Cannabinoid compounds and uses thereof

Abstract

The present invention relates to a group of synthetic cannabinoid compounds, which have the structural formula I defined herein. The present invention also relates to compositions comprising these compounds, methods of preparing these compounds, intermediates useful in the preparation of these compounds, and to the use of these compounds as medicaments, especially for the treatment of conditions associated with seizure, such as epilepsy.

Description

CANNABINOID COMPOUNDS AND USES THEREOFRELATED APPLICATIONSThe present application is related to, and claims the benefit of, GB 2315506.2 filed on 10 October 2023 (10.10.2023), the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0001] The present invention relates to a group of synthetic cannabinoid compounds and to the use of these compounds as research tools and medicaments, especially for the treatment of conditions associated with seizure, such as epilepsy.BACKGROUND TO THE INVENTION

[0002] Epilepsy is a disabling neurological disorder, characterized by a predisposition to epileptic seizures caused by abnormal, excessive, or synchronous neuronal activity in the brain. Epilepsy sufferers may experience a substantially impaired quality of life as a result of seizures, comorbid mood and psychiatric disorders, cognitive deficits and the adverse effects of epilepsy medication [Devinsky et al, 2018], Furthermore, seizures can be fatal, either directly due to effects on autonomic and arousal functions, or indirectly due to accidents such as drowning, or motor vehicle accidents.

[0003] Epilepsy is reported to affect 65 million people worldwide [Devinsky et al, 2018], with a lifetime prevalence of 7.6 per 1 ,000 people [Fiest et al, 2017], Whilst the prevalence does not appear to differ by age group or gender, the prevalence and incidence rate of epilepsy are higher in low to middle income countries [Fiest et al, 2017],

[0004] The causes of epilepsy include acquired structural changes to the brain (e.g. as a result of traumatic brain injury, brain tumour, or stroke), infectious diseases (e.g. viral or bacterial disorders), and genetic mutations.

[0005] The International League Against Epilepsy (I LAE) epilepsy classification framework begins with the diagnosis of the type of epileptic seizure and assumes that nonepileptic events have been ruled out. The classification proposes a three-level classification approach for a patient presenting with epileptic seizures, wherein the first level is seizure type, the second level is epilepsy type and the third level is an epilepsy syndrome diagnosis [Scheffer et al, 2017],

[0006] Seizure type classification begins with the determination of whether the initial manifestations of the seizure are of focal onset or generalised onset. If the onset is missed or obscured the seizure is categorised as being of unknown onset [Fisher et al, 2017], Focal onset seizures may be further defined according to the level of awareness and all threeseizure types (focal, generalised and unknown) may be further characterised by motor or nonmotor onset symptoms.

[0007] Epilepsy type classification divides into focal epilepsies, generalised epilepsies, combined generalised & focal epilepsies, and unknown epilepsies. Focal epilepsies include unifocal and multifocal disorders as well as seizures involving one hemisphere. For a diagnosis of Generalised Epilepsy, the patient would typically show generalised spike-wave activity on EEG. Individuals with generalised epilepsies may have a range of seizure types including absence, myoclonic, atonic, tonic, and tonic-clonic seizures. Combined Generalised and Focal Epilepsies covers patients who have both generalised and focal seizures, whereas unknown epilepsies covers situations where the patient has epilepsy but the clinician is unable to determine if the epilepsy type is focal or generalised, because there is insufficient information available [Scheffer et al., 2017],

[0008] Epilepsy syndrome refers to a characteristic cluster of clinical and EEG features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious) [Wirrell et al., 2022], The epilepsy syndrome groups include syndromes with onset in neonates and infancy (up to 24 months of age); syndromes with onset in childhood; syndromes with onset at a variable age; and idiopathic generalised epilepsy syndromes (IGEs). The syndrome groups may also encompass self-limited epilepsies, developmental and epileptic encephalopathies (DEE) and etiology-specific syndromes.

[0009] Examples of neonate and infant epilepsy syndromes include self-limited neonatal epilepsy, infantile epileptic spasms syndrome, Dravet syndrome, glucose transporter 1 deficiency syndrome and Sturge Weber syndrome [Zuberi et al., 2022],

[0010] Examples of syndromes with onset in childhood include childhood occipital visual epilepsy (COVE), Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic atonic seizures (previously known as Doose syndrome) and epilepsy with eyelid myoclonia (previously known as Jeavons syndrome) [Specchio et al., 2022],

[0011] Examples of syndromes with onset at a variable age include sleep-related hypermotor / hyperkinetic epilepsy (SHE), progressive myoclonus epilepsies (PME), febrile- infection related epilepsy syndrome (FIRES) and Rasmussen syndrome [Riney et al., 2022],

[0012] Idiopathic generalised epilepsy syndromes (IGEs) include childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalised tonic-clonic seizures alone (GTCA) [Hirsch et al., 2022],

[0013] In terms of the management of epilepsy, options include anti-seizure drugs (ASDs), dietary therapies, neurostimulation and surgery. ASDs are the primary therapy for epilepsy and aim to reduce the seizure occurrence and severity. Over 20 ASDs have been approved, however, often multiple drugs are required for adequate seizure control. Strict patient adherence to their ASD treatment regimen is also important, as ASDs must be taken between one and four times daily and a single missed dose can lead to recurrence of seizures [Devinsky et al, 2018],

[0014] Cannabidiol (CBD) is one such ASD. In 2018 CBD (Epidiolex®) was approved in the United States for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in children and adults over the age of 2 years. CBD is a naturally occurring cannabinoid compound derived from cannabis species, such as the hemp plant (Cannabis sativa). Unlike other cannabinoids, such as tetrahydrocannabinol (THC), CBD does not bind to CB1 or CB2 receptors (or its binding to the receptors is negligible in terms of inducing a pharmacological effect) and it does not induce the psychotropic effects associated with cannabis.

[0015] Despite the wide range of ASDs available, approximately one-third of patients do not achieve seizure control, no matter how many ASDs are tried using monotherapy or combination drugs [Devinsky et al, 2018], Drug- or treatment-resistant epilepsy is associated with increased risk of injury and death, greater medication burden and adverse effects, and reduced quality-of-life. For these patients, surgery offers the greatest chance of achieving long-term seizure control, but only a minority of patients are good candidates for surgery. Clearly, alternative treatment options for seizures are desirable.

[0016] The present invention has been devised in light of the above considerations.BRIEF SUMMARY OF THE INVENTION

[0017] At its most general, the present invention relates to synthetic cannabinoid compounds. The synthetic cannabinoid compounds display anticonvulsive activity in one or more rodent models of seizure and hence the compounds will be useful for the treatment or prevention of medical conditions such as epilepsy.

[0018] In a first aspect of the invention there is provided a compound of formula (I), or a salt thereof:wherein,R1aand R1 bare independently selected from hydrogen, Ci-salkyl, and halo; or R1aand R1 b, together with the carbon atom to which they are attached, form a cyclopropyl ring;R2is hydrogen, Ci-salkyl, or Cs-ecycloalkyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from halo and NR7R8, wherein R7and R8are independently selected from hydrogen and Ci-salkyl;R3is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R4is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R5is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo; andR6is hydrogen, Ci-ioalkyl, Cs-ecycloalkyl, or halo; and wherein said Ci-ioalkyl is unsubstituted or substituted with one to three groups R6Aselected from halo, hydroxy, Ci-salkoxy, Cs-ecycloalkyl, and 4- to 6- membered heterocyclyl.

[0019] In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the first aspect, or a pharmaceutically acceptable salt thereof, together with one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.

[0020] In a third aspect of the invention, there is provided a compound of the first aspect, or the pharmaceutical composition of the second aspect, for use in a method of treatment.

[0021] In an embodiment of the third aspect, there is provided a compound of the first aspect, or the pharmaceutical composition of the second aspect, for use in the treatment of a condition associated with seizure.

[0022] In a fourth aspect of the invention, there is provided a method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of the first aspect, or the pharmaceutical composition of the second aspect.

[0023] In an embodiment of the fourth aspect, the treatment comprises the treatment of a condition associated with seizure.

[0024] In a fifth aspect of the invention, there is provided a first method of preparing a compound of formula (I), the method comprising:(1a) reacting a compound of formula (II) with a compound of formula (III) to give a compound of formula (IV):wherein:R1a, R1 b, R2, R3, R4, R5and R6are as defined herein;X is chloro, bromo, iodo, or triflate;Y is BF3Z, wherein Z is a suitable counter-cation such as Na or K, or Y is B(OR11)OR12, wherein R11and R12are hydrogen, Ci-ealkyl, or phenyl; or R11and R12, together with the oxygen and boron atoms to which they are attached, form a 5- to 8-membered cyclic boronic ester; and R9and R10are suitable alcohol protecting groups; and(1b) converting a compound of formula (IV) to a compound of formula (I).

[0025] In the fifth aspect of the invention, there is also provided a second method of preparing a compound of formula (I), the method comprising:(1a) reacting a compound of formula (V) with a compound of formula (VI) to give a compound of formula (IV):wherein:R1a, R1 b, R2, R3, R4, R5and R6are as defined herein;X is chloro, bromo, iodo, or triflate;Y is BF3Z, wherein Z is a suitable counter-cation such as Na or K, or Y is B(OR11)OR12, wherein R11and R12are hydrogen, Ci-ealkyl, or phenyl; or R11and R12, together with the oxygen and boron atoms to which they are attached, form a 5- to 8-membered cyclic boronic ester; andR9and R10are suitable alcohol protecting groups; and(1b) converting a compound of formula (IV) to a compound of formula (I).

[0026] In a sixth aspect of the invention, there are provided intermediates useful in the preparation of a compound of the first aspect, wherein the intermediates are compounds of formula (II), formula (V), or formula (IV):wherein:R1a, R1b, R2, R3, R4, R5, R6, R9, R10, X, and Y are as defined herein.

[0027] These and other aspects and embodiments of the invention are described in further detail below.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 shows the effect of vehicle, diazepam and Compound 1 on the latency to Racine Stages 3 (Fig. 1A), 4 (Fig. 1 B), and 5 (Fig. 1C) in the rat kainic acid induced seizure test described in Example 6. Data are presented as median with IQR, the two tails represent highest and lowest values and each dot represents individual data points (n=15 / group); *p<0.05, **p<0.01, ***p<0.001 , ****p<0.0001.

[0029] Figure 2 shows the effect of vehicle, diazepam and Compound 1 on the maximum seizure severity (capped at stage 5) in the rat kainic acid induced seizure test described in Example 6. Data are presented as median with IQR, the two tails represent highest and lowest values and each dot represents individual data points (n=15 / group); *p<0.05, ****p<0.0001.DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention relates to synthetic cannabinoid compounds which are biologically active and hence useful in the treatment of diseases.

[0031] The compounds are structurally related to the naturally-occurring cannabinoid cannabidiol (CBD). CBD is a non-psychoactive cannabinoid which has been used to treat various diseases and disorders. While such treatments hold promise, there remains a need in the art for more effective treatments and this has been brought about by way of novel synthetic cannabinoid compounds.Synthetic Cannabinoids

[0032] Natural cannabidiol (CBD) has the formula:Compounds of Formula (I)

[0033] In one aspect, the present invention provides a compound of formula (I), or a salt thereof:wherein,R1aand R1 bare independently selected from hydrogen, Ci-salkyl, and halo; or R1aand R1 b, together with the carbon atom to which they are attached, form a cyclopropyl ring;R2is hydrogen, Ci-salkyl, or Cs-ecycloalkyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from halo and NR7R8, wherein R7and R8are independently selected from hydrogen and Ci-salkyl;R3is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R4is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R5is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo; andR6is hydrogen, Ci-ioalkyl, Cs-ecycloalkyl, or halo; and wherein said Ci- alkyl is unsubstituted or substituted with one to three groups R6Aselected from halo, hydroxy, Ci-salkoxy, Cs-ecycloalkyl, and 4- to 6- membered heterocyclyl.

[0034] In a preferred embodiment, R1aand R1 bare independently selected from hydrogen, Ci-salkyl, and halo. In a more preferred embodiment, R1aand R1 bare independently selected from hydrogen, methyl, and fluoro. In an even more preferred embodiment, R1aand R1 bare independently selected from hydrogen and methyl. In a most preferred embodiment, R1aand R1 bare both hydrogen. In an embodiment, R1aand R1 bare both methyl. In an embodiment, R1aand R1 bare both fluoro. In an embodiment, R1aand R1 b, together with the carbon atom to which they are attached, form a cyclopropyl ring.

[0035] In a preferred embodiment, R2is hydrogen, Ci-salkyl, or cyclopropyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from halo and NR7R8, wherein R7and R8are independently selected from hydrogen and Ci-salkyl. In a more preferred embodiment, R2is hydrogen, Ci-salkyl, or cyclopropyl; and wherein said Ci- salkyl is unsubstituted or substituted with one to three halo groups. In an even more preferred embodiment, R2is Ci-salkyl or cyclopropyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three halo groups. In a yet more preferred embodiment, R2is Ci-salkyl or cyclopropyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three fluoro groups. In a most preferred embodiment, R2is ethyl or cyclopropyl; and wherein said ethyl is unsubstituted or substituted with one to three fluorogroups. In an embodiment, R2is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, CH2CF3, CH2CH2F, or CH2CH2NMe2. In an embodiment, R2is methyl, ethyl, propyl, isopropyl, cyclopropyl, CH2CF3, CH2CH2F, or CH2CH2NMe2. In an embodiment, R2is ethyl, cyclopropyl, or CH2CF3.

[0036] In a preferred embodiment, R3is hydrogen, C^alkyl, Ci-shaloalkyl, choro or fluoro. In a more preferred embodiment, R3is hydrogen, methyl, CF3, fluoro, or chloro. In an even more preferred embodiment, R3is hydrogen, methyl, fluoro, or chloro. In a most preferred embodiment, R3is hydrogen or fluoro.

[0037] In a preferred embodiment, R4is hydrogen, C^alkyl, Ci-shaloalkyl, choro or fluoro. In a more preferred embodiment, R4is hydrogen, methyl, CF3, fluoro, or chloro. In an even more preferred embodiment, R4is hydrogen, methyl, fluoro, or chloro. In a most preferred embodiment, R4is hydrogen.

[0038] In a preferred embodiment, R5is hydrogen, C^alkyl, Ci-shaloalkyl, choro or fluoro. In a more preferred embodiment, R5is hydrogen, methyl, CF3, fluoro, or chloro. In an even more preferred embodiment, R5is hydrogen, methyl, fluoro, or CF3. In a most preferred embodiment, R5is hydrogen or methyl.

[0039] In a preferred embodiment, R6is Ci- alkyl, Cs-ecycloalkyl, or halo; and wherein said Ci- alkyl is unsubstituted or substituted with one to three groups R6A. In a more preferred embodiment, R6is Ci-salkyl, Cs-ecycloalkyl, or halo; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups R6A. In an even more preferred embodiment, R6isCi-salkyl, Cs-4cycloalkyl, or halo; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups R6A. In a yet more preferred embodiment, R6is Ci-salkyl, C^cycloalkyl, or chloro; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups R6A. In a most preferred embodiment, R6is Ci-salkyl, or C^cycloalkyl; wherein said Ci-salkyl is unsubstituted or substituted with one to three groups R6A. In an embodiment, R6is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl, or chloro; and wherein said methyl, ethyl, and propyl groups are unsubstituted or substituted with one to three groups selected from fluoro, hydroxy, methoxy, C^cycloalkyl, and pyrrolidinyl. In an embodiment, R6is ethyl, propyl, isopropyl, butyl, or pentyl. In an embodiment, R6is propyl.

[0040] In a preferred embodiment, R6Ais independently selected from fluoro, hydroxy, Ci-salkoxy, Cs-ecycloalkyl, and 4- to 6-membered heterocyclyl. In a more preferred embodiment, R6Ais independently selected from fluoro, hydroxy, methoxy, C^cycloalkyl, and 4- to 6-membered heterocyclyl. In an even more preferred embodiment, R6Ais independently selected from fluoro, hydroxy, methoxy, C^cycloalkyl, and pyrrolidinyl. In a most preferred embodiment, R6Ais C^cycloalkyl.

[0041] In a preferred embodiment, the compound of formula I has one of the structural formulae IA to IF (sub-structures of formula I), or a salt thereof:wherein R1a, R1 b, R2, R3, R4, R5and R6are as defined in any of the embodiments set out above and the same preferences apply.

[0042] In an embodiment, there is provided a compound of formula (I C) , or a salt thereof, wherein R2is hydrogen, Ci-salkyl, or cyclopropyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from halo and NR7R8, wherein R7and R8are independently selected from hydrogen and Ci-salkyl; R3is hydrogen, Ci-salkyl, Ci-shaloalkyl, choro or fluoro; and R6is Ci-salkyl, Cs-4cycloalkyl, or chloro; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups R6Aselected from fluoro, hydroxy, methoxy, Cs^cycloalkyl, and 4- to 6- membered heterocyclyl. In an embodiment, there is provided a compound of formula (IC), or a salt thereof, wherein R2is methyl, ethyl, propyl, isopropyl, cyclopropyl, CH2CF3, CH2CH2F, or CH2CH2NMe2; R3is hydrogen or fluoro; and R6is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl, or chloro; and wherein said methyl, ethyl, and propyl groups are unsubstituted or substituted with one to three groups selected from fluoro, hydroxy, methoxy, C^cycloalkyl, and pyrrolidinyl.

[0043] In an embodiment, there is provided a compound of formula (IF), or a salt thereof, wherein R2is hydrogen, Ci-salkyl, or cyclopropyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from halo and NR7R8, wherein R7and R8are independently selected from hydrogen and Ci-salkyl; R3is hydrogen, Ci-salkyl, Ci-shaloalkyl, choro or fluoro; and R5is hydrogen, Ci-salkyl, Ci-shaloalkyl, choro or fluoro. In an embodiment, there is provided a compound of formula (IF), or a salt thereof, wherein R2ismethyl, ethyl, propyl, isopropyl, cyclopropyl, CH2CF3, CH2CH2F, or CH2CH2NMe2; R3is hydrogen or fluoro; and R5is hydrogen or methyl.

[0044] In an embodiment, the compound of formula (I) is selected from the following compounds and salts thereof:4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1 ,5-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-isopropyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-(2-(dimethylamino)ethyl)-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1 ,3,3,5-tetramethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-3,3,5-trimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-3,3-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-3-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-3,5-dimethylindolin-2-one;1-Ethyl-4-(4-ethyl-2,6-dihydroxyphenyl)-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-isopropylphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Butyl-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-pentylphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Chloro-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Butyl-2,6-dihydroxyphenyl)-1-ethylindolin-2-one;4-(4-Butyl-2,6-dihydroxyphenyl)-1-methylindolin-2-one;4-(2,6-Dihydroxy-4-pentylphenyl)-1-methylindolin-2-one;4-(2,6-Dihydroxy-4-pentylphenyl)-1-ethylindolin-2-one;4-(2,6-Dihydroxy-4-pentylphenyl)-1 ,5-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-5-methyl-1-propylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-5-methyl-1-(2,2,2-trifluoroethyl)indolin-2-one;4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-3,3-difluoro-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-7-fluoro-1 ,5-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-7-fluoro-5-methylindolin-2-one;4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-6-fluoro-5-methylindolin-2-one;7-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;6-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;6-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-7-fluoroindolin-2-one;4-(4-cyclopropyl-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Cyclobutyl-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-5-methylindolin-2-one;1-Cyclopropyl-4-(2,6-dihydroxy-4-propylphenyl)indolin-2-one;1-Cyclopropyl-4-(2,6-dihydroxy-4-propylphenyl)-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-7-fluoroindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5,7-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5,6-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-(2,2,2-trifluoroethyl)indolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-(trifluoromethyl)indolin-2-one;1-Cyclopropyl-4-(2,6-dihydroxy-4-propylphenyl)-7-fluoro-5-methylindolin-2-one;1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-dihydroxyphenyl)-7-fluoro-5-methylindolin-2- one;4-(4-(Cyclopropylmethyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-dihydroxyphenyl)-5-methylindolin-2-one;4-(4-(2,2-Difluoropropyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-(1,1-Difluoropropyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-(2-Cyclopropylethyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-(Cyclobutylmethyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-(2-hydroxy-2-methylpropyl)phenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-(2-methoxy-2-methylpropyl)phenyl)-1-ethyl-5-methylindolin-2-one;7-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-methylindolin-2-one;7-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-ethylindolin-2-one;4-(2,6-Dihydroxy-4-(3,3,3-trifluoropropyl)phenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-(pyrrolidin-1-ylmethyl)phenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1,3,3-trimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-3,3,5-trimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-(2-fluoroethyl)-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-fluoroindolin-2-one;4-(2,6-Dihydroxy-4-isobutylphenyl)-1-ethyl-5-methylindolin-2-one; and 4-(2,6-Dihydroxy-4-isopentylphenyl)-1-ethyl-5-methylindolin-2-one.

[0045] In a preferred embodiment, the compound of formula (I) is selected from the following compounds and salts thereof:4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;1-Ethyl-4-(4-ethyl-2,6-dihydroxyphenyl)-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-isopropylphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-7-fluoro-5-methylindolin-2-one;4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-6-fluoro-5-methylindolin-2-one;4-(4-Cyclobutyl-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-(2,2,2-trifluoroethyl)indolin-2-one;1-Cyclopropyl-4-(2,6-dihydroxy-4-propylphenyl)-7-fluoro-5-methylindolin-2-one;1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-dihydroxyphenyl)-7-fluoro-5-methylindolin-2- one;4-(4-(Cyclopropylmethyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-dihydroxyphenyl)-5-methylindolin-2-one;4-(4-(2-Cyclopropylethyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-isobutylphenyl)-1-ethyl-5-methylindolin-2-one; and 4-(2,6-Dihydroxy-4-isopentylphenyl)-1-ethyl-5-methylindolin-2-one.

[0046] In a more preferred embodiment, the compound of formula (I) is selected from the following compounds and salts thereof:4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-7-fluoro-5-methylindolin-2-one; 4-(4-(Cyclopropylmethyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one; and 1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-dihydroxyphenyl)-5-methylindolin-2-one.

[0047] In a most preferred embodiment, the compound of formula (I) is 4-(2,6-Dihydroxy- 4-propylphenyl)-1-ethyl-5-methylindolin-2-one, or a salt thereof.Salts

[0048] In some embodiments, the compounds of formula (I) are provided in free base form.

[0049] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in “Pharmaceutical Salts: Properties, Selection, and Use”, 2ndEdition, 2002, Stahl and Wermuth (Eds), Wiley-VCH, Weinheim, Germany.

[0050] Accordingly, in some embodiments the compounds of formula (I) are provided as salts, for example in a protonated form together with a suitable counter anion.

[0051] Suitable counter anions include both organic and inorganic anions. Example of suitable inorganic anions include those derived from inorganic acids, including chloride (Cl’), bromide (Br), iodide (I’), sulfate (SC>42’), sulfite (SOs2’), nitrate (NOs’), nitrite (NO2 , phosphate (PO ’), and phosphite (POs3’). Examples of suitable organic anions include 2-acetoxybenzoate, acetate, ascorbate, aspartate, benzoate, camphorsulfonate, cinnamate, citrate, edetate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, glutamate, glycolate, hydroxymalate, carboxylate, lactate, laurate, lactate, maleate, malate, methanesulfonate, oleate, oxalate, palmitate, phenylacetate, phenylsulfonate, propionate, pyruvate, salicylate, stearate, succinate, sulfanilate, tartarate, toluenesulfonate, and valerate. Examples of suitable polymeric organic anions include those derived from tannic acid and carboxymethyl cellulose. In an embodiment, the counter anion is chloride or formate, such as formate.

[0052] Alternatively, in some embodiments the compounds of formula (I) are provided as salts, for example in a deprotonated form together with a suitable counter cation.

[0053] Suitable counter cations include both organic and inorganic cations. Examples of suitable inorganic cations include alkali metal ions such as Na+and K+, alkaline earth cations such as Ca2+and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include the ammonium ion (i.e. , NH4+) and substituted ammonium ions (e.g., NHsR+, NH2R2+, NHRs+, NR4+). Examples of substituted ammonium ions include those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline,meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CHs)4+.

[0054] In a preferred embodiment there is provided a compound of formula (I), or a pharmaceutically-acceptable salt thereof.Solvates

[0055] In some embodiments, the compounds of formula (I) are provided in desolvated form, for example, in dehydrated form.

[0056] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compound.

[0057] Accordingly, in some embodiments the compounds of formula (I) are provided in the form of a solvate (a complex of solute (e.g., compound, salt of compound) and solvent). Examples of solvates include hydrates, for example, a mono-hydrate, a di-hydrate and a trihydrate.N-Oxides

[0058] Where compounds of formula (I) contain an sp2nitrogen atom (-N=), for example in a heteroaryl group, it may be convenient to prepare, purify, and / or handle the corresponding N-oxide (-N(^O)=), also denoted as (-N+(O')=).

[0059] Accordingly, in some embodiments certain compounds of formula (I) are provided in the form of an N-oxide. For example, pyridine may be substituted to give pyridine N- oxide.Certain Isomers

[0060] Certain compounds of formula (I) may exist in one or more particular optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, or conformational forms, including but not limited to, D- and L-forms; d- and l-forms; (+) and (-) forms; syn- and antiforms; axial and equatorial forms; boat-, chair-, twist boat-, envelope-, and half chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" or "isomeric forms".

[0061] Specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e. , isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference 2-pyridinyl is not to be construed as a reference to its structural isomer, 3-pyridinyl.

[0062] The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol, imine / enamine, amide / imino alcohol, nitroso / oxime, and lactam / lactim.

[0063] Included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D), and3H (T); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like.

[0064] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.Methods of Synthesis

[0065] Methods for the synthesis of specific example compounds within the scope of formula (I) are set out in the worked examples.

[0066] The invention provides a first method of preparing a compound of formula (I), the method comprising:(1a) reacting a compound of formula (II) with a compound of formula (III) to give a compound of formula (IV):wherein:R1a, R1 b, R2, R3, R4, R5and R6are as defined herein and the same preferences apply;X is chloro, bromo, iodo, or triflate;Y is BF3Z, wherein Z is a suitable counter-cation such as Na or K, or Y isB(OR11)OR12, wherein R11and R12are hydrogen, Ci-ealkyl, or phenyl; or R11and R12, together with the oxygen and boron atoms to which they are attached, form a 5- to 8-membered cyclic boronic ester; andR9and R10are suitable alcohol protecting groups, and(1b) converting a compound of formula (IV) to a compound of formula (I).

[0067] The invention provides a second method of preparing a compound of formula (I), the method comprising:(1a) reacting a compound of formula (V) with a compound of formula (VI) to give a compound of formula (IV):wherein:R1a, R1 b, R2, R3, R4, R5and R6are as defined herein and the same preferences apply;X is chloro, bromo, iodo, or triflate;Y is BF3Z, wherein Z is a suitable counter-cation such as Na or K, or Y is B(OR11)OR12, wherein R11and R12are hydrogen, Ci-ealkyl, or phenyl; or R11and R12, together with the oxygen and boron atoms to which they are attached, form a 5- to 8-membered cyclic boronic ester; andR9and R10are suitable alcohol protecting groups, and(1b) converting a compound of formula (IV) to a compound of formula (I).

[0068] In a preferred embodiment of the first or second method, X is bromo, iodo or triflate. In a more preferred embodiment, X is bromo or iodo. In an even more preferred embodiment, X is bromo.

[0069] In some embodiments of the first or second method, Y is B(OR11)OR12, wherein R11and R12, together with the oxygen and boron atoms to which they are attached, form a 5- to 8-membered cyclic boronic ester. Suitable 5- to 8-membered cyclic boronic esters include those derived from pinacol, neopentyl glycol, 1 ,3-propanediol, catechol, diethanolamine, / V- methyldiethanolamine, / V-phenyldiethanolamine, and / V-methyliminodiacetic acid (MIDA). In

[0070] In a preferred embodiment of the first or second method, Y is B(OR11)OR12, wherein R11and R12are hydrogen, Ci-ealkyl or phenyl; or R11and R12together form, . In a more preferred embodiment, Y isB(OR11)OR12and R11and R12are both hydrogen (a boronic acid); or R11and R12togetherform pinacol boronic ester). In a most preferred embodiment, Y is B(ORR11and R12are both hydrogen (boronic acid).

[0071] In an embodiment of the first or second method, R9and R10are alcohol protecting groups selected from methyl, methoxym ethyl, 2-(trimethylsilyl)ethoxymethyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, benzyl, and 4-methoxybenzyl. In a preferred embodiment, R9and R10are methyl or benzyl. In a more preferred embodiment of the first or second method, R9and R10are both methyl. In another more preferred embodiment of the first or second method, R9and R19are both benzyl.

[0072] Step (1a) of the first and second method may be known as the coupling step. Preferably, step (1a) of the first method comprises reacting a compound of formula (II) with a compound of formula (III) and a palladium catalyst. Preferably, step (1a) of the second method comprises reacting a compound of formula (V) with a compound of formula (VI) and a palladium catalyst. Suitable palladium catalysts include Pd(dppf)Cl2, X-Phos-Pd-G3 ((2- Dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 biphenyl)]palladium(ll) methanesulfonate), SPhos-Pd-G2 (Chloro(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,T-biphenyl)[2-(2'-amino-1 ,T-biphenyl)]palladium(ll)), cataCXium® A Pd G3 ([(Di(1-adamantyl)-butylphosphine)-2-(2'-amino-1 ,1'-biphenyl)]palladium(ll) methanesulfonate), APhos-Pd-G3 ([4-(Di-terf-butylphosphino)-A / ,A / -dimethylaniline-2-(2'- aminobiphenyl)]palladium(ll) methanesulfonate), P(Cys)-Pd-G3 ([(Tricyclohexylphosphine)-2- (2'-aminobiphenyl)]palladium(ll) methanesulfonate), and PEPPSI-IPENT (Dichloro[1 ,3- bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll)). Preferred palladium catalysts are Pd(dppf)Ch and SPhos-Pd-G2 (Chloro(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,T-biphenyl)[2-(2'-amino-1 ,T-biphenyl)]palladium(ll)). In a most preferred embodiment, step (1a) of the first method comprises reacting a compound of formula (II) with a compound of formula (III) in the presence of SPhos-Pd-G2 (Chloro(2- dicyclohexylphosphino-2',6'-dimethoxy-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 biphenyl)]palladium(ll)).

[0073] Preferably, step (1a) of the first method further comprises reacting a compound of formula (II) with a compound of formula (III) and a base. Preferably, step (1a) of the second method further comprises reacting a compound of formula (V) with a compound of formula (VI) and a base. Suitable bases include sodium carbonate (Na2COs), potassium carbonate (K2CO3), caesium carbonate (CS2CO3), and potassium phosphate. In a most preferred embodiment, step (1a) of the first method comprises reacting a compound of formula (II) with a compound of formula (III) in the presence of potassium carbonate (K2CO3).

[0074] Typically, step (1a) of the first or second method is carried out in a solvent. Suitable solvents include dioxane, tetra hydrofuran (THF), dimethylformamide (DMF), cyclopentyl methyl ether (CPME), 1,2-dimethoxyethane (DME), dimethylacetamide (DMA), toluene, ethanol, propanol, isopropanol, butan-1-ol, butan-2-ol, pentanol, water, and mixtures thereof. In a preferred embodiment, the solvent is selected from dioxane, dimethylformamide (DMF),cyclopentyl methyl ether (CPME), water, toluene, ethanol, and mixtures thereof. In a most preferred embodiment, the solvent is a mixture of toluene and ethanol. In an alternative embodiment, the solvent is a mixture of cyclopentyl methyl ether (CPME) and water.

