disclosure is also directed to pharmaceutical compositions comprising FAAH inhibitors of Formula I for use in the treatment and or prevention of neuronal injury or neurodegeneration in patients in need thereof. The disclosure is also directed to kits comprising FAAH inhibitors of Formula I and their use in the treatment of patients in need thereof.

BACKGROUND

[0003] Cannabinoids are a class of diverse chemical compounds that activate cannabinoid receptors. These include the endocannabinoids (eCBs, produced naturally in the body by humans and animals), the phytocannabinoids (produced by various plants), and synthetic cannabinoids (produced chemically by man). The most notable plant cannabinoid is the phytocannabinoid A9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis. However, there exist numerous other cannabinoids with varied effects. The most important known endocannabinoids are anandamide (AEA) and 2-arachidonoyl glycerol (2- AG).

[0004] The cannabinoid receptors (CBRs) CB 1 and CB2 are G-protein-coupled receptors (GPCRs) identified as receptors for cannabinoids. CBl is preferentially expressed in the brain where it mediates the psychoactivity of cannabinoids. High levels of CBl receptors are found in the basal ganglia, hippocampus, cerebellum and cortical structures. CB2 is highly expressed in immune cells (e.g., B cells, natural killer cell, monocytes, microglial cells, neutrophils, T cells, dendritic cells, mast cells). Interactions with these receptors may be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis. It has also been found that CB1 is expressed by some cells of the immune system and that CB2 is expressed by some cells of the central nervous system (CNS).

[0005] Levels of eCBs have been shown to be elevated after neuronal injury, suggesting a potential compensatory response comprising possibly several CB1- and/or CB2-linked signaling events involved in cellular repair. For instance, it is thought that local cerebral ischemia and traumatic brain injury induce an escalating amount of cell death because harmful mediators diffuse from the original lesion site, and evidence suggests that healthy cells surrounding these lesions attempt to protect themselves by producing endocannabinoids and activating cannabinoid receptors. Supporting this view, it was found that blocking CB1 receptors pharmacologically disrupts neuronal maintenance and increases excitotoxic vulnerability. It was also found that mice that lack the receptors are more susceptible to ischemia, seizure induction and neuroinflammation damage.

[0006] Both CB1 and CB2 receptors also play a role in the regulation of CNS autoimmune inflammation. There are a number of potential routes for neuroprotection in

neuroinflamrnatory diseases. This can be achieved by preventing the immune response from either being generated or from entering the CNS. This will prevent direct CNS damage by the immune system. Another route is to slow nerve damage that occurs as a consequence of the immune attack. Cannabinoids have the potential to inhibit both of these pathways, suggesting that cannabinoids could influence the development of progressive neurodegenerative disorders such as multiple sclerosis (MS).

[0007] As a result, there has recently been considerable interest in the potential abilities of cannabinoids or cannabinoid mimetics to act as neuroprotective agents in different pathological situations. The first report in brain ischemia dates back to 1994.

[0008] While activation of CB1 receptors has a psychotropic effect, activation of CB2 receptors alone does not. Therefore, considerable effort has been made to study the potential therapeutic value of activating specifically CB2 receptors even if there is increasing evidence that CBs can induce certain effects independently of CB1 or CB2.

[0009] Of even greater interest is the therapeutic potential of inhibitors of anandamide (AEA) uptake as well as of inhibitors of its degradation by fatty acid amide hydrolase (FAAH) for the treatment of neuronal injury and neurodegeneration. In the latter approach, the beneficial effects of cannabinoid activation (to elevate the endocannabinoid tone) are achieved by inhibition of their degradation rather than by global cannabinoid activation, which is associated with many undesirable effects. In addition, FAAH inhibitors may provide a functionally selective way of enhancing endocannabinoid tone only in those tissues and cells with active synthesis and release of eCBs.

[0010] Experimental work has provided robust evidence of the immunomodulatory and neuroprotective properties of cannabinoids in animal models of both acute neuronal injury and progressive neurodegeneration. For instance, in animal models of stroke and traumatic brain injury, dual modulation with a FAAH transport inhibitor (AM404) and a FAAH inhibitor (AM374), provided cytoskeletal, synaptic, and cellular protection as well as reduction of behavioral correlates with brain damage. Similarly, the FAAH inhibitors URB597 and AM374 were able to achieve positive results in animal models of seizure induced by exposure to neurotoxic substances.

[0011] Evidence has also shown that the cannabinoid receptor system has potential to reduce excitotoxic and oxidative cell damage, two of the hypotheses underlying motor neuron damage in amyotropic lateral sclerosis (ALS), and to have potent anti-inflammatory and neuroprotective effects. It was shown that THC inhibits both excitotoxic and oxidative damage in spinal cord cultures and that THC slows the progression and improves survival in an Amyotropic Lateral Sclerosis (ALS) mouse model (hSODl transgenic mice) even when administered after the onset of disease signs. Furthermore, the selective CB2 agonist AM 1241, which has been found to be effective in models of inflammation and hyperalgesia, was also found to delay disease progression in a mouse model of ALS.

[0012] Furthermore, CBl receptor populations have been shown to be significantly decreased in the basal ganglia during Huntington's disease (HD) progression, leading to the hypothesis that enhancement of CBl receptor signaling may result in symptomatic improvement.

Cannabinoid agonists have been proposed as potential neuroprotective agents in the setting of Huntington's disease, due to their ability to activate CB2 receptors on glial cells, thereby reducing inflammatory events, and to normalize glutamate homeostasis via CBl receptor modulation, hence limiting excitotoxicity. Several CB agonists are currently being studied in the clinic for the treatment of HD.

[0013] In animal models of Parkinson's disease (PD), the FAAH inhibitor URB597 administered together with quinpirole was able to improve the motor deficits of mice treated with reserpine or 6-OHDA. The same compound was shown to minimize the retinal damage observed in ischemic-reperfused samples after high intraocular pressure-induced ischemia in rats.

[0014] Similarly, administration of CB2 agonists to an animal model of MS reduced disease severity. In ABH mice, doses of WIN (5 mg/Kg) (a dual CB1/CB2 receptor agonist) that were devoid of both cannabinomimetic and immunosuppressive effects reduced clinical scores in the remission phase of MS. This was associated with lower neuronal deficit as revealed by increased levels of neurofilaments in the spinal cords compared with the untreated mice. In the chronic relapsing experimental autoimmune encephalomyelitis (CREAE) model of MS, limb spasticity was attenuated by each of the endocannabinoids AEA, 2-AG or PEA, or exogenous cannabinoids or cannabinoid modifiers WIN, AM404 (a transport inhibitor), AM374 (a FAAH inhibitor), VDM11 (a re-uptake inhibitor), OMDM1 (FAAH re-uptake inhibitor), OMDM2 (FAAH re-uptake inhibitor) or UCM707 (FAAH reuptake inhibitor). It appears that both CB1 and CB2 receptors may have a role in this improved symptomatic profile. While the CBl-selective antagonist SR141716A more efficiently antagonized the improvement in spasticity and tremor, the CB2-selective ligand JWH-133 was also able to reduce spasticity, at a dose which was sub-effective via CB1. In support of this conclusion, recent studies in cannabinoid deficient animals have suggested that both CB 1 and CB2 agonism may be of benefit in controlling autoimmunity in experimental autoimmune encephalomyelitis (EAE) animals. In a further investigation, using exogenous CB1 and CB2 selective agents, it was found that although CB1 mediated immunosuppression was detectable, cannabinoid mediated neuroprotection may be more relevant to clinical applications of cannabis in MS. The re-uptake inhibitors OMDM1, OMDM2 and UCM707 were shown to down-regulate inflammatory responses in the spinal cord and ameliorate motor symptoms in experimental models of MS, through the enhancement of AEA levels. In studies employing the Theiler's murine encephalomyelitis virus induced demyelinating disease (TMED-IDD) model, UCM707 treatment during established disease significantly improved the motor function of diseased mice. At the histological level, reduction of microglial activation, diminished major histocompatibility complex class II antigen expression, and decreased cellular infiltrates in the spinal cord (all markers of neuroinflammation) where observed. Additionally in microglial cells, decreased production of proinflammatory cytokines, reduction of nitric oxide (NO) levels and inducible nitric oxide synthase (iNOsynthase) expression was also measured. Cannabinoid agonists are currently under development for the treatment of neuropathic pain and spasticity in MS.

[0015] In line with these results, mice lacking the FAAH enzyme were found to exhibit a more substantial clinical remission than wild-type animals in the CRAE animal model of MS, further suggesting that elevation of endocannabinoid tone may have a neuroprotective effect in MS.

[0016] Disease-modifying drugs, which include anti-inflammatory, immunomodulating and immunosuppressive agents, are administered for the purpose of preventing or postponing long-term disability and have the potential to significantly alter the course of disease when administered to patients in the early stages of multiple sclerosis or following a clinically isolated syndrome, before irreversible axonal injury occurs. Their treatment effect in the progressive stages of the disease, however, appears to be modest, and in fact no long-term studies yet have demonstrated that these drugs are actually able to decrease the incidence of secondary progression. The results of clinical studies with CBs on humans are somewhat equivocal, showing improvements of patient reported subjective measures of pain and spasticity, whereas objective measures failed to be significantly changed. Considering the actions demonstrated experimentally in animal models, cannabinoids or compounds acting on the CB system are still very promising agents to target the aforementioned human diseases.

(0017] Most FAAH inhibitors that have been profiled to date in these conditions are covalent binders that irreversibly modify the enzyme and thus have little therapeutic use. Small molecule inhibitors with different FAAH binding modes may enable condition-specific fine tuning of any associated pharmacotherapeutic/neuroprotective responses while helping to avoid the off-target effects seen so far with covalent FAAH inhibitors. Clearly, there is a need for better methods to treat neuronal injury and neurodegeneration by the administration of non-covalent inhibitors of FAAH with better selectivity and in the case of progressive neurodegenerative disease, with longer duration of action.

SUMMARY

[0018] In one aspect, the invention provides a method of treating or preventing neuronal injury or neurodegeneration in a patient in need thereof, comprising administering a therapeutically or prophylactically effective amount of a FAAH inhibitor of Formula I, or pharmaceutically acceptable salt thereof, alone or in combination with a therapeutically or prophylactically effective amount of one or more additional therapeutic agents to said patient, wherein the compound of Formula I has the structure depicted below:

Formula I and V, W, X, Y are either C or N; Z, J, K, L are C; and M is N; Q¹ is N; Q², Q⁴ and Q⁵ are C; and Q³ is either C or N; a) each of P¹, P², P³, P⁴, P⁵ and P⁶ are C; or b) up to two of P¹, P², P³, P⁴, P⁵ and P⁶ are N and the rest are C:

A and A' taken together are =0; indicates an aromatic bond;

R² is hydroxyl, an optionally independently substituted Ci-3 alkyl, an optionally

independently substituted Ci_-2 alkoxy or an optionally independently substituted cyclopropyl; each of R⁴, R⁵, R⁶ and R⁷ is independently: H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci_-5 alkyl, an optionally independently substituted C_2- 5 alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted C_l-5 alkoxy, -OC(0)(C,_-5 alkyl) , -C(0)(C,_-5 alkyl), -C(0)NR^aR^b ,

-C(0)NR^a(CO)OR^b, -NR (CO)(C alkyl) or -NR^aR^b, wherein R^a and R^b are independently H, an optionally independently substituted alkyl, or an optionally independently substituted C3-6 cycloalkyi; and wherein the optional substituent on each of R⁴, R⁵, R⁶ and R⁷ that is optionally substituted, is independently selected from hydroxyl, halogen, -0(CO)(Ci-6 alkyl), CM alkoxy, or -NR^aR^b, with R^a and R^b as defined above; each of R⁸, R⁹, R¹⁰, R¹' and R¹², when bonded to C, is independently: H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, -S0₂(Ci-₄ alkyl), an optionally independently substituted Ci_-5 alkyl, an optionally independently substituted C_2-5 alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted C₁-5 alkoxy, -C(0)NR^aR or -NR^aR^b, wherein R^a and R^b are independently H, an optionally independently substituted Q.₆ alkyl, or an optionally independently substituted C3.₆ cycloalkyi; and wherein the optional substituent on each of R4, R₅, R_$ and R₇ that is optionally substituted, is independently selected from hydroxyl, halogen or C 1-4 alkoxy; or each of R⁸, R⁹, R¹⁰ R¹¹ and R¹², when bonded to N, is missing;

R¹⁴ is selected from H, a halogen, -NO?, -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci_-5 alkyl, an optionally independently substituted C₂.₅ alkenyl, an optionally independently substituted C₂.₅ alkynyl, an optionally independently substituted Q.5 alkoxy, -C(0)NR^aR^b or -NR R^b, wherein R⁸ and R^b are independently H, an optionally independently substituted C|_₆ alkyl, or an optionally independently substituted C_3-6 cycloalkyi;

R¹⁶ is selected from H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci_-5 alkyl, an optionally independently substituted C_2-5 alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted C₁.5 alkoxy, -C(0)NR^aR^b or -NR^aR^b, wherein R^a and R^b are independently H, optionally independently substituted Ci_₆ alkyl, or an optionally independently substituted C₃.₆ cycloalkyi;

R¹⁵ is missing;

R¹³ is selected from H, a halogen, -NO₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted C_\s alkyl, an optionally independently substituted C_2-5 alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted Ci_5 alkoxy, -C(0)NR^aR^b, or-NR^aR^b, wherein R^a and R^b are independently H, optionally

independently substituted C|_-6 alkyl, or an optionally independently substituted C3_-6

cycloalkyl;

R¹⁷ is selected from H, a halogen, -N0₂, -CN, -C(0)OH, hydroxy 1, an optionally

independently substituted Ci_-5 alkyl, an optionally independently substituted C_2-5 alkenyl, an optionally independently substituted C2-5 alkynyl, an optionally independently substituted Ci_-5 alkoxy, -C(0)NR^aR^b or -NR^aR_b, wherein R^a and R^b are independently H, optionally

independently substituted Ci_-6 alkyl, or an optionally independently substituted C_3-6

cycloalkyl.

[0019] In some aspects, the patient in need thereof is a person who has suffered one or more sudden or acute neuronal events selected from a stroke, brain or spinal cord injury, traumatic brain injury, brain ischemia, ischemia of the eyes, epileptic seizure, seizures associated with brain injury, epileptic seizure of genetic origin, brain damage due to drug abuse or brain damage due to excitotoxic insult. In some aspects, the patient in need thereof is a person who has been diagnosed with or is believed to be at risk of developing a neurodegenerative disorder selected from: a motor neuron disease, multiple sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease or a dementia, a neuroinflammatory disease, or an autoimmune disease.

[0020] In some aspects, the method results in halting or slowing down of neuronal degeneration in a patient that exhibits symptoms associated with neuronal injury or neurodegeneration, prolonged survival or delayed disease progression; in neurogenesis; or in a measurable improvement in a symptom selected from: a cognitive dysfunction, a motor dysfunction, lack of coordination, de- myelination or diminished strength; and in some aspects, also results in an observable or measurable reduction in neuroinfiammation or neuroinflammatory processes or spasticity.

[0021] In a further aspect, the invention also provides a method for the use of a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

[0022] In another aspect, the invention provides pharmaceutical compositions comprising a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents, for use in the treatment of neuronal injury or

neurodegeneration in a patient in need thereof.

[0023] In another aspect, the invention provides the use of a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

[0024] In another aspect, the invention provides a FAAH inhibitor of Formula I, or a

pharmaceutically acceptable salt thereof, for use in the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

[0025] In still a further aspect, the invention provides a kit comprising at least two separate unit dosage forms (A) and (B), wherein (A) is a therapeutic agent, a combination of more than one therapeutic agent, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and (B) is a FAAH inhibitor of Formula I, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is an illustrative diagram of assessment using the clinical scoring scale used in the Examples below, as well as typical daily average responses in the chronic relapsing experimental allergic encephalomyelitis animal model post induction;

[0027] Figure 2 is a graph of mean clinical scores of 2-(5-chloro-l-(4-chlorobenzyl)-2-methyl-lH- indol-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide [Compound No. 13], THC and vehicle treatment groups in relapse phase EAE;

[0028] Figure 3 is a graph of mean RotoRod performance of 2-(5-chloro- 1 -(4-chlorobenzyl)-2- methyl-lH-indol-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide [Compound No. 13], THC- and vehicle treatment groups in pre and post relapse phase EAE;

[0029] Figure 4 is a graph of mean RotoRod performance of 2-(5-chloro-l-(4-chlorobenzyl)-2- methyl-lH-indol-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide [Compound No. 13], THC- and vehicle treatment groups;

[0030] The figures are provided by way of examples and are not intended to limit the scope of the present invention.

DETAILED DESCRIPTION

[0031] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulae. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein but include any methods and materials similar or equivalent to those described herein that could be used in the practice of the present invention. In the event that one or more of the incorporated literature references, patents or similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques or the like, this application controls. The compounds described herein may be defined by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

Therapeutic Methods

[0032] As used herein, the terms "subject" and "patient" are used interchangeably to refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a

"mammal" including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more

preferably a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject or patient is a human.

[0033] As used herein, the term a "patient in need thereof is used to refer to a patient

suffering from neuronal injury or neurodegeneration that occurs as a result of an acute event (e.g., a stroke or central nervous system injury/trauma) or as a result of a chronic

neurodegenerative process. Said acute neuronal injury or progressive neurodegenerative process may affect the neurons of the central nervous system (CNS), composed of the brain and spinal cord, or the peripheral nervous system, and may eventually progress to neuronal death.

[0034] As used herein, the term "neuronal injury" refers to the damage to the function or structure (e.g., cytoskeletal damage) of neurons as a result of an insult (e.g., exposure to neurotoxins) or trauma (e.g., traumatic brain injury, concussive head trauma) to the nervous system. Neuronal injury is associated with, for instance: stroke, ischemic events (e.g., brain ischemia, ischemia of the eyes), seizures of diverse etiology (epileptic, associated with brain injury, of genetic origin), spinal cord injury or trauma, brain damage due to drugs of abuse, or excitotoxic insults of diverse nature.

[0035] As used herein, the term "neurodegeneration" is an umbrella term used to refer to the progressive loss of individual or collective structure or function of neurons, up to and including the death of neurons that is associated with many neurodegenerative diseases.

[0036] As used herein, the term "neurodegenerative disease(s)" is used to refer to medical conditions that are characterized clinically by their insidious onset and chronic progression. In many instances, particular parts of the brain, spinal cord, or peripheral nerves functionally fail and the neurons of the dysfunctional region die. Neuroanatomically localizable functional impairment and "neurodegeneration" associate with recognizable syndromes or conditions that are ideally distinct, although in clinical and even neuropathologic practice substantial overlap exists. Neurodegenerative diseases are often categorized by whether they initially affect cognition, movement, strength, coordination, sensation, or autonomic control.

Frequently, however, patients will present with symptoms and signs referable to more than one system. Either involvement of several systems can occur concomitantly, or else by the time the patient has functionally declined enough to seek medical attention multiple systems have become involved. In many cases, the diagnosis of a neurodegenerative disease cannot be critically 'confirmed' by a simple test.

[0037] The term "neurodegenerative" implies the loss of neurons that cause disease.

However, it is possible that neuronal demise is merely the final stage of a preceding period of neuron dysfunction. It is difficult to know whether clinical decline associates with actual neuron loss, or with a period of neuron dysfunction that precedes neuron loss. Also, particular neurodegenerative diseases are etiologically heterogeneous. In addition to syndromically defining neurodegenerative diseases by what neuro-anatomical system is involved, these disorders are broken down along other clinical lines. Early (childhood, young adulthood, or middle aged adulthood) versus late (old age) onset is an important distinction. Some clinically similar neurodegenerative diseases are sub-categorized by their age of onset, despite the fact that at the molecular level different forms of a particular disease may have very little in common. Sporadic onset versus Mendelian (genetic) inheritance constitutes another important distinction, and many named neurodegenerative diseases have both sporadic (wherein Mendelian inheritance is not recognizable) and Mendelian subtypes.

[0038] A list of example neurodegenerative diseases has been collected below, grouped by their main symptom(s) or impairment(s) in affected subjects. This list is not inclusive, and diseases can present in ways in which they have not been listed herein.

Cognition Movement Strength Coordination ¹ Myelin

Alzheimer's Parkinson's Amyotrophic Spinocerebellar Multiple disease (AD) disease (PD) ; lateral sclerosis atrophies Sclerosis (MS)

(ALS)

Frontotemporal Frontotemporal Friedreich's Charcot Marie dementia dementia Frontotemporal ataxia Tooth

dementia

Dementia with Dementia with Prion disorders

Lewy bodies Lewy bodies Hereditary spastic

paraparesis

Corticobasal Corticobasal

degeneration degeneration

Progressive Progressive

supranuclear supranuclear palsy

palsy

Huntington's

Prion disorders disease (HD)

Multiple system

atrophy

[0039] Some common symptoms of degenerative disorders of the brain are memory loss, personality changes, problems with movement, weakness, or poor balance or coordination.

[0040] The following neurodegenerative diseases may present with memory loss or personality change: Alzheimer's disease, Frontotemporal Dementias, Dementia with Lewy Bodies, Prion diseases.

[0041] The following neurodegenerative diseases may present as problems with movement: Parkinson's disease, Huntington's disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, Multiple System Atrophy.

[0042] The following neurodegenerative diseases may present as weakness: amyotrophic lateral sclerosis, inclusion body myositis, degenerative myopathies.

[0043] The following neurodegenerative diseases can present as poor balance: the spinocerebellar atrophies.

[0044] Disorders of myelin include multiple sclerosis and Charcot-Marie-Tooth disease.

[0045] The term "motor neuron diseases" (MNDs) refers to a group of progressive neurological disorders that destroy motor neurons, the cells that control essential voluntary muscle activity such as speaking, walking, breathing, and swallowing. The best-known motor neuron disease is amyotrophic lateral sclerosis (ALS). Normally, messages from nerve cells in the brain (called upper motor neurons) are transmitted to nerve cells in the brain stem and spinal cord (called lower motor neurons) and from them to particular muscles. Upper motor neurons direct the lower motor neurons to produce movements such as walking or chewing. Lower motor neurons control movement in the arms, legs, chest, face, throat, and tongue. Spinal motor neurons are also called anterior horn cells. Upper motor neurons are also called corticospinal neurons.

[0046] When there are disruptions in the signals between the lowest motor neurons and the muscle, the muscles do not work properly; the muscles gradually weaken and may begin wasting away and develop uncontrollable twitching (called fasciculations). When there are disruptions in the signals between the upper motor neurons and the lower motor neurons, the limb muscles develop stiffness (called spasticity), movements become slow and effortful, and tendon reflexes such as knee and ankle jerks become overactive. Over time, the ability to control voluntary movement can be lost. The following is a list of the most common MNDs: Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, progressive bulbar palsy, also called progressive bulbar atrophy, pseudobulbar palsy, Primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA) and some of its variants (e.g., SMA type I, also called Werdnig-Hoffmann disease, SMA type II, SMA type III also called Kugelberg-Welander disease, congenital SMA with arthrogryposis, Kennedy's disease, also known as progressive spinobulbar muscular atrophy and post-polio syndrome (PPS)).

