GB2458259A - Neuroprotective 3-phenylacrylonitrile (3-PAN) derivatives - Google Patents

Abstract

Use of a compound of the following formula in the treatment or prophylaxis of neurodegeneration: <EMI ID=2.1 HE=29 WI=56 LX=755 LY=857 TI=CF> wherein R1, R2, R3, R4 and R5 are each selected from hydrogen and a substituent; W is selected from hydrogen and saturated C1-6 alkyl; Q is selected from CN and a carbonyl-linked substituent. These compounds are useful as neuroprotectives, for example, in the treatment or prophylaxis of neurodegeneration, a neurodegenerative disease or disorder, etc. In further aspects, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, for example, as neuroprotectives, for example, in the treatment or prophylaxis of neurodegeneration, for example, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), etc.

Description

THERAPEUTIC COMPOUNDS AND THEIR USE

TECHNICAL FIELD

The present invention pertains generally to the field of therapeutic compounds, and more specincally to certain 3-phenyl-acrylonitrile (3-PAN) compounds, as described herein, which, in alia, are useful as neuroprotectives, for example, in the treatment or prophylaxis of neurodegeneration, a neurodegenerative disease or disorder, etc. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, for example, as neuroprotectives, for example, in the treatment or prophylaxis of neurodegeneration, for example, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HO), etc.

BACKGROUND

A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.

This disclosure includes information that may be useful in understanding the present invention, It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly

referenced is prior art.

Parkinson's Disease Parkinson's disease (PD) is a common neurodegenerative disease characterized by disabling motor abnormalities, such as tremor, muscle stiffness, paucity of voluntary movements, and postural instability [Fahn, 2000]. The overall prevalence of PD in Europe and USA is estimated at about 0.3 % of the population, but this figure rises to 1 % of people over 65 years old and is therefore set to become an increasing burden in ageing Western societies [see Fahn, 2000; de Rijk, 1997; LOschmann,1997; Checkoway, 1999].

The primary symptoms of PD are: tremor at rest, usually starting with the hands; increased resistance to voluntary movements (hypokinesia) caused by muscle rigidity and changes to the motor system, leading to stiffness and slowness of movement (bradykinesia) and difficulties in initiating movements (akinesia), stopping movements or changing direction, contributing to the characteristic fast shuffling gait seen in sufferers; a rigid and mask-like face and associated difficulty in forming words and speaking in other than a monotone whisper; the disease is also associated with dementia, depression, urinary tract dysfunction and is also commonly associated with a reduced life expectancy [see Fahn, 2000; Dauer, 2004; Sian, 1999].

The underlying cause of the disease is uncertain but may be the result of some sort of pathological damage, as caused by cerebral ischaemia or viral encephalitis. The disease is only rarely hereditary in nature. The initial damage activates oxidative stress, excitotoxicity and eventual cell apoptosis. Its primary neuropathological effect is the specific loss of the nigrostriatal dopaminergic neurons, whose cell bodies reside in the substantia nigra pars compacta (SNpc) and whose nerve terminals project to the striatum [Dauer, 2004]. The consequent deficit in brain dopamine, which in advanced stages of the disease can reach extreme magnitudes, is responsible for most of the clinical features of PD [Dauer, 2004; Forno, 1996]. The symptoms of the disease only generally become apparent once dopamine levels have fallen by 80 % from their original values [Bernheimer, 1973; Lotharius, 2002]; therefore therapies which can increase these levels, even if only by a small degree, have shown great value in short-term symptomatic relief.

The initial stage of the disease is marked by loss of these dopaminergic neurons; as the disease progresses, more general neurodegeneration is seen and is probably involved in the dementia often associated with the disease. Other neurotransmitters may also play a role in the symptoms seen in PD sufferers, particularly acetylcholine, whose release is normally inhibited by dopamine and which therefore sees elevated levels in PD [Spehlmann, 1976].

Treatment of Parkinson's Disease Treatment and control of the disease generally seeks to compensate for the loss of dopamine from the basal ganglia: this can be achieved by direct dopamine replacement therapies such as L-DOPA. Commonly L-DOPA is given in conjunction with inhibitors of peripheral carboxylases such as carbidopa and benserazide, which permits higher concentrations of L-DOPA to remain intact and enter the brain (Madopar�, Roche) and therefore permits use of a much lower dose of L-DOPA, which diminishes the associated side effects. Alternatively more specific dopamine agonists such as pramipexole (Mirapex�, Boehringer Ingeiheim I Pfizer) and ropinirole (Requip�, GSK) may be used.

Finally drugs can be used which prevent metabolism of dopamine, including COMT inhibitors such as entacapone, which may be given alone (Comtan�, Novartis) or combined with L-DOPA and carbidopa (Stalevo�, Orion I Novartis) or MAO-B inhibitors such as selegiline.

PD is poorly served by all of these therapies, which are only capable of giving short-term relief from the disease symptoms, but cannot slow down disease progression.

Therapy with L-DOPA Thus far, the most potent treatment for PD remains the administration of a metabolic precursor of dopamine (DA), L-DOPA; which, by replenishing the brain with DA, alleviates almost all PD symptoms. Dopamine itself cannot be used as it does not pass through the blood-brain barrier; however L-DOPA is taken up by an active transport mechanism.

Initial responses to L-DOPA are very good, with the majority of patients (>75 %) showing good improvements in rigidity and hypokinesia symptoms and some patients even showing complete recovery. However, chronic administration of L-DOPA often causes side effects which may be as debilitating as PD itself [Fahn, 1989]. These include: motor side effects such as severe involuntary movements (dyskinesia); psychiatric side effects such as confusion, hallucinations and insomnia; rapid variations in clinical state "on-off effect"; nausea, postural hypotension and anorexia. Of equal importance, the efficacy of L-DOPA tends to diminish over time and the duration of action of each dose is increasingly shortened as the number of dopaminergic neurons decrease with disease progression, possibly combined with other effects such as receptor down regulation. This requires ever larger, or more frequent, doses to be given, thus further increasing the likelihood of side effects. Efficacy is frequently lost within a 2 year period and studies on patients receiving L-DOPA over a 5 year period have shown that only 25 % remain with symptoms better than when the treatment started and over 50 % are likely to have ceased therapy due to excessive adverse effects.

There is no supportive evidence that L-DOPA therapy impedes the progressive degeneration of SNpc DA neurons and therefore the disease progresses unchecked and eventually will overcome the effectiveness of the drug. It is even hypothesized that dopamine by itself can contribute to the neurodegenerative processes as seen in PD [Ferger, 1999; Xia, 2001; Hastings, 1996]. Thus, PD patients, a few years after the beginning of symptoms, face a painful dilemma: take no or low doses of L-DOPA to avoid the side effects but be severely parkinsonian, or take high doses of L-DOPA to control PD symptoms and be subjected to severe side effects. Therefore, without undermining the importance of L-DOPA therapy in PD, there is an urgent need to acquire a deeper understanding of the cause of PD, not only to prevent the disease, but also to develop therapeutic strategies aimed at halting its progression in newly diagnosed patients whose minimal disability does not require L-DOPA administration.

Other Therapies for PD To overcome some of the L-DOPA limitations, dopamine agonists were introduced in the treatment of PD [Jenner, 1995; Piccoli, 1995]. Dopamirie agonists act directly at the pre-and post-synaptic dopamine receptors. They have a lower risk for the development of motor complications and provide a greater benefit in symptomatic treatment then monaminoxidase (MAO)-inhibitors. Usually they are well tolerated, but possible side-effects are somnolence, peripheral edema, hallucinations; as well as behavioural changes, including punding and gambling [Goetz, 2005; Pahwa, 2006; Anonym 2002].

Recently ergot-related dopamine agonists, e.g., pergolide, cabergoline, have been associated with cardiac valve fibrosis [Yamamoto, 2006; Zanettini, 2007]. Non-ergot dopamine agonists, e.g. pramipexole and ropinirole, are not associated with these problems, but continued vigilance is required [Yamamoto, 2006; Zanettini, 2007]. The MAO-inhibitor selegiline is usually used in the early stages of the disease and improves motor symptoms as well as daily living scores [Ives, 2004; Palhagen, 2006]. Rasagaline has recently been introduced for the treatment of early and more advanced stages of PD [Parkinson Study Group, 2002; Parkinson Study Group, 2005; Rascol, 2005]. Due to the progressive nature of the disease, drug treatment becomes more complicated and more drugs often have to be added. Follow-up studies indicate that of patients who started on dopamine agonists, half at 3 years and two third at 5 years require L-DOPA supplementation [Rascol, 2005; Holloway, 2004]. After 4 years of treatment quality of life showed no difference between patients who started on L-DOPA, and those who received pramipexole and were later on supplemented with L-DOPA [Holloway, 2004]. Thus, patients with PD who start on MAO-inhibitor or a dopamine agonist will eventually need L-DOPA supplementation.

As the disease progresses, motor complications become inevitable and treatment regimens become more complex. Control of motor function is reduced with fast switches between "on" with dyskinesias, and "off' or frozen [Schapira, 2007]. Dyskinesias can be reduced by amantadine [Metman, 1999; Snow, 2000]. Finally, surgical procedures exist, however patients have to be carefully selected, and these treatments are not feasible for a large population [Schapira, 2007].

Taken together, at present only symptomatic treatment for PD is available, and as discussed, nearly all PD patients will be treated with L-DOPA eventually, thus a neuroprotective therapy aimed at slowing or halting the progression of the disease is urgently needed To this end, and in light of the rarity of available post-mortem PD brain samples, many investigators have focused their research efforts on experimental models of PD such as the one produced by the parkinsonian toxin 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

1 -Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) The MPTP Model of SNpc DA Neuronal Degeneration.

MPTP is a by-product of the chemical synthesis of a meperidine analogue, with potent heroin-like effects. MPTP can induce a parkinsonian syndrome in humans almost indistinguishable from PD [Langston, 1986]. Its recognition as a neurotoxin occurred in early 1982, when several young drug addicts mysteriously developed a syndrome similar to PD after the intravenous use of street preparations of meperidine analogues contaminated with MPTP [Langston, 1983]. Since the discovery that MPTP causes parkinsonism in humans and non-human primates as well as in various other mammalian species, it has been used extensively as a model of PD [Langston, 1986; Heikkila, 1989; Kopin, 1988]. The issue of how close the MPTP model relates to PD has been reviewed in Langston, 1987: in humans and non-human primates, MPTP produces an irreversible and severe parkinsonian syndrome that replicates almost all of the features of PD including tremor, rigidity, slowness of movement, postural instability, and even freezing.

The responses, as well as the complications to traditional anti-parkinsonian therapies, are virtually identical to those seen in PD. However, while it is believed that in PD the neurodegenerative process occurs over several years, MPTP produces a clinical condition consistent with "end stage PD" in a few days [Langston, 1987]. Except for three cases [Langston, 1999], no human pathological material has been available. Thus, the comparison between PD and the MPTP model is largely limited to primates [Forno, 1993].

From neuropathological data, we know that MPTP administration causes damage to the DA pathways identical to that seen in PD [Agid, 1987] with a resemblance that goes beyond the degeneration of SNpc DA neurons. Like PD, MPTP causes greater loss of DA neurons in the SNpc than in the ventral tegmental area [Seniuk, 1990; Muthane, 1994] and greater degeneration of DA nerve terminals in the putamen than in the caudate nucleus [Moratalla, 1992]. Eosinophilic intraneuronal inclusions, called Lewy bodies, so characteristic of PD, have recently been observed in MPTP-induced parkinsonism [Fornai, 2005]; also in MPTP-injected monkeys intraneuronal inclusions reminiscent of Lewy bodies have been described [Forno, 1986]. Only one typical neuropathological feature of PD has been lacking in the MPTP model: according to most published reports pigmented nuclei such as locus coeruleus have been spared, apart from within the SNpc.

Also of note, post-mortem brain samples from PD patients [DiMauro,1993] show a selective defect in complex I, the same mitochondrial electron transport chain complex that is affected by MPTP [Nicklas, 1987; Gluck, 1994]. Abnormalities in parameters of oxidative stress in post-mortem PD brain tissue suggest that this disease is caused by an overproduction of free radicals [Fahn, 1992], the same highly reactive tissue damaging species suspected of being involved in MPTP-induced DA toxicity in vivo [Przedborski, 1992; Schulz, 1995; Hantraye, 1996]. However, despite this impressive resemblance between PD and MPTP model, MPTP has never been recovered from post-mortem brain samples or body fluids of PD patients. Altogether, these findings are consistent with MPTP not causing PD, but providing an excellent experimental model of SNpc DA neurodegeneration.

MPTP Metabolism The metabolism of MPTP is a complex, multistep process [Tipton, 1993]. After its systemic administration, MPTP rapidly crosses the blood-brain barrier and is metabolized to I -methyl-4-phenyl-2,3-dihydropyridin ium (MPD P) by the enzyme monoamine oxidase B (MAO-B) within non-DA cells, and then, probably by spontaneous oxidation, to 1-methyl-4-phenylpyridinium (MPP), the active toxic compound. MPP is then taken up by DA transporters, for which it has high affinity [Mayer, 1986]. Once inside DA neurons, MPP is concentrated by an active process within the mitochondria [Ramsay, 1986].

Alterations in many of these MPTP metabolic steps can modify MPP potency. For instance, blockade of MAO-B by pargyline and deprenyl [Heikkila, 1984] or of DA transporters by mazindol [Javitch, 1985], prevents MPTP-induced DA toxicity. Striatal content of MPP is linearly and positively correlated to the magnitude of DA damage [Giovanni, 1991]. Although all of these aspects are important for the occurrence of MPTP-induced DA toxicity, and thus represent valuable therapeutic targets for PD, none (with the possible exception of the mitochondria translocation) participate in the actual mechanisms by which MPTP kills cells. w,

Mechanism of Action of MPTP Although additional mechanisms cannot be excluded, significant research efforts on MPTP neurotoxic processes have been dedicated to MPP effects on mitochondrial respiration. Once within the mitochondria, MPP impairs mitochondrial respiration by inhibiting complex I of the electron transport chain [Nicklas, 1985; Mizuno, 1987] through its binding at or near the ND-i polypeptide, the same site as the mitochondrial poison rotenone. The inhibition of complex I impedes the flow of electrons along the mitochondrial electron transport chain, leading to a deficit in ATP formation. It appears, however, that complex I activity must be reduced >70% to cause severe ATP depletion [Davey, 1996] and that, in contrast to in vitro MPTP, in vivo MPTP causes only a transient 20% reduction in mouse striatal and midbrain ATP levels [Chan, 1991]. These findings raise the question as to whether MPP-related ATP deficit can be the sole factor underlying MPTP-induced DA neuronal death. Another consequence of complex I inhibition by MPP is an increased production of free radicals, especially of superoxide [Hasegawa, 1990; Rossetti, 1988; Cleeter, 1992]. It may thus be speculated that the initiation of MPP's deleterious cascade of events results from energy failure and oxidative stress, which individually may not be sufficient to kill cells, but in combination may well be. A similar scenario of interplay among mitochondrial dysfunction, energy failure, and oxidative stress has been postulated for PD [Beal, 1995].

The Role of Microglial Activation in Parkinson's Disease The substantia nigra (SN) is relatively rich in microglia compared with other brain regions [Lawson, 1990; Kim, 2000]. In addition, dopaminergic neurons in the SN have a reduced level of intracellular glutathione, making them much more susceptible to a variety of insults, including oxidative stress and activated microglial-mediated injury [Kim, 2000].

The finding of elevated levels of pro-inflammatory cytokines and increased oxidative stress-mediated damage in post-mortem samples of PD suggests that microglia activation might play a significant role in the degenerative process found in PD [Greenamyre, 1999]. Epidemiological studies indicate a correlation between brain injuries in young age and development of PD during later life, implicating that inflammatory processes and microglia activation might play a deleterious role in the development of PD [McGreer, 1988]. Occurrence of antecedent traumatic brain injury seems to increase the risk for developing PD [Factor, 1988] as well as exposure to certain viruses and infectious agents [Casals, 1998], The loss of dopaminergic neurons in PD is associated with an increased glial reaction [McGreer, 1988; Forno, 1992; Banati 1998, Mirza 2000]. The data suggest that activation of microglia may trigger or participate in the neurodegenerative processes in PD. Glial response is more robust in the SNpc than the striatum in PD although the observed damage to the dopaminergic pathway is more severe in the striatum [McGreer, 1988]. This difference might be due to the fact that w dopaminergic neurons present the majority structure in the SNpc, whereas dopaminergic synapses only represent less then 15% of striatal structures [Tennyson, 1974; Pickel 1981]. A dramatic microglial response is found in PD and increased in the areas most affected by dopaminergic cell death [McGreer, 1988].

Other Disorders in which Microcilial Activation has been lmrlicated Alzheimer's Disease Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting 20-million people world-wide [Wancata, 2003]. It is the fourth most common source of death and, due to elongation of life expectancy, it is estimated that the number of affected people doubles every 20 years [von Strauss, 1999; Brookmeyer 1998; Fern, 2005]. AD is characterized by neuronal loss, extracellular deposition of amyloid-f3 (A13) plaques, and the formation of neurofibnillary tangles, leading to cognitive decline dementia [Selkoe, 20011. Probably due to the amyloid deposition, a chronic inflammatory response accompanied by oxidative damage can be observed [Selkoe, 2001]. The initiating step of AD still remains unknown, but it is hypothesized that the production of abnormal A13 is responsible for AD pathogenesis [Selkoe, 2001].

Presently, disease progression cannot be altered by pharmacological treatment [Cummings, 2004] and symptomatic treatment is spare. Of these the use of cholinesterasé inhibitors (ChEI) is questionable and debatable [Kaduszkiewicz, 2005; Pelosi, 2006]. N-methyl-D-aspartate (NMDA) receptor activation is also implicated in the neurodegenerative process and memantine is used as a NMDA-antagonist. This treatment has only shown modest benefit as monotherapy and in combination with ChEls [Shah, 2006].

Neuroinflammation seems to participate in the neurodegenerative process as studies have shown that chronic intake of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk to develop AD [McGeer, 1990; McGeer, 2007]. Due to the progressive nature of AD and the neuronal damage, which can reach immense magnitudes at the time of diagnosis, an improved pharmacological treatment interfering with the neurodegenerative processes is urgently needed.

Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the voluntary motor system, leading to paralysis and eventually death [Rowland, 1995]. The prevalence of ALS is about three to five per 100,000, with an onset generally at the age of forty to fifty. Clinical symptoms manifest as muscle weakness, fasciculations, brisk (or depressed) reflexes, and extensor plantar responses. Furthermore atrophy of the tongue, dysphagia, and dysarthria can be observed in patients with ALS. The disease is of progressive nature leading to the decline of muscular function and thus to paralysis, speech and swallowing disabilities, emotional disturbances and ultimately to death, usually 2-5 years after disease on-set, due to failure of the respiratory system. Loss of the upper motor neurons in the cerebral cortex is the main pathological feature of the disease. Usually degeneration of the corticospinal tract at the level of the spinal cord can be observed. Surviving motor neurons are usually atrophic and many show abnormal accumulation of neurofilament. As of today only few treatments exist to prolong survival in ALS patients to any extent (e.g., mechanical ventilation and riluzole). At present the disease is only partially understood, apoptotic processes with caspase activation, inflammatory processes and microglia activation have been implicated in the disease progression [Almer, 2001; Guegan, 2002; Li, 2000; Alexianu, 2001; Almer, 2002; Drachman, 2002]. There is an urgent need for better neuroprotective treatment to improve quality of life and survival of ALS patients.

Huntington's Disease Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder with a gene defect on chromosome 4, which encodes huntingtin [Anonym, 1993]. The first exon encodes for CAG -the aminoacid glutamine, and in normal patients less then 37 repeats are seen, whereas in Huntington 37-1 20 repeats are present, and the repeat number correlates with severity and age of onset of the disease. The prevelance is usually 4-8 per 100,000 individuals, but can be higher, with 10 per 100,000 in Grampian, Scotland [Harper, 1992; Simpson, 1989]. Symptoms observed in HO include adult-onset personality changes, generalized chorea, and cognitive decline. Eye movement abnormalities (impersistence of gaze and difficulty initiating saccades), dysarthria, dysphagia, pyramidal signs, and ataxia resulting in walking difficulties with imbalance and postural instability are further disease manifestations. A decrease in mitochondrial respiratory chain enzymes II, Ill, IV in caudate nucleus is associated with HO leading to oxidative stress [Cu, 1997; Tabrizi, 1999; Browne, 1997]. The early neuronal injury caused by mutant huntingtin leads to reactive gliosis as evidenced in postmortem brains of HD patients [Myers, 1991; Sapp, 2001]. Treatment options include anticonvulsants to manage muscle spasms in chorea (e.g., valproic acid); antipsychotic agents to improve choreic movements in patients, to help relieve symptoms such as agitation, screaming, combativeness, or violence. Antipsychotics also relieve symptoms such as paranoia, delusions, and hallucinations (e.g., risperidone). Antidepressants are used to help relieve symptoms such as sadness, withdrawal, apathy, sleep problems, and suicidal thoughts (e.g. paroxetine). To interfere with the disturbance in the motor system and restore normal behaviour, dopamine antagonist (e.g., chlorpromazine) and GABA agonists (e.g., baclofen) are used. But all of these treatments are only symptomatic and do not alter -10-disease progression. Even though the cause of the disease is known, it will take a long time until genetic treatment will be available due to difficulties with feasibility of delivery.

Therefore, interference with the neurodegenerative processes would be a big advancement in the therapy of HD.

Multiple Sclerosis Multiple sclerosis (MS) is a common, chronic neurological disease affecting young adults.

The prevalence of the disease lies between 1 in 500 and 1 in 1500. In 1996 MS was classified in clinical subgroups to distinguish different forms of the progressive disorder [Miller, 2007]. The clinical course is variable, but most patients develop locomotor disabilities within 15-30 years after onset. MS is associated with inflammatory, demyelinating and white-matter lesions, and might be important for the disability but also other pathological features might contribute to the pathogenesis in different subtypes [Miller, 2007]. As MS is a complex disease, it still poses a major challenge to understand its pathology and pathogenesis and to create new pharmacological treatments.

Inflammatory changes are prominent in acute MS lesions, resulting in a focus of therapy on on anti-inflammatory strategies for the past three decades [Hemmer, 2007]. Recently immunomodulatory and immunosuppressive agents are increasingly used for the treatment of MS. The range of newly developed treatment options are reviewed by Kleinschnitz, 2007. Furthermore MS presents itself as a heterogeneous disease, thus providing more challenges for providing drug treatment. Pathological data show an involvement of microglia as well as an ongoing neuroinflammatory process as being involved in the pathogenesis of MS, and suggest that microglia precede T-cell infiltration and demyelination [Friese, 2007]. There is a need for effective disease-modifying treatments for progressive forms of MS and interfering with microglia response could well be a reasonable and effective strategy to target MS.

3-PAN Compounds 3-PAN compounds are well known in the literature and their pharmacology has been widely studied. Many of these compounds are inhibitors of tyrosine kinases and are commonly referred to as "tyrphostins" [Gazit, 1989]. Initial studies on these compounds focussed on their use as EGF receptor kinase inhibitors and demonstrated that a number of classes showed good potency, including those shown below (see, e.g., Gazit, 1989; Gazit, 1991). -11 -

R-J" R_A OH R-fIJ' R_JI1' Of these simple derivatives, the most interesting were found to be AG18 and AG126; these derivatives show a substantial poly-pharmacology and have been studied in a number of other diverse systems: including AG18 as a phosphodiesterase inhibitor [Nichols, 2000; Matz, 2003], as a nucleoside transport inhibitor [Huang, 2003] and as a DNA topoisomerase inhibitor [Bendetz-Nezer, 2004]; and AG126 as an acetylcholine antagonist [Kan, 1996] and for prevention of organ dysfunction and circulatory failure in response to LPS-induced cytokine release [Ruetten, 1997].

NC CN NC CN

A018 AG126 O2N''

OH OH

Other derivatives for which substantial poly-pharmacology has been shown include AG490 and AG556 which have been shown to prevent LPS-induced cytokine release [Ruetten, 1997].

AG49j0 AG556yr° However, in spite of the range of activities suggested for these compounds, only passing mention of their potential use in the treatment of neurodegeneration has been made. -12-

AG 126 and AG556 have been shown to prevent LPS / lENa-induced nitric oxide formation [Lockhart, 19981 from microglia. The article mentions the treatment of various neurodegenerative disorders, including the AIDS dementia complex, amyotrophic lateral sclerosis, Down's syndrome, Parkinson's disease and Huntingdon's chorea. However, the article does not present any in vivo data or other evidence whatsoever to support a contention that the compounds are in fact useful in these treatments.

Tyrphostin-A9 and corresponding 3,5-dialkyl derivatives have been mentioned for their ability to promote nerve regeneration [Wang, 2006]. The article mentions treatment of Parkinson's disease and other diseases in which neurodegeneration is seen. Again, the article does not present any in vivo data or other evidence whatsoever to support a contention that the compounds are in fact useful in these treatments. t-buI

I Tyrphostin A9

HO

t-butyl The inventors have identified a class of 3-PAN compounds which are useful for the treatment of neurodegeneration. The inventors have also provided in vivo evidence that these compounds prevent loss of dopamine producing neurons. These compounds represent a highly promising therapy for the treatment of Parkinson's disease and, by their inhibition of the deleterious functions of microglia, other neurodegenerative disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph showing MPTP-induced decrease in striatal dopamine levels (ng/mg wet tissue weight), in the presence or absence of certain 3-PAN compounds. The graph shows that striatal dopamine levels fall from 23.20 in the control group to 7.37 in the untreated group which only received MPTP. The graph also shows that the 3-PAN compounds AG126 (dosage 10 mg I kg, i.p), ABD5O2 (dosage 10 mg/kg, i.p.), ABD5O5 (dosage 10 mg/kg, i.p.), ABD5O9 (dosage 5 mg/kg, i.p.), ABD5I7 (dosage 5 mg/kg, i.p.), ABD522 (dosage 10 mg/kg, i.p.) and ABD571 (dosage 5 mg/kg, i.p.) attenuate this loss in striatal dopamine giving levels of 10.21, 12.08, 10.37, 9.27, 11.17, 9.66 and 11.60 ng / mg wet tissue respectively.

Figure 2 is a graph showing MPTP-induced decrease in striatal TH-positive fibres (OD) in the presence or absence of certain 3-PAN compounds. The graph shows that the density of TH-positive fibres was decreased to 42% of saline (control) values in MPTP-treated mice receiving control solution. Treatment with ABD5O2, ABD5O5, ABD517 or ABD522 leads to a significantly lower reduction of striatal optical density: in comparison with saline levels the percentage of TH-positive striatal fibres remaining after MPTP treatment was 64%, 60%, 60% and 66% of control levels respectively.

Figure 3 is a graph showing MPTP-induced decrease in the number of SNpc dopaminergic neurons, in the presence or absence of certain 3-PAN compounds. The graph shows that the density of TH-positive fibres was decreased from a control value of 10372 � 692 to a value of 3400 � 103 after MPTP injections. Treatment with ABD5O2 or ABDO5 leads to a significantly lower reduction in the number of SNpc dopaminergic neurons: with final values of 4552 � 104 and 4373 � 122 respectively.

SUMMARY OF THE INVENTION

One aspect of the invention pertains to certain 3-phenyl-acrylonitrile compounds (referred to herein as "3-PAN compounds"), as described herein.

Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a 3-PAN compound, as described herein, and a pharmaceutically acceptable carrier or diluent.

Another aspect of the invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of admixing a 3-PAN compound, as described herein, and a pharmaceutically acceptable carrier or diluent.

Another aspect of the present invention pertains to a method of reducing or preventing the destruction of dopaminergic neurons in a subject, comprising, for example, administering to the subject a therapeutically effective amount of a 3-PAN compound, as described herein, preferably in the form of a pharmaceutical composition.

Another aspect of the present invention pertains to a method of reducing or preventing deleterious effects of microglia activation in a subject, comprising, for example, administering to the subject a therapeutically effective amount of a 3-PAN compound, as described herein, preferably in the form of a pharmaceutical composition.

Another aspect of the present invention pertains to a method of neuroprotection of a subject, comprising administering to a subject in need of treatment a therapeutically-effective amount of a 3-PAN compound, as described herein, preferably in the form of a pharmaceutical composition.

-14 -Another aspect of the present invention pertains to a 3-PAN compound, as described herein, for use as a neuroprotective.

Another aspect of the present invention pertains to use of a 3-PAN compound, as described herein, in the manufacture of neuroprotective medicament.

Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of a 3-PAN compound, as described herein, preferably in the form of a pharmaceutical composition.

Another aspect of the present invention pertains to a 3-PAN compound, as described herein, for use in a method of treatment, for example, of the human or animal body by therapy.

Another aspect of the present invention pertains to use of a 3-PAN compound, as described herein, in the manufacture of a medicament for use in treatment.

In one embodiment, the treatment is treatment or prophylaxis of neurodegeneration.

In one embodiment, the treatment is treatment or prophylaxis of a neurodegenerative disease or disorder.

In one embodiment, the treatment is treatment or prophylaxis of a disease or disorder in which dopaminergic neurons are destroyed.

In one embodiment, the treatment is treatment or prophylaxis of a disease or disorder involving deleterious activation of microglia.

In one embodiment, the treatment is treatment or prophylaxis of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS), or Huntington's disease (HO).

Another aspect of the present invention pertains to a kit comprising (a) a 3-PAN compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound. -15-

Another aspect of the present invention pertains to a 3-PAN compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

Another aspect of the present invention pertains to a 3-PAN compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.

Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.

As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

ComDounds One aspect of the present invention relates to certain 3-phenyl-acrylonitrile compounds (for convenience, collectively referred to herein as "3-PAN compounds").

1J-CH=CH-CN 3-Phenyl-acrylonitrile In one embodiment, the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof: R2 R1 wherein: -Q is independently: -CN, -C(=O)R°, -C(O)R°"; -C(=O)NH2-C(=O)NHR°, -C(=O)NR"1R°, -C(=O)OH, or -C(=O)OR°; -16-wherein: RN is independently saturated aliphatic C1aIkyl; each -R° is independently RQA, RQB, or each -L°-is independently saturated aliphatic C1.3alkylene; RA is independently saturated aliphatic C1alkyl, and is optionally substituted; each -R°6 is independently C610carboaryl or C5.10heteroaryl, and is optionally -R°" is independently non-aromatic C47heterocyclic, and is optionally substituted; and wherein: -w is independently -H or saturated aliphatic C13alkyl; each of -R2, -R3, -R4 is independently -H or -Rfl; each of -R1 and -R5 is independently -H or -R2; each -R1 is independently: RtM, -F, -Cl, -Br, -I, -CE3, -OCF3, -OH, LlAOH, OLAOH, -OR, L1-OR, _O_LlAOR, -SH, -SR, -CN, -NO2, -NH2, -NHR', -NR2, NRlRlA3, LANH2, -L-NHR1, -L-NR2, LlANR.2R3, -O-L-NH2, OLlANHRlAl, -O-L-NR'2, -O-L-NRR3, -OC(=O)R", -C(=O)OH, -C(=O)OR"1, -C(=O)NH2, -C(=O)NHR', -C(=O)NR12, C(=O)NRlRlA3, -NHC(=O)R, -NRC(=O)R, -NHC(=O)OR, -NR'(=O)OR", -OC(=O)NH2, -OC(=O)NHR, -OC(=O)NR2, OC(=O)NRRlA3, -NHC(=O)NH2, NHC(=O)NHRlAl, -NHC(=O)NR2, -NHC(=O)NRR3, -NR (=O)NH2, -NR1(=O)NHR, -NR'' (=O)NR'2, NR(=O)NRRlA3, -NHS(=O)2R, NRlMS(=O)2Rt, -S(=O)2NH2, -S(=O)2NHR, -S(=O)2NR'2, -S(=O)2NR'R'3, -S(=O)R, -S(=O)2R', -OS(=O)2R, or -17-wherein: each -L-is independently saturated aliphatic C1.5alkylene; in each group -NR2R''3, R1A2 and R'3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; each -R' is independently: _RlB, _R1B2, _R1B3, _R1B4, -R5, _R1B7, -R8, LlBR4, _L1B_RIB5, _L_RlB6, _L_RlB7, or _L_RlB8; each -R' is independently saturated aliphatic C1alkyl; each RlB2 is independently aliphatic C2.6alkenyl; each -R163 is independently aliphatic C2.6alkynyl; each RlB4 is independently saturated CcycloalkyI; each -R5 is independently C36cycloalkenyl; each -R6 is independently non-aromatic Cheterocyclyl; each RtB7 is independently C610carboaryl; each RlB8 is independently C510heteroaryl; each -L-is independently saturated aliphatic C1alkylene; wherein: each -R184, RlB5, RlB6, RlBl, and RlB8 is optionally substituted, for example, with one or more substituents Rld1 and/or one or more substituents Rlc2, each -R, RlB2, R1B3 and LlB is optionally substituted, for example, with one wherein: each Rld1 is independently saturated aliphatic C1alkyl, phenyl, or benzyl; each Rlc2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -Lw-OH, -O-L'-OH, -OR101, LbDORlDl, _O_LbDORlDl, -SH, -SR', -CN, -NO2, -NH2, -NHR101, -NR'2, _NRlD2R3, -L10-NH2, -L10-NHR, -L10-NR'012, -L10-NR'02R103, -C(=O)OH, -C(=O)OR'", -C(=O)NH2, -C(=O)NHR101, -C(=O)NR1012, or -C(=O)NR'°2R103; wherein: each is independently saturated aliphatic C1alkyl, phenyl, or benzyl; each LlD is independently saturated aliphatic C15alkylene; and in each group.NRw2Ra, R2 and RiD3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N orO; each -R2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L-OH, -O-L-OH, -OR, -L-OR', -O-L-OR1, -SH, -SR, -CN, -NO2, -NH2, -NHR', -NR12, -NRR3, -L-NH2, -L-NHR', -L-NR12, -L-NR2R3, -O-L-NH2, -O-L-NHR, -O-L-NR12, -O-L-NRR3, -OC(=O)R1, -C(=O)OH, -C(=O)OR1, -C(=O)R, -C(=O)NH2, -C(=O)NHR1, -C(=O)NR12, -C(=O)NR2R3, -NHC(=O)R1, -NR(=O)R', -NHC(=O)OR1, -NR(=O)OR1, -OC(=O)NH2, -OC(=O)NHR1, -OC(=O)NR12, -OC(=O)NRR3, -NHC(=O)NH2, -NHC(=O)NHR1, -NHC(=O)NR12, -NHC(=O)NRR3, -NR'(=O)NH2, -NR'(=O)NHR1, -NR1(=O)NR'2, -NR1(=O)NR2R3, -NHS(=O)2R1, -NR'1S(=O)2R1, -S(=O)2NH2, -S(=O)2NHR', -S(=O)2NR12, -S(=O)2NRR, -S(=O)R', -S(=O)2R1, -OS(=O)2R1, or wherein: each -L-is independently saturated aliphatic C15alkylene; in each group -NRR3, R and R3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; each -R1 is independently: -R2, _R2B2, _R2B3, _R2B4, R285 -R266, -R287, _R2BB, _L2B_R2B4, _L2B_R285, _L28_R2B6, _L28_R2B7, or _L2B_R2B8; each R2Bl is independently saturated aliphatic C1alkyl; each -R282 is independently aliphatic C2aIkenyl; each R2B3 is independently aliphatic C2alkynyl; each R2B4 is independently saturated C3.6cycloalkyl; each -R285 is independently C3cycloalkenyl; each R2B6 is independently non-aromatic C3heterocyclyl; each R2B7 is independently C610carboaryl; each -R298 is independently C510heteroaryl; each L2B. is independently saturated aliphatic C1.3alkylene; wherein: each R2B4, R2Bs, R2B6, ..R2B7 and R2B8 is optionally substituted, for example, with one or more substituents R2c1 and/or one or more substituents R2c2, each R2Bi, R2B2 R2B3, and L2B is optionally substituted, for example, with one wherein: each -R2 is independently saturated aliphatic C14alkyl, phenyl, or benzyl; each R2c2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L20-OH, OL2D.OH, OR2w, -L20-0R201, OL2DOR2DI, -SH, -SR21', -ON, -NO2, -NH2, -NHR201, -NR22, _NR2D2R203, -L20-NH2, _L2DN HR2°, L2DNR22, _L2D_NR2D2R203, -C(=O)OH, C(=O)OR2t, -C(=O)NH2, C(=O)NHR2Dt, 0(0)NR2D12 or wherein: each -R21 is independently saturated aliphatic C1alkyl, phenyl, or benzyl; each L2D is independently saturated aliphatic C1alkylene; and in each group -NR202R203, R202 and R2D3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly I ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; with the proviso that if: -Q is -CN; -R1 is -H; -R5 is -H; -R2 is -H and -R4 is -OH, or -R2 is -OH and -R4 is -H; then: -R3 is not -NO2; and -20 -with the proviso that if: -Q is -CN; -R1 is -H; -R5 is -H; -R3 is -OH; then: -R2 and -R4 are not both a group selected from: -H, -R'1, -OF3, -L-OH, -L-OR, LANH2, -L-NHR', LlANRl2, and -L-NR2R'3.