[0075] Optionally, certain additives may be used in step (1a). Suitable additives include caesium fluoride (CsF).

[0076] Step (1a) of the first or second method is typically performed at elevated temperature (above ambient temperature; approximately 20 °C). Methods for providing heat during the reaction are known and include, for example, using a reaction vessel having an external heating jacket or using microwave heating.

[0077] Typically, step (1a) of the first or second method is carried out at a temperature of from 60 °C to 160 °C, preferably 80 °C to 160 °C, more preferably 80 °C to 120 °C. Alternatively, step (1a) of the first or second method is carried out at a temperature of from 100 °C to 150 °C.

[0078] Step (1a) may be performed for sufficient time to allow a desired quantity of the coupling product to form. Typically, the step (1a) of the first method is performed until substantially all of the compound of formula (II) has been consumed. Typically, the step (1a) of the second method is performed until substantially all of the compound of formula (V) has been consumed.

[0079] Typically, the step (1a) is carried out for between 1 hour and 24 hours, such as 1 to 2 hours, 2 to 10 hours, or 10 to 20 hours.

[0080] In a most preferred embodiment, step (1a) of the first method comprises reacting a compound of formula (II) with a compound of formula (III) in the presence of a palladium catalyst (preferably SPhos-Pd-G2) and a base (preferably potassium carbonate).

[0081] Step (1b) of the first or second method may be known as the deprotection step. Step (1b) of the first or second method comprises reacting a compound of formula (IV) under conditions suitable for removal of the R9and R10protecting groups. A skilled person will be able to determine suitable deprotection conditions, depending on the nature of the R11and R12protecting groups.

[0082] In a preferred embodiment, R9and R10are both methyl. In such embodiments, step (1b) comprises reacting a compound of formula (IV) with a Lewis acid, such as BBrs, AlCh, BeCh, trimethylsilyl iodide, pyridine hydrochloride, or HBr. In such embodiments, step (1 b) preferably comprises reacting a compound of formula (IV) with BBrs. In such embodiments, step (1b) is typically carried out in a solvent. Suitable solvents include dichloromethane (DCM) and acetic acid. In such embodiments, step (1b) is typically performed at a temperature of from 0 °C to 30 °C, preferably 0 °C to 20 °C. Alternatively, step (1b) is performed at a temperature of from 80°C to 140 °C.

[0083] In a preferred embodiment, R9and R10are both methyl and step (1b) comprises reacting a compound of formula (IV) with BBrs in DCM at a temperature of 0 °C to 20 °C. In another preferred embodiment, R9and R10are both methyl and step (1 b) comprises reactinga compound of formula (IV) with HBr in acetic acid at a temperature of 80°C to 140 °C (such as 80°C to 100 °C, or 110°C to 130 °C).

[0084] In a preferred embodiment, R9and R10are both benzyl. In such embodiments, step (1b) comprises reacting a compound of formula (IV) with hydrogen in the presence of a suitable catalyst (such as palladium on carbon, or platinum on carbon) and a suitable solvent (such as methanol, ethanol, acetonitrile, or tetrahydrofuran (THF)).

[0085] The invention also provides a compound obtained or obtainable by the first or second method set out in paragraphs

[0066] to

[0084] above.Intermediates

[0086] The invention provides intermediates useful in the preparation of a compound formula (I). An intermediate of the invention is a compound of formula (II):wherein,R1a, R1 b, R2, R3, R4, R5, and X are as defined herein and the same preferences apply.

[0087] In an embodiment there is provided a compound of formula (II), wherein R1aand R1 bare both hydrogen, or both methyl. In an embodiment there is provided a compound of formula (II), wherein R2is hydrogen, Ci-salkyl, or cyclopropyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from fluoro and NR7R8, wherein R7and R8are both Ci-salkyl. In an embodiment there is provided a compound of formula (II), wherein R3is hydrogen, methyl, fluoro, or chloro. In an embodiment there is provided a compound of formula (II), wherein R4is hydrogen, methyl, fluoro, or chloro. In an embodiment there is provided a compound of formula (II), wherein R5is hydrogen, methyl, fluoro, or trifluoromethyl. In an embodiment there is provided a compound of formula (II), wherein X is bromo.

[0088] In an embodiment, there is provided a compound of formula (II) selected from: 4-bromo-1-ethyl-5-methylindolin-2-one;4-Bromo-1 ,5-dimethylindolin-2-one;4-Bromo-1-isopropyl-5-methylindolin-2-one;4-Bromo-5-methyl-1-propylindolin-2-one;4-Bromo-5-methyl-1-(2,2,2-trifluoroethyl)indolin-2-one; 4-Bromo-1-(2,2,2-trifluoroethyl)indolin-2-one;4-Bromo-1-ethylindolin-2-one;4-bromo-1-(2-(dimethylamino)ethyl)-5-methylindolin-2-one;4-Bromo-7-fluoro-1-methylindolin-2-one;4-Bromo-1-ethyl-7-fluoroindolin-2-one;4-Bromo-1-ethyl-7-fluoro-5-methylindolin-2-one;4-Bromo-6-chloro-1-ethyl-7-fluoroindolin-2-one;4-Bromo-1-ethyl-5,7-dimethylindolin-2-one;4-Bromo-1-ethyl-5,6-dimethylindolin-2-one;4-Bromo-1-ethyl-5-(trifluoromethyl)indolin-2-one;4-Bromo-1-ethyl-6- fluoro- 5-methylindolin-2-one;4-Bromo-1-cyclopropylindolin-2-one;4-Bromo-1-cyclopropyl-5-methylindolin-2-one;4-Bromo-1-cyclopropyl-7-fluoro-5-methylindolin-2-one;4-Bromo-1-ethyl-3,3-difluoro-5-methylindolin-2-one;4-Bromo-1 ,3,3,5-tetramethylindolin-2-one;4-Bromo-1-ethyl-3,3,5-trimethylindolin-2-one;4-Bromo-1-ethyl-3,5-dimethylindolin-2-one;4-Bromo-7-chloro-1-ethyl-5-methylindoline-2, 3-dione;4-bromo-6-chloro-1-ethyl-5-methylindoline-2, 3-dione;4-Bromo-6-chloro-1-ethyl-5-methylindolin-2-one; and4-Bromo-7-chloro-1-ethyl-5-methylindolin-2-one.

[0089] In an embodiment, there is provided a compound of formula (II) which is 4-bromo- 1-ethyl-5-methylindolin-2-one.

[0090] A further intermediate of the invention is a compound of formula (V):wherein,R1a, R1 b, R2, R3, R4, R5, and Y are as defined herein and the same preferences apply.

[0091] In an embodiment there is provided a compound of formula (V), wherein R1aand R1 bare both hydrogen, or both methyl. In an embodiment there is provided a compound of formula (V), wherein R2is hydrogen, Ci-salkyl, or cyclopropyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from fluoro and NR7R8, wherein R7and R8are both Ci-salkyl. In an embodiment there is provided a compound of formula (V), wherein R3is hydrogen, methyl, fluoro, or chloro. In an embodiment there is provided a compound of formula (V), wherein R4is hydrogen, methyl, fluoro, or chloro. In an embodiment there is provided a compound of formula (V), wherein R5is hydrogen, methyl, fluoro, or trifluoromethyl. In an embodiment there is provided a compound of formula (V), wherein Y is B(OR11)OR12and R11and R12are hydrogen, alkyl or phenyl; or R11and R12are joined to form a cyclic boronic ester (such as pinacol, neopentyl or catechol boronic esters).In a preferred R11and R12together form -C(Me)2C(Me)2- (a pinacol boronic ester). In an alternative preferred embodiment R11and R12are both hydrogen.

[0092] In an embodiment, there is provided a compound of formula (V) selected from: 1-Ethyl-5-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)indolin-2-one; and 1-Cyclopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)indolin-2-one;

[0093] A further intermediate of the invention is a compound of formula (IV):wherein,R1a, R1 b, R2, R3, R4, R5, and R6are as defined herein and the same preferences apply; andR9and R10are suitable alcohol protecting groups.

[0094] In an embodiment there is provided a compound of formula (IV), wherein R1aand R1 bare both hydrogen, or both methyl. In an embodiment there is provided a compound of formula (V), wherein R2is hydrogen, Ci-salkyl, or cyclopropyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from fluoro and NR7R8, wherein R7and R8are both Ci-salkyl. In an embodiment there is provided a compound of formula (V), wherein R3is hydrogen, methyl, fluoro, or chloro. In an embodiment there is provided a compound of formula (V), wherein R4is hydrogen, methyl, fluoro, or chloro. In an embodiment there is provided a compound of formula (V), wherein R5is hydrogen, methyl, fluoro, or trifluoromethyl. In an embodiment there is provided a compound of formula (IV), wherein R6is Ci-salkyl, Cs-4cycloalkyl, or chloro; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups R6Aselected from fluoro, hydroxy, methoxy, Cs- 4cycloalkyl, and pyrrolidinyl. In an embodiment there is provided a compound of formula (IV), wherein R9and R10are alcohol protecting groups selected from methyl, methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, benzyl, and 4-methoxybenzyl. In a preferred embodiment, R9and R10are methyl or benzyl. In a most preferred embodiment there is provided a compound of formula (IV), wherein R9and R10are methyl. In an alternative preferred embodiment there is provided a compound of formula (IV), wherein R9and R10are benzyl.

[0095] In an embodiment, there is provided a compound of formula (IV) selected from: 4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one; 4-(2,6-Dimethoxy-4-propylphenyl)-1 ,5-dimethylindolin-2-one; 4-(2,6-Dimethoxy-4-propylphenyl)-1-isopropyl-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyllindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-(2-(dimethylamino)ethyl)-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1 ,3,3,5-tetramethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-3,3,5-trimethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-3,3-dimethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-3-methylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-3,5-dimethylindolin-2-one;1-Ethyl-4-(4-ethyl-2,6-dimethoxyphenyl)-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-isopropylphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Butyl-2,6-dimethoxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-pentylphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Chloro-2,6-dimethoxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Butyl-2,6-dimethoxyphenyl)-1-ethylindolin-2-one;4-(4-Butyl-2,6-dimethoxyphenyl)-1-methylindolin-2-one;4-(2,6-Dimethoxy-4-pentylphenyl)-1-methylindolin-2-one;4-(2,6-Dimethoxy-4-pentylphenyl)-1-ethylindolin-2-one;4-(2,6-Dimethoxy-4-pentylphenyl)-1 ,5-dimethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-5-methyl-1-propylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-5-methyl-1-(2,2,2-trifluoroethyl)indolin-2-one;4-(2,6-dimethoxy-4-propylphenyl)-1-ethyl-3,3-difluoro-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-7-fluoro-1 ,5-dimethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-7-fluoro-5-methylindolin-2-one;4-(2,6-dimethoxy-4-propylphenyl)-1-ethyl-6-fluoro-5-methylindolin-2-one;7-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;6-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;6-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-ethyl-7-fluoroindolin-2-one;4-(4-cyclopropyl-2,6-dimethoxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Cyclobutyl-2,6-dimethoxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-methylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-5-methylindolin-2-one;1-Cyclopropyl-4-(2,6-bis(benzyloxy)-4-propylphenyl)indolin-2-one;1-Cyclopropyl-4-(2,6-bis(benzyloxy)-4-propylphenyl)-5-methylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-7-fluoroindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-5,7-dimethylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-5,6-dimethylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-(2,2,2-trifluoroethyl)indolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-5-(trifluoromethyl)indolin-2-one;1-Cyclopropyl-4-(2,6-bis(benzyloxy)-4-propylphenyl)-7-fluoro-5-methylindolin-2-one;1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-bis(benzyloxy)phenyl)-7-fluoro-5-methylindolin-2-one;4-(4-(Cyclopropylmethyl)-2,6-bis(benzyloxy)phenyl)-1-ethyl-5-methylindolin-2-one;1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-bis(benzyloxy)phenyl)-5-methylindolin-2-one;4-(4-(2,2-Difluoropropyl)-2,6-bis(benzyloxy)phenyl)-1-ethyl-5-methylindolin-2-one; 4-(4-(1,1-Difluoropropyl)-2,6-bis(benzyloxy)phenyl)-1-ethyl-5-methylindolin-2-one; 4-(4-(2-Cyclopropylethyl)-2,6-bis(benzyloxy)phenyl)-1-ethyl-5-methylindolin-2-one; 4-(4-(Cyclobutylmethyl)-2,6-bis(benzyloxy)phenyl)-1-ethyl-5-methylindolin-2-one; 4-(2,6-Bis(benzyloxy)-4-(2-hydroxy-2-methylpropyl)phenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-(2-methoxy-2-methylpropyl)phenyl)-1-ethyl-5-methylindolin-2-one; 7-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-methylindolin-2-one;7-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-ethylindolin-2-one;4-(2,6-Dimethoxy-4-(3,3,3-trifluoropropyl)phenyl)-1-ethyl-5-methylindolin-2-one; 4-(2,6-Dimethoxy-4-(pyrrolidin-1-ylmethyl)phenyl)-1-ethyl-5-methylindolin-2-one; 4-(2,6-Dimethoxy-4-propylphenyl)-1,3,3-trimethylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-3,3,5-trimethylindolin-2-one; 4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-(2-fluoroethyl)-5-methylindolin-2-one; 4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-5-fluoroindolin-2-one;1-Ethyl-4-(4-isobutyl-2,6-dimethoxyphenyl)-5-methylindolin-2-one; and 1-Ethyl-4-(4-isopentyl-2,6-dimethoxyphenyl)-5-methylindolin-2-one.

[0096] In an embodiment, there is provided a compound of formula (IV) which is 4-(2,6- Dimethoxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one.Pharmaceutical Compositions

[0097] While it is possible for the compounds of formula (I) to be administered alone, it is preferable to administer a pharmaceutical composition (e.g., a formulation, preparation, or medicament) comprising a compound of formula (I) together with one or more other pharmaceutically acceptable ingredients.

[0098] Accordingly, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a salt thereof, together with one or more pharmaceutically acceptable ingredients.

[0099] Suitable pharmaceutically acceptable ingredients (e.g. carriers, diluents, excipients, etc.) can be found in standard pharmaceutical texts, for example, Remington: The Science and Practice of Pharmacy, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins; and Handbook of Pharmaceutical Excipients, 9th edition, 2020, pub. Pharmaceutical Press.

[0100] Examples of suitable pharmaceutically acceptable ingredients include pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.

[0101] The pharmaceutical composition may be in any suitable form. Examples of suitable forms include liquids, solutions (e.g., aqueous, nonaqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, lozenges,pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.Medical Treatment

[0102] The inventors have found that the compounds of formula (I) are biologically active. The worked examples demonstrate that compounds of formula (I) display anticonvulsant activity in rodent models of generalised seizure. As such, compounds of formula (I), and their salts, as well as pharmaceutical compositions comprising compounds of formula (I), or their salts, will be useful in medical treatment.

[0103] Accordingly, the invention provides a compound of formula (I), or a salt thereof, for use in a method of treatment, for example for use in a method of treatment of the human or animal body by therapy (i.e. a method of therapy).

[0104] The invention also provides a compound of formula (I), or a salt thereof, for use as a medicament.

[0105] The invention also provides a method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I), or a salt thereof.

[0106] The invention also provides the use of compound of formula (I), or a salt thereof, for the manufacture of a medicament.

[0107] The invention also provides the use of a compound of formula (I), or a salt thereof, as a medicament.Conditions Treated

[0108] The inventors have found that the compounds of formula (I) display anticonvulsant activity in rodent models of generalised seizure. Accordingly, the compounds of formula (I), or their salts, as well as pharmaceutical compositions comprising the compounds of formula (I), or their salts, will be useful in the treatment of certain conditions associated with seizure.

[0109] Similarly, the compounds of formula (I), or their salts, as well as pharmaceutical compositions comprising the compounds of formula (I) or their salts, will be useful as medicaments for treating (and in the manufacture of medicaments for treating) certain conditions associated with seizure.Seizure Types

[0110] In an embodiment, the condition associated with seizure is selected from focal onset seizure (focal seizure), generalised onset seizure (generalised seizure), and seizure with unknown onset (unknown onset seizure).

[0111] Focal onset seizures may be further characterised by the level of awareness. In an embodiment, the focal onset seizure is focal onset seizure with awareness. In an embodiment, the focal onset seizure is a focal onset seizure with impaired awareness (with impairment).

[0112] Focal onset seizures may be further characterised by motor onset or non-motor onset features. In an embodiment, the focal onset seizure is a focal onset seizure with a motor onset feature, such as a motor onset feature selected from automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic and tonic. In an embodiment, the focal onset seizure is a focal onset seizure with a non-motor onset feature, such as a nonmotor onset feature selected from autonomic, behaviour arrest, cognitive, emotional and sensory.

[0113] Focal onset seizures may also present with focal to bilateral tonic-clonic propagation. In an embodiment, the focal onset seizure is a focal to bilateral tonic-clonic seizure.

[0114] Generalised onset seizures may be characterised by motor or non-motor (absence) features. In an embodiment, the generalised onset seizure is a generalised onset seizure with a motor feature, such as a motor feature selected from tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic and epileptic spasms. In an embodiment, the generalised onset seizure is a generalised onset seizure with a non-motor (absence) feature, such as a non-motor (absence) feature selected from typical, atypical, myoclonic and eyelid myoclonia.

[0115] Seizures with unknown onset may be characterised by motor or non-motor features. In an embodiment, the unknown onset seizure is an unknown onset seizure with a motor feature, such as a motor feature selected from tonic-clonic and epileptic spasms. In an embodiment, the unknown onset seizure is an unknown onset seizure with a non-motor (absence) feature, such as behavioural arrest.

[0116] In an embodiment, the condition associated with seizure is a seizure type that may be present in one or more of focal onset, generalised onset or unknown onset seizures, such as a seizure type selected from typical absence seizure, atypical absence seizure, atonic seizure, clonic seizure, tonic seizure, tonic-clonic seizure, febrile seizure, focal to bilateral tonic clonic seizure, gelastic and dacrystic seizure, myoclonic seizure, myoclonic-tonic-clonic seizure, myoclonic-atonic seizure, and epileptic (or infantile) spasms.

[0117] In an embodiment, the condition associated with seizure is an epilepsy, such as an epilepsy selected from focal epilepsy, generalised epilepsy, and combined generalised & focal epilepsy.

[0118] In an embodiment, the condition associated with seizure is an epilepsy syndrome, such as an epilepsy syndrome selected from syndromes with onset in neonates and infancy,syndromes with onset in childhood, syndromes with onset at a variable age, and idiopathic generalised epilepsy syndromes (IGEs).

[0119] In an embodiment the condition associated with seizure is an epilepsy syndrome with onset in neonates and infancy, such as an epilepsy syndrome with onset in neonates and infancy selected from self-limited epilepsies (such as self-limited neonatal epilepsy, selflimited familial neonatal-infantile epilepsy, self-limited infantile epilepsy, genetic epilepsy with febrile seizures plus, or myoclonic epilepsy in infancy), developmental and epileptic encephalopathies - DEEs (such as early infantile developmental and epileptic encephalopathy (EIDEE), epilepsy in infancy with migrating focal seizures (EIMFS), infantile epileptic spasms syndrome (West Syndrome), or Dravet syndrome), and aetiology-specific syndromes (such as KCNQ2-DEE, pyridoxine-dependent DEE, pyridox(am)ine 5’-phosphate deficiency DEE, CDKL5-DEE, PCDH19 clustering epilepsy, glucose transporter 1 deficiency syndrome, gelastic seizures with hypothalamic hamartoma, or Sturge Weber syndrome) - further information is provided in the aetiology section below.

[0120] In an embodiment the condition associated with seizure is an epilepsy syndrome with onset in childhood, such as an epilepsy syndrome with onset in childhood selected from self-limited focal epilepsies (such as childhood occipital visual epilepsy (COVE), self-limited epilepsy with autonomic seizures, self-limited epilepsy with centrotemporal spikes, or photosensitive occipital lobe epilepsy (POLE)), DEEs with onset in childhood (such as epilepsy with myoclonic atonic seizures, Lennox Gastaut syndrome, febrile infection-related epilepsy syndrome (FIRES), hemiconvulsion-hemiplegia-epilepsy syndrome, developmental and epileptic encephalopathy with spike-and-wave activation in sleep (EE-SWAS), or Landau-Kleffner syndrome), and genetic generalised epilepsies (such as epilepsy with eyelid myoclonia, or epilepsy with myoclonic absence).

[0121] In an embodiment the condition associated with seizure is an epilepsy syndrome with onset at a variable age, such as an epilepsy syndrome with onset at variable age selected from juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), epilepsy with generalised tonic-clonic seizures alone (GTCA), childhood occipital visual epilepsy (COVE), photosensitive occipital lobe epilepsy (POLE), familial mesial temporal lobe epilepsy (FMTLE), epilepsy with auditory features (EAF), mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), sleep-related hypermotor / hyperkinetic epilepsy (SHE), familial focal epilepsy with variable foci (FFEVF), progressive myoclonus epilepsies (PME), febrile-infection related epilepsy syndrome (FIRES) and Rasmussen syndrome.

[0122] In an embodiment the condition associated with seizure is an idiopathic generalised epilepsy syndrome (IGE), such as an IGE selected from childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalised tonic-clonic seizures alone (GTCA).Aetiology

[0123] In an embodiment, the condition associated with seizure is an epilepsy defined by aetiology (cause), such as an epilepsy having an aetiology selected from structural, genetic, infection, metabolic, and autoimmune.

[0124] In an embodiment, the condition associated with seizure is an epilepsy having a structural aetiology ("structural epilepsy"), such as a structural aetiology selected from focal cortical dysplasia (FCD), hypothalamic hamartoma (HH), hypoxic ischemic encephalopathy (HIE), incontinent pigment (IP), mesial temporal sclerosis (MTS), neurofibromatosis type 1, multiple sclerosis (MS), encephalotrigeminal angiomatosis (Sturge Weber syndrome; SWS), traumatic brain injury (TBI); periventricular nodular heterotopia (PVNH), polymicrogyria (PMG), tuberous sclerosis complex (TSC), and brain tumours.

[0125] In an embodiment, the condition associated with seizure is an epilepsy having a genetic aetiology (“genetic epilepsy”), such as a genetic aetiology selected from Angelman Syndrome, PCDH19 mutation, ring chromosome 20 syndrome (RC20), CACNA1A mutation, CDKL5 deficiency disorder, GRIN2A mutation, SCN8A mutation, SLC2A1 (Glutl deficiency syndrome), TBCK mutation, Rett syndrome (MECP2 mutation), SYNGAP1 mutation, KCNQ2 mutation, STXBP1 mutation, SCN1A mutation, CHD2 mutation, PRRT2 mutation, SLC6A1 mutation, and GATORI-related epilepsy.

[0126] In an embodiment, the condition associated with seizure is an epilepsy having an infection aetiology (“infection epilepsy”), such as an infection aetiology selected from neurocysticercosis, cerebral malaria, TORCH infections (toxoplasmosis, other agents, rubella / German measles, cytomegalovirus, and herpes simplex), bacterial meningitis, viral encephalitis, tuberculosis, and human immunodeficiency virus (HIV).

[0127] In an embodiment, the condition associated with seizure is an epilepsy having a metabolic aetiology (“metabolic epilepsy”), such as a metabolic aetiology selected from glucose transporter type 1 (Glut 1) deficiency syndrome (SLC2A1), vitamin dependent metabolic disorders (such as pyridoxine, P5P or folinic acid dependent disorders), creatine transporter disorders, mitochondrial disorders, and storage disorders.

[0128] In an embodiment, the condition associated with seizure is an epilepsy having an autoimmune aetiology (“autoimmune epilepsy”), such as an autoimmune aetiology selected from Rasmussen syndrome, antiNMDA receptor encephalitis, limbic encephalitis (e.g. LGI1 antibody, or CASPR2 antibody related limbic encephalitis), and GAD65 antibody related epilepsy.Subject / Patient

[0129] The method of treatment typically comprises administering a compound of formula (I), or a salt thereof, to a subject or patient.

[0130] The subject / patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, arat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orang-utan, gibbon), or a human.

[0131] The subject / patient may be any of its forms of development, for example, the subject / patient may be a neonate, an infant, a child or an adult.

[0132] In a preferred embodiment, the subject / patient is a human, more preferably an adult human.

[0133] The subject / patient may also be a non-human mammal used in laboratory research, such as a rodent. Rodents include rats, mice, guinea pigs and chinchillas.Routes of Administration

[0134] The method of treatment may comprise administering a compound of formula (I), or a salt thereof, to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e. , at the site of desired action).

[0135] The route of administration may be oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection or infusion, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; or by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0136] The method of treatment typically comprises administering a therapeutically effective amount of a compound of formula (I), or a salt thereof, to a subject.

[0137] Appropriate dosages of the compounds of formula (I), their salts, as well as pharmaceutical compositions comprising the compounds of formula (I), or their salts, can vary from patient to patient. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound of formula (I), the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other active agents, compounds, and / or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.The dosage and route of administration will ultimately be at the discretion of the clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.

[0138] Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating clinician.Other Aspects and Embodiments

[0139] Each and every compatible combination of the embodiments described above is explicitly discloses herein, as if each and every combination was individually and explicitly recited.

[0140] Carious further aspects and embodiment of the present invention will be apparent to those skilled in the arti in view of the present disclosure.

[0141] Where used, “and / or” is to be taken as a specific disclosure of each of the relevant components or features alone as well as a specific disclosure of the combination of the components or features. For example, “A and / or B” is to be taken as specific disclosure of each of i) A, ii) B, and iii) A and B, just as if each were set out individually.

[0142] Where used, “selected from” a list of members is to be taken as a specific disclosure of the relevant members alone. For example, “selected from A, B, and C” is to be taken as a specific disclosure of each of i) A, ii) B, and iii) C, just as if each were set out individually.

[0143] Where used, “one or more selected from” a list of members is to be taken as a specific disclosure of the relevant members alone as well as a specific disclosure of the combination of the members. For example, “one or more selected from A, B, and C” is to be taken as specific disclosure of each of i) A, ii) B, iii) C, iv) A and B, v) A and C, vi) B and C, and vii) A and B and C, just as if each were set out individually.

[0144] Unless context dictates otherwise, the descriptions and definitions of the features set out above are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments which are described.Definitions

[0145] The following definitions are provided in order to aid understanding understanding of the invention.

[0146] An alkyl group is a monovalent saturated hydrocarbon group. The alkyl group may be a Ci-ealkyl group, for example a C1.4, C1.3 or a Ci-2alkyl group. In this context, the prefix (e.g. Ci-e) denotes the number of carbon atoms in the hydrocarbon backbone. The alkyl group may be linear or branched. Examples of linear Ci-ealkyl groups include methyl (-Me),ethyl (-Et), n-propyl (-nPr), n-butyl (-nBu), n-pentyl (-Amyl) and n-hexyl. Examples of branched Ci-ealkyl groups include iso-propyl (-iPr), iso-butyl (-iBu), sec-butyl (-sBu), tert-butyl (-tBu), iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, iso-hexyl, sec-hexyl, tert-hexyl and neohexyl.

[0147] An alkoxy group is a monovalent group consisting of an alkyl group singly bonded to oxygen and in which the free valency resides on the oxygen atom. The alkoxy group may be a Ci-salkoxy group, for example a Ci or a C2 alkoxy group. In this context, the prefix (e.g. C1.3) denotes the number of carbon atoms in the alkyl group. The alkoxy group may be linear or branched. Examples of linear Ci^alkoxy groups include methoxy (-OMe), ethoxy (- OEt) and propoxy (-OnPr). Examples of branched Ci^alkoxy groups include isopropoxy (- O'Pr).

[0148] A haloalkyl group is an alkyl group in which one or more hydrogen atoms is replaced with a halogen (e.g. fluorine) atom. The haloalkyl group may be a Ci-shaloalkyl group, for example a Ci or a C2 haloalkyl group. In this context, the prefix (e.g. C1.3) denotes the number of carbon atoms in the hydrocarbon backbone. The haloalkyl group may be linear or branched. Examples of Ci-shaloalkyl groups include fluoroalkyl groups such as monofluoromethyl (-CH2F), difluoromethyl (-CHF2), trifluoromethyl (-CF3), 1 ,1 -difluorethyl (-CF2CH3), pentafluoroethyl (-C2F5) and heptafluoropropyl (-C3F7).

[0149] A cycloalkyl group is a monovalent saturated hydrocarbon group which comprises a ring in which all of the ring atoms are carbon atoms. The cycloalkyl group may be a Cs-ecycloalkyl group, for example a C3-4 or a C5-6 cycloalkyl group. In this context, the prefix (e.g. C3-6) denotes the number of carbon atoms in the ring. Examples of monocyclic Cs-ecycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0150] The term “halo” refers to fluoro, chloro, bromo and iodo.

[0151] A heterocyclyl group is a cycloalkyl group in which one or more ring atoms are heteroatoms, for example N, O and S. The free valency may reside on any ring atom. The heterocyclyl group may be a 4- to 6-membered heterocyclyl group, for example a 4- membered, 5-membered or 6-membered heterocyclyl group. In this context, the prefix (e.g. 4- to 6-) denotes the number or range of ring atoms whether carbon atoms or heteroatoms. Where a nitrogen ring atom is present in a heterocyclyl group, that nitrogen ring atom may be unsubstituted (NH) or substituted with C1.3 alkyl. Where a sulfur ring atom is present in a heterocyclyl group, that sulfur ring atom may be S, S(O) or S(O)2. Examples of 4- to 6- membered heterocyclyl groups include azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl-1 ,1 -dioxide, thiomorpholinyl, thiomorpholinyl-1 ,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl.

[0152] A bond terminating in a wavey lineindicates an attachment point.

[0153] The term “substituted” refers to replacement of a hydrogen atom (-H) in a parent group with an alternative atom or group (the substituent). One or more hydrogen atoms of the parent group may be replaced with one or more substituents in accordance with thenormal rules of chemical valency. For example, where two hydrogen atoms are replaced, they may be bound to the same atom of the parent group (to introduce a substituent having a single divalent attachment point) or they may be bound to different atoms of the parent group (to introduce two substituents each having a single monovalent attachment point, or to introduce a single substituent having two monovalent attachment points). A parent group may have one, two or three substituents. That is, the parent group may be mono-, di- or trisubstituted.

[0154] Epilepsy is considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome (A practical clinical definition of epilepsy by the International League Against Epilepsy (ILAE), 2014).

[0155] The term “generalised seizure” (“generalised onset seizures”) refers to seizures conceptualized as originating at some point within the brain and rapidly engaging bilaterally distributed networks (Operational Classification of Seizure Types by the ILAE, 2017).

[0156] The term “focal seizure” (“focal onset seizures”) refers to seizures originating within networks limited to one hemisphere of the brain. They may be discretely localized or more widely distributed. Focal seizures may originate in subcortical structures (Operational Classification of Seizure Types by the ILAE, 2017). When a subject is awake and aware during a seizure it’s referred to as a focal aware seizure. When a subject is confused or their awareness is affected in some way during a focal seizure, it’s referred to as a focal impaired awareness seizure.

