Method of treatment

Abstract

The present disclosure generally relates to methods of treating Hypoxic-Ischemic Encephalopathy (HIE) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

Description

[0001] METHOD OF TREATMENT

[0002] FIELD

[0003] The present disclosure generally relates to the field of pharmaceutical treatments of Hypoxic-Ischemic Encephalopathy. More specifically, the present disclosure relates to the use of bicyclic compounds in the treatment of Hypoxic-Ischemic Encephalopathy.

[0004] BACKGROUND

[0005] Neonatal Encephalopathy (NE) is a rare condition resulting from brain injury or altered brain function in the perinatal period. In term and late preterm infants, NE is most often caused by a hypoxic-ischemic event and is generally referred to as Hypoxic-Ischemic Encephalopathy (HIE). HIE is defined as damage to the brain due to insufficient oxygen (hypoxia) and blood supply (ischemia) during the perinatal period and it is one of the most common causes of neurological disability and mortality worldwide. Moderate to severe HIE often results in damage to the brain leading to immediate and long-term neurologic sequelae including cerebral palsy, seizures, and neurodevelopmental impairment. The condition can lead to death in up to 20% of infants and lifelong neurologic morbidity in approximately 30% of survivors.

[0006] Clinical criteria for the diagnosis of HIE are based upon the infant’s neurological exam, need for resuscitation in the delivery room, and biochemical measures of tissue anoxia. Infants with HIE require treatment in a neonatal intensive care unit (NICU) setting that can provide therapeutic hypothermia, which is now the standard of care for moderate to severe cases. Although therapeutic hypothermia has improved morbidity and mortality in infants with moderate to severe HIE, approximately 30-50% of newborns still experience neurologic sequelae.

[0007] Current treatments for HIE are limited. Therapeutic hypothermia has become standard of care in the US and other high resource countries for neonates with HIE. Therapeutic hypothermia can be achieved either by whole body cooling or selective head cooling. The window for intervention with hypothermia is 6-8 hours from the event and requires a multidisciplinary team for evaluation, potential NICU transfer, and management. Therapeutic cooling to 33.5 °C is maintained for 72 hours and then gradually discontinued. During this time, critical monitoring and support of other organ systems which may have been impacted by perinatal hypoxia-ischemia and / or affected by therapeutic hypothermia is necessary. Adverse effects seen during therapeutic hypothermia may include bradycardia, hypotension, cardiac arrhythmias, poor oxygenation, electrolyte abnormalities, elevated liver enzymes, abnormal renal function, and coagulopathy; however, the treatment is generally well-tolerated.

[0008] Prior to therapeutic hypothermia, infants with severe HIE had up to a 75% chance of dying in the neonatal period and most survivors had neurologic sequelae. An initial Cochrane review (2007) reported that therapeutic hypothermia reduced mortality of term and late preterm neonates with HIE. A subsequent review, published in 2013 with follow up data in infants 18-24 months, found that evidence shows that therapeutic hypothermia improves survival and development at 18 to 24 months for term and late preterm neonates at risk of brain damage.

[0009] While therapeutic hypothermia reduces the risk of death and major disability, at 18 months, 30% of infants have major neurodevelopmental disabilities defined as cerebral palsy, developmental delay (Bayley or Griffith more than 2 SD (Standard Deviation) below the mean) or intellectual impairment (IQ more than 2 SD below the mean), blindness (vision, 6 / 60 in both eyes), or sensorineural deafness requiring amplification.

[0010] A study of 62,888 infants at 36 weeks gestation or greater, who were cared for in California Perinatal Quality Care Collaborative-participating NICUs between 2010 and 2019, evaluated trends in HIE diagnosis and use of therapeutic hypothermia. It was found that, of those infants with moderate-severe HIE, 25% remain untreated. It was further found that some infants with moderate-severe HIE remain untreated due to late recognition, concomitant medical conditions, or logistical issues with transport to a NICU that provides therapeutic hypothermia.

[0011] SUMMARY

[0012] Although therapeutic hypothermia has improved outcomes for Hypoxic-Ischaemic Encephalopathy (HIE), it fails to completely prevent neurological deficits. Accordingly, there remains a need for alternative and effective therapies for the treatment of Hypoxic-Ischaemic Encephalopathy (HIE) and / or a symptom associated with Hypoxic-Ischaemic Encephalopathy (HIE).

[0013] The subject matter of the present disclosure is predicated in part on the surprising discovery that compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may treat Hypoxic-Ischemic Encephalopathy (HIE) and / or symptoms associated with Hypoxic-Ischemic Encephalopathy (HIE).

[0014] Accordingly, in a first aspect, there is provided a method of treating Hypoxic-Ischemic Encephalopathy (HIE) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof

[0015]

[0016] Formula I;

[0017] wherein X1is selected from the group consisting of NR’, O, and S; X2is selected from the group consisting of CH2, NR’, O, and S; R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle; or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen.