The Double Bond The double bond shown in the following formula with an asterisk (*) may independently be in the E-or Z-orientation. R2 R1

For example, the -CN group (on the right) and the phenyl group (on the left) may be "cis" to one another, as in the following formula:

N

For example, the -ON group (on the right) and the phenyl group (on the left) may be "trans" to one another, as in the following formula: R RW C=N Unless otherwise specified, those chemical structures shown here which are silent with respect to the orientation of the double bond are intended to encompass both orientations.

The GrouD -Q In one embodiment, -Q is independently: -ON, -C(=O)R°, -C(=O)R, -C(=O)NH2,-C(=O)NHR°, C(=O)NRNRQ, -C(=O)OH, or -C(=O)OR°.

-21 -In one embodiment, -Q is independently -ON.

In one embodiment, -Q is independently -C(=O)R° or C(=O)RoN.

In one embodiment, -Q is independently -C(=O)R°.

In one embodiment, -Q is independently -C(=O)R°'.

In one embodiment, -Q is independently -C(=O)NH2, -C(=O)NHR°, or C(O)NRNRo.

In one embodiment, -Q is independently -C(=O)NHR° or..C(0)NRNRO.

In one embodiment, -Q is independently -C(=O)NHR.

In one embodiment, -Q is independently -C(=O)OH or -C(=O)OR°.

In one embodiment, -Q is independently -C(=O)OR°.

In one embodiment, RN, if present, is independently -Me.

The Group -R° In one embodiment, each -R°, if present, is independently RQA, or In one embodiment, each -R°, if present, is independently RQA.

In one embodiment, each -R°, if present, is independently RQB.

In one embodiment, each -R°, if present, is independently LQRQB.

The Group -L° In one embodiment, each -L°-, if present, is independently saturated aliphatic C1.3alkylene.

In one embodiment, each -La-, if present, is independently -CH2-or -CH2CH2-.

The Group RoA In one embodiment, each RQA, if present, is independently saturated aliphatic C1.6alkyl, In one embodiment, each RoA, if present, is independently saturated aliphatic C1aIkyl, In one embodiment, optional substituents on each RoA, if present, are selected from: Rx4, -F, -CI, -Br, -I, -OH, ORx4, -NH2, NHRx4, NRx42, and OC(O)Rx4; wherein each Rx4 is independently saturated aliphatic C1..4alkyl.

-22 -In one embodiment, optional substituents on each -R°, if present, are selected from: -NH2, NHRx4, and NRx42.

In one embodiment, each RQA, if present, is independently saturated aliphatic C1.6aIkyI.

In one embodiment, each if present, is independently saturated aliphatic C1alkyI.

In one embodiment, each RoA, if present, is -Me, -Et, -nPr, or -iPr.

The Grour -R°8 In one embodiment, each RQB, if present, is independently C610carboaryl or C510heteroaryl, and is optionally substituted.

In one embodiment, each -R, if present, is independently C610carboaryl, and is In one embodiment, each RQB, if present, is independently phenyl or naphthyl, and is In one embodiment, each if present, is independently phenyl, and is optionally In one embodiment, each -R°8, if present, is independently C510heteroaryl, and is In one embodiment, each RQB, if present, is independently C6heteroaryI, and is In one embodiment, each if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.

In one embodiment, each -R°6, if present, is independently C910heteroaryl, and is In one embodiment, each -R°6, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.

-23 -In one embodiment, each RB is independently optionally substituted.

In one embodiment, each RQB is independently unsubstituted.

In one embodiment, optional substituents on each -R, if present, are selected from; -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, L3AOH, OL3AOH, OR3A, -L3'-OR3'1, OL3AOR3, -SH, SR3Al, -CN, -NO2, -NH2, -NHR3, -NR12, NR3R3A3, L3ANH2, -L3'-NHR3M, L3ANR3Al2, ..L&NR3R3A3, OL3ANH2, -O-L3"-NH R3AI, -O-L3'-N R3M2, OL3AN R3R3A3, -C(=O)OH, -C(=O)OR311, C(=O)R3M, -C(=O)NH2, -C(=O)NHR3', -C(=O)NR12, C(=O)NR3R3A3, -NHC(=O)R', NR3(=O)R3M, -NHC(=O)OR3M, -NR1(=O)OR1, -OC(=O)NH2, -OC(=O)NHR3M, -OC(=O)NR3°12, OC(=O)NR3R3A3, -NHC(=O)NH2, -NHC(=O)NHR3, -NHC(=O)NR3'12, -NHC(=O)NR3R'3, -NR3(=O)NH2, NR3Al(=O)NHR3, -NR3(=O)NR3M2, NR3A(=O)NRR3, -NHS(=O)2R3, -NR3S(=O)2R, -S(=O)2NH2, -S(=O)2NHR1, -S(=O)2NR32, -S(=O)2NR3R3, -S(=O)R1, -S(=O)2R', -OS(=O)2R1, and -S(=O)2OR3; wherein: each L3A is independently saturated aliphatic C15alkylene; in each group -NRR3, R3A2 and R3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; each R3Al is independently: -R3, -R382, -R303, _R3B4, _R3B5, -R386, -R387, _R3B8, _L3B_R3B4, _L38_R3B5, -L38-R386, _L38_R3B7, or _L3B_R3BB; -24 -each -R381 is independently saturated aliphatic C1.6alkyl; each R3B2 is independently aliphatic C2alkenyl; each R3B3 is independently aliphatic C2.6alkynyl; each R3B4 is independently saturated C3cycloalkyl; each -R355 is independently C3cycloalkenyl; each R3B6 is independently non-aromatic C3heterocyclyl; each -R387 is independently C610carboaryl; each R3B8 is independently C5.1oheteroaryl; each L3B is independently saturated aliphatic C13alkylene; wherein: each R3B4, R3B5, R3B6, -R387, and R3BB is optionally substituted, for example, with one or more substituents R3cl and/or one or more substituents R3c2, each R3Bl, R3B2, R3B3, and L3B is optionally substituted, for example, with one wherein: each R3dl is independently saturated aliphatic C14alkyl, phenyl, or benzyl; each R3c2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L30-OH, -O-L30-OH, OR3Dt, _L3D_OR3Dl, -SH, -SR3, -CN, -NO2, -NH2, _NHR3D1, -NR32, _NR302R3D3, -L30-N H2, -L30-NHR3, L3DNR32, L3DN R3D2R3D3, -C(=O)OH, -C(=O)0R301, -C(=O)NH2, -C(=O)NHR3, -C(=O)NR32, or C(O)NR3D2R3D3; wherein: each R3Dl is independently saturated aliphatic C1.4alkyl, phenyl, or benzyl; each -L30-is independently saturated aliphatic C15alkylene; and in each group NR3D2R3o3, R3D2 and R303, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N orO.

In one embodiment, optional substituents on each if present, are selected from: -R1, -F, -Cl, -Br, -I, -CF3, -OCF3, -25- -OH, L3AOH, OL3AOH, OR3M, -L3'-OR, OL3AOR3, -SH, SR3Al, -NH2, -NHR1, NR3M2, NR3A2R3A3, 5.L3ANH2, L3ANHRaI, L3ANR3 2. LNR3R3A3, OC(O)R3Al, C(=O)R3AI, -C(=O)NH2, -C(=O)NHR3, -C(=O)N R3M2, C(=O)NR3R3A3, -NHC(=O)R3, NR3(=O)R3Al, -NHC(=O)OR31, NR(=O)ORaA, -OC(=O)NH2, OC(=O)NHR3At, -OC(=O)NR3"2, and OC(=O)NR3A2R33.

In one embodiment, optional substituents on each RQB, if present, are selected from: -F, -Cl, -Br, -I, -CE3, -OCF3, -OH, L3AOH, -O-L-OH, OR3At, L3AOR3, OL3&OR3, -SH, -SR31, -NH2, NHR3M, NR3M2, and NR3R3A3.

In one embodiment, each L3A, if present, is independently -(CH2)3-, wherein n3 is independently 1 to 4.

In one embodiment, each -L-, if present, is independently -CH2-or -CH2CH2-.

In one embodiment, each NRR3A3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C13alkyl, -CF3, and -F.

In one embodiment, each NR3R3A3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C13a1ky1, -CE3, and -F.

In one embodiment, each R3M, if present, is independently: -R381, -R384, _R3B6, _R3B7, _R3B8, _L38_R3B4, _L38_R3B6, _L3B_R387, or _L3B_R388.

-26 -In one embodiment, each R3M, if present, is independently: _R3BI, _R3B7, _R3B8, _L3B_R3B7, or _L3B_R3B8.

In one embodiment, each R3A, if present, is independently: _R3BI, _R3B7, or _L3B_R3B1.

In one embodiment, each R3B&, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.

In one embodiment, each R3B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally In one embodiment, each R3B7, if present, is independently phenyl, and is optionally In one embodiment, each R3B8, if present, is independently C56heteroaryl, and is In one embodiment, each R3B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.

In one embodiment, each -R388, if present, is independently C9.10heteroaryl, and is In one embodiment, each R3B8, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.

In one embodiment, each -L38-, if present, is independently -CH2-or -CH2CH2-.

In one embodiment, each L3B, if present, is independently -CH2-.

In one embodiment, each -R3, if present, is independently saturated aliphatic C1alkyJ.

In one embodiment, each R3c2 is independently: -F, -Cl, -Br, -I, -OH, -27 -_OR3D1, -CN, -NO2, -NH2, -NHR301, -NR3012, or -NR302R303.

In one embodiment, each -R301, if present, is independently saturated aliphatic C1aIkyl.

In one embodiment, each L3D, if present, is independently (CH2)m3, wherein m3 is independently 1 to 4.

In one embodiment, each -L30-, if present, is independently -CH2-or -CH2CH2-.

In one embodiment, each NR3D2R3D3, if present, is independently azetidino, pyrrolidirio, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C13a1ky1, -CF3, and -F.

In one embodiment, each NR3D2R3D3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C13alkyl, -CF3, and -F.

In one embodiment, optional substituents on each -R°8, if present, are selected from: Rx3, -F, -CI, -Br, -I, -OH, ORx3, -NH2, NHRX3, NRx32, and -OC(O)R'3; wherein each Rx3 is independently saturated aliphatic C14alkyl.

The Group RaN In one embodiment, -R°', if present, is independently non-aromatic C4.7heterocyclic, and In one embodiment, RQN, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted, for example, with one or more groups selected from C1.3alkyl, -CF3, and -F.

In one embodiment, -R°", if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C1.3alkyl, -CF3, and -F.

In one embodiment, RQN, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C1.3aIkyl, -CF3, and -F.

The Group-W In one embodiment, -w is independently -H or saturated aliphatic C13alkyI.

In one embodiment, -w is independently -H or -Me.

In one embodiment, -w is independently -H.

The Groups -R' and -R5 In one embodiment, each of -R1 and -R5 is independently -H or -R2.

In one embodiment, each of -R1 and -R5 is independently -H.

The Groups -R2, -R3. -R4 In one embodiment, each of -R2, -R3, -R4 is independently -H or In one embodiment, -R3 is independently -R1.

In one embodiment: -R2 is independently -H or -Rfl; -R3 is independently -R1; and -R4 is independently -H or In one embodiment: -R2 is independently -H; -R3 is independently -Re'; and -R4 is independently -H; or -R2 is independently -R1; -R3 is independently -Rfl; and -R4 is independently -H; or -R2 is independently -H; -R3 is independently -Rfl; and -R4 is independently -Re'.

In one embodiment: -R2 is independently -R1; -R3 is independently -R1; and -R4 is independently -H; or -R2 is independently -H; -R3 is independently -Re'; and -R4 is independently -R1.

In one embodiment: -R2 is independently -R'; -R3 is independently -R1; and -R4 is independently -H.

In one embodiment: -R2 is independently -H; -R3 is independently -R1; and -R4 is independently -R".

WJW1LP6494975 -29 -In one embodiment: -R2 is independently -H; -R3 is independently -R1; and -R4 is independently -H.

The Group -R1 In one embodiment, each -R1, if present, is independently: -F, -CI, -Br, -I, -CF3, -OCF3, -OH, LAOH, OLlAOH, -OR'1, -L-OR1, -O-L-OR, -SH, -SR, -CN, -NO2, -NH2, -NHR, -NR12, -NR1R3, -L'-NH2, LANHRlAl, -L-NR2, -O-L-NH2, OLlANHR, -C(=O)OH, C(=O)ORlAl, -C(=O)R, -C(=O)NH2, -C(=O)NHR, ..C(0)NR1M2, -C(=O)NRR3, -NHC(=O)R', -NRC(=O)R', -NHC(=O)OR'M, -NR1(=O)OR, -OC(=O)NH2, -OC(=O)NHR, -OC(=O)NR'2, -OC(=O)NRR3, -NHC(=O)NH2, -NHC(=O)NHR1'', -NHC(=O)NR11'12, -NHC(=O)NR1R143, -NR(=O)NH2, -NR(=O)NHR, -NR1(=O)NR2, NR(=O)NRRI#\3, -NHS(=O)2R, -NR S(=O)2R1A, -S(=O)2NH2, -S(=O)2NHR, -S(=O)2NR'2, -S(=O)2NR'R"3, -S(=O)R'1, -S(=O)2R, -OS(O)2R, or S(=O)2ORlM; wherein: each is independently saturated aliphatic C15alkylene; in each group -NRR3, R1 and R1A3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N orO; each -R is independently: _R1B1, _R1B2, -R183, _R1B4, -R185, _R1B8, -R187, _R1B8, _L1B_R1B4, _LIB_R185, -L16-R186, _LlB_R1B7, or _LlB_R8; WJW/1P6494975 each -R' is independently saturated aliphatic C1alkyl; each RlB2 is independently aliphatic C2alkenyl; each -R3 is independently aliphatic C2alkynyl; each RB4 is independently saturated C3cycIoalkyI; each -R185 is independently C36cycloalkenyl; each RB6 is independently non-aromatic Cheterocyctyl; each RlB7 is independently C610carboaryl; each RlB8 is independently C5.1oheteroaryl; each -L-is independently saturated aliphatic C13alkylene; wherein: each RlB4, -R5, -R6, ..R1B7 and RlB8 is optionally substituted, for example, with one or more substituents Rlcl and/or one or more substituents Rlc2, each -R181, RlB2, -R3, and LlB is optionally substituted, for example, with one wherein: each R1c is independently saturated aliphatic C1alkyl, phenyl, or benzyl; each Rlc2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, LlDOH, -O-L-OH, -OR, LlDORlol, -O-L'°-0R101, -SH, -SR', -CN, -NO2, -NH2, -NHR, -NR1012, NRD2Rm3, Lm_NH2, -L°-NHR'°1, LbDNRlD2, -L1'-NR2R103, -C(=O)OH, -C(=O)0R101, -C(=O)NH2, -C(=O)NHR, -C(=O)NR1012, or -C(O)NR2R°3; wherein: each Rmi is independently saturated aliphatic C1aIkyl, phenyl, or benzyl; each LlD is independently saturated aliphatic C15alkylene; and in each group NRbo2RlD3, R2 and R3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N orO.

In one embodiment, each -R1, if present, is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -31 - -OH, -L"-OH, -O-L-OH, ORl4M, LlAOR, -O-L1-OR, -SH, -SR', -NH2, -NHR, -NR12, NR2RlA3, -L-NH2, -L-NHR', ..L1A.NR1A12P -L-NRR3, -OC(=O)R', -C(=O)NH2, -C(=O)NHR11, -C(=O)NR2, -C(=O)NRR13, -NHC(=O)R, -NR(=O)R, NHC(=O)ORlAl, NRlM(=O)OR, -OC(=O)NH2, -OC(=O)NHR1, -OC(=O)NR2, or -OC(O)NRR3.

In one embodiment, each -R1, if present, is independently: -F, -Cl, -Br, -I, -CE3, -OCF3, -OH, -L-OH, OLlAOH, -OR, LORlM, -O-L1'-OR"", -SH, -SR'1, -NH2, NHRA, -NR2, or -NR2R1'3.

In one embodiment, each -R1, if present, is independently: -F, -Cl, -Br, -I, -OH, ORlM, -NH2, -NHR, -NR2, or -OC(=O)R".

In one embodiment, each -R"1, if present, is independently -OH, -OR, or -OC(=O)R'.

In one embodiment, each _LA, if present, is independently -(CH2)1-, wherein ni is independently 1 to 4.

In one embodiment, each LlA, if present, is independently -CH2-or -CH2CH2-.

In one embodiment, each NRlP2RA3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C,3alkyl, -CF3, and -F.

-32 -In one embodiment, each NRhI2RA3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C13a1ky1, -CF3, and -F.

In one embodiment, each -R11, if present, is independently: -R181, -R4, _R1B6, -R187, -R188, _L1B_R1B4, _L1B_RIB6, _LlB_R7, or In one embodiment, each -R, if present, is independently: -R1, _R1B7, -R8, _L_RlB7, or -L-R8.

In one embodiment, each -R, if present, is independently: _R1B1, _R1B7, or _Ll B_RlB7.

In one embodiment, each RlB6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.

In one embodiment, each -R6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally In one embodiment, each RlB7, if present, is independently phenyl, and is optionally In one embodiment, each RlB8, if present, is independently CheteroaryI, and is In one embodiment, each -R8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.

In one embodiment, each -R8, if present, is independently C910heteroaryl, and is In one embodiment, each RlBe, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.

In one embodiment, each -L18-, if present, is independently -CH2-or -CH2CH2-.

In one embodiment, each -L-, if present, is independently -CH2-.

In one embodiment, each -R1, if present, is independently saturated aliphatic C1alkyI.