[0157] The term “seizure with unknown onset” (“unknown onset seizures”) refers to seizures whose onset is missed (e.g. because the subject was asleep or alone) or obscured. These seizures may be later classified as focal onset or generalised onset when more information becomes available (Operational Classification of Seizure Types by the ILAE, 2017).

[0158] The term "pharmaceutically acceptable" pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each ingredient (e.g. carrier, diluent, excipient, etc.) must also be "acceptable" in the sense of being compatible with the other ingredients of the composition.

[0159] The term "therapeutically-effective amount" pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen.

[0160] A “tonic-clonic seizure” occurs in two phases, a tonic phase typically involving muscle stiffening and loss of consciousness, and a clonic phase typically involving rhythmically jerking of the limbs.WORKED EXAMPLES

[0161] Certain aspects and embodiments of the invention will now be illustrated by way of example and with reference to the figures described above.Analytical MethodsNMR

[0162] Bruker Avance 400MHz, 5mm QNP probe H, C, F, P, single Z gradient, two channel instrument running TopSpin 2.1

[0163] Bruker Avance III 400MHz, 5mm BBFO Plus probe, single Z gradient, two channel instrument running TopSpin 3.1.LCMSAbbreviationsExample 1 : Synthesis of Compounds

[0164] In general, the compounds of the invention can be prepared by Suzuki reaction of an appropriate protected dihydroxyphenylboronic acid with an appropriate 4-haloindolin-2- one, followed by deprotection of the resulting intermediate (General Methods 6 and 7).,

[0165] Alternatively the reversed Suzuki reaction may be employed using an indolinone- boronic ester and a protected halodihydroxybenzene. (General Method 8)

[0166] Final compounds may purified by column chromatography on silica gel, reverse phase preparative HPLC, or both methods in succession as required.

[0167] Additional manipulations may be carried out on the protected intermediates to change the nature of the R groups as described for specific final compounds.

[0168] Aryl halide and boronic acid precursors can be purchased from commercial sources, prepared according to literature procedures or synthesised according to one of the following methods.Synthesis of IntermediatesIntermediate 1: 1-lsopropyl-3,5-dimethoxybenzene

[0169] Isopropylmagnesium chloride solution (2M in tetrahydofuran, 14 mL, 27.6 mmol) solution was added dropwise to zinc chloride (2M in 2-methyltetrahydrofuran, 14 mL, 27.6 mmol) under a nitrogen atmosphere at 20°C. The suspension formed was then stirred for 2 hours at room temperature. In a separate flask 1-bromo-3,5-dimethoxy-benzene (3.00 g, 13.8 mmol) and Pd-PEPPSI(TM)-IPent catalyst (219 mg, 0.276 mmol) and dissolved in toluene (92 mL) under a nitrogen atmosphere. The solution was degassed with nitrogen, cooled in an ice / water bath and treated with. 20.7 mL of the prepared organozinc suspension was added and the reaction mixture was allowed to warm to room temperature and stirred for 80 min. A further 13.8 mL of the organozinc suspension was added to the solution at room temperature and the reaction was stirred for an additional 30 min. 2M Hydrochloric acid (100 mL) was added and the layers were separated. The aqueous layer was further extracted with diethyl ether (2 x 100 mL) and the combined organic layers were washed with brine, dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 5-20% diethyl ether in cyclohexane to give a yellow oil (2.9g). NMR analysis showed this to be a 4:1 mixture of the desired product and inseparable starting material. To obtain complete conversion the impure product was dissolved in toluene (73 mL), treated with Pd-PEPPSI(TM)-IPent catalyst (175 mg, 0.220 mmol) degassed with nitrogen, cooled in an ice-bath and treated with 20.7 mL of organozinc suspension, prepared as previously. After 2.5 hours 2M hydrochloric acid (100 mL) was added (100 mL) and the layers were separated. The aqueous layer was further extracted with diethyl ether (2 x 100 mL) and the combined organic layers were washed with brine, dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 12% diethyl ether in cyclohexane to give the title compound as a pale yellow oil (1.80 g, 54%).1H NMR (400 MHz, CDCh) 66.39 (d, J=2.3 Hz, 2H), 6.30 (t, J=2.3 Hz, 1 H), 3.79 (s, 6H), 2.88 - 2.80 (m, 1 H), 1.23 (d, J=6.9 Hz, 6H).General Method 1

[0170] General Method 1 is illustrated using the synthesis of Intermediate 2.Intermediate 2. (2,6-Dimethoxy-4-propyl-phenyl)boronic acid

[0171] 1 ,3-Dimethoxy-5-propyl-benzene (10.0 g, 55.5 mmol) was stirred in tetrahydrofuran (230 mL) at 0°C under an atmosphere of nitrogen and n-butyllithium solution (2.5 M in hexanes, 27 mL, 66.6 mmol) was added over 10 minutes. The reaction mixture was stirred for 1 hour at 0°C then cooled to -78°C, treated with trimethyl borate (19 mL, 166 mmol) and allowed to warm to room temperature over 150 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (150 mL) and ethyl acetate (200 mL) was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were dried (magnesium sulfate) andconcentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-50% ethyl acetate in dichloromethane to give the title compound as a white solid (10.1 g, 81%).1H NMR (400 MHz, CDCI3) 8 7.17 (s, 2H), 6.45 (s, 2H), 3.90 (s, 6H), 2.59 (t, J=7.7 Hz, 2H), 1.72 - 1.62 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).

[0172] General Method 1 , using the appropriate dimethoxyarene, was also used to generate the following intermediates:Intermediate 3: (4-Ethyl-2,6-dimethoxyphenyl)boronic acid

[0173] 1H NMR (400 MHz, DMSO) 8 7.72 (s, 2H), 6.41 (s, 2H), 3.69 (s, 6H), 2.56 (q, J=7.6 Hz, 2H), 1.17 (t, J=7.6 Hz, 3H).Intermediate 4: (4-Butyl-2,6-dimethoxyphenyl)boronic acid

[0174] 1H NMR (400 MHz, DMSO) 8 7.72 (s, 2H), 6.39 (s, 2H), 3.69 (s, 6H), 2.55 (t, J=7.9 Hz, 2H), 1.60 - 1.51 (m, 2H), 1.37 - 1.28 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).Intermediate 5: (2,6-Dimethoxy-4-pentylphenyl)boronic acid

[0175] 1H NMR (400 MHz, CDCI3) 8 7.16 (s, 2H), 6.45 (s, 2H), 3.90 (s, 6H), 2.60 (t, J=7.8 Hz, 2H), 1.68 - 1.58 (m, 2H), 1.39 - 1.30 (m, 4H), 0.91 (t, J=6.9 Hz, 3H).Intermediate 6: (4-Cyclopropyl-2,6-dimethoxyphenyl)boronic acid

[0176] 1-Cyclopropyl-3,5-dimethoxybenzene starting material was prepared according to literature procedure (Molander, Gary A. et al, Journal of Organic Chemistry (2008), 73(19), 7481-7485).1H NMR (400 MHz, CDC ) 8 7.15 (s, 2H), 6.33 (s, 2H), 3.89 (s, 6H), 1.95 - 1.88 (m, 1 H), 1.04 - 1 .01 (m, 2H), 0.79 - 0.73 (m, 2H).Intermediate 7 (4-Cyclobutyl-2,6-dimethoxyphenyl)boronic acid

[0177] 1-Cyclobutyl-3,5-dimethoxybenzene starting material was prepared according to literature procedure (Molander, Gary A. et al, Journal of Organic Chemistry (2008), 73(19), 7481-7485.1H NMR (400 MHz, DMSO) 8 7.72 (s, 2H), 6.41 (s, 2H), 3.70 (s, 6H), 3.54 - 3.44 (m, 1 H), 2.31 - 2.23 (m, 2H), 2.16 - 2.06 (m, 2H), 2.01 - 1.90 (m, 1 H), 1.85 - 1.76 (m, 1 H).Intermediate 8: (4-lsopropyl-2,6-dimethoxyphenyl)boronic acid

[0178] 1H NMR (400 MHz, CDCI3) 8 7.18 (s, 2H), 6.50 (s, 2H), 3.91 (s, 6H), 2.96 - 2.85 (m, 1 H), 1.27 (d, J=7.0 Hz, 6H).Intermediate 9: (2,6-Bis(benzyloxy)-4-propylphenyl)boronic acidStep 1 : 2-Bromo-5-propylbenzene-1,3-diol

[0179] 5-Propylbenzene-1 ,3-diol (22.1 g, 0.145 mol) in methyl alcohol (450 mL) was cooled in an ice / water bath and stirred. / V-Bromosuccinimide (77.4 g, 0.435 mol) was added in portions over 1 hour maintaining an internal temperature of below 10°C. On complete addition the reaction was stirred at room temperature for 20h.The reaction was cooled in an ice-salt bath and a solution of sodium sulfite (40.2 g, 318 mmol) and NaOH (12.7 g, 317 mmol) in water (600 mL) was added in portions over 10 minutes. The reaction mixture was stirred for 2 hours then acidified with 1 M aqueous hydrochloric acid (220 mL) and extracted with ethyl acetate (2 x 600 mL). The combined organic layers were dried (magnesium sulfate) and the residue was purified by column chromatography on silica, eluting with 0-30% ethyl acetate in cyclohexane to give the title compound as a white solid (28.4 g, 84%).1H NMR (400 MHz, CDCh) 8 6.45 (s, 2H), 5.25 (s, 2H), 2.48 (t, J=7.6 Hz, 2H), 1.61 - 1.57 (m, 2H), 0.95 - 0.90 (t, J=7.2 Hz, 3H).Step 2: (((2-Bromo-5-propyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzene

[0180] 2-Bromo-5-propylbenzene-1 ,3-diol (28.4 g, 0.123 mol) in / V, / V-dimethylformamide (400 mL) was treated with potassium carbonate (84.9 g, 0.614 mol) followed by benzyl bromide (32 mL, 0.270 mol). The reaction mixture was stirred for 90 minutes, then concentrated in vacuo and the residue was partitioned between water (1 L) and diethyl ether(1 L). The layers were separated, and the aqueous layer was extracted with diethyl ether (3 x 400 mL). The combined organic layers were washed with 4% LiCI (300 mL), dried (magnesium sulfate) and concentrated in vacuo. The residue triturated with n-pentane (500 mL) to give the title compound as a pink solid (46.4 g, 92%).1H NMR (400 MHz, CDCL) 8 7.49 (d, J=7.3 Hz, 4H), 7.41 - 7.31 (m, 6H), 6.45 (s, 2H), 5.15 (s, 4H), 2.50 (t, J=7.6 Hz, 2H), 1.63 - 1.53 (m, 2H), 0.88 (t, J=7.3 Hz, 3H).Step 3: (2,6-Bis(benzyloxy)-4-propylphenyl)boronic acid

[0181] (((2-Bromo-5-propyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzene (20.0 g, 48.6 mmol) in tetrahydrofuran (750 mL) was cooled in a dry ice / acetone bath and treated with 2.5 M n-Butyllithium solution (29 mL, 72.9 mmol). After 5 minutes trimethyl borate (16 mL, 0.146 mol) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride (300 mL), poured into water (1 L) an extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography silica gel, eluting with 5-30% ethyl acetate in cyclohexane to give the title compound as a white solid (11.4 g, 42%).1H NMR (400 MHz, CDCh) 8 7.42 - 7.36 (m, 10H), 7.14 (s, 2H), 6.54 (s, 2H), 5.13 (s, 4H), 2.57 (t, J=7.6 Hz, 2H), 1.69 - 1.59 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).General Method 2

[0182] General Method 2 is illustrated using the synthesis of Intermediate 10.Intermediate 10: 4-Bromo- 7-fluoro-5-methylindoline-2, 3-dione

[0183] 5-Bromo-2-fluoro-4-methyl-aniline (2.04 g, 10.0 mmol), hydroxylamine hydrochloride (2.08 g, 30.0 mmol) and sodium sulfate (9.94 g, 70.0 mmol) in water (50 mL) and 2 M aqueous hydrochloric acid (0.93 mL, 1.86 mmol) were treated with chloral hydrate (1.98 g, 12.0 mmol) and heated at 95°C for 6 hours (timer). The reaction mixture was cooled to room temperature and the precipitate was collected by filtration. The filtrate was washed with water, dried under vacuum, dissolved in sulfuric acid (30 mL) and heated at 80°C for 30 minutes. The reaction mixture was poured into ice / water (150 mL) and the precipitate was collected by filtration and dried under vacuum to give the title compound as a dark red solid (1.60 g, 62%).1H NMR (400 MHz, CDCh) 8 7.73 (s, 1H), 7.25 (d, J=9.8 Hz, 1 H), 2.39 (s, 3H).

[0184] General Method 2, using an appropriate aniline, was also used to generate the following compounds.Intermediate 11: 4-Bromo-5, 7-dimethylindoline-2, 3-dione

[0185] 1H NMR (400 MHz, DMSO) 5 11.11 (s, 1 H), 7.39 (s, 1 H), 2.26 (s, 3H), 2.13 (s, 3H).Intermediate 12: 4-Bromo-5,6-dimethylindoline-2, 3-dione

[0186] 1H NMR (400 MHz, DMSO) 8 6.35 (s, 1 H), 2.18 (s, 3H), 2.10 (s, 3H). Exchangeable NH proton not observed. Obtained as a 5:1 mixture of regioisomers; data reported for major isomer only. The unwanted minor regioisomer was removed during purification at a later stage of the synthesis.Intermediate 13: 4-Bromo-5-(trifluoromethyl)indoline-2, 3-dione

[0187] The desired product was obtained as the larger of a 3:1 mixture of regioisomers which could be separated by column chromatography.1H NMR (400 MHz, DMSO) 8 11.51 (1 H, s), 7.93 (1 H, d, J=8.5 Hz), 7.01 (1 H, d, J=8.3 Hz).Intermediate 14: 4-Bromo-6-chloro- 7-fluoroindoline-2, 3-dione1H NMR (400 MHz, CDCI3) 8 7.89 (br s, 1 H), 7.34 (d, J=5.2 Hz, 1 H).Intermediate 15: 4-Bromo-7-chloroindoline-2, 3-dione1H NMR (400 MHz, CDCI3) 8 7.93 (br s, 1 H), 7.40 (d, J=8.8 Hz, 1 H), 7.24 (d, J=8.6 Hz, 1 H).Intermediate 16: 4-Bromo-6-fluoro-5-methylindoline-2, 3-dione1H NMR (400 MHz, DMSO) 5 11.22 (s, 1 H), 6.77 (d, J=9.4 Hz, 1 H), 2.20 (d, J=2.5 Hz, 3H).General Method 3

[0188] General Method 3 is illustrated using the synthesis of Intermediate 17.Intermediate 17: 4-Bromo-1-ethyl-5-methylindolin-2-oneStep 1 : 4-Bromo-1-ethyl-5-methylindoline-2, 3-dione

[0189] 4-Bromo-5-methyl-indoline-2, 3-dione (2.00 g, 8.33 mmol) was stirred in N,N- dimethylformamide (25 mL) at 0°C and sodium hydride (400 mg, 60% dispersion in mineral oil, 10.0 mmol) was added slowly. A solution of bromoethane (0.93 mL, 12.5 mmol) in N,N- dimethylformamide (5 mL) was added and the reaction mixture allowed to warm to room temperature over 2 hours then quenched with saturated ammonium chloride solution (20 mL) followed by water (20 mL) and ethyl acetate (40 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with water (40 mL), dried (magnesium sulfate) and concentrated in vacuo to give the title compound as an orange solid (2.01 g, 90%).1H NMR (400 MHz, DMSO) 8 7.61 (dq, J=0.6, 3.1 Hz, 1 H), 7.14 (d, J=8.0 Hz, 1 H), 3.69 (q, J=7.2 Hz, 2H), 2.32 (s, 3H), 1.16 (t, J=7.2 Hz, 3H).Step 2: 4-Bromo-1-ethyl-5-methylindolin-2-one

[0190] 4-Bromo-1-ethyl-5-methyl-indoline-2, 3-dione (2.00 g, 7.46 mmol) in ethanol (50 mL) was treated with hydrazine monohydrate (9.0 mL, 0.186 mol). The reaction mixture was heated under reflux for 4 days then cooled to room temperature and acidified to pH2 with 1M hydrochloric acid, diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (50 mL), dried (magnesium sulfate) and concentrated in vacuo to give the title compound as a yellow solid (1.61 g, 85%).1H NMR (400 MHz, DMSO) 8 7.26 (qd, J=0.8, 8.0 Hz, 1 H), 6.97 (d, J=7.9 Hz, 1 H), 3.67 (q, J=7.2 Hz, 2H), 3.32 (s, 2H), 2.32 (s, 3H), 1.13 (t, J=7.2 Hz, 3H).

[0191] General Method 3, using an appropriate indoline-2, 3-dione and alkyl halide, was also used to generate the following compounds.Intermediate 18: 4-Bromo-1,5-dimethylindolin-2-one

[0192] Potassium carbonate was used in place of sodium hydride for the alkylation step.1H NMR (400 MHz, CDCI3) 8 7.16 (d, J=7.8 Hz, 1 H), 6.67 (d, J=7.8 Hz, 1 H), 3.47 (s, 2H), 3.18 (s, 3H), 2.38 (s, 3H).Intermediate 19: 4-Bromo-1-isopropyl-5-methylindolin-2-one

[0193] 1H NMR (400 MHz, CDCI3) 8 7.11 (d, J=8.0 Hz, 1 H), 6.84 (d, J=8.0 Hz, 1 H), 4.67 - 4.59 (m, 1 H), 3.45 (s, 2H), 2.37 (s, 3H), 1.45 (d, J=7.0 Hz, 6H).Intermediate 20: 4-Bromo-5-methyl-1-propylindolin-2-one

[0194] Potassium carbonate was used in place of sodium hydride for the alkylation step.1H NMR (400 MHz, DMSO) 8 7.24 (d, J=7.7 Hz, 1 H), 6.96 (d, J=7.9 Hz, 1 H), 3.59 (t, J=7.2 Hz, 2H), 3.51 (s, 2H), 2.31 (s, 3H), 1.57 (dd, J=7.3, 14.4 Hz, 2H), 0.86 (t, J=7.4 Hz, 3H).Intermediate 21: 4-Bromo-5-methyl-1-(2,2,2-trifluoroethyl)indolin-2-one

[0195] Potassium carbonate was used in place of sodium hydride for the alkylation step. Propanol was used in place of ethanol for the Wolff-Kishner step.1H NMR (400 MHz, CDCI3) 8 7.18 (d, J=7.7 Hz, 1 H), 6.77 (d, J=8.0 Hz, 1 H), 4.28 (q, J=8.7 Hz, 2H), 3.57 (s, 2H), 2.39 (s, 3H).Intermediate 22: 4-Bromo- 1-(2,2,2-trifluoroethyl)indolin-2-one

[0196] Potassium carbonate was used in place of sodium hydride for the alkylation step. Propanol was used in place of ethanol for the Wolff-Kishner step.1H NMR (400 MHz, CDCI3) 8 7.24 - 7.17 (m, 2H), 6.87 (d, J=7.7 Hz, 1 H), 4.30 (q, J=8.7 Hz, 2H), 3.58 (s, 2H).Intermediate 23: 4-Bromo- 1-ethylindolin-2-one

[0197] 1H NMR (400 MHz, CDCI3) 8 7.17 - 7.15 (m, 2H), 6.79 - 6.76 (m, 1 H), 3.75 (q, J=7.2 Hz, 2H), 3.47 (s, 2H), 1.26 (t, J=7.2 Hz, 3H).Intermediate 24: 4-bromo- 1-(2-(dimethylamino)ethyl)-5-methylindolin-2-one

[0198] Potassium carbonate was used in place of sodium hydride for the alkylation step.1H NMR (400 MHz, CDCI3) 8 7.15 - 7.12 (m, 1 H), 6.71 (d, J=8.0 Hz, 1 H), 3.79 (t, J=7.1 Hz, 2H), 3.48 (s, 2H), 2.53 (t, J=7.2 Hz, 2H), 2.37 (s, 3H), 2.30 (s, 6H).Intermediate 25: 4-Bromo-7-fluoro-1-methylindolin-2-one

[0199] 1H NMR (400 MHz, CDCI3) 8 7.08 (dd, J=3.9, 9.0 Hz, 1 H), 6.93 (dd, J=8.8, 11.1 Hz, 1 H), 3.49 (s, 2H), 3.41 (d, J=2.6 Hz, 3H).Intermediate 26: 4-Bromo-1-ethyl-7-fluoroindolin-2-one

[0200] 1H NMR (400 MHz, CDCI3) 8 7.09 (dd, J=3.8, 9.0 Hz, 1 H), 6.94 (dd, J=9.1 , 11.0 Hz, 1 H), 3.90 (dq, J=1.0, 7.1 Hz, 2H), 3.49 (s, 2H), 1.28 (dt, J=0.8, 7.2 Hz, 3H).Intermediate 27: 4-Bromo- 1-ethyl-7-fluoro-5-methylindolin-2-one

[0201] Potassium carbonate was used in place of sodium hydride for the alkylation step.1H NMR (400 MHz, CDCh) 8 6.94 (qd, J=0.8, 11.9 Hz, 1 H), 3.87 (dq, J=1.1 , 7.1 Hz, 2H), 3.49 (s, 2H), 2.35 (s, 3H), 1.27 (dt, J=0.7, 7.1 Hz, 3H).Intermediate 28: 4-Bromo-6-chloro- 1-ethyl-7-fluoroindolin-2-one

[0202] 1H NMR (400 MHz, CDCh) 8 7.20 (d, J=5.8 Hz, 1 H), 3.90 (dq, J=1.6, 7.2 Hz, 2H), 3.47 (s, 2H), 1.29 (dt, J=0.9, 7.1 Hz, 3H).Intermediate 29: 4-Bromo- 1-ethyl-5, 7-dimethylindolin-2-one

[0203] 2-Propanol was used in place of ethanol for the Wolff-Kishner step.1H NMR (400 MHz, CDCh) 6 6.90 (s, 1 H), 3.95 (q, J=7.1 Hz, 2H), 3.43 (s, 2H), 2.45 (s, 3H), 2.32 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).Intermediate 30: 4-Bromo- 1-ethyl-5, 6-dimethylindolin-2-one

[0204] Potassium carbonate was used in place of sodium hydride for the alkylation step.1H NMR (400 MHz, DMSO) 8 6.91 (s, 1 H), 3.65 (q, J=7.1 Hz, 2H), 3.49 (s, 2H), 2.33 (s, 3H), 2.27 (s, 3H), 1.13 (t, J=7.1 Hz, 3H).Intermediate 31: 4-Bromo- 1-ethyl-5-(trifluoromethyl)indolin-2-one

[0205] Potassium carbonate was used in place of sodium hydride for the alkylation step.1H NMR (400 MHz, CDCh) 8 7.64 (d, J=8.2 Hz, 1 H), 6.83 (d, J=8.4 Hz, 1 H), 3.78 (q, J=7.2 Hz, 2H), 3.53 (s, 2H), 1.27 (t, J=7.4 Hz, 3H).Intermediate 32: 4-Bromo- 1-(2-fluoroethyl)-5-methylindolin-2-one

[0206] Potassium carbonate was used in place of sodium hydride for the alkylation step. 1-Propanol was used in place of ethanol for the Wolff-Kishner step.1H NMR (400 MHz, CDCh) 8 7.15 (dq, J=0.8, 3.1 Hz, 1 H), 6.78 (d, J=7.9 Hz, 1 H), 4.65 (td, J=4.8, 47.0 Hz, 2H), 3.99 (td, J=4.9, 26.0 Hz, 2H), 3.51 (s, 2H), 2.38 (s, 3H).Intermediate 33: 4-Bromo-7-chloro- 1 -methylindoline-2, 3-dione

[0207] The title compound was prepared according to a procedure similar to step 1 of General Method 3, using potassium carbonate in place of sodium hydride.1H NMR (400 MHz, CDCh) 8 7.35 (d, J=8.8 Hz, 1 H), 7.19 (d, J=8.6 Hz, 1 H), 3.64 (s, 3H).Intermediate 34: 4-Bromo-7-chloro- 1 -ethylindoline-2, 3-dioneThe title compound was prepared according to a procedure similar to step 1 of General Method 3, using potassium carbonate in place of sodium hydride.1H NMR (400 MHz, CDCh) 8 7.35 (d, J=8.6 Hz, 1 H), 7.19 (d, J=8.8 Hz, 1 H), 4.22 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).Intermediate 35: 4-Chloro- 1 -ethyl-5-fluoroindoline-2, 3-dioneThe title compound was prepared according to a procedure similar to step 1 of General Method 3.1H NMR (400 MHz, CDCh) 8 7.37 (t, J=8.7 Hz, 1 H), 6.78 (dd, J=3.2, 8.7 Hz, 1 H), 3.80 (q, J=7.3 Hz, 2H), 1.31 (t, J=7.3 Hz, 3H).Intermediate 36: 4-Bromo- 1-ethyl-6-fluoro-5-methylindolin-2-oneStep 1 : 4-Bromo-1-ethyl-6-fluoro-5-methylindoline-2, 3-dioneThe title compound was prepared according to a procedure similar to step 1 of General Method 3, using potassium carbonate in place of sodium hydride.1H NMR (400 MHz, DMSO) 8 7.28 (d, J=10.0 Hz, 1 H), 3.69 (q, J=7.2 Hz, 2H), 2.22 (d, J=2.6 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H).Step 2: 4-Bromo-1-ethyl-6-fluoro-5-methylindolin-2-oneZinc dust (1303 mg, 19.9 mmol) was suspended in dry tetrahydrofuran (15 mL) under a nitrogen atmosphere and treated with titanium(IV) chloride (1.1 mL, 9.96 mmol). The reaction mixture was heated at 60°C and stirred for 4 hours then cooled and treated with a solution of 4-Bromo-1-ethyl-6-fluoro-5-methylindoline-2, 3-dione (380 mg, 1.33 mmol, 1.00 eq) in tetrahydrofuran (3 mL) and stirred overnight. The reaction mixture was combined with that of a test reaction which has been run on 100 mg of starting material under the same conditions, quenched with 2N HCI (5 mL), diluted with water (75 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried (phase separating paper) and concentrated in vacuo. The residue was purified by column chromatography on 25g silica gel, eluting with 0-100% ethyl acetate in cyclohexane to give the title compound as a yellow solid (198 mg, 43%).1H NMR (400 MHz, DMSO) 8 7.09 (d, J=10.2 Hz, 1H), 3.66 (q, J=7.2 Hz, 2H), 3.48 (d, J=1.3 Hz, 2H), 2.23 (d, J=2.5 Hz, 3H), 1.11 (t, J=7.2 Hz, 3H).General Method 4

[0208] General Method 4 is illustrated using the synthesis of Intermediate 37.Intermediate 37: 4-Bromo-1-cyclopropylindolin-2-oneStep 1 : 4-Bromo-1-cyclopropylindoline-2, 3-dione4-Bromoindoline-2, 3-dione (1600 mg, 7.08 mmol), cyclopropylboronic acid (1216 mg, 14.2 mmol) and sodium carbonate (1501 mg, 14.2 mmol) were stirred vigorously in dichloromethane (90 mL) and copper(ll) acetate (1286 mg, 7.08 mmol) followed by 2,2'- bipyridyl (1106 mg, 7.08 mmol) were added. The reaction mixture was left open to the airand stirred overnight. Dichloromethane (50 mL) and saturated aqueous ammonium chloride solution (100 mL) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-40% ethyl acetate in cyclohexane to give the title compound as an orange solid (1.30 g, 69%).1H NMR (400 MHz, CDCI3) 8 7.43 (t, J=8.1 Hz, 1 H), 7.26 (dd, J=0.7, 8.2 Hz, 1 H), 7.15 (dd, J=0.7, 7.9 Hz, 1H), 2.71 - 2.65 (m, 1 H), 1.16 - 1.11 (m, 2H), 0.99 - 0.93 (m, 2H).Step 2: 4-Bromo-1-cyclopropylindolin-2-one

[0209] The title compound was prepared according to a procedure similar to step 2 of General Method 3.1H NMR (400 MHz, CDCh) 8 7.18 - 7.15 (m, 2H), 7.05 - 7.01 (m, 1 H), 3.44 (s, 2H), 2.66 - 2.60 (m, 1 H), 1.11 - 1.04 (m, 2H), 0.93 - 0.88 (m, 2H).

[0210] General Method 4 was also used to prepare the following intermediatesIntermediate 38: 4-Bromo- 1-cyclopropyl-5-methylindolin-2-one

[0211] 1H NMR (400 MHz, CDCI3) 8 7.15 (d, J=7.9 Hz, 1H), 6.93 (d, J=7.9 Hz, 1 H), 3.43 (s, 2H), 2.65 - 2.59 (m, 1H), 2.37 (s, 3H), 1.09 - 1.02 (m, 2H), 0.92 - 0.86 (m, 2H).Intermediate 39: 4-Bromo- 1-cyclopropyl-7-fluoro-5-methylindolin-2-one

[0212] 1H NMR (400 MHz, CDCI3) 8 6.94 (qd, J=0.8, 11.8 Hz, 1 H), 3.45 (s, 2H), 2.87 - 2.81 (m, 1 H), 2.35 (s, 3H), 1.07 - 1.02 (m, 2H), 0.98 - 0.94 (m, 2H).Intermediate 40: 4-Bromo- 1-ethyl-3,3-difluoro-5-methylindolin-2-one4-Bromo-1-ethyl-5-methyl-indoline-2, 3-dione (2.39 g, 8.29 mmol, prepared according to the first step of General Method 3) was dissolved in dichloromethane (28 mL) at -78 °C and treated with (diethylamino)sulfur trifluoride (2.2 mL, 16.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight then quenched with saturatedaqueous sodium hydrogen carbonate solution (30 mL) and stirred for 20 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL) The combined organic layers were dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 5-60% ethyl acetate in cyclohexane to give the title compound as a pale brown solid (1.43 g, 59%).1H NMR (400 MHz, CDCh) 8 7.33 (d, J=8.0 Hz, 1 H), 6.76 (d, J=8.0 Hz, 1H), 3.72 (q, J=7.2 Hz, 2H), 2.39 (s, 3H), 1.28 (t, J=7.2 Hz, 3H).General Method 5

[0213] General Method 5 is illustrated using the synthesis of Intermediate 41.Intermediate 41: 1-Ethyl-5-methyl-4-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)indolin-2- oneCPME

[0214] 4-Bromo-1-ethyl-5-methylindolin-2-one (3.00 g, 11.8 mmol), bis(pinacolato)diboron (4.50 g, 17.7 mmol), potassium acetate (3.48 g, 35.4 mmol) and bis(triphenylphosphine)- palladium(ll) dichloride (0.83 g, 1.18 mmol) were suspended in cyclopentyl methyl ether (80 mL) and heated to 100°C for 1 day. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (2 x 100 mL), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography silica gel, eluting with 0-30% ethyl acetate in cyclohexane to give the title compound (2.93 g, 82%) as a yellow oil which solidified on standing.1H NMR (400 MHz, CDCI3) 8 7.06 (d, J=8.0 Hz, 1 H), 6.77 (d, J=7.9 Hz, 1H), 3.75 (q, J=7.2 Hz, 2H), 3.69 (s, 2H), 2.49 (s, 3H), 1.34 (s, 12H), 1.23 (t, J=7.2 Hz, 3H).