[0047] As used herein, the term "neuroprotection" includes the set of mechanisms and strategies used to protect against neuronal injury or degeneration in the CNS, following acute events (e.g., stroke or nervous system injury/trauma) or that occurs as a symptom of chrome neurodegenerative diseases (e.g., Parkinson's, Alzheimer's, Multiple Sclerosis, Huntington's, ALS). The goal of neuroprotection is to limit neuronal dysfunction/death after CNS injury or onset of neuronal degeneration and attempt to maintain the highest possible integrity of cellular interactions in the brain resulting in an undisturbed neural function. There is a wide range of neuroprotection products available or under investigation and some products can potentially be used in more than one disorder, as many of the underlying mechanisms of damage to neural tissues (in both acute disorders and in chronic neurodegenerative diseases) are similar. In the instant disclosure, "neuroprotection" is achieved by using a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt or composition thereof, either alone or in combination with another therapeutic agent, to impart a protective effect in the CNS against neurodegenerative disease or neuronal injury.

[0048] As used herein, a "neuroprotecting agent" is any pharmaceutical product that is used to achieve partial or complete neuroprotection. In general, products with neuroprotective effects may be grouped into one or more of the following categories:

~ Free radical trappers/scavengers (antioxidants)

— Anti-excitotoxic agents

— Apoptosis (programmed cell death) inhibitors

— Anti-inflammatory agents

— Neurotrophic factors

— Metal ion chelators

— Ion channel modulators

— Gene therapy

[0049] As used herein, the term "neurotoxicity" is used to define what occurs when exposure to natural or artificial toxic substances, which are called "neurotoxins", alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or kill neurons. Neurotoxicity can result, for instance, from exposure to substances used in chemotherapy, radiation treatment, drug therapies, abuse of certain drugs, and organ transplants, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and also to some endogenous substances that occur in the body.

[0050] As used herein, the term "neurotoxic" is used to describe a substance, condition or state that damages the nervous system, usually by killing or disrupting the normal structure or function of neurons. The term is generally used to describe a condition or substance that has been shown to result in observable physical damage. The presence of neurocognitive deficits, alone, is not usually considered sufficient evidence of neurotoxicity, as many existing substances may impair neurocognitive performance without resulting in the death of neurons. This may be due to the direct action of the substance, with the impairment and neurocognitive deficits being temporary, and resolving when the substance is metabolized from the body. In some cases the level or exposure-time may be critical, with some substances only becoming neurotoxic in certain doses or time periods. Some of the most common naturally occurring brain toxins that lead to neurotoxicity as a result of excessive dosage are endogenous substances such as beta amyloid (Αβ), glutamate and oxygen radicals. When present in excessive concentrations in the CNS they can lead to neurotoxicity and neuronal death (apoptosis).

[0051] As used herein, the term "excitotoxicity" is used to refer to the pathological process by which nerve cells are damaged and/or killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and A PA receptor are over-activated. "Excitotoxins" like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of endogenous glutamate, can cause excitotoxicity by allowing high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes. These enzymes then go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. Excitotoxicity occurs in many diseases or conditions that may be acute (e.g., hypoglycemia, seizures, stroke, epileptic seizures, or spinal cord injury, traumatic brain injury) or chronic neurodegenerative disease (e.g., dementias, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, multiple sclerosis and Parkinson's disease).

[0052] For instance, this pathologic phenomenon can occur after brain injury and spinal cord injury, wherein, within minutes after spinal cord injury, damaged neurons within the lesion site spill glutamate into the extracellular space where glutamate can stimulate presynaptic glutamate receptors to enhance the release of additional glutamate. Brain trauma or stroke can cause ischemia, in which blood flow is reduced to inadequate levels. Ischemia is then followed by accumulation of glutamate and aspartate in the extracellular fluid, causing cell death, which is aggravated by lack of oxygen and glucose. The biochemical cascade resulting from ischemia and involving excitotoxicity is called the ischemic cascade.

[0053] "Glial cells", sometimes called "neuroglia" or simply "glia" are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain and in other parts of the nervous system such as in the autonomic nervous system.

In the human brain, there is roughly one glia for every neuron. There is currently believed to be four main functions of glial cells: to surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy pathogens and remove dead neurons (immunoregulation). For over a century, it was believed that they did not play any role in neurotransmission. That idea is now discredited; it is known that they do modulate neurotransmission, although the mechanisms are not yet well understood.

[0054] The term "neuroinflammation" refers to the process in which the brain responds to infections, diseases and injuries (collectively usually referred to as "insults")

Neuroinflammation involves immune cells of the hematopoietic system (lymphocytes, monocytes and macrophages) as well as microglial cells of the CNS. Neuroinflammation disrupts the blood-brain barrier (BBB), allowing cells from the hematopoietic system to leave the blood stream and come in contact to the injury site. The immune cells respond to injuries by eliminating debris and, synthesizing and releasing a host of powerful regulatory substances, like the complements, cytokines, chemokines, glutamate, interleukins, nitric oxide, reactive oxygen species and transforming growth factors. These substances may have both beneficial and harmful effects on the cellular environment, creating further damages. Mature astrocytes are also activated following injury to the CNS. Astrocytic activation is believed to be necessary for containing the immune response, repairing the BBB and attenuating further neuronal death.

[0055] In the CNS, neuroinflammation occurs following traumatic brain injuries, spinal cord injuries and cerebral strokes. It involves immune cells from the hematopoietic and central nervous system. It is now also well documented that neuroinflammation is actively involved in neurological diseases and disorders, like AD, PD, ALS, depression, epilepsy, HD, MS and PD. For instance, in AD, there is a correlation between local inflammation, and presence of amyloid plaques and neurofibrillary tangles.

[0056] While an acute insult may trigger "oxidative and nitrosative stress", it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. In contrast,

"chronic neuroinflammation" is a long-standing and often self-perpetuating

neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines.

[0057] "Neurogenesis" occurs in the brain and neuronal stem cells (NSCs) reside in the CNS of adult mammals, in various species including humans. NSCs are the self-renewing multipotent cells that generate the main phenotypes of the nervous system. Neurogenesis is known to be modulated in the brain of patients and in animal models of neurological diseases and disorders, like Alzheimer's disease (AD), epilepsy and Huntington's disease (HD).This suggests that the adult brain may be amenable to repair and that adult neurogenesis may contribute to the functioning, and physiology and pathology of the CNS, particularly to the etiology of neurological diseases and disorders.

[0058] As used herein, the term "treat", "treating" or "treatment" with regard to a disorder or disease refers to alleviating or abrogating the cause and/or the effects of the disorder or disease. As used herein, the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of the progression, severity and/or duration of a condition that can be treated with a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of said condition, resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound of Formula I or a pharmaceutically acceptable salt or pharmaceutical composition thereof ). In specific embodiments, the terms "treat,"

"treatment" and "treating" refer to the amelioration of at least one measurable physical parameter of a condition that can be treated with a FAAH inhibitor of Formula I. In other embodiments the terms "treat", "treatment" and "treating" refer to the inhibition of the progression of said condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.

[0059J In particular, the terms "treat", "treatment" and "treating" as it pertains to the use of a

FAAH inhibitor of Formula I as a neuroprotecting agent as described in the instant disclosure, refers to the halting, ameliorating or slowing down of neuronal degeneration in a patient that exhibits the symptoms associated with neuronal injury or neurodegeneration, or achieving prolonged neural survival, or delayed disease progression. The treatment with a

FAAH inhibitor of Formula I or a pharmaceutically acceptable salt or composition thereof, may also result in neurogenesis or creation of new neurons. These processes manifest themselves in a halting or slowing of progression of the disease or in the improving of one or more symptoms associated with it.

[0060] As used herein, the terms "prevent", "preventing" and "prevention" with regard to a disorder or disease that can be treated with a FAAH inhibitor of Formula I or a

pharmaceutically acceptable salt or composition thereof, refer to averting the cause and/or effects of a disease or disorder prior to the disease or disorder manifesting itself. The terms "prophylaxis" or "prophylactic use", as used herein, refer to any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease. As used herein, the terms "prevent", "prevention" and "preventing" may refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject.

[0061] In one aspect, the invention provides a method of treating or preventing neuronal injury or neurodegeneration in a patient in need thereof, comprising administering a therapeutically or prophylactically effective amount of a FAAH inhibitor of Formula I, or pharmaceutically acceptable salt thereof, alone or in combination with a therapeutically or prophylactically effective amount of one or more additional therapeutic agents to said patient.

[0062] It also provides a method for the use of a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

[0063] In another aspect, the invention provides a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

[0064] In another aspect, the invention provides pharmaceutical compositions comprising a FAAH inhibitor of Formula I, or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents, for use in the treatment of neuronal injury or neurodegeneration in a patient in need thereof.

[0065] In still a further aspect, the invention provides a kit comprising at least two separate unit dosage forms (A) and (B), wherein (A) is a therapeutic agent, a combination of more than one therapeutic agent, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and (B) is a FAAH inhibitor of Formula I, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [0066] In one embodiment of the above methods, compositions and kits, the patient in need thereof is a person who has suffered one or more sudden or acute neuronal events selected from a stroke, brain or spinal cord injury, traumatic brain injury, brain ischemia, ischemia of the eyes, epileptic seizure, seizures associated with brain injury, epileptic seizure of genetic origin, brain damage due to drug abuse or brain damage due to excitotoxic insults of diverse nature.

[0067] In some embodiments, the sudden or acute neuronal event is a stroke.

[0068] In other embodiments, the sudden or acute neuronal event is brain or spinal cord injury.

[0069] In other embodiments, the sudden or acute neuronal event is an epileptic seizure.

[0070] In other embodiments, the sudden or acute neuronal event is brain damage due to abuse of one or more drugs.

[0071] In other embodiments, the sudden or acute neuronal event is brain damage due to an excitotoxic insult. In some embodiments, the excitotoxic insult is caused by excessive concentrations of endogenous neurotransmitters. In other embodiments, the excitotoxic insult is caused by an exogenous substance.

[0072] In another embodiment of the above methods, compositions and kits, the patient in need thereof is a person who has been diagnosed or is believed to be at risk of developing a neurodegenerative disorder selected from: a motor neuron disease, multiple sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease or a dementia.

[0073] In some embodiments, the neurodegenerative disease or disorder is a motor neuron disease. In some embodiments said motor neuron disease is selected from Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, progressive bulbar palsy, also called progressive bulbar atrophy, pseudobulbar palsy, Primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA) and some of its variants (e.g., SMA type I, also called Werdnig-Hoffrnann disease, SMA type II, SMA type III also called Kugelberg- Welander disease, congenital SMA with arthrogryposis, Kennedy's disease, also known as progressive spinobulbar muscular atrophy and post- polio syndrome (PPS)). In other embodiments, the neuron motor disease is ALS.

[0074] In some embodiments, the neurodegenerative disease or disorder is multiple sclerosis. [0075] In some embodiments, the neurodegenerative disease or disorder is Parkinson's disease.

[0076] In some embodiments, the neurodegenerative disease or disorder is Huntington's disease.

[0077] In some embodiments, the neurodegenerative disease or disorder us Alzheimer's disease or a dementia.

[0078] In some embodiments, the neurodegenerative disease is a neuroinflammatory disease. In other embodiments, the neurodegenerative disease is an autoimmune disease.

[0079] In some embodiments of the above methods and uses, the administration of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another therapeutic agent, results in: halting or slowing down of neuronal degeneration in a patient that exhibits symptoms associated with neuronal injury or neurodegeneration, prolonged survival or delayed disease progression. In other embodiments, it may result in neurogenesis.

[0080] In some embodiments of the above methods and uses, the administration of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another therapeutic agent, results in the improvement of a symptom selected from: a cognitive dysfunction, a motor dysfunction, lack of coordination, de-myelination or diminished strength.

[0081] In some embodiments of the above methods and uses, the administration of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another therapeutic agent, to a patient in need thereof, is aimed at treating a symptom selected from: sleep disturbances, depression, anxiety, pain, erectile dysfunction, spasticity, bladder dysfunctions, fatigue, acute exacerbations, itching, nausea, vomiting, dizziness, walking difficulties, tremors. In some of these embodiments, the patient has been diagnosed with multiple sclerosis.

[0082] In some embodiments of the above methods and uses, the administration of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another therapeutic agent, also results in an observable or measurable reduction in neuroinflammation or neuroinflammatory processes. [0083] In some embodiments of the above methods and uses, the administration of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another therapeutic agent, also results in a simultaneous observable or measurable reduction in spasticity.

[0084] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, the FAAH inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt thereof:

Formula I and V, W, X, Y are either C or N; Z, J, K, L are C; and M is N;

Q¹ is N; Q², Q⁴ and Q⁵ are C; and Q³ is either C or N; a) each of P¹, P², P³, P⁴, P⁵ and P⁶ are C; or b) up to two of P¹, P², P³, P⁴, P⁵ and P⁶ are N and the rest are C;

A and A' taken together are =0; indicates an aromatic bond; R² is hydroxyl, an optionally independently substituted Ci_-3 alkyl, an optionally

independently substituted Ci_-2 alkoxy or an optionally independently substituted cyclopropyl; each of R⁴, R⁵, R⁶ and R⁷ is independently: H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted C1.5 alkyl, an optionally independently substituted C_2- 5 alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted C1.5 alkoxy, -OC(0)(C_(-5 alkyl) , -C(0)(C,.₅ alkyl), -C(0)NR^aR^b ,

-C(0)NR^a(CO)OR^b, -NR^a(CO)(C_M alkyl) or -NR^aR^b, wherein R^a and R^b are independently H, an optionally independently substituted Q.₆ alkyl, or an optionally independently substituted C₃.₆ cycloalkyl; and wherein the optional substituent on each of R⁴, R⁵, R⁶ and R⁷ that is optionally substituted, is independently selected from hydroxyl, halogen, -0(CO)(Ci-6 alkyl), Ci^ alkoxy, or -NR^aR^b, with R^a and R^b as defined above; each of R⁸, R⁹, R¹⁰, R¹¹ and R¹², when bonded to C, is independently: H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, -S0₂(C 1.4 alkyl), an optionally independently substituted C\.s alkyl, an optionally independently substituted C₂.₅ alkenyl, an optionally independently substituted C₂.s alkynyl, an optionally independently substituted Ci-5 alkoxy, -C(0)NR⁸R or -NR^aR^b, wherein R^a and R^b are independently H, an optionally independently substituted Ci.₆ alkyl, or an optionally independently substituted C_3-6 cycloalkyl; and wherein the optional substituent on each of R4, R5, R_$ and R₇ that is optionally substituted, is independently selected from hydroxyl, halogen or C alkoxy; or each of R⁸, R⁹, R¹⁰ R¹¹ and R¹², when bonded to N, is missing;

R¹⁴ is selected from H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci_-5 alkyl, an optionally independently substituted C_2-5 alkenyl, an optionally independently substituted C_2-s alkynyl, an optionally independently substituted Ci._$ alkoxy, -C(0)NR R or -NR^aR^b, wherein R^a and R^b are independently H, an optionally independently substituted Ci_-6 alkyl, or an optionally independently substituted C_3-6 cycloalkyl;

R¹⁶ is selected from H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted Q.5 alkyl, an optionally independently substituted C₂.₅ alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted Ci_-5 alkoxy, -C(0)NR^aR^b, or -NR^aR^b, wherein R^a and R^b are independently H, optionally independently substituted Ci-₆ alkyl, or an optionally independently substituted C_3-6

cycloalkyl;

R¹⁵ is missing;

R¹³ is selected from H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted .5 alkyl, an optionally independently substituted C_2-s alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted Ci_-5 alkoxy, -C(0)NR^aR^b or -NR^aR^b, wherein R^a and R^b are independently H, optionally independently substituted Ci-6 alkyl, or an optionally independently substituted C_3-6 cycloalkyl;

R¹⁷ is selected from H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci_-5 alkyl, an optionally independently substituted C_2-5 alkenyl, an optionally independently substituted C2.5 alkynyl, an optionally independently substituted Ci_5 alkoxy, -C(0)NR^aR^b or -NR^aR_b, wherein R^a and R^b are independently H, optionally independently substituted Ci_-6 alkyl, or an optionally independently substituted C_3-6 cycloalkyl.

[0085] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, up to two of up to one of P¹, P², P³, P⁴, P⁵ and P⁶ is N and the rest are C in said FAAH inhibitor of Formula I. In other embodiments, one of P¹, P², P³, P⁴, P⁵ and P⁶ is N and the rest are C in said FAAH inhibitor of Formula I. In other embodiments, each of Pi, P₂, P3, P₄, P5 and P₆ is C in said FAAH inhibitor of Formula I.

[0086] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, R² is a C 1.3 alkyl or cyclopropyl in said FAAH inhibitor of Formula I. In other embodiments, R² is methyl in said FAAH inhibitor of Formula I.

[0087] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, one or two of R⁸, R⁹, R¹⁰, R^{1 1} and R¹² are independently selected from a halogen and the rest are H in said FAAH inhibitor of Formula I. In other embodiments, one or two of R⁸, R⁹, R¹⁰, R^{1 1} and R¹² are CI or F and the rest are H in said FAAH inhibitor of Formula I.

[0088] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, R¹⁰ is a halogen in said FAAH inhibitor of Formula I. In some embodiments, one of R⁸ and R is a halogen and the other is H in said FAAH inhibitor of Formula I. In other embodiments, R¹⁰ is CI or F; and R⁸, R⁹, R¹¹ and R¹² are H in said compound of Formula I. In still other embodiments, R¹⁰ is CI or F; R⁸ is CI or F; and R⁹, R^{1 1} and R¹² are H in said compound of Formula I.

[0089] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, R⁴ and R⁷ are H in said FAAH inhibitor of Formula I.

[0090] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, R⁶ is H in said FAAH inhibitor of Formula I.

[0091] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, R⁵ is selected from: ethoxy, methoxy, ethyl, methyl, halogen and H in said FAAH inhibitor of Formula I. In other embodiments, R⁵ is selected from chloro, methoxy, methyl and H in said compound of Formula I. In still other embodiments, R⁵ is methoxy in said compound of Formula I. In a further embodiment, R⁵ is methyl in said compound of Formula I.

[0092] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, R¹⁴ or R¹⁶ is selected from a halogen or an optionally independently substituted methoxy and both R_]3 and R|₇ are H in said FAAH inhibitor of Formula I. In other embodiments, R¹⁴ or R¹⁶ is -OCH₃ and the other is hydrogen in said compound of Formula I.

[0093] In some embodiments, one of Ri₄ or R|₆ is halogen or an optionally independently substituted methoxy and the other is hydrogen, and both Ri₃ and R| are H.

[0094] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, the FAAH inhibitor of Formula I is selected from the following list of compounds of Table 1:

Table 1.

N-(2-cUoro-4-pyridinyl)-l-[(2,4-dicUorophenyl)methyl]-5-methoxy-2-methyl-a- oxo- 1 H-Indole-3 -acetamide

5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-l-[[4- (trifluoromethyl)phenyl]methyl]- 1 H-Indole-3-acetamide

5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -[[4- (trifluoromethoxy)phenyl]methyl]- 1 H-Indole-3-acetamide

l-[(6-chloro-3-pyridinyl)methyl]-5-methoxy-N-(2-me1hoxy-4-pyridinyl)-2-metliyl- a-oxo- 1 H-Indole-3 -acetamide

5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-l-[(4-methylphenyl)methyl]-a- oxo-1 H-Indole-3 -acetamide

5-methoxy-l-[(4-memoxyphenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3 -acetamide

5-fluoro-l-[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

5-chloro-l-[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

5-chloro-l-[(4-chlorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

l-[(4-fluorophenyl)memyl]-5-memoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

1 -[(4-fluorophenyl)methyl] -N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole- 3-acetamide

1 -[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo- 1 H- Indole-3-acetamide

l-[(4-cWorophenyl)methyl]-5-memoxy-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

l-[(4-chlorophenyl)methyl]-N-(2-fluoro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

l-[(4-cUorophenyl)memyl]-N-(2-ethoxy-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3-acetamide

l-[(4-chlorophenyl)methyl]-5-fluoro-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

l-[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-fluoro-2-methyl-a-oxo-lH- Indole-3-acetamide

l-[(4-chlorophenyl)methyl]-5-fluoro-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

l-[(4-chlorophenyl)memyl]-5-ethoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

l-[(4-chlorophenyl)memyl]-N-(2-chloro-4-pyridinyl)-5-ethoxy-2-methyl-a-oxo-lH- Indole-3-acetamide 1 -[(4-chlorophenyl)methyl] -N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole- 3-acetamide

l-[(4-cUorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2-methyl-a-oxo-lH-Indole-3- acetamide

1 -[(4-cWorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo- 1 H- Indole-3 -acetamide

1 -[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2,5-dimethyl-a-oxo- 1 H- Indole-3-acetamide

l-[(4-cUoro-2-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2- methyl-a-oxo- 1 H-Indole-3-acetamide

l-[(4-chloro-2-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

l-[(4-cUoro-2-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a- oxo- lH-Indole-3-acetamide

l-[(3-cUorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

l-[(2-cUorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

l-[(2-chloro-4-fluorophenyl)methyl]-5-raethoxy-N-(2-methoxy-4-pyridinyl)-2- methyl-a-oxo- 1 H-Indole-3 -acetamide

l-[(2-cWoro-4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

l-[(2-cMoro-4-fluorophenyl)methyl]-N-(2-metlioxy-4-pyridmyl)-2,5-dimethyl-a- oxo- 1 H-Indole-3-acetamide

l-[(2,4-difluorophenyl)methyl]-5-memoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo-1 H-Indole-3-acetamide

l-[(2,4-difluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-lH- Indole-3-acetamide

l-[(2,4-dicUorophenyl)memyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo-1 H-Indole-3-acetamide

l-[(2,4-dicmorophenyl)memyl]-5-fluoro-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3-acetamide

l-[(2,4-dichlorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-lH- Indole-3-acetamide

l-[(2,4-dichlorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3-acetamide

5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-l -(phenylmethyl)- 1 H- Indole-3-acetamide N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -(phenylmethyl)- 1 H-Indole-3 - acetamide

N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-l-(phenylmethyl)-lH-Indole-3- acetamide

5-chloro- 1 -[(4-chlorophenyl)methyl] -N-(2-chloro-4-pyridinyl)-2-methyl-a-oxo- 1 H- Indole-3-acetamide

5-chloro-l-[(4-chlorophenyl)methyl]-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

l-[(4-cWorophenyl)methyl]-N-(2-cUoro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3-acetamide

1 -[(4-chlorophenyl)methyl]-5-hydroxy-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3- acetamide

1 -[(4-cWorophenyl)methyl]-5-ethoxy-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3- acetamide

1 -[(4-chlorophenyl)methyl] -2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3 -acetamide

1 -[(4-chlorophenyl)methyl]-5-methyl-2-( 1 -methylethyl)-a-oxo-N-4-pyridinyl- 1 H- Indole-3-acetamide

l-[(4-cUorophenyl)methyl]-2,5-dimethyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

1 -[(2,4-dicUorophenyl)methyl]-5-methoxy-2-methyl-a-oxo-N-4-pyridinyl- 1 H- Indole-3-acetamide

l-[(4-chlorophenyl)methyl]-5-methoxy-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

[0095] In some embodiments of the above methods, pharmaceutical compositions, kits and uses, the FAAH inhibitor of Formula I is selected from those depicted in Table 2 below:

Table 2.



30

31

33













40

41

42

43

44







Definitions

[0096] The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

[0097] As used herein, the term "cyano" refers to -CN or -C≡N.