[0018] In another aspect, there is provided use of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof

[0019]

[0020] Formula I;

[0021] wherein X1is selected from the group consisting of NR’, O, and S; X2is selected from the group consisting of CH2, NR’, O, and S; R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle; or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen; in the manufacture of a medicament for the treatment of Hypoxic-Ischemic Encephalopathy (HIE).

[0022] In a further aspect, there is provided a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0023]

[0024] Formula I;

[0025] wherein X1is selected from the group consisting of NR’, O, and S; X2is selected from the group consisting of CH2, NR’, O, and S; R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle; or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen; for use in treating Hypoxic-Ischemic Encephalopathy (HIE).

[0026] It will be appreciated that other aspects, embodiments, and examples of the compounds, pharmaceutical compositions, methods, or uses, are further described herein.

[0027] BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 shows the chemical structure of cG-2-AllylP (also known as “NNZ-2591”).

[0029] Figure 2 shows a graph of the results of cG-2-AllylP in an oxygen-glucose deprivation in vitro model.

[0030] Figure 3 shows a graph of the results of the effects of cG-2-AllylP in an excitotoxic in vitro model of neuronal cell death.

[0031] Figure 4 shows a graph of the results of the effects of cG-2-AllylP or vehicle in a rat model of hypoxic-ischemic brain injury.

[0032] Figure 5 shows a graph of the results of the effects of cG-2-AllylP on infarct size in rats following transient ischemia was induced by middle cerebral artery occlusion (MCAO) induced by endotholin-1.

[0033] Figure 6 shows a graph of the results of the effects of cG-2-AllylP on IGF-1 concentrations in ipsilateral brain at post-natal day 51 (P51).

[0034] Figure 7 shows a graph of the results of the effects of cG-2-AllylP on IGF-1 concentrations in ipsilateral brain at post-natal day 65 (P65).

[0035] Figure 8 shows a graph of the results of the effects of cG-2-AllylP on IL-1β and CXCL5 concentrations in brain tissue at post-natal day 51 (P51).

[0036] Figure 9 shows a graph of the results of the effects of cG-2-AllylP on additional neuroinflammatory markers in brain tissue at post-natal day 51 (P51). Figure 10 shows a graph of the results of the effects of cG-2-AllylP on righting reflex results at post-natal day 9 (P9).

[0037] DETAILED DESCRIPTION

[0038] General Definitions

[0039] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., chemistry, biochemistry, medicinal chemistry, microbiology and the like).

[0040] As used herein, the term “and / or”, e.g., “X and / or Y”, shall be understood to mean either " X and Y" or " X or Y" and shall be taken to provide explicit support for both meanings or for either meaning, e.g., A and / or B includes the options i) A, ii) B, or iii) A and B.

[0041] As used herein, the term “about”, unless stated to the contrary, refers to + / - 20%, typically + / - 10%, typically + / - 5%, of the designated value.

[0042] As used herein, the terms “a”, “an”, and “the” include both singular and plural aspects, unless the context clearly indicates otherwise.

[0043] It is to be appreciated that certain features that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

[0044] Throughout the present specification, various aspects and components of the invention can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 5, from 3 to 5 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, 5, 5.5 and 6, unless where integers are required or implicit from context. This applies regardless of the breadth of the disclosed range. Where specific values are required, these will be indicated in the specification. Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0045] The phrase “consisting of’ means the enumerated elements and no others.

[0046] The phrase “consisting essentially of’ means the enumerated elements and their equivalents.

[0047] It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents form part of the common general knowledge in the art in the United States, Australia, or in any other country.

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will prevail. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0049] As used herein, the term “subject” refers to any organism susceptible to a disease or condition. For example, the subject can be a mammal, primate, livestock (e.g., sheep, cow, horse, pig), companion animal (e.g., dog, cat), or laboratory animal (e.g., mouse, rabbit, rat, guinea pig, hamster). In one embodiment, the subject is a mammal. In one example, the subject is human. In one embodiment, the disease or condition is Hypoxic-Ischemic Encephalopathy (HIE).