[0215] General Method 5, using the appropriate bromoindolinone, was also used to prepare the following compounds.Intermediate 42: 1-Cyclopropyl-5-methyl-4-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2- yl)indolin-2-oneCPME

[0216] 1H NMR (400 MHz, CDCh) 8 7.08 (d, J=6.9 Hz, 1H), 7.02 (d, J=8.1 Hz, 1 H), 3.66 (s, 2H), 2.64 - 2.58 (m, 1H), 2.48 (s, 3H), 1.33 (s, 12H), 1.07 - 1.01 (m, 2H), 0.90 - 0.85 (m, 2H).Intermediate 43: 4-Bromo-1,3,3,5-tetramethylindolin-2-one

[0217] 4-Bromo-5-methyl-indolin-2-one (300 mg, 1.33 mmol) and potassium carbonate (550 mg, 3.98 mmol) in / V, / V-dimethylformamide (6.0 mL) were treated with lodomethane (0.25 mL, 3.98 mmol). The reaction mixture was stirred overnight, then treated with further potassium carbonate (183 mg, 1.33 mmol) and iodomethane (0.17 mL, 2.65 mmol) and stirred for a further 5 days. The reaction mixture was partitioned between ethyl acetate (60 mL) and water (60 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 60 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography eluting with 0-30% ethyl acetate in cyclohexane to give the title compound as an off-white solid (177 mg, 50%).1H NMR (400 MHz, DMSO) 8 7.30 (d, J=7.9 Hz, 1H), 6.99 (d, J=8.1 Hz, 1 H), 3.14 (s, 3H), 2.33 (s, 3H), 1.42 (s, 6H).Intermediate 44: 4-Bromo- 1-ethyl-3, 3, 5-trimethylindolin-2-one

[0218] 4-Bromo-1-ethyl-5-methyl-indolin-2-one (397 mg, 1.56 mmol) in N,N- dimethylformamide (5.0 mL) was treated with sodium hydride (156 mg, 60% dispersion in mineral oil, 3.91 mmol) and the suspension stirred for 30 minutes at 0°C. lodomethane (0.29 mL, 4.69 mmol) was added and the reaction mixture allowed to warm to room temperature over 1 hour then quenched with saturated aqueous ammonium chloride solution (5 mL) and water (5 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), dried (phase separating paper) and concentrated in vacuo to give the title compound as a brown oil (468 mg, 106% crude yield). This was used without further purification in subsequent reactions.1H NMR (400 MHz, CDCI3) 8 7.14 (d, J=7.8 Hz, 1 H), 6.72 (d, J=7.8 Hz, 1 H), 3.74 (q, J=7.2 Hz, 2H), 2.38 (s, 3H), 1.53 (s, 6H), 1.24 (t, J=7.2 Hz, 3H).Intermediate 45: 3,5-Bis(benzyloxy)-4-bromobenzaldehyde

[0219] (3,5-Bis(benzyloxy)-4-bromophenyl)methanol (4090 mg, 10.2 mmol) (prepared according to the procedure reported by Goehl, Matthias et al, European Journal of Organic Chemistry (2015), 2015(28), 6249-6258) in dichloromethane (200 mL) was treated withmanganese(IV) oxide (8906 mg, 0.102 mol) and stirred for 2 days. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a white solid (3790 mg, 93%).1H NMR (400 MHz, CDCh) 8 9.87 (s, 1H), 7.52 - 7.31 (m, 10H), 7.12 (s, 2H), 5.25 (s, 4H).Intermediate 46: (((2-Bromo-5-(cyclopropylmethyl)-1,3- phenylene) bis(oxy) ) bis(methylene) ) di benzeneStep 1 : (3,5-Bis(benzyloxy)-4-bromophenyl)(cyclopropyl)methanol

[0220] 3,5-Bis(benzyloxy)-4-bromobenzaldehyde (3300 mg, 8.31 mmol) in tetra hydrofuran (50 mL) was cooled in an ice / water bath and treated with 1 M Cyclopropylmagnesium bromide solution in 2-Me THF (9.1 mL, 9.14 mmol). After 90 minutes the reaction was quenched with saturated ammonium chloride solution (30 mL), diluted with water (200 mL), extracted with ethyl acetate (2 x 150 mL). The organic layers were dried (phase separating paper) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-50% diethyl ether in cyclohexane to give the title compound as a white solid (2050 mg, 56%).1H NMR (400 MHz, CDCh) 8 7.50 - 7.29 (m, 10H), 6.70 (s, 2H), 5.18 (s, 4H), 3.94 (dd, J=2.0, 8.3 Hz, 1H), 1.90 (d, J=3.0 Hz, 1H), 1.12 - 1.06 (m, 1 H), 0.63 - 0.55 (m, 1 H), 0.53 - 0.45 (m, 1 H), 0.44 - 0.37 (m, 1 H), 0.31 - 0.25 (m, 1H).Step 2: (((2-Bromo-5-(cyclopropylmethyl)-1,3-phenylene)bis(oxy))bis(methylene))- dibenzene

[0221] (3,5-Bis(benzyloxy)-4-bromophenyl)(cyclopropyl)methanol (1500 mg, 3.41 mmol) in dichloromethane (60 mL) cooled in an ice / water bath was treated with triethylsilane (5.5 mL, 34.1 mmol) followed by trifluoroacetic acid (1.8 mL, 23.9 mmol). After 15 minutes the reaction was quenched with 7N ammonia in methanol (10 mL), poured into half-saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried (phase separating paper) and concentrated in vacuo. The crude produce was combined with that from a test reaction which had been run on 500 mg scale under identical conditions and purified by column chromatography on silica gel, eluting with 0-50% dichloromethane in cyclohexane to give the title compound as a white solid (1420 mg, 3.35 mmol, 74% combined for 2 reactions).1H NMR (400 MHz, CDCh) 8 7.51 - 7.48 (m, 4H), 7.41 - 7.36 (m, 4H), 7.34 - 7.28 (m, 2H), 6.53 (s, 2H), 5.16 (s, 4H), 2.45 (d, J=6.9 Hz, 2H), 0.95 - 0.84 (m, 1 H), 0.51 - 0.46 (m, 2H), 0.15 - 0.10 (m, 2H).Intermediate 47: (((2-Bromo-5-(1, 1-difluoropropyl)-1 ,3- phenylene) bis(oxy) ) bis(methylene) ) di benzeneStep 1 : 1-(3,5-Bis(benzyloxy)-4-bromophenyl)propan-1-ol

[0222] 3,5-Bis(benzyloxy)-4-bromobenzaldehyde (1.00 g, 2.52 mmol) in tetra hydrofuran (2.0 mL) under nitrogen was cooled in an ice / water bath and treated with 3 M ethylmagnesium bromide solution (1.3 mL, 3.78 mmol). The reaction mixture was warmed to room temperature, stirred for 3 hours, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were washed with brine, dried (hydrophobic frit) and concentrated in vacuo to give the title compound as an off-white solid (811 mg, 56%) which was used without further purification in the next step.1H NMR (400 MHz, DMSO) 8 7.52 - 7.32 (m, 10H), 6.82 (s, 2H), 5.24 (d, J=4.7 Hz, 1 H), 5.19 (s, 4H), 4.42 (q, J=5.6 Hz, 1 H), 1.62 - 1.53 (m, 2H), 0.78 (t, J=6.9 Hz, 3H).Step 2: 1-(3,5-Bis(benzyloxy)-4-bromophenyl)propan-1-one

[0223] 1-(3,5-Bis(benzyloxy)-4-bromophenyl)propan-1-ol (811 mg, 1.90 mmol) in dichloromethane (21 mL) was treated with Dess-Martin periodinane (885 mg, 2.09 mmol) in one portion at room temperature. The reaction mixture was stirred overnight then diluted with dichloromethane, washed with a saturated solution of sodium hydrogen carbonate, dried (hydrophobic frit) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 0-100% ethyl acetate in cyclohexane to give the title compound as a yellow solid (746 mg, 55%).1H NMR (400 MHz, DMSO) 8 7.53 - 7.33 (m, 12H), 5.31 (s, 4H), 3.06 (q, J=7.2 Hz, 2H), 1.08 (t, J=7.2 Hz, 3H).Step 3: (((2-Bromo-5-(1,1-difluoropropyl)-1,3- phenylene)bis(oxy))bis(methylene))dibenzene

[0224] 1-(3,5-Bis(benzyloxy)-4-bromophenyl)propan-1-one (1.75 g, 4.11 mmol) in chloroform (40 mL) was treated with Deoxo-Fluor(R) (50% in toluene) (21 mL, 57.6 mmol) and ethanol (1 drop) and the reaction mixture was heated to 80°C for 24 hours. Further Deoxo-Fluor(R) (50% in toluene) (11 mL, 57.6 mmol) added and the reaction mixture was heated for a further 24 hours then concentrated in vacuo. The residue was suspended in ethyl acetate (75 mL), washed with saturated aqueous sodium hydrogen carbonate (75mL) and brine (50 mL), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 10-50% ethyl acetate in cyclohexane to give the title compound as a yellow solid (620 mg, 34%).1H NMR (400 MHz, DMSO) 8 7.57 - 7.53 (m, 4H), 7.50 - 7.44 (m, 4H), 7.43 - 7.37 (m, 2H), 6.99 (s, 2H), 5.33 (s, 4H), 2.27 (qt, J=8.2, 15.7 Hz, 2H), 0.90 (t, J=7.5 Hz, 3H).Intermediate 48: (( (2-Bromo-5-(2, 2-difluoropropyl)- 1 ,3-phenylene) bis(oxy))bis(methylene))- dibenzeneStep 1 : 1-(3,5-Bis(benzyloxy)-4-bromophenyl)propan-2-one

[0225] 3,5-Bis(benzyloxy)-4-bromobenzaldehyde (1.00 g, 2.52 mmol) and butylamine (0.55 mL, 5.54 mmol) in toluene (5 mL) were heated at 100°C overnight then cooled and concentrated in vacuo. The residue was dissolved in acetic acid (5 mL), treated with nitroethane (0.29 mL, 4.03 mmol) and heated at 100°C for 3.5 hours. Ice (5 g) was added and the precipitate was collected by filtration, slurried in methanol (2 mL), water (10 mL) and acetic acid (3.4 mL), treated with iron powder (1.15 g, 20.5 mmol) and heated at 60°C for 90 minutes. The reaction mixture was partitioned between dichloromethane and water, the layers were separated and the organic layer was dried (hydrophobic frit) and concentrated in vacuo. Analysis of the residue suggested that the reduction was incomplete so the residue was redissolved in acetic acid (40 mL), treated with iron powder (2 g) and heated at 90°C for 90 minutes. The reaction mixture was diluted with dichloromethane (200 mL) and washed with water (200 mL). The aqueous layer was extracted with dichloromethane (200 mL) and the combined organic layers were washed with saturated sodium hydrogen carbonate solution (2 x 200 mL), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 5-50% ethyl acetate in cyclohexane to give the title compound as an off-white solid (770 mg, 70%).1H NMR (400 MHz, CDCh) 8 7.47 (d, J=7.3 Hz, 4H), 7.42 - 7.36 (m, 4H), 7.34 - 7.29 (m, 2H), 6.46 (s, 2H), 5.16 (s, 4H), 3.58 (s, 2H), 2.05 (s, 3H).Step 2: (((2-Bromo-5-(2,2-difluoropropyl)-1,3-phenylene)bis(oxy))bis(methylene))- dibenzene

[0226] 1-(3,5-Bis(benzyloxy)-4-bromophenyl)propan-2-one (770 mg, 1.81 mmol in dichloromethane (18 mL) was treated with (diethylamino)sulfur trifluoride (0.72 mL, 5.43 mmol) at 0°C. The reaction was left to slowly warm to room temperature and stirred overnight. Further (diethylamino)sulfur trifluoride (0.72 mL, 5.43 mmol) was added and the reaction was stirred for 24 hours. Additional (diethylamino)sulfur trifluoride (1.2 mL, 9.05 mmol) was added reaction was stirred for a further 24 hours then quenched with saturated aqueous sodium hydrogen carbonate solution (70 mL). The layers were separated and the aqueous phase was extracted with dichlorometahne (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 5-40% ethyl acetate in cyclohexane to give the title compound as a white solid (440 mg, 54%).1H NMR (400 MHz, CDCh) 8 7.48 (d, J=7.4 Hz, 4H), 7.38 (t, J=7.4 Hz, 4H), 7.33 - 7.29 (m, 2H), 6.50 (s, 2H), 5.17 (s, 4H), 3.03 (t, J=15.3 Hz, 2H), 1.40 (t, J=18.4 Hz, 3H).Intermediate 49: ( ( (2-Bromo-5-(2-cyclopropylvinyl) - 1, 3-phenylene)bis( oxy) ) bis(methylene) ) - dibenzene

[0227] Sodium hydride (60% dispersion in mineral oil, 265 mg, 6.62 mmol) in tetra hydrofuran (40 mL) was treated with cyclopropylmethyl(triphenyl)phosphonium bromide (2.63 g, 6.62 mmol), followed by 3,5-bis(benzyloxy)-4-bromobenzaldehyde (2.20 g, 5.09 mmol). The suspension was stirred at room temperature for 18 hours then heated at 60°C for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (10 mL), diluted with brine (20 mL) and washed with ethyl acetate (2 x 50 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-25% dichloromethane in cyclohexane to give the title compound as a colourless solid (1.54 g, 69%).1H NMR (400 MHz, DMSO): (0.65:0.35 mixture of stereoisomers) 5 7.53 - 7.29 (m, 10H), 6.85 (s, 0.7H), 6.78 (s, 1.3H), 6.42 (d, J=15.9 Hz, 0.35H), 6.22 (d, J=11.6 Hz, 0.65H), 5.99 (dd, J=9.2, 15.7 Hz, 0.35H), 5.24 (s, 2.6H), 5.20 (s, 1.4H), 5.08 (dd, J=10.2, 11.4 Hz, 0.65H), 1.64 - 1.49 (m, 1 H), 0.86 - 0.80 (m, 0.7H), 0.76 - 0.70 (m, 1 ,3H), 0.56 - 0.51 (m, 0.7H), 0.44 - 0.38 (m, 1.24H).Intermediate 50: (((2-Bromo-5-(cyclobutylidenemethyl)-1,3- phenylene) bis(oxy) ) bis(methylene) ) di benzene

[0228] (4-Bromobutyl)triphenylphosphonium bromide (2.26 g, 4.72 mmol) and potassium terf-butoxide (1.05 g, 9.44 mmol) in tetrahydrofuran (10 mL) were heated at reflux for 30 minutes then treated with a solution of 3,5-bis(benzyloxy)-4-bromobenzaldehyde (1.36 g, 3.15 mmol) in tetrahydrofuran (5 mL). The resulting suspension heated at reflux overnight then cooled to room temperature, diluted with cyclohexane (75 mL) and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with 0-50% dichloromethane in cyclohexane to give the title compound as a colourless solid (998 mg, 73%).1H NMR (400 MHz, DMSO) 8 7.48 - 7.45 (m, 4H), 7.43 - 7.38 (m, 4H), 7.35 - 7.31 (m, 2H), 6.60 (s, 2H), 6.05 - 6.01 (m, 1H), 5.20 (s, 4H), 2.95 - 2.87 (m, 2H), 2.85 - 2.77 (m, 2H), 2.09 - 1.99 (m, 2H).Intermediate 51: (2,6-Bis(benzyloxy)-4-propylphenyl)boronic acidStep 1 : (((2-Bromo-5-(prop-1-en-1-yl)-1,3-phenylene)bis(oxy))bis(methylene))- dibenzene

[0229] Ethyltriphenylphosphonium bromide (956 mg, 2.58 mmol) in 2- methyltetrahydrofuran (20 mL) was cooled in an ice / water bath and treated with 2.5 M n- butyllithium solution in hexanes (0.94 mL, 2.34 mmol). After 2 hours the reaction mixture was cooled in a dry ice / acetone bath and treated with 3,5-dibenzyloxy-4-bromo-benzaldehyde (930 mg, 2.34 mmol) in 2-methyltetrahydrofuran (5 mL). The reaction mixture was stirred at - 78°C for 2 hours then allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL), diluted with ethyl acetate (100 mL), washed with water (2 x 100 mL), dried (phase separating paper) and concentrated in vacuo. The residue was purified by column chromatography on 40g silica gel, eluting with 0-50% dichloromethane in cyclohexane to give the title compound (290 mg, 30%). NMR showed the desired product as a mixture of E / Z isomers.1H NMR (400 MHz, CDCL) 8 7.52 - 7.28 (m, 10H), 6.60 (s, 0.8H), 6.52 (s, 1.2H), 6.33 - 6.14 (m, 1.6H), 5.80 - 5.72 (m, 0.4H), 5.17 (s, 4H), 1.86 (dd, J=1.4, 6.3 Hz, 1.3H), 1.71 (dd, J=1.8, 7.2 Hz, 1.7H).Step 2: (2,6-Bis(benzyloxy)-4-propylphenyl)boronic acid

[0230] (((2-Bromo-5-(prop-1-en-1-yl)-1,3-phenylene)bis(oxy))bis(methylene))dibenzene (290 mg, 0.708 mmol, mixture of E / Z isomers) in tetrahydrofuran (10 mL) was cooled in a dry ice / acetone bath and treated with 2.5 M n-butyllithium solution in hexanes (0.43 mL, 1.06 mmol). After 5 minutes trimethyl borate (0.24 mL, 2.13 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight, then quenched with saturated aqueous ammonium chloride (5 mL), poured into water (50 mL) an extracted with ethyl acetate (100 mL). The aqueous layer was acidified with 2M HCI and extracted with further ethyl acetate (2 x 50mL). The combined organic layers were dried (phase separating paper) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-40% ethyl acetate in cyclohexane to give the title compound as a white solid (174 mg, 66%).1H NMR (400 MHz, CDCh) (Mixture of E / Z isomers) 8 7.44 - 7.34 (m, 10H), 7.17 (s, 1.1H), 7.12 (s, 0.9H), 6.67 (s, 0.9H), 6.60 (s, 1.1 H), 6.39 - 6.26 (m, 1.5H), 5.89 - 5.80 (m, 0.5H), 5.15 (s, 4H), 1.91 (d, J=5.3 Hz, 1.3H), 1.78 (dd, J=2.0, 7.1 Hz, 1.7H).Intermediate 52: 1-(3, 5-Bis(benzyloxy)-4-bromophenyl)-2-methylpropan-2-olStep 1 : Methyl 2-(3,5-bis(benzyloxy)-4-bromophenyl)acetate

[0231] 3,5-Bis(benzyloxy)-4-bromobenzoic acid (1000 mg, 2.42 mmol) (prepared according to the method reported in US20080280875) suspended in dichloromethane (20 mL) was cooled in an ice bath and treated with oxalyl chloride (0.32 mL, 3.63 mmol) and / V, / V-dimethylformamide (0.1 mL). The reaction mixture was warmed to room temperature over 3.5 hours then concentrated in vacuo. The residue was dissolvedin tetrahydrofuran (30 mL), cooled in an ice / water bath and treated with (trimethylsilyl)diazomethane solution (1.8 to 2.4 M in hexanes, 3.0 mL) was added and allowed to warm to room temperature overnight. The reaction mixture was quenched with acetic acid (0.28 mL, 4.84 mmol) concentrated in vacuo. The residue was suspended in methanol (60 mL) and a solution of silver benzoate (665 mg, 2.90 mmol) in triethylamine (10 mL, 72.6 mmol) was added dropwise forming a dark brown / black suspension which was stirred at room temperature for 1 day. The reaction mixture was filtered, washed through with ethyl acetate (50 mL) the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and saturated aqueous ammonium chloride solution (100 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organics were dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-20% ethyl acetate in cyclohexane to give the title compound as a yellow oil that solidified on standing (1.05 g, 49%).1H NMR (400 MHz, CDCI3) 8 7.51 - 7.47 (m, 4H), 7.42 - 7.36 (m, 4H), 7.34 - 7.29 (m, 2H), 6.56 (s, 2H), 5.16 (s, 4H), 3.65 (s, 3H), 3.53 (s, 2H).Step 2: 1-(3,5-Bis(benzyloxy)-4-bromophenyl)-2-methylpropan-2-ol

[0232] Methyl 2-(3,5-bis(benzyloxy)-4-bromophenyl)acetate (818 mg, 1.85 mmol) in tetra hydrofuran (20 mL) at 0°C was treated with methylmagnesium bromide solution (1.4 mL, 3M in 2-methyltetrahydrofuran, 4.26 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight, then treated with further methylmagnesium bromide solution (0.43 mL, 3M in 2-methyltetrahydrofuran, 1.30 mmol), stirred for a further 60 minutes, then quenched with saturated aqueous ammonium chloride solution (30 mL) and washed with ethyl acetate (2 x 30 mL), the layers were separated and the aqueous was extracted with ethyl acetate (30 mL). The combined organic layers were dried (phase separating paper) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-30% ethyl acetate in cyclohexane to give the title compound as a yellow oil (685 mg, 67%).1H NMR (400 MHz, CDCI3) 8 7.49 - 7.27 (m, 10H), 6.45 (s, 2H), 5.17 (s, 4H), 2.64 (s, 2H), 1.11 (s, 6H). Exchangeable OH proton not observed.Intermediate 53: (((2-Bromo-5-(2-methoxy-2-methylpropyl)-1,3- phenylene) bis(oxy) ) bis(methylene) ) di benzene

[0233] 1-(3,5-Bis(benzyloxy)-4-bromophenyl)-2-methylpropan-2-ol (280 mg, 0.634 mmol) in / V, / V-dimethylformamide (4 mL) was treated with sodium hydride (63 mg, 60% dispersion in mineral oil, 1.59 mmol) followed by iodomethane (0.16 mL, 2.54 mmol). After 24 hours at room temperature the reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organicextracts were washed with water (2 x 10 mL), dried (phase separating paper) and concentrated in vacuo to give the title compound as a yellow oil (285 mg, 100% crude yield) which was used without further purification in subsequent reactions.1H NMR (400 MHz, CDCh) 8 7.49 - 7.46 (m, 4H), 7.39 - 7.35 (m, 4H), 7.33 - 7.27 (m, 2H), 6.46 (s, 2H), 5.16 (s, 4H), 3.18 (s, 3H), 2.64 (s, 2H), 1.02 (s, 6H).Intermediate 54: 4-Bromo-1-ethyl-3,5-dimethylindolin-2-oneStep 1 : 4-Bromo-1-ethyl-3-hydroxy-3,5-dimethylindolin-2-one

[0234] 4-Bromo-1-ethyl-5-methyl-indoline-2, 3-dione (2.05 g, 7.65 mmol) in tetra hydrofuran (30 mL) was cooled in an ice / water bath and treated with methylmagnesium bromide solution in diethyl ether (3.0 mL, 3M, 9.00 mmol) stirred for 1 hour. The reaction was quenched with saturated ammonium chloride solution (10 mL), diluted with water (40 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 30 mL), dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-25% ethyl acetate in dichloromethane to give the title compound as a yellow solid (1.80 g, 83%).1H NMR (400 MHz, CDCh) 8 7.18 (d, J=7.9 Hz, 1H), 6.72 (d, J=7.9 Hz, 1 H), 3.72 (q, J=7.4 Hz, 2H), 2.77 (s, 1H), 2.38 (s, 3H), 1.77 (s, 3H), 1.25 (t, J=7.2 Hz, 3H).Step 2: 4-Bromo-1-ethyl-3,5-dimethylindolin-2-one

[0235] 4-Bromo-1-ethyl-3-hydroxy-3,5-dimethylindolin-2-one (982 mg, 3.46 mmol) in acetic acid (12 mL) was treated with tin(ll) chloride (1.30 g, 6.86 mmol) added followed by hydrochloric acid (37%, 1.5 mL, 17.6 mmol) and heated at 88°C for 90 minutes. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL followed by 2 x 30 mL). The combined organic phases were washed with water (3 x 50 mL), dried (hydrophobic frit) and concentrated in vacuo to give the title compound as a light brown solid (947 mg, 97%).1H NMR (400 MHz, CDCh) 8 7.14 (d, J=7.8 Hz, 1H), 6.70 (d, J=7.9 Hz, 1H), 3.73 (q, J=7.2 Hz, 2H), 3.43 (q, J=7.5 Hz, 1 H), 2.37 (s, 3H), 1.59 (d, J=7.5 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H).Intermediates 55 and 56: 4-Bromo-7-chloro-1-ethyl-5-methylindoline-2, 3-dione and 4-bromo- 6-chloro- 1-ethyl-5-methylindoline-2, 3-dione

[0236] Trichloroisocyanuric acid (484 mg, 2.08 mmol) was suspended in Sulfuric acid (40 mL, 0.750 mol) at 0°C and 4-bromo-5-methyl-indoline-2, 3-dione (1000 mg, 4.17 mmol) was added in portions over 10 min. The reaction was warmed to room temperature and stirred at room temperature for 16 hours then diluted with water (150 mL) and basified to pH10 with 50% aqueous potassium hydroxide solution and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried (magnesium sulfate) and concentrated in vacuo. The residue was subjected to column chromatography on silica gel, eluting with 10-90% ethyl acetate in dichloromethane. Poor separation was achieved and a mixture of chlorinated products was obtained (900 mg). Without further purification this was dissolved in N,N- dimethylformamide (9.6 mL), treated with potassium carbonate (884 mg, 6.40 mmol) and iodoethane (0.39 mL, 4.80 mmol) and stirred overnight. The reaction mixture was poured into saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (25 mL), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 5-20% ethyl acetate in cyclohexane to give 4-bromo-6-chloro-1-ethyl- 5-methylindoline-2, 3-dione (200 mg, 16% over 2 steps) as the faster running product and 4- bromo-7-chloro-1-ethyl-5-methylindoline-2, 3-dione (369 mg, 22% over two steps) as the slower running product.

[0237] 4-Bromo-6-chloro-1-ethyl-5-methyl-indoline-2, 3-dione:1H NMR (400 MHz, CDCh) 8 6.91 (s, 1 H), 3.77 (q, J=7.3 Hz, 2H), 2.49 (s, 3H), 1.31 (t, J=7.3 Hz, 3H). NOE observed between the NCH2 protons at 3.37 and the aromatic proton at 6.91 ; no NOE observed between the methyl group at 2.49 and the aromatic proton at 6.91.

[0238] 4-Bromo-7-chloro-1-ethyl-5-methyl-indoline-2, 3-dione:1H NMR (400 MHz, CDCh) 8 7.37 (q, J=0.7 Hz, 1 H), 4.19 (q, J=7.3 Hz, 2H), 2.36 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). NOE observed between the aromatic proton at 7.37 and the methyl group at 2.36; no NOE observed between the NCH2 protons at 4.29 and the aromatic proton at 7.37.Intermediate 57: 4-Bromo-6-chioro- 1-ethyi-5-methyiindoiin-2-one

[0239] The title compound was prepared according to a procedure similar to step 2 of General Method 3.1H NMR (400 MHz, CDCh) 8 7.11 (s, 1 H), 4.11 (q, J=7.1 Hz, 2H), 3.47 (s, 2H), 2.34 (s, 3H), 1.29 (t, J=7.1 Hz, 3H).Intermediate 58: 4-Bromo-7-chloro- 1-ethyl-5-methylindolin-2-one

[0240] The title compound was prepared according to a procedure similar to step 2 of General Method 3.1H NMR (400 MHz, CDCI3) 8 6.82 (s, 1 H), 3.71 (q, J=7.2 Hz, 2H), 3.44 (s, 2H), 2.48 (s, 3H), 1.25 (t, J=7.2 Hz, 3H).Large Scale Synthesis of Intermediate 17: 4-Bromo-1-ethyl-5-methylindolin-2-oneStep 1 : 4-Bromo-1-ethyl-5-methylindoline-2, 3-dione

[0241] A 2 L reactor was charged with 4-Bromo-5-methyl-indoline-2, 3-dione (75 g, 312.43 mmol), potassium carbonate (63.02 g, 456.0 mmol, 1.5 eq.) and / V, / V-dimethylformamide (300 mL). lodoethane (30 mL, 373 mmol, 1.2 eq.) was then added to the reaction mixture via funnel over 5-10 minutes and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then cooled to 0 °C followed by the addition of water (900 mL) over 10 minutes. The resulting suspension was stirred for a further 30 min, then filtered and the remaining cake was washed with water (3 x 150 mL) and allowed to air-dry overnight. The solid was then dried in a vacuum oven at 40 °C / 100 mbar over 48 hours to afford 4-bromo-1-ethyl-5-methyl-indoline-2, 3-dione (79.4 g, 296 mmol, 95% Yield).Step 2: 4-Bromo-1-ethyl-5-methylindolin-2-one

[0242] A 2 L reactor fitted was charged with 4-bromo-1-ethyl-5-methyl-indoline-2, 3-dione (50 g, 186.49 mmol), hydrazine (73 mL, 1175 mmol, 50% mass, 6.3 eq.) and propan-1-ol (500 mL). The reaction mixture was heated to reflux overnight. Additional charges of hydrazine (18 mL, 289.8 mmol, 50 mass%, 1.6 eq.) and propan-1-ol (50 mL) were added to the reaction mixture and the mixture stirred for a further 24 hours at reflux. The reaction mixture was then cooled to 60 °C and water (1500 mL) was added. The resulting suspension was stirred and cooled further to 20 °C, and then stirred for 1 hour. The mixture was then filtered and the remaining cake was washed with water (3 x 250 mL) and allowed to air-dry for 1 hour. The solid was then dried in a vacuum oven at 40 °C / 100 mbar over 48 hours to afford 4-bromo-1-ethyl-5-methyl-indolin-2-one (43.45 g, 171 mmol, 92% Yield).Synthesis of Final CompoundsGeneral Method 6General Method 6 is illustrated using the synthesis of Compound 1Compound 1 : 4-(2,6-Dihvdroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-oneStep 1 : 4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one

[0243] (2,6-Dimethoxy-4-propylphenyl)boronic acid (352 mg, 1.57 mmol), 4-bromo-1-ethyl- 5-methylindolin-2-one (333 mg, 1.31 mmol) and potassium carbonate (543 mg, 3.93 mmol) in cyclopentyl methyl ether (6.00 mL) and water (1.80 mL) were treated with SPhos Pd G2 (94 mg, 0.131 mmol) and the reaction tube heated in a microwave reactor at 120°C for 1 hour. A second reaction was carried out using the same reagents and conditions and the reaction mixtures were combined, filtered through celite and washed through with ethyl acetate (100 mL). The filtrate was washed with saturated aqueous sodium bicarbonate solution (100 mL) and the aqueous layer was back-extracted with ethyl acetate (100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-30% ethyl acetate in cyclohexane to give the title compound as a brown solid (796 mg, 80%).1H NMR (400 MHz, CDCI3) 8 7.17 (d, J=7.9 Hz, 1 H), 6.73 (d, J=7.9 Hz, 1 H), 6.46 (s, 2H), 3.76 (q, J=7.2 Hz, 2H), 3.71 (s, 6H), 3.18 (s, 2H), 2.64 (t, J=7.7 Hz, 2H), 2.05 (s, 3H), 1.75 - 1.67 (m, 2H), 1.28 (t, J=7.1 Hz, 3H), 1.00 (t, J=7.3 Hz, 3H).Step 2: 4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one

[0244] 4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one (796 mg, 2.25 mmol) in dichloromethane (15 mL) was treated with 1 M boron tribromide (1M in dichloromethane) (9.0 mL, 9.01 mmol) and stirred for 1 hour at room temperature. The reaction mixture was cooled and methanol (5 mL) was cautiously added dropwise. The resulting solution was concentrated in vacuo and the residue was co-evaporated with methanol (2 x 20 mL) followed by 7N ammonia in methanol (20 mL). The residue was partitioned between water (50 mL) and ethyl acetate (50 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried (phase separating paper) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 20-60% ethyl acetate in cyclohexane, to give the title compound as a white solid (456 mg, 62%).1H NMR (400 MHz, DMSO) 8 8.97(s, 2H), 7.10 (d, J=8.0 Hz, 1 H), 6.83 (d, J=7.9 Hz, 1 H), 6.24 (s, 2H), 3.68 (q, J=7.1 Hz, 2H), 3.07 (s, 2H), 2.41 (t, J=7.6 Hz, 2H), 2.01 (s, 3H), 1.61 - 1.53 (m, 2H), 1.16 (t, J=7.1 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (ESI): m l z 326.2 (M+1). HPLC purity: 98.9%.