[0098] The term "hydroxyl" or "hydroxy" refers to -OH. [0099] The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C|.Ci₂ alkyl indicates that the group may have from 1 to 12 (both inclusive) carbon atoms in it (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 orl2). The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogen atoms have been replaced by halo (e.g., perfluoroalkyl). The terms "arylalkyl" or "aralkyl" refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group.

Examples of "arylalkyl" or "aralkyl" include, but are not limited to, benzyl and 9-fluorenyl groups.

[00100] The term "alkenyl" refers to a linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond, wherein the alkenyl radical includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Unless otherwise specified, an alkenyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). Examples include, but are not limited to, vinyl, allyl and the like.

[00101] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Unless otherwise specified, an alkynyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms).

Examples include, but are not limited to, ethynyl, propynyl, and the like.

[00102] The term "alkoxy" refers to an -O-(alkyl) radical. Thus, for example, alkoxy or alkoxyl can refer to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen atom. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower alkoxy refers to groups containing one to four carbons.

[00103] The term "cycloalkyl" as employed herein includes saturated monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons, wherein any ring atom capable of substitution can be substituted by a substituent. Examples of cycloalkyl moieties include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, cyclohexyl and adamantyl. [00104] The term "carbocycle" as employed herein includes saturated, partially unsaturated or unsaturated monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons, wherein any ring atom capable of substitution can be substituted by a substituent. Carbocycles can be aromatic, e.g., a phenyl ring is an example of a carbocycle. A subset of the carbocycles is the non-aromatic carbocycles.

[00105] In some embodiments, two independent occurrences of a variable may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered, heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring. Example rings that are formed when two independent occurrences of a substituent are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of a substituent that are bound to the same atom and are taken together with that atom to form a ring, where both occurrences of the substituent are taken together with the atom to which they are bound to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the group is attached to the rest of the molecule by a single point of attachment; and b) two independent occurrences of a substituent that are bound to different atoms and are taken together with both of those atoms to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the ring that is formed has two points of attachment with the rest of the molecule. For example, where a phenyl group is substituted with two occurrences of -OR⁰ as in Formula Ό :

the two occurrences of -OR°, wherein R° is, for example Me, may be taken together with the carbon atoms to which they are bound to form a fused 6-membered oxygen-containing ring as in Formula D₂:

D₂

[00106] It will be appreciated that a variety of other rings can be formed when two independent occurrences of a substituent are taken together with the atom(s) to which each substituent is bound and that the examples detailed above are not intended to be limiting. [00107] The term "substituents" refers to a group "substituted" on an alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group or other group at any atom of the group. The group can be singly or multiply substituted and where multiply substituted, the substituents are independent. Suitable substituents include, without limitation : F, CI, Br, I, alkyl, alkenyl, alkynyl, alkoxy, acyloxy, halo, hydroxy, cyano, nitro, amino, SO₃H, sulfate, phosphate, perfluoroalkyl, perfluoroalkoxy,

methylenedioxy, ethylenedioxy, carboxyl, oxo, thioxo, imino (alkyl, aryl, aralkyl), S(0)„ alkyl (where n is 0-2), S(0)_n aryl (where n is 0-2), S(0)_n heteroaryl (where n is 0-2), S(0)_n heterocyclyl (where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl, and combinations thereof), ester (alkyl, aralkyl, heteroaralkyl), amide (mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof), sulfonamide (mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof), unsubstituted aryl, unsubstituted heteroaryl, unsubstituted heterocyclyl, and unsubstituted cycloalkyl. In one aspect, the substituents on a group are independently any one single, or any subset of the aforementioned substituents. In some cases the substituents are selected from: F, CI, Br and I. In other cases the substituents are selected from: halogen, optionally independently halogen substituted C₁.C₃ alkyl, optionally independently halogen substituted Ci.C₃ alkoxy, hydroxy, cyano, nitro and amino. In some cases the substituents are selected from aryl groups. In some cases the substituents are selected from heteroaryl groups. In some cases the substituents are selected from:

halogen, hydroxy, and C₁-C3 alkyl. In some cases, the substituents are selected from:

halogen, hydroxy, and C₁-C₃ alkyl and C₁-C₃ alkoxyl.

[00108] Unless only one of the isomers is drawn or named specifically, structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric,

diastereomeric, atropoisomeric and cis-trans isomeric) forms of the structure; for example, the R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical isomers as well as racemates, and mixtures of enantiomers, diastereomers, and cis-trans isomers (double bond or conformational) of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the disclosure.

[00109] The present disclosure also embraces the use of isotopically labeled compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Example isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹ 'c, ^l3C, ¹⁴C, ^,3N, ^,5N, ¹⁵0, ¹⁷0, ^,80, ³²P, ³³P, ³⁵S, ^l8F, ³⁶C1, ^l23I and ^,25I, respectively. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron-emitting isotopes such as ^l50, ¹³N, ^UC, and ¹⁸F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.

Isotopically labeled compounds of the present invention can generally be prepared by following procedures known to those having ordinary skill in the art, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[00110] In some embodiments of the above methods and uses, the FAAH inhibitor of Formula I is administered before a symptom of neurodegeneration develops in said patient. In other embodiments, it is administered after the symptom develops. In further

embodiments, the FAAH inhibitor of Formula I is administered prior to, at the same time or after the initiation of treatment with another therapeutic agent. In some embodiments of the above methods and uses, the FAAH inhibitor is administered after one or more symptoms of neurodegeneration develops in said patient.

[00111] In some embodiments of the above methods and uses, the additional therapeutic agent and the FAAH inhibitor of Formula I are administered simultaneously. In other embodiments of the above methods and uses, the additional therapeutic agent and the FAAH inhibitor are administered sequentially or separately.

[00112] In some embodiments, the above pharmaceutical compositions or kits comprise (a) a FAAH inhibitor as discussed above or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, vehicle or adjuvant. In some embodiments, the pharmaceutical composition or kit comprises (a) an additional therapeutic agent as discussed above, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, vehicle or adjuvant. In some embodiments, the pharmaceutical composition comprises (i) a FAAH inhibitor as discussed above, or a pharmaceutically acceptable salt thereof, (ii) an additional therapeutic agent as discussed above, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable carrier, vehicle or adjuvant. In a further embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent.

Pharmaceutically acceptable salts

[00113] In some embodiments of the methods, uses, pharmaceutical compositions or kits, the FAAH inhibitor may be provided as (i) the compound itself (e.g., as the free base); (ii) a pharmaceutically acceptable salt of the compound; or (iii) part of a pharmaceutical composition. In some embodiments of the above methods, uses, pharmaceutical

compositions and kits, the additional therapeutic agent may be provided as (i) the compound itself (e.g., as the free base); (ii) a pharmaceutically acceptable salt of the compound; (iii) or part of a pharmaceutical composition.

[00114] The phrase "pharmaceutically acceptable salt," as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein. For use in medicine, the salts of the compounds described herein will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds described herein or of their pharmaceutically acceptable salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a

pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.

[00115] Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compounds. In other embodiments the salts can be prepared from the free form of the compound in a separate synthetic step.

[00116] When the compound described herein is acidic or contains a sufficiently acidic bioisostere, suitable "pharmaceutically acceptable salts" refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediarnine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimemylamine tripropylamine, tromethamine and the like.

[00117] When the compound described herein is basic or contains a sufficiently basic bioisostere, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Other exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,

benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3- naphthoate)) salts.

[00118] The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66: 1-19, incorporated herein by reference in its entirety. Compounds, compositions and kits of the invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle.

Combination Therapies

[00119] The compounds and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents. For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents may be administered separately or in conjunction. In addition, the administration of one agent may be prior to, concurrent to, or subsequent to the administration of the other agent.

[00120] When co-administered with other agents, e.g., when co-administered with another neuroprotective medication, an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed. For example, compounds described herein can be administered to a subject in a dosage range from between about 0.001 to about 100 mg/kg body weight/day, from about 0.001 to about 50 mg/kg body weight/day, from about 0.001 to about 30 mg/kg body weight/day, from about 0.001 to about 10 mg/kg body weight/day.

[00121] When "combination therapy" is employed, an effective amount can be achieved using a first amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a second amount of an additional suitable therapeutic agent (e.g. another neuroprotective or neuroprotecting agent).

[00122] In one embodiment of this invention, the compound described herein and the additional therapeutic agent, are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone). In another embodiment, the compound described herein and the additional therapeutic agent, are each administered in an amount which alone does not provide a therapeutic effect (a subtherapeutic dose). In yet another embodiment, the compound described herein can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still another embodiment, the compound described herein can be admimstered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable anti-inflammatory agent is administered in an effective amount.

[00123] As used herein, the terms "in combination" or "co-administration" can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.

[00124] Co-administration encompasses administration of the first and second amounts of the compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. In addition, such co-administration also encompasses use of each compound in a sequential mariner in either order. When coadministration involves the separate administration of the first amount of a compound described herein and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect. For example, the period of time between each administration which can result in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, a compound described herein and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other, within about 5 minutes of each other, etc.

[00125] More, specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound described herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks subsequent to) the administration of a second therapy (e.g., a therapeutic agent) to a subject.

Kits

[00126] The compounds and pharmaceutical formulations described herein may be contained in a kit. The kit may include single or multiple doses of two or more agents, each packaged or formulated individually, or single or multiple doses of two or more agents packaged or formulated in combination. Thus, one or more agents can be present in first container, and the kit can optionally include one or more agents in a second container. The container or containers are placed within a package, and the package can optionally include administration or dosage instructions. A kit can include additional components such as syringes or other means for administering the agents as well as diluents or other means for formulation. Thus, the kits can comprise: a) a pharmaceutical composition comprising a compound of Formula I described herein and a pharmaceutically acceptable carrier, vehicle or diluent; and b) another therapeutic agent and a pharmaceutically acceptable carrier, vehicle or diluent in one or more containers or separate packaging. The kits may optionally comprise instructions describing a method of using the pharmaceutical compositions in one or more of the methods described herein (e.g. preventing or treating one or more of the diseases and disorders described herein). The pharmaceutical composition comprising the compound described herein and the second pharmaceutical composition contained in the kit may be optionally combined in the same pharmaceutical composition.

[00127] A kit includes a container or packaging for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet. The container can be, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.

[00128] An example of a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet.

Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[00129] It may be desirable to provide written memory aid containing information and/or instructions for the physician, pharmacist or subject regarding when the medication is to be taken. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a given day. When the kit contains separate compositions, a daily dose of one or more compositions of the kit can consist of one tablet or capsule while a daily dose of another one or other compositions of the kit can consist of several tablets or capsules. A kit can take the form of a dispenser designed to dispense the daily doses one at a time in the order of their intended use. The dispenser can be equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that have been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

[00130] In some embodiments of the above methods, uses, compositions and kits, the additional therapeutic agent or agents may be selected from one or more of the following:

( 1 ) anti-inflammatory and/or immunosuppressive/immunomodulatory agents such as methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus, corticosteroids, statins, interferon beta, infliximab (Remicade™), etanercept (Enbrel ) or adalimumab (Humira ); other FK-506 type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil (CellCept™, Myfortic™); rapamycin

(sirolimus, Rapamune™); glatiramer acetate (Copaxone™), cladribine (Litak™,

Movectro™) and fingolimod (Gilenya™);

(2) antidepressants such as SSRIs (e.g., fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine), a combined SSRI and 5HT1 A partial agonist (e.g., vilazodone), a tricyclic antidepressant (e.g., imipramine, amitriptiline (Elavil), chlomipramine and nortriptiline), a therapeutic antidepressant (e.g., bupropion and amineptine) or an SNRIs (e.g., venlafaxine and reboxetine);

(3) non-steroidal anti-inflammatory agents (NSAIDs) such as propionic acid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (e.g., acetyl salicylic acid and sulfasalazine) and the pyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); painkillers such as acetaminophen or paracetamol;

(4) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib and lumiracoxib, and opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, buto hanol, dezocine, nalbuphine and pentazocine;

(5) calcium channel blockers such as: dihydropyridine, Amlodipine (Norvasc), Aramdipine (Sapresta), Azelnidipine (Calblock), Barnidipine (HypoCa), Benidipine (Coniel), Cilnidipine (Atelec, Cinalong, Siscard), Clevidipine (Cleviprex), Diltiazem, Efonidipine (Landel), Felodipine (Plendil), Lacidipine (Motens, Lacipil), Lercanidipine (Zanidip), Manidipine (Calslot, Madipine), Nicardipine (Cardene, Carden SR.), Nifedipine (Procardia, Adalat), Nilvadipine (Nivadil), Nimodipine (Nimotop), Nisoldipine (Baymycard, Sular, Syscor), Nitrendipine (Cardif, Nitrepin, Baylotensin), Pranidipine (Acalas), Isradipine (Lomir); phenylalkylamine calcium channel blockers: Verapamil (Calan, Isoptin)

Gallopamil (Procorum, D600); Benzothiazepines: Diltiazem (Cardizem);

nonselective calcium channel inhibitors such as: mibefradil, bepridil and fluspirilene, fendiline;

(6) endothelin receptor antagonists (ERAs): for instance the dual (ET_A and ETB) endothelin receptor antagonist Bosentan (marketed as Tracleer®); sitaxentan, marketed under the name Thelin®; ambrisentan is marketed as Letairis® in U.S; dual/nonselective endothelin antagonist Actelion-1, that entered clinical trials in 2008;

(7) prostacyclin derivatives or analogues: for instance prostacyclin (prostaglandin I₂), Epoprostenol (synthetic prostacyclin, marketed as Flolan®); Treprostinil (Remodulin®), Iloprost (Ilomedin®), Iloprost (marketed as Ventavis®); oral and inhaled forms of

Remodulin® that are under development; Beraprost, an oral prostanoid available in Japan and South Korea;

(8) antihyperlipidemics such as: bile acid sequestrants (e.g., Cholestyramine,

Colestipol, Colestilan and Colesevelam); statins such as Atorvastatin, Simvastatin,

Lovastatin, Fluvastatin, Pitavastatin, Rosuvastatin and Pravastatin; cholesterol absorption inhibitors such as Ezetimibe; other lipid lowering agents such as Icosapent ethyl ester, Omega-3-acid ethyl esters, Reducol; fibric acid derivatives such as Clofibrate, Bezafibrate, Clinofibrate, Gemfibrozil, Ronifibrate, Binifibrate, Fenofirate, Ciprofibrate, Choline fenofibrate; nicotinic acid derivatives such as Acipimox and Niacin; also combinations of statins, niacin, intestinal cholesterol absoφtion-inhibiting supplements (ezetimibe and others) and fibrates; antiplatelet therapies such as Clopidogrel bisulfate;

(9) Anticoagulants, such as the following types:

• Coumarines (Vitamin K antagonists): Warfarin® (Coumadin) mostly used in the

US and UK; Acenocoumarol® and Phenprocoumon®, mainly used in other countries;

Phenindione ®; • Heparin and derivative substances such as: Heparin; low molecular weight heparin, Fondaparinux and Idraparinux; direct thrombin inhibitors such as: Argatroban, Lepirudin, Bivalirudin and Dabigatran; Ximelagatran (Exanta®), not approved in the US; Tissue plasminogen activators, used to dissolve clots and unblock arteries, such as Alteplase;

(10) Antiplatelet drugs: for instance thienopyridines such as Lopidogrel and Ticlopidine; Dipyridamole; Aspirin;

(11) ACE inhibitors, for example the following types:

• Sulfhydryl-containing agents such as Captopril (trade name Capoten®), the first ACE inhibitor and Zofenopril;

• Dicarboxylate-containing agents such as Enalapril (Vasotec/Renitec®); Ramipril (Altace/Tritace/Ramace/Ramiwin®); Quinapril (Accupril®), Perindopril (Coversyl/Aceon®); Lisinopril (Lisodur/Lopril/Novatec Prinivil/Zestril®) and Benazepril (Lotensin®);

• Phosphonate-containing agents such as: Fosinopril;

• Naturally occurring ACE inhibitors such as: Casokinins and lactokinins, which are breakdown products of casein and whey that occur naturally after ingestion of milk products, especially cultured milk; The Lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus or derived from casein also have ACE-inhibiting and antihypertensive functions;

• Other ACE inhibitors such as Alacepril, Delapril, Cilazapril, Imidapril, Trandolapril, Temocapril, Moexipril, Spirapril;

( 12) Supplemental oxygen therapy;

(13) Beta blockers, such as the following types:

• Non-selective agents: Alprenolol®, Bucindolol®, Carteolol®, Carvedilol® (has additional α-blocking activity), Labetalol® (has additional a-blocking activity), Nadolol®, Penbutolol® (has intrinsic sympathomimetic activity), Pindolol® (has intrinsic

sympathomimetic activity), Oxprenonol, Acebutolol, Sotalol, Mepindolol, Celiprolol, Arotinolol, Tertatolol, Amosulalol, Nipradilol, Propranolol® and Timolol®; • βι -Selective agents: Acebutolol® (has intrinsic sympathomimetic activity), Atenolol®, Betaxolol®, Bisoprolol®, Celiprolol®, Dobutamine hydrochloride, Irsogladine maleate, Carvedilol, Talinolol, Esmolol®, Metoprolol® and Nebivolol®;

• p2-Selective agents: Butaxamine® (weak a-adrenergic agonist activity);

(14) Antiarrhythmic agents such as the following types:

• Type I (sodium channel blockers): Quinidine, Lidocaine, Phenytoin, Propafenone

• Type III (potassium channel blockers): Amiodarone, Dofetilide, Sotalol

• Type V: Adenosine, Digoxin

(15) Diuretics such as: Thiazide diuretics, e.g., Chlorothiazide, Chlorthalidone, and Hydrochlorothiazide, Bendroflumethiazide, Cyclopenthiazide, ethyclothiazide,

Polythiazide , Quinethazone, Xipamide, Metolazone, Indapamide, Cicletanine; Loop diuretics, such as Furosemide and Toresamide; potassium-sparing diuretics such as

Amiloride, Spironolactone, Canrenoate potassium, Eplerenone and Triamterene;

combinations of these agents; other diuretics such as Acetazolamid and Carperitide;

(16) Direct acting vasodilators such as Hydralazine hydrochloride, Diazoxide, Sodium nitroprusside, Cadralazine; other vasodilators such as Isosorbide dinitrate and Isosorbide 5- mononitrate;

(17) Exogenous vasodilators such as:

• Adenocard®, an adenosine agonist, primarily used as an anti-arrhythmic;

• Alpha blockers (which block the vasoconstricting effect of adrenaline);

• Alpha- 1 -adrenoceptor antagonists such as Prazosin, Indoramin, Urapidil, Bunazosin, Terazosin, Doxazosin;

• Atrial natriuretic peptide (ANP);

• Ethanol;

• Histamine-inducers, which complement proteins C3a, C4a and C5a work by triggering histamine release from mast cells and basophil granulocytes;

• Tetrahydrocannabinol (THC), major active chemical in marijuana which has minor vasodilatory effects; • Papaverine, an alkaloid found in the opium poppy papaver somniferum;

(18) Bronchodilators: there are two major types of bronchodilator, β₂ agonists and anticholinergics, exemplified below:

• β₂ agonists: Salbutamol® or albuterol (common brand name: Ventolin) and

Terbutaline® are short acting β₂ agonists for rapid relief of COPD symptoms. Long acting β₂ agonists (LABAs) such as Salmeterol® and Formoterol®;

• anticholinergics: Ipratropium® is the most widely prescribed short acting

anticholinergic drug. Tiotropium® is the most commonly prescribed long-acting

anticholinergic drug in COPD;

• Theophylline®, a bronchodilator and phosphodiesterase inhibitor;

(19) Corticosteroids: such as beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone, triamcinolone, dexamethasone, fluticasone, flunisolide and hydrocortisone, and corticosteroid analogs such as budesonide;

(20) Dietary supplements such as, for example: omega-3 oils; folid acid, niacin, zinc, copper, Korean red ginseng root, ginkgo, pine bark, Tribulus terrestris, arginine, Avena sativa, horny goat weed, maca root, muira puama, saw palmetto, and Swedish flower pollen; Vitamin C, Vitamin E, Vitamin K2; Testosterone supplements, Testosterone transdermal patch; Zoraxel, Naltrexone, Bremelanotide (formerly PT-141), Melanotan II, hMaxi-K;

Prelox: a Proprietary mix/combination of naturally occurring ingredients, L-arginine aspartate and Pycnogenol;

(21) Anti-diabetic agents such as insulin and insulin mimetics, sulfonylureas (e.g., Glyburide, Glybenclamide, Glipizide, Gliclazide, Gliquidone, Glimepiride, Meglinatide, Tolbutamide, Chlorpropamide, Acetohexamide, Tolazamide), biguanides, e.g., metformin (Glucophage®), a-glucosidase inhibitors (such as Acarbose, Epalrestat, Voglibose, Miglitol), thiazolidinone compounds, e.g., rosiglitazone (Avandia®), troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) and englitazone; insulin sensitizers such as Pioglitazone and Rosiglitazone; Insulin secretagogues such as Repaglinide, Nateglinide and Mitiglinide; Incretin mimetics such as Exanatide and Liraglutide; Amylin analogues such as Pramlintide; glucose lowering agents such as Chromium picolinate (optimally combined with biotin); dipeptidyl peptidase IV inhibitors such as Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin and Linagliptin; vaccines currently being developed for the treatment of diabetes; AVE-0277, Alum-GAD, BHT-3021, IBC-VSOl; cytokine targeted therapies in development for the treatment of diabetes such as Anakinra, Canakinumab, Diacerein,Gevokizumab, LY- 2189102, MABP-1, GIT-027; drugs in development for the treatment of diabetes such as those contained in Table 3 below:

Table 3.