[0050] As used herein, the term “treating” includes improving, alleviating, reducing, or eliminating one or more symptoms associated with a specific disorder or condition. In one embodiment, the disorder or condition is Hypoxic-Ischemic Encephalopathy (HIE). For example, as used herein, the phrase “treating Hypoxic-Ischemic Encephalopathy” includes improving, alleviating, reducing, or eliminating one or more symptoms associated with Hypoxic-Ischemic Encephalopathy (HIE). As used herein, the term “symptom” includes a finding. As used herein, the term “prevention” includes prophylaxis of the specific disorder or condition, or one or more symptoms associated with a specific disorder or condition. In one embodiment, the one or more symptoms is one or more symptoms associated with Hypoxic-Ischemic Encephalopathy (HIE). For example, as used herein, the phrase “preventing Hypoxic-Ischemic Encephalopathy” refers to preventing the onset or duration of one or more symptoms associated with Hypoxic-Ischemic Encephalopathy (HIE). In some embodiments, the phrase “preventing Hypoxic-Ischemic Encephalopathy” refers to slowing or halting the progression of one or more symptoms of Hypoxic-Ischemic Encephalopathy (HIE). Prevention may be absolute (such that there is no presentation of a particular symptom) or may be effective only in some individuals, to some extent, or for a limited amount of time.

[0051] The present disclosure relates to compounds of Formula I, and pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof.

[0052] Salts may be formed in the case of embodiments of the compound of Formula I which contain a suitable acidic or basic group. Suitable salts of the compound of Formula I include those formed with organic or inorganic acids or bases.

[0053] As used herein, the phrase “pharmaceutically acceptable salt” or a like term refers to pharmaceutically acceptable organic or inorganic salts. It will be appreciated that any reference to “salt” herein can include “pharmaceutically acceptable salts”. Exemplary acid addition salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Exemplary base addition salts include, but are not limited to, ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D-glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl -propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterion. It will also be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transport.

[0054] Those skilled in the art of organic and / or medicinal chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. As used herein, the phrase “pharmaceutically acceptable solvate” or “solvate” refer to an association of one or more solvent molecules and a compound of the present disclosure. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. It will be understood that the present disclosure encompasses solvated forms, including hydrates, of the compounds of Formula I and salts thereof.

[0055] The compounds of the present disclosure may contain chiral (asymmetric) centers or the molecule as a whole may be chiral. The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present disclosure.

[0056] As used herein, the term “stereoisomer” refers to compounds having the same molecular formula and sequence of bonded atoms (i.e., atom connectivity), though differ in the three-dimensional orientations of their atoms in space. As used herein, the term “enantiomers” refers to two compounds that are stereoisomers in that they are non-superimposable mirror images of one another. Relevant stereocenters may be denoted with (R)- or (S)- configuration.

[0057] Those skilled in the art of organic and / or medicinal chemistry will appreciate that the compounds of Formula I and salts thereof may be present in an amorphous form or in a crystalline form. It will be understood that the present disclosure encompasses all forms and polymorphs of the compounds of Formula I and salts thereof.

[0058] As used herein, the term “protecting group” has the meaning conventionally associated with it in organic synthesis / medicinal chemistry, i.e., a chemical group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete.

[0059] As would be understood by the person skilled in the art, a compound of Formula I, or any salt, solvate stereoisomer, or prodrug thereof would be administered in a therapeutically effective amount. The term “therapeutically effective amount”, as used herein, refers to a compound being administered in an amount sufficient to alleviate or prevent to some extent one or more of the symptoms of the disorder or condition being treated. The result can be the reduction and / or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system. In one embodiment, the term “therapeutically effective amount” refers to a compound of Formula I, or any salt thereof, being administered in an amount sufficient to treat and / or prevent one or more symptoms associated with Hypoxic-Ischemic Encephalopathy so as to provide a therapeutic outcome.

[0060] Implicit hydrogen atoms (such as the hydrogen atoms present on the pyrrole ring, etc.) are omitted from the formulae for clarity, but would be understood by the skilled person to be present.

[0061] As used herein, the term “halogen” means fluorine, chlorine, bromine, or iodine.

[0062] As used herein, the term “alkyl” encompasses both straight-chain (i.e., linear) and branched-chain hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl, and hexyl groups. In one example, the alkyl group is of one to six carbon atoms (i.e. C1-6alkyl).

[0063] As used herein, the term “haloalkyl” refers to an “alkyl” group substituted with one or more “halogen” groups according to any examples thereof as separately described above or herein.

[0064] As used herein, the term “alkenyl” refers to both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl groups. In one example, the alkenyl group is of two to six carbon atoms (i.e. C2-6alkenyl).

[0065] As used herein, the term “haloalkenyl” refers to an “alkenyl” group substituted with one or more “halogen” groups according to any examples thereof as separately described above or herein. As used herein, the term “alkynyl” refers to both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups. In one example, the alkynyl group is of two to six carbon atoms (i.e. C2-6alkynyl).

[0066] As used herein, the term “carbocyclyl”, “carbocycle”, “carbocyclic”, or like term, refers to an aromatic or non-aromatic cyclic group of carbon atoms. A carbocyclyl group may, for example, be monocyclic or polycyclic (i.e. bicyclic, tricyclic). A polycyclic carbocyclyl group may contain fused rings. In one example, the carbocyclyl group is of three to ten carbon atoms (i.e. C3-10carbocyclyl). In one example, the carbocyclyl group is of three to seven carbon atoms (i.e. C3-7carbocyclyl). Examples of monocyclic non-aromatic carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl groups. Examples of monocyclic saturated carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Aromatic carbocyclyl groups include phenyl and napthalenyl.