[0245] The following compounds were prepared in an analogous manner to Compound 1 , using general method 6 and reacting the appropriate aryl halide and boronic acid via Suzuki cross-coupling chemistry. Final compounds were purified using normal phase column chromatography, reverse phase preparative HPLC or both methods in succession.Compound 2: 4-(2,6-Dihydroxy-4-propylphenyl)-1 ,5-dimethylindolin-2-one

[0246] 1H NMR1H NMR (400 MHz, DMSO) 8 8.98 (s, 2H), 7.12 (d, J=7.9 Hz, 1 H), 6.80 (d, J=7.9 Hz, 1 H), 6.25 (s, 2H), 3.12 (s, 3H), 3.10 (s, 2H), 2.42 (t, J=7.5 Hz, 2H), 2.02 (s, 3H), 1.62 - 1.55 (m, 2H), 0.94 (t, J=7.3 Hz, 3H). MS (ESI): m / z 312.3 (M+1). HPLC purity: 93.2%.Compound 3: 4-(2,6-Dihydroxy-4-propylphenyl)-1-isopropyl-5-methylindolin-2-one

[0247] 1H NMR (400 MHz, DMSO) 8 8.97 (s, 2H), 7.06 (d, J=8.1 Hz, 1 H), 6.95 (d, J=8.1 Hz, 1 H), 6.23 (s, 2H), 4.56 - 4.48 (m, 1 H), 3.04 (s, 2H), 2.41 (t, J=7.6, 2H), 1.99 (s, 3H), 1.61 - 1.52 (m, 2H), 1.40 (d, J=6.8 Hz, 6H), 0.92 (t, J=7.3 Hz, 3H). MS (ESI): m / z 340.2 (M+1). HPLC purity: 99.7%.Compound 4: 4-(2,6-Dihvdroxy-4-propylphenyl)-1-ethylindolin-2-one

[0248] 1H NMR (400 MHz, DMSO) 8 9.08 (s, 2H), 7.22 (t, J=7.8 Hz, 1 H), 6.89 (dd, J=7.8, 10.1 Hz, 2H), 6.24 (s, 2H), 3.71 (q, J=7.1 Hz, 2H), 3.26 (s, 2H), 2.40 (t, J=7.7 Hz, 2H), 1.60 - 1.51 (m, 2H), 1.18 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (ESI): m / z 312.0 (M+1). HPLC purity: 99.4%. Compound 5: 4-(2,6-Dihydroxy-4-propylphenyl)-1-(2-(dimethylamino)ethyl)-5-methylindolin- 2-one

[0249] 1H NMR (400 MHz, CDCI3) 8 7.21 (d, J=8.1 Hz, 1 H), 6.82 (d, J=7.9 Hz, 1 H), 6.40 (s, 2H), 3.99 (br s, 2H), 3.86 (t, J=7.2 Hz, 2H), 3.23 (s, 2H), 2.70 (t, J=7.2 Hz, 2H), 2.52 (t, J=7.6 Hz, 2H), 2.42 (s, 6H), 2.12 (s, 3H), 1.71 - 1.61 (m, 2H), 0.96 (t, J=7.3 Hz, 3H). MS(ESI): m / z 369.4 (M+1). HPLC purity: 97.2%.Compound 6: 4-(2,6-Dihydroxy-4-propylphenyl)-1 ,3,3,5-tetramethylindolin-2-one

[0250] Dioxane was used in place of cyclopentyl methyl ether in the Suzuki step.1H NMR (400 MHz, DMSO) 8 8.85 (s, 2H), 7.13 (d, J=8.3 Hz, 1 H), 6.83 (d, J=7.9 Hz, 1 H), 6.24 (s,2H), 3.13 (s, 3H), 2.45 (t, J=7.5 Hz, 2H), 1.89 (s, 3H), 1.65 - 1.54 (m, 2H), 1.01 (s, 6H), 0.93 (t, J=7.3 Hz, 3H). MS (ESI): m / z 340.3 (M+1). HPLC purity: 99.4%.Compound 7: 4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-3,3,5-trimethylindolin-2-one

[0251] Dioxane was used in place of cyclopentyl methyl ether in the Suzuki step. The BBrs demethylation step was carried out in a sealed tube at 50°C.1H NMR (400 MHz, DMSO) 8 8.83 (s, 2H), 7.10 (d, J=8.3 Hz, 1 H), 6.86 (d, J=7.8 Hz, 1 H), 6.22 (s, 2H), 3.68 (q, J=7.1 Hz, 2H), 2.43 (t, J=7.6 Hz, 2H), 1.86 (s, 3H), 1.61 - 1.51 (m, 2H), 1.14 (dd, J=7.1 , 7.1 Hz, 3H), 0.99 (s, 6H), 0.91 (t, 7.3 Hz, 3H). MS (ESI): m / z 354.2 (M+1). HPLC purity: 98.9%.Compound 8: 4-(2,6-Dihvdroxy-4-propylphenyl)-3,3-dimethylindolin-2-one

[0252] The bromide starting material is commercially available from suppliers including Fluorochem (Cat # F301474).1H NMR (400 MHz, DMSO) 8 10.24 (s, 1 H), 8.82 (s, 2H), 7.11 (t, J=7.7 Hz, 1 H), 6.76 (dd, J=0.9, 7.6 Hz, 1 H), 6.54 (dd, J=0.9, 7.7 Hz, 1 H), 6.20 (s, 2H), 2.41 (t, J=7.5 Hz, 2H), 1.60 - 1 .53 (m, 2H), 1.00 (s, 6H), 0.91 (t, J=7.3 Hz, 3H). MS (ESI): m I z 298.1 (M+1). HPLC purity: 93.7%.Compound 9: (±)-4-(2,6-Dihvdroxy-4-propylphenyl)-3-methylindolin-2-one

[0253] The bromide starting material was prepared according to literature procedure (Zhang, Lu; et al; Asian Journal of Organic Chemistry (2019), 8(7), 1024-1028).1H NMR (400 MHz, DMSO) 8 10.24 (s, 1 H), 9.05 (s, 1 H), 8.90 (s, 1 H), 7.11 (t, J=7.7 Hz, 1 H), 6.75 (d, J=7.9 Hz, 1 H), 6.71 (d, J=7.7 Hz, 1 H), 6.22 (s, 2H) 3.28 (q, J=7.6 Hz, 1 H), 2.40 (t, J=7.7 Hz, 2H), 1.61 - 1.51 (m, 2H), 0.90 (t, J=7.3 Hz, 3H), 0.86 (d, J=7.6 Hz, 3H). MS (ESI): m I z 298.1 (M+1). HPLC purity: 98.5%.Compound 10: (±)-4-(2,6-Dihvdroxy-4-propylphenyl)-1-ethyl-3,5-dimethylindolin-2-one

[0254] 1H NMR (400 MHz, DMSO) 8 8.96 (s, 1 H), 8.89 (s, 1 H), 7.10 (d, J=7.9 Hz, 1 H), 6.83 (d, J=7.8 Hz, 1 H), 6.24 (d, J=1.5 Hz, 1 H), 6.22 (d, J=1 .3 Hz, 1 H), 3.70 - 3.63 (m, 2H), 3.12 (q, J=7.6 Hz, 1 H), 2.42 (t, J=7.5 Hz, 2H), 1.99 (s, 3H), 1.61 - 1.52 (m, 2H), 1.15 (t, J=7.1 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H), 0.84 (d, J=7.7 Hz, 3H). MS (ESI): m / z 340.4 (M+1). HPLC purity: 98.4%.Compound 11 : 1-Ethyl-4-(4-ethyl-2,6-dihvdroxyphenyl)-5-methylindolin-2-one

[0255] 1H NMR (400 MHz, MeOD) 5 7.20 (d, J=7.9 Hz, 1 H), 6.87 (d, J=8.0 Hz, 1 H), 6.33 (s, 2H), 3.80 (q, J=7.2 Hz, 2H), 3.25 (s, 2H), 2.56 (q, J=7.6 Hz, 2H), 2.12 (s, 3H), 1.31 - 1.23 (m, 6H). Two phenol protons not observed. MS (ESI): m / z 312.4 (M+1). HPLC purity: 99.3%.Compound 12: 4-(2,6-Dihydroxy-4-isopropylphenyl)-1-ethyl-5-methylindolin-2-one

[0256] 1H NMR (400 MHz, DMSO) 8 8.98 (s, 2H), 7.10 (d, J=8.2 Hz, 1 H), 6.83 (d, J=7.9 Hz, 1 H), 6.30 (s, 2H), 3.68 (q, J=7.2 Hz, 2H), 3.08 (s, 2H), 2.77 - 2.69 (m, 1 H), 2.01 (s, 3H), 1.20 - 1.15 (m, 9H). MS (ESI): m / z 326.3 (M+1). HPLC purity: 99.8%.Compound 13: 4-(4-Butyl-2,6-dihvdroxyphenyl)-1-ethyl-5-methylindolin-2-one

[0257] 1H NMR (400 MHz, DMSO) 8 8.97 (s, 2H), 7.10 (d, J=8.2 Hz, 1 H), 6.83 (d, J=7.9 Hz, 1 H), 6.24 (s, 2H), 3.68 (q, J=7.2 Hz, 2H), 3.08 (s, 2H), 2.44 (t, J=7.7 Hz, 2H), 2.01 (s, 3H), 1.59 - 1.50 (m, 2H), 1.40 - 1.31 (m, 2H), 1.16 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (ESI): m / z 340.4 (M+1). HPLC purity: 98.2%.Compound 14: 4-(2,6-Dihvdroxy-4-pentylphenyl)-1-ethyl-5-methylindolin-2-one

[0258] 1H NMR (400 MHz, DMSO) 8 8.97 (s, 2H), 7.10 (d, J=8.2 Hz, 1 H), 6.83 (d, J=7.9 Hz, 1 H), 6.24 (s, 2H), 3.68 (q, J=7.1 Hz, 2H), 3.07 (s, 2H), 2.43 (t, J=7.7 Hz, 2H), 2.01 (s, 3H), 1.60 - 1.52 (m, 2H), 1.36 - 1.29 (m, 4H), 1.16 (t, J=7.1 Hz, 3H), 0.89 (t, J=6.9 Hz, 3H).MS (ESI): m / z 354.4 (M+1). HPLC purity: 98.3%.Compound 15: 4-(4-Chloro-2,6-dihvdroxyphenyl)-1-ethyl-5-methylindolin-2-one

[0259] 1H NMR (400 MHz, DMSO) 8 9.66 (s, 2H), 7.12 (d, J=7.9 Hz, 1 H), 6.86 (d, J=7.9 Hz, 1 H), 6.46 (s, 2H), 3.68 (q, J=7.2 Hz, 2H), 3.08 (s, 2H), 2.00 (s, 3H), 1.16 (t, J=7.2 Hz,3H). MS (ESI): m / z 318.0 (M+1). HPLC purity: 99.8%.Compound 16: 4-(4-Butyl-2,6-dihvdroxyphenyl)-1-ethylindolin-2-one

[0260] 1H NMR (400 MHz, DMSO) 8 9.08 (s, 2H), 7.22 (t, J=7.8 Hz, 1 H), 6.92 - 6.86 (m, 2H), 6.24 (s, 2H), 3.71 (q, J=7.1 Hz, 2H), 3.26 (s, 2H), 2.43 (t, J=7.6 Hz, 2H), 1.58 - 1.48 (m,2H), 1.40 - 1.28 (m, 2H), 1.18 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H). MS (ESI): m / z 326.24 (M+1). HPLC purity: 99.1%.Compound 17: 4-(4-Butyl-2,6-dihvdroxyphenyl)-1-methylindolin-2-one

[0261] 1H NMR (400 MHz, DMSO) 8 9.07 (s, 2H), 7.22 (t, J=7.8 Hz, 1 H), 6.88 (d, J=7.8 Hz, 1 H), 6.85 (d, J=7.8 Hz, 1 H), 6.23 (s, 2H), 3.26 (s, 2H), 3.13 (s, 3H), 2.42 (t, J=7.6 Hz, 2H), 1.56 - 1.48 (m, 2H), 1.38 - 1.30 (m, 2H), 0.91 (t, J=7.3 Hz, 3H). MS (ESI): m / z 312.2(M+1). HPLC purity: 99.7%.Compound 18: 4-(2,6-Dihydroxy-4-pentylphenyl)-1-methylindolin-2-one

[0262] 1H NMR (400 MHz, DMSO) 8 9.07 (s, 2H), 7.22 (t, J=7.8 Hz, 1 H), 6.88 (d, J=7.8 Hz, 1 H), 6.85 (d, J=7.8 Hz, 1 H), 6.23 (s, 2H), 3.26 (s, 2H), 3.13 (s, 3H), 2.41 (t, J=7.6 Hz, 2H), 1.59 - 1.49 (m, 2H), 1.35 - 1.28 (m, 4H), 0.88 (t, J=6.9 Hz, 3H). MS (ESI): m I z 326.3 (M+1). HPLC purity: 99.3%.Compound 19: 4-(2,6-Dihvdroxy-4-pentylphenyl)-1-ethylindolin-2-one

[0263] 1H NMR (400 MHz, DMSO) 8 9.09 (s, 2H), 7.22 (t, J=7.8 Hz, 1 H), 6.89 (dd, J=7.8,11.9 Hz, 2H), 6.24 (s, 2H), 3.71 (q, J=7.1 Hz, 2H), 3.26 (s, 2H), 2.41 (t, J=7.6 Hz, 2H), 1.59 - 1.50 (m, 2H), 1.32 (d, J=26.8 Hz, 4H), 1.20 - 1.15 (m, 3H), 0.89 (t, J=6.8 Hz, 3H). MS (ESI): m / z 340.2 (M+1). HPLC purity: 99.5%.Compound 20: 4-(2,6-Dihydroxy-4-pentylphenyl)-1 ,5-dimethylindolin-2-one

[0264] 1H NMR (400 MHz, DMSO) 8 8.96 (s, 2H), 7.10 (d, J=7.6 Hz, 1 H), 6.78 (d, J=7.9 Hz, 1 H), 6.23 (s, 2H), 3.11 (s, 3H), 3.09 (s, 2H), 2.42 (t, J=7.6 Hz, 2H), 2.02 - 1.99 (m, 3H), 1.57 - 1.53 (m, 2H), 1.36 - 1.28 (m, 4H), 0.92 - 0.86 (m, 3H). MS (ESI): m / z 340.5 (M+1).HPLC purity: 99.1%.Compound 21 : 4-(2,6-Dihydroxy-4-propylphenyl)-5-methyl-1-propylindolin-2-one

[0265] 1H NMR (400 MHz, DMSO) 8 8.97 (s, 2H), 7.09 (d, J=8.2 Hz, 1 H), 6.82 (d, J=7.9 Hz, 1 H), 6.24 (s, 2H), 3.60 (t, J=7.2 Hz, 2H), 3.09 (s, 2H), 2.42 (t, J=7.7 Hz, 2H), 2.01 (s,3H), 1.65 - 1.54 (m, 4H), 0.96 - 0.88 (m, 6H). MS (ESI): m / z 340.2 (M+1). HPLC purity:98.1%.Compound 22: 4-(2,6-Dihydroxy-4-propylphenyl)-5-methyl-1-(2,2,2-trifluoroethyl)indolin-2- one

[0266] 1H NMR (400 MHz, DMSO) 8 9.04 (s, 2H), 7.13 (d, J=8.0 Hz, 1 H), 6.96 (d, J=7.9 Hz, 1 H), 6.25 (s, 2H), 4.58 (q, J=9.5 Hz, 2H), 3.22 (s, 2H), 2.42 (t, J=7.6 Hz, 2H), 2.02 (s, 3H), 1.63 - 1.53 (m, 2H), 0.93 (t, J=7.3 Hz, 3H). MS (ESI): m / z 380.3 (M+1). HPLC purity: 99.0%.Compound 23: 4-(2,6-dihvdroxy-4-propylphenyl)-1-ethyl-3,3-difluoro-5-methylindolin-2-one

[0267] 1H NMR (400 MHz, DMSO) 8 8.95 (s, 2H), 7.42 (d, J=8.1 Hz, 1 H), 7.09 (d, J=8.1 Hz, 1 H), 6.21 (s, 2H), 3.73 (q, J=7.2 Hz, 2H), 2.43 (t, J=7.7 Hz, 2H), 1 .95 (s, 3H), 1 .64 - 1 .54 (m, 2H), 1.20 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (ESI): m / z 362.3 (M+1). HPLC purity: 98.0%.Compound 24: 4-(2,6-Dihydroxy-4-propylphenyl)-7-fluoro-1 ,5-dimethylindolin-2-one

[0268] 1H NMR (400 MHz, CDCI3) 8 7.16 (dd, J=8.6, 11.3 Hz, 1 H), 6.99 (dd, J=4.3, 8.6 Hz, 1 H), 6.40 (s, 2H), 5.43 (s, 2H), 3.49 (s, 2H), 3.48 (d, J=2.8 Hz, 3H), 2.51 (t, J=7.7 Hz, 2H),1.60-1.70 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). MS (ESI): m / z 316.2 (M+1). HPLC purity: 99.4%.Compound 25: 4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-7-fluoro-5-methylindolin-2-one

[0269] 1H NMR (400 MHz, DMSO) 8 9.02 (s, 2H), 7.03 (d, J=13.1 Hz, 1 H), 6.24 (s, 2H), 3.77 (q, J=7.0 Hz, 2H), 3.15 (s, 2H), 2.41 (t, J=7.6 Hz, 2H), 2.00 (s, 3H), 1.61 - 1.52 (m, 2H),1.20 (t, J=7.0 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H). MS (ESI): m I z 344.2 (M+1). HPLC purity: 99.3%.Compound 26: 4-(2,6-dihvdroxy-4-propylphenyl)-1-ethyl-6-fluoro-5-methylindolin-2-one

[0270] 1H NMR (400 MHz, DMSO) 8 9.10 (s, 2H), 6.89 (d, J=9.9 Hz, 1 H), 6.25 (s, 2H), 3.67 (q, J=7.1 Hz, 2H), 3.07 (s, 2H), 2.41 (t, J=7.6 Hz, 2H), 1.89 (d, J=2.5 Hz, 3H), 1.63 - 1.53 (m, 2H), 1.15 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H). MS (ESI): m / z 344.2 (M+1).HPLC purity: 98.6%.Compound 27: 7-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one

[0271] 1H NMR (400 MHz, MeOD) 8 6.92 (s, 1 H), 6.19 (s, 2H), 3.77 (q, J=7.2 Hz, 2H), 3.20 (s, 2H), 2.48 (t, J=7.1 Hz, 2H), 2.11 (s, 3H), 1.61-1.71 (m, 2H), 1.26 (t, J=7.4 Hz, 3H),0.98 (t, J=7.3 Hz, 3H). Two phenol protons not observed. MS (ESI): m / z 360.3 (M+1). HPLC purity: 94.6%.Compound 28: 6-Chloro-4-(2,6-dihvdroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one

[0272] 81H NMR (400 MHz, DMSO) 8 9.08 (s, 2H), 7.14 (s, 1 H), 6.24 (s, 2H), 4.00 (q,J=7.0 Hz, 2H), 3.14 (s, 2H), 2.41 (t, J=7.7 Hz, 2H), 1.98 (s, 3H), 1.61 - 1.52 (m, 2H), 1.22 (t, J=7.0 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (ESI): m / z 360.2 (M+1). HPLC purity: 98.3%.Compound 29: 6-Chloro-4-(2,6-dihvdroxy-4-propylphenyl)-1-ethyl-7-fluoroindolin-2-one

[0273] 1H NMR (400 MHz, DMSO) 8 9.29 (s, 2H), 6.98 (d, J=6.3 Hz, 1 H), 6.24 (s, 2H), 3.81 (q, J=7.0 Hz, 2H), 3.36 (s, 2H), 2.39 (t, J=8.0 Hz, 2H), 1.55 (qt, J=7.4, 7.2 Hz, 2H), 1.21 (t, J=7.0 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H). MS (ESI): m / z 364.3 (M+1). HPLC purity: 99.1 %.Compound 30: 4-(4-cvclopropyl-2,6-dihvdroxyphenyl)-1-ethyl-5-methylindolin-2-one

[0274] 1H NMR (400 MHz, DMSO) 8 8.98 (s, 2H), 7.09 (d, J=8.5 Hz, 1 H), 6.82 (d, J=9.4 Hz, 1 H), 6.12 (s, 2H), 3.67 (q, J=7.2 Hz, 2H), 3.06 (s, 2H), 2.07 (s, 3H), 1.78 - 1.71 (m, 1 H), 1.16 (t, J=6.8 Hz, 3H), 0.93 - 0.87 (m, 2H), 0.60 - 0.55 (m, 2H). MS (ESI): m I z 324.4 (M+1).HPLC purity: 99.4%.Compound 31 : 4-(4-Cvclobutyl-2,6-dihvdroxyphenyl)-1-ethyl-5-methylindolin-2-one

[0275] 1H NMR (400 MHz, DMSO) 8 9.01 (s, 2H), 7.10 (d, J=7.9 Hz, 1 H), 6.83 (d, J=8.0 Hz, 1 H), 6.27 (s, 2H), 3.68 (q, J=7.2 Hz, 2H), 3.44 - 3.34 (m, 1 H), 3.08 (s, 2H), 2.30 - 2.21(m, 2H), 2.10 - 1.90 (m, 6H), 1.83 - 1.76 (m, 1 H), 1.16 (t, J=7.4 Hz, 3H). MS (ESI): m / z338.6 (M+1). HPLC purity: 95.9%.General Method 7

[0276] General Method 7 is illustrated using the synthesis of Compound 32Step 1 : 4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-methylindolin-2-oneThe title compound was prepared according to a procedure similar to step 1 of General Method 6.1H NMR (400 MHz, CDCI3) 8 7.32 (t, J=7.8 Hz, 1 H), 7.25 - 7.20 (m, 6H), 7.15 - 7.11 (m, 4H), 7.06 (d, J=7.8 Hz, 1 H), 6.78 (d, J=7.7 Hz, 1 H), 6.53 (s, 2H), 5.00 (s, 4H), 3.29 (s, 2H), 3.22 (s, 3H), 2.56 (t, J=7.7 Hz, 2H), 1.67 - 1.58 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).Step 2: 4-(2,6-Dihydroxy-4-propylphenyl)-1-methylindolin-2-one

[0277] 4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-methylindolin-2-one (144 mg, 0.302 mmol) in ethanol (7 mL) and ethyl acetate (7 mL) was hydrogenated over palladium on carbon (10%, 64 mg) using a balloon of hydrogen for 20 hours. The reaction mixture was filtered and washed through with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by reverse phase preparative HPLC to give the title compound as an off-white solid (64 mg, 71 %).1H NMR (400 MHz, DMSO) 8 9.09 (s, 2H), 7.23 (t, J=7.8 Hz, 1 H), 6.87 (t, J=7.5 Hz, 2H), 6.24 (s, 2H), 3.26 (s, 2H), 3.13 (s, 3H), 2.39 (t, J=7.6 Hz, 2H), 1.63 - 1.53 (m, 2H), 0.91 (t, J=7.3 Hz, 3H). MS (ESI): m I z 298.2 (M+1). HPLC purity: 99.5%.

[0278] The following compounds were also prepared by General Method 7, using the appropriate aryl halide and boronic acid. Final compounds were purified using normal phase column chromatography, reverse phase preparative HPLC or by both methods in succession.

[0279] The bromide starting material was purchased from Enamine (Cat # EN300- 697285).1H NMR (400 MHz, DMSO) 8 10.21 (s, 1 H), 8.94 (s, 2H), 7.00 (d, J=8.2 Hz, 1 H), 6.63 (d, J=7.8 Hz, 1 H), 6.23 (s, 2H), 3.02 (s, 2H), 2.41 (t, J=7.7 Hz, 2H), 1.98 (s, 3H), 1.61 - 1.52 (m, 2H), 0.93 (t, J=7.3 Hz, 3H). MS (ESI): m / z 298.3 (M+1). HPLC purity: >99.5%.e

[0280] Pure ethanol was used as solvent for the hydrogenation step in place of an ethanol / ethyl acetate mixture.1H NMR (400 MHz, DMSO) 8 9.09 (s, 2H), 7.23 (t, J=7.8 Hz, 1 H), 6.99 (dd, J=0.8, 7.7 Hz, 1 H), 6.88 (dd, J=0.9, 7.7 Hz, 1 H), 6.23 (s, 2H), 3.22 (s, 2H), 2.68 - 2.61 (m, 1 H), 2.39 (dd, J=7.7, 7.7 Hz, 2H), 1.60 - 1.51 (m, 2H), 1.04 - 0.98 (m, 2H), 0.92 (t, J=7.3 Hz, 3H), 0.82 - 0.76 (m, 2H). MS (ESI): m I z 324.1 (M+1). HPLC purity: 98.9%.Compound 35: 1-Cyclopropyl-4-(2,6-dihydroxy-4-propylphenyl)-5-methylindolin-2-one

[0281] 1H NMR (400 MHz, DMSO) 8 8.96 (s, 2H), 7.11 (d, J=7.9 Hz, 1 H), 6.90 (d, J=7.9 Hz, 1 H), 6.23 (s, 2H), 3.04 (s, 2H), 2.68 - 2.59 (m, 1 H), 2.41 (t, J=7.6 Hz, 2H), 2.00 (s, 3H), 1 .61 - 1.54 (m, 2H), 1 .02 - 0.96 (m, 2H), 0.93 (t, J=7.3 Hz, 3H), 0.80 - 0.74 (m, 2H).MS (ESI): m I z 338.3 (M+1). HPLC purity: 99.6%.Compound 36: 4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-7-fluoroindolin-2-one

[0282] 1H NMR (400 MHz, DMSO) 8 9.13 (s, 2H), 7.11 (dd, J=8.7, 11.7 Hz, 1 H), 6.85 (dd, J=4.5, 8.6 Hz, 1 H), 6.23 (s, 2H), 3.80 (q, J=6.9 Hz, 2H), 3.34 (s, 2H), 2.39 (t, J=7.6 Hz, 2H), 1.61 - 1.51 (m, 2H), 1.21 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H). MS (ESI): m l z 330.2 (M+1). HPLC purity: 99.6%.Compound 37: 4-(2,6-Dihvdroxy-4-propylphenyl)-1-ethyl-5,7-dimethylindolin-2-one

[0283] 1H NMR (400 MHz, DMSO) 5 8.93 (s, 2H), 6.87 (s, 1 H), 6.23 (s, 2H), 3.87 (q, J=7.1 Hz, 2H), 3.03 (s, 2H), 2.48 (s, 3H), 2.41 (t, J=7.7 Hz, 2H), 1.95 (s, 3H), 1.61 - 1.52 (m, 2H), 1.18 (t, J=7.1 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (ESI): m l z 340.2 (M+1). HPLC purity:98.1%.Compound 38: 4-(2,6-Dihvdroxy-4-propylphenyl)-1-ethyl-5,6-dimethylindolin-2-one

[0284] 1H NMR (400 MHz, DMSO) 5 8.94 (s, 2H), 6.79 (s, 1 H), 6.23 (s, 2H), 3.67 (q, J=7.1 Hz, 2H), 3.02 (s, 2H), 2.41 (t, J=7.7 Hz, 2H), 2.28 (s, 3H), 1.88 (s, 3H), 1.61 - 1.52 (m, 2H),1.16 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (ESI): m l z 340.3 (M+1). HPLC purity:99.6%.Compound 39: 4-(2,6-Dihvdroxy-4-propylphenyl)-1-(2,2,2-trifluoroethyl)indolin-2-one

[0285] 1H NMR (400 MHz, DMSO) 8 9.15 (s, 2H), 7.25 (t, J=7.8 Hz, 1 H), 7.04 (d, J=7.8Hz, 1 H), 6.95 (d, J=7.8 Hz, 1 H), 6.25 (s, 2H), 4.62 (q, J=9.4 Hz, 2H), 3.41 (s, 2H), 2.40 (t, J=7.6 Hz, 2H), 1.61 - 1.51 (m, 2H), 0.93 (t, J=7.3Hz, 3H). MS (ESI): m I z 366.0 (M+1). HPLC purity: 97.3%.Compound 40: 4-(2,6-Dihvdroxy-4-propylphenyl)-1-ethyl-5-(trifluoromethyl)indolin-2-one

[0286] The hydrogenation step was carried out under transfer conditions, using 1-methyl-1 ,4-cyclohexadiene as the hydrogen source in refluxing ethanol.1H NMR (400 MHz, DMSO) 5 9.03 (s, 2H), 7.65 (d, J=8.1 Hz, 1 H), 7.13 (d, J=8.3 Hz, 1 H), 6.21 (s, 2H), 3.75 (dd, J=7.3, 14.1 Hz, 2H), 3.06 (s, 2H), 2.42 (t, J=7.6 Hz, 2H), 1.63 - 1.53 (m, 2H), 1.19 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H).MS (ESI): m l z 380.2 (M+1). HPLC purity: 98.6%.Compound 41 : 1-Cvclopropyl-4-(2,6-dihvdroxy-4-propylphenyl)-7-fluoro-5-methylindolin-2- one

[0287] The hydrogenation step was carried out under transfer conditions, using 1-methyl-1 ,4-cyclohexadiene as the hydrogen source in refluxing ethanol.1H NMR (400 MHz, DMSO) 5 8.99 (s, 2H), 7.00 (d, J=12.8 Hz, 1 H), 6.23 (s, 2H), 3.09 (s, 2H), 2.87 - 2.80 (m, 1 H), 2.40 (t, J=7.6 Hz, 2H), 1.99 (s, 3H), 1.62 - 1 .52 (m, 2H), 0.97 - 0.84 (m, 7H). MS (ESI): m I z 356.3 (M+1). HPLC purity: 99.4%.Compound 42: 1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-dihydroxyphenyl)-7-fluoro-5- methylindolin-2-one

[0288] The hydrogenation step was carried out under transfer conditions, using 1-methyl-1 ,4-cyclohexadiene as the hydrogen source in refluxing ethanol.1H NMR (400 MHz, DMSO) 5 9.00 (s, 2H), 7.00 (d, J=12.6 Hz, 1 H), 6.32 (s, 2H), 3.09 (s, 2H), 2.87 - 2.79 (m, 1 H), 2.37(d, J=6.9 Hz, 2H), 1.99 (s, 3H), 0.98 - 0.84 (m, 5H), 0.53 - 0.47 (m, 2H), 0.20 - 0.15 (m, 2H).MS (ESI): m I z 368.3 (M+1). HPLC purity: 99.0%.General Method 8General Method 8 is illustrated using the synthesis of Compound 43.Compound 43: 4-(4-(Cvclopropylmethyl)-2,6-dihvdroxyphenyl)-1-ethyl-5-methylindolin-2-oneStep 1 : 4-(2,6-Bis(benzyloxy)-4-(cyclopropylmethyl)phenyl)-1-ethyl-5-methylindolin-2- one

[0289] (((2-Bromo-5-(cyclopropylmethyl)-1,3-phenylene)bis(oxy))bis(methylene))- dibenzene (700 mg, 1.65 mmol), 1-ethyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)indolin-2-one (747 mg, 2.48 mmol) and potassium carbonate (686 mg, 4.96 mmol,) in cyclopentyl methyl ether (12 mL) and water (3 mL) were degassed with nitrogen and treated with SPhos Pd G2 (119 mg, 0.165 mmol). The reaction mixture was heated in a microwave reactor at 150°C for 60 minutes. A second reaction was carried out using the same conditions and amounts of reagents and the reaction mixtures were combined, diluted with ethyl acetate (100 mL), washed with water (100 mL), dried (phase separating paper) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-40% diethyl ether in cyclohexane to give the title compound as a colourless oil which solidified on standing (640 mg, 38% over 2 reaction batches).1H NMR (400 MHz, CDCh) 8 7.25 - 7.19 (m, 7H), 7.11 - 7.08 (m, 4H), 6.75 (d, J=7.9 Hz, 1H), 6.61 (s, 2H), 5.00 (s, 4H), 3.77 (q, J=7.2 Hz, 2H), 3.13 (s, 2H), 2.52 (d, J=6.8 Hz, 2H), 2.11 (s, 3H), 1.30 (t, J=7.2 Hz, 3H), 1.00 - 0.91 (m, 1H), 0.54 - 0.49 (m, 2H), 0.19 - 0.14 (m, 2H).Step 2: 4-(4-(Cyclopropylmethyl)-2,6-dihydroxyphenyl)-1 -ethyl-5-methylindolin-2-one

[0290] 4-(2,6-Bis(benzyloxy)-4-(cyclopropylmethyl)phenyl)-1-ethyl-5-methylindolin-2-one (640 mg, 1.24 mmol) in ethanol (30 mL) and ethyl acetate (30 mL) was hydrogenated over 10% palladium on carbon (132 mg) under a balloon of hydrogen for 4 hours. The reaction mixture was filtered through celite, washed through with copious ethanol and ethyl acetate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-100 % ethyl acetate in dichloromethane to give the title compound as a white solid (284 mg, 0.842 mmol, 68%).1H NMR (400 MHz, DMSO) 8 9.04 (s, 2H), 7.15 (d, J=8.0 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 6.39 (s, 2H), 3.74 (q, J=7.1 Hz, 2H), 3.14 (s, 2H), 2.44(d, J=6.9 Hz, 2H), 2.07 (s, 3H), 1 .22 (t, J=7.2 Hz, 3H), 1.05 - 0.96 (m, 1 H), 0.59 - 0.54 (m, 2H), 0.27 - 0.22 (m, 2H). MS (ESI): m I z 338.4 (M+1). HPLC purity: 98.0%.