PPARalpha

Agonists/

Aleslitazar Roche Phase III

PPARgamma

Agonists

K(ATP) Channel

Blockers/

Dipeptidyl

Peptidase IV

(CD26; DPP-IV;

Atorvastatin DP-IV)

GlaxoSmithKline Phase III calcium/glimepiride Inhibitors/ HMG-

CoA Reductase

Inhibitors/

TNFSF6

Expression

Inhibitors

BYK-324677 Nycomed Phase III

Insulin

Dr. Reddy's Sensitizers/

Balaglitazone Phase III

Laboratories PPARgamma

Partial Agonists

Chugai SGLT-2

CSG-452 Phase III

Pharmaceutical Inhibitors

Johnson &

Johnson/ SGLT-2

Canaaliflozin Phase III

Mitsubishi Tanabe Inhibitors

Pharma

SGLT-2

Canagliflozin metformin Johnson & Inhibitors/

Phase III hydrochloride Johnson Insulin

Sensitizers

SGLT-2

AstraZeneca/

Dapaeliflozin/Metformin Inhibitors/

Bristol-Myers Phase III hydrochloride Insulin

Squibb

Sensitizers

Insulin

Secretagogues/

Dulaelutide Lilly Phase III

GLP-1 Receptor

Agonists

Boehringer SGLT-2

Empaeliflozin Phase III

Ingelheim/ Lilly Inhibitors

SGLT-2

Inhibitors/

Dipeptidyl

Boehringer

Empagliflozin linaeliptin Peptidase IV Phase III

Ingelheim/ Lilly

(CD26; DPP-IV;

DP-IV)

Inhibitors Dipeptidyl

Peptidase IV

Gemigliptin LG Life Sciences (CD26; DPP-IV; Phase III

DP-IV)

Inhibitors

Hepatic-directed vesicle Diasome

Phase III insulin Pharmaceuticals

Human isophane insulin Wockhardt Phase III

IN-105 Biocon Phase III

Insulin

Insulin Secretagogues/

Novo Nordisk Phase III dealudec/liraglutide GLP-1 Receptor

Agonists

Insulin glareine Sanofi Phase III

Astellas Pharma/ SGLT-2

Ipraeliflozin L-proline Phase III

Kotobuki Inhibitors

LY-2605541 Lilly Phase III

LY-2963016 Lilly Phase III

Insulin

Lixisenatide/Insulin Secretagogues/

Sanofi Phase III glargine GLP-1 Receptor

Agonists

PPARalpha

Chong un Dang Agonists/

Lobeglitazone sulfate Pharm (CKD PPARgamma Phase III

Pharm) Agonists/ Insulin

Sensitizers

SGLT-2

Luseoeliflozin Taisho Phase III

Inhibitors

Otelixizumab Tolerx Anti-CD3 Phase III

Sodium Channel

Ranolazine Gilead Phase III

Blockers

National Institute

Recombinant human

of Health Phase III insulin

Sciences

PPARgamma

Agonists/ Insulin

Sensitizers/

Sitaeliptin phosphate

Dipeptidyl

monohvdrate/pioglitazone Merck & Co. Phase III

Peptidase IV

hvdrochloride

(CD26; DPP-IV;

DP-IV)

Inhibitors Dipeptidyl

Peptidase IV

(CD26; DPP-IV;

DP-IV)

Sitagliptin/atorvastatin Inhibitors/ HMG-

Merck & Co. Phase III calcium CoA Reductase

Inhibitors/

TNFSF6

Expression

Inhibitors

Free Fatty Acid

Receptor 1

TAK-875 Takeda (FFARl; GPR40) Phase III

Agonists/ Insulin

Secretagogues

Cannabinoid

TT-401 7TM Pharma Phase I

CB1 Antagonists

Transition

TT-401 Phase I

Therapeutics

PPARalpha

Cadila Healthcare

Ligands/

ZYH-2 (d/b/a Zydus Phase I

PPARgamma

Cadila)

Ligands

Cadila Healthcare

Cannabinoid

ZYO-1 (d/b/a Zydus Phase I

CB1 Antagonists

Cadila)

701645 Cellonis

Phase I Biotechnologies

701499 Cellonis

Phase I Biotechnologies

743300 University of

California, San Phase I Francisco

448661 University of

Phase I Pittsburgh

National Institute

AD-1 Clinical

Pharma Res Dev

Colesevelam Bile Acid

Daiichi Sankyo Clinical hydrochloride Sequestrants

National Health

Research

DBPR-108 IND Filed

Institutes/

ScinoPharm

Nodlin Biolaxy IND Filed Glucose- Dependent

Insulinotropic

Receptor (GDIR,

GPR119)

PSN-491 Prosidion Agonists/ IND Filed

Dipeptidyl

Peptidase IV

(CD26; DPP-IV;

DP-IV)

Inhibitors

Lyn Kinase

Tolimidone Melior Discovery IND Filed

Activators

Cadila Healthcare

GLP-1 Receptor

ZYD-1 (d/b/a Zydus IND Filed

Agonists

Cadila)

Cadila Healthcare

GLP-1 Receptor

ZYOG-1 (d/b/a Zydus IND Filed

Agonists

Cadila)

(22) HDL cholesterol-increasing agents such as Anacetrapib, MK-524A, CER-001, DRL- 17822, Dalcetrapib, JTT-302, RVX-000222, TA-8995;

(23) Antiobesity drugs such as Methamphetamine hydrochloride, Amfepramone hydrochloride (Tenuate ®), Phentermine (lonamin ®), Benzfetamine hydrochloride (Didrex ®), Phendimetrazine tartrate (Bontril®, Prelu-2 ®, Plegine ®), Mazindol (Sanorex ®), Orlistat (Xenical ®), Sibutramine hydrochloride monohydrate (Meridia ®, Reductil ®), Rimonabant (Acomplia ®), Amfepramone, Chromium picolinate, RM-493, TZP-301;

combination such as Phentermine/Topiramate, Bupropion/Naltrexone,

Sibutramine/Metformin, Bupropion SR/Zonisamide SR, Salmeterol, xinafoate/fluticasone propionate; Lorcaserin hydrochloride, Phentermine/topiramate, Bupropion/naltrexone, Cetilistat, Exenatide, KI-0803, Liraglutide, Metformin hydrochloride,

Sibutramine Metformin, 876167, ALS-L-1023, Bupropion SR/Zonisamide SR, CORT- 108297, Canagliflozin, Chromium picolinate, GSK-1521498, LY-377604, Metreleptin, Obinepitide, P-57AS3, PSN-821, Salmeterol xinafoate/fluticasone propionate, Sodium tungstate, Somatropin (recombinant), TM-30339, TTP-435, Tesamorelin, Tesofensine, Velneperit, Zonisamide, BMS-830216, ALB-127158, AP-1030, ATHX-105, AZD-2820, AZD-8329, Beloranib hemioxalate, CP-404, HPP-404, ISIS-FGFR4Rx, Insulinotropin, KD- 3010PF, 05212389, PP-1420, PSN-842, Peptide YY3-36, Resveratrol, S-234462; S-234462, Sobetirome, TM-38837, Tetrahydrocannabivarin, ZYO-1, beta-Lapachone; (24) Angiotensin receptor blockers such as Losartan, Valsartan, Candesartan cilexetil, Eprosaran, Irbesartan, Telmisartan, Olmesartran medoxomil, Azilsartan medoxomil;

(25) Renin inhibitors such as Aliskiren hemifumirate;

(26) Centrally acting alpha-2-adrenoceptor agonists such as Methyldopa, Clonidine, Guanfacine;

(27) Adrenergic neuron blockers such as Guanethidine, Guanadrel;

(28) Imidazoline 1-1 receptor agonists such as Rimenidine dihydrogen phosphate and Moxonidine hydrochloride hydrate;

(29) Aldosterone antagonists such as Spironolactone and Eplerenone;

(30) Potassium channel activators such as Pinacidil;

(31) Dopamine Dl agonists such as Fenoldopam mesilate; other dopamine agonists such as Ibopamine, Dopexamine and Docarpamine;

(32) 5-HT2 antagonists such as etanserin;

(33) Drugs that are currently being developed for the treatment of arterial hypertension such as the ones contained in Table 4 below:

Table 4.

Mechanism

Drug Name Organization Status of Action

Angiotensin

ATI

Antagonists/

Angiotensin

Azilsartan Takeda Registered

AT2

Antagonists/

Insulin

Sensitizers

Angiotensin

ATI

Dainippon Antagonists/

Amlodipine besvlate/irbesartan Pre-Registered

Sumitomo Pharma Calcium

Channel

Blockers

Angiotensin

ATI

Azilsartan/amlodipine besilate Takeda Phase III

Antagonists/

Insulin Sensitizers/

Calcium

Channel

Blockers

Angiotensin

ATI

Ajinomoto/ Antagonists/

Cilnidipine/valsartan Phase III

Mochida Calcium

Channel

Blockers

Angiotensin

Fimasartan Boryung ATI Phase III

Antagonists

Angiotensin

ATI

Antagonists/

Dipeptidyl

Peptidase IV

(CD26; DPP- IV; DP-IV)

Irbesartan/atorvastatin Hanmi Phase III

Inhibitors/

HMG-CoA

Reductase

Inhibitors/

TNFSF6

Expression

Inhibitors

Angiotensin

Irbesartan/trichlormethiazide Shionogi ATI Phase III

Antagonists

Angiotensin

ATI

Losartan

Antagonists/

potassium hvdrochlorothiazide/a Merck & Co. Phase III

Calcium

mlodipine besvlate

Channel

Blockers

Angiotensin

Pratosartan Boryung ATI Phase III

Antagonists

ACT-280778 Actelion Phase II

Mineralocorti

coid Receptor

Amiloride Hemodynamic (MR)

Phase II hydrochloride/spironolactone Therapeutics Antagonists/

Na+/H+

Exchanger (NHE)

Inhibitors/

Epithelial

Sodium

Channels

(ENaC)

Blockers/

K(V)1.5

Channel

Blockers/

K(V)4.3

Channel

Blockers

Angiotensin vaccine/CoVaccine

BTG Phase II HT

Anti-

Cytos

CYT006-AneOb Angiotensin Phase II

Biotechnology

II

Cholecalciferol Emory University Phase II

ClC-2

Sucampo

Cobiprostone Channel Phase II

Pharmaceuticals

Activators

INT-001 IntelGenx Phase II

Angiotensin

ATI

Antagonists/

Neprilysin

LCZ-696 Novartis (Enkephalinas Phase II e, Neutral

Endopeptidas

e, NEP)

Inhibitors

LFF-269 Novartis Phase II

Growth

Hormone

Release

Octreotide acetate Chiasma Phase II

Inhibitors/

Somatostatin

Agonists Atrial

Natriuretic

Peptide A

Palatin (NPRl;

PL-3994 Phase II

Technologies Guanylate

Cyclase A)

Receptor

Agonists

Rostafuroxine Sigma-Tau Phase II

Phosphodieste

rase V

SLx-2101 NT Life Sciences Phase II

(PDE5A)

Inhibitors

Endothelin

Encysive

TBC-3711 ETA Receptor Phase II

Pharmaceuticals

Antagonists

Phosphodieste

Dong-A Falk rase V

Udenafil Phase II

Pharma (PDE5A)

Inhibitors

Angiotensin

ATI

Antagonists/

Dipeptidyl

Peptidase IV

(CD26; DPP-

Atorvastatin calcium/losartan HanAll IV; DP-IV)

Phase I potassium BioPharma Inhibitors/

HMG-CoA

Reductase

Inhibitors/

TNFSF6

Expression

Inhibitors

Dopamine

beta-

BIA-5-1058 BIAL Phase I monooxygena

se Inhibitors

CS-3150 Daiichi Sankyo Phase I

Dainippon Renin

DSP-9599 Phase I

Sumitomo Pharma Inhibitors Actelion/ Merck &

MK-1597 Renin

Phase I Co. Inhibitors

MK-4618 Merck & Co. Phase I

MK-5478 Merck & Co. Phase I

MK-7145 Merck & Co. Phase I

MK-8266 Merck & Co. Phase I

MK-8457 Merck & Co. Phase I

Angiotensin

Mitsubishi Tanabe

MP- 157 AT2 Phase I

Pharma

Agonists

Mineralocorti

Mitsubishi Tanabe coid Receptor

MT-3995 Phase I

Pharma (MR)

Antagonists

Phosphodieste

rase V

Mirodenafil hydrochloride SK Chemicals Phase I

(PDE5A)

Inhibitors

NV-04 Novo gen Antioxidants Phase I

Angiotensin

ATI

Antagonists/

Nifedipine/Candesartan cilexetil Bayer Calcium Phase I

Channel

Blockers/

Antioxidants

Glutamyl

Aminopeptida

Quantum se

OGC-001 Phase I

Genomics (Aminopeptid

ase A)

Inhibitors Na+/H+

Exchanger

RDX-5791 Ardelyx Phase I

type 3 (NHE- 3) Inhibitors

Renin

TAK-272 Takeda Phase I

Inhibitors

Angiotensin

TAK-591 Takeda AT2 Phase I

Antagonists

Vitae Renin

VTP-27999 Phase I

Pharmaceuticals Inhibitors

VPAC2

Vasomera PhaseBio (VIP2) Phase I

Agonists

Calcium

Sihuan

Tvlerdipine hydrochloride Channel IND Filed

Pharmaceutical

Blockers

(34) Vasopressin antagonists such as Tolvaptan;

(35) Calcium channel sensitizers such as Levosimendan or activators such as Nicorandil;

(36) PDE-3 inhibitors such as Amrinone, Milrinone, Enoximone, Vesnarinone,

Pimobendan, Olprinone;

(37) Adenylate cyclase activators such as Colforsin dapropate hydrochloride;

(38) Positive inotropic agents such as Digoxin and Metildigoxin; metabolic cardiotonic agents such as Ubidecarenone; brain naturetic peptides such as Nesiritide;

(39) Drugs that are currently in development for the treatment of heart failure such as those listed in Table 5 below:

Table 5.

AAVl/SERCA2a AmpliPhi Phase II Biosciences/

Celladon/ Mount

Sinai School of

Medicine

Albiglutide GlaxoSmithKline GLP-1 Receptor Phase II

Agonists

Allogeneic Mesoblast Phase II mesenchymal

precursor cells

AlsterMACS Miltenyi Biotec Phase II

BAY-94-8862 Bayer Mineralocorticoid Phase II

Receptor (MR)

Antagonists

COR-1 Corimmun Phase II

CXL-1020 Cardioxyl Nitric Oxide Phase II

Pharmaceuticals Donors

Cenderitide Nile Therapeutics Guanylate Cyclase Phase II

Activators

Endometrial ERCell/ Phase II regenerative cells Medistem

JNJ-39588146 Johnson & Phase II

Johnson

Omecamtiv Amgen/ Cardiac Myosin Phase II mecarbil Cytokinetics Activators

PL-3994 Palatin Atrial Natriuretic Phase II

Technologies Peptide A (NPR1;

Guanylate Cyclase

A) Receptor

Agonists Remestemcel-L Osiris Phase II

TRV- 120027 Trevena Angiotensin ATI Phase II

Receptor Ligands

Urocortin 2 Neurocrine CRF2 Agonists Phase II

Biosciences

AAV6-CMV- Imperial College Phase I/II SERCA2a

Anakinra National Institutes IL-1 Receptor Phase I/II of Health (NIH) Antagonists

LipiCell Bioheart Instituto Phase I/II de Medicina

Regenerativa

ALD-201 Cytomedix/ Texas Phase I

Heart Institute

BAY- 1021189 Bayer Phase I

BAY- 1067197 Bayer Adenine Receptor Phase I

Agonists

BAY-86-8050 Bayer Drugs Acting on Phase I

Vasopressin (A VP)

Receptors

BIA-5-1058 BIAL Dopamine beta- Phase I monooxygenase

Inhibitors

CSCs University of Phase I

Louisville

Calcitonin gene VasoGenix Phase I related peptide JVS-100 Juventas Phase I

Therapeutics

MvoCell SDF-1 Bioheart Phase I

Myoblast Advanced Cell Phase I

Technology

(ACT)

RO- 1160367 Serodus 5-HT4 Phase I

Antagonists

Recombinant Acorda/ Phase I

human glial Vanderbilt

growth factor 2 University

[^"18F1LMI-1195 Lantheus Medical Phase I

Imaging

677950 Kyoto Prefectural Phase I

University of

Medicine

(40) Drugs currently in development for the treatment of pulmonary hypertension such as those listed in Table 6 below:

Table 6

Drugs in current development for the treatment of female sexual dysfunction- such as those listed in Table ? below: Table

(42) Drugs used for the treatment of erectile dysfunction such as Alprostadil, Aviptadil, Phentolamine mesilate, Weige, Alprostadil;

(43) Drugs currently in development for the treatment of male sexual dysfunction such as those listed in Table 8 below:

Table 8

YHD-1023 Yuhan Phase II

INT-007 IntelGenx Phase I

Selective Androgen

Receptor

LY-2452473 Lilly Phase I

Modulators

(SARM)

Albert

Einstein

College of

Medicine/

hMaxi-K Ion Channel Phase I

Innovations/

Mount Sinai

School of

Medicine

KH-204 KMSI Clinical

Chong Kun

Phosphodiesterase

Dang Pharm

CKD-533 V (PDE5A) Preclinical

(CKD

Inhibitors

Pharm)

MP-52 Biopharm Preclinical

Dopamine Dl

Fabre- Agonists/

TGHW01AP Preclinical

Kramer Dopamine D2

Agonists

Drugs in development for the ireatment of sleep apnea such as those listed i Tabl

Table 9

(45) Drugs currently In development for the treatment of metabolic syndrome such as those listed in Tables 10 and 1 1 below:

Table 10

Table 11

(46) Antiobesity drugs: Methamphetamiae hydrochloride (DesoxynTM), Arafepramone hydrochloride (TenuaieTM), Phentermine (lonaminTM), Benzfetamine hydrochloride (DiclrexTM), Phendimetrazine tartrate (BontrilTM, Pre!u-2TM PlegineTM), Mazindol (SanorexTM), Orlistat (XenicalTM), Sibutramiue hydrochloride monohydrate (xMeridiaTM, ReductilTM), Rimonabant (AcompliaTM);

(4?) Drugs marketed, for the treatment of Alzheimer's disease; Idebenone (AvaaTM), Tacrine hydrochloride (CognexTM), Galanta.mi.ne hydrobroinide (RemiiiylTM), Donepezil hydrochloride (AriceptTM), Rivastigniine tartrate (ExelonTM), Memantine hydrochloride ( Axura, EbixaTM);

(48) The drug riluzole (Rilutek®), the only prescribed, drag approved by the U.S. Food and Drug Administration to treat AL.S;

(49) Other drugs used to treat symptoms associated with neuron motor diseases: muscle relaxants such as baclofen, tizanidine, and the benzodiazepines to reduce spasticity; Botulinum toxin to treat jaw spasms or drooling; excessive saliva can be treated with amitriptyline, glycopyolate, and atropine or by botulinum injections into tlie salivary glands; Combtnations of dextroniethoiphan and quinidine to reduce pseudobulbar affect; Nuedexta, a combination product incorporating the NMEA an ia gonis t/sigma- 1 agonist

dextromethorphan hydrobromide and the CYP450 2D6 inhibitor quinidine sulfate, which was launched in 20.1 1 , and prolongs exposure of dextromethorphan is the first and only FDA- approved treatment for PBA, and whose safety and efficacy have been demonstrated in patients with MS and ALS; Anticonvulsatits and nonsteroidal anti-inflammatory drugs to relieve pain, and antidepressants for treating depression. Panic attacks can be treated with benzodiazepines: some individuals may eventually require stronger medicines such as tnorphirte to cope with musculoskeletal abnormalities or pain, and opiates to provide comfort care in terminal stages of the disease;

(50) Antispastic drugs: (R)-(-)-Baclofen, Arbadofen, D-Baclotett, l-Baclofen Tiza dine hydrochloride (Sirdalud, Ternelin. Zanafiex), Eperisone hydrochloride (Myonal);

(51) Neuroprotective agents such as the antibiotic ceftriaxone, which may be neuroprotective in ALS, dexpramipexole.

(52) One of the following investigational therapies, currently being studied for the treatment of amyotrophic lateral sclerosis, listed below in Table 12 :

Table 12

Mecobalamin Eisai Phase

II/III

Anakinra Charite IL-1 Receptor Phase

Universitaetsmedizin Antagonists II Berlin

Ciclosporin Maas Biolab Calcineurin (PP- Phase

2B) Inhibitors/ II Cyclophilin D

Inhibitors/ INS

Expression

Inhibitors

Lithium Hopitaux de Paris Glycogen Phase carbonate Synthase Kinase 3 II

(GSK-3)

Inhibitors

NP-001 Neuraltus Phase

II

RPI-MN ReceptoPharm Viral Entry Phase

Inhibitors II

Rasaeiline University of MAO-B Phase mesilate Kansas Inhibitors II

Tirasemtiv Cytokinetics Troponin Phase

Activators II

HYNR-CS CoreStem Phase

I/II

NTF-SC BrainStorm Cell Phase

Therapeutics/ I/II Hadassah Medical

Organization

Pvrimethamine Cornell University STAT-3 Phase

Inhibitors/ I/II

Dihydrofolate

Reductase (DHFR)

Inhibitors/

Pharmacological

Chaperones

sNN-0029 NeuroNova Phase

I/II

1223249 GlaxoSmithKline Anti-Nogo-A Phase I

AAD-2004 Neurotech Non-Steroidal Phase I

Pharmaceuticals Antiinflammatory

Drugs/ Antioxidants/

Antiamyloidogenic

Agents/ Cytokine

Production

Inhibitors/ Free

Radical

Scavengers

ISIS-SODlRx Isis Pharmaceuticals SOD1 Expression Phase I

Inhibitors

MnDTEIP Aeolus Antioxidants/ Phase I

Pharmaceuticals Superoxide

Dismutase (SOD)

Mimetics

Sarsasapogenin Phytopharm Neurotrophic Phase I

Agents

Spinal cord Neuralstem Phase I stem cells

Zinc acetate Synthetic Biologies Phase I

689371 TCA Cellular Phase I

Therapy

NuroPro Power3 Medical Clinical

Products

(53) One of the currently marketed therapies, specifically used for the treatment of patients with multiple sclerosis: Interferons (Interferon beta- lb (Extavia, Betaseron, Betaferon), Interferon beta- la (Avonex), Interferon beta- la (Rebif), Interferon alfa-nl (Sumiferon MP)); Copolymer- 1 Glatiramer acetate (Copaxone); Immunomodulators:

Mitoxantrone hydrochloride (Novantrone), fingolimod hydrochloride (Gilenya), Cladribine (Movectro); Monoclonal antibodies: Natalizumab (Tysabri); Symptomatic therapies:

Nabiximols (Sativex); Fampridine (Ampyra);

(54a) Other symptomatic treatments for symptoms associated with MS, including dalfampridine (Ampyre) for walking difficulties; nabiximols (Sativex), antispasmodics (e.g., dantrolene (Dantrium), baclofen (Baclofen, Intrathecal Baclofen, Lioresal), tizanidine (Zanaflex)), diazepam (Valium) or botulinum toxin (Botox) for spasticity; isoniazid

(Liniazid) for tremor, anticonvulsants (phenytoin, nortriptyline), , or amitriptyline for paroxymal pain (paresthesias); gabapentin for dysesthesias); carbamazepine for trigeminal neuralgia; hydroxyzine (Atarax) for paroxysmal itching, memantine or choimesterase inhibitors for cognitive deficit; anticholinergic drugs, darifenaein, tamsulosin. terazosin, prazosin (Minipress), oxybulinin (Oxytroi), propantheline bromide (Pro-Banthine), trospium chloride (Sanctum), imipramide (Tofranil), sotifenacin succinate (Vesicare), tolterodine

(Detrai) for bladder dysfunction desmopressin for urinary frequency, PDE5 inhibitors, papaverineor alprostadit for sexual dysfunction; SSRIs (duloxetme hydrochloride,

veniafaxine, paroxetine, fluoxetine, sertraline), bupropion for depression; modafinil

(Provigil), amantadine or amphetamines for fatigue; mineral oil, docusate (Colace), syllium h drophilic rnucilioid (Metasnucil), magnesium hydroxide (Milk of Magnesia), glycerin suppositories, docusate, sodium phosphate or bisaeiodyl for constipation; sulfamethoxazole (Bactrim, Septra), ciprofloxacin (Cipro) or nitrofurantoin, (Macrodantin), methenamine or phenazopyridine (Pyridium) for urinary tract infections; meclizine (Antivert, Bonamine) for nausea, vomiting and dizziness; dexaniethasone, prednisone, adrenocorticotropic hormone or methylprednisoione for acute exacerbations; dextrometliorpan plus quinine for pseudobulbar effect;

(54b) Cannabi.oo.ids, such as the following: Tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), and Dodeca-2E,4E,8Z, 10E/Z-tetraenoic--acid-isobutylaniides (from Echinacea species); Cannabigerol, Cannabichromene,Caniiabicyeiol, Cannabivarin,