In one embodiment, each -R2 is independently: -F, -Cl, -Br, -I, -OH, -CN, -NO2, -NH2, -NHR'°1, -NR312, or -NR'°2R103.

In one embodiment, each -R", if present, is independently saturated aliphatic C1alkyl.

In one embodiment, each LlD, if present, is independently (CH2)m1, wherein ml is independently 1 to 4.

In one embodiment, each -Lw-, if present, is independently -CH2-or -CH2CH2-.

In one embodiment, each NRm2R3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C13aIkyl, -CF3, and -F.

In one embodiment, each -NR2R103, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C13alkyl, -CE3, and -F.

In one embodiment, each -R1 is independently: RXI, -F, -Cl, -Br, -I, -OH, _ORX1, -NH2, NHRxl, NRxl2, or -OC(=O)R; wherein each -R is independently saturated aliphatic C1alkyI.

In one embodiment, each -R1 is independently -OH, -OR, or -OC(O)R.

In one embodiment, -R3 is independently -OC(=O)R.

In one embodiment, -R4 is independently -OC(=O)R. wJv

-34 -In one embodiment: -R2 is independently ORx or -OC(=O)R; -R3 is independently -OH; and -R4 is independently -H.

In one embodiment: -R2 is independently -OH, -OR, or -R3 is independently OC(=O)Rxl; and -R4 is independently -H.

In one embodiment: -R2 is independently -OH; -R3 is independently OC(=O)RxI; and -R4 is independently -H.

In one embodiment: -R2 is independently OC(=O)Rxl; -R3 is independently -OH, ORxl, or OC(=O)Rxt; and -R4 is independently -H.

In one embodiment: -R2 is independently OC(=O)Rxl; -R3 is independently -OH; and -R4 is independently -H.

In one embodiment: -R2 is independently -OC(O)R; -R3 is independently -OC(O)R; and -R4 is independently -H.

The Group -R2 In one embodiment, each -R1'2, if present, is independently: -R1, -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L-OH, -O-L-OH, -OR', -L-OR1, OLMORl, -SH, SRMl, -CN, -NO2, -35 - -NH2, -NHR1, -NR12, -NRR3, -L-NH2, -L-NHR1, -L-NR12, -L-NRR3, -O-L-NH2, -O-L-NHR1, -O-L-NR12, -O-L-NRR3, -OC(=O)R2'', -C(=O)OH, -C(=O)OR1, -C(=O)NH2, -C(=O)NHR1, -C(=O)NR12, -C(O)NRR3, -NHC(=O)R', -NR1(=O)R1, -NHC(=O)0R2'1, -NR1(=O)OR1, -OC(=O)NH2, -OC(=O)NHR2M, -OC(=O)NR2''12, -OC(=O)NRR3, -NHC(=O)NH2, -NHC(=O)NHR1, -NHC(=O)NR22, -NHC(=O)NRR3, -NR'1(=O)NH2, -NR1(=O)NHR', -NR1 (=O)NR12, -NR1(=O)NRR3, -NHS(=O)2R', -NR1 S(=O)2R1, -S(=O)2NH2, -S(=O)2NHR1, -S(=O)2NR12, -S(=O)2NR2RM3, -S(=O)R1, -S(=O)2R1, OS(=O)2RMl, or -S(O)2OR1; wherein: each -L-is independently saturated aliphatic C15alkylene; in each group -NR2R3, R and R3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N orO; each -R1 is independently: -R2, _R2B2, _R2B3, _R2B4, _R2B5, -R286, _R2B7, -R268, _L2B_R2B4, _L2B_R2B5, -L28-R286, _L2B_R2B7, or each -R281 is independently saturated aliphatic C1alkyl; each RzB2 is independently aliphatic C2.alkenyl; each R2B3 is independently aliphatic C24alkynyl; each R2B4 is independently saturated C3cycloalkyl; each R2B5 is independently C3cycloalkenyl; each -R286 is independently non-aromatic Cheterocyclyl; each R2B7 is independently C610carboaryl; each R2B8 is independently C10heteroaryl; each L2B is independently saturated aliphatic C1alkylene; wherein: each R2B4, R2Bs, -R286, -R287, and R2B8 is optionally substituted, for example, with one or more substituents R2dl and/or one or more substituents R2c2, each R2Bl, -R282, R2B3, and L2B is optionally substituted, for example, with one -36 -whe rein: each R2c1 is independently saturated aliphatic C,atkyl, phenyl, or benzyl; each.R2c2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L20-OH, OL2D.OH, -OR2, _L2D_OR2Dl, OL21-OR2'', -SH, -SR201, -CN, -NO2, -NH2, -NHR201, -NR22, NR2D2R2D3, L2DNH2, -L20-NHR2, -L2'NR2 2 L2DNR2D2R2D3, -C(=O)OH, -C(=O)0R201, -C(=O)NH2, -C(=O)NHR2, -C(=O)NR2012, or -C(=O)NR202R203; wherein: each -R201 is independently saturated aliphatic C1alkyl, phenyl, or benzyl; each L2D is independently saturated aliphatic C15alkylene; and in each group NR2D2R2D3, R2D2 and R203, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N orO.

In one embodiment, each -R2, if present, is independently: -R', -F, -Cl, -Br, -I, -CE3, -OCF3, -OH, -La-OH, -O-L-OH, -OR1, -L-OR1, -O-L-OR', -SH, -SR1, -NH2, -NHR1, -NR12, -NRR3, -L-NH2, -L-NHR1, -L-NR'2, -L-NRR, -OC(=O)R1, -C(=O)R1, -C(=O)NH2, -C(=O)NHR1, -C(=O)NR'2, -C(=O)NRR3, -NHC(=O)R', NRMl(=O)Rl, -NHC(=O)ORM1, -NR1(=O)OR', -OC(=Q)NH2, -OC(=O)NHR1, -OC(=O)NR12, or -OC(=O)NR2R3.

In one embodiment, each -R2, if present, is independently: -37 - -F, -CI, -Br, -I, -CE3, -OCF3, -OH, L2AOH, -O-L-OH, -OR1, -L-OR2, OL&OR1, -SH, -SR1, -NH2, -NHR', -NR12, or NR2R2A3.

In one embodiment, each -L-, if present, is independently -(CH2)2-, wherein n2 is independently 1 to 4.

In one embodiment, each -L2'-, if present, is independently -CH2-or -CH2CH2-.

In one embodiment, each -NR2R3, if present, is independently azetidino, pyrrolidino, imidazolidirio, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from C13alkyl, -CE3, and -F.

In one embodiment, each -NR2R3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C13a1ky1, -CF3, and -F.

In one embodiment, each -R1, if present, is independently: _R2Bt, _R2B4, -R286, _R2B7, _R2B8, _L2B_R2B4, _L2B_R2B6, -L28-R287, or _L28_R2B8.

In one embodiment, each -R1, if present, is independently: -R2, _R2B?, _R2B8, or _L23_R2B8.

In one embodiment, each -R1, if present, is independently: _R2B, _R2B7, or _L2B_R2B7.

In one embodiment, each R2B6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.

In one embodiment, each R2B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally -38 -In one embodiment, each -R287, if present, is independently phenyl, and is optionally In one embodiment, each R2Ba, if present, is independently C6heteroaryI, and is In one embodiment, each -R288, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.

In one embodiment, each -R288, if present, is independently C910heteroaryl, and is In one embodiment, each -R288, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyt, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.

In one embodiment, each -L28-, if present, is independently -CH2-or -CH2CH2-.

In one embodiment, each -L28-, if present, is independently -CH2-.

In one embodiment, each -R2, if present, is independently saturated aliphatic C1.4aIkyI.

In one embodiment, each R2c2 is independently: -F, -Cl, -Br, -I, -OH, -OR201, -CN, -NO2, -NH2, -NHR201, -NR22, or -NR202R203.

In one embodiment, each -R21', if present, is independently saturated aliphatic C1.4aIkyI.

In one embodiment, each L2D, if present, is independently (CH2)m2, wherein m2 is independently 1 to 4.

In one embodiment, each -L20-, if present, is independently -CH2-or -CH2CH2-.

In one embodiment, each -NR202R203, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and -39 -is optionally substituted, for example, with one or more groups selected from C13a1ky1, -CE3, and -F.

In one embodiment, each NR2D2R2D3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted, for example, with one or more groups selected from C13a1ky1, -CE3, and -F.

In one embodiment, each -R"2 is independently: -R, -F, -Cl, -Br, -I, -OH, -OR, -NH2, NHRx2, -NR2, or -OC(=O)R; wherein each -R' is independently saturated aliphatic C1alkyl.

Molecular Weight In one embodiment, the 3-PAN compound has a molecular weight of from 154 to 1200.

In one embodiment, the bottom of range is 160, 175, 200, 225, 250, 275, 300, or 350.

In one embodiment, the top of range is 1100, 1000, 900, 800, 700, or 600.

In one embodiment, the range is from 160 to 600.

Combinations Each and every compatible combination of the embodiments described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited.

Examples of Specific Embodiments In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof: Synth. Code No Structure Reg. No.

NC CN

1 ABD5O2 CAS 27508-35-6 NO2

NC CN

CAS

2 AB0503 HO 15728-34-4 o,,. Et

-40 -Synth. Code No Structure Reg. No.

NC CN

ii7 CAS 3 ABD5O4 Me...

17229-41-3 0.. Et

NC CN

4 ABD5O5 118409-57-7

CAS

HO

OH

NC CN

CAS

17229-42-4 AB0506 EtLf) 0.. Me

NC CN

BRN

6 ABD5O7 F 6801971

F

NC CN

7 ABD5O8 CAS 2826-28-0 Me,,-LJ Me

NC CN

8 ABD5O9 6506726

BRN Me

OH

NC CN

9 ABD517 2700-23-4

CAS 02N

-41 -Synth. Code No Structure Reg. No.

NC CN

ABD518 -

F Me

NC CN

11 ABD521 CAS MeA() 2972-80-7 0,. Me

NC CN O(X

BRN

12 ABD522 3369400 OyMe

NC CN

13 ABD533 -

LJ Me

F

NC CN

14 ABD571 CAS 3696-12-6 Me

NC CN

ABD582 -

F Me -42 -

Synth. Code No Structure Reg. No.

NC CN

17 ABD594 Me 133550057 18 ABD595 -In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof: Synth. Code No Structure Reg. No. NCrJL CAS 16 ABD593 HOCX 118409-59-9 23 ABD6O3 FMe - ABD6O9 FMe -In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof: w -43 -Synth. Code No Structure Reg. No. NC1IEt 19 ABD6O2 -Me NCEt CAS 24 ABD6O4 126716-40-3 In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceuticafly acceptable salts, hydrates, and solvates thereof: Synth. Code No Structure Reg. No. 26 ABD61O -Substantially Purified Forms One aspect of the present invention pertains to 3-PAN compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.

In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.

Unless specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially -44 -purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.

In one embodiment, the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.

Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.

In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.

Isomers Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomerjc, tautomeric, conformational, or anomeric forms, including but not limited to, cis-and trans-forms; E-and Z-forms; c-, t-, and r-forms; endo-and exo-forms; R-, S-, and meso-forrns; D-and L-forms; d-and I-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn-and anti-forms; synclinal-and anticlinal-forms; a-and 13-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C17alkyl includes n-propyl -45 -and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

__ \ ,OH -H /CC\ /CC\ keto enol enolate Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including H, 2H (0), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; 0 may be in any isotopic form, including 160 and 180; and the like.

Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. Salts

It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et a!., 1977, Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO-), then a salt may be formed with a suitable cation.

Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na and K, alkaline earth cations such as Ca2 and Mg2, and other cations such as AI3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4) and substituted ammonium ions (e.g., NH3R, NH2R2, NHR3, NR.).

Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, -46 -meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 If the compound is cationic, or has a functional group which may be cationic (e.g., -NH2 may be -NH34), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

Hydrates and Solvates It may be convenient or desirable to prepare, purify, and/or handle a corresponding sot vate of the compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tn-hydrate, etc. Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof.

Chemically Protected Forms It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which -47 -otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).

Unless otherwise specified, a reference to a particular compound also includes chemically protected forms thereof.

A wide variety of such "protecting," blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be deprotected" to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc).

For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-N H-Teoc), as a 2,2,2-trichioroethyloxy amide (-N H-Troc), as an allyloxy amide (-NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O.).

-48 -For example, a carboxylic acid group may be protected as an ester for example, as: an C1.7alkyl ester (e.g., a methyl ester; a t-butyl ester); a C17haloalkyl ester (e.g., a C17trihaloalkyl ester); a triC17alkylsilyl-C17a1ky1 ester; or a C5aryl-C1.7atkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.

For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).

P rod rug s It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.

Unless otherwise specified, a reference to a particular compound also includes prodrugs thereof.

For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(0)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Chemical Synthesis Several methods for the chemical synthesis of 3-PAN compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.

Examples of some suitable methods for the synthesis of 3-PAN compounds are described below.

WJW1LP6494975 -49 -In one approach, the appropriate aryl aldehyde or aryl ketone is reacted with a suitable malononitrile, cyanoacetamide or other cyano group-containing compound, by a Knoevenagel condensation. The reaction is commonly carried out in ethanol, in the presence of a catalytic quantity of a suitable base, such as piperidine as described by Gazit et al, 1989. Examples of such methods are shown in the following scheme.

Scheme 1

NC CN

R1_O) NC..,.CN o NCJt.. _5jJ)LNH R1 o NCJL NC R-(T Ej0Et R' o NCA.. NC OPh R1-yOPh R'

C CN

R1_J'' NC.CN R1__J In another approach, cyanoacetamide is substituted prior to condensation by preparation of a cyanacetate ester followed by nucleophilic attack by a suitable amine. The substituted cyanoacetamide is then condensed with a suitable aryl aldehyde or aryl ketone as described above. An example of such a method is shown in the following scheme.

-50 -Scheme 2 0 EtOH/H2S04 0 NCJt... NC,JL OH OEt

HN 2 R

In another approach, the cyanomethyl ketone starting material may be prepared by a method similar to that described in Gazit et al, 1991. One such example involves reaction of de-protonated tert-butyl cyanoacetate with the required aryl acid chloride, followed by decomposition with trifluoroacetic acid to give the desired starting material. The cyanomethyl ketone may then be condensed with the desired aromatic aldehyde or ketone as described above. An example of such a method is shown in the following scheme.

Scheme 3 R2 � 1. -R2_-'J'' 2TFA R1_f RI_IJ} In another approach, the required aryl aldehyde or aryl ketone may be prepared by nucleophilic substitution of a chioromethyl derivative, using a method similar to that described in Gazit et al, 1993. The aldehyde or ketone may then be condensed with the -51 -required cyano-compound. An example of such a method is shown in the following scheme.

Scheme 4

HS

I ON

NCCN

In another approach, it may be necessary or preferred to first prepare a methoxy derivative and later remove this protecting group. This may be done, for example, by reaction with BBr3. An example of such a method is shown in the following scheme.

Scheme 5 0 0 FtIIe NC,I.. F_J'I BBr3 F'" OMe OH In another approach, it may be necessary or preferred to first prepare the acetate derivative of a hydroxyl derivative, either as a final compound or to permit purification.

The acetate group may be removed at a later stage if required. The acetate may be prepared by reaction of the hydroxyl derivative with acetic arihydride in the presence of pyridine, and may be removed by hydrolysis with NaOH in ethanol/THF. An example of such a method is shown in the following scheme.

WJW/LP6494975 -52 -Scheme 6 HOJII' NCCN HOj1Jh( Ac20 I pyridine ACO,1T' OH NC CN OAc 1MNaOH/EtOH/THF I

HO

Compositions One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising a 3-PAN compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.

Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing a 3-PAN compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. Uses

The compounds described herein are useful, for example, for reducing or preventing the destruction of dopaminergic neurons; for reducing or preventing deleterious effects of microglia activation in a subject; as neuroprotectives; in the treatment or prophylaxis of neurodegeneration, etc. Use in Methods of Preventing Destruction of Dopaminerpic Neurons The 3-PAN compounds described herein are useful in the treatment of diseases and disorders in which dopaminergic neurons are destroyed.

One aspect of the present invention pertains to a method of reducing or preventing the destruction of dopaminergic neurons in a subject, comprising, for example, administering to the subject a therapeutically effective amount of a 3-PAN compound, as described herein, preferably in the form of a pharmaceutical composition.

-53 -Use in Methods of Reducing or Preventing Deleterious Effects of Microglia Activation The 3-PAN compounds described herein are useful in the treatment of diseases and disorders involving deleterious microglia activation.

One aspect of the present invention pertains to a method of reducing or preventing deleterious effects of microglia activation in a subject, comprising, for example, administering to the subject a therapeutically effective amount of a 3-PAN compound, as described herein, preferably in the form of a pharmaceutical composition.

Use as a Neuroprotective Another aspect of the present invention pertains to a method of neuroprotection of a subject, comprising administering to a subject in need of treatment a therapeutically-effective amount of a 3-PAN compound, as described herein, preferably in the form of a pharmaceutical composition.

Another aspect of the present invention pertains to a 3-PAN compound, as described herein, for use as a neuroprotective.

Another aspect of the present invention pertains to use of a 3-PAN compound, as described herein, in the manufacture of neuroprotective medicament.

Use in Methods of TheraDy Another aspect of the present invention pertains to a 3-PAN compound, as described herein, for use in a method of treatment, for example, of the human or animal body by therapy.

Use in the Manufacture of Medicaments Another aspect of the present invention pertains to use of a 3-PAN compound, as described herein, in the manufacture of a medicament for use in treatment.

In one embodiment, the medicament comprises the 3-PAN compound.

Methods of Treatment Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a -54 - 3-PAN compound, as described herein, preferably in the form of a pharmaceutical composition.

Conditions Treated In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment or prophylaxis of neurodegeneration.

In one embodiment, the treatment is treatment or prophylaxis of a neurodegenerative disease or disorder.

In one embodiment, the treatment is treatment or prophylaxis of a disease or disorder in which dopaminergic neurons are destroyed.

In one embodiment, the treatment is treatment or prophylaxis of a disease or disorder involving deleterious activation of microglia.

In one embodiment, the treatment is treatment or prophylaxis of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS), or Huntington's disease (HD).