[0291] General Method 8, using the appropriate bromide and boronate ester, was also used to prepare the following compounds. Final compounds were purified using normal phase column chromatography, reverse phase preparative HPLC or by both methods in succession.Compound 44: 1-Cvclopropyl-4-(4-(cvclopropylmethyl)-2,6-dihvdroxyphenyl)-5-methylindolin- 2-one

[0292] 1H NMR (400 MHz, DMSO) 8 9.03 (s, 2H), 7.17 (d, J=8.0 Hz, 1 H), 6.96 (d, J=7.9 Hz, 1 H), 6.39 (s, 2H), 3.10 (s, 2H), 2.72 - 2.64 (m, 1 H), 2.43 (d, J=6.9 Hz, 2H), 2.07 (s, 3H), 1.06 - 0.98 (m, 3H), 0.86 - 0.80 (m, 2H), 0.59 - 0.54 (m, 2H), 0.27 - 0.22 (m, 2H). MS (ESI): m I z 350.3 (M+1). HPLC purity: 97.7%.Compound 45: 4-(4-(2,2-Difluoropropyl)-2,6-dihvdroxyphenyl)-1-ethyl-5-methylindolin-2-one

[0293] The hydrogenation step was carried out at atmospheric pressure in an H-Cube using a 10% Pd / C CatCart and methanol as the solvent.1H NMR (400 MHz, DMSO) 8 9.15 (s, 2H), 7.11 (d, J=7.9 Hz, 1 H), 6.85 (d, J=7.9 Hz, 1 H), 6.35 (s, 2H), 3.68 (q, J=7.1 Hz, 2H), 3.09 (s, 2H), 3.06 (t, J=16.5 Hz, 2H), 2.01 (s, 3H), 1.59 (t, J=18.7 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H). MS (ESI): m l z 362.2 (M+1). HPLC purity: 98.6%.

[0295] The hydrogenation step reduced the double bond in the intermediate alongside the debenzylation.1H NMR (400 MHz, MeOD) 5 7.18 (d, J=7.9 Hz, 1 H), 6.85 (d, J=7.9 Hz, 1 H), 6.30 (s, 2H), 3.79 (q, J=7.2 Hz, 2H), 3.22 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.10 (s, 3H), 1.52 (q, J=7.4 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H), 0.78 - 0.72 (m, 1 H), 0.47 - 0.42 (m, 2H), 0.08 - 0.03 (m, 2H). 2 Phenolic protons not observed. MS (ESI): m I z 352.5 (M+1). HPLC purity: 98.0%.Compound 48: 4-(4-(Cvclobutylmethyl)-2,6-dihvdroxyphenyl)-1-ethyl-5-methylindolin-2-one

[0296] The hydrogenation step was carried out under transfer conditions in refluxing ethanol, using 1-methyl-1 ,4-cyclohexadiene and the hydrogen source and reduced the double bond in the intermediate alongside the debenzylation.1H NMR (400 MHz, CDCI3) 8 7.29 (d, J=8.1 Hz, 1 H), 6.84 (d, J=8.0 Hz, 1 H), 6.37 (s, 2H), 4.85 (s, 2H), 3.78 (q, J=7.2 Hz, 2H), 3.27 (s, 2H), 2.66 - 2.54 (m, 3H), 2.14 (s, 3H), 2.12 - 2.03 (m, 2H), 1.93 - 1.80 (m, 2H),1.78 - 1.67 (m, 2H), 1 .29 (t, J=7.3 Hz, 3H). MS (ESI): m I z 352.3 (M+1). HPLC purity: 99.3%.Compound 49: 4-(2,6-Dihvdroxy-4-(2-hvdroxy-2-methylpropyl)phenyl)-1-ethyl-5- in-2-one

[0297] The hydrogenation step was carried out under transfer conditions in refluxing ethanol, using 1-methyl-1 ,4-cyclohexadiene as the hydrogen source.1H NMR (400 MHz, CDC ) 8 7.28 (d, J=8.0 Hz, 1 H), 6.84 (d, J=7.8 Hz, 1 H), 6.44 (s, 2H), 5.70 (s, 2H), 3.78 (q, J=7.5 Hz, 2H), 3.27 (s, 2H), 2.68 (s, 2H), 2.15 (s, 3H), 1.72 (s, 1 H), 1.29 (t, J=7.2 Hz, 3H), 1.23 (s, 6H). MS (ESI): m l z 356.3 (M+1). HPLC purity: 99.8%.Compound 50: 4-(2,6-Dihvdroxy-4-(2-methoxy-2-methylpropyl)phenyl)-1-ethyl-5- in-2-one

[0298] The hydrogenation step was carried out under transfer conditions in refluxing ethanol, using 1-methyl-1 ,4-cyclohexadiene and the hydrogen source.1H NMR (400 MHz, DMSO) 8 8.94 (s, 2H), 7.10 (d, J=7.9 Hz, 1 H), 6.83 (d, J=7.9 Hz, 1 H), 6.27 (s, 2H), 3.68 (q, J=7.1 Hz, 2H), 3.19 (s, 3H), 3.08 (s, 2H), 2.57 (s, 2H), 2.01 (s, 3H), 1.16 (t, J=7.1 Hz, 3H), 1.10 (s, 6H). MS (ESI): m l z 370.5 (M+1). HPLC purity: 98.7%.General Method 9General Method 9 is illustrated using the synthesis of Compound 51.Compound 51: 7-Chloro-4-(2,6-dihvdroxy-4-propylphenyl)-1-methylindolin-2-oneStep 1 : 7-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1 -methylindoline-2, 3-dione

[0299] 4-Bromo-7-chloro-1-methyl-indoline-2, 3-dione (370 mg, 1.35 mmol), (2,6- dimethoxy-4-propyl-phenyl)boronic acid (362 mg, 1.62 mmol) and cesium carbonate (878 mg, 2.70 mmol) in / V, / V-dimethylformamide (10 mL) was degassed with nitrogen, treated with tetrakis(triphenylphosphine)palladium(0) (156 mg, 0.135 mmol) and heated in a microwave reactor at 100°C for 1 hour. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-50% ethyl acetate in cyclohexane to give the title compound as a red-orange solid (337 mg, 67%).1H NMR (400 MHz, CDCh) 8 7.45 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.46 (s, 2H), 3.69 (s, 6H), 3.64 (s, 3H), 2.66 - 2.61 (m, 2H), 1.75 - 1.66 (m, 2H), 1.01 (dd, J=7.3, 7.3 Hz, 3H).Step 2: 7-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1 -methylindolin-2-one

[0300] 7-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-methylindoline-2, 3-dione (337 mg,0.901 mmol) in 1-propanol (5 mL) was treated with hydrazine monohydrate (0.87 mL, 18.0 mmol) and heated at reflux for two days. Further hydrazine monohydrate (0.87 mL, 18.0 mmol) was added and the reaction mixture was refluxed for a further 2 days then poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried (phase separating paper) and concentrated in vacuo. The residue was purified by column chromatography on 25g silica gel, eluting with 0-100% ethyl acetate in cyclohexane to give the title compound as an orange solid (130 mg, 0.361 mmol, 40%).1H NMR (400 MHz, CDCh) 8 7.22 (d, J=8.4 Hz, 1 H), 6.87 (d, J=8.4 Hz, 1H), 6.46 (s, 2H), 3.72 (s, 6H), 3.59 (s, 3H), 3.31 (s, 2H), 2.62 (t, J=7.7 Hz, 2H), 1.74 - 1.66 (m, 2H), 1.00 (t, J=7.3 Hz, 3H).Step 3: 7-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-methylindolin-2-one

[0301] The title compound was prepared according to a procedure similar to the second step of General Method 6.1H NMR (400 MHz, DMSO) 8 9.19 (s, 2H), 7.21 (d, J=8.5 Hz, 1 H), 6.86 (d, J=8.5 Hz, 1 H), 6.23 (s, 2H), 3.46 (s, 3H), 3.33 (s, 2H), 2.39 (t, J=7.6 Hz, 2H), 1.59 - 1.52 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). MS (ESI): m / z 332.0 (M+1). HPLC purity: 96.3%.

[0302] General Method 9 was also used to synthesise the following compound.Compound 52: 7-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-ethylindolin-2-one

[0303] 1H NMR (400 Hz, CDCI3) 8 7.35 (d, J=8.3 Hz, 1 H), 6.98 (d, J=8.4 Hz, 1 H), 6.39 (s, 2H), 5.60 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.48 (s, 2H), 2.50 (t, J=7.7 Hz, 2H), 1.68 - 1.59 (m, 2H), 1.36 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H). MS (ESI): m I z 346.3 (M+1). HPLC purity: 99.5%.Specific Synthetic Procedures

[0304] The following compounds were prepared using the specific routes described below.Compound 53: 4-(2,6-Dihydroxy-4-(3,3,3-trifluoropropyl)phenyl)-1-ethyl-5-methylindolin-2- oneStep 1 : 4-(2,6-Dimethoxy-4-(3,3,3-trifluoropropyl)phenyl)-1-ethyl-5-methylindolin-2-one

[0305] 4-(4-Chloro-2,6-dimethoxy-phenyl)-1-ethyl-5-methyl-indolin-2-one (200 mg, 0.578 mmol), potassium trifluoro(3,3,3-trifluoropropyl)boranuide (177 mg, 0.868 mmol) and potassium carbonate (160 mg, 1.16 mmol) in cyclopentyl methyl ether (3.0 mL) and water (1 .0 mL) were purged with nitrogen for 5 minutes and treated with SPhos Pd G2 (42 mg, 0.0578 mmol). The reaction mixture was heated in a microwave reactor at 120°C for 35 minutes then treated with further potassium trifluoro(3,3,3-trifluoropropyl)boranuide (90 mg, 0.441 mmol), potassium carbonate (40 mg, 0.289 mmol) and SPhos Pd G2 (42 mg, 0.0578mmol) were added and the reaction mixture heated at 120°C for a further 40 minutes. The mixture was diluted with ethyl acetate (5 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (4 x 5 mL). The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with 0-60% ethyl acetate in cyclohexane to give the title compound as a pale yellow gum (200 mg, 85%).1H NMR (400 MHz, CDCh) 8 7.18 (d, J=7.9 Hz, 1 H), 6.75 (d, J=8.4 Hz, 1 H), 6.47 (s, 2H), 3.76 (q, J=7.6 Hz, 2H), 3.72 (s, 6H), 3.16 (s, 2H), 2.95 - 2.90 (m, 2H), 2.55 - 2.42 (m, 2H), 2.03 (s, 3H), 1.29 (t, J=7.3 Hz, 3H).Step 2: 4-(2,6-Dihydroxy-4-(3,3,3-trifluoropropyl)phenyl)-1 -ethyl-5-methylindolin-2-one

[0306] The title compound was prepared according to a procedure similar to the second step of General Method 6.1H NMR (400 MHz, DMSO) 8 9.16 (s, 2H), 7.15 (d, J=8.1 Hz, 1 H), 6.89 (d, J=8.1 Hz, 1 H), 6.35 (s, 2H), 3.73 (q, J=7.1 Hz, 2H), 3.11 (s, 2H), 2.76 - 2.70 (m, 2H), 2.66 - 2.57 (m, 2H), 2.05 (s, 3H), 1 .21 (t, J=7.2 Hz, 3H). MS (ESI): m I z 380.2 (M+1). HPLC purity: >99.5%.Compound 54: 4-(2,6-Dihvdroxy-4-(pyrrolidin-1-ylmethyl)phenyl)-1-ethyl-5-methylindolin-2- oneStep 1 : 4-(1-Ethyl-5-methyl-2-oxoindolin-4-yl)-3,5-dimethoxybenzaldehyde

[0307] The title compound was prepared according to a procedure similar to the first step of General Method 8.1H NMR (400 MHz, DMSO) 8 10.03 (s, 1 H), 7.34 (s, 2H), 7.17 (d, J=7.9 Hz, 1 H), 6.91 (d, J=8.0 Hz, 1 H), 3.78 (s, 6H), 3.69 (q, J=7.2 Hz, 2H), 3.02 (s, 2H), 1.93 (s, 3H), 1.17 (t, J=7.2 Hz, 3H).Step 2: 4-(2,6-Dimethoxy-4-(pyrrolidin-1-ylmethyl)phenyl)-1-ethyl-5-methylindolin-2- one

[0308] 4-(1-Ethyl-5-methyl-2-oxoindolin-4-yl)-3,5-dimethoxybenzaldehyde (148 mg, 0.436 mmol) and pyrrolidine (0.046 mL, 0.545 mmol) in dichloromethane (5.0 mL) were treatedwith sodium triacetoxyborohydride (116 mg, 0.545 mmol) and stirred overnight. Further pyrrolidine (0.046 mL, 0.545 mmol), sodium triacetoxyborohydride (116 mg, 0.545 mmol) and dichloromethane (2 mL) and the reaction mixture was stirred at room temperature for 1 day. Dichloromethane (10 mL) and water (10 mL) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (10 mL) and the combined organic layers were dried (phase separating paper) and concentrated in vacuo. The residue was absorbed onto a 5 g SCX cartridge, washed with dichloromethane (40 mL), eluted with 2N ammonia in methanol (40 mL) and concentrated in vacuo to give the title compound as an orange glass (140 mg, 81%) which was used in the next step without further purification.1H NMR (400 MHz, CDCh) 8 7.17 (d, J=7.2 Hz, 1 H), 6.74 (d, J=7.8 Hz, 1 H), 6.65 (s, 2H), 3.79 - 3.70 (m, 8H), 3.17 (s, 2H), 2.61 (br s, 4H), 2.06 - 2.01 (m, 5H), 1.86 (br s, 4H), 1.29 (t, J=7.4 Hz, 3H).Step 3: 4-(2,6-Dihydroxy-4-(pyrrolidin-1-ylmethyl)phenyl)-1-ethyl-5-methylindolin-2- one

[0309] The title compound was prepared using a method similar to the second step of General Method 6. Isolated as a 0.5 equivalent formate salt.1H NMR (400 MHz, DMSO) 8 9.04 (s, 2H), 8.17 (s, 0.5H), 7.10 (d, J=8.0 Hz, 1 H), 6.83 (d, J=7.9 Hz, 1 H), 6.38 (s, 2H), 3.67 (q, J=7.1 Hz, 2H), 3.45 (s, 2H), 3.07 (s, 2H), 2.48 - 2.44 (m, 4H), 2.00 (s, 3H), 1.74 - 1.68 (m, 4H), 1.16 (t, J=7.1 Hz, 3H). MS (ESI): m / z 367.3 (M+1). HPLC purity: 99.5%.Compound 55: 4-(2,6-Dihydroxy-4-propylphenyl)-1 ,3,3-trimethylindolin-2-oneStep 1 : 4-(2,6-Dimethoxy-4-propylphenyl)-3,3-dimethylindolin-2-one

[0310] The title compound was prepared according to a procedure similar to the first step of General Method 6, using dioxane in place of cyclopentyl methyl ether.1H NMR (400 MHz, DMSO) 8 10.31 (s, 1 H), 7.13 (t, J=7.7 Hz, 1 H), 6.78 (dd, J=0.9, 7.7 Hz, 1 H), 6.55 (s, 2H),6.53 (dd, J=1.1 , 7.8 Hz, 1 H), 3.60 (s, 6H), 2.62 (t, J=7.6 Hz, 2H), 1.72 - 1.64 (m, 2H), 0.95 (t, J=7.3 Hz, 3H), 0.89 (s, 6H).Step 2: 4-(2,6-Dimethoxy-4-propylphenyl)-1,3,3-trimethylindolin-2-one

[0311] 4-(2,6-Dimethoxy-4-propylphenyl)-3,3-dimethylindolin-2-one (220 mg, 0.648 mmol) in / V, / V-dimethylformamide (5 mL) was treated with sodium hydride (60% dispersion in mineral oil, 78 mg, 1.94 mmol) followed by iodomethane (0.12 mL, 1.94 mmol). The reaction mixture was stirred at room temperature for 72 hours, quenched with saturated ammonium chloride solution (3 mL), diluted with ethyl acetate (25 mL) and washed with water (4 x 25 mL). The organic layer was dried (phase separating paper) and concentrated in vacuo to afford the crude title compound as a white solid (189 mg, 83%).1H NMR (400 MHz, CDCh) 8 7.31 (t, J=7.8 Hz, 1 H), 6.85 (dd, J=0.8, 7.8 Hz, 1 H), 6.78 (dd, J=0.7, 7.7 Hz, 1 H), 6.44 (s, 2H), 3.67 (s, 6H), 3.24 (s, 3H), 2.65 (t, J=7.7 Hz, 2H), 1.76 - 1.67 (m, 2H), 1.07 (s, 6H), 1.00 (t, J=7.3 Hz, 3H).Step 3: 4-(2,6-Dihydroxy-4-propylphenyl)-1,3,3-trimethylindolin-2-one

[0312] The title compound was prepared according to a procedure similar to the second step of General Method 6.1H NMR (400 MHz, DMSO) 8 8.86 (s, 2H), 7.22 (t, J=7.7 Hz, 1 H), 6.91 (dd, J=0.8, 7.9 Hz, 1 H), 6.63 (dd, J=0.8, 7.8 Hz, 1 H), 6.20 (s, 2H), 3.14 (s, 3H), 2.44 - 2.39 (m, 2H), 1.61 - 1 .53 (m, 2H), 1.03 (s, 6H), 0.91 (t, J=7.3 Hz, 3H). MS (ESI): m I z 326.4 (M+1). HPLC purity: 99.3%.Step 1 : 4-(2,6-Bis(benzyloxy)-4-propylphenyl)-5-methylindolin-2-one

[0313] The title compound was prepared according to a procedure similar to the first step of General Method 7, using dioxane in place of cyclopentyl methyl ether.1H NMR (400 MHz, DMSO) 8 10.24 (s, 1 H), 7.27 - 7.22 (m, 6H), 7.15 - 7.11 (m, 4H), 7.06 (d, J=8.1 Hz, 1 H), 6.70(s, 2H), 6.68 (d, J=7.9 Hz, 1 H), 5.05 (s, 4H), 2.92 (s, 2H), 2.57 (t, J=7.3 Hz, 2H), 1.96 (s, 3H), 1.68 - 1.59 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).Step 2: 4-(2,6-Bis(benzyloxy)-4-propylphenyl)-3,3,5-trimethylindolin-2-one

[0314] 4-(2,6-Dibenzyloxy-4-propyl-phenyl)-5-methyl-indolin-2-one (710 mg, 1.49 mmol) in tetra hydrofuran (15.0 mL) at 0°C was treated with potassium tert-butoxide (667 mg, 5.95 mmol) in portions over 5 minutes followed by copper(l) bromide dimethyl sulfide complex (61 mg, 0.297 mmol) in one portion. The reaction mixture was stirred at 0°C for 40 minutes then iodomethane (0.17 mL, 2.68 mmol) was added dropwise slowly over 40 minutes. The reaction mixture was allowed to warm to 10°C over 2 hours then was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-60% ethyl acetate in cyclohexane to give the title compound as a pale orange solid (440 mg, 59%).1H NMR (400 MHz, DMSO) 10.21 (s, 1 H), 7.30 - 7.12 (m, 10H), 7.07 (d, J=9.6 Hz, 1 H), 6.72 (d, J=7.7 Hz, 1H), 6.68 (s, 2H), 5.06 (d, J=12.7 Hz, 2H), 4.97 (d, J=12.7 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.86 (s, 3H), 1.69 - 1.62 (m, 2H), 0.94 - 0.88 (m, 9H).Step 3: 4-(2,6-Dihydroxy-4-propylphenyl)-3,3,5-trimethylindolin-2-one

[0315] The title compound was prepared according to a procedure similar to the second step of General Method 7.1H NMR (400 MHz, DMSO) 8 10.13 (s, 1H), 8.79 (s, 2H), 7.02 - 6.99 (m, 1 H), 6.69 - 6.66 (m, 1 H), 6.24 (s, 2H), 2.43 (t, J=7.6 Hz, 2H), 1.85 - 1.84 (m, 3H), 1.62 - 1.55 (m, 2H), 0.98 (s, 6H), 0.92 (t, J=7.4 Hz, 3H). MS (ESI): m I z 326.2 (M+1). HPLC purity: 99.4%.Compound 57: 4-(2,6-Dihvdroxy-4-propylphenyl)-1-(2-fluoroethyl)-5-methylindolin-2-one

[0316] [[2,6-Dibenzyloxy-4-[prop-1-enyl]phenyl]boronic acid (407 mg, 1.09 mmol, 4- bromo-1-(2-fluoroethyl)-5-methyl-indolin-2-one (219 mg, 0.805 mmol) and potassium carbonate (335 mg, 2.42 mmol) in cyclopentyl methyl ether (8 mL) and water (2 mL) were degassed with nitrogen and treated with SPhos Pd G2 (60 mg, 0.0833 mmol). The reaction mixture was heated in a microwave at 140°C for 5 minutes then treated with further SPhos Pd G2 (45 mg, 0.0624 mmol) and heated at 140°C for a further 30 minutes. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (3 x 15 mL). The organic phases were combined, washed with water (2 x 20 mL), dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography on silica geleluting with 0-100% diethyl ether in cyclohexane, followed by column chromatography on silica gel, eluting with 0-25% ethyl acetate in dichloromethane to give 4-(2,6-bis(benzyloxy)- 4-(prop-1-en-1-yl)phenyl)-1-(2-fluoroethyl)-5-methylindolin-2-one (mixture of E / Z isomers) (396 mg, 0.661 mmol, 82%). This was dissolved in ethanol (12 mL) treated with 1-methyl- 1,4-cyclohexadiene (1.2 mL, 10.7 mmol, 10% palladium on carbon (83 mg, 0.0780 mmol) was added and the reaction mixture was heated at reflux for 4 hours then cooled, filtered through celite and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-100% ethyl acetate in cyclohexane followed by preparative HPLC to give the title compound as an off-white solid (163 mg, 72%).1H NMR (400 MHz, DMSO) 8 9.00 (s, 2H), 7.09 (d, J=8.0 Hz, 1 H), 6.87 (d, J=7.9 Hz, 1 H), 6.25 (s, 2H), 4.64 (td, J=4.9, 47.3 Hz, 2H), 3.98 (td, J=4.9, 26.6 Hz, 2H), 3.13 (s, 2H), 2.42 (t, J=7.6 Hz, 2H), 2.01 (s, 3H), 1.64 - 1.53 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).Compound 58: 4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-fluoroindolin-2-oneStep 1 : 4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-5-fluoroindoline-2, 3-dione

[0317] The title compound was prepared using a method similar to the first step of General Method 7.1H NMR (400 MHz, CDC ) 8 7.30 - 7.17 (m, 11H), 6.73 (dd, J=3.4, 8.5 Hz, 1H), 6.54 (s, 2H), 5.05 (d, J=12.0 Hz, 2H), 4.97 (d, J=11.8 Hz, 2H), 3.73 (q, J=7.2 Hz, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.72 - 1.62 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 0.96 (t, J=7.3 Hz, 3H).Step 2: 4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1 -ethyl-5-fluoroindolin-2-one4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-5-fluoroindoline-2, 3-dione (503 mg, 0.961 mmol) in ethanol (7.0 mL) was treated with hydrazine monohydrate (1.2 mL, 24.0 mmol) and the resulting mixture heated at 90°C for 3 days. Potassium hydroxide (270 mg, 4.80 mmol) was added and the reaction mixture was heated at 90°C for a further 18 hours then acidified to pH 1 with 2M HCI, diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL).The combined organic layers were washed with brine (30 mL), dried (hydrophobic frit), and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-50% ethyl acetate in cyclohexane to give the title compound as a brown solid (234 mg, 48%).1H NMR (400 MHz, CDCI3) 8 7.29 - 7.14 (m, 10H), 7.05 (t, J=9.2 Hz, 1 H), 6.73 (dd, J=3.7, 8.5 Hz, 1 H), 6.54 (s, 2H), 5.03 (s, 4H), 3.75 (q, J=7.2 Hz, 2H), 3.24 (s, 2H), 2.61 - 2.54 (m, 2H), 1.69-1.60 (m, 2H), 1.28 (t, J=7.0 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H).Step 3: 4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-fluoroindolin-2-one

[0318] The title compound was prepared using a method similar to the second step of General Method 7.1H NMR (400 MHz, DMSO) 8 9.24 (s, 2H), 7.07 (dd, J=8.7, 10.0 Hz, 1 H), 6.94 (dd, J=4.0, 8.5 Hz, 1 H), 6.24 (s, 2H), 3.70 (q, J=7.1 Hz, 2H), 3.24 (s, 2H), 2.41 (t, J=7.6 Hz, 2H), 1.61 - 1.52 (m, 2H), 1.17 (t, J=7.1 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). HPLC purity: >99.5%. MS (ESI): m / z 330.2 (M+1).Compound 59: 4-(2,6-Dihvdroxy-4-isobutylphenyl)-1-ethyl-5-methylindolin-2-oneStep 1 : 2-Bromo-1,3-dimethoxy-5-(2-methylprop-1-en-1-yl)benzene

[0319] Isopropyltriphenylphosphonium iodide (4.59 g, 10.6 mmol) suspended in tetra hydrofuran (40 mL) was cooled in an ice / water bath and treated with 2.5 M n- butyllithium solution (3.9 mL, 9.79 mmol). The reaction mixture was stirred for 30 minutes during which time it turned from being a yellow suspension to a red solution. 4-Bromo-3,5- dimethoxy-benzaldehyde (2.00 g, 8.16 mmol) in tetrahydrofuran (10 mL) was added and the reaction mixture was stirred for two hours, then saturated ammonium chloride solution (15 mL) and partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (200 mL) and the combined organic layers were dried (phase separating paper) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-100% diethyl ether in cyclohexane to give the title compound as a colourless oil (1.08 g, 49%).1H NMR (400 MHz, CDCL) 8 6.44 (s, 2H), 6.24 - 6.21 (m, 1 H), 3.88 (s, 6H), 1 .90 (d, J=1 .3 Hz, 3H), 1 .88 (d, J=1 .3 Hz, 3H).Step 2: 4-(2,6-Dimethoxy-4-(2-methylprop-1-en-1-yl)phenyl)-1-ethyl-5-methylindolin-2- one

[0320] The title compound was prepared according to a procedure similar to the first step of General Method 8.1H NMR (400 MHz, CDCI3) 8 7.17 (d, J=7.9 Hz, 1 H), 6.74 (d, J=7.8 Hz, 1 H), 6.52 (s, 2H), 6.33 - 6.30 (m, 1 H), 3.76 (q, J=7.2 Hz, 2H), 3.71 (s, 6H), 3.19 (s, 2H), 2.06 (s, 3H), 1.96 (d, J=1.3 Hz, 3H), 1.95 (d, J=1 .4 Hz, 3H), 1.54 (s, 3H), 1.28 (t, J=7.2 Hz, 3H).Step 3: 1-Ethyl-4-(4-isobutyl-2,6-dimethoxyphenyl)-5-methylindolin-2-one

[0321] A solution of 4-(2,6-dimethoxy-4-(2-methylprop-1-en-1-yl)phenyl)-1-ethyl-5- methylindolin-2-one (280 mg, 0.766 mmol) in ethanol (10 mL) and ethyl acetate (10 mL) was stirred over palladium on carbon (10%, 82 mg) under a balloon of hydrogen for two days, then filtered through celite and washed through with copious ethyl acetate and ethanol. The filtrate was concentrated in vacuo to give the title compound as a white solid (218 mg, 77%).1H NMR (400 MHz, CDCI3) 8 7.17 (d, J=7.9 Hz, 1 H), 6.74 (d, J=7.9 Hz, 1 H), 6.43 (s, 2H), 3.75 (q, J=7.2 Hz, 2H), 3.71 (s, 6H), 3.18 (s, 2H), 2.52 (d, J=7.3 Hz, 2H), 2.05 (s, 3H), 1.98 - 1.90 (m, 1 H), 1.28 (t, J=7.2 Hz, 3H), 0.96 (d, J=6.7 Hz, 6H).Step 4: 4-(2,6-Dihydroxy-4-isobutylphenyl)-1-ethyl-5-methylindolin-2-one