Cannabidivarin, Tetrahydrocannabivarin, Cannabichromevarin, Cannabigerovarin,

Cannabigerol onomethyl Ether; Dronabinol (Marinol), Nabilone (Cesamet, a synthetic cannabinoid and an analog of Marinol), Sativex (cannabinoid extract oral spray containing THC, CBD, and other cannabmotds used for neuropathic pain and spasticity), Rimonabant (SR141716, a selective cannabinoid (CBj) receptor inverse agonist used as an anti-obesity drug under the proprietary name Acomplia, also used for smokin cessation); other notable synthetic cannabinoids include: JWH-018, CP-55940, Diraethylheplylpyran, HU-210, HU- 33.1 , SRI 44528, WIN 55,212-2, JWH-133, Levonantradol (Nantrodolum) and AM-2201 ;

(55a) One of the following investigation treatments currently being studies for the treatment of patients with MS, listed in Table 13;

Table 13

Dimethyl fumarate Biogen Idee NF-kappaB Pre- (NFKB) Registered Activation

Inhibitors/ Nuclear

Factor, Erythroid

Derived 2, Like 2

(Nrf2) Activators/

elch-like ECH- Associated Protein

1 (Keapl, INrf2)

Ligands

Teriflunomide Sanofi MMP-2 Pre-

(Gelatinase A) Registered

Inhibitors/ MMP-9

(Gelatinase B)

Inhibitors/

Dihydroorotate

Dehydrogenase

(DHODH)

Inhibitors/ MMP9

Expression

Inhibitors

Alemtuzumab Bayer Schering Anti-CD52 Phase III

Pharma/ Genzyme

Daclizumab Abbott/ Biogen Idee Anti-CD25 (IL-2 Phase III

Receptor)

GGS Chemo-Sero- Phase III

Therapeutic Research

Inst/ Teijin Pharma

Interferon beta- la BioPartners Phase III

Laquinimod Active Biotech/ Teva Phase III sodium

Masitinib mesylate AB Science FGFR3 Inhibitors/ Phase III

Angiogenesis

Inhibitors/ KIT (C- KIT) Inhibitors/

Lyn Kinase

Inhibitors/

Tyrosine Kinase

Inhibitors/

Inhibitors of

Signal

Transduction

Pathways

Ocrelizumab Roche Anti-CD20 Phase III

DNA Gyrase

Inhibitors

Annodafinil University of alpha 1- Phase

Missouri Adrenoceptor II/III

Agonists

Estriol Synthetic Biologies Phase

II/III

ATH-012 Advancell/ Neurotec Phase II

Pharma

Aimspro Daval Phase II

BAF-312 Novartis Lysophospholipid Phase II edgl (S1P1)

Receptor Ligands/

Lysophospholipid edg8 (S1P5)

Receptor Ligands

BGC-20-0134 BTG Phase II

BHT-3009 Bayhill Therapeutics Phase II

Boswellic acids Universitaetsklinikum Phase II

Hamburg-Eppendorf

CNDO-201 Ovamed Phase II

Cvclophosphamide Accentia Apoptosis Phase II

Inducers/ BCL2

Expression

Inhibitors/

LGALS1

Expression

Inhibitors

Firategrast GlaxoSmithKline Integrin Phase II alpha4beta7

(LPAM-1)

Antagonists/

Integrin

alpha4betal

(VLA-4)

Antagonists

Flupirtine maleate Bayer Voltage-Gated Phase II

K(V) 7 (KCNQ)

Channel

Activators

Heat Shock CBio Phase II Protein 10 Human leukocyte HemispheRx Phase II interferon alpha

ISIS- 107248 Antisense ITGA4 Expression Phase II

Therapeutics/ Isis Inhibitors Pharmaceuticals

Ibudilast MediciNova Leukotriene Phase II

CysLTl (LTD4)

Antagonists/

Macrophage

Migration

Inhibitory Factor

(MIF) Modulators/

TLR4 (LPS)

Receptor

Antagonists/

Mediator Release

Inhibitors/

Phosphodiesterase

Inhibitors

Idebenone National Institutes of Calcium Channel Phase II

Health (NIH)/ Modulators/

Santhera Antioxidants

Lamotrieine University College Glutamate Release Phase II

London Inhibitors/ Sodium

Channel Blockers

MIS Innate Therapeutics Phase II

Minocycline EMD Serono Poly(ADP- Phase II hydrochloride ribose)polymerase- 1 (PARP-1)

Inhibitors/ 30S

Ribosomal Protein

Inhibitors/ Protein

Arginine

Deiminase

Inhibitors

Nanocort Galapagos Phase II

ONO-4641 Merck Serono/ Ono Lysophospholipid Phase II edgl (S1P1)

Receptor Agonists

Ofatumumab Genmab/ Anti-CD20 Phase II

GlaxoSmithKline

Ponesimod Actelion/ Roche Lysophospholipid Phase II edgl (S1P1)

Receptor Agonists Prolactin University of Phase II Calgary

Receptin ReceptoPharm Phase II

Riluzole University of Glutamate Release Phase II

California, San Inhibitors/ Sodium

Francisco Channel Blockers/

K(V)4.3 Channel

Blockers

Secukinumab Novartis Anti-IL-17 Phase II

Tabalumab Lilly Anti-BlyS (BAFF; Phase II

TNFSF13B)

Tovaxin Opexa Therapeutics Phase II

762801 University of Phase II

Cambridge/

University of

Edinburgh

ATX-MS-1467 Apitope Phase I/II

740427 Jiangsu Beike Phase I/II

Biotech

1223249 Glaxo SmithKline Anti-Nogo-A Phase I

2018682 GlaxoSmithKline Lysophospholipid Phase I edgl (S1P1)

Receptor Agonists

ARX-424 Merck KGaA Phase I

AS-111793 Veraalis MMP-12 Phase I

(Macrophage

Elastase)

Inhibitors

ASP-4058 Astellas Pharma Phase I

BIIB-033 Biogen Idee Anti-LINGO-1 Phase I

CI-201 Vascular Biogenics Phase I

(d b/a VBL Ther)

DA-3051 Dong-A Phase I

Dronabinol Echo Cannabinoid Phase I

Pharmaceuticals Receptor Agonists/

Antioxidants

GNbACl GeNeuro Phase I

GSK-2018682 GlaxoSmithKline Phase I LAS-186323 Almirall Dihydroorotate Phase I

Dehydrogenase

(DHODH)

Inhibitors

MOR-103 MorphoSys Anti-GM-CSF Phase I

MT-1303 Mitsubishi Tanabe Sphingosine Phase I

Pharma Kinase 1 (SphKl)

Inhibitors

NTx-488 Stem Cell Phase I

Therapeutics/

University of

Calgary

PDA-001 Celgene Phase I

PEGvlated Allozyne Phase I interferon beta- 1 b

Plovamer acetate Merck KGaA Phase I

RPC-1063 Receptos Lysophospholipid Phase I edgl (S1P1)

Receptor Agonists

RTL-1000 Artielle Phase I

ImmunoTherapeutics

SAR-339658 Glenmark Platelets Adhesion Phase I

Pharmaceuticals Inhibitors/ Integrin

alpha2betal

(VLA-2)

Antagonists

742752 Case Western Phase I

Reserve University/

Cleveland Clinic

Foundation/

University Hospitals

(UH)

Li81 faelv) Biogen Idee Anti-LINGO-1 Clinical

VX15/Anti- Vaccinex Angiogenesis IND Filed SEMA4D Inhibitors/

Semaphorin 4D

Inhibitors

XP-23829 XenoPort IND Filed

AMG-369 Amgen Lysophospholipid Preclinical edgl (S1P1)

Receptor Agonists/

Lysophospholipid

Enzyme (ACE)

Inhibitors

MAK-5206 MAKScientific Fatty Acid Amide Preclinical

Hydrolase

(FAAH)

Inhibitors

MORAb-022 Morphotek Preclinical

MS1-TX TxCell Preclinical

MveloXen Pharmsynthez/ Preclinical

Xenetic Biosciences

NTF-SC BrainStorm Cell Preclinical

Therapeutics

NU-400 Nuron Biotech Preclinical

P-1104 PharmaEssentia Preclinical

PLX-I Pluristem Angiogenesis Preclinical

Inducers

PRX-167700 Proximagen Anti-VAP-1 Preclinical

PV-267 Provid Preclinical

Thymosin B4 RegeneRx Cytokine Preclinical

Biopharmaceuticals Modulators/

Angiogenesis

Inducers/

Apoptosis

Inhibitors

VPM-5001 Vakzine Projekt Preclinical

Management

VSN-16R Canbex Therapeutics Cannabinoid Preclinical

Receptor Agonists

VX- 15/2503 Vaccinex Semaphorin 4D Preclinical

Inhibitors

Vertrexate Verrow Folate Preclinical

Pharmaceuticals Antagonists/

Dihydrofolate

Reductase (DHFR)

Inhibitors

sHIeM22 Acorda Preclinical

754560 Royan Institute Preclinical (55b) One of the following agents currently under development for MS neuroprotection, as shown below in Table 14:

Table 14

(56) The only marketed drug for the treatment of patients with HD: Tetrabenazine (XenazineTM);

(57) Drugs used to treat symptoms associated with HD: haloperidol or benzodiazepines such as clonazepam for chorea and psychiatric symptoms such as agitation, hallucinations and psychotic delusions; fluphenazine, olanzapine, riluzole and amantadine for treating chorea, and atypical antipsychotics such as olanzapine for psychosis and agitation, beta- blockers for aggressiveness; SSRIs or mirtazapine for depression.

(58) One of the following investigational treatments, currently bein investigated for the treatment of HD, as shown below in Table 15: Table 15

Neurodegenerative Antagonists

Disorders

4-Chlorokvnurenine VistaGen NMDA Glycine B Preclinical

Receptor

Antagonists

AAVl.shHD2.1 AmpliPhi HD Expression Preclinical

Biosciences/ Sirna Inhibitors

Therapeutics

AC-0523 Accera/ Neuera Preclinical

Pharmaceuticals

ALN-HTT Alnylam HD Expression Preclinical

Pharmaceuticals/ Inhibitors

Medtronic

CERE- 120 Ceregene Preclinical

EPI-743 Edison Preclinical

Pharmaceuticals

Ganelioside GM1 University of Preclinical

Alberta

NSD-726 NeuroSearch Preclinical

NtCell Living Cell Preclinical

Technologies

(LCT)

Smilagenin CHDI Foundation Neurotrophic Preclinical

Agents/

Neurotrophic

Factor Enhancers

(59) Dopaminergic agents, including the dopamine precursor levodopa as well as direct or indirect dopamine agonists; drugs generally used in combination with levodopa to control specific symptoms of PD or to enhance levodopa activity; some representative drugs marketed for the treatment of patients with PD:

• Anticholinergic drugs: Trihexyphenidyl hydrochloride (Artane), Procyclidine hydrochloride (Kemadrin), Benzatropine mesilate (Cogentin), Biperiden (Akineton), Orphenadrine hydrochloride (Disipal), Metixene hydrochloride (Tremaril);

• Dopamine receptor agonists: Apomorphine hydrochloride (Apofin), Amantadine hydrochloride (Symmetrel), Piribedil (Trivastan), Bromocriptine mesilate (Parlodel), Lisuride maleate (Dopergin), Dihydro-alpha-ergokryptine mesylate (Daverium), Pergolide mesylate (Permax, Parkotil), Cabergoline (Cabaser), Ropinirole hydrochloride (Requip), Talipexole dihydrochloride (Domin), Pramipexole hydrochloride (Mirapex, Sifrol), Rotigotine (Neupro);

• Dopamine precursors: Levodopa (Larodopa), Melevodopa hydrochloride (Levomet);

• Dopamine uptake inhibitor: BLS-602/BLS-605 or SEP-226330;

• L-Noradrenaline precursor: Droxidopa (DOPS);

• MAO-B inhibitors: Selegiline hydrochloride (Deprenyl), Rasagiline mesilate

(Azilect);

• NMDA antagonists: Budipine hydrochloride (Parkinsan);

• Ion channel modulators, Zonisamide (Trerief);

• COMT inhibitors: Tolcapone (Tasmar)*, Entacapone (Comtess, Comtan), Stalevo® (combination of entacapone, levodopa and carbidopa);

• an AADC enzyme inhibitor (carbidopa or benserazide) or an AADC inhibitor (entacapone or tolcapone);

• Combination products: Levodopa/carbidopa (Synemet), Levodopa benserazide hydrochloride (Madopar), Levodopa/carbidopa/entacapone (Stalevo), Melevodopa hydrochloride/carbidopa (Levomet Complex);

• Anticholinergic drugs: Procyclidine hydrochloride (Kemadrin), Benzatropine mesilate (Cogentin), Biperiden (Akineton). Orphenadrine hydrochloride (Disipal) Metixene hydrochloride (Tremaril), Apomorphine hydrochloride (Apofin);

(60) Drugs currently under investigation for the treatment of PD, as shown below in Table 16:

Table 16

Inhibitors

AP-09004 Intec Pharma Phase II

CE E-120 Ceregene Phase II

Exenatide University College Insulin Secretagogues/ Phase II

London GLP-1 Receptor

Agonists

Ganglioside GM1 LZ Therapeutics/ Phase II

Thomas Jefferson

University

Isradipine Northwestern Calcium Channel Phase II

University Blockers

Mavoelurant Novartis mgluR5 Antagonists Phase II

NLX-P101 Neurologix Phase II

Nicotine Hopitaux de Paris Nicotinic Receptor Phase II

Agonists

Nitisinone Biotie Therapies 4- Phase II

Hydroxyphenylpyruvate

Dioxygenase (4HPPD)

Inhibitors

Piclozotan Asubio 5-HT1A Receptor Phase II hydrochloride Agonists

hvdrate

RX-10100 Rexahn Drugs Acting on Phase II

Dopaminergic

Transmission/ Drugs

Acting on Serotonergic

Transmission

Smilasenin Phytopharm Neurotrophic Agents/ Phase II

Neurotrophic Factor

Enhancers

Varenicline tartrate Rush University Nicotinic alpha3beta4 Phase II

Medical Center Agonists/ Nicotinic

alpha7 Agonists/

Nicotinic alpha4beta2 Partial Agonists

XP- XenoPort Dopamine Precursors Phase II

21279/Carbidopa

Lenti-TH-AADC- Oxford Phase I/II CH1 BioMedica

ND-0611 NeuroDerm Phase I/II

PTX-200 Phytrix Phase I/II

XP-21279 XenoPort Dopamine Precursors Phase I/II rAAV-hAADC Genzyme Phase I/II sNN-0031 NeuroNova Phase I/II

AAD-2004 Neurotech Non-Steroidal Phase I

Pharmaceuticals Antiinflammatory

Drugs/ Antioxidants/

Antiamyloidogenic

Agents/ Cytokine

Production Inhibitors/

Free Radical

Scavengers

AZD-3241 AstraZeneca Myeloperoxidase Phase I

Inhibitors

Affitope PD01A AFFiRiS Phase I

GC-2101 Green Cross Phase I

Neu-120 Neurim NMDA Modulators Phase I

Pharmaceuticals

Ordopidine NeuroSearch Dopamine Receptor Phase I

Modulators

SPN-803 Superaus Phase I

ST-1535 Sigma-Tau Adenosine A2A Phase I

Antagonists

V-81444 Vernalis Adenosine A2A Phase I

Antagonists

Π23Ι1ΜΝ1-420 Inst for Adenosine A2A Phase I

Neurodegenerative Antagonists

Disorders

Himantane Russian Academy MAO-B Inhibitors/ Clinical of Medical NMDA Antagonists/

Sciences Dopamine-Releasing

Drugs

NuroPro Power3 Medical Clinical Products

GCC-1290K Green Cross IND Filed

Neural regenerating SanBio IND Filed cells

4-Chlorokvnurenine VistaGen NMDA Glycine B Preclinical

Receptor Antagonists

AAV2-GDNF Georgetown Preclinical

University/

University of

California,

Oakland

AC-8632 Accera/ Neuera Acetyl-CoA Preclinical

Pharmaceuticals Carboxylase 1 (ACC1)

Inhibitors/ Acetyl-CoA

Carboxylase 2 (ACC2)

Inhibitors

AEOL-11207 Aeolus Antioxidants/ Lipid Preclinical

Pharmaceuticals Peroxidation Inhibitors

AGT-110 ArmaGen TNF-alpha Modulators Preclinical

Technologies

AGT-ml 10 ArmaGen TNF-alpha Modulators Preclinical

Technologies

AGT-ml l5 ArmaGen Preclinical

Technologies

AMR-103 Amarin Dopamine Precursors Preclinical

AMRS-001 Amarantus Preclinical

Biosciences

AMT-090 Amsterdam Preclinical

Molecular

Therapeutics

(AMT)

AT-3375 Amicus Pharmacological Preclinical

Therapeutics Chaperones

ATG-ml90 ArmaGen Preclinical

Technologies

AVE-8112 Sanofi Phosphodiesterase IV Preclinical

Inhibitors

Beperminogene AnGes Angiogenesis Inducers Preclinical perplasmid

Davunetide Allon Neurotrophic Agents Preclinical Therapeutics

Fasudil Michigan State Rho Kinase Inhibitors/ Preclinical hydrochloride University Calcium Sensitizers

HIRMAb-GDNF ArmaGen Preclinical

Technologies

ITI-002 Intracellular Dopamine Receptor Preclinical

Therapies Modulators/

Phosphodiesterase I

Inhibitors

KW-6356 Kyowa Hakko Adenosine A2A Preclinical

Kirin Antagonists

MITO-4565 BioWest Apoptosis Inhibitors Preclinical

Therapeutics

NNZ-2591 Neuren Preclinical

Pharmaceuticals

NP-003 Neuraltus Preclinical

NP-201 NuPathe/ Dopamine Receptor Preclinical

SurModics Agonists

NtCell Living Cell Preclinical

Technologies

(LCT)

ORS-1006 Arrien Protein Kinase Preclinical

Pharmaceuticals Inhibitors

PBT-434 Prana Preclinical

Biotechnology

PD-61-W3 ProteoTech Preclinical

PK-236 Obio Preclinical

Pharmaceutical

ReN-004 ReNeuron Preclinical

ReS9-S7 reMYND Preclinical

SCH-900800 Merck & Co. Preclinical

SR-3306 Scripps Research SAPKla (J K2) Preclinical

Institute Inhibitors/ SAPKlb

(JNK3) Inhibitors/

SAPKlc (JNK1)

Inhibitors

T-9001 QRxPharma Preclinical

TBS-3 Trimel Preclinical

Pharmaceuticals TGHW01AP Fabre-Kramer Dopamine Dl Agonists/ Preclinical

Dopamine D2 Agonists

TRx-0014 TauRx Nitric Oxide Production Preclinical

Therapeutics Inhibitors/ Tau

Aggregation Inhibitors/

MAO Inhibitors

TTT-3002 Tautatis Flt3 (FLK2/STK1) Preclinical

Inhibitors/ Apoptosis

Inducers/ Leucine-Rich

Repeat Kinase 2

(LRRK2; Dardarin)

Inhibitors/ Tau

Aggregation Inhibitors

WS-CoOlO Zymes Antioxidants Preclinical

(61) Other drugs used to treat symptoms associated with PD: The tricyclic antidepressant amitriptyline; selective serotonin re-uptake inhibitors (SSRIs), dual serotonin/noradrenaline re-uptake inhibitors (SNRIs) and the dopamine agonists pramipexole and ropinirole;

donepezil and rivastigmine for the treatment of dementia in parkinsonian patients; donepezil is also recommended for the treatment of dementia with Lewy bodies; clozapine is probably the most effective drug for treating symptoms of psychosis in PD patients, together with quetiapine;

(62) Drugs currently in development for the treatment of stroke such as those shown below in Table 17:

Table 17

DP-b99 D-Pharm Chelating Agents Phase III

Desmoteplase Lundbeck Phase III

Edoxaban tosilate Daiichi Sankyo Coagulation Factor Phase III

Xa Inhibitors/

Inhibitors of Blood

Coagulation

Pathways

GK-501 Ipsen Phase III

Human Albumin Medical Phase III

University of

South Carolina/

University of

Calgary/

University of

Miami (UM)

OnabotulinumtoxinA Allergan Phase III

Prasuerel Daiichi Sankyo P2Y12 (P2T) Phase III

Antagonists

249320 GlaxoSmithKline Myelin Associated Phase II

Glycoprotein

(MAG) Antagonists

ALD-401 Cytomedix Phase II

AX-200 Sygnis Pharma Phase II

Arimoclomol Orpha2yme Phase II maleate

Cutamesine M's Science sigmal Receptor Phase II hydrochloride Agonists/

Acetylcholine

Release Enhancers

Donepezil Mayo Clinic Acetylcholinesterase Phase II hydrochloride Inhibitors

GM-602 Genervon Phase II

MAPC Athersys Phase II

NTx-265 Stem Cell Phase II

Therapeutics

Nefiracetam Hamilton Phase II

Pharmaceuticals/

Neuren

Pharmaceuticals

Niacin Henry Ford Phase II Health System

Ocriplasmin ThromboGenics Phase II

PDA-001 Celgene Phase II

PF-3049423 Pfizer Phase II

Pioelitazone University of PPARgamma Phase II hydrochloride Texas System Agonists/ Insulin

Sensitizers

THR-18 Thrombotech Plasminogen Phase II

Activator Inhibitor

(PAI-1) Inhibitors

Tecarfarin ARYx Vitamin K Epoxide Phase II

Therapeutics Reductase (VKER,

VKOR) Inhibitors

Tenecteplase Natl. Inst. Neurol. Phase II

Dis. and Stroke

Troplasminogen alfa Vernalis Phase II tat-NR2B9c Arbor Vita/ Postsynaptic Phase II

NoNO Density-95 (PSD- 95) Protein

Inhibitors

CNTO-0007 Johnson & Phase I/II

Johnson

Caffeinol Univ Texas Phase I/II

Health Sci Center

at Houston

CellBeads Biocompatibles Phase I/II

Fampridine Acorda Potassium Channel Phase I II

Blockers

Glvbenclamide Remedy K(ATP) Channel Phase I/II

Pharmaceuticals Blockers

MNC All India Institute Phase I/II of Medical

Sciences

Neural regenerating SanBio Phase I/II cells

Revacept Corimmun Platelets Adhesion Phase I/II

Inhibitors

772515 Sapporo Medical Phase I/II

University 774419 University of Phase I/II Texas System

742863 All India Institute Phase I II of Medical

Sciences

689453 Stemedica Phase I/II

Carbamvlated Lundbeck Phosphodiesterase Phase I ervthropoietin Inhibitors

D-JNKI-1 Xigen SAPK1 (JNK) Phase I

Inhibitors

Deferoxamine Beth Israel Antimetabolites/ Phase I

Deaconess APP Expression

Medical Center Inhibitors/ Chelating

Agents

KN-38-7271 KeyNeurotek Cannabinoid CB1 Phase I

Agonists/

Cannabinoid CB2

Agonists

Lovastatin Natl. Inst. Neurol. HMG-CoA Phase I

Dis. and Stroke Reductase

Inhibitors

MP-124 Mitsubishi NAD+ ADP- Phase I

Tanabe Pharma Ribosyltransferase

(poly(ADP- ribose)polymerase;

PARP) Inhibitors

Methamphetamine Sinapis Pharma Phase I hydrochloride

NEU-2000 JW NMDA Phase I

Pharmaceutical/ Antagonists/

Neurotech Antioxidants

Pharmaceuticals

ReN-001 ReNeuron Phase I

SAR-104772 Sanofi Carboxypeptidase U Phase I

(TAFIa) Inhibitors

SAR-126119 Sanofi Carboxypeptidase U Phase I

(TAFIa) Inhibitors

Sildenafil citrate Henry Ford Phosphodiesterase Phase I

Hospital V (PDE5A)