In one embodiment, the treatment is treatment or prophylaxis of: Alexander's disease; Alper's disease; ataxia telangiectasia; bovine spongiform encephalopathy (BSE); Canavan disease; Cockayne syndrome; corticobasal degeneration; Creutzfeldt-Jakob disease; HJV-associated dementia; Kennedy's disease; Krabbe's disease; Lewy body dementia; multiple system atrophy; narcolepsy; neuroborreliosis; Pelizaeus-Merzbacher disease; Pick's disease; primary lateral sclerosis; -55 -prion diseases; Refsum's disease; Sandhoffs disease; Schilder's disease; subacute combined degeneration of spinal cord secondary to pernicious anaemia; schizophrenia; Spielmeyer-Vogt-Sjogren-Batten disease; spinocerebellar ataxia; spinal muscular atrophy; Steele-Richardson-Olszewski disease; tabes dorsalis.

Treatment The term "treatment," as used herein in the context of treating a disease or disorder, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disease or disorder, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the disease or disorder, amelioration of the disease or disorder, and cure of the disease or disorder. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the disease or disorder, but who are at risk of developing the disease or disorder, is encompassed by the term "treatment." For example, treatment includes the prophylaxis of Parkinson's disease (PD), reducing the incidence of Parkinson's disease (PD), alleviating the symptoms of Parkinson's disease (PD), etc. The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.

Combination Therapies The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.

For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, -56 -including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.

For example, it may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1, 2, 3, 4) agents or therapies that regulates cell growth or survival or differentiation via a different mechanism, thus treating several characteristic features of cancer development.

One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents.

The particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.

The agents (i.e., the compound described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).

The agents (i.e., the compound described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

Other Uses The 3-PAN compounds described herein may also be used as cell culture additives, for example, to reduce or prevent deleterious activation of microglia, to inhibit or prevent the destruction of dopaminergic neurons, etc. The 3-PAN compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.

The 3-PAN compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other neuroprotectives, etc. -57 -Kits One aspect of the invention pertains to a kit comprising (a) a 3-PAN compound as described herein, or a composition comprising a 3-PAN compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.

The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.

Routes of Administration The 3-PAN compound or pharmaceutical composition comprising the 3-PAN compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

The Subject/Patient The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.

In one preferred embodiment, the subject/patient is a human.

-58 -Formulations While it is possible for the 3-PAN compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one 3-PAN compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one 3-PAN compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.

The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical ExciDients, 5th edition, 2005.

The formulations may be prepared by any methods well known in the art of pharmacy.

Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.

The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof. -59-

Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.

The compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.

Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth.

Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier.

Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions -60 - (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners.

Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.

Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-i,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.

Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono-or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend ol branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.

Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid -62 -or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.

Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.

Typically, the concentration of the compound in the liquid is from about 1 ng/ml to about pg/mI, for example from about 10 ng/mI to about 1 pg/mI. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

Dosage It will be appreciated by one of skill in the art that appropriate dosages of the 3-PAN compounds, and compositions comprising the 3-PAN compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular 3-PAN compound, the route of administration, the time of administration, the rate of excretion of the 3-PAN compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the disease or disorder, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of 3-PAN compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.

-63 -Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

In general, a suitable dose of the 3-PAN compound is in the range of about 10 pg to about 250mg (more typically about 100 pg to about 25mg) per kilogram body weight of the subject per day Where the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.

EXAMPLES

The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

Chemical Synthesis Synthesis 1 2-(4-Chloro-3-nitrobenzylidene)rnalononitrile (ABD5O2)

NC CN NO2

Method A: 4-Chloro-3-nitrobenzaldehyde (2 g) was suspended in ethanol (40 mL).

Malononitrile (1.5 mL) and piperidine (12 drops) were added and the mixture refluxed for 4 hours. After cooling, water was added and the precipitate filtered. The precipitate was recrystallised from ether / petrol (product is yellow streak on TLC plate) and the resultant solid purified by column chromatography (ethyl acetate / petrol) to give a yellow solid, recrystallised (ethyl acetate / petrol) to give yellow crystals. 1H NMR (CDCI3): 6 7.76 (1 H, d, J = 7.0 Hz), 7.78 (IH, s), 8.15 (1H, d, J = 7.0 Hz) and 8.30 (1H, s).

-64 -Synthesis 2 2-(3-Ethoxy-4-hydroxybenzylidene)malononitrile (ABD5O3)

NC CN

HO 0.. Et

Using a method analogous to Method A, with 3-ethoxy-4-hydroxybenzaldehyde and malononitrile, the title compound was obtained as pale yellow crystals. 13C NMR (CDCI3): 614.6,65.1,78.0,111.0,113.7,114.5,115.2,124.0,129.0,146.4,152.4 and 159.4. 1H NMR (CDCI3): 6 1.49 (3H, t, J = 7.0 Hz), 4.19 (2H, q, J 7.0 Hz), 6.43 (1H, s), 7.01 (1H, d, J = 8.2 Hz), 7.28 (1H, dd, J = 8.2 Hz), 7.61 (1H, s) and 7.70 (1H, s).

Synthesis 3 2-(3-Ethoxy-4-methoxybenzylidene)malononitrile (AB D504)

NC CN Me-. 0.. Et

Using a method analogous to Method A, with 3-ethoxy-4-methoxybenzaldehyde and malononitrile, the title compound was obtained as a white powder. 13C NMR (CDCI3): 6 14.6, 56.3, 64.7, 78.2,111.2, 111.7, 113.6,114.5, 124.2,128.2, 148.9,155.1 and 159.3.

Synthesis 4 2-(3, 4-Dihydroxybenzylidene)malononitrile (ABD5O5)

NC CN

HO

OH

Using a method analogous to Method A, with 3, 4-dihydroxybenzaldehyde and malononitrile, the title compound was obtained as a yellow powder. 1H NMR (DMSO-d6): 66.94 (1H, s), 7.29 (1H, s), 7.54 (1H, s), 8.19 (1H, s) and 10.23 (2H, br s). 13C NMR (DMSO-d6): 674.5, 114.3, 115.3, 116.0, 116.2, 123.3, 127.0, 146.0, 153.3 and 160.7.

-65 -Synthesis 5 2-(4-Ethoxy-3-methoxybenzylidene)malononjtrile (ABD5O6)

NC CN Ek. 0.. Me

Using a method analogous to Method A, with 4-ethoxy-3-methoxybenzaldehyde and malononitrile, the title compound was obtained as pale yellow needles. 13C NMR (DMSO-d6): 14.5, 56.1, 64.9, 78.0, 111.0, 111.9, 113.7, 114.6, 124.0, 128.3,149.6, 154.4 and 159.2.

Synthesis 6 2-(3,4-Difluorobenzylidene)malononitrile (ABD5O7) F''" Using a method analogous to Method A, with 3, 4-difluorobenzatdehyde and malononitrile, the title compound was obtained as yellow needles. 13C NMR (CDCI3): a 84.0, 112.1, 113.2, 119.0 (d, J = 18.6 Hz), 119.3 (d, J = 20.5 Hz), 127.9 (d, J = 1.9 Hz), 128.6 (d, J = 2.9 Hz), 150.6 (dd, J = 249.7, 13.7 Hz), 154.0 (dd, J = 274.4, 12.7 Hz) and 157.4.

Synthesis 7 2-(4-Dimethylaminobenzylidene)matononjtrile (ABD5O8)

NC CN Me Me

Using a method analogous to Method A, with 4-dimethylaminobenzaldehyde and malononitrile, the title compound was obtained as large dark orange crystals. 13C NMR (CDCI3): 640.2,71.6, 111.6,115.0, 116.1, 119.2,133.9,154.3 and 158.1.

-66 -Synthesis 8 2-(3-Hydroxy-4-methoxybenzylidene)malononitrile (ABD5O9)

NC CN

Me)L(J

OH

Using a method analogous to Method A, with 3-hydroxy-4-methoxybenzaldehyde and malononitrile, the title compound was obtained as large dark orange crystals. 1H NMR (DMSO-d6): a 3.89 (3H, s), 7.15 (1H, d, J = 8.5 Hz), 7.44 (it-I, d, J = 8.5 Hz), 7.53 (1H, s), 8.28 (1H, s)and 9.85 (1H, s). 13C NMR (DMSO-d6): a 56.0, 76.2, 112.3, 114.0, 114.0, 1152,124.4,126.4,147.0,153.9 and 160.7.

Synthesis 9 2-(4-Nitrobenzylidene)malononitrile (ABD51 7)

NC CN 02N

Using a method analogous to Method A, with 4-nitrobenzaldehyde and malononitrile, the title compound was obtained as yellow flakes. 3C NMR (DMSO-d6): 6 86.0, 112.5, 113.6, 124.6, 131.6, 136.7, 149.7 and 159.4. 1H NMR (DMSO-d): 6 8.12 (2H, d, J = 7.9 Hz), 8.41 (2H, d, J = 7.9 Hz) and 8.70 (1H, s).

Synthesis 10 2-(4-Fluoro-3-methylbenzylidene)malononitrile (ABD518)

NC CN

F

Using a method analogous to Method A, with 4-fluoro-3-methylbenzaldehyde and malononitrile, the title compound was obtained as yellow crystals. 13C NMR (CDCI3): 6 14.6(d, J = 3.9 Hz), 81.8, 112.7, 113.8, 116.7(d, J = 23.4 Hz), 127.1 (d, J = 8.8 Hz), 127.3 (d, J = 5.9 Hz), 130.9 (d, J = 8.8 Hz), 134.6 (d, J = 6.8 Hz), 158.7 and 164.9 (d, J = 258.8 Hz).

-67 -Synthesis 11 2-(3,4-Dimethoxybenzylidene)malononitrile (ABD52 1)

NC CN Me 0.. Me

Using a method analogous to Method A, with 3,4-dimethoxylbenzaldehyde and malononitrile, the title compound was obtained as yellow crystals. 13C NMR (CDCI3): 6 56.1,56.4, 78.4, llO.8,lll.l,113.6,114.5,124.3,128.3,149.5, 154.9 and 159.2.

Synthesis 12 2-(3,4-Diacetoxybenzylidene)malononitrile (ABD522)

NC CN MeO O Me 0

2-(3,4-Dihydroxybenzylidene)malononjtrile (1 g) was dissolved in acetic anhydride (30 mL) and pyridine (5 mL) was added. The mixture was stirred at room temperature for hours then at 50°C for 1 hour and poured into ice water. The water was decanted and the remaining residue dissolved in DCM and washed repeatedly with water and dilute K2C03 solution. Evaporation and purification by column chromatography (chloroform) gave the title compound as a white powder. 13C NMR (CDCI3): 6 20.6, 20.7, 83.6, 112.2, 113.4, 124.8, 125.6,129.1,129.4,142.8, 146.9, 157.8,167.4 and 167.8.

Synthesis 13 2-(3-Fluoro-4-methylbenzylidene)malononitrile (ABD533)

NC CN Me

F

Using a method analogous to Method A, with 3-fluoro-4-methylbenzaldehyde and malononitrile, the title compound was obtained as yellow crystals. 3C NMR (CDCI3): 6 15.2 (d, J = 2.9 Hz), 82.9, 112.5, 113.6, 116.4 (d, J = 23.4 Hz), 127.0 (d, J = 2.0 Hz), 130.2 (d, J = 7.8 Hz), 132.7 (d, J = 5.9 Hz), 133.3 (d, J = 17.6 Hz), 158.6 and 161.2 (d, J = 248.0 Hz).

-68 -Synthesis 14 2-(4-Hydroxy-3-methoxybenzylidene)malononitrile (ABD571)

NC CN

HO Me

Using a method analogous to Method A, with vanillin and malononitrile, the title compound was obtained as a yellow powder. 1H NMR (DMSO-d6): 6 3.80 (3H, s), 6.97 (1H, d, J = 8.2 Hz), 7.48 (1H, d, J = 8.5 Hz), 7.62 (1H, s), 8.23 (1H, s) and 10.82 (1H, br s). 13C NMR (DMSO-d6): 655.5,75.0, 113.0, 114.3, 115.1, 116.1, 123.1, 127.8,147.9, 153.9 and 160.6.

Synthesis 15 2-(4-Fluoro-3-methoxybenzylidene)malononitrile (ABD582)

NC CN FMe

Using a method analogous to Method A, with 4-fluoro-3-methoxybenzaldehyde and malononitrile, the title compound was obtained as orange needles. 13C NMR (CDCI3): 6 56.4, 82.0, 111.1, 112.8,113.7, 117.2(d, J = 19.5 Hz), 126.3 (d, J = 7.8 Hz), 127.7(d, J = 3.9 Hz), 128.6, 148.8, 156.1 (d, J = 260.7), and 158.8.

Synthesis 16 3-(3,4-Dihydroxyphenyl)-2-cyanoacrylamjde (AB0593)

NC NH2

HO

OH

Using a method analogous to Method A, with 3,4-dihydroxybenzaldehyde and cyanoacetamide, the title compound was obtained as orange needles. 13C NMR (CDCI3): 6101.1, 115.7, 116.3, 117.3, 123.4, 125.3, 145.7, 150.7 and 163.5. 1H NMR (DMSO-d6): 66.87 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 7.3 Hz), 7.54 (1H, s), 7.60 (1H, s), 7.72 (1H, s), 7.94 (1H, s) and 9.85 (2H, brs).

Synthesis 17 2-(3-FIuoro-4-methoxybenzylidene)malononjtrile (ABD594)

NC CN Me

F

Using a method analogous to Method A, with 3-fluoro-4-methoxybenzaldehyde and malononitrile, the title compound was obtained as orange needles. 13C NMR (CDCI3): O 56.6, 80.4, 112.9, 113.4, 114.0, 117.4 (d, J = 20.5 Hz), 124.0 (d, J = 7.8 Hz), 129.6, 152.0 (d, J = 250.0 Hz), 153.3 and 157.9.

Synthesis 18 2-(4-Fluoro-3-hydroxybenzylidene)malononttrile (ABD595) 2-(4-Fluoro-3-methoxybenzylidene)malononjtrjle (1 g) was dissolved in 0CM and stirred under N2 in a ice bath bath. 1 M BBr3 in 0CM (20 mL) was added and the mixture stirred overnight whilst warming to room temperature. 3 M HCI (100 mL) was added and the mixture extracted with ethyl acetate (3 x 70 mL), dried and evaporated to give a yellow I brown oil. The oil was purified by column chromatography (x 2). TLC showed an initial composition of starting material (fast), title compound (medium) and a further spot (slow) in equal quantities, as well as a baseline residue (un-demethylated). 13C NMR (DMSO-d6): ö 80.5(d, J = 2.0 Hz), 113.2, 114.3, 117.4, 118.6, 124.2, 128.2 (d, J = 2.9 Hz), 145.9 (d, J = 12.7 Hz), 154.6 (d, J = 253.9 Hz) and 160.3. 1H NMR (DMSO-d6): 6 7.40 (2H, d, 7.3 Hz), 7.64 (1H, d, J = 7.6 Hz), 8.42 (1H, s), 10.71 (1H, s).

Synthesis 19 Ethyl 2-cyano-3-(4-fluoro-3-methoxyphenyj)ac,ylate (AB D602)

F Me

-70 - Using a method analogous to Method A, with 4-fluoro-3-methoxybenzaldehyde and ethyl- 2-cyano acetate, the title compound was obtained as fine yellow crystals. 1H NMR (CDCI3): O 1.38 (3H, t, J = 7.0 Hz), 3.93 (3H, s), 4.36 (2H, q, J = 7.0 Hz), 7.15 (1H, t, J = 8.8 Hz), 7.39 (1H, m), 7.81 (1H, d, J = 8.2 Hz) and 8.15 (1H, s). 13C NMR (CDCI3): O 14.2, 56.3, 62.8, 102.4, 114.2, 115.7, 116.8 (d, J = 19.5 Hz), 126.3 (d, J = 6.8 Hz), 128.2 (d, J = 2.9 Hz), 148.4, 154.0, 155.3 (d, J = 258.8) and 162.4.

Synthesis 20 Ethyl 2-cyanoacetate NCLEt Cyanoacetic acid (5 g) was suspended in ethanol (100 mL). Concentrated H2S04 (2 mL) was added and the mixture heated to reflux for 18 hrs. The ethanol was evaporated under vacuum, the residue diluted with water and extracted with 0CM. The organic phase was dried with Na2SO4 and evaporated to give a clear oil.

Synthesis 21 2-Cyano-N-(4-fluorobenzyl)acetamide NCJL� Ethyl 2-cyanoacetate (2.5 g) and 4-fluorobenzylamine (1.8 g) were refluxed in acetonitrile (20 mL) for 4 hours. The solvents were evaporated to give a clear oil, which was crystallised from ethyl acetate / petrol to give a pale orange solid.

Synthesis 22 2-Cyano-N-(4-methoxybenzyl)acetamide NCLNO_Me Ethyl 2-cyanoacetate (1.4 g) and 4-fluorobenzylamine (1.5 g) were refluxed in acetonitrile (20 mL) for 4 hours. The solvents were evaporated to give a clear oil, which was crystallised from ethyl acetate / petrol to give a white powder.

-71 -Synthesis 23 2-Cyano-3-(4-fluoro-3-methoxyphenyl)-N-(4-fluorobenzyl)acrylamide (AB0603)

F Me

Using a method analogous to Method A, with 4-fluoro-3-methoxybenzaldehyde and 2-cyano-N-(4-fluorobenzyl)acetamide, the title compound was obtained as fine yellow crystals. 1H NMR (CDCI3): 6 3.92 (3H, s), 4.55 (2H, d, J = 5.5 Hz), 6.71 (1H, m), 7.03 (2H, t, J = 8.5 Hz), 7.29 (2H, t, J = 8.8 Hz), 7.40 (1H, m), 7.67 (1H, d, J = 6.4 Hz), and 8.30 (1H, s).

Synthesis 24 Ethyl 2-cyano-3-(3,4-dihydroxyphenyl)acrylate (A8D604)

HO

Using a method analogous to Method A, with 3,4-dihydroxybenzaldehyde and ethyl-2-cyano acetate, the title compound was obtained as a yellow solid. 1H NMR (DMSO-d6): 6 1.28 (3H, t, J = 7.0 Hz), 4.66 (2H, q, J = 7.0 Hz), 6.90 (IH, d, J = 8.5 Hz), 7.40 (1H, d, J = 8.2 Hz), 7.66 (1H, d, J = 1.6 Hz), 8.12 (1H, s) and 10.00 (2H, brs). 3C NMR (DMSO-d6): 6 14.1,61.9,96.5, 115.8, 116.2, 116.5, 122.9, 127.2, 145.9, 152.2, 155.0 and 162.8.

