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WO2024170772A1 - Epigallocatechin-3-gallate (egcg) analogs for use in the treatment of diseases in which an increase of nad+ is beneficial such as glaucoma - Google Patents

Epigallocatechin-3-gallate (egcg) analogs for use in the treatment of diseases in which an increase of nad+ is beneficial such as glaucoma Download PDF

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Publication number
WO2024170772A1
WO2024170772A1 PCT/EP2024/054065 EP2024054065W WO2024170772A1 WO 2024170772 A1 WO2024170772 A1 WO 2024170772A1 EP 2024054065 W EP2024054065 W EP 2024054065W WO 2024170772 A1 WO2024170772 A1 WO 2024170772A1
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WO
WIPO (PCT)
Prior art keywords
fluoro
benzo
oxazin
methyl
phenyl
Prior art date
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PCT/EP2024/054065
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French (fr)
Inventor
Pete WILLIAMS
Andrea Brancale
Carmine VARRICCHIO
Melissa Isabella JÖE
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Mim Neurosciences Ab
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Filing date
Publication date
Priority claimed from GBGB2302306.2A external-priority patent/GB202302306D0/en
Priority claimed from GBGB2305880.3A external-priority patent/GB202305880D0/en
Application filed by Mim Neurosciences Ab filed Critical Mim Neurosciences Ab
Publication of WO2024170772A1 publication Critical patent/WO2024170772A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to novel compounds, compositions comprising such compounds, and the use of such compounds and compositions in medicine.
  • the present invention relates to the use of such compounds and compositions in methods for the treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD + is beneficial, such as those associated with a decline in NAD + .
  • the present invention may relate to the use of such compounds and compositions in methods for the treatment and/or prevention of ophthalmic diseases, such as glaucoma.
  • Nicotinamide adenine dinucleotide the cell’s hydrogen carrier for redox enzymes, is an important coenzyme that regulates various metabolic pathways, including glycolysis, ⁇ -oxidation, and oxidative phosphorylation. It is an essential cofactor that mediates various redox reactions through the transfer of electrons between NAD + (oxidized form of NAD) and NADH (reduced form of NAD).
  • NAD + serves as a substrate for poly(ADP-ribose) polymerase (PARP), sirtuin, and NAD glycohydrolase (CD38 and CD157), as well as regulating DNA repair, gene expression, energy metabolism, and stress responses (see, for example, Yaku et al. Sci. Rep. 2019, 9, p. 13102; Verdin E. Science 2015, 350(6265), p. 1208; Covarrubias A. J. et al. Nat. Rev. Mol. Cell Biol. 2021, 22, p. 119; Coleman M. P. et al. Nat. Rev. Neurosci. 2020, 21, p. 183).
  • NAD was first described in 1906 as a cell component that enhanced alcohol fermentation.
  • NAD + is one of the most abundant molecules in the human body, required for approximately 500 different enzymatic reactions. NAD + is in a constant state of synthesis, degradation, and recycling, not only in the cytoplasm but also within major organelles including the nucleus, Golgi apparatus, and peroxisomes. As a result, the concentration and distribution of NAD + and its metabolites are different depending on the cell compartment and change in response to physiological stimuli and cellular stress.
  • NAD + has two main pools, the “free” pool and the protein-associated “bound” pool, and the ratio of these pools varies across different organelles, cell types, tissues and even the age of individuals. There is also evidence that there are rapid, local fluctuations of NAD + (see, for example, Rajman et al.; vide supra). With the exception of neurons, mammalian cells cannot import NAD + , so they must synthesize it either de novo by the kynurenine pathway from tryptophan (trp), or forms of vitamin B 3 such as nicotinamide (NAM) or nicotinic acid (NA). To maintain NAD + levels, most NAD + is recycled via salvage pathways rather than generated de novo.
  • trp tryptophan
  • NAM nicotinamide
  • NA nicotinic acid
  • NAD + is salvaged from NAM, the product of cyclic ADP ribose hydrolase (CD38) and poly (ADP-ribose) polymerase (PARPs) or from the various forms of niacin taken up in the diet including NAM, NA, NR (nicotinamide riboside), and nicotinamide mononucleotide (NMN)
  • NAM cyclic ADP ribose hydrolase
  • PARPs poly (ADP-ribose) polymerase
  • NAD production in neurons is primarily controlled through two terminal enzymes: NMNAT1 (localized to the nucleus) and NMNAT2 (localized in the cytoplasm/Golgi).
  • NMNAT2 is emerging as an extremely important NAD producing enzyme in axons, protecting from axon degeneration. Protein expression of NMNAT2 is exclusive to neurons, reflecting that >99% of neuronal volume is accounted for by the axoplasm. NMNAT2 activity is necessary for axonal survival, particularly through axonal production of NAD, and is integral to protection against axon degeneration (see, for example, Mayer et al. J. Biol. Chem. 2010, 285(51), p. 40387).
  • NAD + synthesis in mammals is largely determined by the first step in the salvage pathway that converts NAM to NMN, which, in mammals, is carried out by nicotinamide phosphoribosyltransferase (NAMPT) (see, for example, Nikiforov et al. vide supra).
  • NAMPT nicotinamide phosphoribosyltransferase
  • Many studies have demonstrated that NAD + levels (or NAD + generating capacity, or capacity to maintain or replenish NAD + levels) decrease with aging in various tissues of rodents and humans, and the decline of NAD levels is involved in the pathogenesis of aging-related diseases, such as obesity, diabetes, and Alzheimer’s disease (see, for example, Katsyuba et al. EMBO J. 2017, 36, p.
  • a compound of formula In is provided: .
  • a compound of the invention as hereinbefore defined, in the manufacture of a medicament for use in the treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD + is beneficial.
  • a method of treating and/or preventing a disease, disorder and/or condition in which an increase of NAD + is beneficial comprising administering to a patient in need thereof (i.e.
  • references herein to compounds of particular aspects of the invention will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention. Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skill in the art to which this invention pertains.
  • a disease, disorder and/or condition in which an increase of NAD + is beneficial may also refer to a disease, disorder and/or condition associated with a decline in NAD + levels. This further includes a disease, disorder and/or condition in which elevating NAD + may be beneficial. This further includes a disease, disorder and/or condition in which the activity of NMNAT2 is/has declining/declined, and/or in which increasing the activity of NMNAT2 may be beneficial.
  • NMNAT2 refers to the NAD + biosynthetic enzyme nicotinamide monoucleotide adenylyltransferase 2.
  • this further includes a disease, disorder and/or condition in which mitochondrial dysfunction occurs and/or in which adenosine triphosphate (ATP) is depleted.
  • a disease, disorder and/or condition in which an increase of NAD + is beneficial include those in which low NAD + has been demonstrated, or in which mutations to genes in the pathways that generate NAD, protein alterations or modifications in the proteins in the pathways that generate NAD, or increased and/or decreased levels thereof have been demonstrated.
  • the levels of NAD + may have an effect on the liver function, kidney function, skeletal muscle function, cardiac function, endothelial and vascular function, DNA repair and cancer, immunity and inflammation, neuronal function, fertility and stem cell turnover, muscle function and muscle stem cell renewal, diabetes, pancreatic function and insulin control, control of fat content, low-density lipoprotein (LDL) and lipogenesis, and aging and longevity.
  • diseases, disorders and/or conditions in which an increase of NAD + is beneficial includes central nervous system diseases, peripheral nervous system diseases and/or aging diseases.
  • central nervous system diseases include addiction, Arachnoid cysts, attention deficit/hyperactivity disorder (ADHD), autism, brain tumours, catalepsy, encephalitis, epilepsy/seizures, infection, locked-in syndrome, meningitis, migraine, multiple sclerosis, myelopathy, Tourette’s, neurodegenerative disorders (e.g. Alzheimer’s, Huntington’s disease and other trinucleotide repeat disorders (e.g. cerebral ataxia, fragile x, Friedreich’s ataxia, SCA7 cerebral ataxia and associated diseases, and myotonic dystrophies), Parkinson’s disease, etc.), Bell’s palsy, cerebral palsy, epilepsy, motor neurone disease, and neurofibromatosis.
  • ADHD attention deficit/hyperactivity disorder
  • peripheral nervous system diseases include diseases of the endocrine system (e.g. diabetes and hypothyroidism), peripheral neuropathy (such as inherited and acquired optic neuropathies (e.g. Leber's hereditary optic neuropathy (LHOA), Leber's congenital amaurosis (LCA) and autosomal dominant optic atrophy (ADOA)), diseased that are caused by a virus (e.g. Guillain-Barre syndrome), conditions that compress nerves (e.g. carpal tunnel syndrome), autoimmune diseases and/or inflammatory diseases (e.g.
  • viruses such as shingles, cytomegalovirus, Epstein-Barr virus and human immunodeficiency virus (HIV)
  • kidney dysfunction e.g. where large amounts of toxins build up in the body and damage the peripheral nerves
  • cancers e.g. those that put pressure on surrounding nerves or tumours that arise directly from nerve tissue
  • chemotherapy and/or radiotherapy induced peripheral neuropathy or those due to exposure to toxins (e.g. medicine, industrial toxins, such as lead, mercury or arsenic, heavy alcohol consumption, etc.), physical injury (e.g. trauma, damage during surgery, or repetitive stress), genetical diseases (e.g.
  • aging diseases include aging-associated diseases or age-related diseases such as age-related macular degeneration (AMD; wet and dry), Alzheimer's disease, atherosclerosis, Benign Prostatic Hyperplasia (BPH), cancer, Parkinson's disease, stroke, progeroid syndromes, including diseases associated with aging (such as sensory changes (e.g.
  • aging diseases may also refer to aging itself or age-related processes, or age-related processes that may make cells susceptible to other stressors.
  • compounds of the invention may be of use in slowing (i.e. delaying) the aging process.
  • a disease, disorder and/or condition in which an increase of NAD + is beneficial includes mitochondrial diseases and/or diseases with strong mitochondrial components or those associated with mitochondrial dysfunction.
  • diseases may be Leber congenital amaurosis, Leber Hereditary Optic Neuropathy (LHON), autosomal dominant optic atrophy (ADOA, including ADOA plus), Leigh syndrome, etc.
  • a disease, disorder and/or condition in which an increase of NAD + is beneficial further includes ophthalmic diseases, heart diseases, type 2 diabetes, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, Charcot- Marie-Tooth disease, HIV neuropathy, peripheral neuropathies, neurodegenerative diseases, hair loss, cognitive diseases, skin diseases, severe acute neurodegenerative insults, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, Ischemic and other injuries, traumatic injuries, retinopathies (including retinopathy of prematurity), diabetic retinopathy, Wolfram’s syndrome, and accelerated aging (e.g. progeria).
  • ophthalmic diseases heart diseases, type 2 diabetes, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, Charcot- Marie-Tooth disease, HIV neuropathy, peripheral neuropathies, neurodegenerative diseases, hair loss, cognitive diseases, skin diseases, severe acute neurodegenerative insults, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, Ischemic and other injuries
  • ophthalmic diseases include age-related eye disorders, glaucoma, retinal degenerative diseases, age-related macular degeneration, diabetic retinopathy, Leber’s hereditary optic neuropathy, Leber’s congenital amaurosis, optic neuritis, autosomal dominant optic atrophy, Behr’s syndrome, optic trauma, optic nerve, optic chiasm, retina, or other visual tract damaged or compressed by tumour, and retinal detachment.
  • the disease, disorder and/or condition is glaucoma.
  • glaucoma includes open-angle glaucoma and angle-closure glaucoma, not limited to, but including normal-tension glaucoma or low tension glaucoma, and pseudoexfoliative glaucoma and acquired, secondary glaucoma.
  • causes for a decline in NAD + includes oxidative stress, decline in mitochondria production, age, genetic expression, DNA function, healthy inflammatory response, neuroinflammatory response, chemotherapy and/or radiotherapy, ocular medication, high intraocular pressure, neuro-trauma (e.g. optical nerve, orbital crush, traumatic brain injury, spinal cord injury, etc.) and use of steroid medication.
  • the disease, disorder and/or condition may be associated with a decline in ocular NAD + , retinal and optical nerve NAD + and, more particularly, retinal NAD + .
  • the compounds of the invention, and therefore compositions and kits comprising the same, as described herein, are useful as pharmaceuticals.
  • a compound of the invention, as hereinbefore defined i.e. a compound as defined in the first aspect of the invention, including all embodiments and particular features thereof), for use as a pharmaceutical (or for use in medicine).
  • references to compounds as defined in the first aspect of the invention will include references to compounds of formula I (including all embodiments thereof, such as compounds of formulae Ia to If, as defined hereinafter) and pharmaceutically acceptable salts thereof.
  • compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. “protected”) derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention.
  • Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the active compounds to which they are metabolised) may therefore be described as “prodrugs” of compounds of the invention.
  • references to prodrugs will include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time, following enteral or parenteral administration (e.g. oral or parenteral administration). All prodrugs of the compounds of the invention are included within the scope of the invention. Furthermore, certain compounds of the invention may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such. Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the active compounds of the invention to which they are metabolised), may also be described as “prodrugs”.
  • the present invention will also encompass prodrugs of compounds of the invention as known to those skilled in art (for example, where compounds of the invention contain one or more carboxylic acid, such acids may be present in the form of corresponding esters thereof).
  • compounds of the invention are therefore useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds that possess pharmacological activity.
  • compounds of the invention may be particularly useful in treating and/or preventing a disease, disorder and/or condition in which an increase of NAD + is beneficial.
  • references to the “treatment” of a particular condition (or, similarly, to treating that condition) will take their normal meanings in the field of medicine.
  • the terms may refer to achieving a reduction in the severity and/or frequency of occurrence of one or more clinical symptom associated with the condition, as adjudged by a physician attending a patient having or being susceptible to such symptoms.
  • prevention will include references to the prophylaxis of the disease or disorder (and vice-versa).
  • such term may refer to achieving a reduction (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction) in the likelihood of the patient (or healthy subject) developing the condition (which may be understood as meaning that the condition of the patient changes such that patient is diagnosed by a physician as having, e.g.
  • references to “prevention” may refer to reducing the likelihood that the patient will experience the effects of a disease, disorder and/or condition in which an increase of NAD + is beneficial and/or the likelihood to developing a disease, disorder and/or condition in which an increase of NAD + is beneficial.
  • references to “treating” may refer to reducing the severity of the effects of a disease, disorder and/or condition in which an increase of NAD + is beneficial.
  • references to a “patient” (or to “patients”) will refer to a living subject being treated, including mammalian (e.g.
  • references to a patient will refer to human patients.
  • references to “patients” (and thereof also to “subjects”) also should be considered to refer to individuals displaying no symptoms of the relevant condition, for whom compounds of the invention may be used as a preventative (as defined hereinbefore).
  • references to patients may also include references to animals, such as non-mammalian animals (e.g. birds) and, particularly, mammalian animals (e.g.
  • the treatment or prevention as described herein is performed in a human (such as an adult human).
  • a human such as an adult human
  • the skilled person will understand that such treatment or prevention will be performed in a patient (or subject) in need thereof.
  • the need of a patient (or subject) for such treatment or prevention may be assessed by those skilled the art using routine techniques.
  • treatment may include treatment of acute infections and/or preventative treatments.
  • the terms “disease” and “disorder” may be used interchangeably.
  • therapeutically effective amount will refer to an amount of a compound that confers a therapeutic effect on the patient (or subject) to which it is administered.
  • a therapeutic effect may be observed in a manner that is objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).
  • the effect may be observed (e.g. measured) in a manner that is objective, using appropriate tests as known to those skilled in the art.
  • Examples of such tests include quantification methods, such as chromatography coupled to mass spectrometry (e.g. LC–MS or UPLC-MS), fluorescence resonance energy transfer (FRET) probes, high-performance liquid chromatography, enzymatic assays, cycling assays or the use of bioluminescent biosensors.
  • quantification methods such as chromatography coupled to mass spectrometry (e.g. LC–MS or UPLC-MS), fluorescence resonance energy transfer (FRET) probes, high-performance liquid chromatography, enzymatic assays, cycling assays or the use of bioluminescent biosensors.
  • compounds of the invention may be defined as being those that possess an effect on the levels (e.g. provide, where possible, a detectable increase in the levels) of NAD + . More particularly, compounds of the invention may be able to increase the levels of NAD + , for example, as may be demonstrated, where possible, in the tests described herein (e.g. in the examples).
  • the term “increase of the levels of NAD + ” includes those that fully, and those that partially, increase the levels of NAD + and/or restore the levels of NAD + to baseline. It is to be understood that “baseline” may refer to individual normal baseline levels, such as levels at a normal, unstressed, or undiseased physiological state, e.g. levels at which the cellular homeostasis is maintained. Compounds of the invention may thus selectively increase the levels of NAD + . Compounds of the invention are, thus, expected to be useful in those conditions in which an increase of NAD + is desired or required as described hereinbefore, such as age-related eye disorders, in particular glaucoma. Pharmaceutical compositions As described herein, compounds of the invention are useful as pharmaceuticals.
  • Such compounds may be administered alone or may be administered by way of known pharmaceutical compositions/formulations.
  • a pharmaceutical formulation comprising a compound of the invention as defined herein, and optionally one or more pharmaceutically-acceptable excipient, for use in the treatment and/or prevention of a disease, disorder and/or condition in which increase of NAD + is beneficial (as defined herein).
  • a pharmaceutical composition comprising a compound of the invention as defined herein, and optionally one or more pharmaceutically-acceptable excipient.
  • the term pharmaceutically-acceptable excipients includes references to vehicles, adjuvants, carriers, encapsulating agents, diluents, pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like.
  • excipients may include adjuvants, diluents or carriers.
  • the pharmaceutical composition comprises at least one pharmaceutically-acceptable excipient.
  • a process for the preparation of a pharmaceutical formulation (which may also be referred to as a pharmaceutical composition), as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable excipient (e.g. adjuvant, diluent and/or carrier).
  • pharmaceutically-acceptable excipient e.g. adjuvant, diluent and/or carrier.
  • references herein to compounds of the invention being for particular uses (and, similarly, to uses and methods of use relating to compounds of the invention) may also apply to pharmaceutical compositions comprising compounds of the invention, as described herein.
  • compounds of the invention may act systemically and/or locally (i.e.
  • compositions as described herein will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • Pharmaceutical compositions as described herein will include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the pharmaceutical formulation is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection (e.g. intravitreal, periocular, sub-retinal, intracameral or intrascleral), suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical (e.g. ocular or corneal absorption) or intraocular (e.g. intraocular implant) administration.
  • a solid e.g. a solid dispersion
  • liquid e.g.
  • such formulations may also include slow-release formulations, which may comprise encapsulating agents.
  • the compound in the preparation of pharmaceutical formulations for oral administration, the compound may be mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or compressed into tablets.
  • solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g. compounds of the invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
  • active compounds e.g. compounds of the invention, and optionally additional therapeutic agents
  • hard gelatine capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g.
  • solutions or suspensions containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol.
  • liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials.
  • Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • the compound in the preparation of pharmaceutical formulations for topical administration, the compound may be mixed with suitable ingredients including alcohols, acids, thickeners, preservatives, salts, water, sugars, pH stabilizing agents, oils, surfactants, emulsifiers, etc.
  • suitable ingredients including alcohols, acids, thickeners, preservatives, salts, water, sugars, pH stabilizing agents, oils, surfactants, emulsifiers, etc.
  • suitable ocular administration system includes topical (e.g. conjunctival inserts (e.g. eye drops, emulsions), contact lenses, gels, nanoparticles, mucoadhesive polymers, ointments, solutions, suspensions) or intraocular (e.g. implants, nanoparticles, inserts) administration.
  • compositions that may be mentioned include those in which the active ingredient is present in an amount that is at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
  • compounds of the invention may be administered (for example, as formulations as described hereinabove) at varying doses, with suitable doses being readily determined by one of skill in the art.
  • Oral, pulmonary and topical dosages may range from between about 0.01 ⁇ g/kg of body weight per day ( ⁇ g/kg/day) to about 200 ⁇ g/kg/day.
  • treatment with such compounds may comprise administration of a formulation typically containing between about 0.01 ⁇ g to about 2000 mg of the active ingredient(s).
  • doses may range from between about 0.001 to about 10 ⁇ g/kg/hour during constant rate infusion.
  • treatment may comprise administration of such compounds and compositions in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily (e.g. twice daily with reference to the doses described herein).
  • the term “about” (or similar terms, such as “approximately”) will be understood as indicating that such values may vary by up to 10% (particularly, up to 5%, such as up to 1%) of the value defined. It is contemplated that, at each instance, such terms may be replaced with the notation “ ⁇ 10%”, or the like (or by indicating a variance of a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted. For the avoidance of doubt, the skilled person (e.g.
  • treatment with compounds of the invention may further comprise (i.e. be combined with) further treatment(s) or preventative methods for the same condition.
  • treatment with compounds of the invention may be combined with means for the treatment of a disease, disorder and/or condition in which the increase of NAD + is beneficial (such as those mentioned hereinbefore, e.g. glaucoma), such as treatment with one or more other therapeutic agent that is useful in the treatment or prevention of a disease, disorder and/or condition in which the increase of NAD + is beneficial and/or one or more physical method used in the treatment or prevention of a disease, disorder and/or condition in which the increase of NAD + is beneficial (such as treatment through surgery), as known to those skilled in the art.
  • compounds of the invention may also be combined with one or more other (i.e. different) therapeutic agents (i.e.
  • Such combination products that provide for the administration of a compound of the invention in conjunction with one or more other therapeutic agent may be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the one or more other therapeutic agent).
  • Therapeutic agents useful in the treatment and/or prevention of a disease, disorder and/or condition in which the increase of NAD + is beneficial include medications for central nervous system diseases, peripheral nervous system diseases and aging diseases, as defined hereinbefore, mitochondrial diseases and/or diseases with strong mitochondrial components or those associated with mitochondrial dysfunction.
  • Such therapeutic agents include those used in the treatment and/or prevention of diseases associated with liver function, kidney function, skeletal muscle function, cardiac function, endothelial and vascular function, DNA repair and cancer, immunity and inflammation, neuronal function, fertility and stem cell turnover, muscle function and muscle stem cell renewal, diabetes, pancreatic function and insulin control, control of fat content, low-density lipoprotein (LDL) and lipogenesis, and aging and longevity.
  • LDL low-density lipoprotein
  • Such therapeutic agents further include those used in the treatment and/or prevention of ophthalmic diseases, heart diseases, type 2 diabetes, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, Charcot-Marie-Tooth disease, HIV neuropathy, peripheral neuropathies, neurodegenerative diseases, hair loss, cognitive diseases, skin diseases, severe acute neurodegenerative insults, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, Ischemic and other injuries, traumatic injuries, retinopathies (including retinopathy of prematurity), diabetic retinopathy, Wolfram’s syndrome, and accelerated aging.
  • ophthalmic diseases heart diseases, type 2 diabetes, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, Charcot-Marie-Tooth disease, HIV neuropathy, peripheral neuropathies, neurodegenerative diseases, hair loss, cognitive diseases, skin diseases, severe acute neurodegenerative insults, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, Ischemic and other injuries, traumatic injuries, retinopathies (including
  • the active ingredients may be administered together in the same formulation, or administered separately (simultaneously or sequentially) in different formulations.
  • Such combination products provide for the administration of compounds of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combination product (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
  • a combination product i.e.
  • composition such as a pharmaceutical formulation
  • a composition comprising: (I) a compound of the invention, as hereinbefore defined (i.e. in the first aspect of the invention, including all embodiments and particular features thereof); and (II) one or more other therapeutic agent that is useful in the treatment and/or prevention of a disease, disorder and/or condition in which the increase of NAD + is beneficial (as described herein), wherein each of components (I) and (II) is formulated in admixture, optionally with one or more pharmaceutically-acceptable excipient.
  • a kit-of-parts comprising: (a) a pharmaceutical formulation as hereinbefore defined (i.e.
  • a process for the preparation of a kit-of-parts as hereinbefore defined which process comprises bringing into association components (a) and (b), as hereinbefore defined, with and at least one pharmaceutically-acceptable excipient.
  • references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.
  • a process for the preparation of a kit-of-parts as hereinbefore defined which process comprises bringing into association components (a) and (b).
  • references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.
  • kits-of-parts as hereinbefore defined, by bringing the two components “into association with” each other, we include that the two components of the kit-of-parts may be: (A) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or (B) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy.
  • kit of parts comprising: (i) one of components (a) and (b) as defined herein; together with (ii) instructions to use that component in conjunction with the other of the two components.
  • kits-of-parts described herein may comprise more than one formulation including an appropriate quantity/dose of a compound of the invention, and/or more than one formulation including an appropriate quantity/dose of the other therapeutic agent, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and/or physical form(s).
  • administration in conjunction with we include those respective formulations are administered, sequentially, separately or simultaneously, as part of a medical intervention directed towards treatment of the relevant condition.
  • the term “administration in conjunction with” includes that the two active ingredients (i.e. a compound of the invention and a further agent for the treatment and/or prevention of a disease, disorder and/or condition in which the increase of NAD + is beneficial, or compositions comprising the same) are administered (optionally repeatedly) either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment and/or prevention of the relevant condition, than if either agent is administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment and/or prevention.
  • the two active ingredients i.e. a compound of the invention and a further agent for the treatment and/or prevention of a disease, disorder and/or condition in which the increase of NAD + is beneficial, or compositions comprising the same
  • the two active ingredients i.e. a compound of the invention and a further agent for the treatment and/or prevention of a disease, disorder and/or condition in which the increase of NAD + is beneficial, or compositions
  • references to other therapeutic agents that are “useful” in a certain manner will refer to agents that are known to be suitable for use in that manner (e.g. agents commonly used for that purpose). Such references may therefore be replaced with references to agents “suitable for” the relevant purpose.
  • the term “in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration of the other component.
  • the terms “administered simultaneously” and “administered at the same time as” includes instances where the individual doses of the compound of the invention and the additional compound for the treatment of, e.g. cancer, or pharmaceutically acceptable salts thereof, are administered within 48 hours (e.g. within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other.
  • the terms “administered simultaneously” and “administered at the same time as” includes instances where the individual doses of the compound of the invention and the additional compound for the treatment of, e.g. eye diseases, are administered within 48 hours (e.g. within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes) and up to 3 months (e.g. 2 months, 1 month or 2 weeks) of each other.
  • Compounds of the invention include compounds of formula I, including all embodiments and particular features thereof, and pharmaceutically acceptable salts thereof.
  • Particular compounds of formula I include those in which R 1 , R 2 , R 3 and R 4 independently represent H, OH, F, Cl, NH2, -OMe or -C(O)Me; In particular embodiments that may be mentioned, R 1 , R 2 , R 3 and R 4 independently represent H or F. In more particular embodiments that may be mentioned, R 1 , R 2 , R 3 and R 4 each represent H.
  • R 1 , R 2 , R 3 and R 4 independently represent H, OH, F, Cl, NH2, -OMe or -C(O)Me;
  • R 8b represents H, -CH2-[C(O)-(4-methoxyphenyl)], -CH2-[C(O)-(4-fluorophen
  • R 5 and R 6 independently represent H, methyl or phenyl
  • R 1 , R 2 , R 3 and R 4 independently represent H, F or NH2 (e.g. H or F, such as H)
  • each R 8b independently represents H, methyl, -CH 2 -[C(O)(4-methoxyphenyl)], -CH 2 - [C(O)(4-fluorophenyl)], -CH2-[(5-methanol)-2-furyl], 2-hydroxyethyl, -C(O)-CH2- cyclopentoxy, -C(O)-N(H)-(4-flurorophenyl), -C(O)-(3-fluorophenyl), -CH2-(4- fluorobenzyl) or -CH 2 -[C(O)-(4-cyanophenyl)];
  • ma and mc independently represent 0 or 1;
  • R 9a and R 9c independently represent H,
  • R 5 and R 6 independently represent H, methyl or phenyl
  • R 1 , R 2 , R 3 and R 4 independently represent H, F or NH 2 (e.g.