Inhibitors

Sothrombomodulin PAION Inhibitors of Blood Phase I alfa Coagulation

Pathways/

Thrombin

Inhibitors

PHN011/012/013 PhytoHealth Phase 0

04RD33 Oxygen Preclinical

Biotherapeutics

(63) Compounds currently under investigation for the treatment of traumatic brain injury such as those shown below in Table 18:

Table 18

VAS-203 vasopharm Endothelial Nitric Phase

Oxide Synthase II

(NOS-3) Inhibitors

AbelaDrue-200 Abela Phase

Pharmaceuticals mi

Minocycline Wayne State Poly(ADP- Phase hydrochloride University ribose)polymerase- I/II

1 (PARP-1)

Inhibitors/ 30S

Ribosomal Protein

Inhibitors/ Protein

Arginine

Deiminase

Inhibitors

DP-b99 D-Pharm Chelating Agents Phase

I

SAR- 127963 Sanofi Phase

I

TT-301 Transition IL-lbeta Phase

Therapeutics Production I

Inhibitors/ TNF- alpha Production

Inhibitors

(64) an anti-dyskinetic agent such as amantadine (Symmetrel); fipamezole, sarizotan or saletracetam;

(65) antipsychotic medication such as clozapine (Clozaril®), ziprasidone (Geodon®), risperidone (Risperdal®), quetiapine (Seroquel®), olanzapine (Zyprexa®) or ACP-103;

(66) monoamine oxidase B (MAO B) inhibitor such as selegiline (Eldepryl®, Atapryl®, Carbex®) or rasagiline (Azilect®);

(67) an additional PD agent such as Coenzyme Q10, an anti-apoptotic drug (e.g., CEP 1347 and CTCT346), an adenosine A2A receptor antagonist (e.g., istradefylline or preladenant) or an 5HT1 A 5HT1B agonist (e.g., eltoprazine);

(68) a treatment for orthostatic hypotension such as L-DOPS (L-threo- dihydroxyphenylserine; Droxidopa ®), fludrocortisone, midodrine, pidolol or clonidine;

(69) antiepileptic drugs: • Benzodiazepines: Diazepam (Valium), Clonazepam (Klonopin), Clobazam (Frisium), Lorazepam (Ativan), Diazepam (Diastat);

• Barbiturates: Clobazam (Frisium) Phenobarbital (Luminal) Methylphenobarbital (Mebaral) Primidone (Mysoline);

• Valproates: Valproic acid (Depakene) Valproate semisodium(Depakote) Valpromide (Depamide) Valproic acid sodium salt (Valerin);

• Gamma-aminobutyric acid analogues: Vigabatrin (Sabril) Gabapentin (Neurontin) Pregabalin (Lyrica);

• Iminostilbenes: Carbamazepine (Tegretol) Oxcarbazepine (Trileptal);

• Hydantoins: Phenytoin sodium (Dilantin) Mephenytoin (Mesantoin) Fosphenytoin sodium (Cerebyx);

• SuccinimidesMethsuximide (Celontin) Ethosuximide (Zarontin);

• MiscellaneousAcetazolamide (Diamox) Clomethiazole edisilate (Heminevrin) Zonisamide (Excegran) Lamotrigine (Lamictal) Felbamate (Felbatol/Taloxa)* Topiramate (Topimax) Tiagabine hydrochloride (Gabitril) Levetiracetam (Keppra) Rufinamide

(Inovelon) Stiripentol (Diacomit) Lacosamide (Vimpat) Eslicarbazepine acetate (Zebinix) Retigabine (Trobalt, Potiga);

(70) FAAH inhibitors: e.g., OL-135, LY2183240, URB-597, CAY-10402, PF-750, BMS-469908, SSR-411298, TK-25, PF-04457845, PF-3845, SA-47, JNJ-245, JNJ-28833155 and JNJ-1661010;

(71) other pain relieving agents such as gabapentin, topical capsaicin, tanezumab, esreboxetine; opiate receptor agonists such as morphine, propoxyphene (Darvon™), tramadol, buprenorphin; cannabinoid receptor agonists such as dronabinol, A9-THC, CP- 55940, WTN-55212-2, HU-210;

(72) agents used for migraines, such as sumatriptan, zolmitriptan, naratriptan, eletriptan, rauwolscine, yohimbine, metoclopramide;

(73) agents designed to treat tobacco abuse: e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban™) and nicotine replacement therapies; ADD/ADHD agents: e.g., Ritalin™ (methylphemdate hydrochloride), Strattera™ (atomoxetine hydrochloride), Concerta™ (methylphemdate hydrochloride) and Adderall™ (amphetamine aspartate; amphetamine sulfate; dextroamphetamine saccharate; and dextroamphetamine sulfate); agents to treat alcoholism, such as opioid antagonists (e.g., naltrexone (also known under the tradename Re Via M) and nalmefene), disulfiram (also known under the tradename Antabuse™), and acamprosate (also known under the tradename Campral™)); agents for reducing alcohol withdrawal symptoms such as benzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin™);

(74) agents used to treat glaucoma: e.g., direct-acting miotics (cholinergic agonists), indirect acting miotics (cholinesterase inhibitors), carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide, brinzolamide, dorzolamide, selective adrenergic agonists (e.g., apraclonidine, brimonidine), beta-blockers (timolol, betaxolol, carteolol, levobetaxolol, levobunolol, metipranolol), osmotic diuretics (e.g., glycerin, mannitol);

(75) anti-emetic agents: e.g., 5HT3 antagonists such as ondansetron, granisetron, metoclopramide;

(76) disease-modifying anti-rheumatic drugs (DMARDS) such as methotrexate, azathioptrine, leflunomide, pencillinamine, gold salts, mycophenolate mofetil,

cyclophosphamide, CP-690,550; biological response modifiers (BRMs) such as Enbrel™, Remicade™, IL-1 antagonists; NSAIDS such as piroxicam, naproxen, indomethacin, ibuprofen and the like; COX-2 selective inhibitors such as Celebrex™; COX-1 inhibitors such as Feldene™; immunosuppressives such as steroids, cyclosporine, tacrolimus, rapamycin and the like;

(77) GABA modulators such as lacosamide and propofol;

(78) GI agents: e.g., laxatives (e.g., lubiprostone (Amitiza™), Fybogel®, Regulan®, Normacol® and the like), a gastrointestinal agent used for the treatment of idiopathic chronic constipation and constipation-predominant IBS, GI motility stimulants (e.g., domperidone, metoclopramide, mosapride, itopride), antispasmodic drugs (e.g., anticholinergics such as hyoscyamine or dicyclomine); anti-diarrheal medicines such loperamide (Imodium™) and bismuth subsalicylate (as found in Pepto Bismol™ and Kaopectate™), GCC (Guanylate Cyclase C) agonists (e.g., linaclotide), 5HT4 agonists (e.g., tegasarod), 5HT3 antagonists (e.g.,alosetron, ramosetron, ondansetron).

(79) drugs marketed to treat urinary incontinence:

• Calcium antagonists: Flavoxate hydrochloride (Genurin, Urispas); • Anticholinergic agents: Oxybutynin chloride (Dirropan), Propiverine hydrochloride (Dutrottorm) Tolterodine tartrate (Detrusitol) Trosphim chloride (Spasmex) Oxybutynin chloride, extended-release (Ditropan-XL) Oxybutynin chloride, transdermal system (Oxytroi.) Solifenacin succinate (Vesicare) Darifenacin hydrobromide (Eriabiex) Imidafenacin (Uritos, Staybla) Fesoterodine -ftimarate (Toviaz) Oxybutynin chloride gel (Gelnique);

® Beta3-adrenoceptor antagonists: Mirabegron (Betanis);

• Neurotransmitter re-uptake inhibitors: Du!oxetine hydrochloride (Yentreve);

• Vasopressin analogues: Desmopressin acetate (Stimate); » Botulinum toxins: OnabotiiiinumtoxinA (Botox);

» Combination products: Tamsuiosin hydrochloride/toherodine tartrate (Roiiflo OD);

(80) drags marketed for the treatment of insomnia: Flurazepam hydrochloride (Dalmane),

Quazepam (Dorai), Temazepam (Restoril), Estazolam (Eurodin), Flunitrazepam (Rohypnol), Brotizolam (Lendormine), Zolpidem tartrate (Stiinox), Etizolam (Depas), Triazolam

(Halcion), Zopiclone (Imovane), Zaleplon (Sonata), Eszopieione (Lunesta), Ramelteon

(Rozerem), Doxepin hydrochloride (Silenor), Amobarbital (Amytal), Secobarbital sodium (Seconal);

(81) drugs used to treat anxiety, such as those listed in Table 19:

Table 19

(Valium) treatment of

moderate to severe anxiety and anxiety accompanying depression

Clorazepate Sanofi/Abbott 1967 Short-term dipotassium treatment of (Tranxene) moderate to

severe anxiety and anxiety accompanying depression

Medazepam Roche 1968 Short-term (Rudotel) treatment of moderate to severe anxiety and anxiety accompanying depression

Prazepam Pfizer 1973 Short-term (Prazene, treatment of Centrax) moderate to

severe anxiety and anxiety accompanying depression

Clobazam Sanofi 1975 Short-term (Frisium) treatment of moderate to severe anxiety and anxiety accompanying depression

Nordazepam Sanofi 1975 Short-term (Tranxilium) treatment of moderate to severe anxiety and anxiety accompanying depression

Ketazolam Pflzer/Novartis 1980 Short-term (Anseren) treatment of moderate to severe anxiety and anxiety accompanying depression

Ethvl loflazepate Sanofi 1982 Short-term (Victan) treatment of moderate to severe anxiety and anxiety accompanying depression

Halazepam Merck & Co. 1982 Short-term (Paxipam) treatment of moderate to severe anxiety and anxiety accompanying depression

Benzodiazepines (intermediate-acting)

Oxazepam Pfizer 1964 Short-term (Serax) treatment of moderate to severe anxiety and anxiety accompanying depression

Lorazepam Pfizer 1971 Short-term (Ativan) treatment of moderate to severe anxiety and anxiety accompanying depression

Bromazepam Roche 1974 Short-term (Lexotanil) treatment of moderate to severe anxiety and anxiety accompanying depression

Benzodiazepines (short-acting)

Clonazepam Roche 1975 Short-term (Klonopin) treatment of moderate to severe anxiety and anxiety accompanying depression

Clotiazepam Mitsubishi 1979 Short-term (Rizen) Pharma treatment of moderate to severe anxiety and anxiety accompanying depression

Alprazolam Pfizer 1983 Short-term (Xanax) treatment of

moderate to severe anxiety and anxiety accompanying depression, panic disorder, generalized anxiety disorder

Brotizolam Boehringer 1984 Short-term (Lendorm) Ingelheim treatment of moderate to severe anxiety and anxiety accompanying depression

L-Type calcium channel blockers

Pregabalin Pfizer 2006 Generalized (Lyrica) anxiety disorder

Selective serotonin re-uptake inhibitors (SSRIs)

Fluvoxamine Abbott 1985 OCD, social maleate anxiety disorder

(Floxyfral)

Fluoxetine Lilly 1987 OCD, hydrochloride premenstrual

(Prozac) dysphoric disorder

Citalopram Lundbeck 1989 Panic disorder hvdrobromide

(Cipramil)

Sertraline Pfizer 1990 OCD, panic hydrochloride disorder, PTSD,

(Zoloft) social anxiety disorder, premenstrual dysphoric disorder Paroxetine GlaxoSmithKline 1991 OCD, panic hydrochloride disorder, social (Seroxat, Paxil) anxiety disorder,

PTSD, premenstrual dysphoric disorder

Escitalopram Lundbeck 2002 Panic disorder, oxalate GAD, social (Cipralex, anxiety disorder, Lexapro) OCD

Serotonin and norepinephrine re-uptake inhibitors (SNRIs)

Venlafaxine Pfizer 1994 GAD, social hydrochloride anxiety disorder (Effexor XR)

Duloxetine Lilly 2007 GAD

hydrochloride

(Cymbalta)

5-HT1A partial agonists

Buspirone Bristol-Myers 1985 Anxiety, phobic hydrochloride Squibb neuroses, anxiety

(Buspar) with depression

Tandospirone Sumitomo 1996 GAD

citrate (SedieD

5-HT3 antagonists

Cvamemazine Sanofi 1972 Short-term (Tercian) treatment of

anxiety

Noncardioselective beta-blockers

Propranolol AstraZeneca 1964 Situational hydrochloride anxiety, GAD

(Inderal)

Oxprenolol Novartis 1968 Situational hydrochloride anxiety, GAD

(Trasicor)

Histamine HI antagonists

Hydroxyzine Pfizer 1957 Symptomatic hydrochloride treatment of

(Atarax) anxiety

Antipsychotic agents

Trifluoperazine GlaxoSmithKline 1958 Nonpsychotic hydrochloride anxiety (Stelazine)

Fluphenazine Bristol-Myers 1959 Anxiety and

hydrochloride Squibb agitation (adjunct (Prolixin) therapy)

Tricyclic antidepressants

Clomipramine Novartis 1967 Obsessional and hydrochloride phobic states

(Anafranil)

Carpipramine Pierre Fabre 1977 Anxiety (not

(Prazinil) specified)

MAO-A inhibitors

Moclobemide Roche 1990 Social phobia

(Manerix,

Aurorix)

Other anxiolytics

Meprobamate Pfizer 1955 Short-term

(Equanil) treatment of

anxiety

Pharmaceutical compositions and their methods of administration

[00131] The compounds herein disclosed, and their pharmaceutically acceptable salts, thereof may be formulated as pharmaceutical compositions or "formulations".

[00132] A typical formulation is prepared by mixing a compound described herein, or a pharmaceutically acceptable salt thereof, and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound described herein is being formulated. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (e.g., one described in the GRAS (Generally

Recognized as Safe) database) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[00133] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., one or more of the compounds described herein, a pharmaceutically acceptable salt thereof, or a stabilized form of the compound, such as a complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. A compound having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.

[00134] A compound described herein or a pharmaceutically acceptable salt thereof is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.

Pharmaceutical formulations of compounds described herein, or a pharmaceutically acceptable salt thereof, may be prepared for various routes and types of administration.

Various dosage forms may exist for the same compound. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain

approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total composition (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

[00135] The pharmaceutical compositions described herein will be formulated, dosed, and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles, and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular human or other mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual patient.

[00136] The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The therapeutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more of its symptoms.

[00137] The term "prophylactically effective amount" refers to an amount effective in preventing or substantially lessening the chances of acquiring a disorder or in reducing the severity of the disorder or one or more of its symptoms before it is acquired or before the symptoms develop further.

[00138] In some embodiments, a prophylactically effective amount of a FAAH inhibitor is one that prevents the occurrence, progression or reoccurrence of

neurodegeneration. In further embodiments, a prophylactically effective amount of a FAAH inhibitor is one that prevents the occurrence or reoccurrence of neurodegeneration in a subject suffering from a neurodegenerative disease. In other embodiments, a prophylactically effective amount of a FAAH inhibitor is one that prevents the occurrence or reoccurrence of neurodegeneration in a subject who has suffered an acute neuronal injury.

[00139] Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride;

hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol;

cyclohexanol; 3-pentanol; and m-cresol); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin- microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in

Remington's: The Science and Practice of Pharmacy, 21^st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter "Remington's").

[00140] "Controlled drug delivery systems" supply the drug to the body in a manner precisely controlled to suit the drug and the conditions being treated. The primary aim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time. The term "controlled release" is often used to refer to a variety of methods that modify release of drug from a dosage form. This term includes preparations labeled as "extended release", "delayed release", "modified release" or "sustained release".

[00141] "Sustained-release preparations" are the most common applications of controlled release. Suitable examples of sustained-release preparations include

semipermeable matrices of solid hydrophobic polymers containing the compound, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric acid.

[00142] "Gastroretentive formulations" are preparations designed to have increased retention in the stomach cavity. In some cases, they are used where a drug is preferentially or primarily absorbed via the stomach, is designed to treat the stomach directly, or where drug dissolution or absorbtion is aided drug absorbtion is aided by prolonged exposure to gastric acids. Examples of gastroretentive formulations include but are not limite to, high-density formulations, where the density of the formulation is higher than gastric fluid; floating formulations, which can float on top of gastic fluids due to increased buoyancy or lower density of the formulation; temporarily expandable formulations that are temporarily larger than the gastric opening; muco- and bio-adhesive formulations; swellable gel formulations; and in situ gel forming formulations. (See, e.g., Bhardwaj, L. et al. African J. of Basic & Appl. Sci. 4(6): 300-312 (2011)).

[00143] "Immediate-release preparations" may also be prepared. The objective of these formulations is to get the drug into the bloodstream and to the site of action as rapidly as possible. For instance, for rapid dissolution, most tablets are designed to undergo rapid disintegration to granules and subsequent disaggregation to fine particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate.

[00144] Implantable devices coated with a compound of this invention are another embodiment of the present invention. The compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a "drug depot", thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562;

5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

[00145] The formulations include those suitable for the administration routes detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[00146] The terms "administer", "administering" or "administration" in reference to a compound, composition or formulation of the invention means introducing the compound into the system of the animal in need of treatment. When a compound of the invention is provided in combination with one or more other active agents, "administration" and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.

[00147] The compositions described herein may be administered systemically or locally, e.g.: orally (e.g. using capsules, powders, solutions, suspensions, tablets, sublingual tablets and the like), by inhalation (e.g. with an aerosol, gas, inhaler, nebulizer or the like), to the ear (e.g. using ear drops), topically (e.g. using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc), ophthalmically (e.g. with eye drops, ophthalmic gels, ophthalmic ointments), rectally (e.g. using enemas or suppositories), nasally, buccally, vaginally (e.g. using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc), via an implanted reservoir or the like, or parenterally depending on the severity and type of the disease being treated. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular embodiments, the compositions are administered orally, intraperitoneally or intravenously.

[00148] The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00149] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution-retarding agents such as paraffin, f absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Tablets may be uncoated or may be coated by known techniques including microencapsulation to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. A water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be employed.

[00150] Formulations of a compound described herein that are suitable for oral administration may be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs. Formulations of a compound intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.

[00151] Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

[00152] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethyleneglycol or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.

[00153] The active compounds can also be in microencapsulated form with one or more excipients as noted above. [00154] When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.

[00155] Sterile injectable forms of the compositions described herein (e.g., for parenteral administration) may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of injectable formulations.

[00156] Oily suspensions may be formulated by suspending a compound described herein in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

[00157] Aqueous suspensions of compounds described herein contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.

Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, raethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

[00158] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00159] In order to prolong the effect of a compound described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable drug- depot forms are made by forming microencapsuled matrices of the compound in

biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Drug-depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[00160] The injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS^1M model 5400 intravenous pump.

[00161] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Other formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays.

[00162] The pharmaceutical compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the ear, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[00163] Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[00164] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

[00165] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or, preferably, as solutions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as

benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, between 0.075 % and 20% w/w. When formulated in an ointment, the active ingredients may be employed with either an oil-based, paraffinic or a water-miscible ointment base.

[00166] Alternatively, the active ingredients may be formulated in a cream with an oil- in-water cream base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

[00167] The oily phase of emulsions prepared using compounds described herein may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. A hydrophilic emulsifier may be included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulgents and emulsion stabilizers suitable for use in the formulation of compounds described herein include Tween™-60, Span™-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. [00168] The pharmaceutical compositions may also be administered by nasal aerosol or by inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance

bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. Formulations suitable for intrapulmonary or nasal administration may have a mean particle size in the range of, for example, 0.1 to 500 microns (including particles with a mean particle size in the range between 0.1 and 500 microns in increments such as 0.5, 1, 30, 35 microns, etc.), which may be administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.

[00169] The pharmaceutical composition (or formulation) for use may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[00170] The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[00171] In another aspect, a compound described herein or a pharmaceutically acceptable salt, co-crystal, solvate or pro-drug thereof may be formulated in a veterinary composition comprising a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route. EXAMPLES

[00172] All references provided in the Examples are herein incorporated by reference in their entirety. As used herein, all abbreviations, symbols and conventions are consistent with those used in the contemporary scientific literature. See, e.g. Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2^nd Ed., Washington, D.C.: American Chemical Society, 1997, herein incorporated by reference in its entirety.

Background

[00173] Although the experimental autoimmune encephalomyelitis mouse disease model of MS is most commonly used to study the (auto) immune component of MS, previous investigations showed distinct, non-immunological components of the disease and reported the first objective evidence for both control of signs arising from the disease (Baker et al, 2000) and neuroprotection by cannabinoid receptor agonists in EAE (Pryce et al, 2003, Croxford et al, 2008). This is further reinforced by the observation that cannabinoid receptor 1 (CB1) deficient mice are much more susceptible to neurodegeneration induced by EAE than wild type animals.

[00174] Natural ligands for the cannabinoid receptors are termed endocannabinoids of which there are two main compounds, 2-Arachidonyl Glycerol (2-AG) and anandamide (AEA), which are produced in response to post synaptic nerve stimulation and act presynaptically at CB1 receptors to downregulate further neurotransmitter release. It is hypothesised that during inflammatory insults in the CNS during EAE or MS, excessive levels of excitatory neurotransmitters such as glutamine are produced leading to overexcitation of neurons and eventual dystrophy and death. This over-production of

neurotransmitters has been attributed, in part, to a deficiency of endocannabinoids that can limit the over-production of neurotransmitters, in some EAE studies (Witting et al, 2006). In support of this hypothesis, fatty acid amide hydrolase (FAAH, the enzyme responsible for the degradation of anandamide) deficient mice, which have elevated levels of anandamide, accumulate less nerve damage as a consequence of EAE (Webb et al, 2008, unpublished observations in this laboratory).

[00175] These observations have led to the hypothesis that the elevation of anandamide levels, achieved by the delivery of an exogenous compound 2-(5-chloro-l-(4- cUoroben.^l)-2-methyl-lH-indol-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide (Compound No. 13 of Table 1, above), which inhibits the activity of the anandamide degradative enzyme FAAH, will also have a neuroprotective potential in an experimental mouse model of MS.

Experimental design

[00176] EAE was induced in female Biozzi ABH mice as previously described (Baker et al, 1990, Al-Izki et al, 2012). Mice were immunized with spinal cord homogenate in complete Freunds adjuvant on day 0 and day 7 in 2 sites in the flank. Clinical signs typically developed around day 14-15 post immunization. Animals were allowed to have an initial acute disease attack (up to 7 days), followed by a period of remission, animals were monitored daily and clinical scores were assessed over the course of disease under the UK Home Office Animal Procedures Act 1986. For clinical scoring details, see below, and Figure 1.

[00177] At day 28, in the first remission phase of the disease, baseline motor control and performance was assessed by placing mice on an accelerating (4-40 rpm) RotaRod treadmill (ENV-575M, Med Associates Inc., St Albans, VT, USA) over a maximum 5 minute observation period. The trial was terminated when the mouse either, fell from the RotaRod spindle, or if the mouse failed to tolerate the revolving spindle by holding on to the spindle for two consecutive revolutions.