[0322] The title compound was prepared according to a procedure similar to the second step of General Method 6.1H NMR (400 MHz, DMSO) 8 8.96 (s, 2H), 7.10 (d, J=8.8 Hz, 1 H), 6.83 (d, J=7.7 Hz, 1 H), 6.21 (s, 2H), 3.69 (q, J=6.8 Hz, 2H), 3.08 (s, 2H), 2.31 (d, J=7.3 Hz, 2H), 2.01 (s, 3H), 1.88 - 1.76 (m, 1 H), 1.17 (t, J=7.3 Hz, 3H), 0.90 (d, J=6.8 Hz, 6H). HPLC purity: 98.9%. MS (ESI): m / z 340.3 (M+1).Compound 60: 4-(2,6-Dihydroxy-4-isopentylphenyl)-1-ethyl-5-methylindolin-2-oneStep 1 : 2-Bromo-1,3-dimethoxy-5-(3-methylbut-1-en-1-yl)benzeneIsobutyltriphenylphosphonium bromide (13.03 g, 32.6 mmol) was suspended in tetra hydrofuran (120 mL) at 0°C and treated with n-butyllithium solution (2.5 M in hexanes, 16 mL, 39.2 mmol). The reaction mixture was stirred for 30 minutes then treated with 4- bromo-3,5-dimethoxy-benzaldehyde (8.00 g, 32.6 mmol) in tetrahydrofuran (30 mL). The reaction was stirred at 0°C for 2 hours then quenched with saturated ammonium chloride solution (50 mL), diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (2 x 20 mL), water (2 x 20 mL) and brine (2 x 20 mL). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-100 % ethyl acetate in cyclohexane to give the title compound as a pale yellow oil (6.30 g, 68%).1H NMR (400 MHz, CDCh) 8 6.32 - 6.19 (m, 1.5H), 5.52 (dd, J=10.3, 11.6 Hz, 0.5H), 3.91 (s, 3H), 3.89 (s, 3H), 2.92 - 2.83 (m, 0.5H), 2.54 - 2.42 (m, 0.5H), 1.11 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H). 1:1 mixture of E / Z isomers observed.Step 2: 4-(2,6-Dimethoxy-4-(3-methylbut-1-en-1-yl)phenyl)-1-ethyl-5-methylindolin-2- one

[0323] The title compound was prepared according to a procedure similar to similar to the second step of General Method 8. NMR was not assigned due complexities caused by presence of significant impurities and E / Z isomers.Step 3: 1-Ethyl-4-(4-isopentyl-2,6-dimethoxyphenyl)-5-methylindolin-2-one

[0324] 4-(2,6-Dimethoxy-4-(3-methylbut-1-en-1-yl)phenyl)-1-ethyl-5-methylindolin-2-one (530 mg, 1.26 mmol) in ethanol (20 mL) and ethyl acetate (20 mL) was treated with palladium on carbon (10%, 134 mg, 0.126 mmol) and 1 -methyl- 1,4-cyclohexadiene (0.71 mL, 6.28 mmol) under a nitrogen atmosphere. The reaction mixture was heated at reflux overnight. Further 1-methyl-1 ,4-cyclohexadiene (0.71 mL, 6.28 mmol, 5.00 eq) was added and the reaction mixture was heated for a further 24 hours, then filtered through celite, washed through with copious ethanol and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-100% ethyl acetate in cyclohexane to give the title compound as a yellow oil (457 mg, 95%).1H NMR (400 MHz, CDCh) 8 7.17 (d, J=8.2 Hz, 1 H), 6.73 (d, J=7.8 Hz, 1 H), 6.46 (s, 2H), 3.78 - 3.74 (m, 2H), 3.71 (s, 6H), 3.18 (s, 2H), 2.68 - 2.63 (m, 2H), 2.06 (s, 3H), 1.71 - 1.62 (m, 1 H), 1.31 - 1.22 (m, 5H), 0.99 (d, J=6.8 Hz, 6H). Several impurities observed: data reported for major component only.Step 4: 4-(2,6-Dihydroxy-4-isopentylphenyl)-1-ethyl-5-methylindolin-2-one

[0325] The title compound was prepared according to a procedure similar to the second step of General Method 6.1H NMR (400 MHz, DMSO) 8 8.97 (s, 2H), 7.10 (d, J=8.2 Hz, 1 H), 6.83 (d, J=7.9 Hz, 1 H), 6.24 (s, 2H), 3.68 (q, J=7.1 Hz, 2H), 3.07 (s, 2H), 2.47 - 2.41 (m, 2H), 2.01 (s, 3H), 1.63 - 1.55 (m, 1 H), 1.49 - 1.41 (m, 2H), 1.16 (t, J=7.2 Hz, 3H), 0.93 (d, J=6.7 Hz, 6H). HPLC purity: 98.0%. MS (ESI): m / z 354.4 (M+1).Large Scale Synthesis of Compound 1: 4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5- methylindolin-2-oneStep 1 : 4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one

[0326] To a 50 L reactor was charged Intermediate 17 (709 grams, 2.79 mol, 1 eq) and (2,6-Dimethoxy-4-propylphenyl)boronic acid (937.8 g, 4.19 mol, 1.5 eq). Toluene (12.8 L) was charged to the reactor and the mixture was stirred at ambient temperature. Potassium carbonate (1.157 Kg, 8.37 mol, 3 eq) was charged to the reactor followed by SPhos Pd G2 (40.21 g, 0.02 eq, 55.80 mmol). Ethanol (3.55 L) was charged to the reactor and 3 nitrogen / vacuum purge cycles were completed to ensure complete removal of oxygen species from the reaction mixture. The reaction mixture was heated at reflux (100 °C) for 16 hours, whereupon sampling of a reaction aliquot confirmed complete conversion of Intermediate 17 to product. The reaction mixture was cooled to ambient temperature, filtered over Celite® to remove insoluble material, and the solids were washed with ethyl acetate (3 L). The filtrate was concentrated under vacuum and the residue was diluted with ethyl acetate (5 vol, 3.5 L) and poured back in to the reactor, followed by the addition of water (8 vol, 5.7 L) and brine (2 vol, 1.4 L). The mixture was stirred and then the lower aqueous layer was separated, and the organic layer was washed with 0.5 M NaOH (3 x 4 L). The lower aqueous layer was discarded and the organic layer was dried over anhydrous sodium sulphate (250 g) and concentrated under vacuum. Heptane (4 L) was added to the residue and evaporated to ensure complete removal of toluene and ethanol. Further heptane (2 L) was added to the remaining residue and the suspension was stirred at room temperature for 1 hour. The solids were filtered and washed with heptane (2 L). The cake dried in a vacuum oven at 40 °C for 22 hours to yield a beige coloured solid (1110 g; 77% pure by HPLC containing some residual boronic acid).Step 2: 4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one

[0327] A 5 L reactor was connected via an outlet to an empty round- bottomed flask, which was connected to another round-bottomed flask containing aminoethanol (to quench the evolved MeBr). The reactor was charged with 4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-5- methylindolin-2-one (549.4 g, 1.55 mol, 1 eq) followed by the addition of glacial acetic acid (1.37 L) and hydrobromic acid (48% in water, 1.37 L). Continuous nitrogen sparge was introduced into the reactor. The reaction mixture was heated at reflux for 24 hours, whereupon sampling of a reaction aliquot confirmed complete conversion to product. The reaction mixture was cooled to 50 °C and water (2.75 L) was charged to the reactor. Themixture was cooled to 0 °C and the reaction mixture was stirred overnight. The precipitated solids were filtered, washed with ice-cold water (4 L) and dried under vacuum on the filter for 30 minutes until visibly dry. The solids were then transferred to drying trays and dried in a vacuum oven at 40 °C for 17 hours to yield a beige solid (408.5 g; 81%).Example 2: Evaluation of the Anticonvulsive properties of Compounds using the Mouse Maximal Electroshock Seizure Threshold Model using Minimal Sample Sizes ini MEST)

[0328] The maximal electroshock seizure threshold (MEST) test is widely utilized preclinically to evaluate pro- or anti-convulsive properties of test compounds (Ldscher et al., 1991).

[0329] In the MEST test the ability of a drug to alter the seizure threshold current required to induce hind limb tonic extensor convulsions is measured according to an “up and down” method of shock titration (Kimball et al., 1957). An increase in seizure threshold is indicative of an anticonvulsive effect. Antiepileptic drugs including diazepam with clinically proven efficacy against generalised tonic-clonic seizures, exhibit anticonvulsive properties in this test in the mouse (Lbscher et al., 1991).

[0330] Conversely, a reduction in seizure threshold is indicative of a proconvulsive effect as observed with known convulsive agents such as picrotoxin.

[0331] The ability of a test compound to alter the stimulus intensity, expressed as current (mA), required to induce the presence of tonic hind limb extensor convulsions, is assessed in the MEST. The outcome of the presence (+) or absence (0) of tonic hind limb extensor convulsions observed from a current to produce tonic hind limb extension in 50% of animals in the treatment group (CC50) determines the seizure threshold for the treatment group and the effects were then compared to the CC50 of the vehicle control group.

[0332] In the mini-MEST test, a lower n number is used.General MethodMice:

[0333] Male C57BL / 6J mice were housed in groups of 6. Mice were kept under standard conditions (12 hour light cycle; light intensity of 25-75 lux) and fed a diet of certified rodent CR 14% protein rodent diet (LabDiet® 4CR4). Mice were 8-9 weeks old at the start of the study.Study Details:

[0334] Naive mice were acclimatised to the procedure room in their home cages for up to 7 days, with food and water available ad libitum.

[0335] All animals were weighed at the beginning of the study and randomly assigned to treatment groups based on a mean distribution of body weight across groups. All animals were dosed at 10 mL / kg via intraperitoneal (i.p) injection, with either vehicle, test compound at 5-50 mg / kg, or diazepam at 2.5 mg / kg.

[0336] Animals were individually assessed for the production of a tonic hind limb extensor convulsion at 30 min post-dose for vehicle, 15-30 min post-dose for test compound (dependent on compound) and 30 min post-dose for diazepam, from a single electroshock.

[0337] The first animal within a treatment group was given a shock at the expected or estimated CCso current. For subsequent animals, the current was lowered or raised depending on the convulsions outcome from the preceding animal in log scale intervals.

[0338] Data generated from each treatment group were used to calculate the CCso ± SEM values for the treatment group.Compound Preparation:

[0339] Vehicle 1 (for ip injection): 5% ethanol, 10% Solutol® (Kolliphor® HS 15), 85% saline. 1 mL of ethanol, 2 mL of solutol™ were warmed to 60°C, in 17 mL of 0.9% saline.

[0340] Vehicle 2 (for po): 0.5% HMPC and 0.1% Tween™80 in distilled water.

[0341] Vehicle 3 (for po): 5% NMP, 30% PEG400, 9% TPGS, 5% PCP K30, 51% distilled water.

[0342] Positive control: diazepam was used at 2.5mg / kg in a 1 :2:17 ethanol:solutol™:saline formulation (as used for vehicle).

[0343] Test compounds: The indicated compounds were used at 5-50mg / kg in for the indicated vehicle. The indicated compound was weighed out and vehicle was added. The mixture was stirred and sonicated until a homogeneous suspension was obtained.Sample Collection:

[0344] Each animal was humanely killed immediately after production of a convulsion by concussion of the brain from striking the cranium, followed by the confirmation of permanent cessation of the circulation from decapitation in accordance with The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986. Terminal blood and brain collection were performed following decapitation.

[0345] Blood was collected in Lithium-heparin or K2EDTA tubes and centrifuged at 4°C for 10 minutes at 1500 x g. The resulting plasma was removed (100 pL) and split into 2 aliquots of 0.5 mL Eppendorf tubes containing 100 pL of ascorbic acid (100 mg / mL) for stabilisation. Brains were removed, washed in saline and halved. Each half was placed into separate 2 mL screw cap cryovials, weighed and frozen on cardice.Results

[0346] Table 1 to Table 25 show the results for each study group.Table 1 : Evaluation study group 12dosed in vehicle 2. Table 2: Evaluation study group 21dosed in vehicle 1 ;2dosed in vehicle 2.Table 3: Evaluation study group 31dosed in vehicle 1Table 4: Evaluation study group 42dosed in vehicle 2Table 5: Evaluation study group 51dosed in vehicle 1Table 6: Evaluation study group 61dosed in vehicle 1 Table 7: Evaluation study group 72dosed in vehicle 2Table 8: Evaluation study group 82dosed in vehicle 2Table 9: Evaluation study group 92dosed in vehicle 2Table 10: Evaluation study group 101dosed in vehicle 1 ;2dosed in vehicle 2.Table 11 : Evaluation study group 112dosed in vehicle 2.Table 12: Evaluation study group 122dosed in vehicle 2Table 13: Evaluation study group 131dosed in vehicle 1 ;2dosed in vehicle 2.Table 14: Evaluation study group 142dosed in vehicle 2Table 15: Evaluation study group 152dosed in vehicle 2;3dosed in vehicle 3Table 16: Evaluation study group 162dosed in vehicle 2Table 17: Evaluation study group 172dosed in vehicle 2Table 18: Evaluation study group 182dosed in vehicle 2Table 19: Evaluation study group 192dosed in vehicle 2Table 20: Evaluation study group 202dosed in vehicle 2 Table 21 : Evaluation study group 212dosed in vehicle 2Table 22: Evaluation study group 222dosed in vehicle 2;3dosed in vehicle 3Table 23: Evaluation study group 232dosed in vehicle 2Table 24: Evaluation study group 242dosed in vehicle 2Table 25: Evaluation study group 251dosed in vehicle 1Conclusions

[0347] The results shown in Table 1 to Table 25 demonstrate that certain test compounds raise CC50 values compared to vehicle. This data demonstrates that certain test compounds display anticonvulsant activity in a mouse model of generalised seizure. Thus, the test compounds may be useful in medical treatment, such as in the treatment of seizure.Example 3: Evaluation of the Anticonvulsive properties of Compounds using the Mouse Maximal Electroshock Seizure Threshold Model (MEST)

[0348] The maximal electroshock seizure threshold (MEST) test is widely utilized preclinically to evaluate pro- or anti-convulsive properties of test compounds (Loscher et al., 1991).

[0349] In the MEST test the ability of a drug to alter the seizure threshold current required to induce hind limb tonic extensor convulsions is measured according to an “up and down” method of shock titration (Kimball et al., 1957). An increase in seizure threshold is indicative of an anticonvulsive effect. Antiepileptic drugs including diazepam with clinically provenefficacy against generalised tonic-clonic seizures, exhibit anticonvulsive properties in this test in the mouse (Lbscher et al., 1991).

[0350] Conversely, a reduction in seizure threshold is indicative of a proconvulsive effect as observed with known convulsive agents such as picrotoxin.

[0351] The ability of a test compound to alter the stimulus intensity, expressed as current (mA), required to induce the presence of tonic hind limb extensor convulsions, is assessed in the MEST. The outcome of the presence (+) or absence (0) of tonic hind limb extensor convulsions observed from a current to produce tonic hind limb extension in 50% of animals in the treatment group (CC50) determines the seizure threshold for the treatment group and the effects were then compared to the CC50 of the vehicle control group.General MethodMice:

[0352] Male C57BL / 6J mice were housed in groups of 6. Mice were kept under standard conditions (12 hour light cycle; light intensity of 25-75 lux) and fed a diet of certified rodent CR 14% protein rodent diet (LabDiet® 5CR4). Mice were 8-9 weeks old at the start of the study.Study Details:

[0353] Naive mice were acclimatised to the procedure room in their home cages for up to 7 days, with food and water available ad libitum.

[0354] All animals were weighed at the beginning of the study and randomly assigned to treatment groups (n=12 / group) based on a mean distribution of body weight across groups. All animals were dosed at 10 mL / kg via: a. intraperitoneal (ip) injection, with either vehicle, test compound in vehicle, sodium valproate in vehicle, or diazepam in vehicle; or b. oral gavage (p.o.), with either vehicle, test compound in vehicle, or diazepam in vehicle.

[0355] Animals were individually assessed for the production of a tonic hind limb extensor convulsion at 30 min post-dose for vehicle, 15-60 min post-dose for test compound (dependent on compound), 30 min post-dose for sodium valproate and 30 min post-dose for diazepam, from a single electroshock.

[0356] The first animal within a treatment group was given a shock at the expected or estimated CC50 current. For subsequent animals, the current was lowered or raised depending on the convulsions outcome from the preceding animal in 5 mA intervals.

[0357] Data generated from each treatment group were used to calculate the CC50 ± SEM values for the treatment group.Compound Preparation:

[0358] Vehicle 1 (for ip injection): 1 :2:17 ethanol: Kolliphor® HS 15:saline. 1 mL of ethanol and 2 mL of Kolliphor® HS 15 (solutol) were warmed to 60°C and 17 mL of 0.9% saline was added slowly.

[0359] Vehicle 2 (for ip injection): 1 :1:18 ethanol:Kolliphor®EL:saline: 1.6 mL of ethanol and 1.6 mL of Kolliphor®EL (Cremaphor®) were warmed to 60°C and 28.8 mL of 0.9% saline was added slowly.

[0360] Vehicle 3 (used for po): 0.5% HMPC and 0.1% Tween™80 in distilled water.

[0361] Diazepam: diazepam was used at 2.5 mg / kg (0.25 mg / mL) in the indicated vehicle. Diazapam was weighed out and vehicle was added. The mixture was stirred and vortexed and sonicated until a homogeneous suspension was obtained. Prepared immediately prior to dosing.

[0362] Sodium valproate: sodium valproate was used at 15 mg / kg (15 mg / mL) in the indicated vehicle. Sodium valproate was weighed out and vehicle was added. The mixture was stirred and vortexed and sonicated until a homogeneous suspension was obtained. Prepared immediately prior to dosing.

[0363] Test compounds: The indicated compounds were used at 5-200 mg / kg in the indicated vehicle. The indicated compound was weighed out and vehicle was added. The mixture was stirred and sonicated until a homogeneous suspension was obtained. Prepared immediately prior to dosing.Sample Collection:

[0364] Each animal was humanely killed immediately after production of a convulsion by concussion of the brain from striking the cranium, followed by the confirmation of permanent cessation of the circulation from decapitation in accordance with The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986. Terminal blood and brain collection were performed following decapitation.

[0365] Blood was collected in K2-EDTA tubes (BD Microtainer, BD, USA) and centrifuged at 4°C for 10 minutes at 1500 x g. The resulting plasma was removed (100 pL) and split into 2 aliquots of 0.5 mL Eppendorf tubes containing 100 pL of ascorbic acid (100 mg / mL) for stabilisation. Brains were removed and halved. Each half was placed into separate 5 mL Eppendorf tubes, weighed and frozen on cardice.Results

[0366] Table 26 to Table 27 show the results for the tested compounds.Table 26: MEST results for Compound 1 (n = 12)2dosed in vehicle 2;3dosed in vehicle 3; *** p<0.001 when compared to the vehicle group; ***statistical significance not determined as CC50 was not reached.Table 27: MEST results for Compound 6 (n = 12)2dosed in vehicle 2;3dosed in vehicle 3; “ p<0.001 when compared to the vehicle group; ***statistical significance not determined as CC50 was not reached, **non-significantConclusions

[0367] The results shown in Table 26 to Table 27 demonstrate that the test compounds raise CC50 values compared to vehicle. In addition, a dose response was observed in all cases. This data demonstrates that the test compounds display anticonvulsant activity in a mouse model of generalised seizure. Thus, the test compounds may be useful in medical treatment, such as in the treatment of seizure.Example 4: Evaluation of the Anticonvulsive properties of Compounds using the Mouse 6 Hz (44 mA) model of partial seizures

[0368] The 6 Hz (44 mA) model of partial seizures, which detects anticonvulsant activity, follows that described by Brown et al. 1953.

[0369] In the 6 Hz test, the ability of a compound to reduce the severity and number of seizures is assessed by measuring protection from electrically-evoked forelimb clonus. Adecrease in forelimb clonus score is indicative of protection from seizure and an anticonvulsive effect.

[0370] When conducted at a 44 mA stimulus intensity in mice, the 6 Hz test can differentiate compounds with potential for the treatment of focal-onset seizures that are often resistant to current anti-epileptic drugs. Antiepileptic drugs such as cannabidiol exhibit anticonvulsive effects in this test (Klein et al., 2017).General MethodMice:

[0371] Male RjOrl: Swiss mice (Janvier Labs, 53940 Le Genest-Saint-lsle, France), 5 weeks old, weighing 27 - 38 g at the beginning of the experiment. Animals were acclimatized to the Test Facility for at least 5 days after delivery and randomly housed in groups of 5 to 8 in macroIon cages on wood litter with free access to food and water.

[0372] The animal house was maintained under artificial lighting (12 hours) between 7:00 and 19:00 in a controlled ambient temperature of 22 ± 2°C and relative humidity between 30- 70%.Study Details:

[0373] Before transcorneal stimulation, a drop of tetracaine solution (1 %) was applied on each eye of the mouse for local anesthesia. Between 1-10 minutes later and at the designated pre-treatment (see below), the mice were administered a rectangular current (44 mA, rectangular pulse: 0.2 ms pulse width, 3 s duration, (6 Hz) via corneal electrodes connected to a constant current shock generator (Ligo Basile: type 7801).

[0374] The results for the number of seizures as reflected by forelimb clonus were recorded immediately after current administration. Forelimb clonus was scored as absent (0 = no forelimb clonus), mild (1 = clonus with one forelimb) and strong (2 = clonus with both forelimbs). The experimenters were blinded to the treatment.

[0375] Test compound was administered at 10 mL / kg via oral gavage (p.o.) at 10, 25, 50 and 100 mg / kg 60 minutes before the test, and was compared with vehicle administered at the corresponding timepoint.

[0376] Valproate (200 mg / kg) administered intraperitoneally (i.p.) 30 minutes before the test was used as reference substance and was compared with the vehicle group, administered p.o. 60 minutes before the test.

[0377] Each study group comprised 20 mice.

[0378] Due to the number of animals tested, the experiment was divided in 2 subexperiments with 10 mice per group and per sub-experiment.Compound Preparation:

[0379] Vehicle: 0.5% HPMC and 0.1 % Tween 80 in distilled water.

[0380] Positive control: valproate (200 mg / kg) physiological saline.

[0381] Test compounds: 10-100 mg / kg in vehicle.Sample Collection:

[0382] The euthanasia and tissue collection method, which was designed to minimize animal suffering and to ensure good quality of biological samples, was adapted from basic procedures commonly used in studies performed in rodents.

[0383] At the end of test, the mice treated with the test substance were placed under isoflurane anaesthesia (5% for induction and 2% for maintenance, under 100% 02). Approximately 500 pL of blood were collected by cardiac puncture using a sterile disposable syringe. The blood samples were immediately transferred into pre-labelled tubes containing K2-EDTA. After sealing each tube, the blood samples were manually agitated and stored on ice until centrifugation (within 30 minutes of sampling). The samples were centrifuged at +4°C, at 1500 g, for 10 minutes. Once separated, the resulting plasma was stabilised immediately with 100 mg / mL ascorbic acid (aq) in a 1:1 v / v ratio (2 aliquots of 100 pL).Ascorbic acid was prepared fresh on the day of use. The samples were stored at -80°C until shipment.

[0384] Each animal was humanely killed immediately after blood collection in compliance with Council Directive No. 2010 / 63 / UE of September 22nd2010 on the protection of animals used for scientific purposes and French decree No. 2013-118 of February 1st2013 on the protection of animals Animal Health regulations. The brain hemispheres were dissected, weighed, placed in separate pre-labelled vials and snap frozen on liquid nitrogen. The vials were stored upright at approximately -80°C and protected from light until transport to the bioanalysis site for analysis.Statistical Analysis:

[0385] Data were discrete values so considered to be non-normally distributed based on validation data, therefore non-parametric tests were utilized. Quantitative data (scores) with the test substance were analyzed by comparing test compound-treated groups with the 1:2:17 vehicle control using Kruskal-Wallis test with Dunn’s multiple comparisons test when the Kruskal-Wallis test was significant. Quantitative data with the reference substance were analyzed using Mann- Whitney II test as compared to saline vehicle.Results

[0386] Table 28 shows the results for the tested compound.Table 28: 6 Hz Partial Seizure Test Results for Compound 1 (n = 20)*not significant; **p<0.01 ; ***p<0.001 .Conclusions

[0387] The results shown in Table 28 demonstrate that the test compounds are able to suppress seizures compared to control. This data demonstrates that the test compounds display anticonvulsant activity in a mouse model of partial seizure. Thus, the test compounds may be useful in medical treatment, such as in the treatment of seizure.Example 5: Evaluation of the Anticonvulsive properties of Compounds using the Mouse Audiogenic Seizure Test

[0388] The Audiogenic Seizure Test, which detects anticonvulsant activity, follows that described by Durmuller et al., 1993. Mice of the DBA / 2 strain undergo an age-dependent sequence of convulsions (wild-running, clonic convulsion, tonic convulsion and respiratory arrest) within 60 seconds of exposure to a loud sound of 110-120 dB. The type of convulsions are consistent with aspects of generalised seizure in humans.

[0389] Antiepileptic drugs such as sodium valproate and carbamazepine protect DBA / 2 mice from clonic convulsions, tonic convulsions and respiratory arrest, indicative of an anticonvulsant effect (De Sarro et al., 2017).General MethodMice:

[0390] Male DBA / 2 mice (3 - 4 weeks old) were supplied by Janvier Labs (53940 Le Genest-Saint-lsle, France); weight range 6 - 13 g at the beginning of the experiment. Animals were acclimatized to the Test Facility for 1 day after delivery and randomly housed in groups of 5 in macroIon cages on wood litter with free access to food and water.

[0391] The animal house was maintained under artificial lighting (12 hours) between 7:00 and 19:00 in a controlled ambient temperature of 22 ± 2°C and relative humidity between 30- 70%.Study Details:

[0392] Mice were individually transferred (at 3 - 5 minutes intervals) from the preparation room into an adjacent experimental room and body temperature was measured using a rectal thermometer (Digital Laboratory Thermometer: Model BAT-12). Immediately after, they were placed in a Plexiglas jar (Diameter = 40 cm; Height = 35 cm) mounted with an electric bell (110-120 dB, supplier Leroy Merlin, France). Upon activating the bell, the occurrences and latencies to wild running fits, clonic and tonic seizures were measured. Deaths were also recorded. The bell was activated until a tonic seizure occurred, or for a maximum of 60 seconds.

[0393] The experiment included groups of 10 mice per group.

[0394] The test substance was administered at 10 mL / kg via oral gavage (p.o.) at 5, 10, 25, 50 and 100 mg / kg 60 minutes before the test, and was compared with vehicle administered at the corresponding timepoint.

[0395] Diazepam administered at 2 mg / kg p.o. 60 minutes before the test, was used as reference substance and was compared with vehicle control group at the corresponding timepoint.

[0396] Due to the number of animals tested, the experiment was divided in 2 subexperiments on 2 separate days with 5 mice per group in each sub-experiment.Compound Preparation:

[0397] Vehicle: 0.5% HPMC and 0.1 % Tween 80 in distilled water.

[0398] Positive control: diazepam 2 mg / kg in 0.2% HPMC in distilled water.

[0399] Test compounds: 5-100 mg / kg in a 1 :2:17 in vehicle.Sample Collection:

[0400] The euthanasia and tissue collection method, which was designed to minimize animal suffering and to ensure good quality of biological samples, was adapted from basic procedures commonly used in studies performed in rodents.

[0401] At the end of each sub-experiment, the mice treated with the test substance were placed under isoflurane anesthesia (5% for induction and 2% for maintenance, under 100% O2). Maximum volume of blood was collected by cardiac puncture using a sterile disposable syringe. The blood samples were immediately transferred into pre-labelled tubes containing K2-EDTA. After sealing each tube, the blood samples were manually agitated and stored on ice until centrifugation (within 30 minutes of sampling). The samples were centrifuged at +4°C, at 1500 g, for 10 minutes. Once separated, the resulting plasma was stabilised immediately with 100 mg / mL ascorbic acid (aq) in a 1:1 v / v ratio (2 aliquots of 100 pL: 50 pL plasma + 50pL ascorbic acid at 100 mg / mL). Ascorbic acid was prepared fresh on the day of use. The samples were stored at -80°C until shipment.

[0402] Each animal was humanely killed immediately after blood collection in compliance with Council Directive No. 2010 / 63 / UE of September 22nd 2010 on the protection of animals used for scientific purposes and French decree No. 2013-118 of February 1st 2013 on the protection of animals Animal Health regulations. The brain hemispheres were dissected, weighed, placed in separate pre-labelled vials and snap frozen on liquid nitrogen. The vials were stored upright at approximately -80°C and protected from light until transport to the bioanalysis site for analysis. Any spare animals, plus animals not treated with the test substance, were sacrificed by cervical dislocation after isoflurane anaesthesia.Statistical Analysis:

[0403] Data were tested for normality using d’Agostino-Pearson Test and found to not follow a normal distribution. Statistical outliers were not identified or removed because no behavioural outliers were identified. Quantitative data (latencies) with the test substance were analyzed by comparing treated groups with vehicle control using Kruskal-Wallis test followed by Dunn’s multiple comparisons test. Quantitative data with the reference substance were analyzed using Mann-Whitney II test. Quantal data (frequencies) were analyzed by comparing treated groups with vehicle control using Fisher’s Exact Probability test.Results

[0404] Table 29 to Table 31 show the test results for Compound 1.Table 29: Audiogenic Seizure Test (wild running) for Compound 1 (n = 10)*not significant; **p<0.01 ; ***p<0.001Table 30: Audiogenic Seizure Test (clonic convulsions) for Compound 1 (n = 10)*not significant; **p<0.01 ; ***p<0.001Table 31 : Audiogenic Seizure Test (tonic extensions) for Compound 1 (n = 10)*not significant; ***p<0.001 Conclusions

[0405] The results shown in Table 29 to Table 31 demonstrate that the test compounds display anticonvulsant activity in a model of generalised seizure using mice prone to audiogenic seizures. The test compounds reduced the incidence of each of the measuredseizure endpoints (wild-running, clonic convulsions and tonic convulsions compared) to control. The test compounds also increased the time to onset (latency) of each of the seizure endpoints (wild-running, clonic convulsions and tonic convulsions). Thus, the test compounds may be useful in medical treatment, such as in the treatment of seizure.Example 6: Evaluation of the Anticonvulsive Properties of Compound 1 using the Rat Acute Kainic Acid Induced Seizure Test

[0406] Kainic acid (kainite) is known to induce repetitive seizures and neuronal damage in the hippocampus (Nadler et al., 1978) and amygdala (Ben-Ari and Lagowska, 1978), reminiscent of temporal lobe epilepsy (TLE) in humans characterised by focal onset seizures. The kainic acid (KA) model of seizure is considered to induce seizure symptoms suitable for studying the mechanism and treatment of focal onset seizures (Stables et al., 2002, 2003).