  • each R 8b independently represents H, methyl, -CH2-[C(O)(4-methoxyphenyl)], -CH2- [C(O)(4-fluorophenyl)], -CH2-[(5-methanol)-2-furyl], 2-hydroxyethyl, -C(O)-CH2- cyclopentoxy, -C(O)-N(H)-(4-flurorophenyl), -C(O)-(3-fluorophenyl), -CH 2 -(4- fluorobenzyl) or -CH 2 -[C(O)-(4-cyanophenyl)];
  • ma and mc both represent 0;
  • R 9a and R 9c independently represent H; and each R 9g independently represents H, methyl, phenyl, -CH 2 -[C(O)(NH)(2- chlorobenzyl)], -CH2-[C(O)(NH)(benzyl
  • particular compounds of formula I include those in which X represents –CH 2 -, and q represents 1, thereby providing a compound of formula Ib, or a pharmaceutically acceptable salt thereof, such as wherein: Y represents -NH- or -O-; R 1 , R 2 , R 3 and R 4 independently represent H, F, Cl, -OH, -OMe, -C(O)Me or NH2 (e.g.
  • H or F such as H
  • n 0 or 1
  • Z represents -CH2-,–C(H)-[OC(O)(3,4,5-trihydroxybenzoyl)]-, -C(H)-(phenyl), - [C(H)(tertbutyl)]- or -[C(H)(OH)]-, such as -CH 2 -, –C(H)-[OC(O)(3,4,5- trihydroxybenzoyl)]-, -[C(H)(tertbutyl)]- or -[C(H)(OH)]-; and R 5 and R 6 independently represent H, methyl, phenyl, 3,4-dihydroxyphenyl, 3,4,5- trihydroxyphenyl, -C(O)OEt or 3,4-dimethoxyphenyl.
  • R 1 , R 2 , R 3 and R 4 independently represent H, F, OH, or NH 2 (e.g.
  • H or F such as H
  • q represents 0 or 1
  • R 5 and R 6 independently represent H, methyl, phenyl or 4-methoxyphenyl (e.g. H, methyl or phenyl).
  • R 1 , R 2 , R 3 and R 4 independently represent H, -OH or F (e.g.
  • R 1 , R 2 , R 3 and R 4 independently represent H or F (e.g. H); each R 8b individually represents H, C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo or aryl optionally substituted with -CF3 (e.g.
  • R 5 and R 6 individually represent H, methyl, cyclohexyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of halo (e.g. F or Cl), -CN, -OR 7a (e.g. methoxy, ethoxy or isopropoxy) or C 1-3 alkyl (e.g.
  • R 5 and R 6 individually represent H, methyl, or phenyl
  • Z represents -CH2- or –C(H)(phenyl)-.
  • More particular compounds of formula I that may be mentioned include those in which X and Y each represent -N(R 8b )-, and n and q individually represent 1, thereby providing a compound of formula Ie, or a pharmaceutically acceptable salt thereof, such as wherein: R 1 , R 2 , R 3 and R 4 independently represent H or F (e.g.
  • each R 8b individually represent H or methyl;
  • R 5 and R 6 individually represent H, methyl or phenyl;
  • Z represents -CH2- or –C(H)(phenyl)-.
  • particular compounds of formula I that may be mentioned include those in which q represents 0, and n represents 1, thereby providing a compound of formula If, or a pharmaceutically acceptable salt thereof, such as wherein: R 1 , R 2 , R 3 and R 4 independently represent H, F or -OH (e.g.
  • R 1 , R 2 , R 3 and R 4 independently represent H or F (e.g. H); ma and mc represent 0; R 8b represents H or -(2-hydroxyethyl); R 9g represents H; and/or R 5 and R 6 independently represent H, methyl or phenyl.
  • compounds of formula Ib that may be mentioned include those wherein: R 1 , R 2 , R 3 and R 4 independently represent H, F, NH2 or -OH (e.g. H or F, such as H); Y represents -O- or -N(H)-; n represents 0 or 1; Z represents –CH 2 -, -C(H)(OH)-, -C(H)(OC(O)(3,4,5-trihydroxyphenyl))- or – C(H)(tertbutyl)-; and/or R 5 and R 6 independently represent H, methyl, phenyl or (3,4-dihydroxyphenyl), (3,4,5- trihydroxyphenyl).
  • R 1 , R 2 , R 3 and R 4 independently represent H, F, NH2 or -OH (e.g. H or F, such as H); Y represents -O- or -N(H)-; n represents 0 or 1; Z represents –CH 2 -, -C
  • compounds of formula Ie that may be mentioned include those wherein: R 1 , R 2 , R 3 and R 4 independently represent H or F (e.g. H); Z represents –CH 2 -; and/or R 8b independently represent H or methyl.
  • compounds of formula If that may be mentioned include those wherein: R 1 , R 2 , R 3 and R 4 independently represent H or F (e.g. H); Z represents -CH 2 -; R 5 represents H; X represents -O-; and Y represents C(H).
  • compounds of formula Ia that may be mentioned include those wherein: R 5 and R 6 independently represent H or phenyl; R 1 , R 2 , R 3 and R 4 independently represent H or F; R 8b represents H; both ma and mc represent 0; both R 9g represent H.
  • compounds of formula Ie that may be mentioned include those wherein: R 1 , R 2 , R 3 and R 4 independently represent H or F; R 8b represents H; R 5 and R 6 individually represent H or phenyl optionally substituted with a F atom (e.g. 4-fluorophenyl); Z represents -CH 2 -.
  • compounds of formula Ib that may be mentioned include those wherein: Y represents -NH-; R 1 , R 2 , R 3 and R 4 independently represent H or F; n Represents 1; Z represents -C(H)-(phenyl); both R 5 and R 6 represent H.
  • Particular compounds of the invention that may be mentioned include those compounds as described in the examples provided herein, and pharmaceutically acceptable salts thereof.
  • compounds of the invention include those compounds in non-salt form and in the form of any pharmaceutically acceptable salt thereof (which may include the salt form present in such examples).
  • particular compounds of the invention include: 2,2-dimethylchroman-7-ol, 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2-yl)benzonitrile, 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one, 6,8-difluorochroman-4-one, 7-chlorochroman-6-amine, 2-methyl-2,3-dihydrobenzofuran-5-ol, 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one, 2,2-dimethylchroman-6-amine, 7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one, 7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one, 7-hydroxy-4-methylchroman-2-one, 7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][
  • More particular compounds of the invention include: 2-methyl-2,3-dihydrobenzofuran-5-ol, 2,2-dimethylchroman-6-amine, 7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,8-difluoro-2H-chromene, 6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline, 3-(tert-butyl)-6-fluoro-1,2,3,4-tetrahydroquinoline, 2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanol, 6,7-difluoro-2-phenyl-3,4-dihydro-2H-
  • the compound for use according to the invention is selected from: 2,2-dimethylchroman-7-ol, 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2-yl)benzonitrile, 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one, 6,8-difluorochroman-4-one, 7-chlorochroman-6-amine, 2-methyl-2,3-dihydrobenzofuran-5-ol, 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one, 2,2-dimethylchroman-6-amine, 7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one, 7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one, 7-hydroxy-4-methylchroman-2-one, 7-fluoro-2-methyl-3,4-dihydro-2H-
  • a compound of formula I, Formula I or a pharmaceutically acceptable salt thereof wherein X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and q are as defined herein, with the proviso that the compound of formula I is not: 2,2-dimethylchroman-7-ol, 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2-yl)benzonitrile, 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one, 6,8-difluorochroman-4-one, 7-chlorochroman-6-amine, 2-methyl-2,3-dihydrobenzofuran-5-ol, 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one, 2,2-dimethylchroman-6-amine, 7-hydroxy-3-(2-methoxyphenyl)
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration).
  • Salts may also be prepared using techniques known to those skilled in the art, such as by exchanging a counter- ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Particular acid addition salts include those formed by reaction with corresponding acids, thus protonating the compound of the invention, to form carboxylate salts (e.g.
  • sulphonate salts e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxy-ethanesulphonate, 1- or 2- naphthalene-sulphonate or 1,5-naphthalene-disulphonate salts
  • Particular base addition salts include salts formed by reaction with corresponding bases, thus removing a proton from compounds of the invention, to form salts with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts.
  • compounds of the invention may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof, and may also exist as oils.
  • compounds of the invention may also exist in solution (i.e. in solution in a suitable solvent).
  • compounds of the invention may exist in aqueous solution, in which case compounds of the invention may exist in the form of hydrates thereof.
  • Compounds of the invention may contain double bonds and, unless otherwise indicated, may thus exist as E (ent ought) and Z (zusammen) geometric isomers about each individual double bond. Unless otherwise specified, all such isomers and mixtures thereof are included within the scope of the invention. Compounds of the invention may also exhibit tautomerism.
  • All tautomeric forms and mixtures thereof are included within the scope of the invention (particularly those of sufficient stability to allow for isolation thereof).
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism (i.e. existing in enantiomeric or diastereomeric forms).
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers i.e. enantiomers
  • the desired enantiomer or diastereoisomer may be obtained from appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution; for example, with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst, all of which methods and processes may be performed under conditions known to the skilled person. Unless otherwise specified, all stereoisomers and mixtures thereof are included within the scope of the invention.
  • C1-6alkyl groups (where 6 is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (e.g. forming a C 3 -cycloalkyl group).
  • such groups may also be part cyclic (so forming a C4-partial cycloalkyl group).
  • cycloalkyl groups that may be mentioned include cyclopropyl, cyclopentyl and cyclohexyl.
  • part cyclic alkyl groups (which may also be referred to as “part cycloalkyl” groups) that may be mentioned include cyclopropylmethyl.
  • such groups may also be multicyclic (e.g. bicyclic or tricyclic) and/or spirocyclic.
  • alkyl groups that may be mentioned include straight chain (i.e. not branched and/or cyclic) alkyl groups.
  • alkyl groups as described herein may also act as linker groups (i.e. groups joining two or more parts of the compound as described), in which case such groups may be referred to as “alkylene” groups, respectively.
  • linker groups i.e. groups joining two or more parts of the compound as described
  • groups may be referred to as “alkylene” groups, respectively.
  • heteroatoms will take their normal meaning as understood by one skilled in the art.
  • Particular heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen and sulfur (e.g. oxygen, nitrogen and sulfur, such as oxygen and nitrogen).
  • aryl may refer to C6-14 (e.g. C6-10) aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, be either wholly or partly aromatic.
  • C6-10 aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyl, and the like).
  • the point of attachment of substituents on aryl groups may be via any suitable carbon atom of the ring system.
  • aryl groups that may form part of compounds of the invention are those that are chemically obtainable, as known to those skilled in the art.
  • Particular aryl groups that may be mentioned include phenyl and naphthyl, such as phenyl.
  • references to heteroaryl (with may also be referred to as heteroaromatic) groups may refer to 5- to 14- (e.g. 5- to 10-) membered heteroaromatic groups containing one or more heteroatoms (such as one or more heteroatoms selected from oxygen, nitrogen and/or sulfur).
  • heteroaryl groups may comprise one, two, or three rings, of which at least one is aromatic.
  • heteroaryl/heteroaromatic groups may, where appropriate, be located on any suitable atom in the ring system, including a heteroatom (e.g. on a suitable N atom).
  • the point of attachment of heteroaryl/heteroaromatic groups may be via any atom in the ring system including (where appropriate) a heteroatom.
  • Bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which instances, the point of attachment of the polycyclic heteroaryl/heteroaromatic group may be via any ring including the benzene ring or the heteroaryl/heteroaromatic or heterocyclyl ring.
  • heteroaryl groups that may form part of compounds of the invention are those that are chemically obtainable, as known to those skilled in the art.
  • Various heteroaryl groups will be well- known to those skilled in the art, such as pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl
  • heteroaryl includes polycyclic (e.g. bicyclic) groups in which one ring is aromatic (and the other may or may not be aromatic).
  • heteroaryl groups that may be mentioned include groups such as benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole, 3,4-dihydrobenz[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4- tetrahydroquinolinyl, thiochromanyl and the like.
  • groups such as benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole, 3,4-dihydrobenz[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4- tetra
  • aromatic groups may be depicted as cyclic groups comprising therein a suitable number of double bonds to allow for aromaticity.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
  • the compounds of the invention also include deuterated compounds, i.e. compounds of the invention in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
  • aryl optionally substituted by one or more groups independently selected from halo, -CN, NO 2 , -OR 7a , and C 1-3 alkyl
  • substituents where possible may be positioned on the same or different atoms.
  • Such optional substituents may be present in any suitable number thereof (e.g. the relevant group may be substituted with one or more such substituents, such as one such substituent).
  • groups are referred to herein as being optionally substituted it is specifically contemplated that such optional substituents may be not present (i.e. references to such optional substituents may be removed), in which case the optionally substituted group may be referred to as being unsubstituted.
  • a dashed bond i.e. “- - -”, or the like
  • a bond dissected with a wavy line may indicate the bond forming the attachment of the relevant moiety to the core molecule (i.e. the compound of the compound of formula I to which the substituent is attached).
  • compounds of the invention that are the subject of this invention include those that are obtainable, i.e. those that may be prepared in a stable form. That is, compounds of the invention include those that are sufficiently robust to survive isolation, e.g. from a reaction mixture, to a useful degree of purity.
  • Novel compounds may be defined as compounds of formula I, including all embodiments and combinations of embodiments thereof. Particular such compounds of formula I (including all embodiments and features thereof) may be novel.
  • a compound of formula I or a pharmaceutically accpetable salt thereof.
  • compounds of formula I include those wherein X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and q are as defined hereinbefore, with the proviso that the compound of formula I is not selected from the list consisting of: 2,2-dimethylchroman-7-ol, 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2-yl)benzonitrile, 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one, 6,8-difluorochroman-4-one, 7-chlorochroman-6-amine, 2-methyl-2,3-dihydrobenzofuran-5-ol, 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one, 2,2-dimethylchroman-6-amine, 7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one
  • the compound of formula I is a compound of formula Ia, Ib, Ic or Ie (each of which is as hereinbefore defined, including all embodiments thereof).
  • the compound of formula I is a compound of formula Ie.
  • the compound of formula I is: 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine, 2-(6,8-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4- methoxyphenyl)ethenone, 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,8-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-phenyl-3,4
  • a process for the preparation of a combination product or kit-of-parts as hereinbefore defined comprises bringing into association a compound of the invention, as hereinbefore defined, with the other therapeutic agent that is useful in the treatment of the relevant disease or disorder, and at least one pharmaceutically-acceptable excipient.
  • references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.
  • the two components of the kit-of-parts may be: (i) provided as separate formulations (i.e.
  • the reaction may be performed under standard cross coupling reactions wherein X 1 is a suitable leaving group (e.g. a halogen group).
  • X 1 is a suitable leaving group (e.g. a halogen group).
  • This includes the presence of a catalytic amount of palladium catalyst (e.g. chloro(2-dicyclohexylphosphino-2 ⁇ ,4 ⁇ ,6 ⁇ -triisopropyl-1,1 ⁇ - biphenyl)[2-(2 ⁇ -amino-1,1 ⁇ -biphenyl)]palladium(II)), a suitable base (e.g. cesium carbonate), in a suitable solvent (e.g. 1,4-dioxane).
  • the reaction may be performed at above room temperature (e.g. 130 °C) and/or under microwave irradiation.
  • a compound of formula II may be prepared via the reaction of a compound of formula III with a compound of formula IV: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, Z, n and q are as defined hereinbefore.
  • the reaction may be carried out under standard etherification reactions including the presence of a suitable salt (e.g. potassium iodide), a suitable base (e.g. potassium carbonate), in a suitable solvent (e.g. dimethyl sulfoxide, dimethylformamide). The reaction may be carried out at room temperature.
  • a suitable salt e.g. potassium iodide
  • a suitable base e.g. potassium carbonate
  • a suitable solvent e.g. dimethyl sulfoxide, dimethylformamide
  • substituents as defined herein, and substituents thereon may be modified one or more times, after or during the processes described above for the preparation of compounds of the invention by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, dehydrogenations, alkylations, dealkylations, acylations, hydrolyses, esterifications, etherifications, halogenations and nitrations.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
  • protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be applied and removed in accordance with techniques that are well-known to those skilled in the art and as described hereinafter.
  • protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • the type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
  • the use of protecting groups is fully described in “Protective Groups in Organic Synthesis”, 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.
  • the compounds of the invention have properties rendering them particularly suitable for treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD + is beneficial, such as those associated with a decline in NAD + .
  • Compounds of the invention may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.
  • Figure 1A shows the distribution of NMNAT2 in the human retina.
  • Figure 1B shows NMNAT2 expression (scRNA-seq) in RGC, AC, BP, HZ, Rod, Cone, Astrocyte, Myeloid, Müller, RPE and vascular cells.
  • Figures 2A to 2C show that increasing NMNAT2 provides RGC neuroprotection, wherein figure 2A demonstrates the axotomy, figure 2B demonstrates the genetic depletion and figure 2C demonstrates the inducible OHT.
  • Figures 3A and 3B show that EGCG provides neuroprotection against RGC injury.
  • Figures 4A and 4B show that EGCG provides neuroprotection against human RGCs.
  • Figures 5A, 5B and 5C show that EGCG neuroprotection is NAD-dependent in the explant model.
  • Figures 6A and 6B show that EGCG neuroprotection is Nmnat2-dependent in the explant model.
  • Figures 7A, 7B and 7C show that EGCG provides neuroprotection against glaucoma.
  • Figures 8A and 8B show that whole green tea polyphenols provide neuroprotection.
  • Figures 9 to 12 show the NAD-boosting effect of molecules of formula I at 5 ⁇ M of the various molecules of formula I ( Figure 9), at 5 ⁇ M of the various molecules of formula I and 100 ⁇ M of nicotinamide (NAM) ( Figure 10), at 50 ⁇ M of the various molecules of formula I ( Figure 11) and at 50 ⁇ M of the various molecules of formula I and 100 ⁇ M of nicotinamide (NAM) ( Figure 12).
  • Figure 13 shows that EGCG neuroprotection is NAD-dependent in the explant model.
  • Figures 14 and 15 show the NAD-boosting effect of molecules of formula I at 0.5 ⁇ M ( Figure 14) and 5 ⁇ M (Figure 15).
  • Figure 16 shows the NAD-boosting effect of molecules of formula I at 50 ⁇ M of the various molecules of formula I.
  • Figure 17 shows the fold change mitochondrial potential, assessed with JC-1, in primary cortical mouse cells after 2-hour incubation with compounds at 5 and 50 ⁇ M.
  • Figures 18 to 20 show stability in human (Figure 18), rat (Figure 19) and mouse (Figure 20) liver microsomes (in vitro).
  • Figure 21 shows fraction unbound in human plasma.
  • Figure 22 shows plasma stability in human plasma over 4 hours.
  • Figure 23 shows fraction unbound in mouse plasma.
  • Figure 24 shows plasma stability in mouse plasma over 4 hours.
  • Figure 25 shows kinetic stability of the compounds of the invention.
  • Figure 26 shows apparent permeability constant in Caco-2 cells, apical to basolateral (A-B).
  • Figure 27 shows compounds incubated with mouse retina in retinal explant model over three days.
  • Figure 28 shows fold change in NAD in cortex (C), spleen (S), liver (L) and muscle (M) following 2 hour incubation with compounds of the invention at 50 ⁇ M.
  • C cortex
  • S spleen
  • L liver
  • M muscle
  • NMNAT2 expression in retinal ganglion cells The following experiment was performed in order to investigate the expression of NMNAT2 in various human cells.
  • the distribution of NMNAT2 in human retina was investigated. Human eyes were selected from the St. Erik Hospital histopathology archive, which houses eyes enucleated due to ocular disease (predominantly ocular tumor or glaucoma). The eyes selected had an ocular tumor that did not result in any obvious retinal structural deformation. Wax sections of 3 ⁇ m were cut from 12 existing paraffin embedded eyes.
  • NMNAT2 was most strongly stained within the ganglion cell layer (GCL) compared to the inner nuclear layer (INL) in the central retina.
  • GCL ganglion cell layer
  • INL inner nuclear layer
  • NMNAT2 staining was also present in other RGC relevant layers such as nerve fiber layers and inner plexiform layers.
  • retinal ganglion cells demonstrated the strongest average NMNAT2 expression compared to other retinal cells tested) and was detectable in >75% of RGCs.
  • the different retinal cells tested were neuronal (namely, Amacrine cells (‘AC’), Bipolar cells (‘BP’), Horizontal cells (‘HZ’), rod cells (‘Rod’) and cone cells (‘Cone’)) and non-neuronal (namely, Astrocyte, Myeloid, Müller, retinal pigment epithelium (‘RPE’) and Vascular epithelium) cells.
  • Biological Assay 2 Effect of hNMNAT2 gene therapy (hNMNAT2 GT) The following study was performed in order to investigate the effect of the levels of NMNAT2.
  • CMV cytomegalovirus
  • the transfection was successful with more than 90% yield for RGCs as was demonstrated by significant green fluorescent protein (GFP) expression in cell somas and axons. The expression remained robust even at 3 days ex vivo (‘3 DEV’).
  • EGCG provides neuroprotection against RGC injury This study was performed in order to study the effect of EGCG in RGC injury. In the retinal explant model, axotomy drove rapid loss of RGCs over 3 days in culture (3 days ex vivo; ‘3 DEV’ or ‘D3’).
  • EGCG Epigallocatechin gallate
  • Table 3A Condition Mean SD p-value when compared to D0 D0 59.22222222 5.867676682 D3 31.02777778 12.68394289 0.000585709 D3 EGCG 5 ⁇ M 52.83333334 5.836665714 0.087932236 D3 EGCG 20 ⁇ M 50.77222222 4.849990453 0.021599974 D3 EGCG 50 ⁇ M 55.92777778 5.936718759 0.356459454
  • Table 3B Condition Mean SD p-value when compared to D0 D0 10.99166667 0.435220249 D3 9.838888889 2.01134744 0.20001371 D3 EGCG 5 ⁇ M 10.80833333 0.490209703 0.508878515 D3 EGCG 20 ⁇ M 11.73611111 1.196913468 0.182708084 D3 EGCG 50 ⁇ M 11.14444445 1.679241451 0.833536795
  • Table 3C Condition Mean SD p-value when compared to
  • Soma diameters (‘RBPMS’; Figure 3D) and nuclear diameters (Figure 3E) were also less variable suggesting that EGCG-treated retinas had healthier surviving cells.
  • Table 4A Data is shown in Table 4A below, wherein ‘SD’ stands for standard deviation.
  • Table 4A Condition Mean SD p-value when compared to D0 D0 100 0 D7 39.36212133 14.91111499 0.007244858 D7 EGCG 50 ⁇ M 64.89484063 20.55918904 0.008879252 All results were normalized to ‘D0’ (i.e. control) to account for variation by person and by time from death. Significant loss of RGCs occurred by ‘D7’ (i.e. 7 days) and this was significantly less with EGCG treatment. This is demonstrated in Figure 4B. Data is shown in Table 4B below, wherein ‘SD’ stands for standard deviation.
  • EGCG neuroprotection is NAD-dependent in the explant model
  • FK866 FK866 hydrochloride hydrate, Sigma Aldrich Product number F8557, CAS Number:658084-64-1, which is a nicotinamide phosphoribosyltransferase (Nampt) inhibitor
  • Nampt nicotinamide phosphoribosyltransferase
  • FK866 alone had no significant effect on cell (as demonstrated using DAPI+; Figure 5B) or RGC (as seen using RBPMS; Figure 5C) survival at DEV 3 at the dose used (10 ⁇ M FK866).
  • mice were either wild-type (WT; 100% Nmnat2) or compound heterozygotes (Het; 25% Nmnat2). This is demonstrated in Figure 6A, wherein ‘d0’ refers to immediate and ‘d3’ refers to 3 days ex vivo.
  • EGCG treatment of Het mice returned the % loss to a level consistent with mice with higher Nmnat2 levels. This was consistent with evidence (see Biological Assay 9) that EGCG increased Nmnat2 activity to approximately 200% (i.e. the Het retinas which had 25% expression of Nmnat2 exhibited cell loss to the same degree as gtE mice which had 50% Nmnat2, since 25% Nmnat2 at 200% capacity was equivalent to 50% Nmnat2).
  • EGCG provided significant protection against RGC loss by day 14 of OHT. RGC loss was less variable with the higher EGCG dose.
  • Table 8A Condition Mean SD p-value when compared to D0 D0 59.22222222 5.867676682 D3 31.02777778 12.68394289 0.000585709 D3 EGCG 5 ⁇ M 52.83333334 5.836665714 0.087932236 D3 EGCG 50 ⁇ M 55.92777778 5.936718759 0.356459454 D3 GTP 0.1 ⁇ g 52.77777778 7.772935 0.136113885 D3 GTP 1 ⁇ g 51.27777778 3.165204342 0.015330534
  • Table 8B Condition Mean SD p-value when compared to D0 D0 103.5833333 8.114287811 D3 72.11111111 12.3727598 0.000395433 D 3 EGCG 5 ⁇ M 95 6.910539456 0.076806805 D 3 EGCG 50 ⁇ M 91.97222222 6.908462336 0.023539897 D 3 GTP 0.1 ⁇ g 91.47222222 8.191063334
  • One cortex hemisphere equals to one sample. This is demonstrated in Figure 9.
  • Data is shown in Table 9 below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples) and ‘Nic’ stands for Nicotinamide.
  • SD stands for standard deviation
  • Ctrl refers to the control sample (non-treated samples)
  • Nic stands for Nicotinamide.
  • Mean NAD fold change compared to non-treated samples (control), standard deviation and p-value from a two-sided t-test.
  • One cortex hemisphere equals to one sample. NAD values were quantified in a luminescence-based assay with dissociated cortical neurons from 10 to 12 weeks old C57BL/6J mice, treated with EGCG and compounds of Examples 1 to 63 at 5 ⁇ M for two hours. One cortex hemisphere equals a sample. Dissociated cortical neuronal suspension treated with EGCG and compounds of Examples 1 to 63 at 5 ⁇ M and nicotinamide at 100 ⁇ M for two hours. Mean NAD fold change compared to non-treated samples (control), standard deviation and p-value from a two-sided t-test. This is demonstrated in Figure 10.
  • One cortex hemisphere equals to one sample.
  • Dissociated cortical neuronal suspension treated with EGCG and compounds of Examples 1 to 63 at 50 ⁇ M for two hours.
  • Data is shown in Table 11 below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples) and ‘Nic’ stands for Nicotinamide.
  • One cortex hemisphere equals to one sample.
  • Data is shown in Table 12 below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples) and ‘Nic’ stands for Nicotinamide.
  • Cortical hemispheres were cut up into smaller pieces in 800 ⁇ L dispase. The cut-up cortical hemispheres were placed on a heating block at 37°C, 350 rpm for 30 min before dissociation by gentle trituration. The cell concentration of cortical cell suspensions was determined with a hemocytometer. Cell suspensions were diluted to 1 million cells/mL, and incubated with Examples 19, 20, 22 to 24, 27, 29, 51, 52 and 63 at 5 and 50 ⁇ M for 2 h at 37°C. In the last 30 mins of incubation, 200 ⁇ M JC-1 in DMSO was added to the samples to an end concentration of 2 ⁇ M.
  • the reaction is initiated by the addition of 1 mM NADPH.
  • a sample was withdrawn from the incubation and the reaction was terminated by the addition of cold acetonitrile.
  • the amount of parent compound remaining was analysed by LC-MS/MS. Results are demonstrated in figures 18 to 20. Data is shown in Table 15 (mouse liver microsome), Table 16 (human liver microsome) and Table 17 (rat liver microsome).