[00178] Mice were then re-immunized at day 28 with spinal cord homogenate in complete Freunds adjuvant to induce an EAE relapse which typically developed at day 35. The drug dosing regime commenced at day 32 of disease before the commencement of clinical relapse until the termination of the experiment at day 50 in the second remission phase, when a second RotaRod performance assessment was performed. Animals were assigned for each treatment group according to RotaRod score with highest scoring mouse assigned to group 1, next highest to group 2, next highest to group 3, next highest to group 1 etc. Spinal cords, brain and plasma were collected from each animal at the termination of the experiment.

Test compounds:

[00179] 1. 2-(5-chloro- 1 -(4-chlorobenzyl)-2-methyl- 1 H-indol-3 -yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (30 mg/kg delivered PO daily) formulated 1:1 :8 DMSO: Cremophor: Saline. n=13.

[00180] 2. THC (2.5 mg/kg delivered IP daily) formulated 1:1:18 Alcohol: Cremophor: Saline as positive control. n=13 (1 animal died during the relapse phase).

[001811 3. Vehicle (delivered PO daily) 1:1:8 DMSO:Cremophor.Saline as negative control. n=14 (3 animals died during the relapse phase).

Clinical Disease Scoring.

[00182] Animals were weighed and scored daily from day 10 onwards. At

approximately day 13, mice lost more than 1.5g overnight. Weight loss continued for a few days. On about day 15, clinical signs start (this was ascending paralysis that started with the tail). (See Figure 1.) This was scored as follows (Figure 1):

[00183] Normal = 0

[00184] Fully flaccid tail = 1. Tail is completely paralyzed. Tail does not lift but has some tone. E.g. Tail can bend round finger. Lift the mouse by the scruff of the neck and the tail will helicopter = (1) = 0.5. This is the typical score of remission 1.

[00185] Impaired righting reflex. = 2. When turned on back, the animal does not right itself. If it rights itself slowly it received a score of (2) = 1.5.

[00186] Hindlimb paresis = 3. Significant loss of motor function of the hindlimbs. Hindlimb gait disturbance = (3) = 2.5. This is typical score of remission 2-3.

[00187] Complete hindlimb paralysis = 4. Both hind limbs drag. Limbs virtually paralyzed but have some minor movement or one leg fully paralyzed = 3.5= (4).

[00188] Moribund/Death = 5. If forelimbs became paralyzed, the animal was euthanized. We have set a weight loss limit of about 35% from the day 10 weight. However, animals that will die lose the ability to thermoregulate and appear cold to the touch.

[00189] Relapse = Increase of Disease Score, usually accompanied with weight loss.

Results

[00190] All treatment groups showed an equivalent level of disease during the relapse phase of EAE, indicating a lack of any immunosuppressive activity of the treatments. (Figure 3). This is important as it is necessary for any inference of neuroprotective activity that the level of CNS inflammation be comparable between the groups.

[00191] There was a highly significant improvement in clinical scores in the THC- treated group versus vehicle treated animals at day 50 (P=<0.001; Figure 3). There was also a significant improvement in the 2-(5-chloro-l-(4-chlorobenzyl)-2-methyl-lH-indol-3-yl)-N- (2-methoxypyridin-4-yl)-2-oxoacetamide -treated group versus vehicle treated animals at day 50 (P=<0.001; see Figure 2.)

(00192] There was a significant improvement in motor performance in the THC- treated group versus vehicle treated animals at day 50 (P=<0.003; Figure 3). There was also a significant improvement in motor performance in the 2-(5-chloro-l-(4-chlorobenzyl)-2- methyl-lH-indol-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide -treated group versus vehicle treated animals at day 50 (P=<0.016; Figure 4). Statistical analysis between treatment groups was assessed by t-test using SigmaStat software.

[00193] There was a significant improvement in percentage RotaRod performance calculated from baseline measurements at day 28 in the THC-treated group versus vehicle treated animals at day 50 (P=<0.002; Figure 4). There was also a significant improvement in percentage RotaRod performance calculated from baseline measurements at day 28 in the 2- (5-chloro- 1 -(4-chloroberi2yl)-2 -methyl- 1 H-indol-3-yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide treated group versus vehicle treated animals at day 50 (P=<0.005; Figure 4). Statistical analysis between groups was assessed by t-test using SigmaStat software.

[00194] These data clearly show that elevation of anandamide levels in mice treated with the FAAH inhibitor 2-(5-chloro-l-(4-chlorobenzyl)-2-methyl-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide has a significant neuroprotective effect when administered during the relapsing phase of EAE in Biozzi ABH mice compared to vehicle treated animals. The level of neuroprotection is not as high as seen with the classical CB1 receptor agonist THC but given that anandamide is not as effective an agonist as THC, this is to be expected. These results show that elevating anandamide levels via FAAH inhibition can still produce significant neuroprotective effects and importantly without the significant psychoactive effects such as sedation associated with CB1 agonists such as THC.

[00195] These data indicate that elevation of anandamide via FAAH inhibitors such as 2-(5-chloro- 1 -(4-chlorobenzyl)-2-methyl- 1 H-indol-3 -yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide may be therapeutically useful not only in MS, where their use may slow the rate of disease progression but also in other neurodegenerative conditions where similar mechanisms may be operating.

REFERENCES

[00196] Al-Izki, Pryce G, Jackson SG, Giovannoni G, Baker D. Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. J Mult Scler. 2011 [Epub. 1 Apr].

[00197] Al-Izki, Sarah, Gareth Pryce, Janet K, O'Neill, Colin Butter, Gavin

Giovannoni, Sandra Amor and David Baker. Practical Guide to the Induction of Relapsing Progressive Experimental Autoimmune Encephalomyelitis in the Biozzi ABH Mouse. Mult. Scler. Rel. Dis. 1 :29-38. 2012.

[001981 Baker D, O'Neill JK.,. Wilcox C, Gschmeissner S, Butter C and Turk JL. Induction of chronic relapsing experimental allergic encephalomyelitis in Siozzi mice. J. Neuroimmunol 1990; 28: 261-270.

[00199] Baker D, Pryce G, Croxford JL, Brown P, Huffman JW, Pertwee RG, Layward L. Cannabinoids control spasticity and tremor in an animal model of multiple sclerosis. Nature 2000; 404:84-87.

[00200] Baker D, Pryce G, Croxford JL, Brown P, A.Makrylannis, JW Pertwee R, Layward L and Di Marzo V. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J, 2001; 15:300-302.

[00201] Bolton C, O'Neill JK, Allen 5 J and Baker 0 ( 1997) Regulation of chronic relapsing experimental allergic encephalomyelitis (CREAE) by endogenous and exogenous glucocorticoids. Int Archs Allery Immunol 114: 74-80.

[00202] Croxford JL, Pryce G, Jackson SI, Ledent C, Giovannoni G, Pertweee RG, Yamamura T, Baker D. Cannabinoid-mediated neuroprotection, not immunosuppression, may be relevant to multiple sclerosis. J. Neurolmmunol.2008193:120- 129.

[00203] Kilkenny C, Browne W, Cuthill IC, Emerson M, Altaian DG; NC3Rs Reporting Guidelines Working Group. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010 160:1577.

[00204] Maresz K, Pryce G, Ponomarev ED, Marsicano G, Croxford JL, Shiver LP,

Ledent C, Cheng X, Caarrier E, Mann MK, Giovannoni G, Pertwee RG, Yamamura T,

Buckley NE, Hillard CJ, Lutz B, Baker D, Ditttel BN. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T Cells. Nat Medicine 2007 13:492-497.

[00205] O'Neill JK, Baker D, Davison AN, Maggon KK, Jaffee BD and Turk JL. Therapy of chronic relapsing experimental allergic encephalomyelitis and the role of the blood-brain barrier: elucidication by the action of brequinar sodium. J. Neuroimmunol. 1991; 38; 53-62.

[00206] Pryce G, Ahmed Z, Hankey DRJ, Jackson SL, Croxford Jl , Pocock JM, Ledent C, Petzold A, Thompson AJ, Giovannoni G, Cuzner ML. and Baker D. Cannabinoids inhibit neurodegeneration in multiple sclerosis models. Brain. 2003 126 2191-202.

[00207] Pryce G, O'Neill JKA, Croxford JL, Amor S, Hankey DRJ, Giovannoni G, Baker D. Immunological tolerance that eliminates relapses, falls to halt secondary progression in a chronic multiple sclerosis model. J. Neuroimmunol. 2005; 165:41- 52.

[00208] Webb, M., Luo, L., Ma, J.Y and Tham, C.S. Genetic deletion of Fatty Acid Amide Hydrolase results in improved long-term outcome in chronic autoimmune

encephalitis. Neurosci, Lett. 439: 106-110. 2008.

[00209] Witting, A., Chen, L., Cudaback, E., Straiker, A., Walter, L., Rickman, B., Moller, T., Brosnan C. and Stella, N. Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection. Proc Natl Acad Sci U S A. 103:6362-6367. 2008.

OTHER EMBODIMENTS

[00210] All publications and patents referred to in this disclosure are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Should the meaning of the terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meaning of the terms in this disclosure are intended to be controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments of the present invention. One skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.

Claims

We claim:

1. A method of treating or preventing neuronal injury or neurodegeneration in a patient in need thereof, comprising administering to said patient a therapeutically or prophylactically effective amount of a FAAH inhibitor of Formula I, or pharmaceutically acceptable salt thereof, alone or in combination with a therapeutically or prophylactically effective amount of one or more additional therapeutic agents, wherein the compound of Formula I has the structure depicted below:

Formula I and V, W, X, Y are either C or N; Z, J, , L are C; and M is N; Q¹ is N; Q², Q⁴ and Q⁵ are C; and Q³ is either C or N; a) each of P¹, P², P³, P⁴, P⁵ and P⁶ are C; or b) up to two of P¹, P², P³, P⁴, P^s and P⁶ are N and the rest are C;

A and A' taken together are =0; ¹ indicates an aromatic bond;

R² is hydroxyl, an optionally independently substituted C1.3 alkyl, an optionally

independently substituted C|.₂ alkoxy or an optionally independently substituted cyclopropyl; each of R⁴, R⁵, R⁶ and R⁷ is independently: H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci_5 alkyl, an optionally independently substituted C₂. 5 alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted C,_-5 alkoxy, -OC(0)(C_1-5 alkyl) , -C(0)(C|_-5 alkyl), -C(0)NR R^b,,

-C(0)NR^a(CO)OR^b, -NR^a(CO)(C_M alkyl) or -NR^aR^b, wherein R^a and R^b are independently H, an optionally independently substituted Ci_-6 alkyl, or an optionally independently substituted C3_-6 cycloalkyl; and wherein the optional substituent on each of R⁴, R⁵, R⁶ and R⁷ that is optionally substituted, is independently selected from hydroxyl, halogen, -0(CO)(Ci_-6 alkyl), C alkoxy, or -NR^aR^b, with R^a and R^b as defined above; each of R⁸, R⁹, R¹⁰, R¹¹ and R¹², when bonded to C, is independently: H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl,— S0₂(C alkyl), an optionally independently substituted C1.5 alkyl, an optionally independently substituted C_2-s alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted Q .5 alkoxy, -C(0)NR^aR^b or -NR^aR^b, wherein R^a and R^b are independently H, an optionally independently substituted Ci_-6 alkyl, or an optionally independently substituted C_3-6 cycloalkyl; and wherein the optional substituent on each of R4, R5, R¾ and R₇ that is optionally substituted, is independently selected from hydroxyl, halogen or C 1-4 alkoxy; or each of R⁸, R⁹, R¹⁰ R¹¹ and R¹², when bonded to N, is missing;

R¹⁴ is selected from H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci_-5 alkyl, an optionally independently substituted C₂-₅ alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted Ci_-5 alkoxy, -C(0)NR^aR^b or -NR^aR^b, wherein R^a and R^b are independently H, an optionally independently substituted Ci.₆ alkyl, or an optionally independently substituted C3.6

cycloalkyl; R¹⁶ is selected from H, a halogen, -N0₂, -CN, -C(0)OH, hydroxy 1, an optionally independently substituted C1.5 alkyl, an optionally independently substituted C_2-5 alkenyl, an optionally independently substituted C_2-5 alkynyl, an optionally independently substituted Ci_-5 alkoxy, -C(0)NR^aR^b or -NR^aR^b, wherein R^a and R^b are independently H, optionally independently substituted Ci.₆ alkyl, or an optionally independently substituted C_3-6 cycloalkyl;

R¹⁵ is missing;

R¹³ is selected from H, a halogen, -N0₂, -CN, -C(0)OH, hydroxy 1, an optionally independently substituted Q.5 alkyl, an optionally independently substituted C_2-5 alkenyl, an optionally independently substituted C₂.₅ alkynyl, an optionally independently substituted C s alkoxy, -C(0)NR⁸R or -NR^aR^b, wherein R^a and R^b are independently H, optionally independently substituted Ci.₆ alkyl, or an optionally independently substituted C_3-6 cycloalkyl;

R¹⁷ is selected from H, a halogen, -N0₂, -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci-s alkyl, an optionally independently substituted C_2-5 alkenyl, an optionally independently substituted C2.5 alkynyl, an optionally independently substituted Ci-5 alkoxy, -C(0)NR^aR^b or -NR^aR_b, wherein R^a and R^b are independently H, optionally independently substituted Ci_-6 alkyl, or an optionally independently substituted C₃.₆ cycloalkyl.

2. The method of claim 1, wherein the patient in need thereof is a person who has suffered one or more sudden or acute neuronal events selected from a stroke, brain or spinal cord injury, traumatic brain injury, brain ischemia, ischemia of the eyes, epileptic seizure, seizures associated with brain injury, epileptic seizure of genetic origin, brain damage due to drug abuse or brain damage due to excitotoxic insult.

3. The method of claim 2, wherein the sudden or acute neuronal event is a stroke.

4. The method of claim 2, wherein, the sudden or acute neuronal event is brain or spinal cord injury.

5. The method of claim 2, wherein, the sudden or acute neuronal event is an epileptic seizure.

6. The method of claim 2, wherein, the sudden or acute neuronal event is brain damage due to drug abuse.

7. The method of claim 2, wherein the sudden or acute neuronal event is brain damage due to an excitotoxic insult.

8. The method of claim 7, wherein the excitotoxic insult is caused by excessive concentrations of endogenous neurotransmitters.

9. The method of claim 7, wherein the excitotoxic insult is caused by an exogenous substance.

10. The method of claim 1, wherein the patient in need thereof is a person who has been diagnosed with or is believed to be at risk of developing a neurodegenerative disorder selected from: a motor neuron disease, multiple sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease or a dementia, a neuromflammatory disease, or an autoimmune disease.

11. The method of claim 10, wherein the neurodegenerative disease or disorder is a motor neuron disease.

12. The method of claim 11, wherein said motor neuron disease is selected from

Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, progressive bulbar palsy, also called progressive bulbar atrophy, pseudobulbar palsy, Primary lateral sclerosis (PLS), progressive muscular atrophy, and spinal muscular atrophy (SMA).

13. The method of claim 12, wherein said motor neuron disease is spinal muscular atrophy selected from SMA type I, also called Werdnig-Hoffmann disease; SMA type II; SMA type III also called Kugelberg-Welander disease; congenital SMA with arthrogryposis; Kennedy's disease, also known as progressive spinobulbar muscular atrophy or post- polio syndrome (PPS).

14. The method of claim 12, wherein said motor neuron disease is ALS.

15. The method of claim 10, wherein the neurodegenerative disease or disorder is multiple sclerosis.

16. The method of claim 15, wherein a symptom of multiple sclerosis is treated, wherein the symptom is selected from sleep disturbances, depression, anxiety, pain, erectile dysfunction, spasticity, bladder dysfunctions, fatigue, acute exacerbations, itching, nausea, vomiting, dizziness, walking difficulties, and tremors.

17. The method of claim 10, wherein the neurodegenerative disease or disorder is Parkinson's disease.

18. The method of claim 10, wherein the neurodegenerative disease or disorder is Huntington's disease.

19. The method of claim 10, wherein the neurodegenerative disease or disorder is Alzheimer's disease or a dementia.

20. The method of claim 10, wherein the neurodegenerative disease is a

neuroinflammatory disease.

21. The method of claim 10, wherein the neurodegenerative disease is an autoimmune disease.

22. The method of any one of claims 1 to 21, wherein said method results in one of the following measurable results: halting or slowing down of neuronal degeneration in a patient that exhibits symptoms associated with neuronal injury or neurodegeneration, prolonged survival or delayed disease progression.

23. The method of claim 1 , wherein said method results in neurogenesis.

24. The method of claim 1, wherein said method results in a measurable improvement in a symptom selected from: a cognitive dysfunction, a motor dysfunction, lack of coordination, de-myelination or diminished strength.

25. The method of claim 24, wherein said method also results in an observable or measurable reduction in neuroinflammation or neuroinflammatory processes.

26. The method of claim 24 or claim 25, wherein said method results in an observable or measurable reduction in spasticity.

27. The method of any one of claims 1 to 26, wherein up to two of P¹, P², P³, P⁴, P⁵ and P⁶ is N and the rest are C in said compound of Formula I.

28. The method of claim 27, wherein one of P ¹ , P², P³, P⁴, P⁵ and P⁶ is N and the rest are C in said compound of Formula I.

29. The method of claim 27, wherein P¹, P², P³, P⁴, P⁵ and P⁶ are C in said compound of Formula I.

30. The method of any one of claims 1 to 29, wherein R² is a C1-C3 alkyl or cyclopropyl in said compound of Formula I.

31. The method of claim 30, wherein R² is methyl in said compound of Formula I.

32. The method of any one of claims 1 to 31 , wherein one or two of R⁸, R⁹, R¹⁰, R¹¹ and R¹² are halogen and the rest are H in said compound of Formula I.

33. The method of claim 32, wherein one or two of R⁸, R⁹, R¹⁰, Rⁿ and R¹² are CI or F and the rest are H in said compound of Formula I.

34. The method of claim 32, wherein R¹⁰ is a halogen in said compound of Formula I.

35. The method of claim 32, wherein one of R⁸ and R¹² is halogen and the other is H in said compound of Formula I.

36. The method of claim 34, wherein R¹⁰ is CI or F and R⁸, R⁹, R¹¹ and R¹² are H in said compound of Formula I.

37. The method of claim 34, wherein R¹⁰ is CI or F; R⁸ is CI or F; and R⁹, R¹¹ and R¹² are H in said compound of Formula I.

38. The method of any one of claims 1 to 37, wherein R⁴ and R⁷ are H in said compound of Formula I.

39. The method of any one of claims 1 to 38, wherein R⁶ is H in said compound of Formula I.

40. The method of any one of claims 1 to 39, wherein R⁵ is selected from: ethoxy, methoxy, ethyl, methyl, halogen and H in said compound of Formula I.

41. The method of claim 40, wherein R⁵ is selected from chloro, methoxy, methyl and H in said compound of Formula I.

42. The method of claim 41, wherein R⁵ is methoxy in said compound of Formula I.

43. The method of compound 41 , wherein R⁵ is methyl in said compound of Formula I.

44. The method of any one of claims 1 to 43, wherein one ofR¹⁴ or R¹⁶ is a halogen or an optionally independently substituted methoxy and the other is hydrogen, and wherein both R¹³ and R¹⁷ are H in said compound of Formula I.

45. The method of claim 44, wherein R¹⁴or R¹⁶ is -OCH₃ and the other is hydrogen in said compound of Formula I.

46. The method of claim 1, wherein said compound of Formula I is selected from one of the following compounds listed below: l-[(4-cUorophenyl)methyl]-N-(3-fluoro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo-

1.

1 H-Indole-3-acetamide

2. 1 -[(2,4-difluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo- 1 H- Indole-3-acetamide

3. N-(2-cUoro-4-pyridinyl)-5-me1hoxy-l-[(4-niethoxyphenyl)methyl]-2-methyl-a-oxo- 1 H-Indole-3-acetamide

4. N-(2-chloro-4-pyridinyl)-l-[(4-fluorophenyl)methyl]-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3-acetamide

5. N-(2-chloro-4-pyridinyl)-l-[(2,4-dichlorophenyl)methyl]-5-methoxy-2-methyl-a- oxo- 1 H-Indole-3 -acetamide

6. 5-raethoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -[[4- (trifluoromethyl)phenyl]methyl] - 1 H-Indole-3 -acetamide

7. 5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -[[4- (trifluoromethoxy)phenyl]methyl]- 1 H-Indole-3-acetamide

8. l-[(6-cUoro-3-pyridmyl)methyl]-5-methoxy-N-(2-raemoxy-4-pyridinyl)-2-methyl- a-oxo- 1 H-Indole-3-acetamide

9. 5-methoxy-N-(2-memoxy-4-pyridinyl)-2-methyl-l-[(4-methylphenyl)methyl]-a- oxo- 1 H-Indole-3-acetamide

10. 5-memoxy-l-[(4-memoxyphenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3-acetamide

5-fluoro-l-[(4-fluorophenyl)methyl]-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo-

11.

1 H-Indole-3-acetamide

5-chloro-l-[(4-fluorophenyl)methyl]-N-(2-raethoxy-4-pyridinyl)-2-methyl-a-oxo-

12.

1 H-Indole-3-acetamide

13. 5-chloro-l-[(4-cMorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

14. l-[(4-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

1 -[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-

15.

3-acetamide

16. l-[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3-acetamide

17. l-[(4-chlorophenyl)memyl]-5-methoxy-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

18. l-[(4-chlorophenyl)methyl]-N-(2-fluoro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

19. l-[(4-chlorophenyl)methyl]-N-(2-ethoxy-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3-acetamide

20. l-[(4-chlorophenyl)methyl]-5-fluoro-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

21. l-[(4-cmorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-fluoro-2-methyl-a-oxo-lH- Indole-3 -acetamide

22. l-[(4-chlorophenyl)methyl]-5-fluoro-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

23. l-[(4-cUorophenyl)methyl]-5-ethoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

24. 1 -[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-ethoxy-2-methyl-a-oxo- 1 H- Indole-3 -acetamide

25. 1 -[(4-chlorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl- -oxo- 1 H-Indole- 3-acetamide

26. 1 -[(4-chlorophenyl)methyl] -N-(2-chloro-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3- acetamide

27. 1 -[(4-chlorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2, 5-dimethyl-a-oxo- 1 H- Indole-3-acetamide

28. 1 -[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2,5-dimethyl-a-oxo- 1 H- Indole-3-acetamide

29. l-[(4-chloro-2-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2- methyl-a-oxo- 1 H-Indole-3-acetamide

30. l-[(4-clUoro-2-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

31. l-[(4-chloro-2-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a- oxo- 1 H-Indole-3-acetamide

32. l-[(3-cUorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

33. l-[(2-clUorophenyl)memyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

34. l-[(2-chloro-4-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2- methyl-a-oxo- 1 H-Indole-3-acetamide

35. l-[(2-chloro-4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

36. l-[(2-cWoro-4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridmyl)-2,5-dimethyl-a- oxo- 1 H-Indole-3-acetamide

37. l-[(2,4-difluorophenyl)methyl]-5-memoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo-1 H-Indole-3 -acetamide

l-[(2,4-difluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-lH-

38.