[0407] This study evaluated the anticonvulsant efficacy of Compound 1 at 25, 50, 100 and 200 mg / kg doses against kainic acid induced seizure. The primary endpoint is a reduction in the number of rats exhibiting both Racine stages 4 and 5, as compared to controls. The positive control, diazepam at 5 mg / kg, has consistently demonstrated efficacy at this endpoint, but does not reduce the number of rats exhibiting Racine stage 3.General MethodRats:

[0408] Male Wistar rats (Charles River, Sulzfeld, Germany) aged 6-7 weeks (150-180 g upon arrival), were housed in groups of 2-4 in standard caging with free access to food and water on a 12h / 12h light / dark cycle from arrival (lights on at 7:00am). Animals were acclimatised to the test facility for at least 7 days following arrival. At the start of the study their weight range was 175 g to 235 g.Study Details:

[0409] All animals were tail marked and weighed at the beginning of the study. The animals were randomly assigned to 6 treatment groups (n=15 per group) selected from vehicle , diazepam ( and Compound 1. All animals were dosed via oral gavage (p.o.) with either vehicle (at 10 mL / kg), Compound 1 (25-200 mg at 10 mL / kg) or diazepam (5 mg / kg at 1mL / kg). The pre-treatment time for diazepam was 60 min, while for all other groups it was 120 min.

[0410] Rats were placed into individual clear Perspex cages for the observation period (experimenters were blinded to the treatment groups). After the pre-treatment time, the rats were injected subcutaneously with 15 mg / kg of kainic acid solution (3 mg / mL in 0.9% NaCI physiological saline) and the animals were observed for 150 min following kainic acid injection (experimenters were blinded to the treatment groups) to record the latency ofseizure onset (Racine stage 3, 4 and 5) and the number of animals manifesting each Racine stage (stages 3, 4 and 5) using a modified Racine scale (Table 32). Where an animal did not manifest a specific Racine stage, the maximum observation time (150 min) was given as its latency value. Time of euthanasia was recorded for each rat. Any unusual response to KA / compounds were recorded in the raw data.

[0411] When the animals reached a humane endpoint (score 5 continuously for 1 min or score 5 in brief but repeated bouts for 10 min or score 6) or at the end of the observation period, they were humanely killed immediately by concussion of the brain from striking the cranium, followed by the confirmation of permanent cessation of the circulation from decapitation in accordance with The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986. Terminal blood and brain collection were performed following decapitation.Table 32: Modified Racine scale for seizure scoring (modified from Ben-Ari etal., 1981)Compound preparation:

[0412] Vehicle (15% w / v SBE-p-CD (Captisol), 0.5% w / v HPMC, 0.1% v / v Tween 80 in water): 1 g of HPMC was dissolved in 100 mL of water at 60 °C with stirring, 0.2 mL Tween 80 was added, the solution was transferred to a 200 mL volumetric flask and made up to volume with purified water. Weigh 15.0g of SBE-p-CD into a beaker (taking into account the water content of the SBE-p-CD as per the CoA) and dissolve in 100 mL of previously prepared 0.5 % w / v HPMC 0.1 % v / v Tween 80 in water in a 100 mL volumetric flask.

[0413] Compound 1 was formulated as 2.5, 5, 10, or 20 mg / mL homogeneous suspensions in the vehicle (15% w / v SBE-p-CD (Captisol), 0.5% w / v HPMC, 0.1% v / v Tween 80 in water) to enable dosing of 25, 50, 100 or 200 mg / kg Compound 1 respectively via 10 mL / kg samples.

[0414] Diazepam was formulated as a 5 mg / mL homogeneous suspension in 1% w / v methylcellulose in de-ionised water.Sample Collection:

[0415] Terminal blood and brain were collected from the Compound 1-dosed animals. Blood was collected in K2-EDTA tubes and centrifuged at 4°C for 10 min, at 1500 x g. Theresulting plasma was removed (>200 pL) and stored in two 0.5 mL polypropylene tubes. Brains were removed and hemispheres separated. Each hemisphere was placed into 5 mL plastic tubes, weighed and frozen on cardice.Statistical Analysis:

[0416] Data were tested for normality using d’Agostino-Pearson and shown to not follow a normal distribution, therefore a non-parametric test was utilized. Incidence data (actuals) were analysed using one-sided Fisher’s Exact tests (GraphPad Prism 9.4.0). Latency data (actuals) were analysed using a single Kruskal-Wallis test. If the Kruskal-Wallis test was significant (p<0.05) then a Dunn’s multiple comparison test compared each group vs the vehicle group. Latency data (Figure 1) are presented as median with IQR, the two tails represent highest and lowest values and each dot represents individual data points. n=15 / group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Percent change calculations were computed as the difference between Vehicle and each Treatment group proportion, divided by the Vehicle proportion.Results

[0417] Table 33 shows the results for the number of rats manifesting each Racine stage (stages 3, 4 and 5) using the modified Racine scale described in Table 32.Table 33: MEST results for Compound 1 (n = 12)aData expressed as occurrence / group size; percentage protected as % change from vehicle response; p value using one-sided Fisher’s Exact test.bStatistics not performed on number of animals reaching humane endpoint due to no a priori hypothesis.

[0418] No adverse events were observed due to diazepam or Compound 1 administration. Severe bradypnea was observed in 6 rats due to kainic acid administration (1 rat from the vehicle group, 2 rats from the Compound 1 25 mg / kg group, 2 rats from the Compound 1 50 mg / kg group and 1 rat from the Compound 1 100 mg / kg group).

[0419] In the vehicle group administered KA (15 mg / kg s.c.), 100% of rats displayed Racine stage 3, 93% displayed Racine stage 4, and 80% displayed Racine stage 5 (Table 33). Four out of fifteen (27%) rats displayed tonic seizure or prolonged clonic seizure and one out of 15 (7%) showed severe bradypnea, meaning that 33% of rats reached the humane endpoint before the end of the 150 min observation period.

[0420] Diazepam at 5 mg / kg significantly reduced the number of rats exhibiting Racine stages 3, 4 and 5 as compared to vehicle (-27, -71 and -83% from vehicle response, respectively).

[0421] Compound 1 at 200 mg / kg significantly reduced the number of rats exhibiting Racine stages 3 and 4, as compared to vehicle (-40 and -43% from vehicle response, respectively). Compound 1 at 25, 50, 100 and 200 mg / kg significantly reduced the number of rats exhibiting Racine stage 5 as compared to vehicle (-50, -58, -67 and -58% from vehicle response, respectively).

[0422] The latency to Racine stages 3, 4 and 5 was also measured for the six rat groups and is shown in Figure 1.

[0423] Diazepam at 5 mg / kg, as well as Compound 1 at 200 mg / kg (but not 25, 50 or 100 mg / kg) significantly increased the latency to Racine stage 3 as compared to vehicle (Fig. 1A; H (5) = 23.56, p=0.0003). Diazepam at 5 mg / kg (but not Compound 1) significantly increased the latency to Racine stage 4 as compared to vehicle (Fig. 1 B; H (5) = 20.64, p= 0.0009). Diazepam at 5 mg / kg, as well as Compound 1 at 50, 100 and 200 mg / kg (but not 25 mg / kg) significantly increased the latency to Racine stage 5 as compared to vehicle (Fig. 1C; H (5) = 21.09, p = 0.0008).

[0424] The maximum Racine seizure score experienced by the study rats was also recorded (equivalent to the maximum Racine stage experience by each animal, as defined in Table 32). This data is shown in Figure 2 for the six treatment groups. Diazepam at 5 mg / kg and Compound 1 at 200 mg / kg (but not 25 mg / kg, 50 mg / kg, or 100 mg / kg) significantly decreased the maximum seizure severity, as compared to vehicle (H (5) = 20.89, p = 0.0009).Conclusions

[0425] The results of the rat acute kainic acid induced seizure test shown that Compound 1 at 200 mg / kg significantly reduced the number of rats exhibiting Racine stages 3 and 4, and at 25 to 200 mg / kg doses it significantly reduced the number of rats exhibiting Racine stage 5 behaviour, compared to vehicle. Therefore, there is a clear anticonvulsive effect of Compound 1 in a model of focal onset seizure. Thus, the compounds may be useful in medical treatment, such as in the treatment of seizure.Tests - Conclusions

[0426] The above results described in Examples 2 to 6 demonstrate that the test compounds display anti-convulsive activity in several different and complementary rodent models of seizure (mini-MEST; MEST; 6 Hz; audiogenic; and kainic acid induced seizure models). Thus, the compounds of formula (I) may be useful in medical treatment, such as in the treatment of seizure.REFERENCES

[0427] A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The contents of each of these references is incorporated herein.1. Devinsky et al., “Epilepsy”, Nature Reviews Disease Primers, 2018, 3, article number 18024.2. Fiest et al., “Prevalence and incidence of epilepsy: a systematic review and metaanalysis of international studies”, Neurology, 2017, 88, 296-303.3. Scheffer et al., “I LAE classification of the epilepsies: Position paper of the I LAE Commission for Classification and Terminology” Epilepsia, 2017, 58(4), 512-521.4. Fisher et al., “Operational classification of seizure types by the I LAE: Position paper of the I LAE Commission for Classification and Terminology” Epilepsia, 2017, 58(4), 522- 530.5. Wirrell et al., “Methodology for classification and definition of epilepsy syndromes with list of syndromes: Report of the I LAE Task Force on Nosology and Definitions” Epilepsia, 2022, 63, 1333-1348.6. Zuberi et al., “I LAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the I LAE Task Force on Nosology and Definitions” Epilepsia, 2022, 63, 1349-1397.7. Specchio et al., “I LAE classification and definition of epilepsy syndromes with onset in childhood: Position statement by the I LAE Task Force on Nosology and Definitions” Epilepsia, 2022, 63, 1398-1442.8. Riney et al., “I LAE classification and definition of epilepsy syndromes with onset at a variable age: Position statement by the I LAE Task Force on Nosology and Definitions” Epilepsia, 2022, 63, 1443-1474.9. Hirsch et al., “ILAE definition of Idiopathic Generalized Epilepsy Syndromes: Position statement by the ILAE Task Force on Nosology and Definitions” Epilepsia, 2022, 63, 1475-1499.10. Ldscher et al., “ The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models.”, Epilepsy Res., 1991 , Vol. 8, 79-84.11. Kimball et al., “Chemical protection against ionizing radiation: I. Sampling methods for screening compounds in radiation protection studies in mice.”, Radiat. Res., 1957, Vol. 7, 1-12.12. Brown et al., “Comparative assay of antiepileptic drugs by ‘psychomotor’ seizure test and minimal electroshock threshold test”, J. Pharmacol. Exp. Ther. 1953, 107, 273-283.13. Klein et al., “Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP)”, Neurochem Res, 2017, 42(7), 1939-1948.14. Durmuller et al., “Proconvulsant and anticonvulsant effects of Evans blue dye in rodents”, NeuroReport, 1993, 4, 683-686.15. De Sarro et al., “Genetically epilepsy-prone rats (GEPRs) and DBA / 2 mice: Two animal models of audiogenic reflex epilepsy for the evaluation of new generation AEDs”, Epilepsy & Behavior, 2017, 71,165-173.16. Nadler et al., “Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells”, Nature, 1978, 271, 676-677.17. Ben-Ari and Lagowska, “Epileptogenic action of intra-amygdaloid injection of kainic acid”, Comptes Rendus Hebd Seances Acad Sci Serie Sci Nat., 1978, 287, 813-816.18. Stables et al., “Models for epilepsy and epileptogenesis: report from the NIH workshop, Bethesda, Maryland”, Epilepsia, 2002, 43, 1410-1420.19. Stables et al., “Therapy discovery for pharmacoresistant epilepsy and for diseasemodifying therapeutics: summary of the NIH / NINDS / AES models II workshop”, Epilepsia, 2003, 44, 1472-1478.20. Ben-Ari et al., “Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline and pentetrazole: metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy”, Neuroscience, 1981 , 6, 1361.

Claims

CLAIMS1. A compound of formula (I), or a salt thereof:wherein,R1aand R1 bare independently selected from hydrogen, Ci-salkyl, and halo; or R1aand R1 b, together with the carbon atom to which they are attached, form a cyclopropyl ring;R2is hydrogen, Ci-salkyl, or Cs-ecycloalkyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from halo and NR7R8, wherein R7and R8are independently selected from hydrogen and Ci-salkyl;R3is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R4is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R5is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo; andR6is hydrogen, Ci-ioalkyl, Cs-ecycloalkyl, or halo; and wherein said Ci- alkyl is unsubstituted or substituted with one to three groups R6Aselected from halo, hydroxy, Ci-salkoxy, Cs-ecycloalkyl, and 4- to 6- membered heterocyclyl.

2. The compound according to claim 1 , wherein R1aand R1 bare independently selected from hydrogen, Ci-salkyl, and halo; such as hydrogen, methyl, and fluoro.

3. The compound according to claim 2, wherein R1aand R1 bare both hydrogen, or both methyl.

4. The compound according to any of claims 1 to 3, wherein R2is hydrogen, Ci-salkyl, or cyclopropyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from fluoro and NR7R8, wherein R7and R8are independently selected from hydrogen and Ci-salkyl.

5. The compound according to any of claims 1 to 3, wherein R2is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, CH2CF3, CH2CH2F, or CH2CH2NMe2; such as ethyl, cyclopropyl, or CH2CF3.

6. The compound according to any of claims 1 to 5, wherein R3is hydrogen, methyl, trifluoromethyl, fluoro, or chloro; such as hydrogen, methyl, fluoro, or chloro.Ill7. The compound according to claim 6, wherein R3is hydrogen or fluoro.

8. The compound according to any of claims 1 to 7, wherein R4is hydrogen, methyl, trifluoromethyl, fluoro, or chloro; such as hydrogen, methyl, fluoro, or chloro.

9. The compound according to claim 8, wherein R4is hydrogen.

10. The compound according to any of claims 1 to 9, wherein R5is hydrogen, methyl, trifluoromethyl, fluoro, or chloro; such as hydrogen, methyl, fluoro, or trifluoromethyl.

11. The compound according to claim 10, wherein R5is hydrogen or methyl; such as methyl.

12. The compound according to any of claims 1 to 11 , wherein R6is Ci-ioalkyl, Cs-ecycloalkyl, or halo; and wherein said C oalkyl is unsubstituted or substituted with one to three groups R6A.

13. The compound according to claim 12, wherein R6is Ci-salkyl, or C^cycloalkyl and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups R6A.

14. The compound according to any of claims 1 to 13, wherein R6Ais independently selected from fluoro, hydroxy, methoxy, C^cycloalkyl, and 4- to 6-membered heterocyclyl; such as fluoro, hydroxy, methoxy, C^cycloalkyl, and pyrrolidinyl.

15. The compound according to any of claims 1 to 11 , wherein R6is ethyl, propyl, isopropyl, butyl, or pentyl; such as propyl.

16. The compound according to claim 1, wherein the compound is a compound of any of formulae (IA) to (IF):(IA) (IB) (IC)wherein R1a, R1 b, R2, R3, R4, R5and R6are as defined in any of claims 1 to 15.

17. The compound according to claim 1 , wherein the compound is selected from the following compounds and salts thereof:4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1 ,5-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-isopropyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-(2-(dimethylamino)ethyl)-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1 ,3,3,5-tetramethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-3,3,5-trimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-3,3-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-3-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-3,5-dimethylindolin-2-one;1-Ethyl-4-(4-ethyl-2,6-dihydroxyphenyl)-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-isopropylphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Butyl-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-pentylphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Chloro-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Butyl-2,6-dihydroxyphenyl)-1-ethylindolin-2-one;4-(4-Butyl-2,6-dihydroxyphenyl)-1-methylindolin-2-one;4-(2,6-Dihydroxy-4-pentylphenyl)-1-methylindolin-2-one;4-(2,6-Dihydroxy-4-pentylphenyl)-1-ethylindolin-2-one;4-(2,6-Dihydroxy-4-pentylphenyl)-1 ,5-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-5-methyl-1-propylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-5-methyl-1-(2,2,2-trifluoroethyl)indolin-2-one;4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-3,3-difluoro-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-7-fluoro-1,5-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-7-fluoro-5-methylindolin-2-one;4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-6-fluoro-5-methylindolin-2-one;7-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;6-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;6-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-ethyl-7-fluoroindolin-2-one;4-(4-cyclopropyl-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Cyclobutyl-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-5-methylindolin-2-one;1-Cyclopropyl-4-(2,6-dihydroxy-4-propylphenyl)indolin-2-one;1-Cyclopropyl-4-(2,6-dihydroxy-4-propylphenyl)-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-7-fluoroindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5,7-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5,6-dimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-(2,2,2-trifluoroethyl)indolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-(trifluoromethyl)indolin-2-one;1-Cyclopropyl-4-(2,6-dihydroxy-4-propylphenyl)-7-fluoro-5-methylindolin-2-one;1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-dihydroxyphenyl)-7-fluoro-5- methylindolin-2-one;4-(4-(Cyclopropylmethyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-dihydroxyphenyl)-5-methylindolin-2-one;4-(4-(2,2-Difluoropropyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-(1 ,1-Difluoropropyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-(2-Cyclopropylethyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-(Cyclobutylmethyl)-2,6-dihydroxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-(2-hydroxy-2-methylpropyl)phenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-(2-methoxy-2-methylpropyl)phenyl)-1-ethyl-5-methylindolin-2-one;7-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-methylindolin-2-one;7-Chloro-4-(2,6-dihydroxy-4-propylphenyl)-1-ethylindolin-2-one;4-(2,6-Dihydroxy-4-(3,3,3-trifluoropropyl)phenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-(pyrrolidin-1-ylmethyl)phenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1 ,3,3-trimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-3,3,5-trimethylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-(2-fluoroethyl)-5-methylindolin-2-one;4-(2,6-Dihydroxy-4-propylphenyl)-1-ethyl-5-fluoroindolin-2-one;4-(2,6-Dihydroxy-4-isobutylphenyl)-1-ethyl-5-methylindolin-2-one; and4-(2,6-Dihydroxy-4-isopentylphenyl)-1-ethyl-5-methylindolin-2-one.

18. A pharmaceutical composition comprising a compound according to of any of claims 1 to 17, or a pharmaceutically acceptable salt thereof, together with one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants, masking agents, colouring agents, flavouring agents, and sweetening agents.

19. A compound according to any of claims 1 to 17, a salt thereof, or a pharmaceutical composition according to claim 18, for use in a method of treatment.

20. The compound or the pharmaceutical composition for the use according to claim 19 wherein the treatment is the treatment of a condition associated with seizure.

21. The compound or the pharmaceutical composition for the use according to claim 20, wherein the condition associated with seizure is selected from focal onset seizure, generalised onset seizure, and unknown onset seizure.

22. The compound or the pharmaceutical composition for the use according to claim 20, wherein the condition associated with seizure is a seizure type selected from absence seizure, atypical absence seizure, atonic seizure, clonic seizure, tonic seizure, tonic- clonic seizure, febrile seizure, focal to bilateral tonic clonic seizure, gelastic and dacrystic seizure, myoclonic seizure, myoclonic-tonic-clonic seizure, myoclonic-atonic seizure, and epileptic (or infantile) spasms.

23. The compound or the pharmaceutical composition for the use according to claim 20, wherein the condition associated with seizure is selected from focal epilepsy, generalised epilepsy, and combined generalised & focal epilepsy.

24. The compound or the pharmaceutical composition for the use according to claim 20, wherein the condition associated with seizure is an epilepsy syndrome selected from syndromes with onset in neonates and infancy, syndromes with onset in childhood, syndromes with onset at a variable age, and idiopathic generalised epilepsy syndromes (IGEs).

25. The compound or the pharmaceutical composition for use according to claim 20, wherein the condition associated with seizure is an epilepsy having an aetiology selected from structural, genetic, infection, metabolic, and autoimmune.

26. A method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to any of claims 1 to 17, a salt thereof, or a pharmaceutical composition according to claim 18.

27. The method according to claim 26, wherein the treatment is treatment of a condition associated with seizure.

28. The method according to claim 27, wherein the condition associated with seizure is selected from focal onset seizure, generalised onset seizure, and unknown onset seizure.

29. The method according to claim 27, wherein the condition associated with seizure is a seizure type selected from absence seizure, atypical absence seizure, atonic seizure, clonic seizure, tonic seizure, tonic-clonic seizure, febrile seizure, focal to bilateral tonic clonic seizure, gelastic and dacrystic seizure, myoclonic seizure, myoclonic-tonic- clonic seizure, myoclonic-atonic seizure, and epileptic (or infantile) spasms.

30. The method according to claim 27, wherein the condition associated with seizure is selected from focal epilepsy, generalised epilepsy, and combined generalised & focal epilepsy.31 . The method according to claim 27, wherein the condition associated with seizure is an epilepsy syndrome selected from syndromes with onset in neonates and infancy, syndromes with onset in childhood, syndromes with onset at a variable age, and idiopathic generalised epilepsy syndromes (IGEs).

32. The method according to claim 27, wherein the condition associated with seizure is an epilepsy having an aetiology selected from structural, genetic, infection, metabolic, and autoimmune.

33. Use of a compound according to any of claims 1 to 17, a salt thereof, or a pharmaceutical composition according to claim 18, for the manufacture of a medicament.

34. Use of a compound according to any of claims 1 to 17, a salt thereof, or a pharmaceutical composition according to claim 18, in a method of treatment.

35. A method of preparing a compound of formula (I) according to any of claims 1 to 15, the method comprising:(1a) reacting a compound of formula (II) with a compound of formula (III) to give a compound of formula (IV):where:R1a, R1 b, R2, R3, R4, R5and R6are as defined in any of claims 1 to 15;X is chloro, bromo, iodo, or triflate;Y is BF3Z, wherein Z is a suitable counter-cation such as Na or K, or Y is B(OR11)OR12, wherein R11and R12are hydrogen, Ci-ealkyl, or phenyl; or R11and R12, together with the oxygen and boron atoms to which they are attached, form a 5- to 8-membered cyclic boronic ester; andR9and R10are suitable alcohol protecting groups; and(1b) converting a compound of formula (IV) to a compound of formula (I).

36. A method of preparing a compound of formula (I) according to any of claims 1 to 15, the method comprising:(1a) reacting a compound of formula (V) with a compound of formula (VI) to give a compound of formula (IV):where:R1a, R1 b, R2, R3, R4, R5and R6are as defined in any of claims 1 to 15;X is chloro, bromo, iodo, or triflate;Y is BF3Z, wherein Z is a suitable counter-cation such as Na or K, or Y is B(OR11)OR12, wherein R11and R12are hydrogen, Ci-ealkyl, or phenyl; or R11and R12, together with the oxygen and boron atoms to which they are attached, form a 5- to 8-membered cyclic boronic ester; andR9and R10are suitable alcohol protecting groups, and(1b) converting a compound of formula (IV) to a compound of formula (I).

37. The method according to claim 35 or 36, wherein X is bromo or iodo, such as bromo.

38. The method according to any one of claims 35 to 37, wherein Y is B(OR11)OR12, wherein R11and R12are hydrogen, Ci-ealkyl or phenyl; or R11and R12together form39. The method according to claim 38, wherein R11and R12are both hydrogen; or R11andR12together form40. The method according to any one of claims 35 to 39, wherein R9and R10are both methyl; or R9and R19are both benzyl.

41. The method according to any one of claims 35 to 40, wherein step (1a) is carried out in the presence of a palladium catalyst, and optionally a base.

42. The method according to any one of claims 35 to 41 , wherein step (1a) is carried out at a temperature of from 60 °C to 160 °C.

43. A compound obtained or obtainable by the method according to any one of claims 35 to 42.

44. A compound of formula (II):wherein R1aand R1 bare independently selected from hydrogen, Ci-salkyl, and halo; or R1aand R1 b, together with the carbon atom to which they are attached, form a cyclopropyl ring;R2is hydrogen, Ci-salkyl, or Cs-ecycloalkyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from halo and NR7R8, wherein R7and R8are independently selected from hydrogen and Ci-salkyl;R3is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R4is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R5is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo; andX is chloro, bromo, iodo, or triflate.

45. The compound of formula (II) according to claim 44 selected from:4-Bromo-1-ethyl-5-methylindolin-2-one;4-Bromo-1 ,5-dimethylindolin-2-one;4-Bromo-1-isopropyl-5-methylindolin-2-one;4-Bromo-5-methyl-1-propylindolin-2-one;4-Bromo-5-methyl-1-(2,2,2-trifluoroethyl)indolin-2-one;4-Bromo-1-(2,2,2-trifluoroethyl)indolin-2-one;4-Bromo-1-ethylindolin-2-one;4-Bromo-1-(2-(dimethylamino)ethyl)-5-methylindolin-2-one;4-Bromo-7-fluoro-1-methylindolin-2-one;4-Bromo-1-ethyl-7-fluoroindolin-2-one;4-Bromo-1-ethyl-7-fluoro-5-methylindolin-2-one;4-Bromo-6-chloro-1-ethyl-7-fluoroindolin-2-one;4-Bromo-1-ethyl-5,7-dimethylindolin-2-one;4-Bromo-1-ethyl-5,6-dimethylindolin-2-one;4-Bromo-1-ethyl-5-(trifluoromethyl)indolin-2-one;4-Bromo-1-ethyl-6- fluoro- 5-methylindolin-2-one;4-Bromo-1-cyclopropylindolin-2-one;4-Bromo-1-cyclopropyl-5-methylindolin-2-one;4-Bromo-1-cyclopropyl-7-fluoro-5-methylindolin-2-one;4-Bromo-1-ethyl-3,3-difluoro-5-methylindolin-2-one;4-Bromo-1 ,3,3,5-tetramethylindolin-2-one;4-Bromo-1-ethyl-3,3,5-trimethylindolin-2-one;4-Bromo-1-ethyl-3,5-dimethylindolin-2-one;4-Bromo-7-chloro-1-ethyl-5-methylindoline-2, 3-dione;4-Bromo-6-chloro-1-ethyl-5-methylindoline-2, 3-dione;4-Bromo-6-chloro-1-ethyl-5-methylindolin-2-one; and4-Bromo-7-chloro-1-ethyl-5-methylindolin-2-one.

46. A compound of formula (IV):wherein R1aand R1 bare independently selected from hydrogen, Ci-salkyl, and halo; or R1aand R1 b, together with the carbon atom to which they are attached, form a cyclopropyl ring;R2is hydrogen, Ci-salkyl, or Cs-ecycloalkyl; and wherein said Ci-salkyl is unsubstituted or substituted with one to three groups selected from halo and NR7R8, wherein R7and R8are independently selected from hydrogen and Ci-salkyl;R3is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R4is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R5is hydrogen, Ci-salkyl, Ci-shaloalkyl, or halo;R6is hydrogen, Ci-ioalkyl, Cs-ecycloalkyl, or halo; and wherein said Ci- alkyl is unsubstituted or substituted with one to three groups R6Aselected from halo, hydroxy, Ci-salkoxy, Cs-ecycloalkyl, and 4- to 6- membered heterocyclyl; and R9and R10are suitable alcohol protecting groups.

47. The compound of formula (IV) according to claim 46 selected from:4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1 ,5-dimethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-isopropyl-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyllindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-(2-(dimethylamino)ethyl)-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1 ,3,3,5-tetramethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-3,3,5-trimethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-3,3-dimethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-3-methylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-3,5-dimethylindolin-2-one;1-Ethyl-4-(4-ethyl-2,6-dimethoxyphenyl)-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-isopropylphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Butyl-2,6-dimethoxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-pentylphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Chloro-2,6-dimethoxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Butyl-2,6-dimethoxyphenyl)-1-ethylindolin-2-one;4-(4-Butyl-2,6-dimethoxyphenyl)-1-methylindolin-2-one;4-(2,6-Dimethoxy-4-pentylphenyl)-1-methylindolin-2-one;4-(2,6-Dimethoxy-4-pentylphenyl)-1-ethylindolin-2-one;4-(2,6-Dimethoxy-4-pentylphenyl)-1 ,5-dimethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-5-methyl-1-propylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-5-methyl-1-(2,2,2-trifluoroethyl)indolin-2-one;4-(2,6-dimethoxy-4-propylphenyl)-1-ethyl-3,3-difluoro-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-7-fluoro-1,5-dimethylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1-ethyl-7-fluoro-5-methylindolin-2-one;4-(2,6-dimethoxy-4-propylphenyl)-1-ethyl-6-fluoro-5-methylindolin-2-one;7-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;6-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-ethyl-5-methylindolin-2-one;6-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-ethyl-7-fluoroindolin-2-one;4-(4-cyclopropyl-2,6-dimethoxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(4-Cyclobutyl-2,6-dimethoxyphenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-methylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-5-methylindolin-2-one;1-Cyclopropyl-4-(2,6-bis(benzyloxy)-4-propylphenyl)indolin-2-one;1-Cyclopropyl-4-(2,6-bis(benzyloxy)-4-propylphenyl)-5-methylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-7-fluoroindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-5,7-dimethylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-5,6-dimethylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-(2,2,2-trifluoroethyl)indolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-5-(trifluoromethyl)indolin-2-one;1-Cyclopropyl-4-(2,6-bis(benzyloxy)-4-propylphenyl)-7-fluoro-5-methylindolin-2-one;1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-bis(benzyloxy)phenyl)-7-fluoro-5- methylindolin-2-one;4-(4-(Cyclopropylmethyl)-2,6-bis(benzyloxy)phenyl)-1-ethyl-5-methylindolin-2-one;1-Cyclopropyl-4-(4-(cyclopropylmethyl)-2,6-bis(benzyloxy)phenyl)-5-methylindolin-2- one;4-(4-(2,2-Difluoropropyl)-2,6-bis(benzyloxy)phenyl)-1-ethyl-5-methylindolin-2-one;4-(4-(1 ,1-Difluoropropyl)-2,6-bis(benzyloxy)phenyl)-1-ethyl-5-methylindolin-2-one;4-(4-(2-Cyclopropylethyl)-2,6-bis(benzyloxy)phenyl)-1-ethyl-5-methylindolin-2-one;4-(4-(Cyclobutylmethyl)-2,6-bis(benzyloxy)phenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-(2-hydroxy-2-methylpropyl)phenyl)-1-ethyl-5-methylindolin-2- one;4-(2,6-Bis(benzyloxy)-4-(2-methoxy-2-methylpropyl)phenyl)-1-ethyl-5-methylindolin-2-one;7-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-methylindolin-2-one;7-Chloro-4-(2,6-dimethoxy-4-propylphenyl)-1-ethylindolin-2-one;4-(2,6-Dimethoxy-4-(3,3,3-trifluoropropyl)phenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-(pyrrolidin-1-ylmethyl)phenyl)-1-ethyl-5-methylindolin-2-one;4-(2,6-Dimethoxy-4-propylphenyl)-1 ,3,3-trimethylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-3,3,5-trimethylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-(2-fluoroethyl)-5-methylindolin-2-one;4-(2,6-Bis(benzyloxy)-4-propylphenyl)-1-ethyl-5-fluoroindolin-2-one; 1-Ethyl-4-(4-isobutyl-2,6-dimethoxyphenyl)-5-methylindolin-2-one; and1-Ethyl-4-(4-isopentyl-2,6-dimethoxyphenyl)-5-methylindolin-2-one.

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