  • Table 16 MLM: t1/2 (in vitro, MLM: Clint (in MLM: E (in vitro) Compound min) vitro, NjL/min/mg) 23 6 232.2 0.88 63 25.1 55.3 0.63 69 20.4 68.12 0.68 71 42.2 32.86 0.51 73 10.8 128.52 0.8
  • the drug molecules at a concentration of 0.1, 1, and 10 ⁇ M are added to plasma and dialyzed against isotonic phosphate buffer (67 mM, pH 7.4). After dialysis, the drug concentration in the buffer and plasma was quantified by LC-MS/MS analysis. In parallel the stability of the drug molecule in plasma is determined by incubating drug- spiked plasma (0.1, 1, and 10 ⁇ M, respectively) at 37°C for 4 hours, meanwhile the control plasma sample was kept in the freezer. The concentration of the compound in both samples was quantified by LC-MS/MS analysis. Plasma amount: 50% of human plasma and 10% mouse plasma. The freeze plasma sample is replacing the standard curve.
  • LC-MS/MS system used consists of a Waters Acquity UPLC coupled to a Waters XEVO TQ-S micro mass spectrometer (electrospray ionization, ESI).
  • the test compounds were optimized on a Waters Acquity UPLC XEVO TQ-S micro system (Waters Corp.) operating in multiple reaction monitoring (MRM) mode with positive or negative electrospray ionization. Compounds were optimized by using the QuanOptimize software (Waters Corp.).
  • the Caco-2 filters were washed with prewarmed HBSS before the experiment, and thereafter the experiment was started by applying the donor solution on the apical or basolateral side.
  • the transport experiments were carried out at pH 7.4 in both the apical and basolateral chambers. 5 ⁇ M enalaprilat was used as membrane integrity control in each filter.
  • the apparent permeability coefficient (P app ) of enalaprilat for a tight monolayer has been determined to be ⁇ 1 x 10 -6 cm/s.
  • the experiments were performed at 37°C and with a stirring rate of 500 rpm.
  • the receiver compartment was sampled at 30 minutes, and at 30 minutes also a final sample from the donor chamber was taken to calculate the mass balance of the compound.
  • mice were euthanized by cervical dislocation, retinas dissected free in cold HBSS and flat mounted on cell culture inserts ganglion cell layer up. Retinas were removed from culture and fixed in 3.7% PFA at 3 days ex vivo for cell counts. Control eyes were processed immediately following enucleation. For cell counts, retinas were dissected following 1 hour of fixation. Media was changed on day 2 and fixed on day 3 with 3,7% PFA in PBS for 30 minutes. After fixation, the flat-mounted retinas were permeabilized with 0.1% Triton X-100 in PBS for 60 mins and blocked in 2% Bovine Serum Albumin (BSA) in Hanks’ Balanced Salts Solution (HBSS) for 60 mins in room temperature (RT).
  • BSA Bovine Serum Albumin
  • RNA-binding protein with multiple splicing (RBPMS) diluted in PBS at 2.56 ⁇ g/mL) was applied and maintained over three nights at 4°C, following five repeated washes for 10 mins.
  • the secondary antibody was applied and maintained for 4 hours in RT.
  • Retinas were washed 5 times for 10 mins before being labelled with 5 ⁇ g/mL nuclear Hoescht 33342 nuclear stain diluted in PBS.
  • the retinas were washed once in PBS before being mounted using Fluoromount-G and glass coverslip. Slides were sealed with nail varnish.
  • RGC density was assessed by counting RBPMS+ cells in the ganglion cell layer.

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Abstract

Described herein are compounds of formula (I) or a pharmaceutically-acceptable salt thereof, for use in the treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD+ is beneficial, wherein R1, R2, R3, R4, R5, R6, X, Y, Z, n and q have meanings provided in the description.

Description

COMPOUNDS FOR USE IN THE TREATMENT OF DISEASES IN WHICH AN INCREASE OF NAD+ IS BENEFICIAL Field of the Invention The present invention relates to novel compounds, compositions comprising such compounds, and the use of such compounds and compositions in medicine. In particular, the present invention relates to the use of such compounds and compositions in methods for the treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD+ is beneficial, such as those associated with a decline in NAD+. For example, the present invention may relate to the use of such compounds and compositions in methods for the treatment and/or prevention of ophthalmic diseases, such as glaucoma. Background of the Invention The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. Nicotinamide adenine dinucleotide (NAD), the cell’s hydrogen carrier for redox enzymes, is an important coenzyme that regulates various metabolic pathways, including glycolysis, ǃ-oxidation, and oxidative phosphorylation. It is an essential cofactor that mediates various redox reactions through the transfer of electrons between NAD+ (oxidized form of NAD) and NADH (reduced form of NAD). NAD+ serves as a substrate for poly(ADP-ribose) polymerase (PARP), sirtuin, and NAD glycohydrolase (CD38 and CD157), as well as regulating DNA repair, gene expression, energy metabolism, and stress responses (see, for example, Yaku et al. Sci. Rep. 2019, 9, p. 13102; Verdin E. Science 2015, 350(6265), p. 1208; Covarrubias A. J. et al. Nat. Rev. Mol. Cell Biol. 2021, 22, p. 119; Coleman M. P. et al. Nat. Rev. Neurosci. 2020, 21, p. 183). NAD was first described in 1906 as a cell component that enhanced alcohol fermentation. It was not until 1936 that it was shown that NAD is required for redox reactions (see, for example, Rajman et al. Cell Metab. 2018, 27(3), p. 529). NAD+ is one of the most abundant molecules in the human body, required for approximately 500 different enzymatic reactions. NAD+ is in a constant state of synthesis, degradation, and recycling, not only in the cytoplasm but also within major organelles including the nucleus, Golgi apparatus, and peroxisomes. As a result, the concentration and distribution of NAD+ and its metabolites are different depending on the cell compartment and change in response to physiological stimuli and cellular stress. NAD+ has two main pools, the “free” pool and the protein-associated “bound” pool, and the ratio of these pools varies across different organelles, cell types, tissues and even the age of individuals. There is also evidence that there are rapid, local fluctuations of NAD+ (see, for example, Rajman et al.; vide supra). With the exception of neurons, mammalian cells cannot import NAD+, so they must synthesize it either de novo by the kynurenine pathway from tryptophan (trp), or forms of vitamin B3 such as nicotinamide (NAM) or nicotinic acid (NA). To maintain NAD+ levels, most NAD+ is recycled via salvage pathways rather than generated de novo. The majority of NAD+ is salvaged from NAM, the product of cyclic ADP ribose hydrolase (CD38) and poly (ADP-ribose) polymerase (PARPs) or from the various forms of niacin taken up in the diet including NAM, NA, NR (nicotinamide riboside), and nicotinamide mononucleotide (NMN) (see, for example, Covarrubias et al. Nat. Rev. Mol. Cell. Biol. 2021, 22(2), p. 119). NAD production in neurons is primarily controlled through two terminal enzymes: NMNAT1 (localized to the nucleus) and NMNAT2 (localized in the cytoplasm/Golgi). NMNAT2 is emerging as an extremely important NAD producing enzyme in axons, protecting from axon degeneration. Protein expression of NMNAT2 is exclusive to neurons, reflecting that >99% of neuronal volume is accounted for by the axoplasm. NMNAT2 activity is necessary for axonal survival, particularly through axonal production of NAD, and is integral to protection against axon degeneration (see, for example, Mayer et al. J. Biol. Chem. 2010, 285(51), p. 40387). The rate of NAD+ synthesis in mammals is largely determined by the first step in the salvage pathway that converts NAM to NMN, which, in mammals, is carried out by nicotinamide phosphoribosyltransferase (NAMPT) (see, for example, Nikiforov et al. vide supra). Many studies have demonstrated that NAD+ levels (or NAD+ generating capacity, or capacity to maintain or replenish NAD+ levels) decrease with aging in various tissues of rodents and humans, and the decline of NAD levels is involved in the pathogenesis of aging-related diseases, such as obesity, diabetes, and Alzheimer’s disease (see, for example, Katsyuba et al. EMBO J. 2017, 36, p. 2670; Yoshino et al. Cell Metab. 2018, 27, p. 513). As the maintenance of adequate NAD+ biosynthesis is paramount for cell survival and function, three main approaches to increase NAD+ levels are supplementation with NAD+ precursors, activation of NAD biosynthetic enzymes, and inhibition of NAD+ degradation. Nevertheless, at present there remains a need for treatments for and/or means for the prevention of diseases, disorders and/or conditions associated with a decrease in NAD+ and therefore in which an increase of NAD+ is beneficial. Description of the Invention It has now surprisingly been found that compounds of formula I are suitable for use in the treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD+ is beneficial. New methods and medical uses In a first aspect of the invention, there is provided a compound of formula I
Figure imgf000004_0001
or a pharmaceutically-acceptable salt thereof, for use in the treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD+ is beneficial, wherein: R1, R2, R3 and R4 independently represent H, halo, -OR7a, -N(R8a)2, -C(O)C1-3alkyl, -CN, -C(O)OR7b or NO2; one or both of X and Y independently represents -[C(R9a)2]ma-O-, -[C(R9b)2]mb-S-, -[C(R9c)2]mc-N(R8b)-, or -[C(R9d)2]md-N=, wherein ma, mb, mc and md each represent 0, 1 or 2, and wherein the position of the carbon moiety indicates the point of attachment to the essential benzene ring, and, where applicable, the other of X and Y independently represents -[C(R9e)2]me-, -C(R9f)=, or -C(O)-, wherein me represents 1 or 2, and wherein the single bond in -C(R9f)= indicates the point of attachment to the essential benzene ring, with the proviso that the sum of ma, mb, mc, md and me, where present, is not greater than 2; n represents 0 or 1; wherein (a) when n represents 1, and (b) neither of X and Y represents -[C(R9d)2]md-N= or -C(R9f)=, then the dashed line represents an optional bond; when the dashed line does not represent a bond and X does not represent -[C(R9d)2]md-N= or -C(R9f)=, then Z represents -C(R9g)2- or -C(O)-, or when the dashed line represents a bond or X represents -[C(R9d)2]md-N= or -C(R9f)=, then Z represents -C(R9h)-, with the provisos that, when X represents -C(O)- then Z cannot represent -C(O)-, and when n represents 0, then X and Y do not both represent -[C(R9d)2]md-N=; q represents 1 or, when the dashed line represents a bond or Y represents -[C(R9d)2]md-N= or -C(R9f)=, q represents 0; R5 and R6 independently represent H, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN, NH2 or NO2, -C(O)OC1-3alkyl, or aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, CF3, -OR7a, NH2 or C1-3alkyl; q represents 0 or 1, with the proviso that when q represents 0, one of the dashed bonds may represent a bond; R7a and R7b independently represent H or C1-3alkyl; R8a and R8b independently represent H, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, -[C(R10a)2]saC(O)R11a, -[C(R10b)2]sbC(O)NHR11b, C1-3alkyl substituted by aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl optionally substituted with halo or OH, C1-3alkyl substituted by heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl optionally substituted with halo or OH, or C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2; sa and sb each represent 0, 1, 2 or 3; each R9, R9a, R9b, R9c, R9d, R9e, R9f, R9g and R9h independently represent H, halo, -OR7a, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or -N(R12)2, -OC(O)R13, -[C(R14)2]scC(O)N(R15)(R16), or aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; sc represents 0, 1 or 2; R10a and R10b independently represent H, halo, -OR7a, -CN or NO2, C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, or -C(O)-C1-3alkyl; R11a and R11b independently represent C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, C1-6alkoxy-C1-6alkyl, or aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; each R12 represents H, C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, or -C(O)-C1-3alkyl; R13 represents aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; each R14 represents H, halo, -OR7a, -CN or NO2, C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, or -C(O)-C1-3alkyl; and R15 and R16 independently represent H, C1-3alkyl optionally substituted by halo, -OR7a, -CN, NO2 or aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; or alternatively R15 and R16 together represent a -C4-6alkylene-group, thereby forming a ring optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2. In a particular embodiment of the invention, there is provided a compound of formula I
Figure imgf000008_0001
or a pharmaceutically-acceptable salt thereof, for use in the treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD+ is beneficial, wherein: R1, R2, R3 and R4 independently represent H, halo, -OR7a, -N(R8a)2, -C(O)C1-3alkyl, -CN, -C(O)OR7b or NO2; one or both of X and Y independently represents -[C(R9a)2]ma-O-, -[C(R9b)2]mb-S-, -[C(R9c)2]mc-N(R8b)-, or -[C(R9d)2]md-N=, wherein ma, mb, mc and md each represent 0, 1 or 2, and wherein the position of the carbon moiety indicates the point of attachment to the essential benzene ring, and, where applicable, the other of X and Y independently represents -[C(R9e)2]me-, -C(R9f)=, or -C(O)-, wherein me represents 1 or 2, and wherein the single bond in -C(R9f)= indicates the point of attachment to the essential benzene ring, with the proviso that the sum of ma, mb, mc, md and me, where present, is not greater than 2; n represents 0 or 1; wherein (a) when n represents 1, and (b) neither of X and Y represents -[C(R9d)2]md-N= or -C(R9f)=, then the dashed line represents an optional bond; when the dashed line does not represent a bond and X does not represent -[C(R9d)2]md-N= or -C(R9f)=, then Z represents -C(R9g)2- or -C(O)-, or when the dashed line represents a bond or X represents -[C(R9d)2]md-N= or -C(R9f)=, then Z represents -C(R9h)-, with the provisos that, when X represents -C(O)- then Z cannot represent -C(O)-, and when n represents 0, then X and Y do not both represent -[C(R9d)2]md-N=; q represents 1 or, when the dashed line represents a bond or Y represents -[C(R9d)2]md-N= or -C(R9f)=, q represents 0; R5 and R6 independently represent H, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, -C(O)OC1-3alkyl, or aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, CF3, -OR7a or C1-3alkyl; q represents 0 or 1, with the proviso that when q represents 0, one of the dashed bonds may represent a bond; R7a and R7b independently represent H or C1-3alkyl; R8a and R8b independently represent H, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, -[C(R10a)2]saC(O)R11a, -[C(R10b)2]sbC(O)NHR11b, C1-3alkyl substituted by aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl optionally substituted with halo or OH, C1-3alkyl substituted by heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl optionally substituted with halo or OH, or C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2; sa and sb each represent 0, 1, 2 or 3; each R9, R9a, R9b, R9c, R9d, R9e, R9f, R9g and R9h independently represent H, halo, -OR7a, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or -N(R12)2, -OC(O)R13, -[C(R14)2]scC(O)N(R15)(R16), or aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; sc represents 0, 1 or 2; R10a and R10b independently represent H, halo, -OR7a, -CN or NO2, C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, or -C(O)-C1-3alkyl; R11a and R11b independently represent C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, C1-6alkoxy-C1-6alkyl, or aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; each R12 represents H, C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, or -C(O)-C1-3alkyl; R13 represents aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; each R14 represents H, halo, -OR7a, -CN or NO2, C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, or -C(O)-C1-3alkyl; and R15 and R16 independently represent H, C1-3alkyl optionally substituted by halo, -OR7a, -CN, NO2 or aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; or alternatively R15 and R16 together represent a -C4-6alkylene-group, thereby forming a ring optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2. Unless specified otherwise, the aforementioned compounds of formula I (including pharmaceutically acceptable salts thereof) that are disclosed herein for use in the treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD+ is beneficial are referred to together hereinafter as “compounds of the invention”. For the avoidance of doubt, it is to be understood by the skilled person that when X and Y independently represent -[C(R9a)2]ma-O-, -[C(R9b)2]mb-S-, -[C(R9c)2]mc-N(R8b)-, or -[C(R9d)2]md-N=, then the terminal carbon moiety is bound to the essential benzene ring. For example, when X and Y independently represent -[C(R9c)2]mc-N(R8b)- or - [C(R9a)2]ma-O- and each R9c and R9a represents H, then the terminal “-(CH2)-” in each such moiety is bound to the essential benzene ring, thereby providing a portion of the compound of formula I corresponding to that shown in formulae Ig to Ij as appropriate:
Figure imgf000012_0001
For example, when n represents 0 and q represents 0, then compounds of formulae Il* and Il** are provided: . Further, when X represents -C(R9f)=, then a compound of formula Im is provided:
Figure imgf000013_0001
. For the avoidance of doubt, it is to be understood by the skilled person that when Y represents -C(R9f)=, then a compound of formula In is provided:
Figure imgf000013_0002
. According to a further aspect of the invention, there is provided the use of a compound of the invention, as hereinbefore defined, in the manufacture of a medicament for use in the treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD+ is beneficial. In a yet further aspect of the invention, there is provided a method of treating and/or preventing a disease, disorder and/or condition in which an increase of NAD+ is beneficial, comprising administering to a patient in need thereof (i.e. a patient in need of such treatment and/or prevention) a therapeutically effective amount of a compound of the invention, as herein defined. For the avoidance of doubt, the skilled person will understand that references herein to compounds of particular aspects of the invention (such as the first aspect of the invention, i.e. referring to compounds of formula I as defined in the first aspect of the invention) will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention. Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skill in the art to which this invention pertains. As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Throughout the specification and claims, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. For the avoidance of doubt, throughout the specification and claims, unless the context requires otherwise, the terms “NAD+”, “NADH”, and “NAD” may be used interchangeably. The skilled person will understand that “a disease, disorder and/or condition in which an increase of NAD+ is beneficial” may also refer to a disease, disorder and/or condition associated with a decline in NAD+ levels. This further includes a disease, disorder and/or condition in which elevating NAD+ may be beneficial. This further includes a disease, disorder and/or condition in which the activity of NMNAT2 is/has declining/declined, and/or in which increasing the activity of NMNAT2 may be beneficial. It is to be understood that “NMNAT2” refers to the NAD+ biosynthetic enzyme nicotinamide monoucleotide adenylyltransferase 2. For the avoidance of doubt, this further includes a disease, disorder and/or condition in which mitochondrial dysfunction occurs and/or in which adenosine triphosphate (ATP) is depleted. It is to be understood that “a disease, disorder and/or condition in which an increase of NAD+ is beneficial” include those in which low NAD+ has been demonstrated, or in which mutations to genes in the pathways that generate NAD, protein alterations or modifications in the proteins in the pathways that generate NAD, or increased and/or decreased levels thereof have been demonstrated. The levels of NAD+ may have an effect on the liver function, kidney function, skeletal muscle function, cardiac function, endothelial and vascular function, DNA repair and cancer, immunity and inflammation, neuronal function, fertility and stem cell turnover, muscle function and muscle stem cell renewal, diabetes, pancreatic function and insulin control, control of fat content, low-density lipoprotein (LDL) and lipogenesis, and aging and longevity. Examples of diseases, disorders and/or conditions in which an increase of NAD+ is beneficial, as defined herein, includes central nervous system diseases, peripheral nervous system diseases and/or aging diseases. Examples of central nervous system diseases include addiction, Arachnoid cysts, attention deficit/hyperactivity disorder (ADHD), autism, brain tumours, catalepsy, encephalitis, epilepsy/seizures, infection, locked-in syndrome, meningitis, migraine, multiple sclerosis, myelopathy, Tourette’s, neurodegenerative disorders (e.g. Alzheimer’s, Huntington’s disease and other trinucleotide repeat disorders (e.g. cerebral ataxia, fragile x, Friedreich’s ataxia, SCA7 cerebral ataxia and associated diseases, and myotonic dystrophies), Parkinson’s disease, etc.), Bell’s palsy, cerebral palsy, epilepsy, motor neurone disease, and neurofibromatosis. Examples of peripheral nervous system diseases include diseases of the endocrine system (e.g. diabetes and hypothyroidism), peripheral neuropathy (such as inherited and acquired optic neuropathies (e.g. Leber's hereditary optic neuropathy (LHOA), Leber's congenital amaurosis (LCA) and autosomal dominant optic atrophy (ADOA)), diseased that are caused by a virus (e.g. Guillain-Barre syndrome), conditions that compress nerves (e.g. carpal tunnel syndrome), autoimmune diseases and/or inflammatory diseases (e.g. rheumatoid arthritis and lupus), infections including viruses (such as shingles, cytomegalovirus, Epstein-Barr virus and human immunodeficiency virus (HIV)), kidney dysfunction (e.g. where large amounts of toxins build up in the body and damage the peripheral nerves), cancers (e.g. those that put pressure on surrounding nerves or tumours that arise directly from nerve tissue), chemotherapy and/or radiotherapy induced peripheral neuropathy, or those due to exposure to toxins (e.g. medicine, industrial toxins, such as lead, mercury or arsenic, heavy alcohol consumption, etc.), physical injury (e.g. trauma, damage during surgery, or repetitive stress), genetical diseases (e.g. born with peripheral nerve disorder), autonomic neuropathy, axillary nerve dysfunction, chronic inflammatory polyneuropathy, common peroneal nerve dysfunction, distal median nerve dysfunction, femoral nerve dysfunction, ganglioneuroma, glossopharyngeal neuralgia, hereditary neuropathies, hereditary spastic paraplegia, Isaac's syndrome, and paraesthesia. Examples of aging diseases include aging-associated diseases or age-related diseases such as age-related macular degeneration (AMD; wet and dry), Alzheimer's disease, atherosclerosis, Benign Prostatic Hyperplasia (BPH), cancer, Parkinson's disease, stroke, progeroid syndromes, including diseases associated with aging (such as sensory changes (e.g. hearing loss, visual acuity, vestibular function), muscle strength and fat changes, immunosenescence, urologic changes, somatic diseases and multiple chronic conditions (such as cardiovascular diseases, hypertension, cancer, osteoarthritis, diabetes mellitus, osteoporosis, multiple chronic conditions), physical function (such as walking speed, mobility disability, disability in activities of daily living, falls, frailty, continence), and psychological and cognitive (such as cognitive aging, dementia, depression)). For the avoidance of doubt, ‘aging diseases’ may also refer to aging itself or age-related processes, or age-related processes that may make cells susceptible to other stressors. Thus, compounds of the invention may be of use in slowing (i.e. delaying) the aging process. A disease, disorder and/or condition in which an increase of NAD+ is beneficial, as defined hereinbefore, includes mitochondrial diseases and/or diseases with strong mitochondrial components or those associated with mitochondrial dysfunction. Examples of such diseases may be Leber congenital amaurosis, Leber Hereditary Optic Neuropathy (LHON), autosomal dominant optic atrophy (ADOA, including ADOA plus), Leigh syndrome, etc. A disease, disorder and/or condition in which an increase of NAD+ is beneficial, as defined hereinbefore, further includes ophthalmic diseases, heart diseases, type 2 diabetes, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, Charcot- Marie-Tooth disease, HIV neuropathy, peripheral neuropathies, neurodegenerative diseases, hair loss, cognitive diseases, skin diseases, severe acute neurodegenerative insults, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, Ischemic and other injuries, traumatic injuries, retinopathies (including retinopathy of prematurity), diabetic retinopathy, Wolfram’s syndrome, and accelerated aging (e.g. progeria). Examples of ophthalmic diseases include age-related eye disorders, glaucoma, retinal degenerative diseases, age-related macular degeneration, diabetic retinopathy, Leber’s hereditary optic neuropathy, Leber’s congenital amaurosis, optic neuritis, autosomal dominant optic atrophy, Behr’s syndrome, optic trauma, optic nerve, optic chiasm, retina, or other visual tract damaged or compressed by tumour, and retinal detachment. In a particular embodiment, the disease, disorder and/or condition is glaucoma. It is to be understood that ‘glaucoma’ includes open-angle glaucoma and angle-closure glaucoma, not limited to, but including normal-tension glaucoma or low tension glaucoma, and pseudoexfoliative glaucoma and acquired, secondary glaucoma. Examples of causes for a decline in NAD+ includes oxidative stress, decline in mitochondria production, age, genetic expression, DNA function, healthy inflammatory response, neuroinflammatory response, chemotherapy and/or radiotherapy, ocular medication, high intraocular pressure, neuro-trauma (e.g. optical nerve, orbital crush, traumatic brain injury, spinal cord injury, etc.) and use of steroid medication. In certain embodiments, the disease, disorder and/or condition may be associated with a decline in ocular NAD+, retinal and optical nerve NAD+ and, more particularly, retinal NAD+. As indicated herein, the compounds of the invention, and therefore compositions and kits comprising the same, as described herein, are useful as pharmaceuticals. Thus, there is provided a compound of the invention, as hereinbefore defined (i.e. a compound as defined in the first aspect of the invention, including all embodiments and particular features thereof), for use as a pharmaceutical (or for use in medicine). For the avoidance of doubt, references to compounds as defined in the first aspect of the invention will include references to compounds of formula I (including all embodiments thereof, such as compounds of formulae Ia to If, as defined hereinafter) and pharmaceutically acceptable salts thereof. Although compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. “protected”) derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the active compounds to which they are metabolised) may therefore be described as “prodrugs” of compounds of the invention. As used herein, references to prodrugs will include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time, following enteral or parenteral administration (e.g. oral or parenteral administration). All prodrugs of the compounds of the invention are included within the scope of the invention. Furthermore, certain compounds of the invention may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such. Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the active compounds of the invention to which they are metabolised), may also be described as “prodrugs”. The skilled person will understand that the present invention will also encompass prodrugs of compounds of the invention as known to those skilled in art (for example, where compounds of the invention contain one or more carboxylic acid, such acids may be present in the form of corresponding esters thereof). For the avoidance of doubt, compounds of the invention are therefore useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds that possess pharmacological activity. As described herein, compounds of the invention may be particularly useful in treating and/or preventing a disease, disorder and/or condition in which an increase of NAD+ is beneficial. The skilled person will understand that references to the “treatment” of a particular condition (or, similarly, to treating that condition) will take their normal meanings in the field of medicine. In particular, the terms may refer to achieving a reduction in the severity and/or frequency of occurrence of one or more clinical symptom associated with the condition, as adjudged by a physician attending a patient having or being susceptible to such symptoms. As used herein, the term “prevention” (and, similarly, preventing) will include references to the prophylaxis of the disease or disorder (and vice-versa). In particular, such term may refer to achieving a reduction (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction) in the likelihood of the patient (or healthy subject) developing the condition (which may be understood as meaning that the condition of the patient changes such that patient is diagnosed by a physician as having, e.g. requiring treatment for, the relevant disease or disorder). For example, when used in relation to a disease, disorder and/or condition in which an increase of NAD+ is beneficial, references to “prevention” may refer to reducing the likelihood that the patient will experience the effects of a disease, disorder and/or condition in which an increase of NAD+ is beneficial and/or the likelihood to developing a disease, disorder and/or condition in which an increase of NAD+ is beneficial. Similarly, references to “treating” may refer to reducing the severity of the effects of a disease, disorder and/or condition in which an increase of NAD+ is beneficial. As used herein, references to a “patient” (or to “patients”) will refer to a living subject being treated, including mammalian (e.g. human) patients, and as such “patients” may also be referred to as “subjects”, and vice versa. In particular, references to a patient will refer to human patients. References to “patients” (and thereof also to “subjects”) also should be considered to refer to individuals displaying no symptoms of the relevant condition, for whom compounds of the invention may be used as a preventative (as defined hereinbefore). For the avoidance of doubt, references to patients may also include references to animals, such as non-mammalian animals (e.g. birds) and, particularly, mammalian animals (e.g. cats, dogs, rabbits, rodents, polecats, weasels, ferrets, badgers, horses, sheep, pigs, goats, cows, primates, and the like). In particular embodiments, the treatment or prevention as described herein is performed in a human (such as an adult human). For the avoidance of doubt, the skilled person will understand that such treatment or prevention will be performed in a patient (or subject) in need thereof. The need of a patient (or subject) for such treatment or prevention may be assessed by those skilled the art using routine techniques. The skilled person will understand that treatment may include treatment of acute infections and/or preventative treatments. As used herein, the terms “disease” and “disorder” (and, similarly, the terms condition, illness, medical problem, and the like) may be used interchangeably. As used herein, the term therapeutically effective amount (and similar terms such as effective amount and the like) will refer to an amount of a compound that confers a therapeutic effect on the patient (or subject) to which it is administered. A therapeutic effect may be observed in a manner that is objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect). In particular, the effect may be observed (e.g. measured) in a manner that is objective, using appropriate tests as known to those skilled in the art. Examples of such tests include quantification methods, such as chromatography coupled to mass spectrometry (e.g. LC–MS or UPLC-MS), fluorescence resonance energy transfer (FRET) probes, high-performance liquid chromatography, enzymatic assays, cycling assays or the use of bioluminescent biosensors. In particular embodiments, compounds of the invention may be defined as being those that possess an effect on the levels (e.g. provide, where possible, a detectable increase in the levels) of NAD+. More particularly, compounds of the invention may be able to increase the levels of NAD+, for example, as may be demonstrated, where possible, in the tests described herein (e.g. in the examples). The term “increase of the levels of NAD+” includes those that fully, and those that partially, increase the levels of NAD+ and/or restore the levels of NAD+ to baseline. It is to be understood that “baseline” may refer to individual normal baseline levels, such as levels at a normal, unstressed, or undiseased physiological state, e.g. levels at which the cellular homeostasis is maintained. Compounds of the invention may thus selectively increase the levels of NAD+. Compounds of the invention are, thus, expected to be useful in those conditions in which an increase of NAD+ is desired or required as described hereinbefore, such as age-related eye disorders, in particular glaucoma. Pharmaceutical compositions As described herein, compounds of the invention are useful as pharmaceuticals. Such compounds may be administered alone or may be administered by way of known pharmaceutical compositions/formulations. In a second aspect of the invention, there is provided a pharmaceutical formulation comprising a compound of the invention as defined herein, and optionally one or more pharmaceutically-acceptable excipient, for use in the treatment and/or prevention of a disease, disorder and/or condition in which increase of NAD+ is beneficial (as defined herein). In other aspects of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as defined herein, and optionally one or more pharmaceutically-acceptable excipient. As used herein, the term pharmaceutically-acceptable excipients includes references to vehicles, adjuvants, carriers, encapsulating agents, diluents, pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like. In particular, such excipients may include adjuvants, diluents or carriers. In a particular embodiment of the second aspect of the invention, the pharmaceutical composition comprises at least one pharmaceutically-acceptable excipient. In another aspect of the invention, there is also provided a process for the preparation of a pharmaceutical formulation (which may also be referred to as a pharmaceutical composition), as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable excipient (e.g. adjuvant, diluent and/or carrier). For the avoidance of doubt, references herein to compounds of the invention being for particular uses (and, similarly, to uses and methods of use relating to compounds of the invention) may also apply to pharmaceutical compositions comprising compounds of the invention, as described herein. The skilled person will understand that compounds of the invention may act systemically and/or locally (i.e. at a particular site), and may therefore be administered accordingly using suitable techniques known to those skilled in the art. The skilled person will understand that compounds and compositions as described herein will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form. Pharmaceutical compositions as described herein will include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. Thus, in particular embodiments, the pharmaceutical formulation is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection (e.g. intravitreal, periocular, sub-retinal, intracameral or intrascleral), suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical (e.g. ocular or corneal absorption) or intraocular (e.g. intraocular implant) administration. For the avoidance of doubt, in such embodiments, compounds of the invention may be present as a solid (e.g. a solid dispersion), liquid (e.g. in solution) or in other forms, such as in the form of micelles. For the avoidance of doubt, such formulations may also include slow-release formulations, which may comprise encapsulating agents. For example, in the preparation of pharmaceutical formulations for oral administration, the compound may be mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or compressed into tablets. Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g. compounds of the invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Similarly, hard gelatine capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration. Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use. For example, in the preparation of pharmaceutical formulations for topical administration, the compound may be mixed with suitable ingredients including alcohols, acids, thickeners, preservatives, salts, water, sugars, pH stabilizing agents, oils, surfactants, emulsifiers, etc. Examples of typical ocular administration system includes topical (e.g. conjunctival inserts (e.g. eye drops, emulsions), contact lenses, gels, nanoparticles, mucoadhesive polymers, ointments, solutions, suspensions) or intraocular (e.g. implants, nanoparticles, inserts) administration. Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in an amount that is at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight. The skilled person will understand that compounds of the invention may be administered (for example, as formulations as described hereinabove) at varying doses, with suitable doses being readily determined by one of skill in the art. Oral, pulmonary and topical dosages (and subcutaneous dosages, although these dosages may be relatively lower) may range from between about 0.01 μg/kg of body weight per day (μg/kg/day) to about 200 μg/kg/day. For example, when administered orally, treatment with such compounds may comprise administration of a formulation typically containing between about 0.01 μg to about 2000 mg of the active ingredient(s). When administered intravenously, doses may range from between about 0.001 to about 10 μg/kg/hour during constant rate infusion. Advantageously, treatment may comprise administration of such compounds and compositions in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily (e.g. twice daily with reference to the doses described herein). When used herein in relation to a specific value (such as an amount), the term “about” (or similar terms, such as “approximately”) will be understood as indicating that such values may vary by up to 10% (particularly, up to 5%, such as up to 1%) of the value defined. It is contemplated that, at each instance, such terms may be replaced with the notation “±10%”, or the like (or by indicating a variance of a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted. For the avoidance of doubt, the skilled person (e.g. the physician) will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. Although the above- mentioned dosages are exemplary of the average case, there can, of course, be individual instances where higher or lower dosage ranges are merited, and such doses are within the scope of the invention. Combinations and kits-of-parts The skilled person will understand that treatment with compounds of the invention may further comprise (i.e. be combined with) further treatment(s) or preventative methods for the same condition. In particular, treatment with compounds of the invention may be combined with means for the treatment of a disease, disorder and/or condition in which the increase of NAD+ is beneficial (such as those mentioned hereinbefore, e.g. glaucoma), such as treatment with one or more other therapeutic agent that is useful in the treatment or prevention of a disease, disorder and/or condition in which the increase of NAD+ is beneficial and/or one or more physical method used in the treatment or prevention of a disease, disorder and/or condition in which the increase of NAD+ is beneficial (such as treatment through surgery), as known to those skilled in the art. As described herein, compounds of the invention may also be combined with one or more other (i.e. different) therapeutic agents (i.e. agents that are not compounds of the invention) that are useful in the treatment and/or prevention of a disease, disorder and/or condition in which the increase of NAD+ is beneficial. Such combination products that provide for the administration of a compound of the invention in conjunction with one or more other therapeutic agent may be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the one or more other therapeutic agent). Therapeutic agents useful in the treatment and/or prevention of a disease, disorder and/or condition in which the increase of NAD+ is beneficial include medications for central nervous system diseases, peripheral nervous system diseases and aging diseases, as defined hereinbefore, mitochondrial diseases and/or diseases with strong mitochondrial components or those associated with mitochondrial dysfunction. Such therapeutic agents include those used in the treatment and/or prevention of diseases associated with liver function, kidney function, skeletal muscle function, cardiac function, endothelial and vascular function, DNA repair and cancer, immunity and inflammation, neuronal function, fertility and stem cell turnover, muscle function and muscle stem cell renewal, diabetes, pancreatic function and insulin control, control of fat content, low-density lipoprotein (LDL) and lipogenesis, and aging and longevity. Such therapeutic agents further include those used in the treatment and/or prevention of ophthalmic diseases, heart diseases, type 2 diabetes, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, Charcot-Marie-Tooth disease, HIV neuropathy, peripheral neuropathies, neurodegenerative diseases, hair loss, cognitive diseases, skin diseases, severe acute neurodegenerative insults, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, Ischemic and other injuries, traumatic injuries, retinopathies (including retinopathy of prematurity), diabetic retinopathy, Wolfram’s syndrome, and accelerated aging. When compounds of the invention are “combined” with other therapeutic agents in the aforementioned, the active ingredients may be administered together in the same formulation, or administered separately (simultaneously or sequentially) in different formulations. Such combination products provide for the administration of compounds of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combination product (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent). Thus, according to another aspect of the invention, there is provided a combination product (i.e. a composition, such as a pharmaceutical formulation) comprising: (I) a compound of the invention, as hereinbefore defined (i.e. in the first aspect of the invention, including all embodiments and particular features thereof); and (II) one or more other therapeutic agent that is useful in the treatment and/or prevention of a disease, disorder and/or condition in which the increase of NAD+ is beneficial (as described herein), wherein each of components (I) and (II) is formulated in admixture, optionally with one or more pharmaceutically-acceptable excipient. In a further aspect of the invention, there is provided a kit-of-parts comprising: (a) a pharmaceutical formulation as hereinbefore defined (i.e. in the first aspect of the invention); and (b) one or more other therapeutic agent that is useful in the treatment and/or prevention of a disease, disorder and/or condition in which the increase of NAD+ is beneficial (as described herein), optionally in admixture with one or more pharmaceutically-acceptable excipient, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction (i.e. concomitantly or sequentially) with the other. In a further aspect of the invention, there is provided a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, the other therapeutic agent, and at least one (e.g. pharmaceutically-acceptable) excipient. In a yet further aspects of the invention, there is provided a process for the preparation of a kit-of-parts as hereinbefore defined, which process comprises bringing into association components (a) and (b), as hereinbefore defined, with and at least one pharmaceutically-acceptable excipient. As used herein, references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other. In a yet further aspect of the invention, there is provided a process for the preparation of a kit-of-parts as hereinbefore defined, which process comprises bringing into association components (a) and (b). As used herein, references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other. Thus, in relation to the process for the preparation of a kit-of-parts as hereinbefore defined, by bringing the two components “into association with” each other, we include that the two components of the kit-of-parts may be: (A) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or (B) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy. Thus, there is further provided a kit of parts comprising: (i) one of components (a) and (b) as defined herein; together with (ii) instructions to use that component in conjunction with the other of the two components. The kits-of-parts described herein may comprise more than one formulation including an appropriate quantity/dose of a compound of the invention, and/or more than one formulation including an appropriate quantity/dose of the other therapeutic agent, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and/or physical form(s). With respect to the kits-of-parts as described herein, by “administration in conjunction with” (and similarly “administered in conjunction with”) we include those respective formulations are administered, sequentially, separately or simultaneously, as part of a medical intervention directed towards treatment of the relevant condition. Thus, in relation to the present invention, the term “administration in conjunction with” (and similarly “administered in conjunction with”) includes that the two active ingredients (i.e. a compound of the invention and a further agent for the treatment and/or prevention of a disease, disorder and/or condition in which the increase of NAD+ is beneficial, or compositions comprising the same) are administered (optionally repeatedly) either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment and/or prevention of the relevant condition, than if either agent is administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment and/or prevention. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of, treatment and/or prevention of a particular condition will depend upon the condition to be treated and/or prevented, but may be achieved routinely by the skilled person. As used herein, references to other therapeutic agents that are “useful” in a certain manner (e.g. in the treatment of a certain disease or disorder) will refer to agents that are known to be suitable for use in that manner (e.g. agents commonly used for that purpose). Such references may therefore be replaced with references to agents “suitable for” the relevant purpose. Further, in the context of the present invention, the term “in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration of the other component. When used in this context, the terms “administered simultaneously” and “administered at the same time as” includes instances where the individual doses of the compound of the invention and the additional compound for the treatment of, e.g. cancer, or pharmaceutically acceptable salts thereof, are administered within 48 hours (e.g. within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other. Similarly, the terms “administered simultaneously” and “administered at the same time as” includes instances where the individual doses of the compound of the invention and the additional compound for the treatment of, e.g. eye diseases, are administered within 48 hours (e.g. within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes) and up to 3 months (e.g. 2 months, 1 month or 2 weeks) of each other. Compounds of the invention As described herein, compounds of the invention include compounds of formula I, including all embodiments and particular features thereof, and pharmaceutically acceptable salts thereof. Particular compounds of formula I that may be mentioned include those in which R1, R2, R3 and R4 independently represent H, OH, F, Cl, NH2, -OMe or -C(O)Me; In particular embodiments that may be mentioned, R1, R2, R3 and R4 independently represent H or F. In more particular embodiments that may be mentioned, R1, R2, R3 and R4 each represent H. More particular compounds of formula I that may be mentioned include those in which: R1, R2, R3 and R4 independently represent H, OH, F, Cl, NH2, -OMe or -C(O)Me; X and Y independently represent -CH2-, -O-, -N(H)-, -S-, -C(O)-, -C(H)(Me)-, -N=, - N(Me)-, -C(H)-, -C(Me)-, -N(R8b)-, -CH2-N(H)-, -CH2-O-, wherein the terminal “-(CH2)-” in -CH2-N(H)- or -CH2-O- is bound to the essential benzene ring; R8b represents H, -CH2-[C(O)-(4-methoxyphenyl)], -CH2-[C(O)-(4-fluorophenyl)], - CH2-[(5-methanol)-2-furyl], methyl, butyl, 2-hydroxyethyl, -C(O)-CH2-cyclopentoxy, - C(O)-N(H)-(4-flurorophenyl), -C(O)-(3-fluorophenyl), 4-trifluorobenzyl, 4- fluorobenzyl, 1-phenylethyl, -CH2-(4-fluorobenzyl), -CH2-[C(O)-(4-cyanophenyl)], for example, H, -CH2-[C(O)-(4-methoxyphenyl)], -CH2-[C(O)-(4-fluorophenyl)], -CH2-[(5- methanol)-2-furyl], methyl, 2-hydroxyethyl, -C(O)-CH2-cyclopentoxy, -C(O)-N(H)-(4- flurorophenyl), -C(O)-(3-fluorophenyl), -CH2-(4-fluorobenzyl), -CH2-[C(O)-(4- cyanophenyl)]; Z represents -CH2-, -C(Me)-, -C(H)(Me)-, -C(2-fluorophenyl)-, -C(2-methoxyphenyl)-, -C(4-methoxyphenyl)-, -C(H)(phenyl)-, -C(O)-, -C(H)-, -C[(H)(OC(O)(3,4,5- trihydroxyphenyl))]-, -[C(H)(tertbutyl)]-, -[C(H)(OH)]-, -{C(H)[-(CH2)C(O)N (R15R16)]}-, -CH(OH)-; n represents 0 or 1; R5 and R6 independently represent H, methyl, cyclohexyl, 4-fluorophenyl, 4- methoxyphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 3,4,5-trihydroxyphenyl, phenyl, tertbutyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, -C(O)OEt or 3,4- dimethoxyphenyl, for example, H, methyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 3,4,5-trihydroxyphenyl, phenyl, tertbutyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, - C(O)OEt or 3,4-dimethoxyphenyl); q represents 0 or 1; and/or R15 and R16 independently represent H, -CH2-(2-chlorophenyl), -CH2-(benzyl), -CH2- (phenyl), for example, H, -CH2-(2-chlorophenyl), -CH2-(benzyl), or alternatively R15 and R16 together represent a -C4-alkyl-group, thereby forming a ring. For the avoidance of doubt, unless otherwise stated, for specific structural formulae representing embodiments of the compounds of formula I, the definitions of the substituents represented will, in the first definition thereof, be as defined for compounds of formula I, including all embodiments thereof. As described herein, particular compounds of formula I that may be mentioned include those in which n represents 1, q represents 1, Z represents -C(R9g)2-, X represents –[C(R9c)2]mcN(R8b)-, Y represents –[C(R9a)2]maO-, and ma and mc are as defined hereinbefore, thereby providing a compound of formula Ia,
Figure imgf000031_0001
or a pharmaceutically acceptable salt thereof, such as (i.e. in a particular embodiment) wherein: R5 and R6 independently represent H, methyl or phenyl; R1, R2, R3 and R4 independently represent H, F or NH2 (e.g. H or F, such as H); each R8b independently represents H, methyl, -CH2-[C(O)(4-methoxyphenyl)], -CH2- [C(O)(4-fluorophenyl)], -CH2-[(5-methanol)-2-furyl], 2-hydroxyethyl, -C(O)-CH2- cyclopentoxy, -C(O)-N(H)-(4-flurorophenyl), -C(O)-(3-fluorophenyl), -CH2-(4- fluorobenzyl) or -CH2-[C(O)-(4-cyanophenyl)]; ma and mc independently represent 0 or 1; R9a and R9c independently represent H; and each R9g independently represents H, methyl, phenyl, -CH2-[C(O)(NH)(2- chlorobenzyl)], -CH2-[C(O)(NH)(benzyl)] or -CH2-[C(O)(pyrrolidine)]. As described herein, particular compounds of formula Ia that may be mentioned include those wherein: R5 and R6 independently represent H, methyl or phenyl; R1, R2, R3 and R4 independently represent H, F or NH2 (e.g. H or F, such as H); each R8b independently represents H, methyl, -CH2-[C(O)(4-methoxyphenyl)], -CH2- [C(O)(4-fluorophenyl)], -CH2-[(5-methanol)-2-furyl], 2-hydroxyethyl, -C(O)-CH2- cyclopentoxy, -C(O)-N(H)-(4-flurorophenyl), -C(O)-(3-fluorophenyl), -CH2-(4- fluorobenzyl) or -CH2-[C(O)-(4-cyanophenyl)]; ma and mc both represent 0; R9a and R9c independently represent H; and each R9g independently represents H, methyl, phenyl, -CH2-[C(O)(NH)(2- chlorobenzyl)], -CH2-[C(O)(NH)(benzyl)] or -CH2-[C(O)(pyrrolidine)]. As described herein, particular compounds of formula I that may be mentioned include those in which X represents –CH2-, and q represents 1, thereby providing a compound of formula Ib,
Figure imgf000032_0001
or a pharmaceutically acceptable salt thereof, such as wherein: Y represents -NH- or -O-; R1, R2, R3 and R4 independently represent H, F, Cl, -OH, -OMe, -C(O)Me or NH2 (e.g. H or F, such as H); n represents 0 or 1; Z represents -CH2-,–C(H)-[OC(O)(3,4,5-trihydroxybenzoyl)]-, -C(H)-(phenyl), - [C(H)(tertbutyl)]- or -[C(H)(OH)]-, such as -CH2-, –C(H)-[OC(O)(3,4,5- trihydroxybenzoyl)]-, -[C(H)(tertbutyl)]- or -[C(H)(OH)]-; and R5 and R6 independently represent H, methyl, phenyl, 3,4-dihydroxyphenyl, 3,4,5- trihydroxyphenyl, -C(O)OEt or 3,4-dimethoxyphenyl. As described herein, particular compounds of formula I that may be mentioned include those in which Z represents -C(O)-and n represents 1, thereby providing a compound of formula Ic, or a pharmaceutically acceptable salt thereof, such as wherein: R1, R2, R3 and R4 independently represent H, F, OH, or NH2 (e.g. H or F, such as H); X and Y independently represent -O-, -N(H)-, -S-, -C(H)(Me)-, -N=, -N(Me)- or -CH2O- ; and q represents 0 or 1; R5 and R6 independently represent H, methyl, phenyl or 4-methoxyphenyl (e.g. H, methyl or phenyl). For the avoidance of doubt, unless otherwise stated the position of the carbon moiety of X and Y groups as described herein indicates the point of attachment to the essential benzene ring. As described herein, particular compounds of formula I that may be mentioned include those in which X represents -C(O)- and n represents 1, thereby providing a compound of formula Id,
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, such as wherein: R1, R2, R3 and R4 independently represent H, -OH or F (e.g. H or F, such as H); Y represents -O-; Z represents (a) when the dashed line represents a bond, -C(Me), -C(2-fluorophenyl)-, -C(2- methoxyphenyl)- or -[C(4-methoxyphenyl)]-; and (b) when the dashed line does not represent a bond, -CH2-; and R5 and R6 independently represent H, methyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl. As described herein, particular compounds of formula I that may be mentioned include those in which X and Y each represent -N(R8b)-, and n and q individually represent 1, thereby providing a compound of formula Ie,
Figure imgf000034_0001
or a pharmaceutically acceptable salt thereof, such as wherein: R1, R2, R3 and R4 independently represent H or F (e.g. H); each R8b individually represents H, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo or aryl optionally substituted with -CF3 (e.g. methyl, n-butyl, ethylphenyl, -CH2-(4-trifluoromethylphenyl), or -[C(R10a)2]saC(O)R11a; such as: H, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo (e.g. methyl, n-butyl, ethylphenyl, -CH2-(4-trifluoromethylphenyl)), or -[C(R10a)2]saC(O)R11a, (for example H or methyl); R5 and R6 individually represent H, methyl, cyclohexyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of halo (e.g. F or Cl), -CN, -OR7a (e.g. methoxy, ethoxy or isopropoxy) or C1-3alkyl (e.g. methyl, ethyl, isopropyl or tertbutyl); (for example, R5 and R6 individually represent H, methyl, or phenyl); and Z represents -CH2- or –C(H)(phenyl)-. More particular compounds of formula I that may be mentioned include those in which X and Y each represent -N(R8b)-, and n and q individually represent 1, thereby providing a compound of formula Ie,
Figure imgf000035_0001
or a pharmaceutically acceptable salt thereof, such as wherein: R1, R2, R3 and R4 independently represent H or F (e.g. H); each R8b individually represent H or methyl; R5 and R6 individually represent H, methyl or phenyl; and Z represents -CH2- or –C(H)(phenyl)-. As described herein, particular compounds of formula I that may be mentioned include those in which q represents 0, and n represents 1, thereby providing a compound of formula If,
Figure imgf000035_0002