Indole-3 -acetamide

39. l-[(2,4-dichlorophenyl)memyl]-5-memoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3-acetamide

40. l-[(2,4-diclUorophenyl)memyl]-5-fluoro-N-(2-memoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3-acetamide

41. 1 -[(2,4-dichlorophenyI)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H- Indole-3-acetamide

42. l-[(2,4-dichlorophenyl)memyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3 -acetamide

43. 5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -(phenylmethyl)- 1 H- Indole-3-acetamide

44. N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -(phenylmethyl)- 1 H-Indole-3- acetamide

45. N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo- 1 -(phenylmethyl)- 1 H-Indole-3 - acetamide

46. 5-chloro-l-[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2-methyl-a-oxo-lH- Indole-3 -acetamide

47. 5-chloro- 1 -[(4-chlorophenyl)methyl]-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3- acetamide

48. l-[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

49. l-[(4-cWorophenyl)methyl]-5-hydroxy-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

50. l-[(4-chlorophenyl)methyl]-5-ethoxy-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

51.

1 -[(4-chlorophenyl)methyll-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3-acetamide

52. 1 -[(4-chlorophenyl)methyl] -5-methyl-2-( 1 -methylethyl)-a-oxo-N-4-pyridinyl- 1 H- Indole-3-acetamide

1 -[(4-chlorophenyl)methyl]-2,5-dimethyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3-

53.

acetamide

54. 1 -[(2,4-dichlorophenyl)methyl] -5-methoxy-2-methyl-a-oxo-N-4-pyridinyl- 1 H- Indole-3 -acetamide

55. l-[(4-cUorophenyl)methyl]-5-methoxy-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

47. The method of claim 1, wherein the compound of Formula I is selected from those depicted in Table A below:

(Table A)

Structure

150

152

153

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

48. The method according to any one of claims 1 to 47, wherein said patient is a human.

49. The method according to any one of claims 1 to 48, wherein said FAAH inhibitor is administered before a symptom of neuronal injury or neurodegeneration develops in said patient.

50. The method according to any one of claims 1 to 48, wherein said FAAH inhibitor is administered after a symptom of neuronal injury or neurodegeneration develops in said patient.

51. A method of treating or preventing neuronal injury or neurodegeneration in a patient in need thereof, comprising administering a therapeutically or prophylactically effective amount of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof to said patient in combination with a therapeutically or prophylactically effective amount of one or more additional therapeutic agents.

52. The method according to claim 51 , wherein the additional therapeutic agent is selected from one or more of the following:

(1) anti-inflammatory and/or immunosuppressive/immunomodulatory agents;

(2) antidepressants;

(3) non-steroidal anti-inflammatory agents (NSAIDs);

(4) cyclooxygenase-2 (COX-2) inhibitors;

(5) calcium channel blockers;

(6) endothelin receptor antagonists (ERAs);

(7) prostacyclin derivatives or analogues;

(8) antihyperlipidemics;

(9) anticoagulants;

(10) antiplatelet drugs;

(11) ACE inhibitors;

(12) supplemental oxygen therapy;

(13) beta blockers

(14) antiarrhythmic agents;

(15) diuretics;

(16) direct acting vasodilators;

(17) exogenous vasodilators;

(18) bronchodilators;

(19) corticosteroids;

(20) dietary supplements;

(21) anti-diabetic agents;

(22) HDL cholesterol-increasing agents;

(23) antiobesity drugs;

(24) angiotensin receptor blockers; (25) renin inhibitors;

(26) centrally acting alpha-2-adrenoceptor agonists;

(27) adrenergic neuron blockers;

(28) imidazoline I- 1 receptor agonists;

(29) aldosterone antagonists;

(30) potassium channel activators;

(31) dopamine Dl agonists;

(32) 5-HT2 antagonists;

(33) drugs for the treatment of arterial hypertension

(34) vasopressin antagonists;

(35) calcium channel sensitizers;

(36) PDE-3 inhibitors;

(37) adenylate cyclase activators;

(38) positive inotropic agents;

(39) drugs for the treatment of heart failure;

(40) drugs for the treatment of pulmonary hypertension;

(41) drugs for the treatment of female sexual dysfunction;

(42) drugs used for the treatment of erectile dysfunction;

(43) drugs for the treatment of male sexual dysfunction;

(44) drugs for the treatment of sleep apnea;

(45) drugs for the treatment of metabolic syndrome;

(46) antiobesity drugs;

(47) drugs for the treatment of Alzheimer's disease;

(48) Riluzole (Rilutek®);

(49) muscle relaxants; drugs to treat jaw spasms or drooling; drugs to treat excessive saliva; drugs to reduce pseudobulbar affect; anticonvulsants; drugs to treat panic attacks; pain medications;

(50) antispastic drugs;

(51) neuroprotective agents;

(52) drugs for the treatment of ALS;

(53) drugs for the treatment of MS;

(54a) drugs for the treatment of symptoms of MS;

(54b) cannabinoids;

(55) drugs used for neuroprotection in MS patients;

(56) drugs for the treatment of patients with HD;

(57) drugs used to treat symptoms associated with HD;

(58) dnvestigational treatments for HD;

(59) dopaminergic agents;

(60) drugs for the treatment of PD;

(61) drugs used to treat symptoms associated with PD

(62) drugs for the treatment of stroke;

(63) drugs for the treatment of traumatic brain injury;

(64) anti-dyskinetic agents

(65) antipsychotic medications;

(67) Coenzyme Q10, an anti-apoptotic drug, an adenosine A2A receptor antagonist or an 5HT1A/5HT1B agonist;

(68) treatments for orthostatic hypotension;

(69) antiepileptic drugs:

(70) other FAAH inhibitors;

(71) other pain relieving agents;

(72) agents used for migraines;

(73) agents designed to treat tobacco abuse; (74) agents used to treat glaucoma;

(75) anti-emetic agents;

(76) disease-modifying anti-rheumatic drugs (DMARDS);

(77) GABA modulators;

(78) GI agents;

(79) drugs for treating urinary incontinence;

(80) drugs marketed for the treatment of insomnia; and

(81) drugs used to treat anxiety.

53. The method according to either of claims 51 or 52, wherein said FAAH inhibitor of Formula I is admimstered prior to, at the same time or after the imtiation of treatment by an additional therapeutic agent.

54. The method according to claim 53, wherein said additional therapeutic agent and said FAAH inhibitor of Formula I are administered simultaneously.

55. The method according to claim 53, wherein said additional therapeutic agent and said FAAH inhibitor of Formula I are administered sequentially.

56. A pharmaceutical composition comprising a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents for use in the treatment of prevention of neuronal injury or

neurodegeneration in a patient in need thereof.

57. The pharmaceutical compostion of claim 56, further comprising a pharmaceutically acceptable carrier, vehicle or diluent.

58. A pharmaceutical composition comprising a FAAH inhibitor selected from the list below, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents for use in the treatment of prevention of neuronal injury or neurodegeneration in a patient in need thereof.

l-[(4-chlorophenyl)methyl]-N-(3-fluoro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo-

1.

1 H-Indole-3 -acetamide

2. l-[(2,4-difluorophenyl)memyl]-N-(2-memoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3 -acetamide

3. N-(2-chloro-4-pyridmyl)-5-methoxy-l-[(4-methoxyphenyl)methyl]-2-methyl-a-oxo- 1 H-Indole-3-acetamide

4. N-(2-cUoro-4-pyridinyl)-l-[(4-fluorophenyl)methyl]-5-methoxy-2-methyl-a-oxo- lH-Indole-3-acetamide

5. N-(2-chloro-4-pyridinyl)-l-[(2,4-dichlorophenyl)methyl]-5-methoxy-2-methyl-a- oxo- 1 H-Indole-3-acetamide

6. 5-methoxy-N-(2-methoxy-4-pjoidinyl)-2-methyl-a-oxo- 1 -[[4- (trifluoromethyl)phenyl]methyl] - 1 H-Indole-3 -acetamide

7. 5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -[[4- (trifluoromethoxy)phenyl]methyl]- 1 H-Indole-3-acetamide

8. l-[(6-chloro-3-pyridinyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl- a-oxo- 1 H-Indole-3 -acetamide

9. 5-methoxy-N-(2-memoxy-4-pyridinyl)-2-methyl-l-[(4-methylphenyl)methyl]-a- oxo-lH-Indole-3-acetamide

10. 5-methoxy-l-[(4-memoxyphenyl)methyl]-N-(2-memoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3-acetamide

5-fluoro-l-[(4-fluorophenyl)memyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-

11.

1 H-Indole-3-acetamide

5-chloro-l-[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-

12.

1 H-Indole-3 -acetamide

13. 5-cUoro-l-[(4-cUorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

14. l-[(4-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

15. 1 -[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole- 3 -acetamide

16. l-[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3 -acetamide

17. l-[(4-chlorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

18. l-[(4-chlorophenyl)methyl]-N-(2-fluoro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

l-[(4-chlorophenyl)memyl]-N-(2-ethoxy-4-pyridinyl)-5-methoxy-2-methyl-a-oxo-

19.

1 H-Indole-3-acetamide

20. l-[(4-clUorophenyl)methyl]-5-fluoro-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

l-[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-fluoro-2-methyl-a-oxo-lH-

21.

Indole-3 -acetamide

22. l-[(4-chlorophenyl)methyl]-5-fluoro-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

23. l-[(4-chlorophenyl)methyl]-5-ethoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

24. l-[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-ethoxy-2-methyl- -oxo-lH- Indole-3-acetamide

25. l-[(4-cUorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-lH-Indole- 3-acetamide

26. 1 -[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3- acetaraide

27. 1 -[(4-clJorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimetliyl-a-oxo- 1 H- Indole-3 -acetamide

28. 1 -[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2,5-dimethyl-a-oxo- 1 H- Indole-3 -acetamide

29. l-[(4-cmoro-2-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2- methyl-a-oxo- 1 H-Indole-3 -acetamide

30. l-[(4-chloro-2-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

31. l-[(4-clUoro-2-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a- oxo- 1 H-Indole-3 -acetamide

32. l-[(3-cmorophenyl)memyl]-5-memoxy-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

33. l-[(2-cmorophenyl)methyl]-5-methoxy-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

34. l-[(2-chloro-4-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2- methyl-a-oxo- 1 H-Indole-3-acetamide

35. l-[(2-chloro-4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

36. l-[(2-cWoro-4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a- oxo- 1 H-Indole-3-acetamide

37. l-[(2,4-difluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3-acetamide

38. l-[(2,4-difluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-lH- Indole-3 -acetamide

39. l-[(2,4-dicWorophenyl)memyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3-acetamide

40. l-[(2,4-dicWorophenyl)memyl]-5-fluoro-N-(2-memoxy-4-pyridinyl)-2-methyl- - oxo- 1 H-Indole-3-acetamide

41. l-[(2,4-dichlorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-lH- Indole-3 -acetamide

42. l-[(2,4-dicWorophenyl)memyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3 -acetamide

43. 5-methoxy-N-(2-methoxy-4-pyridinyl)-2-raethyl-a-oxo- 1 -(phenylmethyl)- 1 H- Indole-3-acetamide

44. N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-l-(phenylmethyl)-lH-Indole-3- acetamide

45. N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo- 1 -(phenylmethyl)- 1 H-Indole-3- acetamide

46. 5-chloro- 1 -[(4-chIorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2-methyl-a-oxo- 1 H- Indole-3 -acetamide

47. 5-chloro- 1 -[(4-chlorophenyl)methyl]-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3- acetamide

48. l-[(4-cUorophenyl)memyl]-N-(2-cUoro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3-acetamide

49. l-[(4-clUorophenyl)memyl]-5-hydroxy-2-niethyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

50. l-[(4-cUorophenyl)memyl]-5-emoxy-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

51.

1 -[(4-chlorophenyl)methyl]-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3-acetamide

52. l-[(4-chlorophenyl)memyl]-5-methyl-2-(l-raethylemyl)-a-oxo-N-4-pyridinyl-lH- Indole-3-acetamide

1 -[(4-chlorophenyl)methyl]-2,5-dimethyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3 -

53.

acetamide

54. l-[(2,4-dicMorophenyl)memyl]-5-methoxy-2-memyl-a-oxo-N-4-pyridinyl-lH- Indole-3-acetamide

55. 1 -[(4-chlorophenyl)methyl]-5-methoxy-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3 - acetamide

59. The pharmaceutical compostion of claim 58, further comprising a pharmaceutically acceptable carrier, vehicle or diluent.

60. A pharmaceutical composition comprising a FAAH inhibitor selected from Table A in claim 47, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents for use in the treatment of prevention of neuronal injury or neurodegeneration in a patient in need thereof.

61. The pharmaceutical compostion of claim 60, further comprising a pharmaceutically acceptable carrier, vehicle or diluent.

62. The use of a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

63. The use of a FAAH inhibitor selected from the list below, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

l-[(4-cUorophenyl)methyl]-N-(3-fluoro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo-

1.

1 H-Indole-3-acetamide

2. 1 -[(2,4-difluorophenyl)methyl]-N-(2-methoxy-4-pyridmyl)-2,5-dimethyl-a-oxo- 1 H- Indole-3-acetamide

3. N-(2-chloro-4-pyridinyl)-5-methoxy-l-[(4-methoxyphenyl)methyl]-2-methyl-a-oxo- 1 H-Indole-3-acetamide

4. N-(2-chloro-4-pyridinyl)-l-[(4-fluorophenyl)methyl]-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3-acetamide

5. N-(2-chloro-4-pyridinyl)-l-[(2,4-dichlorophenyl)methyl]-5-methoxy-2-methyl-a- oxo- 1 H-Indole-3-acetamide

6. 5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-l-[[4- (trifluoromethyl)phenyl]methyl] - 1 H-Indole-3 -acetamide

7. 5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -[[4- (trifluoromethoxy)phenyl]methyl]-lH-Indole-3-acetamide

8. l-[(6-clUoro-3-pyridinyl)memyl]-5-methoxy-N-(2-memoxy-4-pyridinyl)-2-methyl- a-oxo-1 H-Indole-3-acetamide

9. 5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl- 1 -[(4-methylphenyl)methyl] -a- oxo- 1 H-Indole-3 -acetamide

10. 5-methoxy-l-[(4-methoxyphenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3 -acetamide

5-fluoro-l-[(4-fluorophenyl)memyl]-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo-

11.

1 H-Indole-3-acetamide

5-cUoro-l-[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-

12.

1 H-Indole-3-acetamide

13. 5-cWoro-l-[(4-clUorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

14. l-[(4-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyI)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

1 -[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-

15.

3-acetamide

16. l-[(4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3 -acetamide

17. l-[(4-chlorophenyl)methyl]-5-methoxy-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

18. l-[(4-chlorophenyl)methyl]-N-(2-fluoro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3-acetamide

19. l-[(4-cUorophenyl)methyl]-N-(2-ethoxy-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3-acetamide

20. l-[(4-chlorophenyl)methyl]-5-fluoro-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

21. 1 -[(4-cWorophenyl)raethyl]-N-(2-chloro-4-pyridinyl)-5-fluoro-2-methyl-a-oxo- 1 H- Indole-3-acetamide

22. 1 -[(4-chlorophenyl)methyl]-5-fluoro-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3 - acetamide

23. l-[(4-cWorophenyl)memyl]-5-emoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

24. l-[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-ethoxy-2-methyl-a-oxo-lH- Indole-3 -acetamide

25. l-[(4-chlorophenyl)memyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-lH-Indole- 3-acetamide

26. l-[(4-chlorophenyl)methyI]-N-(2-chloro-4-pyridinyl)-2-methyl-a-oxo-lH-Indole-3- acetamide

27. l-[(4-chlorophenyl)memyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3-acetamide

28. l-[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3 -acetamide

29. l-[(4-cWoro-2-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2- methyl-a-oxo- 1 H-Indole-3 -acetamide

30. l-[(4-chloro-2-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

31. l-[(4-chloro-2-fluorophenyl)methyl]-N-(2-methoxy-4-pyridmyl)-2,5-dimethyl-a- oxo- 1 H-Indole-3 -acetamide

32. l-[(3-cUorophenyl)methyl]-5-methoxy-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

33. l-[(2-chlorophenyl)methyl]-5-methoxy-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

34. l-[(2-clUoro-4-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2- methyl-a-oxo- 1 H-Indole-3 -acetamide

35. l-[(2-chloro-4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

36. l-[(2-chloro-4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a- oxo- 1 H-Indole-3 -acetamide

37. l-[(2,4-difluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3 -acetamide

38. 1 -[(2,4-difluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H- Indole-3 -acetamide

39. l-[(2,4-dicldorophenyl)methyl]-5-memoxy-N-(2-methoxy-4-pyridinyI)-2-methyl-a- oxo- 1 H-Indole-3 -acetamide

40. l-[(2,4-dichlorophenyl)memyl]-5-fluoro-N-(2-memoxy-4-pyridmyl)-2-methyl-a- oxo- 1 H-Indole-3 -acetamide

41. 1 -[(2,4-dichlorophenyl)memyl]-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H- Indole-3-acetamide

42. 1 -[(2_s4-dicUorophenyl)methyl]-N-(2-memoxy-4-pyridinyl)-2,5-dimethyl-a-oxo- 1 H- Indole-3-acetamide

43. 5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -(phenylmethyl)- 1 H- Indole-3-acetamide

44. N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -(phenylmethyl)- 1 H-Indole-3- acetamide

45. N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-l-(phenylmethyl)-lH-Indole-3- acetamide

46. 5-chloro- 1 -[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2-methyl-a-oxo- 1 H- Indole-3 -acetamide

47. 5-cMoro-l-[(4-cUorophenyl)memyl]-2-memyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

48. l-[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

49. l-[(4-chlorophenyl)memyl]-5-hydroxy-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

50. l-[(4-chlorophenyl)methyl]-5-ethoxy-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

51.

l-[(4-chlorophenyl)methyl]-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3-acetamide

52. 1 -[(4-chlorophenyl)methyl] -5-methyl-2-( 1 -methylethyl)-a-oxo-N-4-pyridinyl- 1 H- Indole-3-acetamide

l-[(4-chlorophenyl)methyl]-2,5-dm emyl-a-oxo-N-4-pyrid-nyl-lH-Indole-3-

53.

acetamide

54. 1 -[(2,4-dichlorophenyl)methyl] -5-methoxy-2-methyl-a-oxo-N-4-pyridinyl- 1 H- Indole-3 -acetamide

55. l-[(4-chIorophenyl)methyl]-5-methoxy-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

64. The use of a FAAH inhibitor selected from Table A in claim 47, or a

pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

65. A FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

66. A FAAH inhibitor selected from the list below, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

18. l-[(4-cUorophenyl)methyl]-N-(2-fluoro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3-acetamide

19. l-[(4-cUorophenyl)methyl]-N-(2-ethoxy-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3-acetamide

20. l-[(4-cUorophenyl)methyl]-5-fluoro-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetaraide

21. l-[(4-cMorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-fluoro-2-methyl-a-oxo-lH- Indole-3 -acetamide

22. 1 -[(4-chlorophenyl)methyl]-5-fluoro-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3- acetamide

23. l-[(4-cUorophenyl)methyl]-5-ethoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

24. 1 -[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-ethoxy-2-methyl-a-oxo- 1 H- Indole-3-acetamide

25. l-[(4-cUorophenyl)melhyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-lH-Indole- 3 -acetamide

26. l-[(4-cUorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2-methyl-a-oxo-lH-Indole-3- acetamide

27. l-[(4-chlorophenyl)methyl]-N-(2-methoxy-4-pyridmyl)-2,5-dimethyl-a-oxo-lH- Indole-3-acetamide

28. l-[(4-cWorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3-acetamide

29. l-[(4-chloro-2-fluorophenyi)methyl]-5-memoxy-N-(2-methoxy-4-pyridinyl)-2- methyl-a-oxo- 1 H-Indole-3-acetamide

30. l-[(4-chloro-2-fluorophenyl)raethyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

31. l-[(4-cUoro-2-fluorophenyl)methyl]-N-(2-methoxy-4-pyridmyl)-2,5-dimethyl-a- oxo- 1 H-Indole-3 -acetamide

32. l-[(3-chlorophenyl)memyl]-5-memoxy-N-(2-memoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

33. l-[(2-cWorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

34. l-[(2-chloro-4-fluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2- methyl-a-oxo- 1 H-Indole-3 -acetamide

35. l-[(2-cmoro-4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 H-Indole-3-acetamide

36. l-[(2-chloro-4-fluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a- oxo- 1 H-Indole-3-acetamide

37. l-[(2,4-difluorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3-acetamide

38. l-[(2,4-difluorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-lH- Indole-3 -acetamide

39. l-[(2,4-dichlorophenyl)methyl]-5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo- 1 H-Indole-3-acetamide

40. l-[(2,4-dicUorophenyl)methyl]-5-fluoro-N-(2-methoxy-4-pyridinyl)-2-methyl-a- oxo-lH-Indole-3-acetamide

41. l-[(2,4-dichlorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo-lH- Indole-3-acetamide

42. l-[(2,4-dichlorophenyl)methyl]-N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo-lH- Indole-3-acetamide

43. 5-methoxy-N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- 1 -(phenylmethyl)- 1 H- Indole-3 -acetamide

44. N-(2-methoxy-4-pyridinyl)-2-methyl-a-oxo- i -(phenylmethyl)- 1 H-Indole-3- acetamide

45. N-(2-methoxy-4-pyridinyl)-2,5-dimethyl-a-oxo- 1 -(phenylmethyl)- 1 H-Indole-3- acetamide

46. 5-chloro- 1 -[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-2-methyl-a-oxo- 1 H- Indole-3 -acetamide

47. 5-chloro- 1 -[(4-chlorophenyl)methyl]-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3 - acetamide

48. l-[(4-chlorophenyl)methyl]-N-(2-chloro-4-pyridinyl)-5-methoxy-2-methyl-a-oxo- 1 H-Indole-3 -acetamide

49. l-[(4-chlorophenyl)methyl]-5-hydroxy-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

50. l-[(4-chlorophenyl)memyl]-5-ethoxy-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3- acetamide

51.

l-[(4-chlorophenyl)methyl]-2-methyl-a-oxo-N-4-pyridinyl-lH-Indole-3-acetamide

52. l-[(4-chlorophenyl)methyl]-5-methyl-2-(l-memylemyl)-a-oxo-N-4-pyridinyl-lH- Indole-3-acetamide

1 -[(4-clUorophenyl)memyl]-2,5-dimethyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3-

53.

acetamide

54. l-[(2,4-dichlorophenyl)methyl]-5-memoxy-2-memyl-a-oxo-N-4-pyridinyl-lH- Indole-3-acetamide

55. 1 -[(4-chlorophenyl)methyl]-5-methoxy-2-methyl-a-oxo-N-4-pyridinyl- 1 H-Indole-3- acetamide

A FAAH inhibitor selected from Table A of claim 47, or a pharmaceutically acceptable salt thereof, for the use in the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.

68. A kit comprising at least two separate unit dosage forms (A) and (B), wherein (A) is a therapeutic agent, a combination of more than one therapeutic agents, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and (B) is a FAAH inhibitor of Formula I, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; wherein the additional therapeutic agent(s) is selected from those provided in claim 52.

69. The method of claim 1, wherein a symptom of neuronal injury or neurodegeneration is treated, wherein the symptom is selected from one or more of sleep disturbances, depression, anxiety, pain, erectile dysfunction, spasticity, bladder dysfunctions, fatigue, acute exacerbations, itching, nausea, vomiting, dizziness, walking difficulties and tremors.

70. The pharmaceutical composition of any one of claims 56 to 61 for treating a symptom of neuronal injury or neurodegeneration, wherein the symptom is selected from one or more of sleep disturbances, depression, anxiety, pain, erectile dysfunction, spasticity, bladder dysfunctions, fatigue, acute exacerbations, itching, nausea, vomiting, dizziness, walking difficulties, and tremors.