Synthesis 25 2-Cyano-3-(4-fluoro-3-methoxyphenyl)-N-(4-methoxybenzyl)acrylamide (ABD6O9) FMe Me Using a method analogous to Method A, with 4-fluoro-3-methoxybenzaldehyde and 2-cyano-N-(4-methoxybenzyl)acetamide, the title compound was obtained as fine yellow -72 -crystals. 1H NMR (CDCI3): O 3.72 (3H, s), 3.88 (3H, s), 4.34 (2H, s), 6.89 (2H, d, J = 7.9 Hz), 6.99 (1H, m), 7.25 (2H, d, J = 7.0 Hz), 7.61 (1H, m), 7.77 (1H, d, J 7.6 Hz), 8.19 (1H, s) and 8.96 (1H, s).

Synthesis 26 2-Benzoyl-3-(3-hydroxy-4-methoxyphenyl)acrylonitrile (ABD6 10) MeiJ' Using a method analogous to Method A, with 3-hydroxy-4-methoxybenzaldehyde and benzoylacetonitrite, the title compound was obtained as a yellow solid. 1H NMR (DMSO-d6) O 3.97 (3H, s), 6.94 (1H, d, J = 8.5 Hz), 7.40 (1H, d, J = 8.2 Hz), 7.50 (2H, d, J = 7.6 Hz), 7.61 (1H, m), 7.66 (1H, s), 7.85 (2H, d, J = 7.3 Hz) and 7.96 (1H, s). 13C NMR (DMSO-d6): ö56.3, 107.3, 110.8, 116.6, 117.5, 125.4,126.1,128.6,129.3,133.2,136.2, 146.0, 151.2, 155.6 and 189.5.

Biolociical Methods Screening of candidate compounds was performed using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration as an in vivo model for Parkinson's disease. Compounds were assessed for their ability to prevent neurodegeneration as assessed by a number of parameters.

Prevention of MPTP-lnduced Neurodegeneration Animals and Treatment: Test compounds were prepared as 1.25 or 2.5 mg/mL in 10% DMSO I 30% lEG I 60% PBS and were dosed to 12 week old C57BL6JCRL mice at a final concentration of 5 or mg/kg. Animals were dosed twice daily throughout the duration of the study. Animals were pre-treated for 3 days either with 100 pL test compound or with 100 pL control solution (DMSOITEG/PBS). Neurodegeneration was induced in test animals by MPTP (30 mg/kg i.p.) in saline on day 4 and injections repeated for total of 5 consecutive days [Tatton, 1997], whilst a control group received only saline. Dosing with test compounds or control solution then continued for a further 21 days when the study was terminated.

Sample Preparation: 21 days after the last MPTP treatment, mice were decapitated, and the brain quickly removed. Half of one striatum was dissected out, snap-frozen on dry ice, and stored at 80°C for HPLC analysis. The remaining part of each brain was immersed for 24 hours in 4% PEA, and cryoprotected in 30% sucrose in 0.1 M PBS for 2 days at 4°C. These brains were frozen in dry ice-cooled isopentane, stored at -80°C and used for immunohistochemistry.

MPTP Metabolism: Striatal 1-methyl-4-phenylpyridinium (MPP levels were determined in four mice. Mice received 10 mg/kg i.p. AG126 30 minutes before MPTP (30 mg/kg i.p.) administration. 90 minutes after MPTP administration, the mice were sacrificed, the striata were dissected out, and the striatal tissue content of MPP measured by HPLC with UV-detection (wavelength = 295 nm) as in Teismann, 2003.

TH Immuno-and Nissl staining: Frozen brains were serially sectioned (30 pm) through the entire midbrain and striatum on a cryostat. Sections were incubated free floating with a TH polyclonal anti-TH antibody (1:1000; Calbiochem). The second antibody was a recognizing biotinylated-conjugated polyclonal goat anti-rabbit antibody (1:200; Vector Laboratories), and a horseradish peroxidase-conjugated avidin/biotin complex (Vector). Colour was generated with 3,3'-diaminobenzidine (DAB) and H202. Cell counts were done by stereology as described below.

HPLC Analysis of Striatal DA, DOPAC, and HVA: On the day of the assay, tissue samples were sonicated in 30 vol. (w/v) of 0.1 M perchloric acid. After centrifugation (14,000 x g, 20 minutes, 4°C), 2OpL of supernatant was injected onto a C18 Acclaim 120 column (Dionex, ldstein, Germany). The mobile phase (pH = 4.3) consisted of 90% 6.973g/L sodium acetate, 7.355 g/L citric acid, 105 mg/L octane sulfonic acid, 48 mg/L sodiumEDTA solution and 10% methanol. Flow rate was 1 mL/minute. Peaks were detected by an electrochemical detector (Coulochem II, ESA); the detector potential was set at 320 mV using a glassy carbon electrode and an Ag/AgCl reference electrode. Data were collected and processed using the Chromeleon computer system (Dionex).

-74 -SNpc Neuronal Counts & Stereology: To assess the effects of MPTP on TH-and Nissi-stained SNpc cells, the total number of TH-and Nissi-stained cells was counted bilaterally in the SNpc throughout its entire rostro-caudal axis from saline-and MPTP-injected mice by using the unbiased method for cell count, the optical fractionator [West 1991) as described below. Throughout the study, the investigator was blinded to the treatment status (i.e., MPTP vs. saline). For this analysis, a Zeiss Axiophot photomicroscope equipped with a Zeiss planapochromat 100X oil objective and a CCD camera was used to generate digitised images that were analyzed on a Dell computer using the data analysis software, Stereo Investigator (MicroBrightField Europe, Magdeburg, Germany) [Bloom, 1997]. This method of cell countin does not depend upon the determination of a volume of reference and/or density, but rather relies on random, systematic sampling from a known fraction of a structure's total volume, and neuron number is estimated by extrapolating from this known fraction [West, 1991; West 1993). The mathematical formula for estimating total cell number and the algorithm for cell count are presented in detail in West, 1993. In agreement with this method, cell counts were performed by counting the number of neurons in the left SNpc of every fourth section throughout the entire extent of the SNpc.

To confirm that all counted sections contain the SNpc, each stained section was examined using a standard mouse atlas [Franklin, 1997] as anatomical reference.

Because the stains may not penetrate through the entire depth of the section, cells were only counted in that portion of the section where staining was visible, and this depth was divided by the total thickness of the section, measured by visualising staining on both surfaces. To avoid double counting of cells with unusual shapes, Nissi-stained and TH-immunoreactive cells were counted only when their nuclei were optimally visualized, which occurred only in one focal plane. Neurons were differentiated from non-neuronal cells (i.e., glia), in the Nissi stain by the exclusion of cells that did not have a clearly defined nucleus, cytoplasm, and a prominent nucleolus; although some small neurons may have been excluded, these criteria should reliably exclude all non-neuronal cells.

Striatal optical density: Striata were stained for TH as described above. After staining, the striata were mounted on gelatinized microscope slides, dehydrated and cover-slipped. Striatal optical density was assessed using the Scionlmage (NIH) program as in Teismann, 2003. Striata were scanned using an EPSON scanner, and images stored as tif-files. Using Scionimage, scanned files were calibrated for optical density (OD) and the scale set to pixels. The striata were then outlined and the mean OD measured. As a reference the mean 00 of the cortex was measured as well. The final value for striatal OD was the measured striatal OD minus the measured cortical 00. This was performed for every section and then averaged to give the final 00 value for the striatum.

-75 -Statistics: All values were expressed as means � standard error of the mean (SEM). Differences between means were analysed using a two-tailed Student's t-test. Differences among means were analysed using one-or two-way analysis of variance (ANOVA) with the different types of mice, treatment or time as the independent factors. When ANOVA showed significant differences, pair-wise comparisons between means were tested by Newman-Keuls post-hoc testing. All data sets were subjected to normality test and equality of variance test, and were either or both criteria violated, the appropriate nonparametric test was used. In all analyses, the null hypothesis was rejected at the 0.05 level. All statistical analyses and all Vmax and Km determinations by non-linear fitting were performed using SigmaStat for Windows-2.0.

Biological Data Biological Study 1 The biological activity of the 3-PAN compounds was compared for a range of related derivatives using the MPTP model for neurodegeneration using the assays described above. For example, dopamine levels were determined for several 3-PAN compounds following treatment with MPTP as described above, using the HPLC analysis technique described above. The results are summarised in Table 1 and in Figure 1.

The 3-PAN compounds AG 126 (dosage 10 mg/kg, i.p), ABD5O2 (dosage 10 mg/kg, i.p.), ABD5O5 (dosage 10 mg/kg, i.p.), ABD5O9 (dosage 5 mg/kg, i.p.), ABD517 (dosage 5 mg/kg, i.p.), ABD522 (dosage 10 mg/kg, i.p.) and AB0571 (dosage 5 mg/kg, i.p.) were investigated in vivo using the MPTP model for neurodegeneration, assessed by striatal dopamine levels.

The striatal dopamine level data are illustrated in Table 1 and in Figure 1. The reported values are means � SEM for two to ten mice per group. Groups were compared with the Bonferroni posthoc test. < 0.05 compared to MPTP-treated mice receiving DMSO.

-76 -

Table 1

Dopamine levels (ng/mg of wet tissue) in striatum 21 days after treatment with MPTP Treatment group Dopamine (nglmg) DMSO (10%) + saline 23.20 � 1.55 DMSO (10%) + MPTP 7.37 � 0.70 AG126 + MPTP 10.21 � 2.71 502 + MPTP 12.08 � 1.20 505 + MPTP 10.37 � 0.718* 509 + MPTP 9.27 � 1.07 517+MPTP 11.17�0.40 522 + MPTP 9.66 � 0.31 571 +MPTP 11.60� 3.13 Figure 1 is a graph showing striatal dopamine levels for each study group: the graph shows that, after 29 days, the untreated control group had dopamine levels of 23.20 ng/mg of wet tissue; in the MPTP control group, dopamine levels had fallen to 7.37 ng/mg wet tissue, in the MPTP groups treated with 3-PAN compounds, a partial rescue of dopamine levels had been achieved and values between 9.27 and 12.08 ng/mg wet tissue were recorded.

The data show that administration of MPTP leads to a substantial loss of striatal dopamine and that treatment with 3-PAN compounds can attenuate this loss.

The data also demonstrate that 3-PAN compounds can reverse neurodegeneration as modelled by measurement of striatal dopamine levels, and therefore that treatment with these compounds has the potential to prevent or reduce the symptoms of Parkinson's disease.

Biological Study 2 The biological activity of the 3-PAN compounds was compared for a range of related derivatives using the MPTP model for neurodegeneration using the assays described previously. For example, the density of TH-positive fibres in the striatum was determined in the presence or absence of several 3-PAN compounds following treatment with MPTP as described above, analysed using the staining techniques described above. The results are summarised in Figure 2.

The 3-PAN compounds, ABD5O2 (dosage 10 mg/kg, i.p.), ABD5O5 (dosage 10 mg/kg, i.p.), ABD517 (dosage 5 mg/kg, i.p.),and AB0522 (dosage 10 mg/kg, i.p.) were -77 -investigated in vivo using the MPTP model for neurodegeneration, assessed using density of TH-positive fibres as described above.

Figure 2 is a graph showing the density of TH-positive fibres in the striatum for each study group; the graph shows that, after 29 days, the density of TH-positive fibres was decreased to 42% of saline values in the MPTP-treated mice receiving only control solution. Co-treatment with different 3-PAN derivatives gives to a significantly smaller reduction in striatal optical density: compared to saline levels the percentage of TH-positive striatal fibres remaining after treatment with ABD5O2, ABD5O5, ABD517 and ABD522 were 64%, 60%, 60%, and 66%, respectively. Reported values are means � SEM for two to four mice per group. Groups were compared with the Newman-Keuls post hoc test. P < 0.05 for 3-PAN treatment groups compared to MPTP-treated mice receiving DMSO.

The data show that administration of MPTP leads to a substantial loss of striatal TH-positive fibres and that treatment with 3-PAN compounds can attenuate this loss.

The data also demonstrate that 3-PAN compounds can reverse neurodegeneration as modelled by measurement of striatal TH-positive fibres, and therefore that treatment with these compounds has the potential to prevent or reduce the symptoms of Parkinson's disease.

Biological Study 3 The biological activity of the 3-PAN compounds was compared for a range of related derivatives using the MPTP model for neurodegeneration using the assays described previously. For example, the number of SNpc dopaminergic neurons was determined in the presence or absence of several 3-PAN compounds following treatment with MPTP as described above, analysed using the staining techniques described above. The results are shown in Figure 3.

The 3-PAN compounds, ABD5O2 (dosage 10 mg/kg, i.p.) and ABD5O5 (dosage 10 mg/kg, i.p.), were investigated in vivo using the MPTP model for neurodegeneration, assessed using the number of SNpc dopaminergic neurons as described above.

Figure 3 is a graph showing the number of SNpc dopaminergic neurons for each study group: Stereological counts of SNpc dopaminergic neurons, defined by TH staining, showed that the number of neurons was reduced from a control value of 10372 � 692 to a value of 3400 � 103 after MPTP injections; pre-treatment with ABD5O2 or ABD5O5 gave significantly smaller reductions and the number of SNpc dopaminergic neurons were 4552 � 104 and 4373 � 122 respectively. Reported values are means � SEM for two to three -78 -mice per group. Groups were compared with the Newman-Keuls post hoc test. P < 0.05 for 3-PAN treatment groups compared to MPTP-treated mice receiving DMSO.

The data show that administration of MPTP leads to a substantial drop in the number of SNpc dopaminergic neurons, and that treatment with 3-PAN compounds can attenuate this reduction.

The data also demonstrate that 3-PAN compounds can reverse neurodegeneration as modelled by number of SNpc dopaminergic neurons, and therefore that treatment with these compounds has the potential to prevent or reduce the symptoms of Parkinson's disease.

Biological Study 4 The ability of 3-PAN compounds to prevent the conversion of MPTP to its toxic rnetabolite MPP was investigated as described above.

The 3-PAN compound AG126 (dosage 10 mg/kg, i.p.) was investigated in vivo for prevention of MPTP metabolism using the MPTP metabolism assay as described above.

MPTP administration was not altered due to AG126 pre-treatment. MPP levels were 20.33 � 1.16 ug/g wet tissue weight in mice pre-treated with DMSO and 20.16 � 1.55 ug/g wet tissue weight in mice which were pre-treated with AG126.

The data show that 3-PAN compounds do not act simply by blocking the formation of the toxic intermediate MPP. It can be inferred that the mode of action is a general one which prevents neurodegeneration rather than being one restricted solely to the MPTP model.

The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.

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Claims (48)

1. -88 -CLAI MSA compound for use in a method of treatment or prophylaxis of neurodegeneration, wherein said compound is a compound selected from compounds of the following formula and pharmaceutically acceptable salts, hydrates, and solvates thereof:

   Nwherein: -Q is independently: -CN, -C(=O)R°, C(O)RQN; -C(O)NH2,-C(=O)NHR°, C(=O)NRNRQ, -C(=O)OH, or -C(=O)OR°; wherein: -R'" is independently saturated aliphatic C14alkyl; each -R° is independently -R°', RQB, or each -L°-is independently saturated aliphatic C1..3alkylene; RQA is independently saturated aliphatic C1.6alkyl, and is optionally each RoB is independently C610carboaryl or C510heteroaryl, and is RQN is independently non-aromatic C47heterocyclic, and is optionally and wherein: -w is independently -H or saturated aliphatic C13alkyl; each of -R2, -R3, -R4 is independently -H or -R1; each of -R' and -R5 is independently -H or -R2; each -R1 is independently: -F, -Cl, -Br, -I, -CE3, -OCF3, -OH, -L'-OH, -O-L''-OH, -OR", -L-OR, -89 --SH, -SR, -CN, -NO2, -NH2, -NHR, -NR2, _NR1A2R1A3, -L-NH2, _LlANHR, .LNRlAl2, LlANR2R3, -O-L1t'-NH2, -O-L'-NHR', OLNR1M2, OC(=O)RlM, -C(=O)OH, -C(=O)OR', -C(=O)R, -C(=O)NH2, -C(=O)NHR, -C(=O)NR"12, C(=O)NRlA2RlA3, NHC(=O)RlM, ..NRC(Q)RlAl, -NHC(=O)OR, -NR''(=O)OR', -OC(=O)NH2, -OC(=O)NHR, -OC(=O)NR"12, -OC(=O)NR2R3, -NHC(=O)NH2, -NHC(=O)NHR1'1, -NHC(=O)NR'2, -NHC(=O)NR2R3, -NR(=O)NH2, -NR'(=O)NHR1, -NR1(=O)NR2, ..NR1A1A(0)NR1A2R1A3 -NHS(=Q)2R'1, ..NR1A1S(=O)2R1AI -S(=O)2NH2, -S(=O)2NHR', -S(=O)2NR'12, -S(=O)2NRR'3, -S(=O)R, S(=O)2RlAl, -OS(=O)2R', or wherein: each -L-is independently saturated aliphatic C15alkylene; in each group -NRR"3, R1 and RIA3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly
2. 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; each -R is independently: _R1BI, _R1B2, ..R1B3 _R1B4, _R1B5, _R1B6, _R1B7, _R1B8, _LlB_RIB4, _L_RlB$, _L_RlB6, _L_RlB7, or each -R181 is independently saturated aliphatic C1alkyl; each -R182 is independently aliphatic C2alkenyl; each RlB3 is independently aliphatic C2alkynyl; each.R1B4 is independently saturated Ccycloalkyl; each -R185 is independently C3cycIoalkenyl; each RlB6 is independently non-aromatic C3heterocyclyl; each RB7 is independently C610carboaryl; each -R188 is independently C510heteroaryl; each LlB is independently saturated aliphatic C1..3alkylene; wherein: -90 -each.R1B4, -R'85, -R6, -R187, and -R168 is optionally substituted with one or more substituents -R' and/or one or more substituents Rlc2, each -R181, RlB2, -R3, and LlB is optionally substituted with one or more wherein: each -R1 is independently saturated aliphatic C1alkyl, phenyl, or benzyl; each -R2 is independently: -F, -Cl, -Br, -I, -CE3, -OCF3, -OH, -L'°-OH, -O-L11-OH, -OR1, LlDORt, -O-L10-OR, -SH, -SR, -CN, -NO2, -NH2, -NHR1, -NR1012, -NR102R103, -L10-NH2, -L-NHR, -L10-NR'°12, _LmNRbo2RlD3, -C(=O)OH, -C(=O)OR, -C(0)NH2, -C(=O)NHR101, -C(=O)NR1012, or C(=O)NRlD2R3; wherein: each -R101 is independently saturated aliphatic C1aIkyl, phenyl, or benzyl; each -L10-is independently saturated aliphatic C15alkylene; and in each group NRlD2R3, R32 and R1D3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; each -R2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L-OH, -O-L-OH, -OR1, -L-OR1, -O-L-0R1, -SH, -SR, -CN, -NO2, -NH2, -NHR, -NR12, -NRR, -L-NH2, -L-NHR, -L-NR12, -L-NRR3, -O-L-NH2, -O-L-NHR1, OL2&NR12, -O-L-NRR3, -C(=O)OH, -C(=O)OR', -91 --C(=O)R1, -C(=O)NH2, -C(=O)NHR1, -C(=O)NR12, -C(O)NRR, -NHC(=O)R1, NR2c(=O)R, -NHC(=O)OR1, -NR(=O)OR', -OC(=O)NH2, -OC(=O)NHR1, -OC(=O)NR12, -OC(O)NRR3, -NHC(=O)NH2, -NHC(=O)NHR1, -NHC(=O)NR12, -NHC(=O)NRR3, -NR1(=O)NH2, -NR1(=O)NHR1, -NR1(=O)NR12, -NR1(=O)NR2R3, -NHS(=O)2R'1, -NR'S(=O)2R1, -S(=O)2NH2, -S(=O)2NHR1, -S(=O)2NR'2, S(=O)2NRR2A3, -S(=O)R', -S(=O)2R1, -OS(=O)2R1, or -S(=O)2OR1; wherein: each -Lu-is independently saturated aliphatic C1.5alkylene; in each group -NR2R3, R and R3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly I ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; each -R1 is independently: _R2BI, _R2B2, _R2B3, _R2B4, .R2B5 R286 -R287, _R2B8, _L2B_R2B4, _L2B_R2B5, _L2B_R2B6, _L28_R2B7, or _L2B_R2B8; each -R2 is independently saturated aliphatic C1.6aIkyl; each -R282 is independently aliphatic C2alkenyl; each R2B3 is independently aliphatic C2.6alkynyl; each R2B4 is independently saturated Ccycloalkyl; each -R285 is independently C3cycloalkenyl; each -R286 is independently non-aromatic C3heterocyclyl; each -R287 is independently C6,0carboaryl; each -R2 is independently C10heteroaryl; each L2B is independently saturated aliphatic C13alkylene; wherein: each -R264, R2B5, R2B6 R2B?, and R2B8 is optionally substituted with one or more substituents R2dl and/or one or more substituents R2c2, each -R2, R2B2, R2B3, and L2B is optionally substituted with one or more wherein: each R2d1 is independently saturated aliphatic C1alkyl, phenyl, or benzyl; each R2c2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -92 - -OH, -L20-OH, -O-L20-OH, -OR201, -L20-0R201, -0L20..0R201 -SH, -SR201, -CN, -NO2, -NH2, -NHR201, -NR2012, -NR202R203, -L20-NH2, -L20-NHR201, L2DNR2Dl2, -L20-NR202R203, -C(=O)OH, -C(=O)0R201, -C(=O)NH2, -C(O)NHR201, -C(=O)NR2012, or C(=O)NR2D2R2D3; wherein: each -R20' is independently saturated aliphatic C14alkyl, phenyl, or benzyl; each L2D is independently saturated aliphatic C15alkylene; and in each group NR2D2R2D3, R202 and R203, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; with the proviso that if: -Q is -CN; -R1 is -H; -R5 is -H; -R2 is -H and -R4 is -OH, or -R2 is -OH and -R4 is -H; then: -R3 is not -NO2; and with the proviso that if: -Q is -CN; -R1 is -H; -R5 is -H; -R3 is -OH; then: -R2 and -R4 are not both a group selected from: -H, -R, -CF3, -L-OH, -L-OR, LANH2, LlANHR, LlANRl2, and *** 2. A compound according to claim 1, wherein -Q is independently -CN.
3. 3. A compound according to claim 1, wherein -Q is independently -C(=O)R° or C(=O)RQN.
4. 4. A compound according to claim 1, wherein -Q is independently -C(=O)R°.
5. 5. A compound according to claim 1, wherein -Q is independently -C(=O)R°'.
6. 6. A compound according to claim 1, wherein -Q is independently -C(=O)NH2, -C(=O)NHR°, or C(=O)NRNRo.
7. 7. A compound according to claim 1, wherein -Q is independently -C(0)NHR° or C(=O)NRNRQ.

   -93 -
8. 8. A compound according to claim 1, wherein -Q is independently -C(0)NHR°.
9. 9. A compound according to claim 1, wherein -Q is independently -C(=O)OH or -C(=O)OR°.
10. 10. A compound according to claim 1, wherein -Q is independently -C(=O)OR°.
11. 11. A compound according to claim 1, wherein -Q is independently -C(O)R° or C(=O)RoN.
12. 12. A compound according to claim 1, wherein -Q is independently -C(0)NH2, -C(=O)NHR°, or C(=O)NRNRo.
13. 13. A compound according to claim 1, wherein -Q is independently -C(=O)OH or -C(=O)OR.
14. 14. A compound according to any one of claims ito 13, wherein RN, if present, is independently -Me. * **
15. 15. A compound according to any one of claims 1 to 14, wherein each -R°, if present, is independently RoA.
16. 16. A compound according to any one of claims ito 14, wherein each -R°, if present, is independently -R°8.
17. 17. A compound according to any one of claims i to 14, wherein each -R°, if present, is independently -L°-R°8. * **
18. 18. A compound according to any one of claims 1 to 17, wherein each -L°-, if present, is independently -CH2-or -CH2CH2-.
19. 19. A compound according to any one of claims ito 18, wherein each if present, is independently saturated aliphatic C1alkyl, and is optionally substituted.