or a pharmaceutically acceptable salt thereof, such as wherein: R1, R2, R3 and R4 independently represent H, F or -OH (e.g. H or F, such as H); Z represents -CH2- or –C(H)(Me)-; R5 represents H, methyl, phenyl; X represents -O-; and Y represents N, C(Me) or C(H). In a particular embodiment, compounds of formula Ia that may be mentioned include those wherein: R1, R2, R3 and R4 independently represent H or F (e.g. H); ma and mc represent 0; R8b represents H or -(2-hydroxyethyl); R9g represents H; and/or R5 and R6 independently represent H, methyl or phenyl. In a particular embodiment, compounds of formula Ib that may be mentioned include those wherein: R1, R2, R3 and R4 independently represent H, F, NH2 or -OH (e.g. H or F, such as H); Y represents -O- or -N(H)-; n represents 0 or 1; Z represents –CH2-, -C(H)(OH)-, -C(H)(OC(O)(3,4,5-trihydroxyphenyl))- or – C(H)(tertbutyl)-; and/or R5 and R6 independently represent H, methyl, phenyl or (3,4-dihydroxyphenyl), (3,4,5- trihydroxyphenyl). In a particular embodiment, compounds of formula Ie that may be mentioned include those wherein: R1, R2, R3 and R4 independently represent H or F (e.g. H); Z represents –CH2-; and/or R8b independently represent H or methyl. In a particular embodiment, compounds of formula If that may be mentioned include those wherein: R1, R2, R3 and R4 independently represent H or F (e.g. H); Z represents -CH2-; R5 represents H; X represents -O-; and Y represents C(H). In a further particular embodiment, compounds of formula Ia that may be mentioned include those wherein: R5 and R6 independently represent H or phenyl; R1, R2, R3 and R4 independently represent H or F; R8b represents H; both ma and mc represent 0; both R9g represent H. In a further particular embodiment, compounds of formula Ie that may be mentioned include those wherein: R1, R2, R3 and R4 independently represent H or F; R8b represents H; R5 and R6 individually represent H or phenyl optionally substituted with a F atom (e.g. 4-fluorophenyl); Z represents -CH2-. In a further particular embodiment, compounds of formula Ib that may be mentioned include those wherein: Y represents -NH-; R1, R2, R3 and R4 independently represent H or F; n Represents 1; Z represents -C(H)-(phenyl); both R5 and R6 represent H. Particular compounds of the invention that may be mentioned include those compounds as described in the examples provided herein, and pharmaceutically acceptable salts thereof. For the avoidance of doubt, where such compounds of the invention include compounds in a particular salt form, compounds of the invention include those compounds in non-salt form and in the form of any pharmaceutically acceptable salt thereof (which may include the salt form present in such examples). Thus, particular compounds of the invention that may be mentioned include: 2,2-dimethylchroman-7-ol, 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2-yl)benzonitrile, 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one, 6,8-difluorochroman-4-one, 7-chlorochroman-6-amine, 2-methyl-2,3-dihydrobenzofuran-5-ol, 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one, 2,2-dimethylchroman-6-amine, 7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one, 7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one, 7-hydroxy-4-methylchroman-2-one, 7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 7-fluoro-2,2-dimethylchroman-4-one, 6,8-difluoro-2H-chromene, 7-hydroxychroman-4-one, 6-hydroxy-2,2-dimethylchroman-4-one, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate, (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine, 2-(6,8-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4- methoxyphenyl)ethenone, 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,8-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 2-(6-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4-fluorophenyl)ethenone, 5,7-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, (5-((7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)furan-2-yl)methanol, 6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane, 3-(tert-butyl)-6-fluoro-1,2,3,4-tetrahydroquinoline, 2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanol, 2-(cyclopentyloxy)-1-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethenone, N-(4-fluorophenyl)-2-methyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide, (3-fluorophenyl)(2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)methanone, N-(2-chlorobenzyl)-2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)acetamide, N-benzyl-2-(4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)acetamide, 2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1-(pyrrolidin-1- yl)ethenone, 2H-benzo[b][1,4]thiazin-3(4H)-one, 6-fluoro-1,2,3,4-tetrahydroquinoline, 6,7-difluoroquinoxalin-2(1H)-one, 6-amino-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-fluoro-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)-one, 6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 4-(2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetyl)benzonitrile, 7-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-amino-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6,7-difluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine, 6,7-difluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, (2R,3R)-7-methoxy-2-phenylchroman-3-ol, 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, (2R,3R)-2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5- trihydroxybenzoate, ethyl 6-acetyl-7-hydroxychroman-2-carboxylate, 2,4-dimethyl-2H-chromene-6,7-diol, (2S,3R)-2-phenylchroman-3-ol, (2S,3R)-2-(3,4-dimethoxyphenyl)-5,7-dimethoxychroman-3-ol, 2-phenylchroman, 2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1,4-dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-methyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-3-phenyl-1-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinoxaline, 1-butyl-6,7-difluoro-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-phenethyl-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline, 2-cyclohexyl-6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-3-phenyl-1,2,3,4-tetrahydroquinoline, 6-fluoro-3-(4-methoxyphenyl)-3,4-dihydroquinoxalin-2(1H)-one, and pharmaceutically acceptable salts thereof. More particular compounds of the invention that may be mentioned include: 2-methyl-2,3-dihydrobenzofuran-5-ol, 2,2-dimethylchroman-6-amine, 7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,8-difluoro-2H-chromene, 6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline, 3-(tert-butyl)-6-fluoro-1,2,3,4-tetrahydroquinoline, 2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanol, 6,7-difluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, (2R,3R)-2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5- trihydroxybenzoate, 2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1,4-dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-methyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-3-phenyl-1-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinoxaline, 1-butyl-6,7-difluoro-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-phenethyl-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline, 2-cyclohexyl-6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-3-phenyl-1,2,3,4-tetrahydroquinoline, 6-fluoro-3-(4-methoxyphenyl)-3,4-dihydroquinoxalin-2(1H)-one, and pharmaceutically acceptable salts thereof. In one embodiment of the invention, the compound for use according to the invention is selected from: 2,2-dimethylchroman-7-ol, 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2-yl)benzonitrile, 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one, 6,8-difluorochroman-4-one, 7-chlorochroman-6-amine, 2-methyl-2,3-dihydrobenzofuran-5-ol, 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one, 2,2-dimethylchroman-6-amine, 7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one, 7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one, 7-hydroxy-4-methylchroman-2-one, 7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 7-fluoro-2,2-dimethylchroman-4-one, 6,8-difluoro-2H-chromene, 7-hydroxychroman-4-one, 6-hydroxy-2,2-dimethylchroman-4-one, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine, 2-(6,8-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4- methoxyphenyl)ethenone, 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,8-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 2-(6-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4-fluorophenyl)ethenone, 5,7-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, (5-((7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)furan-2-yl)methanol, 6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane, 3-(tert-butyl)-6-fluoro-1,2,3,4-tetrahydroquinoline, 2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanol, 2-(cyclopentyloxy)-1-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethenone, N-(4-fluorophenyl)-2-methyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide, (3-fluorophenyl)(2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)methanone, N-(2-chlorobenzyl)-2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)acetamide, N-benzyl-2-(4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)acetamide, 2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1-(pyrrolidin-1- yl)ethenone, 2H-benzo[b][1,4]thiazin-3(4H)-one, 6-fluoro-1,2,3,4-tetrahydroquinoline, 6,7-difluoroquinoxalin-2(1H)-one, 6-amino-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-fluoro-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)-one, 6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 4-(2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetyl)benzonitrile, 7-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-amino-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6,7-difluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine, 6,7-difluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, (2R,3R)-7-methoxy-2-phenylchroman-3-ol, 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, (2R,3R)-2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5- trihydroxybenzoate, ethyl 6-acetyl-7-hydroxychroman-2-carboxylate, 2,4-dimethyl-2H-chromene-6,7-diol, (2S,3R)-2-phenylchroman-3-ol, (2S,3R)-2-(3,4-dimethoxyphenyl)-5,7-dimethoxychroman-3-ol, 2-phenylchroman, 2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1,4-dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-methyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-3-phenyl-1-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinoxaline, 1-butyl-6,7-difluoro-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-phenethyl-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline, 2-cyclohexyl-6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-3-phenyl-1,2,3,4-tetrahydroquinoline, 6-fluoro-3-(4-methoxyphenyl)-3,4-dihydroquinoxalin-2(1H)-one. In another embodiment of the invention, there is a compound of formula I,
Figure imgf000043_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R1, R2, R3, R4, R5, R6, n and q are as defined herein, with the proviso that the compound of formula I is not: 2,2-dimethylchroman-7-ol, 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2-yl)benzonitrile, 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one, 6,8-difluorochroman-4-one, 7-chlorochroman-6-amine, 2-methyl-2,3-dihydrobenzofuran-5-ol, 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one, 2,2-dimethylchroman-6-amine, 7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one, 7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one, 7-hydroxy-4-methylchroman-2-one, 7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 7-fluoro-2,2-dimethylchroman-4-one, 6,8-difluoro-2H-chromene, 7-hydroxychroman-4-one, 6-hydroxy-2,2-dimethylchroman-4-one, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate, (2R,3R)-7-methoxy-2-phenylchroman-3-ol, 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, (2R,3R)-2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5- trihydroxybenzoate, ethyl 6-acetyl-7-hydroxychroman-2-carboxylate, 2,4-dimethyl-2H-chromene-6,7-diol, (2S,3R)-2-phenylchroman-3-ol, (2S,3R)-2-(3,4-dimethoxyphenyl)-5,7-dimethoxychroman-3-ol, 2-phenylchroman, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoxaline, and 2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol. In a further embodiment of the invention, there is a compound of formula I which is: 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine, 2-(6,8-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4- methoxyphenyl)ethenone, 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,8-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 2-(6-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4-fluorophenyl)ethenone, 5,7-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, (5-((7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)furan-2-yl)methanol, 6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane, 3-(tert-butyl)-6-fluoro-1,2,3,4-tetrahydroquinoline, 2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanol, 2-(cyclopentyloxy)-1-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethenone, N-(4-fluorophenyl)-2-methyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide, (3-fluorophenyl)(2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)methanone, N-(2-chlorobenzyl)-2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)acetamide, N-benzyl-2-(4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)acetamide, 2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1-(pyrrolidin-1- yl)ethenone, 2H-benzo[b][1,4]thiazin-3(4H)-one, 6-fluoro-1,2,3,4-tetrahydroquinoline, 6,7-difluoroquinoxalin-2(1H)-one, 6-amino-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-fluoro-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)-one, 6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 4-(2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetyl)benzonitrile, 7-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-amino-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6,7-difluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine, 6,7-difluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine. Compounds are named according to IUPAC nomenclature generated by the program ChemDraw Ultra 12.0. Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared using techniques known to those skilled in the art, such as by exchanging a counter- ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. Particular acid addition salts that may be mentioned include those formed by reaction with corresponding acids, thus protonating the compound of the invention, to form carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, Į-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxy-benzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodide salts), sulphonate salts (e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxy-ethanesulphonate, 1- or 2- naphthalene-sulphonate or 1,5-naphthalene-disulphonate salts) or sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like. Particular base addition salts that may be mentioned include salts formed by reaction with corresponding bases, thus removing a proton from compounds of the invention, to form salts with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts. For the avoidance of doubt, compounds of the invention may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof, and may also exist as oils. Where compounds of the invention exist in crystalline and part crystalline forms, such forms may include solvates, which are included in the scope of the invention. For the avoidance of doubt, compounds of the invention may also exist in solution (i.e. in solution in a suitable solvent). For example, compounds of the invention may exist in aqueous solution, in which case compounds of the invention may exist in the form of hydrates thereof. Compounds of the invention may contain double bonds and, unless otherwise indicated, may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. Unless otherwise specified, all such isomers and mixtures thereof are included within the scope of the invention. Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention (particularly those of sufficient stability to allow for isolation thereof). Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism (i.e. existing in enantiomeric or diastereomeric forms). Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers (i.e. enantiomers) may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired enantiomer or diastereoisomer may be obtained from appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution; for example, with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst, all of which methods and processes may be performed under conditions known to the skilled person. Unless otherwise specified, all stereoisomers and mixtures thereof are included within the scope of the invention. For the avoidance of doubt, the skilled person will understand that where a particular group is depicted herein as being bound to a ring system via a floating bond (i.e. a bond not shown as being bound to a particular atom within the ring), the relevant group may be bound to any suitable atom within the relevant ring system (i.e. the ring within which the floating bond terminates). Unless otherwise specified, C1-6alkyl groups (where 6 is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (e.g. forming a C3-cycloalkyl group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic (so forming a C4-partial cycloalkyl group). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclopentyl and cyclohexyl. Similarly, part cyclic alkyl groups (which may also be referred to as “part cycloalkyl” groups) that may be mentioned include cyclopropylmethyl. When there is a sufficient number of carbon atoms, such groups may also be multicyclic (e.g. bicyclic or tricyclic) and/or spirocyclic. For the avoidance of doubt, particular alkyl groups that may be mentioned include straight chain (i.e. not branched and/or cyclic) alkyl groups. For the avoidance of doubt, alkyl groups as described herein may also act as linker groups (i.e. groups joining two or more parts of the compound as described), in which case such groups may be referred to as “alkylene” groups, respectively. For the avoidance of doubt, as used herein, references to heteroatoms will take their normal meaning as understood by one skilled in the art. Particular heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen and sulfur (e.g. oxygen, nitrogen and sulfur, such as oxygen and nitrogen). As may be used herein, the term aryl may refer to C6-14 (e.g. C6-10) aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, be either wholly or partly aromatic. C6-10 aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyl, and the like). For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any suitable carbon atom of the ring system. For the avoidance of doubt, the skilled person will understand that aryl groups that may form part of compounds of the invention are those that are chemically obtainable, as known to those skilled in the art. Particular aryl groups that may be mentioned include phenyl and naphthyl, such as phenyl. As may be used herein, references to heteroaryl (with may also be referred to as heteroaromatic) groups may refer to 5- to 14- (e.g. 5- to 10-) membered heteroaromatic groups containing one or more heteroatoms (such as one or more heteroatoms selected from oxygen, nitrogen and/or sulfur). Such heteroaryl groups may comprise one, two, or three rings, of which at least one is aromatic. Substituents on heteroaryl/heteroaromatic groups may, where appropriate, be located on any suitable atom in the ring system, including a heteroatom (e.g. on a suitable N atom). The point of attachment of heteroaryl/heteroaromatic groups may be via any atom in the ring system including (where appropriate) a heteroatom. Bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which instances, the point of attachment of the polycyclic heteroaryl/heteroaromatic group may be via any ring including the benzene ring or the heteroaryl/heteroaromatic or heterocyclyl ring. For the avoidance of doubt, the skilled person will understand that heteroaryl groups that may form part of compounds of the invention are those that are chemically obtainable, as known to those skilled in the art. Various heteroaryl groups will be well- known to those skilled in the art, such as pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl and purinyl. For the avoidance of doubt, the oxides of heteroaryl/heteroaromatic groups are also embraced within the scope of the invention (e.g. the N-oxide). As stated above, heteroaryl includes polycyclic (e.g. bicyclic) groups in which one ring is aromatic (and the other may or may not be aromatic). Hence, other heteroaryl groups that may be mentioned include groups such as benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole, 3,4-dihydrobenz[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4- tetrahydroquinolinyl, thiochromanyl and the like. For the avoidance of doubt, where a ring is depicted having circle therein, its presence shall indicate that the relevant ring is aromatic. Alternatively, aromatic groups may be depicted as cyclic groups comprising therein a suitable number of double bonds to allow for aromaticity. The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Hence, the compounds of the invention also include deuterated compounds, i.e. compounds of the invention in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium. For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which two or more alkyl groups are present, those groups may be the same or different. Also for the avoidance of doubt, when a term such as “halo” is employed herein, this will be understood by the skilled person to mean halogen atoms, e.g. fluoride, chloride, bromide, iodide. Unless otherwise stated, the same reasoning will apply to other such terms used herein. Further for the avoidance of doubt, when it is specified that a substituent is itself optionally substituted by one or more substituents (e.g. aryl optionally substituted by one or more groups independently selected from halo, -CN, NO2, -OR7a, and C1-3alkyl), these substituents where possible may be positioned on the same or different atoms. Such optional substituents may be present in any suitable number thereof (e.g. the relevant group may be substituted with one or more such substituents, such as one such substituent). For the avoidance of doubt, where groups are referred to herein as being optionally substituted it is specifically contemplated that such optional substituents may be not present (i.e. references to such optional substituents may be removed), in which case the optionally substituted group may be referred to as being unsubstituted. Where used herein, a dashed bond (i.e. “- - -”, or the like) may indicate that the bond is optionally present, as indicated in the circumstances. Where used herein, a bond dissected with a wavy line may indicate the bond forming the attachment of the relevant moiety to the core molecule (i.e. the compound of the compound of formula I to which the substituent is attached). For the avoidance of doubt, the skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are obtainable, i.e. those that may be prepared in a stable form. That is, compounds of the invention include those that are sufficiently robust to survive isolation, e.g. from a reaction mixture, to a useful degree of purity. Novel compounds As described herein, compounds of the invention may be defined as compounds of formula I, including all embodiments and combinations of embodiments thereof. Particular such compounds of formula I (including all embodiments and features thereof) may be novel. In a further aspect of the invention, there is provided a compound of formula I, or a pharmaceutically accpetable salt thereof. In particular embodiments, compounds of formula I include those wherein X, Y, Z, R1, R2, R3, R4, R5, R6, n and q are as defined hereinbefore, with the proviso that the compound of formula I is not selected from the list consisting of: 2,2-dimethylchroman-7-ol, 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2-yl)benzonitrile, 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one, 6,8-difluorochroman-4-one, 7-chlorochroman-6-amine, 2-methyl-2,3-dihydrobenzofuran-5-ol, 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one, 2,2-dimethylchroman-6-amine, 7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one, 7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one, 7-hydroxy-4-methylchroman-2-one, 7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 7-fluoro-2,2-dimethylchroman-4-one, 6,8-difluoro-2H-chromene, 7-hydroxychroman-4-one, 6-hydroxy-2,2-dimethylchroman-4-one, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate, (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate, (5-((7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)furan-2-yl)methanol, 3-(tert-butyl)-6-fluoro-1,2,3,4-tetrahydroquinoline, 2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanol, 2-(cyclopentyloxy)-1-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethenone, N-(4-fluorophenyl)-2-methyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide, (3-fluorophenyl)(2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)methanone, N-benzyl-2-(4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)acetamide, 2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1-(pyrrolidin-1- yl)ethenone, 2H-benzo[b][1,4]thiazin-3(4H)-one, 6-fluoro-1,2,3,4-tetrahydroquinoline, 6,7-difluoroquinoxalin-2(1H)-one, 6-amino-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one, (2R,3R)-7-methoxy-2-phenylchroman-3-ol, 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, (2R,3R)-2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5- trihydroxybenzoate, ethyl 6-acetyl-7-hydroxychroman-2-carboxylate, 2,4-dimethyl-2H-chromene-6,7-diol, (2S,3R)-2-phenylchroman-3-ol, (2S,3R)-2-(3,4-dimethoxyphenyl)-5,7-dimethoxychroman-3-ol, 2-phenylchroman, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoxaline, and 2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol. In particular embodiments, the compound of formula I is a compound of formula Ia, Ib, Ic or Ie (each of which is as hereinbefore defined, including all embodiments thereof). For example, in particular embodiments, the compound of formula I is a compound of formula Ie. In a further embodiment, there is a compound of formula Ia as defined hereinbefore with the proviso that the compound is not 7-fluoro-2-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazine. In a yet further embodiment, there is a compound of formula Ib as defined hereinbefore and wherein Y represents -N(R8b)-. In a yet another embodiment, there is a compound of formula Ic as defined hereinbefore and wherein X represents -N(R8b)-. In a further embodiment, there is a compound of formula Ie as defined hereinbefore. In a particular embodiments, the compound of formula I is: 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine, 2-(6,8-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4- methoxyphenyl)ethenone, 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,8-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 2-(6-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4-fluorophenyl)ethenone, 5,7-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane, 7-fluoro-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)-one, 6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 4-(2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetyl)benzonitrile, 7-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-amino-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6,7-difluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine, 6,7-difluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,7-difluoro-1,4-dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-methyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-3-phenyl-1-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinoxaline, 1-butyl-6,7-difluoro-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-phenethyl-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline, 2-cyclohexyl-6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-3-phenyl-1,2,3,4-tetrahydroquinoline, or 6-fluoro-3-(4-methoxyphenyl)-3,4-dihydroquinoxalin-2(1H)-one, or a pharmaceutically acceptable salt thereof. Preparation of compounds Compounds of the invention, as described hereinbefore, may be prepared in accordance with techniques that are well known to those skilled in the art, such as those described in the examples provided hereinafter. Thus, in a further aspect of the invention there is provided a process for the preparation of a pharmaceutical composition/formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable excipient. In further aspects of the invention, there is provided a process for the preparation of a combination product or kit-of-parts as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with the other therapeutic agent that is useful in the treatment of the relevant disease or disorder, and at least one pharmaceutically-acceptable excipient. As used herein, references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other. Thus, in relation to the process for the preparation of a kit-of-parts as hereinbefore defined, by bringing the two components “into association with” each other, we include that the two components of the kit-of-parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or (ii) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy. Compounds of the invention as described herein may be prepared in accordance with techniques that are well known to those skilled in the art, such as those described in the examples provided hereinafter. According to an aspect of the invention there is provided a process for the preparation of a compound of formula I as hereinbefore defined, comprising the step of reacting a compound of formula II:
Figure imgf000054_0001
wherein R1, R2, R3, R4, R5, R6, X, Y, Z, n and q are as defined hereinbefore. The reaction may be performed under standard cross coupling reactions wherein X1 is a suitable leaving group (e.g. a halogen group). This includes the presence of a catalytic amount of palladium catalyst (e.g. chloro(2-dicyclohexylphosphino-2Ļ,4Ļ,6Ļ-triisopropyl-1,1Ļ- biphenyl)[2-(2Ļ-amino-1,1Ļ-biphenyl)]palladium(II)), a suitable base (e.g. cesium carbonate), in a suitable solvent (e.g. 1,4-dioxane). The reaction may be performed at above room temperature (e.g. 130 °C) and/or under microwave irradiation. In certain embodiments, there is also provided a compound of formula II. Compounds of formula II may be prepared via the reaction of a compound of formula III with a compound of formula IV: wherein R1, R2, R3, R4, R5, R6, X, Y, Z, n and q are as defined hereinbefore. For example, wherein Y represents -O-, the reaction may be carried out under standard etherification reactions including the presence of a suitable salt (e.g. potassium iodide), a suitable base (e.g. potassium carbonate), in a suitable solvent (e.g. dimethyl sulfoxide, dimethylformamide). The reaction may be carried out at room temperature. Compounds of formulae II, III and IV are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia “Comprehensive Organic Synthesis” by B. M. Trost and I. Fleming, Pergamon Press, 1991. Further references that may be employed include “Heterocyclic Chemistry” by J. A. Joule, K. Mills and G. F. Smith, 3rd edition, published by Chapman & Hall, “Comprehensive Heterocyclic Chemistry II” by A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, 1996 and “Science of Synthesis”, Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006. The skilled person will understand that the substituents as defined herein, and substituents thereon, may be modified one or more times, after or during the processes described above for the preparation of compounds of the invention by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, dehydrogenations, alkylations, dealkylations, acylations, hydrolyses, esterifications, etherifications, halogenations and nitrations. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. The skilled person may also refer to “Comprehensive Organic Functional Group Transformations” by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995 and/or “Comprehensive Organic Transformations” by R. C. Larock, Wiley-VCH, 1999. Compounds of the invention may be isolated from their reaction mixtures and, if necessary, purified using conventional techniques as known to those skilled in the art. Thus, processes for preparation of compounds of the invention as described herein may include, as a final step, isolation and optionally purification of the compound of the invention. It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups. The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes. Protecting groups may be applied and removed in accordance with techniques that are well-known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in “Protective Groups in Organic Synthesis”, 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference. Without wishing to be bound by theory, it is believed that the compounds of the invention have properties rendering them particularly suitable for treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD+ is beneficial, such as those associated with a decline in NAD+. Compounds of the invention may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise. In particular, compounds of the invention may have the advantage that they are more efficacious and/or exhibit advantageous properties in vivo. Brief Description of the Figures Figure 1A shows the distribution of NMNAT2 in the human retina. Figure 1B shows NMNAT2 expression (scRNA-seq) in RGC, AC, BP, HZ, Rod, Cone, Astrocyte, Myeloid, Müller, RPE and vascular cells. Figures 2A to 2C show that increasing NMNAT2 provides RGC neuroprotection, wherein figure 2A demonstrates the axotomy, figure 2B demonstrates the genetic depletion and figure 2C demonstrates the inducible OHT. Figures 3A and 3B show that EGCG provides neuroprotection against RGC injury. Figures 4A and 4B show that EGCG provides neuroprotection against human RGCs. Figures 5A, 5B and 5C show that EGCG neuroprotection is NAD-dependent in the explant model. Figures 6A and 6B show that EGCG neuroprotection is Nmnat2-dependent in the explant model. Figures 7A, 7B and 7C show that EGCG provides neuroprotection against glaucoma. Figures 8A and 8B show that whole green tea polyphenols provide neuroprotection. Figures 9 to 12 show the NAD-boosting effect of molecules of formula I at 5μM of the various molecules of formula I (Figure 9), at 5μM of the various molecules of formula I and 100 μM of nicotinamide (NAM) (Figure 10), at 50μM of the various molecules of formula I (Figure 11) and at 50μM of the various molecules of formula I and 100 μM of nicotinamide (NAM) (Figure 12). Figure 13 shows that EGCG neuroprotection is NAD-dependent in the explant model. Figures 14 and 15 show the NAD-boosting effect of molecules of formula I at 0.5μM (Figure 14) and 5μM (Figure 15). Figure 16 shows the NAD-boosting effect of molecules of formula I at 50μM of the various molecules of formula I. Figure 17 shows the fold change mitochondrial potential, assessed with JC-1, in primary cortical mouse cells after 2-hour incubation with compounds at 5 and 50 μM. Figures 18 to 20 show stability in human (Figure 18), rat (Figure 19) and mouse (Figure 20) liver microsomes (in vitro). Figure 21 shows fraction unbound in human plasma. Figure 22 shows plasma stability in human plasma over 4 hours. Figure 23 shows fraction unbound in mouse plasma. Figure 24 shows plasma stability in mouse plasma over 4 hours. Figure 25 shows kinetic stability of the compounds of the invention. Figure 26 shows apparent permeability constant in Caco-2 cells, apical to basolateral (A-B). Figure 27 shows compounds incubated with mouse retina in retinal explant model over three days. Figure 28 shows fold change in NAD in cortex (C), spleen (S), liver (L) and muscle (M) following 2 hour incubation with compounds of the invention at 50 μM. For the avoidance of doubt, the numbering used in figure legends refers to the numbering of compounds of the examples as provided herein. Examples The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention. In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context). Experimental procedures Starting materials and intermediates used in the synthesis of compounds described herein are commercially available or can be prepared by the methods described herein or by methods known in the art. Experiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were used. Mass spectrometry data are reported from liquid chromatography-mass spectrometry (LC-MS) using electrospray ionization. Chemical shifts for NMR data are expressed in parts per million (ppm, į) referenced to residual peaks from the deuterated solvent used. For syntheses referencing general procedures, reaction conditions (such as length of reaction or temperature) may vary. In general, reactions were followed by thin layer chromatography or LC-MS, and subjected to work-up when appropriate. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents/gradients were chosen to provide an appropriate Rf and/or retention time. Where applicable, compound names indicated in respect of the following examples have been generated using the structure naming function of ChemBioDraw Ultra, Version 12.0. Example compounds Example compounds as described in the table below were either obtained commercially or prepared in accordance with the general procedures indicated. General procedure I
Figure imgf000059_0001
2-Chlorophenol (1 eq.), K2CO3 (1.5 eq.), chloroacetamide (1.0 eq.) and KI (0.1 eq.) were added to a flask. The mixture was stirred at room temperature for 4 to 5 h. After reaction completion, the resulting mixture was concentrated in vacuum, and the residue was partitioned between brine solution and EtOAc. The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated. The crude product was purified using silica gel column chromatography (Biotage Isolera One system) using n-hexane/EtOAc as eluent to afford the pure compound. General
Figure imgf000059_0002
A microwave tube with a magnetic stir bar was charged 2-((2-chlorobenzyl)oxy)acetyl chloride (1 eq.), Cs2CO3 (1.5 eq.) and Pd Xphos G2 (0.1 eq.) sealed with a septum, and degassed by alternating vacuum evacuation and nitrogen (three times) before anhydrous dioxane (0.3 M) was added by a syringe. The reaction mixture was irradiated at the MW for 30 min at 130°C. After the reaction was complete, the mixture was dissolved in EtOAc, filtered on Celite, and washed with HCl 2 N. The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated. The crude product was purified using silica gel column chromatography (Biotage Isolera Onesystem) using hexane/EtOAc as the eluent to afford the pure compound. III
Figure imgf000060_0001
To a solution of 1,4-benzoxazin-3-one (1 eq.) in THF (0.2M) was added dropwise BH3.SMe solution 2 M in THF (24 eq.) and the mixture was stirred for 2h at room temperature. The reaction was quenched by addition of H2Ƴ at 0°C and was extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated. The crude product was purified using silica gel column chromatography (Biotage Isolera Onesystem) using hexane/EtOAc as the eluent to afford the pure compound. General procedure IV
Figure imgf000060_0002
In an oven-dried round-bottom flask, under a nitrogen atmosphere, the benzomorpholine (1 eq.) was dissolved in dry DMF (0.3 M) and stirred with anhydrous potassium carbonate (1.3 eq. ). After 10 minutes, 2-bromo-acetophenone (1.3 eq.) was added to the reaction mixture and refluxed for 3 h. After reaction completion, the resulting mixture was concentrated in vacuum, and the residue was partitioned between brine solution and EtOAc. The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated. The crude product was purified using silica gel column chromatography (Biotage Isolera One system) using n-hexane/EtOAc as eluent to afford the pure compound. Table of Examples It is to be understood that “General procedure” mentioned in the table below may refer to the general procedures as described hereinabove, as well as commercial sources or public chemical libraries. Example General Structure Procedure Name 1H-NMR, 13C-NMR MS [M+H]+ EGCG Sigma-Aldrich (Product Number: PHR1333) (2R,3R)-5,7-dihydroxy-2-(3,4,5- trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate 1 Enamine library ID: Z839129166 2,2-dimethylchroman-7-ol 2 Enamine library ID: Z56959649 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2- yl)benzonitrile 3 Enamine library ID: Z56959648 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)- 4H-chromen-4-one Enamine library ID: Z384973024 6,8-difluorochroman-4-one Enamine library ID: Z3325148302 7-chlorochroman-6-amine Enamine library ID: Z3037257760 2-methyl-2,3-dihydrobenzofuran-5-ol Enamine library ID: Z276572508 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4- one Enamine library ID: Z2470036257 2,2-dimethylchroman-6-amine Enamine library ID: Z2241101363 7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4- one Enamine library ID: Z2239058230 7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H- chromen-4-one Enamine library: Z1889710262 7-hydroxy-4-methylchroman-2-one Enamine library ID: Z1262237456 7-fluoro-2-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazine Enamine library ID: Z1255388984 7-fluoro-2,2-dimethylchroman-4-one Enamine library F O ID: Z1198275935 F 6,8-difluoro-2H-chromene Enamine library O ID: Z1198180631 HO O 7-hydroxychroman-4-one Enamine library ID: Z1198163333 6-hydroxy-2,2-dimethylchroman-4-one Sigma Aldrich Product no. 80352 (2S,3R)-5,7-dihydroxy-2-(3,4,5- trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate General procedure III 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine 1H NMR (500 MHz, DMSO-d6) į 7.99 (d, J = 8.9 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 6.37 – 6.19 (m, 1H), 5.11 (d, J = 18.7 Hz, 1H),4.24 (s, 2H), 4.18 – 3.97 (m, 1H), 3.22 (dd, J = 12.1, 8.2 Hz, 1H). 13C NMR į 143.8, 139.2, 135.1, 114.5, 110.4, 98.7, 64.0, 38.1. General procedure IV 2-(6,8-difluoro-2-methyl-2H-benzo[b][1,4]oxazin- 4(3H)-yl)-1-(4-methoxyphenyl)ethenone 1H NMR (500 MHz, DMSO-d6) į 8.06 – 7.92 (m, 2H), 7.17 – 7.03 (m, 2H), 6.39 (ddd, J = 10.9, 9.0, 2.9 Hz, 1H), 6.31 (ddd, J = 11.7, 2.9, 1.7 Hz, 1H), 5.11 (d, J = 18.7 Hz, 1H), 4.84 (d, J = 18.7 Hz, 1H), 3.87 (s, 3H), 3.22 (dd, J = 12.1, 8.2 Hz, 1H), 2.51 (dt, J = 40.1, 1.9 Hz, 4H), 1.31 (d, J = 6.3 Hz, 3H). 13C NMR į 195.8, 163.0, 160.4, 153.5, 151.4, 138.3, 134.2, 130.8, 113.8, 97.7, 96.8, 73.7, 58.3, 55.3, 54.1, 17.9. General procedure III 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine 1H NMR (500 MHz, DMSO-d6) į 6.53 (m, 3H), 5.45(bs, 1H), 4.21(m, 2H), 3.19 (m.2H). 13C NMR į 159.6, 157.6, 144.6, 131.9, 114.5, 110.8, 102.0, 64.1, 38.4. General procedure III 6,8-difluoro-2-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazine 1H NMR (500 MHz, DMSO-d6) į 6.33 – 6.17 (m, 2H), 3.33 (dt, J = 12.3, 3.2 Hz, 1H), 2.51 (t, J = 1.9 Hz, 2H), 1.25 (d, J = 6.3 Hz, 3H). 13C NMR į 160.8, 158.8, 137.0, 132.0, 99.0, 73.9, 44.4, 17.7. General H N procedure III F N H 6-fluoro-1,2,3,4-tetrahydroquinoxaline 1H NMR (500 MHz, DMSO-d6) į 6.80 (td, J = 7.7, 1.5 Hz, 1H), 6.51 (dd, J = 7.5, 5.0 Hz, 1H), 6.29 (dd, J = 8.0, 1.6 Hz, 1H), 5.21 – 5.15 (m, 1H), 5.01 – 4.95 (m, 1H), 3.59 – 3.47 (m, 4H). 13C NMR į 161.1, 159.0, 133.5, 116.0, 110.2, 101.5, 40.5, 40.5. General procedure III 6-fluoro-2-phenyl-3,4-dihydro-2H- benzo[b][1,4]oxazine 1H NMR (500 MHz, Chloroform-d) į 7.31 – 7.22 (m, 4H), 6.64 – 6.39 (m, 3H), 5.00 (dd, J = 8.7, 2.5 Hz, 1H), 3.71 (s, 1H), 3.40 (dd, J = 12.1, 2.5 Hz, 1H), 3.23 (dd, J = 12.1, 8.7 Hz, 1H). 13C NMR į 161.2, 161.1, 159.1, 141.5, 138.6, 134.7, 134.6, 128.7, 128.6, 126.1, 126.0, 116.5, 110.5, 102.7, 76.0, 44.5. General O procedure IV F N F O 2-(6-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin- 4(3H)-yl)-1-(4-fluorophenyl)ethenone 1H NMR (500 MHz, Chloroform-d) į 7.98 – 7.92 (m, 2H), 7.42 – 7.30 (m, 5H), 7.24 – 7.18 (m, 2H), 6.81 (dd, J = 7.5, 5.1 Hz, 1H), 6.73 (td, J = 7.7, 1.5 Hz, 1H), 6.67 (dd, J = 8.0, 1.5 Hz, 1H), 5.29 (t, J = 6.9 Hz, 1H), 4.80 (d, J = 12.3 Hz, 1H), 4.67 (d, J = 12.4 Hz, 1H), 4.06 (dd, J = 12.5, 7.0 Hz, 1H), 3.93 (dd, J = 12.5, 7.0 Hz, 1H). 13C NMR į 195.5, 165.6, 163.6, 160.6, 158.5, 141.5, 138.2, 137.2, 132.4, 131.3, 128.6, 126.5, 116.3, 115.7, 101.0, 100.9, 100.7, 74.6, 58.1, 53.0. General H F O N procedure II O F 5,7-difluoro-2-methyl-2H-benzo[b][1,4]oxazin- 3(4H)-one 1H NMR (500 MHz, DMSO-d6) į 6.89 (ddd, J = 11.8, 9.1, 2.9 Hz, 1H), 6.58 (dt, J = 9.2, 2.4 Hz, 1H), 4.72 (q, J = 6.7 Hz, 1H), 1.42 (d, J = 6.8 Hz, 3H). 13C NMR į 168.2, 158.5, 153.1, 146.8, 110.7, 100.0, 98.8, 72.3, 17.1. Enamine library ID: Z1832202336 (5-((7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)- yl)methyl)furan-2-yl)methanol Enamine library N ID: Z1262619363 F N H 6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline General procedure III 7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane 1H NMR (500 MHz, Chloroform-d) į 7.07 - 6.99(m, 3H), 6.74 (dd, J = 7.5, 5.0 Hz, 1H), 5.29 (s, 1H), 4.06 (t, J = 7.1 Hz, 2H), 3.95 (dd, J = 8.5, 1.0 Hz, 2H), 3.03 (td, J = 7.1, 6.3 Hz, 2H). 13C NMR į 158.4, 157.2, 157.2, 156.4, 130.3, 116.3, 116.1, 115.2, 114.8, 67.5, 52.0, 50.0. Enamine library H N ID: Z1136467889 F 3-(tert-butyl)-6-fluoro-1,2,3,4-tetrahydroquinoline Enamine library ID: Z1337784682 2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)- yl)ethanol Enamine library ID: O O Z1228035969 N F O 2-(cyclopentyloxy)-1-(7-fluoro-2H- benzo[b][1,4]oxazin-4(3H)-yl)ethenone Enamine library ID: E216-4939 N-(4-fluorophenyl)-2-methyl-2H- benzo[b][1,4]oxazine-4(3H)-carboxamide Enamine library ID: Z606-0355 (3-fluorophenyl)(2-methyl-2H- benzo[b][1,4]oxazin-4(3H)-yl)methanone Enamine library Cl H ID: F850-2649 N N O F O N-(2-chlorobenzyl)-2-(7-fluoro-4-methyl-3,4- dihydro-2H-benzo[b][1,4]oxazin-3-yl)acetamide Enamine library ID: F850-5003 N-benzyl-2-(4-(4-fluorobenzyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-3-yl)acetamide Enamine library ID: F850-2677 2-(7-fluoro-4-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-3-yl)-1-(pyrrolidin-1- yl)ethenone Enamine library ID: EN300-16263 2H-benzo[b][1,4]thiazin-3(4H)-one Enamine library ID: EN300-36073 6-fluoro-1,2,3,4-tetrahydroquinoline Enamine library ID: EN300-73487 6,7-difluoroquinoxalin-2(1H)-one Enamine library ID: EN300-95793 6-amino-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)- one Enamine library O ID: F N O EN300-104465 H 6-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one Enamine library F O ID: EN300-80692 N O H 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one Enamine library O ID: EN300-22926 H2N N O H 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one General procedure II 7-fluoro-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)- one 1H NMR (500 MHz, Chloroform-d) į 7.00 6.74 (m, 3H), 4.57 – 4.35 (m, 4H). 13C NMR į 169.5, 158.4,153.6, 129.3, 114.7, 114.7, 69.7, 43.7. General procedure III 6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine 1H NMR (500 MHz, Chloroform-d) į 6.51 – 6.33 (m, 3H), 4.30 – 4.13 (m, 2H), 3.37 – 3.25 (m, 2H). 13C NMR į 161.7, 159.6, 141.7, 135.2, 115.3, 64.0. General O procedure II F N O H 6-fluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)- one 1H NMR (500 MHz, Chloroform-d) į 7.33-6.84 (m, 3H), 5.23 (bs, 1H), 1.52 (d, J = 6.8 Hz, 3H). 13C NMR į 168.3, 159.7, 140.2, 116.5, 111.3, 105.2, 105.0, 72.1, 17.1. General procedure IV 4-(2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)- yl)acetyl)benzonitrile 1H NMR (500 MHz, Chloroform-d) į 8.10 – 7.91 (m, 4H), 7.56 – 7.19 (m, 5H), 6.89 -6.62 (m, 3H), 4.80 (d, J = 12.4 Hz, 1H), 4.69 (d, J = 12.4 Hz, 1H), 4.06 (dd, J = 12.4, 7.1 Hz, 1H), 3.93 (dd, J = 12.3, 7.0 Hz, 1H). 13C NMR į 195.2, 160.4, 158.4, 146.3, 138.6, 133.6, 132.6, 118.5, 114.1, 110.3, 104.3, 74.6, 58.3, 53.0. General procedure II 7-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)- one 1H NMR (500 MHz, Chloroform-d) į 7.40 – 7.33 (m, 2H), 7.33 – 7.26 (m, 3H), 6.72 -6.56 (m, 3H), 5.63 (bs, 1H). 13C NMR į 166.2, 160.3, 158.2, 145.7, 135.7, 128.7, 127.8, 124.5, 118.2, 111.6, 102.7, 78.9. General procedure II 7-amino-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)- one 1H NMR (500 MHz, Chloroform-d) į 7.40 – 7.34 (m, 2H), 7.34 – 7.24 (m, 3H), 6.50 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 6.20 (dd, J = 8.3, 2.4 Hz, 1H), 5.58 (s, 1H), 3.50 (s, 2H). 13C NMR į 166.2, 145.9, 145.4, 135.6, 128.8, 128.7, 127.8, 127.8, 122.1, 122.0, 119.1, 110.4, 101.2, 79.0. General procedure II 6,7-difluoro-2-phenyl-2H-benzo[b][1,4]oxazin- 3(4H)-one 1H NMR (500 MHz, Chloroform-d) į 7.44 – 7.28 (m, 5H), 6.81 (dd, J = 10.4, 7.1 Hz, 1H), 6.59 (dd, J = 10.0, 7.4 Hz, 1H), 5.60 (s, 1H). 13C NMR į 166.1, 149.2, 147.9, 145.8, 141.4, 135.7, 135.6, 128.5, 127.7, 123.8, 105.6, 103.9, 78.9. General procedure II 2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- amine 1H NMR (500 MHz, Chloroform-d) į 7.45 – 7.17 (m, 5H), 6.80- 6.27 (m, 3H), 5.32 (dd, J = 7.4, 6.7 Hz, 1H), 4.85 (s, 2H), 4.14 – 3.78 (m, 2H). 13C NMR į 143.8, 138.6, 135.3, 128.6, 115.6, 110.7, 101.1, 76.0, 44.4. General procedure III 6,7-difluoro-2-phenyl-3,4-dihydro-2H- benzo[b][1,4]oxazine 1H NMR (500 MHz, Chloroform-d) į 7.38 – 7.25 (m, 4H), 6.67- 6.54 (m, 3H) 4.95 (dd, J = 8.8, 2.5 Hz, 1H), 3.42 (dd, J = 12.1, 2.5 Hz, 1H), 3.26 (dd, J = 12.1, 8.8 Hz, 1H). 13C NMR į 148.2, 145.3, 141.7, 138.6, 128.7, 125.8, 104.6, 101.1, 76.0, 44.5. SPECS library O O ID: AO- OH 079/15259066 (2R,3R)-7-methoxy-2-phenylchroman-3-ol SPECS library ID: AE- 848/32605045 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one Biosynth Carbosynth Product code: FE22729 (2R,3R)-2-(3,4,5-trihydroxyphenyl)chroman- 3,5,7-triol Biosynth Carbosynth Product code: FE22721 (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7- dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate SPECS library O HO O ID: O AU- O 059/43515412 ethyl 6-acetyl-7-hydroxychroman-2-carboxylate SPECS library ID: AH- 034/11364450 2,4-dimethyl-2H-chromene-6,7-diol SPECS library ID: AO- 079/15259065 (2S,3R)-2-phenylchroman-3-ol SPECS library ID: AO- 079/15259072 (2S,3R)-2-(3,4-dimethoxyphenyl)-5,7- dimethoxychroman-3-ol SPECS library ID: AO- 079/15259082 2-phenylchroman SPECS library ID: AE- 765/20006021 2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol Otava library ID: 2046625 6,7-difluoro-2-phenyl-1,2,3,4- tetrahydroquinoxaline 6,7-difluoro-1,4-dimethyl-2-phenyl-1,2,3,4- tetrahydroquinoxaline 6,7-difluoro-1-methyl-2-phenyl-1,2,3,4- tetrahydroquinoxaline 6,7-difluoro-3-phenyl-1-(4- (trifluoromethyl)benzyl)-1,2,3,4- tetrahydroquinoxaline F N F N H 1-butyl-6,7-difluoro-3-phenyl-1,2,3,4- tetrahydroquinoxaline 6,7-difluoro-1-phenethyl-3-phenyl-1,2,3,4- tetrahydroquinoxaline 6-fluoro-2-(4-methoxyphenyl)-1,2,3,4- tetrahydroquinoxaline 70 7-fluoro-2-(4-methoxyphenyl)-1,2,3,4- tetrahydroquinoxaline 71 6-fluoro-2-(4-fluorophenyl)-1,2,3,4- tetrahydroquinoxaline 72 2-cyclohexyl-6-fluoro-1,2,3,4- tetrahydroquinoxaline 73 6-fluoro-3-phenyl-1,2,3,4-tetrahydroquinoline 74 6-fluoro-3-(4-methoxyphenyl)-3,4- dihydroquinoxalin-2(1H)-one Biological Assays The biological activity of example compounds as described herein above was assessed using the following biological assays. Biological Assay 1: NMNAT2 expression in retinal ganglion cells (RGCs) The following experiment was performed in order to investigate the expression of NMNAT2 in various human cells. The distribution of NMNAT2 in human retina was investigated. Human eyes were selected from the St. Erik Hospital histopathology archive, which houses eyes enucleated due to ocular disease (predominantly ocular tumor or glaucoma). The eyes selected had an ocular tumor that did not result in any obvious retinal structural deformation. Wax sections of 3 μm were cut from 12 existing paraffin embedded eyes. The wax sections were stained with haematoxylin and the NMNAT2 protein was labelled with a monoclonal antibody (Mouse Anti-NMNAT2 antibody (ab56980); visualized using Fast Red chromogen). It was found that NMNAT2 was most strongly stained within the ganglion cell layer (GCL) compared to the inner nuclear layer (INL) in the central retina. The GCL is predominantly comprised of retinal ganglion cells (at a higher density centrally), whereas the INL contains very few retinal ganglion cells. NMNAT2 staining was also present in other RGC relevant layers such as nerve fiber layers and inner plexiform layers. This is demonstrated in Figure 1A (left side), wherein ‘RNFL’ stands for retinal nerve fiber layer, ‘GCL’ stands for ganglion cell layer, ‘IPL’ stands for inner plexiform layer and ‘INL’ stands for inner nuclear layer. The signal intensity of the Fast Red chromogen bound to the antibody labeled NMNAT2 protein was quantified (average pixel intensity; Figure 1A, right side) from captured images. Data is shown in Table 1A (central retina) and Table 1B (peripheral retina) below, wherein ‘SD’ stands for standard deviation. Table 1A Retinal Layer Mean SD RNFL 11.8872727 6.50986957 GCL 16.2627273 12.72123114 IPL 17.5890909 9.523084012 INL 16.2945455 7.726154753 Table 1B Retinal Layer Mean SD RNFL 7.88625 5.602965892 GCL 14.90444444 13.27812874 IPL 20.154 11.02748909 INL 19.46090909 9.674817264 Single cell RNA-sequencing (scRNA-seq.), which has stringent cut-offs for gene expression, confirmed (as demonstrated in Figure 1B) that retinal expression of NMNAT2 was greatest in RGCs (i.e. retinal ganglion cells demonstrated the strongest average NMNAT2 expression compared to other retinal cells tested) and was detectable in >75% of RGCs. The different retinal cells tested were neuronal (namely, Amacrine cells (‘AC’), Bipolar cells (‘BP’), Horizontal cells (‘HZ’), rod cells (‘Rod’) and cone cells (‘Cone’)) and non-neuronal (namely, Astrocyte, Myeloid, Müller, retinal pigment epithelium (‘RPE’) and Vascular epithelium) cells. Biological Assay 2: Effect of hNMNAT2 gene therapy (hNMNAT2 GT) The following study was performed in order to investigate the effect of the levels of NMNAT2. C57BL/6J mice (obtained from SCANBUR) were injected with 1.5 NjL (2.2x1011 gc/ml) adeno-associated virus type 2 (AAV2.2) encoding human NMNAT2 under a cytomegalovirus (CMV) promoter (n = 6 eyes) or left as untreated (n = 12 eyes). The transfection was successful with more than 90% yield for RGCs as was demonstrated by significant green fluorescent protein (GFP) expression in cell somas and axons. The expression remained robust even at 3 days ex vivo (‘3 DEV’). In the mouse axotomy explant model (where retinas are maintained in tissue culture ex vivo; culture media was Neurobasal-A media supplemented by 2 mM L-glutamate, 1% N-2 supplement, 2% B-27 supplement, and 1% penicillin/streptomycin maintained at 37 °C, 5% CO2), the RGC density was significantly reduced at 3 days ex vivo (‘3 DEV’ or ‘D3’) compared to control (i.e. immediate, no culture; ‘0 DEV’ or ‘D0’). NMNAT2 overexpression gave complete protection against RGC loss at 3 DEV (n = 6 eyes for all conditions). This is demonstrated in Figure 2A. Data is shown in Table 2A below, wherein ‘SD’ stands for standard deviation. Table 2A Condition Mean SD p-value when compared to D0 D0 59.22222222 5.867676682 D0 hNMNAT2 GT 57.77777778 4.314918138 0.637589833 D3 31.02777778 12.68394289 0.000585709 D3 hNMNAT2 GT 58.14444445 6.885303729 0.776380956 Genetic depletion of NMNAT2 using compound heterozygous (‘Het’) NMNAT2 knock- out mice (25% Nmnat2 expression; from Michael P Coleman, see Gilley et al. J. Neurosci. 2013, 33(33), p. 13410-13424) lead to significant RGC loss at 3 DEV (n = 5 eyes) compared to control (i.e. immediate, no culture; ‘0 DEV’, n = 6 eyes). NMNAT2 overexpression by AAV hNMNAT2 gene therapy (n = 5 eyes) was significantly protective against RGC loss (10% loss from 0 DEV in hNMNAT2 treated, in comparison to 63% in untreated at 3 DEV). This is demonstrated in Figure 2B. Data is shown in Table 2B below, wherein ‘SD’ stands for standard deviation. Table 2B p-value when compared to Condition Mean SD Het D0 Het D0 41.47777778 2.15062437 Het D3 20.02666667 6.772099625 4.12803E-05 Het D3 hNMNAT2 GT 37.49047619 3.419200158 0.042394552 The rat bead model of ocular hypertension is an inducible model of ocular hypertensive RGC injury (Figure 2C; NT = normotensive control, i.e. no glaucoma; OHT = ocular hypertensive, i.e glaucoma, 14 days). Rats (Brown Norway; SCANBUR) were either naïve (no virus, as in NT (n = 12 eyes) and OHT (n = 9 eyes)) or virus injected 3 weeks before OHT onset with either 1.5 NjL (2.2x1011 gc/ml) AAV2.2 GFP (control virus; n = 12 eyes) or 1.5 NjL (2.2x1011 gc/ml) AAV2.2 human NMNAT2 GFP (n = 9 eyes). 