    -94 -
20. 20. A compound according to any one of claims 1 to 19, wherein optional substituents on each RQA, if present, are selected from: Rx4, -F, -Cl, -Br, -I, -OH, ORx4, -NH2, NHRx4, NRx42, and OC(=O)Rx4; wherein each Rx4 is independently saturated aliphatic C1alkyl.
21. 21. A compound according to any claim 20, wherein optional substituents on each -R, if present, are selected from: -NH2, NHRx4, and NRx42.
22. 22. A compound according to any one of claims 1 to 18, wherein each -R, if present, is independently saturated aliphatic C1alkyI.
23. 23. A compound according to any one of claims ito 18, wherein each -R, if present, is independently saturated aliphatic C1alkyl.
24. 24. A compound according to any one of claims ito 18, wherein each -R, if present, is -Me, -Et, -nPr, or -iPr.
25. 25. A compound according to any one of claims 1 to 24, wherein each -R°6, if present, is independently C610carboaryl or C51oheteroaryl, and is optionally substituted.
26. 26. A compound according to any one of claims 1 to 24, wherein each -R, if present, is independently C610carboaryl, and is optionally substituted.
27. 27. A compound according to any one of claims I to 24, wherein each -R, if present, is independently phenyl or naphthyl, and is optionally substituted.
28. 28. A compound according to any one of claims 1 to 24, wherein each RQB, if present, is independently phenyl, and is optionally substituted.
29. 29. A compound according to any one of claims 1 to 24, wherein each -R, if present, is independently C51oheteroaryl, and is optionally substituted.
30. 30. A compound according to any one of claims 1 to 24, wherein each -R°8, if present, is independently C56heteroaryl, and is optionally substituted.-95 -
31. 31. A compound according to any one of claims 1 to 24, wherein each RoB, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is
32. 32. A compound according to any one of claims I to 24, wherein each -R, if present, is independently C910heteroaryl, and is optionally substituted.
33. 33. A compound according to any one of claims 1 to 24, wherein each RQB, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, be nzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidtnyl, or benzopyridazinyl, and is
34. 34. A compound according to any one of claims 1 to 33, wherein each RQB is
35. 35. A compound according to any one of claims 1 to 33, wherein optional substituents on each -R, if present, are selected from: -R3, -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L-OH, OLaAOH, -OR3, L3AOR3M, -O-L-OR3, -SH, -SR1, -CN, -NO2, -NH2, NHR3M, -NR'2, -NRR3, L3ANH2, -L31'-NHR, LaANR3II2, L3ANR2R3, -O-L-NH2, -O-L-N HR1, OL3AN R3M2, OC(=O)R3Al, -C(=O)OH, C(=O)OR3M, C(=O)R3M, -C(=O)NH2, -C(=O)NHR3M, -C(O)NR12, -C(=O)NR3R3, -NHC(=O)R3M, -NR(=O)R3', -NHC(=O)OR', NR3M(=O)OR, -OC(=O)NH2, -OC(=O)NHR3M, -OC(=O)NR3 2 -OC(=O)NR2R3'3, -NHC(=O)NH2, -NHC(=O)NHR1, -NHC(=O)NR12, NHC(=O)NRR3A3, -96 - -NR3 (=O)NH2, -N R3A1 (=O)NHR3A, NR3M(=O)NR32, -NR1(=O)NR3R3, NHS(=O)2R3Al, NR3AlS(=O)2R3At, -S(=O)2N H2, -S(=O)2NHR31, -S(=O)2NR12, -S(=O)2N R3R3A3, S(=O)R3Al, S(=O)2R3Al, OS(=O)2R3M, and -S(=O)2OR3; wherein: each -L3'-is independently saturated aliphatic C15alkylene; in each group NR3A2R3A3, R3A2 and R3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; each R3M is independently: -R3, _R3B2, _R3B3, _R3B4, R3B5, _R3B6, _R3B7, .R388 _L38_R3B4, _L3B_R365, _L3B_R386, _L3B_R3B7, or _L3B_R3BB; each -R38' is independently saturated aliphatic C1alkyl; each R3B2 is independently aliphatic C26alkenyl; each -R33 is independently aliphatic C2alkynyl; each R3B4 is independently saturated Ccycloalkyl; each R3B5 is independently C6cycloalkenyl; each R3B6 is independently non-aromatic Cheterocyclyl; each -R387 is independently C610carboaryl; each R3B8 is independently C5.10heteroaryl; each L3B is independently saturated aliphatic C13alkylene; wherein: each R3B4, R3Bs, R3B6, R3B7, and -R388 is optionally substituted with one or more substituents R3dl and/or one or more substituents Rac2, each -R381, R3B2, R3B3, and -L38-is optionally substituted with one or more wherein: each R3dl is independently saturated aliphatic C1alkyl, phenyl, or benzyl; each R3c2 is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, L3DOH, -O-L30-OH, -OR301, L3DOR3Dl, -O-L30-0R301, -SH, -SR301, -CN, -NO2, -NH2, -NHR301, -NR3012, -NR302R303, -L30-NH2, L30-NHR301, -L30-NR32, -L30-N R302R3D3, -97 - -C(=O)OH, C(=O)OR3Dl, -C(=O)N H2, -C(=O)NHR301, -C(=O)NR3012, or -C(=O)NR302R303; wherein: each R3Dl is independently saturated aliphatic C1..4alkyl, phenyl, or benzyl; each -L30-is independently saturated aliphatic C1alkyIene; and in each group NR3D2R3D3, R3D2 and R303, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0.
36. 36. A compound according to claim 35, wherein optional substituents on each RoB, if present, are selected from: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L3"-OH, -O-L3'-OH, OR3Al, L3tOR3M, -O-L-OR1, -SH, -SR3, -NH2, NHR3Al, -NR32, NR3R3A3, L3AN H2, L3ANH R', L3ANR3Al2, L3AN R3A2R3A3, -OC(=O)R3, C(=O)R3M, -C(=O)NH2, -C(=O)NHR1, C(=O)NR3M2, C(=O)NR32R3A3, -NHC(=O)R3, NR3A(=O)R3, -NHC(=O)OR3, NR3M(=O)OR3, -OC(=O)NH2, -OC(=O)NHR3M, -OC(=O)NR32, and OC(=O)NR3R3A3.
37. 37. A compound according to claim 35, wherein optional substituents on each -R8, if present, are selected from: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, L3AOH, OL3AOH, OR3At, L3AOR, OLOR3M, -SH, SR3M, -NH2, -NHR3, NRaAl2, and NRR3A3.
38. 38. A compound according to any one of claims 35 to 37, wherein each -L-, if present, is independently -(CH2)3-, wherein n3 is independently 1 to 4.-98 -
39. 39. A compound according to any one of claims 35 to 37, wherein each -L3'-, if present, is independently -CH2-or -CH2CH2-.
40. 40. A compound according to any one of claims 35 to 39, wherein each NR3A2R3A3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1alkyl, -CF3. and -F.
41. 41. A compound according to any one of claims 35 to 39, wherein each NR3R3A3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C13a1ky1, -CF3, and -F.
42. 42. A compound according to any one of claims 35 to 41, wherein each -R3, if present, is independently: -R3, _R3B4, -R356, _R3B7, _R3B8, -L36-R384, _L3B_R3B6, _L3B_R3B7, or _L3B_R3B8.
43. 43. A compound according to any one of claims 35 to 41, wherein each R3M, if present, is independently: -R381, -R387, -R388, -L39-R367, or _L38_R3B8.
44. 44. A compound according to any one of claims 35 to 41, wherein each R3M, if present, is independently: -R381, _R3B7, or _L3B_R381.
45. 45. A compound according to any one of claims 35 to 44, wherein each R3B6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.
46. 46. A compound according to any one of claims 35 to 45, wherein each R3B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.
47. 47. A compound according to any one of claims 35 to 46, wherein each R3B7, if present, is independently phenyl, and is optionally substituted.
48. 48. A compound according to any one of claims 35 to 47, wherein each R3B8, if present, is independently Cheteroaryl, and is optionally substituted. -99 -49 A compound according to any one of claims 35 to 47, wherein each R3B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and A compound according to any one of claims 35 to 47, wherein each -R388, if present, is independently C910heteroaryl, and is optionally substituted.51 A compound according to any one of claims 35 to 47, wherein each R3B8, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.52. A compound according to any one of claims 35 to 51, wherein each -L38-, if present, is independently -CH2-or -CH2CH2-.53. A compound according to any one of claims 35 to 51, wherein each L3B, if present, is independently -CH2-.54. A compound according to any one of claims 35 to 53, wherein each -R3, if present, is independently saturated aliphatic C1alkyl.55. A compound according to any one of claims 35 to 54, wherein each R3c2 is independently: -F, -Cl, -Br, -I, -OH, -OR301, -CN, -NO2, -NH2, -NHR301, -NR32, or..NR3D2R303.56. A compound according to any one of claims 35 to 55, wherein each -R3, if present, is independently saturated aliphatic C1alkyl.57. A compound according to any one of claims 35 to 56, wherein each -L30-, if present, is independently (CH2)m3, wherein m3 is independently 1 to 4.58. A compound according to any one of claims 35 to 56, wherein each -L30-, if present, is independently -CH2-or -CH2CH2-.-100- 59. A compound according to any one of claims 35 to 58, wherein each NR3D2R3D3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1.3alkyl, -CF3. and -F.60. A compound according to any one of claims 35 to 58, wherein each NR3D2R3D3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C13alkyl, -CF3, and -F.61. A compound according to any one of claims 1 to 33, wherein optional substituents on each RQB, if present, are selected from: Rx3, -F, -Cl, -Br, -I, -OH, ..ORX3, -NH2, NHRx3, NRx32, and OC(O)Rx3; wherein each Rx3 is independently saturated aliphatic C1alkyl. ***62. A compound according to any one of claims 1 to 61, wherein -R, if present, is independently non-aromatic C47heterocyclic, and is optionally substituted.63. A compound according to any one of claims 1 to 61, wherein -R°, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted with one or more groups selected from C13alkyl, -CF3, and -F.64. A compound according to any one of claims 1 to 61, wherein RQN, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C13alkyl, -CF3, and -F.65. A compound according to any one of claims 1 to 61, wherein RQN, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C1..3alkyl, -CF3, and -F. ***66. A compound according to any one of claims 1 to 64, wherein -W is independently -H or -Me.-101 - 67. A compound according to any one of claims 1 to 64, wherein -w is independently -H.68. A compound according to any one of claims 1 to 67, wherein each of -R1 and -R5 is independently -H.69. A compound according to any one of claims 1 to 68, wherein -R3 is independently -R1.70. A compound according to any one of claims 1 to 69, wherein: -R2 is independently -H or -R1; -R3 is independently -Rfl; and -R4 is independently -H or 71. A compound according to any one of claims 1 to 69, wherein: -R2 is independently -H; -R3 is independently -Rfl; and -R4 is independently -H; or -R2 is independently -R1; -R3 is independently -Re'; and -R4 is independently -H; or -R2 is independently -H; -R3 is independently -R1; and -R4 is independently -Re'.72. A compound according to any one of claims 1 to 69, wherein: -R2 is independently -R1; -R3 is independently -R; and -R4 is independently -H; or -R2 is independently -H; -R3 is independently -Re'; and -R4 is independently -R1.73. A compound according to any one of claims 1 to 69, wherein: -R2 is independently -Rn'; -R3 is independently -Re'; and -R4 is independently -H.74. A compound according to any one of claims 1 to 69, wherein: -R2 is independently -H; -R3 is independently -R1; and -R4 is independently -R1.75. A compound according to any one of claims 1 to 69, wherein: -R2 is independently -H; -R3 is independently -R1; and -R4 is independently -H.76. A compound according to any one of claims 1 to 75, wherein each -R'1, if present, is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -Lu-OH, -O-L-OH, -OR'1, LlAOR, -O-L-OR, -SH, -SR'1, -CN, -NO2, -NH2, -NHR', -NR12, ..NR1A2R1A3 -L-NH2, -L1-NHR1'M, LlANR2, -O-L-NH2, -O-L-NHR, OLNRlM2, OC(=O)RlAt, -C(=O)OH, -C(=O)OR, -C(=O)R, -C(=O)NH2, ..C(O)NHR, -C(=O)NR2, -C(=O)NRR3, -NHC(=O)R, -NR'C(=O)R, -NHC(=O)OR, -NR'(=O)OR, -OC(=O)NH2, -OC(=O)NHR"1, -OC(=O)NR2, -OC(=O)NRR'3, -NHC(=O)NH2, NHC(=O)NHRlAt, -NHC(=O)NR1'12, -NHC(=O)NR'R3, -NR1(=O)NH2, -NR(=O)NHR'', -NR(=O)NR"2, -NR'(=O)NRR3, -NHS(=O)2R', -NR'S(=O)2R, -S(=O)2NH2, -S(=O)2NHR', S(=O)2NRlM2, -S(=O)2NRR'3, -S(=O)R, -S(O)2R, -OS(=O)2R, or wherein: each -L-is independently saturated aliphatic C15alkylene; in each group -NRR''3, R1 and R1A3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; each -R is independently: _R1B, -R182, _R1B3, _R1B4, -R5, -R186, -R'87, _RB8, -L18-R184, _L1B_R1B5, L18R186, _LlB_R1B7, or _LlB_RIB8; each -R is independently saturated aliphatic C1.alkyl; each -R182 is independently aliphatic C2alkenyl; each RlB3 is independently aliphatic C24alkynyl; each RlB4 is independently saturated Ccycloalkyl; -103-each -R185 is independently C36cycloalkenyl; each RlB6 is independently non-aromatic C3heterocyclyl; each -R'87 is independently C610carboaryl; each -R188 is independently C510heteroaryl; each -L-is independently saturated aliphatic C13alkylene; wherein: each -R4, -R185, RlB6, -R'87, and RlB8 is optionally substituted with one or more substituents R' and/or one or more substituents Rlc2, each RlBl, RlB2, -R3, and -L'8-is optionally substituted with one or more wherein: each Rlcl is independently saturated aliphatic C1alkyl, phenyl, or benzyl; each Rlc2 is independently: -F, -CI, -Br, -I, -CF3. -OCF3, -OH, -L-OH, -O-L10-OH, -OR, -L10-0R101, O_LlDORlD, -SH, SRlDl, -CN, -NO2, -NH2, -NHR101, _NR1DI2, -NR112R'°3, LD_NH2, -L10-NHR, -L10-NR1012, -L-NR102R3, -C(=O)OH, -C(=O)0R1, -C(=O)NH2, -C(=O)NHR, -C(=O)NR1012, or C(=O)NRm2RlD3; wherein: each -R101 is independently saturated aliphatic C1alkyI, phenyl, or benzyl; each -L10-is independently saturated aliphatic C15alkylene; and in each group NRlD2RbD3, R102 and R103, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0.77. A compound according to claim 76, wherein each -R1, if present, is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, LlAOH, -O-L-OH, -OR', -SH, -SR, -104- -NH2, -NHR', -NR'2, -NR2R3, -L-NH2, LlANHR 1, -L"-NR2, -L-NR2R1"3, -C(=O)R', -C(=O)NH2, -C(=O)NHR, -C(=O)NR'2 -C(=O)NRR3, -NHC(=O)R"1, -NR(=O)R1, -NHC(=O)OR1, -NR(=O)OR, -OC(0)NH2, -OC(O)NHR, -OC(=O)NR12, or -OC(=O)NRR113.78. A compound according to claim 76, wherein each -R1, if present, is independently: -R, -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, LlAOH, -O-L-OH, -OR, -L''-OR, -O-L-OR', -SH, -SR, -NH2, NHRlM, NRlAl2, or NR�2RlA3.79. A compound according to claim 76, wherein each -R1, if present, is independently: -R, -F, -Cl, -Br, -I, -OH, -NH2, NHRlAt, -NR'12, or -OC(=O)R.80. A compound according to claim 76, wherein each -R1, if present, is independently -OH, -OR, or -OC(=O)R'.81. A compound according to any one of claims 76 to 80, wherein each LlA, if present, is independently -(CH2)1-, wherein ni is independently 1 to 4.82. A compound according to any one of claims 76 to 80, wherein each if present, is independently -CH2-or -CH2CH2-.83. A compound according to any one of claims 76 to 82, wherein each -NRR3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C13a1ky1, -CF3, and -F.84. A compound according to any one of claims 76 to 82, wherein each -NRR'3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C13alkyl, -CF3, and -F.85. A compound according to any one of claims 76 to 84, wherein each -R, if present, is independently: -R18', _R1B4, _R1B6, _R1B7, -R'8, _L_RlB4, _LB_RlB6, _L_RlB?, or -L-R8.86. A compound according to any one of claims 76 to 84, wherein each -R, if present, is independently: _R1BI, _R1B7, -R8, _LlB_R7, or -L-R8.87. A compound according to any one of claims 76 to 84, wherein each if present, is independently: -R161, _R1B7, or _LIB_R1B7.88. A compound according to any one of claims 76 to 87, wherein each -R186, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.89. A compound according to any one of claims 76 to 87, wherein each -R186, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, or tetrahydropyranyl, and is optionally substituted.90. A compound according to any one of claims 76 to 89, wherein each RlB7, if present, is independently phenyl, and is optionally substituted.91. A compound according to any one of claims 76 to 90, wherein each RlB8, if present, is independently C5heteroaryl, and is optionally substituted.92. A compound according to any one of claims 76 to 90, wherein each RlB8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and -106- 93. A compound according to any one of claims 76 to 90, wherein each RlB8, if present, is independently Cg10heteroaryl, and is optionally substituted.94. A compound according to any one of claims 76 to 90, wherein each RlBB, ii present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyl, and is optionally substituted.95. A compound according to any one of claims 76 to 94, wherein each -L-, if present, is independently -CH2-or -CH2CH2-.96. A compound according to any one of claims 76 to 94, wherein each LlB, if present, is independently -CH2-.97. A compound according to any one of claims 76 to 96, wherein each R1d1, if present, is independently saturated aliphatic C1alkyl.98. A compound according to any one of claims 76 to 97, wherein each -R2 is independently: -F, -Cl, -Br, -I, -OH, -OR101, -CN, -NO2, -NH2, NHRlDl, NRlDl2, or 99. A compound according to any one of claims 76 to 98, wherein each RmI, if present, is independently saturated aliphatic C1.alkyl.100. A compound according to any one of claims 76 to 99, wherein each -L10-, if present, is independently (CH2)mi, wherein ml is independently 1 to 4.101. A compound according to any one of claims 76 to 99, wherein each -Lw-, if present, is independently -CH2-or -CH2CH2-.102. A compound according to any one of claims 76 to 101, wherein each NRbD2Rm3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C13alkyl, -CE3, and -F.103. A compound according to any one of claims 76 to 102, wherein each -NR2R103, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C13alkyl, -CF3, and -F.104. A compound according to any one of claims 1 to 75, wherein each -R1 is independently: -R, -F, -Cl, -Br, -I, -OH, ORx, -NH2, NHRxl, -NR2, or OC(=O)Rxl; wherein each Rxl is independently saturated aliphatic C1alkyl 105. A compound according to claim 104, wherein each -R1 is independently -OH, -OR, or -OC(=O)R.106. A compound according to any one of claims 104 to 105, wherein -R3 is independently OC(=O)Rxt.107. A compound according to any one of claims 104 to 106, wherein -R4 is independently -OC(=O)R.108. A compound according to claim 104, wherein: -R2 is independently ORxl or -OC(O)R; -R3 is independently -OH; and -R4 is independently -H.109. A compound according to claim 104, wherein: -R2 is independently -OH, -OR, or -OC(O)R; -R3 is independently OC(O)Rxt; and -R4 is independently -H.110. A compound according to claim 104, wherein: -R2 is independently -OH; -R3 is independently OC(O)Rx; and -R4 is independently -H.111. A compound according to claim 104, wherein: -R2 is independently OC(=O)Rx; -R3 is independently -OH, ORxl, or OC(=O)Rxl; and -R4 is independently -H.-108- 112. A compound according to claim 104, wherein: -R2 is independently -OC(O)R; -R3 is independently -OH; and -R4 is independently -H.113. A compound according to claim 104, wherein: -R2 is independently -OC(=O)R; -R3 is independently -OC(O)R; and -R4 is independently -H.114. A compound according to any one of claims 1 to 113, wherein each -R2, if present, is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -Lu-OH, -O-L-OH, -OR'1, -L-OR1, -O-L-OR2, -SH, -SR1, -CN, -NO2, -NH2, -NHR1, -NR12, -NRR3, -L-NH2, -L-NH R1, -L-NR12, -L-NRR3, -O-L-NH2, -O-L-NHR1, -O-L-NR12, -O-L-NRR3, -OC(=O)R1, -C(=O)OH, -C(=O)OR', -C(=O)R1, -C(=O)NH2, -C(=O)NHR1, -C(=O)NR12, -C(=O)NRR3, -NHC(=O)R1, -NR1(=O)R', -NHC(=O)OR1, -NR1(O)OR1, -OC(=O)NH2, -OC(=O)NHR1, -OC(=O)NR'2, -OC(=O)NRR3, -NHC(=O)NH2, -NHC(=O)NHR1, -NHC(=O)NR12, -NHC(=O)NRR3, -NR1(=O)NH2, -NR'(=O)NHR', -NR1(=O)NR12, -NR1(=O)NRR3, -NHS(=O)2R1, -NR1S(=O)2R', -S(=O)2NH2, -S(=O)2NHRM1, -S(=O)2NR'2, -S(=O)2NRR3, -S(=O)R1, -S(=O)2R1, -OS(=O)2R', or -S(=O)2OR1; wherein: each -La-is independently saturated aliphatic C15alkylene; -log -in each group -NRR3, R and R3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatonis is N, and the other of said exactly 2 ring heteroatoms is independently N or 0; each -R1 is independently: -R281, _R2B2, _R2B3, -R284, -R285, -R286, -R287, _R2B8, _L2B_R284, _L28_R2B5, _L2B_R2B6, _L2B_R287, or _L2B_R288; each R2Bl is independently saturated aliphatic C16a1ky1; each R2B2 is independently aliphatic C2alkenyl; each R2B3 is independently aliphatic C2alkynyl; each -R284 is independently saturated C3cycloa Ikyl; each R2B5 is independently C6cycloalkenyl; each R2B6 is independently non-aromatic Cheterocyclyl; each R2B7 is independently C610carboaryl; each -R288 is independently C5.10heteroaryl; each L2B is independently saturated aliphatic C13alkylene; wherein: each -R284, -R285, -R286, R2B7, and -R288 is optionally substituted with one or more substituents R2dl and/or one or more substituents R2c2, each -R2°, R2B2, -R283, and L2B is optionally substituted with one or more wherein: each R2dl is independently saturated aliphatic C1alkyl, phenyl, or benzyl; each R2c2 is independently: -F, -Cl, -Br, -I, -CF3. -OCF3, -OH, -L20-OH, -O-L20-OH, -0R2°', -L20-OR2", -O-L20-0R201, -SH, SR2D, -CN, -NO2, -NH2, -NHR201, -NR2012, _NR2D2R2D3, -L20-NH2, _L2DNHR2c, L2DNR22, L2DNR2D2R2D3, -C(=O)OH, -C(=O)0R201, -C(=O)NH2, C(=O)NHR2D, -C(=O)NR22, or -C(=O)NR202R3; wherein: each -R2 is independently saturated aliphatic C1alkyI, phenyl, or benzyl; each L2D is independently saturated aliphatic C15alkylene; and in each group NR2D2R2D3, R2D2 and R203, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or 0.115. A compound according to claim 114, wherein each -R2, if present, is independently: -F, -Cl, -Br, -I, -CF3, -OCF3, -OH, -L-OH, OL2AOH, -OR1, -L-OR1, -O-L-OR1, -SH, -SR2, -NH2, NHRMl, -NR12, NR2A2R3, -L-NH2, -L-NHR1, L&NR12, -L-NRR, -OC(=O)R1, -C(=O)NH2, -C(=O)NHR1, -C(=O)NR12, -C(=O)NRR3, -NHC(=O)R1, -NR1 (=O)R1, -NHC(=O)OR1, -NR1(=0)OR1, -OC(=O)NH2, -OC(=O)NHR1, -OC(=O)NR12, or -OC(=O)NRR3.116. A compound according to claim 114, wherein each -R2, if present, is independently: -F, -Cl, -Br, -I, -CE3, -OCF3, -OH, -L-OH, -O-L-OH, -OR', -L-OR1, -O-L-OR1, -SH, -SR1, -NH2, -NHR1, -NR12, or-NR2R3.117. A compound according to any one of claims 114 to 116, wherein each -La-, if present, is independently -(CH2)2-, wherein n2 is independently 1 to 4.118. A compound according to any one of claims 114 to 116, wherein each -La-, if present, is independently -CH2-or -CH2CH2-.119. A compound according to any one of claims 114 to 118, wherein each -NRR3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C1alkyl, -CF3. and -F.120, A compound according to any one of claims 114 to 118, wherein each -NR2R3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C13alkyl, -CF3, and -F.121. A compound according to any one of claims 114 to 120, wherein each -R1, if present, is independently: -R2, -R264, _R2B6, ...R2B7 _R2B8, _L2B_R2B4, _L2B_R286, _L2B_R287, or _L2B_R2B8.122 A compound according to any one of claims 114 to 120, wherein each -R1, if present, is independently: -R281, -R257, _R2B8, _L2B_R2B7, or _L2B_R2B8.123. A compound according to any one of claims 114 to 120, wherein each -R1, if present, is independently: -R2, -R287, or _L2B_R287.124. A compound according to any one of claims 114 to 123, wherein each -R286, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionally substituted.125. A compound according to any one of claims 114 to 123, wherein each R2B6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahyd rofuranyl, or tetrahydropyranyl, and is optionally substituted.126. A compound according to any one of claims 114 to 125, wherein each -R287, if present, is independently phenyl, and is optionally substituted.127. A compound according to anyone of claims 114 to 126, wherein each -R288, if present, is independently Cheteroaryl, and is optionally substituted.128. A compound according to any one of claims 114 to 126, wherein each R2B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyri midinyl, or pyridazinyl, and 129. A compound according to any one of claims 114 to 126, wherein each -R268, if present, is independently C9.10heteroaryl, and is optionally substituted.130. A compound according to any one of claims 114 to 126, wherein each -R288, if present, is independently benzofuranyl, benzothienyl, benzopyrrolyl, benzoimidazolyl, benzopyrazofyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzopyridyl, benzopyrimidinyl, or benzopyridazinyt, and is optionally substituted.131. A compound according to any one of claims 114 to 130, wherein each L2B, if present, is independently -OH2-or -CH2CH2-.132. A compound according to any one of claims 114 to 130, wherein each L2B, if present, is independently -CH2-.133. A compound according to any one of claims 114 to 132, wherein each R2d1, if present, is independently saturated aliphatic C1.4alkyl.134. A compound according to any one of claims 114 to 133, wherein each R2c2 is independently: -F, -Cl, -Br, -I, -OH, -CN, -NO2, -NH2, -NHR201, -NR22, or NR2D2R2D3.135. A compound according to any one of claims 114 to 134, wherein each R2D, if present, is independently saturated aliphatic C1.4alkyl.136. A compound according to any one of claims 114 to 135, wherein each L2D, if present, is independently (CH2)m2, wherein m2 is independently 1 to 4.137. A compound according to any one of claims 114 to 135, wherein each L2D, if present, is independently -CH2-or -CH2CH2-.138. A compound according to any one of claims 114 to 137, wherein each -NR202R203, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, azepino, or diazepino, and is optionally substituted with one or more groups selected from C14alkyl, -CF3, and -F.-113- 139. A compound according to any one of claims 114 to 137, wherein each NR2D2R2D3, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more groups selected from C13a1ky1, -CF3, and -F.140. A compound according to any one of claims 1 to 113, wherein each -R'2 is independently: Rx2, -F, -Cl, -Br, -I, -OH, -OR, -NH2, -NHR, NRx22, or -OC(=O)R; wherein each -R' is independently saturated aliphatic C1alkyl.141. A compound as defined in any one of claims ito 140, for use in a method of treatment or prophylaxis of a neurodegenerative disease or disorder.142. A compound as defined in any one of claims 1 to 140, for use in a method of treatment or prophylaxis of a disease or disorder in which dopaminergic neurons are destroyed.143. A compound as defined in any one of claims 1 to 140, for use in a method of treatment or prophylaxis of a disease or disorder involving deleterious activation of microglia.144. A compound as defined in any one of claims 1 to 140, for use in a method of treatment or prophylaxis of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzhein,er's disease (AD), multiple sclerosis (MS), or Huntington's disease (HD). ** *145. Use of a compound as defined in any one of claims 1 to 140 in the manufacture of a medicament for the treatment of neurodegeneration.146. Use of a compound as defined in any one of claims 1 to 140 in the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder.147. Use of a compound as defined in any one of claims 1 to 140 in the manufacture of a medicament for the treatment of a disease or disorder in which dopaminergic neurons are destroyed.148. Use of a compound as defined in any one of claims 1 to 140 in the manufacture of a medicament for the treatment of a disease or disorder involving deleterious activation of microglia.149. Use of a compound as defined in any one of claims 1 to 140 in the manufacture of a medicament for the treatment of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS), or Huntington's disease (HD).150. A method of treatment of neurodegeneration comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound as defined in any one of claims 1 to 140.151. A method of treatment of a neurodegenerative disease or disorder comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound as defined in any one of claims 1 to 140.152. A method of treatment of a disease or disorder in which dopaminergic neurons are destroyed comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound as defined in any one of claims 1 to 140.153. A method of treatment of a disease or disorder involving deleterious activation of microglia comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound as defined in any one of claims I to 140.154. A method of treatment of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS), or Huntington's disease (HD) comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound as defined in any one of claims 1 to 140.155. A method of reducing or preventing the destruction of dopaminergic neurons in a subject, comprising administering to the subject a therapeutically effective amount of a compound as defined in any one of claims 1 to 140.156. A method of reducing or preventing deleterious effects of microglia activation in a subject, comprising administering to the subject a therapeutically effective amount of a compound as defined in any one of claims 1 to 140.157. A method of neuroprotection of a subject, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound as defined in any one of claims 1 to 140.158 A compound, as defined in any one of claims 1 to 140, for use as a neuroprotective.159. Use of a compound as defined in anyone of claims ito 140 in the manufacture of neuroprotective medicament.160. A compound as defined in any one of claims ito 140.161. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 140, and a pharmaceutically acceptable carrier or diluent.162. A method of preparing a pharmaceutical composition comprising the step of admixing a compound as defined in any one of claims 1 to 140, and a pharmaceutically acceptable carrier or diluent.