14 days of OHT lead to significant RGC loss which was not altered with the control AAV (i.e. GFP only). Retinas treated with AAV NMNAT2 demonstrated significant RGC protection with some variability (such as reflecting the variable nature of the model). This demonstrated that overexpression of Nmnat2 in vivo in a complex disease (i.e. with many neurodegenerative mechanisms, unlike the axotomy explant model) provides good neuroprotection to RGCs. Data is shown in Table 2C below, wherein ‘SD’ stands for standard deviation. Table 2C p-value when compared Condition Mean SD to NT NT 37.20634921 1.689922271 OHT 20.55555556 2.549509756 2.09653E-13 OHT AAV GFP 18.9154321 3.377472752 5.059E-14 OHT AAV hNMNAT2 GT 26.26043504 4.009543376 6.1203E-08 Biological Assay 3: EGCG provides neuroprotection against RGC injury This study was performed in order to study the effect of EGCG in RGC injury. In the retinal explant model, axotomy drove rapid loss of RGCs over 3 days in culture (3 days ex vivo; ‘3 DEV’ or ‘D3’). Epigallocatechin gallate (EGCG) dissolved in the culture media (culture conditions as above in Biological Assay 2) at 5, 20 and 50 μM was robustly protective to RGCs (n = 6 eyes in all conditions). This is demonstrated in Figures 3A to 3D. Data is shown in Tables 3A to 3D below, wherein ‘SD’ stands for standard deviation. Table 3A Condition Mean SD p-value when compared to D0 D0 59.22222222 5.867676682 D3 31.02777778 12.68394289 0.000585709 D3 EGCG 5μM 52.83333334 5.836665714 0.087932236 D3 EGCG 20μM 50.77222222 4.849990453 0.021599974 D3 EGCG 50μM 55.92777778 5.936718759 0.356459454 Table 3B Condition Mean SD p-value when compared to D0 D0 10.99166667 0.435220249 D3 9.838888889 2.01134744 0.20001371 D3 EGCG 5μM 10.80833333 0.490209703 0.508878515 D3 EGCG 20μM 11.73611111 1.196913468 0.182708084 D3 EGCG 50μM 11.14444445 1.679241451 0.833536795 Table 3C Condition Mean SD p-value when compared to D0 D0 103.5833 8.114287811 D3 72.11111 12.3727598 0.000395433 D3 EGCG 5μM 95 6.910539456 0.076806805 D3 EGCG 20μM 92.24524 6.589979854 0.02402906 D3 EGCG 50μM 91.97222 6.908462336 0.023539897 Table 3D Condition Mean SD p-value when compared to D0 D0 8.030556 0.429911705 D3 4.291667 0.180662361 2.56382E-09 D3 EGCG 5μM 7.45 0.395108986 0.035119833 D3 EGCG 20μM 7.91 0.198975152 0.547003684 D3 EGCG 50μM 7.558333 1.168034912 0.374598291 RGC loss (as demonstrated in Figure 3B; ‘RBPMS’) and DAPI+ nuclei loss (Figure 3C) was significant at 3 DEV in untreated retinas, and significantly reduced in EGCG treated retinas. Soma diameters (‘RBPMS’; Figure 3D) and nuclear diameters (Figure 3E) were also less variable suggesting that EGCG-treated retinas had healthier surviving cells. Biological Assay 4: EGCG provides neuroprotection to human RGCs Donor human retina were acquired from the St. Erik Hospital corneal transplant service (24-60 hours postmortem). Retinas were dissected free and 3 mm retinal punches were taken. Punches were either fixed immediately in paraformaldehyde (‘D0’) or maintained in tissue culture for 7 days (‘D7’) with or without EGCG treatments (50 μM EGCG; culture conditions as above in Biological Assay 2 and 3) (n = 5 retinas). This is demonstrated in Figure 4A. Data is shown in Table 4A below, wherein ‘SD’ stands for standard deviation. Table 4A Condition Mean SD p-value when compared to D0 D0 100 0 D7 39.36212133 14.91111499 0.007244858 D7 EGCG 50μM 64.89484063 20.55918904 0.008879252 All results were normalized to ‘D0’ (i.e. control) to account for variation by person and by time from death. Significant loss of RGCs occurred by ‘D7’ (i.e. 7 days) and this was significantly less with EGCG treatment. This is demonstrated in Figure 4B. Data is shown in Table 4B below, wherein ‘SD’ stands for standard deviation. Table 4B Condition Mean SD p-value when compared to D0 D0 100 0 D7 39.36212133 14.91111499 1.71778E-05 D7 EGCG 50μM 64.89484063 20.55918904 0.005103321 Biological Assay 5: EGCG neuroprotection is NAD-dependent in the explant model In order to determine whether the neuroprotection against RGC death afforded by EGCG was dependent on NAD, FK866 (FK866 hydrochloride hydrate, Sigma Aldrich Product number F8557, CAS Number:658084-64-1, which is a nicotinamide phosphoribosyltransferase (Nampt) inhibitor) was used to inhibit Nampt, and, thus, inhibiting NAD production via the NAD salvage pathway (as illustrated in Figure 5; left side). FK866 alone, or FK866 in combination with EGCG were dissolved in the culture media (5 μM EGCG; 10 μM FK866; culture conditions as above in Biological Assay 2 and 3) (n = 6 eyes for all conditions). FK866 alone had no significant effect on cell (as demonstrated using DAPI+; Figure 5B) or RGC (as seen using RBPMS; Figure 5C) survival at DEV 3 at the dose used (10 μM FK866). The neuroprotective effect of EGCG was completely abolished in the presence of FK866 (by DAPI+, Figure 5B; and RBPMS, Figure 5C) suggesting that in the context of RGC injury in this model, the neuroprotective effect of EGCG is derived through an NMN/NAD-dependent mechanism. As a conclusion, this would suggest that EGCG acts on Nmnats but does not confirm it (i.e. requires NMN as a substrate). Data is shown in Tables 5A and 5B below, wherein ‘SD’ stands for standard deviation. Table 5A p-value when Condition Mean SD compared to D0 D0 103.5833333 8.114287811 D3 72.11111111 12.3727598 0.000395433 D3 EGCG 5μM 95 6.910539456 0.076806805 D3 FK86610μM 79.36111111 8.714876598 0.000551215 D3 FK86610μM, EGCG 5μM 72.27777778 5.882806081 1.73635E-05 Table 5B p-value when Condition Mean SD compared to D0 D0 59.22222 5.867676682 D3 31.02778 12.68394289 0.000585709 D3 EGCG 5μM 52.83333 5.836665714 0.087932236 D3 FK86610μM 37.86111 5.939899613 9.30008E-05 D3 FK86610μM, EGCG 5μM 35.19444 2.537314123 3.37263E-06 This is demonstrated in Figure 13. Data is shown in Tables 5C (without FK866) and 5D (with FK866) below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples) and ‘FK’ stands for FK866. Dissociated cortical neuronal suspension treated first with FK866 for 1 hour and then incubated with EGCG and compounds of Examples 19 to 24, 27, 29, 51, 52, and 63 to 74 at 50 μM for two hours. Mean NAD fold change compared to non-treated samples (control), standard deviation and p-value from a two-sided t-test. Table 5C Example 50 μM St.dev p-value Ctrl 1 0.238012 1 EGCG 1.482011321 0.634907 0.035388 19 1.327376111 0.32577 0.166788 20 1.618334025 0.553458 0.107631 22 2.004611114 0.324262 0.002107 23 2.067010649 0.097566 0.000113 24 1.782299328 0.54277 0.054248 27 1.90292936 0.447241 0.016784 29 1.633830829 0.352461 0.026856 51 1.466369221 0.559565 0.200902 52 1.555104175 0.595389 0.160227 63 1.90292936 0.447241 0.016784 64 1.462354118 0.526368 0.183594 65 2.084014672 0.904114 0.091625 66 1.714282502 0.289679 0.007557 67 1.297743744 0.268553 0.157143 68 1.402780823 0.080543 0.024829 69 1.81084105 0.584484 0.060884 70 2.24881684 0.470077 0.005685 71 1.798199855 0.310168 0.005729 72 2.070819348 0.208413 0.000152 73 3.092392374 1.032762 0.023211 74 2.307878055 0.399079 0.001824 Table 5D Example 50 μM + FK866 St.dev p-value Ctrl 0.753801667 0.14525 0.124113 EGCG 1.314866646 0.73543 0.192432 19 0.800656595 0.42071 0.458573 20 0.915964971 0.295737 0.687086 22 1.154438026 0.185536 0.371897 23 1.043044378 0.252888 0.822035 24 0.676505354 0.157442 0.070109 27 0.735701005 0.170131 0.133596 29 1.320874077 0.859484 0.519739 51 0.794423508 0.050115 0.183686 52 0.90313024 0.192452 0.574561 63 0.735701005 0.170131 0.133596 64 0.735105035 0.1892 0.143679 65 0.85447816 0.10108 0.34612 66 1.323511057 0.155562 0.069509 67 0.861560432 0.157245 0.400891 68 1.014888031 0.120376 0.922564 69 1.113358184 0.185069 0.507407 70 0.586605372 0.157011 0.027696 71 0.597890153 0.103426 0.025696 72 1.36556637 0.220888 0.066787 73 1.762213189 0.284948 0.005034 74 0.716375514 0.179535 0.115314 Biological Assay 6: EGCG neuroprotection is Nmnat2-dependent in the explant model In order to determine whether the neuroprotection against RGC death afforded by EGCG was Nmnat2-dependent, EGCG was tested in the retinal axotomy explant model using compound heterozygous Nmnat2 knock-out mice. Mice were either wild-type (WT; 100% Nmnat2) or compound heterozygotes (Het; 25% Nmnat2). This is demonstrated in Figure 6A, wherein ‘d0’ refers to immediate and ‘d3’ refers to 3 days ex vivo. In WT mice, RGC loss was 38% at 3 days ex vivo (n = 6 eyes) and this was completely protected against by EGCG (-5% loss; n = 4 eyes). In Het mice, RGC loss was 63% (n = 3 eyes). While EGCG did reduce RGC loss, the neuroprotective effect was severely diminished (44% loss; n = 6 eyes). This suggested that EGCG worked through an Nmnat2-dependent mechanism. When evaluating the % loss from control (i.e. from d0 of the same genotype, to account for the difference in uninjured RGC density by genotype), EGCG treatment of Het mice returned the % loss to a level consistent with mice with higher Nmnat2 levels. This was consistent with evidence (see Biological Assay 9) that EGCG increased Nmnat2 activity to approximately 200% (i.e. the Het retinas which had 25% expression of Nmnat2 exhibited cell loss to the same degree as gtE mice which had 50% Nmnat2, since 25% Nmnat2 at 200% capacity was equivalent to 50% Nmnat2). This is demonstrated in Figure 6B, wherein ‘WT’ refers to WT mice, ‘gtBay’ refers to mice carrying the Bay gene trap allele of Nmnat2 (75% Nmnat2 expression), ‘gtE’ refers to mice carrying the E gene trap allele of Nmnat2 (50% Nmnat2 expression), and ‘Het’ refers to Het mice (compound heterozygotes carrying both Bay and E alleles, 25% Nmnat2 expression). Data is shown in Table 6 below, wherein ‘SD’ stands for standard deviation. Table 6 p-value when compared to Condition Mean SD genotype appropriate D0 WT D0 50.01333333 2.095842445 WT D3 31.20555556 2.937755504 7.93475E-07 WT D3 EGCG 50μM 53.27976191 2.262144933 0.059611043 Het D0 41.47777778 2.15062437 Het D3 15.28888889 1.209836232 2.59181E-07 Het D3 EGCG 50μM 22.93611111 3.879582119 1.27975E-06 Biological Assay 7: EGCG provides neuroprotection against glaucoma This study was performed in order to investigate the effect of EGCG against glaucoma. EGCG was dissolved in drinking water of rats (Brown Norway; SCANBUR) at 20 mg/kg/d or 40 mg/kg/d beginning 1 week prior to OHT induction (rat bead model of ocular hypertension as in Biological Assay 2) and continuing throughout (n = 12 eyes NT, n = 9 eyes OHT, n = 9 eyes OHT EGCG 20 mg/kg/d, n = 12 eyes OHT EGCG 40 mg/kg/d). EGCG provided significant protection against RGC loss by day 14 of OHT. RGC loss was less variable with the higher EGCG dose. This demonstrated that in a complex disease where RGC injury occurs through multiple mechanisms, EGCG treatment was able to provide significant neuroprotection (at mg dose, equivalent to about 0.25g in 60kg human). This is demonstrated in Figure 7. Data is shown in Table 7 below, wherein ‘SD’ stands for standard deviation. Table 7 p-value when compared Condition Mean SD to NT NT 37.20634921 1.689922271 OHT 20.55555556 2.549509756 2.09653E-13 OHT EGCG 20 mg/kg/d 24.54403292 4.912816183 8.76108E-08 OHT EGCG 40 mg/kg/d 24.79938272 3.379163368 1.10151E-10 Biological Assay 8: Whole green tea polyphenols provide neuroprotection This study was carried out in order to investigate the neuroprotective effect of whole green tea polyphenols. Whole green tea polyphenols (GTP) contain approximately 30% EGCG by weight. In the mouse axotomy explant model (methods as described in in Biological Assay 2 and in Biological Assay 3) GTP dissolved in the culture media provided significant neuroprotection similar to EGCG alone when given at a dose representing the same EGCG content (n = 6 eyes for all conditions). This is demonstrated in Figure 8A. Data is shown in Tables 8A and 8B below, wherein ‘SD’ stands for standard deviation. Table 8A Condition Mean SD p-value when compared to D0 D0 59.22222222 5.867676682 D3 31.02777778 12.68394289 0.000585709 D3 EGCG 5μM 52.83333334 5.836665714 0.087932236 D3 EGCG 50μM 55.92777778 5.936718759 0.356459454 D3 GTP 0.1μg 52.77777778 7.772935 0.136113885 D3 GTP 1μg 51.27777778 3.165204342 0.015330534 Table 8B Condition Mean SD p-value when compared to D0 D0 103.5833333 8.114287811 D3 72.11111111 12.3727598 0.000395433 D3 EGCG 5μM 95 6.910539456 0.076806805 D3 EGCG 50μM 91.97222222 6.908462336 0.023539897 D3 GTP 0.1μg 91.47222222 8.191063334 0.02774755 D3 GTP 1μg 95.66666667 2.442676128 0.045136914 This effect was also observed in rat bead model of ocular hypertension (methods as in Biological Assay 2 and Biological Assay 7) where GTP, given in the drinking water, provided similar neuroprotection to EGCG alone. GTP tolerance was worse in rats than EGCG alone (n = 12 eyes NT, n = 9 eyes OHT, n = 9 eyes OHT EGCG 20 mg/kg/d, n = 12 eyes OHT EGCG 40 mg/kg/d, n = 11 eyes OHT GTP 80 mg/kg/d). This is demonstrated in Figure 8B. Data is shown in Table 8C below, wherein ‘SD’ stands for standard deviation. Table 8C p-value when compared Condition Mean SD to NT NT 37.20634921 1.689922271 OHT 20.55555556 2.549509756 2.09653E-13 OHT EGCG 20 mg/kg/d 24.54403292 4.912816183 8.76108E-08 OHT EGCG 40 mg/kg/d 24.79938272 3.379163368 1.10151E-10 OHT GTP 80 mg/kg/d 21.85589226 3.115572398 1.27683E-12 Biological Assay 9: NAD-boosting effects of EGCG analogues I NAD values were quantified in a luminescence-based assay (NAD/NADH Glo-™, Promega) according to the instructions of the manufacturer with dissociated cortical neurons from 10 to 12 weeks old C57BL/6J mice, treated with EGCG and compounds of Examples 1 to 63 at 5 μM for two hours. One cortex hemisphere equals to one sample. This is demonstrated in Figure 9. Data is shown in Table 9 below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples) and ‘Nic’ stands for Nicotinamide. Dissociated cortical neuronal suspension treated with EGCG and compounds of Examples 1 to 63 at 5 μM for two hours. Mean NAD fold change compared to non-treated samples (control), standard deviation and p-value from a two-sided t-test. Table 9 Mean fold change p-value (t-test, two- Compound compared to Ctrl SD sided, n = 4) Ctrl 1 0.090518025 1 Nic 1.17272792 0.218229886 3.36577E-05 EGCG 1.618481358 0.329466593 2.565E-18 1 0.93848632 0.101255768 0.314742669 2 0.955317657 0.073490145 0.318457037 3 1.338536683 0.389252347 0.043575279 4 0.905874703 0.030337316 0.001223746 5 1.042611866 0.072828554 0.334817963 6 1.133760732 0.121166944 0.112013252 7 0.959527559 0.058369805 0.269095622 8 1.366241892 0.161621594 0.000283834 9 0.917815702 0.112441412 0.24094073 10 1.037216784 0.147173501 0.650691044 11 1.010217351 0.0113356 0.469450743 12 1.380713932 0.249745291 0.006633408 13 0.955005632 0.058666627 0.228611203 14 1.099010666 0.094670713 0.02163662 15 0.993765837 0.066268685 0.869296876 16 1.004839629 0.032083222 0.819619689 17 1.792594045 0.027697965 1.82311E-12 18 1.0873764 0.197244652 0.44236497 19 1.40196574 0.383484406 0.126762394 20 1.478187816 0.172774475 0.010681202 21 1.162872535 0.166999386 0.145269689 22 2.200286531 0.232300452 0.00177081 23 1.98306477 0.130757595 0.00044594 24 1.429695519 0.070978699 0.000430718 25 1.085229354 0.120564279 0.253407311 26 1.178723223 0.080550908 0.016367241 27 1.97440953 0.141258792 0.000616113 28 0.974984655 0.14115531 0.748973264 29 1.698058008 0.126737361 0.001177982 30 1.060693779 0.045659253 0.066616829 31 0.928356085 0.110234801 0.116333608 32 1.018879686 0.237808107 0.884375142 33 0.860946205 0.024243743 3.40231E-06 34 1.02111661 0.065893984 0.582644249 35 1.055106997 0.135090518 0.297302591 36 0.938218551 0.174767064 0.35762846 37 0.878863129 0.097189885 0.015479897 38 1.352822539 0.268955362 0.013074591 39 1.172714481 0.077477575 0.015823256 40 1.229245153 0.13119015 0.037024253 41 1.133663679 0.023428751 2.95093E-06 42 1.136773247 0.114315034 0.093531689 43 1.064274282 0.110020716 0.330256459 44 1.068449176 0.146294872 0.421004155 45 1.068299566 0.112680366 0.314905529 46 1.090463778 0.07906049 0.101381252 47 1.127395534 0.116602552 0.114378788 48 0.767412608 0.080895681 0.007120339 49 1.198688378 0.127525187 0.049789844 50 0.874341201 0.070015173 0.02968651 51 1.743005677 0.195847501 0.004324417 52 1.640476571 0.074160461 0.000126295 53 0.913480473 0.065980764 0.071373274 54 0.967558121 0.1193942 0.629051774 55 1.228821799 0.144380316 0.048234143 56 1.230321054 0.064406731 0.002621264 57 0.896029519 0.037262548 0.003115161 58 1.211039191 0.057292632 0.00194357 59 0.938634157 0.061138994 0.135363451 60 0.984992454 0.075398003 0.726672842 61 0.940506558 0.064278395 0.160224663 62 1.167672839 0.07761811 0.017485995 63 1.63706857 0.246127944 0.000427648 This is demonstrated in Figures 14 and 15. Data is shown in Tables 9A and 9B below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non- treated samples). Dissociated cortical neuronal suspension treated with EGCG and compounds of Examples 64 to 74 at 0.5 μM (Table 9A) and 5 μM (Table 9B) for two hours. Mean NAD fold change compared to non-treated samples (control), standard deviation and p-value from a two-sided t-test. Table 9A Mean fold change p-value (t-test, two- Compound compared to Ctrl SD sided, n = 4) Ctrl 1 0.262346 1 EGCG 1.701488 0.239017 0.002702 64 1.262864 0.318364 0.211564 65 1.042524 0.346647 0.837637 66 1.630335 0.145848 0.000364 67 1.57565 0.056702 0.000316 68 1.555532 0.290916 0.020269 69 1.160436 0.29803 0.399491 70 0.945898 0.343719 0.793227 71 1.067951 0.329736 0.73415 72 1.59362 0.144112 0.00054 73 1.557235 0.225427 0.006472 74 1.568505 0.218867 0.005063 Table 9B Mean fold change p-value (t-test, two- Compound compared to Ctrl SD sided, n = 4) Ctrl 1 0.262346 1 EGCG 1.931153 0.121212 7.63E-06 64 1.953338 0.119115 5.92E-06 65 1.689168 0.148505 0.0002 66 1.878931 0.02315 2.64E-05 67 1.680058 0.056255 9.92E-05 68 1.958037 0.190076 7.88E-05 69 2.018935 0.101539 2.65E-06 70 1.949367 0.134933 9.3E-06 71 1.984552 0.23507 0.000358 72 1.955415 0.138059 9.74E-06 73 1.999457 0.106083 3.23E-06 74 1.061645 0.113815 0.583593 Biological Assay 10: NAD-boosting effects of EGCG analogues II NAD quantified in a luminescence-based assay (NAD/NADH Glo-™, Promega) according to the instructions of the manufacturer with dissociated cortical neurons from 10 to 12 weeks old C57BL/6J mice, treated with EGCG and compounds of Examples 1 to 63 at 5 μM and nicotinamide (NAM) at 100 μM. One cortex hemisphere equals to one sample. NAD values were quantified in a luminescence-based assay with dissociated cortical neurons from 10 to 12 weeks old C57BL/6J mice, treated with EGCG and compounds of Examples 1 to 63 at 5 μM for two hours. One cortex hemisphere equals a sample. Dissociated cortical neuronal suspension treated with EGCG and compounds of Examples 1 to 63 at 5 μM and nicotinamide at 100 μM for two hours. Mean NAD fold change compared to non-treated samples (control), standard deviation and p-value from a two-sided t-test. This is demonstrated in Figure 10. Data is shown in Table 10 below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples) and ‘Nic’ stands for Nicotinamide. Table 10 Mean fold change p-value (t-test, two- Compound SD compared to Ctrl sided, n = 4) Ctrl 1 0.091430159 1 Nic 1.109911388 0.131862653 1.31038E-05 EGCG 1.633986097 0.379484564 2.02334E-23 1 1.069863068 0.102266102 0.267667675 2 1.056378602 0.096989284 0.333962197 3 1.453666449 0.483262432 0.032716839 4 1.006401714 0.030565909 0.760487826 5 1.198932024 0.060559354 0.003076795 6 1.194329541 0.09413108 0.021280259 7 1.096225322 0.045173091 0.01247223 8 1.469873689 0.201284746 0.000250733 9 1.013724781 0.07890811 0.759627882 10 1.067947563 0.097892455 0.2617007 11 1.078115213 0.065494512 0.090481937 12 1.557049118 0.229062006 0.000200935 13 1.074796426 0.01776945 0.000103991 14 1.228134704 0.138016833 0.001922802 15 1.149708849 0.122291844 0.088843315 16 1.121909018 0.078395614 0.045892846 2.01128653 0.013744844 6.44771E-39 1.445895725 0.219962719 0.026067161 1.07978888 0.056789515 0.057447714 1.645489785 0.253757323 0.014115354 1.317437319 0.069726847 0.001104003 2.086392498 0.175146563 0.00092829 2.212311279 0.20540912 0.00113939 1.527977366 0.059755592 4.94916E-05 1.34263763 0.352126345 0.146581896 1.471206369 0.113231781 0.002600384 2.176202217 0.123691532 0.000190384 1.0688628 0.057234593 0.08797509 1.990250859 0.20334843 0.002037927 1.21895615 0.218473614 0.138044598 1.316868287 0.241877913 0.007408286 1.05336441 0.112343718 0.417120708 1.498172704 0.351519973 0.065503245 1.001579145 0.175622725 0.986886925 1.125480194 0.217428481 0.149405633 1.100909247 0.216292198 0.266701278 1.126158259 0.127980567 0.040433814 1.482008974 0.226689178 0.001220337 1.423689203 0.136577244 0.007115839 1.377801481 0.111710384 0.004999523 1.278027056 0.078755326 0.003303317 1.32081295 0.192176081 0.042998454 1.335292881 0.126754276 0.011217924 1.214081659 0.065949466 0.003624723 1.042587274 0.205904582 0.708366377 1.323851582 0.169803933 0.030018404 1.306852785 0.080480841 0.002583485 1.082276666 0.286298663 0.606588012 1.356576038 0.103571465 0.004518341 0.994693756 0.169088179 0.961793047 1.98668061 0.213602157 0.002416343 1.79475906 0.096617087 0.000226647 1.084097574 0.084340503 0.137287254 54 1.06845985 0.052691951 0.071319539 55 1.318277368 0.116745399 0.009957654 56 1.444705352 0.086559927 0.000993452 57 1.122152428 0.031471756 0.000262267 58 1.353873052 0.121402798 0.008243291 59 1.072340731 0.051449115 0.056614847 60 1.106772882 0.048768282 0.011847708 61 1.085482962 0.052643928 0.036216244 62 1.249271057 0.070781653 0.002938982 63 1.513682391 0.149726133 0.024834777 Biological Assay 11: NAD-boosting effects of EGCG analogues III NAD quantified in a luminescence-based (NAD/NADH Glo-™, Promega) according to the instructions of the manufacturer with dissociated cortical neurons from 10 to 12 weeks old C57BL/6J mice, treated with EGCG and compounds of Examples 1 to 63 at 50 μM. One cortex hemisphere equals to one sample. Dissociated cortical neuronal suspension treated with EGCG and compounds of Examples 1 to 63 at 50 μM for two hours. Mean NAD fold change compared to non- treated samples (control), standard deviation and p-value from a two-sided t-test. This is demonstrated in Figure 11. Data is shown in Table 11 below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples) and ‘Nic’ stands for Nicotinamide. Table 11 Mean fold change Compound SD p-value (t-test, two-sided, n = 4) compared to Ctrl Ctrl 1 0.088663461 1 Nic 1.184672043 0.216996696 1.15653E-06 EGCG 1.897221979 0.472317377 1.15339E-18 1 0.998946352 0.040397727 0.966408984 2 0.926886083 0.049669535 0.049282042 3 1.453224786 0.597403813 0.069159609 4 0.94610128 0.054484916 0.140551786 5 1.129006042 0.115385784 0.108742665 1.181905032 0.125203401 0.059229073 1.197773658 0.089184609 0.017067916 1.326188923 0.143609486 0.00026126 1.068465192 0.038456797 0.02428762 0.949963279 0.047882142 0.125582968 1.066485132 0.098643034 0.272968118 1.274187919 0.124647082 0.000296719 1.033587052 0.01618427 0.036563245 1.700341719 0.361119029 0.002089777 1.196946059 0.157704696 0.086097065 1.054933548 0.05052505 0.113629341 2.784870857 0.352205081 0.001969105 1.107063187 0.210327937 0.384709292 1.142453305 0.20826401 0.265154755 1.722179097 0.025429482 8.88503E-14 1.493404119 0.106886209 0.001838408 0.432699695 0.05230478 1.28892E-05 1.759622467 0.074909343 6.95216E-05 1.585137105 0.064693917 6.99835E-05 1.0471122 0.063754158 0.241676043 1.586379653 0.190118346 0.007906553 0.473838919 0.045372505 3.68641E-06 0.991151146 0.159378494 0.919313763 2.177451755 0.142235712 0.000345289 1.957332872 0.196769819 0.002047797 1.193179425 0.054974126 0.002146762 1.151039749 0.093623501 0.04340778 1.072844938 0.191928567 0.504752588 1.441232731 0.098734576 0.001919578 1.13618717 0.062600278 0.01505942 1.573409209 0.217659206 0.01266202 0.996890086 0.069405383 0.937223983 1.872618544 0.283778752 0.008338825 1.113667014 0.105456807 0.117292952 1.628648067 0.186912928 0.006113869 1.177539827 0.249286704 0.249715562 1.109430876 0.056004766 0.020320369 43 1.447062445 0.182840301 0.015327541 44 1.21651419 0.179904054 0.093929118 45 1.130869408 0.087218676 0.052075204 46 0.931792502 0.090418311 0.230003818 47 1.139803367 0.129688778 0.118042683 48 0.920861483 0.08552247 0.159712256 49 1.431242944 0.05825015 0.000111238 50 1.315205655 0.074632493 0.001723562 51 1.351110511 0.0551299 0.000174858 52 1.528948477 0.109024255 0.001587323 53 1.073404716 0.128652893 0.339120132 54 1.111489141 0.135261443 0.197554565 55 1.077582342 0.254699205 0.58643812 56 1.252047097 0.273037427 0.161729006 57 0.996947503 0.063721271 0.93346653 58 1.19791432 0.012711157 1.66865E-12 59 0.926519403 0.045460853 0.035800586 60 1.036283348 0.069319462 0.383704278 61 0.924702 0.044130007 0.029426064 62 1.307374402 0.080074139 0.002626131 63 1.530429566 0.239058829 0.000987882 This is demonstrated in Figure 16. Data is shown in Table 11A below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples). Dissociated cortical neuronal suspension treated with EGCG and compounds of Examples 64 to 74 at 50 μM for two hours. Mean NAD fold change compared to non- treated samples (control), standard deviation and p-value from a two-sided t-test. Table 11A Mean fold change p-value (t-test, two- Compound compared to Ctrl SD sided, n = 4) Ctrl 1 0.262346 1 EGCG 1.431266 0.531705 0.204988 64 0.865108 0.082895 0.216196 65 1.100284 0.081109 0.347328 66 1.401815 0.101372 0.003625 67 1.525976 0.167104 0.002231 68 1.183058 0.065799 0.097513 69 1.446925 0.345022 0.073429 70 1.03899 0.298276 0.832432 71 0.470924 0.134691 0.000981 72 0.816562 0.250312 0.281053 73 1.451892 0.336332 0.066277 Biological Assay 12: NAD-boosting effects of EGCG analogues IV NAD quantified in a luminescence-based assay (NAD/NADH Glo-™, Promega) according to the instructions of the manufacturer with dissociated cortical neurons from 10 to 12 weeks old C57BL/6J mice, treated with EGCG and compounds of Examples 1 to 63 at 50 μM and nicotinamide (NAM) at 100 μM. One cortex hemisphere equals to one sample. Samples treated with EGCG and compounds of Examples 1 to 63 at 50 μM and nicotinamide at 100 μM for two hours. Mean NAD fold change compared to non-treated samples (control), standard deviation and p-value from two-sided t-test. This is demonstrated in Figure 12. Data is shown in Table 12 below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples) and ‘Nic’ stands for Nicotinamide. Table 12 Mean fold change p-value (t-test, two-sided, n Compound SD compared to Ctrl = 4) Ctrl 1 0.072573574 1 Nic 1.141347321 0.167916061 5.79354E-06 EGCG 1.967120429 0.535484504 1.68506E-25 1 1.167352318 0.136792603 0.089880946 2 1.047720354 0.078526154 0.316916042 3 1.736581488 0.836781494 0.04162978 4 1.15551801 0.059408433 0.007897196 5 1.206318933 0.0733019 0.007339954 6 1.255198922 0.144094366 0.036299777 7 1.313942621 0.07794269 0.002288189 8 1.45691249 0.180998085 0.0001494 9 1.155108918 0.050652811 0.003597481 1.018782057 0.048115143 0.519379947 1.198891755 0.188874869 0.124966221 1.409549457 0.1422202 5.24012E-05 1.16716753 0.098606174 0.038689119 1.866639853 0.498727775 0.003660209 1.238865155 0.082235271 0.007174488 1.299996028 0.155437541 0.029092872 2.81284449 0.249873208 0.000649632 1.215926613 0.046247631 0.000473683 1.292649358 0.171029292 0.040298275 1.803000398 0.140852458 0.001144358 1.587270659 0.15881089 0.00450174 0.633685256 0.108555751 0.005206164 1.933077229 0.05071587 1.34805E-06 1.846282952 0.08680776 0.000123504 1.272848059 0.27640167 0.142499704 1.634180686 0.090042699 0.000399384 0.466068353 0.045959009 5.93562E-06 1.180135117 0.164626048 0.115200576 2.166258805 0.214810876 0.001515695 1.888883942 0.260441083 0.006156886 1.384521329 0.262940023 0.060597503 1.275965469 0.110338555 0.013076712 1.233351429 0.138967833 0.041585312 1.556130007 0.175236679 0.007238117 1.219870569 0.057048622 0.00174422 1.456189773 0.114095032 0.003134996 1.213744929 0.076389716 0.007714457 2.082327092 0.230791283 0.002380961 1.296385243 0.164668529 0.035222925 1.719564399 0.15074007 0.002039172 1.363099698 0.193649234 0.032012651 1.191237755 0.106690445 0.033710209 1.659938524 0.262071628 0.014645056 1.309188155 0.146033264 0.022412397 1.272964987 0.123940194 0.01950591 1.095296914 0.083025294 0.101205999 47 1.567862586 0.211595208 0.012043471 48 1.060839577 0.056721171 0.116707849 49 1.53814528 0.015843206 6.03244E-22 50 1.472719026 0.138768236 0.005553455 51 1.674695221 0.121166345 0.001136426 52 1.483039661 0.090550035 0.001030818 53 1.171094125 0.14027809 0.090592384 54 1.240533688 0.134476814 0.035088794 55 1.259695104 0.255435394 0.134460767 56 1.298449865 0.126760079 0.016185776 57 1.148299117 0.067670519 0.015921759 58 1.352532174 0.072305621 0.001061626 59 1.031748508 0.050685256 0.315426896 60 1.074089479 0.089012753 0.194473163 61 1.034290329 0.047670461 0.259523986 62 1.436688423 0.059615558 0.000149207 63 1.548363157 0.081770813 0.004819742 Biological assay 13: assessing mitochondrial potential change with JC-1 C57BL/6J mice (N= 4) were euthanized by cervical dislocation, and the whole cortex was removed and separated by hemisphere. Cortical hemispheres were cut up into smaller pieces in 800 μL dispase. The cut-up cortical hemispheres were placed on a heating block at 37°C, 350 rpm for 30 min before dissociation by gentle trituration. The cell concentration of cortical cell suspensions was determined with a hemocytometer. Cell suspensions were diluted to 1 million cells/mL, and incubated with Examples 19, 20, 22 to 24, 27, 29, 51, 52 and 63 at 5 and 50 μM for 2 h at 37°C. In the last 30 mins of incubation, 200 μM JC-1 in DMSO was added to the samples to an end concentration of 2 μM. Cell suspensions were washed from the dye by spinning down the cells at 3000 g for 5 min and resuspended in pre-warmed HBSS. The samples were spun down and resuspended in 300 μL HBSS and 50 μL of the samples were loaded in a 96-well plate. Fluorescence was recorded with a plate reader, with the excitation/emission for the green monomeric form at 485/535 nm and for the aggregate red form at 535/590 nm. Mitochondria membrane potential was calculated by dividing the red fluorescence with the green fluorescence. This is demonstrated in Figure 17. Data is shown in Table 13 (5 μM) and Table 14 (50 μM) below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples). Mean NAD fold change compared to non-treated samples (control), standard deviation and p-value from a two-sided t-test (n=4). Table 13 Compound Mean SD p-value Ctrl 1 0.016818 1 EGCG 1.174119 0.082331 0.021815 19 0.977912 0.159915 0.800993 20 1.07449 0.094683 0.213782 22 1.368537 0.144228 0.013833 23 1.224607 0.064802 0.004493 24 0.879497 0.07122 0.039412 27 1.165117 0.287194 0.333737 29 1.287988 0.113341 0.013668 51 1.0033 0.157911 0.969406 52 1.100079 0.107993 0.160177 63 1.228323 0.053729 0.001982 Table 14 Compound Mean SD p-value Ctrl 1 0.016818 1 EGCG 0.306887 0.011753 4.52E-09 19 1.058451 0.153992 0.504124 20 1.372737 0.101912 0.022184 22 1.159625 0.074572 0.020647 23 1.100928 0.085007 0.095853 24 1.21802 0.094577 0.017523 27 0.588918 0.05513 0.00029 29 1.09349 0.064382 0.058097 51 1.214977 0.077113 0.009556 52 1.386684 0.117922 0.006559 63 1.036783 0.06272 0.330197 Biological assay 14: determination of human, mouse and rat microsomal metabolic stability Metabolic stability is determined in 0.5 mg/ml human or animal liver microsomes at a compound concentration of 1 μM in 100 mM KPO4 buffer pH 7.4 in a total incubation volume of 500 μL. The reaction is initiated by the addition of 1 mM NADPH. At various incubation times, i.e. at 0, 5, 10, 20, 40 and 60 min, a sample was withdrawn from the incubation and the reaction was terminated by the addition of cold acetonitrile. The amount of parent compound remaining was analysed by LC-MS/MS. Results are demonstrated in figures 18 to 20. Data is shown in Table 15 (mouse liver microsome), Table 16 (human liver microsome) and Table 17 (rat liver microsome). Table 15 MLM: t1/2 (in vitro, MLM: Clint (in MLM: E (in vitro) Compound min) vitro, NjL/min/mg) 23 1.51 921 0.98 63 3.85 359.8 0.94 69 2.89 479.8 0.95 71 12.33 112.4 0.83 73 3.79 366 0.94 Table 16 MLM: t1/2 (in vitro, MLM: Clint (in MLM: E (in vitro) Compound min) vitro, NjL/min/mg) 23 6 232.2 0.88 63 25.1 55.3 0.63 69 20.4 68.12 0.68 71 42.2 32.86 0.51 73 10.8 128.52 0.8 Table 17 MLM: t1/2 (in vitro, MLM: Clint (in MLM: E (in vitro) Compound min) vitro, NjL/min/mg) 23 2.8 495.2 0.94 63 3.28 422.8 0.93 69 1.35 1023.2 0.97 71 3.33 416.6 0.93 73 3.53 392.4 0.93 Biological assay 15: determination of human and mouse plasma protein binding The fraction unbound drug (fu) in plasma from human and mouse (CD1/K2 EDTA) was determined by equilibrium dialysis at 37°C for 4 hours using the RED device. The drug molecules at a concentration of 0.1, 1, and 10 μM are added to plasma and dialyzed against isotonic phosphate buffer (67 mM, pH 7.4). After dialysis, the drug concentration in the buffer and plasma was quantified by LC-MS/MS analysis. In parallel the stability of the drug molecule in plasma is determined by incubating drug- spiked plasma (0.1, 1, and 10 μM, respectively) at 37°C for 4 hours, meanwhile the control plasma sample was kept in the freezer. The concentration of the compound in both samples was quantified by LC-MS/MS analysis. Plasma amount: 50% of human plasma and 10% mouse plasma. The freeze plasma sample is replacing the standard curve. Precipitation by: 150 μL acetonitrile containing 100 nM Warfarin as internal standard The LC-MS/MS system used consists of a Waters Acquity UPLC coupled to a Waters XEVO TQ-S micro mass spectrometer (electrospray ionization, ESI). The test compounds were optimized on a Waters Acquity UPLC XEVO TQ-S micro system (Waters Corp.) operating in multiple reaction monitoring (MRM) mode with positive or negative electrospray ionization. Compounds were optimized by using the QuanOptimize software (Waters Corp.). For chromatographic separation, a C18 BEH 1.7 Njm column was used, with a general gradient of 1% to 90% of mobile phase B over a total running time of 2 min. Mobile phase A consisted of 5% acetonitrile and 0.1% formic acid in purified water, and mobile phase B of 0.1% formic acid in 100% acetonitrile. The flow rate was set to 0.5 ml/min and 5 μL of the sample was injected. Results are demonstrated in figures 21 to 24. Data is shown in Table 18 (human) and Table 19 (mouse). Table 18 Stability Plasma Compound fu (%) (4h, %) 23 1.79 85 63 3.54 92 69 7.93 82 71 5.06 83 73 0.49 79 Table 19 Stability Plasma Compound fu (%) (4h, %) 23 1.84 73 63 3.08 63 69 6.51 46 71 5.08 53 73 1.28 56 Biological assay 17: determination of kinetic solubility The kinetic solubility, utilizing test compound from 10 mM DMSO stock solution, is measured at a final compound concentration of 100 μM and 1% DMSO. The test compound was added to 100 mM potassium phosphate buffer and incubated at 37°C for at least 20 hours in a heater-shaker. After incubation, the samples were centrifuged at 3000 x g at 37°C for 30 min to pellet insoluble material and an aliquot of the supernatant was taken for analysis. After dilution of the sample, the concentration of the dissolved compound was quantified by LC-MS/MS analysis. Results are demonstrated in Figure 25. Data is shown in Table 20 below. Table 20 Compound Solubility Kinetic (μM) 23 12.7 63 34.9 69 21.3 71 34.8 73 9.4 Biological assay 18: Caco2 cell permeability Caco-2 cell monolayers (passages 94-105) were grown on permeable filter support and used for transport study on day 21 after seeding. Before the experiment, a compound solution of 1 μM was prepared and warmed to 37°C. The Caco-2 filters were washed with prewarmed HBSS before the experiment, and thereafter the experiment was started by applying the donor solution on the apical or basolateral side. The transport experiments were carried out at pH 7.4 in both the apical and basolateral chambers. 5 μM enalaprilat was used as membrane integrity control in each filter. The apparent permeability coefficient (Papp) of enalaprilat for a tight monolayer has been determined to be < 1 x 10-6 cm/s. The experiments were performed at 37°C and with a stirring rate of 500 rpm. The receiver compartment was sampled at 30 minutes, and at 30 minutes also a final sample from the donor chamber was taken to calculate the mass balance of the compound. The samples (100 μL) were transferred to a 96-well plate containing 100 μL methanol and Warfarin as is and were sealed until LC-MS/MS analysis. Results are demonstrated in Figure 26. Data is shown in Table 21 below. Table 21 Compound Papp A-B (1E-6 cm/s) Efflux Ratio B-A/A-B 23 42.5 1.15 71 74.4 1.05 73 24.6 1.27 Biological assay 19: retinal explant model and immunolabelling of retinal ganglion cells Flat-mounted retinas were maintained in culture (37°C, 5% CO2) fed by Neurobasal-A media supplemented with 2 mM L-glutamate, 2 % B27, 1 % N2, and 1% penicillin/streptomycin in 6-well (mouse). Mice were euthanized by cervical dislocation, retinas dissected free in cold HBSS and flat mounted on cell culture inserts ganglion cell layer up. Retinas were removed from culture and fixed in 3.7% PFA at 3 days ex vivo for cell counts. Control eyes were processed immediately following enucleation. For cell counts, retinas were dissected following 1 hour of fixation. Media was changed on day 2 and fixed on day 3 with 3,7% PFA in PBS for 30 minutes. After fixation, the flat-mounted retinas were permeabilized with 0.1% Triton X-100 in PBS for 60 mins and blocked in 2% Bovine Serum Albumin (BSA) in Hanks’ Balanced Salts Solution (HBSS) for 60 mins in room temperature (RT). Primary antibody (anti- RNA-binding protein with multiple splicing (RBPMS) diluted in PBS at 2.56 μg/mL) was applied and maintained over three nights at 4°C, following five repeated washes for 10 mins. The secondary antibody was applied and maintained for 4 hours in RT. Retinas were washed 5 times for 10 mins before being labelled with 5 μg/mL nuclear Hoescht 33342 nuclear stain diluted in PBS. The retinas were washed once in PBS before being mounted using Fluoromount-G and glass coverslip. Slides were sealed with nail varnish. RGC density was assessed by counting RBPMS+ cells in the ganglion cell layer. Six images per retina were taken equidistant at 0, 2, 4, 6, 8, and 10 o’clock about a superior to inferior line through the optic nerve head (~1000 Njm eccentricity). Images were cropped to 100 x 100 μm and RBPMS+ cells were counted using the cell counter plugin for Fiji; counts were averaged across the 6 images. Results are demonstrated in Figure 27. Data is shown in Table 22 (0.5 μM), Table 23 (5 μM) and Table 24 (50 μM) below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples). ‘D0’ refers to immediate and ‘D3’ refers to 3 days ex vivo. Mean NAD fold change compared to non-treated samples (control D0 and D3, respectively), standard deviation and p-value from a two-sided t-test. Table 22 Compou Mean SD Change p-value Change p-value nd (D0) (D0) (D3) (D3) Ctrl (D0) 1.611060 6.03934E 42.4246 4.457469 1 1 88 -05 Ctrl (D3) 0.620709 6.03934E 26.33333 3.864367 008 -05 1 1 22 42.90952 3.209537 1.011430 0.839000 1.629475 2.79175E 381 94 175 388 588 -05 23 33.11666 4.253103 0.780600 0.006600 1.257594 0.024491 667 442 505 759 937 684 27 33.36666 11.13390 0.786493 0.147440 1.267088 0.238149 667 717 312 468 608 911 29 29.68333 11.85165 0.699672 0.046394 1.127215 0.534594 333 249 622 11 19 231 63 27.07936 8.420690 0.638293 0.004725 1.028330 0.849235 508 648 892 78 319 293 Table 23 Compou Mean SD Change p-value Change p-value nd (D0) (D0) (D3) (D3) Ctrl (D0) 1.611060 6.03934E 42.4246 4.457469 1 1 88 -05 Ctrl (D3) 0.620709 6.03934E 26.33333 3.864367 008 -05 1 1 22 3.854002 0.645851 0.000104 1.040506 0.642423 27.4 249 651 553 329 88 23 7.651376 0.630766 0.006368 1.016202 0.913742 26.76 056 065 497 532 1 27 33.26666 3.585588 0.784136 0.003117 1.263291 0.009213 667 438 189 552 139 971 29 19.48333 6.395753 0.459246 5.24518E 0.739873 0.054089 333 8 095 -05 418 916 63 28.21111 7.238375 0.664970 0.003185 1.071308 0.591158 111 099 536 714 017 007 Table 24 Compou Mean SD Change p-value Change p-value nd (D0) (D0) (D3) (D3) Ctrl (D0) 1.611060 6.03934E 42.4246 4.457469 1 1 88 -05 Ctrl (D3) 0.620709 6.03934E 26.33333 3.864367 008 -05 1 1 22 6.378566 0.820278 0.058945 1.321518 0.038786 34.8 54 739 592 987 234 23 28.74722 3.297649 0.677607 0.000174 1.091666 0.272129 222 275 333 944 667 634 27 27.99302 8.872465 0.659829 0.008458 1.063026 0.687318 549 169 99 767 285 549 29 36.34615 6.990112 0.856723 0.108074 1.380233 0.015818 385 299 484 71 69 579 63 1.611060 6.03934E 42.4246 4.457469 1 1 88 -05 Biological assay 20: NAD assays in all tissues NAD values were quantified in a luminescence-based assay (NAD/NADH Glo-™, Promega) according to the instructions of the manufacturer with muscle from hindlimb, spleen and liver from 10 to 12 weeks old C57BL/6J mice, treated with EGCG and compounds of Examples 19, 20, 22 to 24, 27, 29, 51, 53 and 63 at 50 μM for two hours. All tissues were finely chopped in a tube and dissociated in dispase and diluted to 2 x 106 cells/mL. Mean NAD fold change compared to non-treated samples (control), standard deviation and p-value from a two-sided t-test. Results are demonstrated Figure 28. Data is presented in in Table 25 (cortex), Table 26 (liver), Table 27 (muscle) and Table 28 (spleen) below, wherein ‘SD’ stands for standard deviation, ‘Ctrl’ refers to the control sample (non-treated samples). Table 25 Compound Mean SD p-value Ctrl EGCG 1 0.061188 1 EGCG 1.363749 1.363749 0.035429 Ctrl 1 0.120392 1 19 1.25867 1.25867 0.033286 20 1.502677 1.502677 0.00276 22 1.325424 1.325424 0.014754 23 1.47137 1.47137 0.002504 24 1.128532 1.128532 0.085042 27 1.191029 1.191029 0.086984 29 1.165967 1.165967 0.042947 51 1.300704 1.300704 0.00444 52 1.167426 1.167426 0.044371 63 1.231525 1.231525 0.042439 Table 26 Compound Mean SD p-value Ctrl EGCG 1 0.099457 1 EGCG 0.929064 0.929064 0.362029 Ctrl Compounds 1 0.090924 1 19 0.944778 0.944778 0.230341 20 0.987381 0.987381 0.747786 22 0.920689 0.920689 0.089027 23 0.961626 0.961626 0.339333 24 0.885714 0.885714 0.180443 27 1.055671 1.055671 0.258816 29 0.931423 0.931423 0.371739 51 0.90495 0.90495 0.250384 52 0.959068 0.959068 0.660026 63 1.021376 1.021376 0.780183 Table 27 Compound Mean SD p-value Ctrl EGCG 1 0.054516 1 EGCG 0.923905 0.923905 0.226987 Ctrl 1 0.125123 1 19 1.082916 1.082916 0.036124 20 0.966513 0.966513 0.487953 22 0.889219 0.889219 0.006696 23 0.95528 0.95528 0.467685 24 1.065795 1.065795 0.564565 27 1.173675 1.173675 0.000816 29 1.108123 1.108123 0.181442 51 1.004956 1.004956 0.965321 52 1.031227 1.031227 0.772822 63 0.869589 0.869589 0.435412 Table 28 Compound Mean SD p-value Ctrl EGCG 1 0.106984 1 EGCG 0.70707 0.70707 0.014091 Ctrl 1 0.096516 1 19 1.076622 1.076622 0.424468 20 0.822993 0.822993 0.101902 22 0.93244 0.93244 0.542639 23 0.946483 0.946483 0.613139 24 1.058419 1.058419 0.271934 27 0.865151 0.865151 0.272555 29 0.807774 0.807774 0.01942 51 0.929947 0.929947 0.204601 52 0.972112 0.972112 0.622923 63 0.812354 0.812354 0.00982 Abbreviations The following abbreviations may be used herein. aq aqueous BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Boc tert-butoxycarbonyl brine saturated aqueous solution of NaCl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide EDCÂHCl N-(3-dimethylaminopropyl)-NĻ-ethylcarbodiimide hydrochloride EtOAc ethyl acetate EtOH ethanol Ex example HATU O-(7-azabenzotriazolyl)-N,N,NĻ,NĻ-tetramethyluronium hexafluorophosphate HOBt 1-hydroxybenzotriazole LAH lithium aluminium hydride MeCN acetonitrile MeOH methanol MW microwave NBS N-bromosuccinimide NMR nuclear magnetic resonance Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) PBS phosphate buffered saline rac racemic rt room temperature tBuOK potassium tert-butoxide tBuONa sodium tert-butoxide TBS tris-buffered saline TFA trifluoroacetic acid THF tetrahydrofuran Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Claims

Claims 1. A compound of formula I
Figure imgf000108_0001
or a pharmaceutically-acceptable salt thereof, for use in the treatment and/or prevention of a disease, disorder and/or condition in which an increase of NAD+ is beneficial, wherein: R1, R2, R3 and R4 independently represent H, halo, -OR7a, -N(R8a)2, -C(O)C1-3alkyl, -CN, -C(O)OR7b or NO2; one or both of X and Y independently represents -[C(R9a)2]ma-O-, -[C(R9b)2]mb-S-, -[C(R9c)2]mc-N(R8b)-, or -[C(R9d)2]md-N=, wherein ma, mb, mc and md each represent 0, 1 or 2, and wherein the position of the carbon moiety indicates the point of attachment to the essential benzene ring, and, where applicable, the other of X and Y independently represents -[C(R9e)2]me-, -C(R9f)=, or -C(O)-, wherein me represents 1 or 2, and wherein the single bond in -C(R9f)= indicates the point of attachment to the essential benzene ring, with the proviso that the sum of ma, mb, mc, md and me, where present, is not greater than 2; n represents 0 or 1; wherein (a) when n represents 1, and (b) neither of X and Y represents –[C(R9d)2]md-N= or -C(R9f)=, then the dashed line represents an optional bond; when the dashed line does not represent a bond and X does not represent -[C(R9d)2]md-N= or -C(R9f)=, then Z represents -C(R9g)2- or -C(O)-, or when the dashed line represents a bond or X represents -[C(R9d)2]md-N= or -C(R9f)=, then Z represents -C(R9h)-, with the provisos that, when X represents -C(O)- then Z cannot represent -C(O)-, and when n represents 0, then X and Y do not both represent -[C(R9d)2]md-N=; q represents 1 or, when the dashed line represents a bond or Y represents -[C(R9d)2]md-N= or -C(R9f)=, q represents 0; R5 and R6 independently represent H, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN, NH2 or NO2, -C(O)OC1-3alkyl, or aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, CF3, -OR7a, NH2 or C1-3alkyl; q represents 0 or 1, with the proviso that when q represents 0, one of the dashed bonds may represent a bond; R7a and R7b independently represent H or C1-3alkyl; R8a and R8b independently represent H, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, -[C(R10a)2]saC(O)R11a, -[C(R10b)2]sbC(O)NHR11b, C1-3alkyl substituted by aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl optionally substituted with halo or OH, C1-3alkyl substituted by heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl optionally substituted with halo or OH, or C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2; sa and sb each represent 0, 1, 2 or 3; each R9, R9a, R9b, R9c, R9d, R9e, R9f, R9g and R9h independently represent H, halo, -OR7a, C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or -N(R12)2, -OC(O)R13, -[C(R14)2]scC(O)N(R15)(R16), or aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; sc represents 0, 1 or 2; R10a and R10b independently represent H, halo, -OR7a, -CN or NO2, C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, or -C(O)-C1-3alkyl; R11a and R11b independently represent C1-6alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, C1-6alkoxy-C1-6alkyl, or aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; each R12 represents H, C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, or -C(O)-C1-3alkyl; R13 represents aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; each R14 represents H, halo, -OR7a, -CN or NO2, C1-3alkyl optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2, or -C(O)-C1-3alkyl; and R15 and R16 independently represent H, C1-3alkyl optionally substituted by halo, -OR7a, -CN, NO2 or aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CN, NO2, -OR7a or C1-3alkyl; or alternatively R15 and R16 together represent a -C4-6alkylene-group, thereby forming a ring optionally substituted with one or more substituents selected from the group consisting of halo, -OR7a, -CN or NO2. 2. A compound as claimed in Claim 1, wherein: R1, R2, R3 and R4 independently represent H, OH, F, Cl, NH2, -OMe or -C(O)Me; X and Y independently represent -CH2-, -O-, -N(H)-, -S-, -C(O)-, -C(H)(Me)-, -N=, - N(Me)-, -C(H)-, -C(Me)-, -N(R8b)-, -CH2-N(H)- or -CH2-O-, wherein the terminal “- (CH2)-” in -CH2-N(H)- or -CH2-O- may be bound to the essential benzene ring; R8b represents H, -CH2-[C(O)-(4-methoxyphenyl)], -CH2-[C(O)-(4-fluorophenyl)], - CH2-[(5-methanol)-2-furyl], methyl, butyl,
2-hydroxyethyl, -C(O)-CH2-cyclopentoxy, - C(O)-N(H)-(4-flurorophenyl), -C(O)-(3-fluorophenyl), 4-trifluorobenzyl, -CH2-(4- fluorobenzyl), 1-phenylethyl, -CH2-(4-fluorobenzyl), -CH2-[C(O)-(4-cyanophenyl)]; Z represents -CH2-, -C(Me)-, -C(H)(Me)-, -C(2-fluorophenyl)-, -C(2-methoxyphenyl)-, -C(4-methoxyphenyl)-, -C(H)(phenyl)-, -C(O)-, -C(H)-, -C[(H)(OC(O)(3,4,5- trihydroxyphenyl))]-, -[C(H)(tertbutyl)]-, -[C(H)(OH)]-, -{C(H)[- (CH2)C(O)N(R15R16)]}- or -C(H)(OH)-; n represents 0 or 1; R5 and R6 independently represent H, methyl, cyclohexyl, 4-fluorophenyl, 4- methoxyphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 3,4,5-trihydroxyphenyl, phenyl, tertbutyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, -C(O)OEt or 3,4-dimethoxyphenyl; q represents 0 or 1; and/or R15 and R16 independently represent H, -CH2-(2-chlorophenyl), -CH2-(benzyl), or alternatively R15 and R16 together represent a -C4-alkyl-group, thereby forming a ring.
3. A compound as claimed in Claim 1 or Claim 2, wherein: R5 and R6 independently represent H, methyl or phenyl; R1, R2, R3 and R4 independently represent H, F or NH2; each R8b independently represents H, methyl, -CH2-[C(O)(4-methoxyphenyl)], -CH2- [C(O)(4-fluorophenyl)], -CH2-[(5-methanol)-2-furyl], 2-hydroxyethyl, -C(O)-CH2- cyclopentoxy, -C(O)-N(H)-(4-flurorophenyl), -C(O)-(3-fluorophenyl), -CH2-(4- fluorobenzyl) or -CH2-[C(O)-(4-cyanophenyl)]; ma and mc both represent 0; R9a and R9c independently represent H; and each R9g independently represents H, methyl, phenyl, -CH2-[C(O)(NH)(2- chlorobenzyl)], -CH2-[C(O)(NH)(benzyl)] or -CH2-[C(O)(pyrrolidine)].
4. A compound as claimed in any one of Claims 1 to 3, wherein a disease, disorder and/or condition in which an increase of NAD+ is beneficial includes central nervous system diseases, peripheral nervous system diseases, and aging diseases.
5. A compound as claimed in any one of the preceding claims, wherein the disease, disorder and/or condition includes ophthalmic diseases, heart diseases, type 2 diabetes, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, Charcot- Marie-Tooth disease, HIV neuropathy, peripheral neuropathies, neurodegenerative diseases, hair loss, cognitive diseases, skin diseases, severe acute neurodegenerative insults, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, Ischemic and other injuries, traumatic injuries, and accelerated aging.
6. A compound as claimed in Claim 5, wherein the ophthalmic diseases include age-related eye disorders, glaucoma, retinal degenerative diseases, age-related macular degeneration, diabetic retinopathy, Leber’s hereditary optic neuropathy, optic neuritis, and retinal detachment.
7. A compound as claimed in any one of the preceding claims, wherein the cause of the decline in NAD+ includes oxidative stress, decline in mitochondria production, age, genetic expression, DNA function, healthy inflammatory response, high intraocular pressure, and use of steroid medication.
8. A compound as claimed in Claim 1, wherein the disease and/or condition is associated with a decline in retinal NAD+.
9. A compound as claimed in any one of the preceding claims, wherein disease and/or condition is glaucoma.
10. A compound as claimed in Claim 9, wherein glaucoma includes open-angle glaucoma, closed-angle glaucoma and normal-tension glaucoma.
11. The compound for use of any one of Claims 1 to 10, wherein the compound is selected from the list consisting of: 2,2-dimethylchroman-7-ol, 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2-yl)benzonitrile, 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one, 6,8-difluorochroman-4-one, 7-chlorochroman-6-amine, 2-methyl-2,3-dihydrobenzofuran-5-ol, 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one, 2,2-dimethylchroman-6-amine, 7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one, 7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one, 7-hydroxy-4-methylchroman-2-one, 7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 7-fluoro-2,2-dimethylchroman-4-one, 6,8-difluoro-2H-chromene, 7-hydroxychroman-4-one, 6-hydroxy-2,2-dimethylchroman-4-one, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate, (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate,3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine, 2-(6,8-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4- methoxyphenyl)ethenone, 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,8-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 2-(6-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4-fluorophenyl)ethenone, 5,7-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, (5-((7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)furan-2-yl)methanol, 6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane, 3-(tert-butyl)-6-fluoro-1,2,3,4-tetrahydroquinoline, 2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanol, 2-(cyclopentyloxy)-1-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethenone, N-(4-fluorophenyl)-2-methyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide, (3-fluorophenyl)(2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)methanone, N-(2-chlorobenzyl)-2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)acetamide, N-benzyl-2-(4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)acetamide, 2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1-(pyrrolidin-1- yl)ethenone, 2H-benzo[b][1,4]thiazin-3(4H)-one, 6-fluoro-1,2,3,4-tetrahydroquinoline, 6,7-difluoroquinoxalin-2(1H)-one, 6-amino-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-fluoro-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)-one, 6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 4-(2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetyl)benzonitrile, 7-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-amino-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6,7-difluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine, 6,7-difluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, (2R,3R)-7-methoxy-2-phenylchroman-3-ol, 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, (2R,3R)-2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5- trihydroxybenzoate, ethyl 6-acetyl-7-hydroxychroman-2-carboxylate, 2,4-dimethyl-2H-chromene-6,7-diol, (2S,3R)-2-phenylchroman-3-ol, (2S,3R)-2-(3,4-dimethoxyphenyl)-5,7-dimethoxychroman-3-ol, 2-phenylchroman, 2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1,4-dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-methyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-3-phenyl-1-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinoxaline, 1-butyl-6,7-difluoro-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-phenethyl-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline, 2-cyclohexyl-6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-3-phenyl-1,2,3,4-tetrahydroquinoline, 6-fluoro-3-(4-methoxyphenyl)-3,4-dihydroquinoxalin-2(1H)-one, and pharmaceutically acceptable salts thereof.
12. A method of treating or preventing a disease and/or condition as defined in any one of Claims 1 to 10 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I as defined in any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof.
13. The use of a compound of formula I as defined in any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating or preventing a disease and/or condition as defined in any one of Claims 1 to 9.
14. A pharmaceutical formulation comprising a compound of formula I as defined in any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically-acceptable excipient, for use in the treatment or prevention of a disease and/or condition as defined in any one of Claims 1 to 10.
15. A combination product comprising: (I) a compound of formula I as defined in any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof; and (II) one or more other therapeutic agent that is useful in the treatment or prevention of a disease and/or condition as claimed in any one of Claims 1 to 10, wherein each of components (I) and (II) is formulated, in admixture with one or more a pharmaceutically-acceptable excipient.
16. A kit-of-parts comprising: (a) a pharmaceutical formulation as defined in Claim 14; and (b) one or more other therapeutic agent that is useful in the treatment or prevention of a disease and/or condition as claimed in any one of Claims 1 to 10, in admixture with one or more pharmaceutically-acceptable excipient, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
17. A compound of formula
Figure imgf000116_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R1, R2, R3, R4, R5, R6, n and q are as defined in any one of Claims 1 to 11, with the proviso that the compound of formula I is not: 2,2-dimethylchroman-7-ol, 4-(6-fluoro-3-methyl-4-oxo-4H-chromen-2-yl)benzonitrile, 6-fluoro-3-methyl-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one, 6,8-difluorochroman-4-one, 7-chlorochroman-6-amine, 2-methyl-2,3-dihydrobenzofuran-5-ol, 3-(2-fluorophenyl)-5,7-dihydroxy-4H-chromen-4-one, 2,2-dimethylchroman-6-amine, 7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one, 7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one, 7-hydroxy-4-methylchroman-2-one, 7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 7-fluoro-2,2-dimethylchroman-4-one, 6,8-difluoro-2H-chromene, 7-hydroxychroman-4-one, 6-hydroxy-2,2-dimethylchroman-4-one, (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate, (5-((7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)furan-2-yl)methanol, 6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline, 3-(tert-butyl)-6-fluoro-1,2,3,4-tetrahydroquinoline, 2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanol, 2-(cyclopentyloxy)-1-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethenone, N-(4-fluorophenyl)-2-methyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide, (3-fluorophenyl)(2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)methanone, N-(2-chlorobenzyl)-2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)acetamide, N-benzyl-2-(4-(4-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)acetamide, 2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1-(pyrrolidin-1- yl)ethenone, 2H-benzo[b][1,4]thiazin-3(4H)-one, 6-fluoro-1,2,3,4-tetrahydroquinoline, 6,7-difluoroquinoxalin-2(1H)-one, 6-amino-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5- trihydroxybenzoate, (2R,3R)-7-methoxy-2-phenylchroman-3-ol, 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, (2R,3R)-2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5- trihydroxybenzoate, ethyl 6-acetyl-7-hydroxychroman-2-carboxylate, 2,4-dimethyl-2H-chromene-6,7-diol, (2S,3R)-2-phenylchroman-3-ol, (2S,3R)-2-(3,4-dimethoxyphenyl)-5,7-dimethoxychroman-3-ol, 2-phenylchroman, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoxaline, and 2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol.
18. A compound as claimed in Claim 17, wherein the compound of formula I is: 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine, 2-(6,8-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4- methoxyphenyl)ethenone, 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,8-difluoro-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 2-(6-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-1-(4-fluorophenyl)ethenone, 5,7-difluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane, 3-(tert-butyl)-6-fluoro-1,2,3,4-tetrahydroquinoline, 2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanol, 2-(cyclopentyloxy)-1-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethenone, N-(4-fluorophenyl)-2-methyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide, (3-fluorophenyl)(2-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)methanone, 7-fluoro-3,5-dihydrobenzo[e][1,4]oxazepin-2(1H)-one, 6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6-fluoro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 4-(2-(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetyl)benzonitrile, 7-fluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 7-amino-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6,7-difluoro-2-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine, 6,7-difluoro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, 6,7-difluoro-1,4-dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-methyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-3-phenyl-1-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinoxaline, 1-butyl-6,7-difluoro-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6,7-difluoro-1-phenethyl-3-phenyl-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 7-fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline, 2-cyclohexyl-6-fluoro-1,2,3,4-tetrahydroquinoxaline, 6-fluoro-3-phenyl-1,2,3,4-tetrahydroquinoline, 6-fluoro-3-(4-methoxyphenyl)-3,4-dihydroquinoxalin-2(1H)-one, or pharmaceutically acceptable salts thereof.
19. A compound as defined in Claim 17 or 18 for use in medicine.
20. A pharmaceutical formulation comprising a compound of formula I as defined in Claim 17 or 18, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically-acceptable excipient.
PCT/EP2024/054065 2023-02-17 2024-02-16 Epigallocatechin-3-gallate (egcg) analogs for use in the treatment of diseases in which an increase of nad+ is beneficial such as glaucoma WO2024170772A1 (en)

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