[0067] As used herein, the term “heterocyclyl” refers to an aromatic or non-aromatic cyclic group which is analogous to a carbocyclic group, but in which from one to three of the carbon atoms is / are replaced by one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. A heterocyclyl group may, for example, be monocyclic or polycyclic (e.g. bicyclic). A polycyclic heterocyclyl may for example contain fused rings. In a bicyclic heterocyclyl group there may be one or more heteroatoms in each ring, or heteroatoms only in one of the rings. A heteroatom may be N, O, or S. Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides. In one example, the heterocyclyl group is of three to ten atoms (i.e. 3-10-membered heterocyclyl). In one example, the heterocyclyl group is of three to seven atoms (i.e. 3-7-membered heterocyclyl). Examples of monocyclic non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl. Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, and benzoazepanyl. Examples of monocyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl groups) include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl. Examples of bicyclic aromatic heterocyclyl groups (also referred to as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxazole.

[0068] As used herein, the term “saturated” refers to a group where all available valence bonds of the backbone atoms are attached to other atoms Representative examples of saturated groups include, but are not limited to, butyl, cyclohexyl, piperidine, and the like.

[0069] As used herein, the term “substituted” refers to a group having one or more hydrogens or other atoms removed from a carbon or suitable heteroatom and replaced with a further group (i.e., substituent).

[0070] As used herein, the term “unsubstituted” refers to a group that does not have any further groups attached thereto or substituted therefore.

[0071] All documents cited or referenced herein, and all documents cited or referenced in herein cited documents, together with any manufacturer’s instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference in their entirety.

[0072] Compounds of Formula I

[0073] It has been surprisingly found that Compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, are useful in a method of treating Hypoxic-Ischaemic Encephalopathy (HIE) in a subject:

[0074]

[0075] Formula I.

[0076] In the above Formula I, X1is selected from the group consisting of NR’, O, and S. In one embodiment, X1is NR’. In one example, X1is NH. In one example, X1is O. In one example, X1is S.

[0077] In the above Formula I, X2is selected from the group consisting of CH2, NR’, O, and S. In one example, X2is CH2. In one embodiment, X2is NR’. In one example, X2is NH. In one example, X2is O. In one example, X2is S. In the above Formula I, R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle.

[0078] That is, in the above Formula I, R1is selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, 3-10-membered heterocycle. In one embodiment, R1is alkyl. In one embodiment, R1is C1-6alkyl. In one example, R1is CH3. In one embodiment, R1is alkenyl. In one embodiment, R1is C2-6alkenyl. In one example, R1is -CH2CHCH2.

[0079] In the above Formula I, R2is selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle. In one example, R2is hydrogen. In one embodiment, R2is alkyl. In one embodiment, R2is C1-6-alkyl. In one example, R2is CH3.

[0080] In the above Formula I, R3is selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle. In one example, R3is hydrogen. In one embodiment, R3is alkyl. In one embodiment, R3is C1-6-alkyl. In one example, R3is CH3.

[0081] In the above Formula I, R4is selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle. In one example, R4is hydrogen.

[0082] In the above Formula I, R5is selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle. In one example, R5is hydrogen.

[0083] In the above Formula I, in one embodiment, R4and R5taken together are -CH2-(CH2)n-CH2-, where n is 0, 1, 2, 3, 4, 5, or 6. In one example, R4and R5taken together are -CH2-(CH2)2-CH2-. That is, in one example, n is 2. In one example, R4and R5taken together are -CH2-(CH2)3-CH2-. That is, in one example, n is 3. In one example, R4and R5are both hydrogen. In the above Formula I, each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle. In one example, R’ is hydrogen, alkyl, or alkenyl. In one example, R’ is hydrogen.

[0084] In the above Formula I, when R1is CH3 and R2is hydrogen, and R3is hydrogen and R4is hydrogen, then R5is not benzyl. In the above Formula I, when R1is hydrogen, then at least one of R2and R3is not hydrogen.

[0085] It will be appreciated that any one or more of the above aspects, embodiments and examples may be combined with each other to provide any one or more further specific embodiments and examples. For example, in the above Formula I: R1is alkyl or alkenyl; R2is hydrogen; R3is hydrogen; R4and R5are each hydrogen or taken together are C3-10carbocycle; X1is NH; X2is CH2; wherein each alkyl, alkenyl, and C3-10carbocycle, is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, haloalkyl, alkenyl, and haloalkenyl; and wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, and alkenyl. In a further example, R1is C1-6alkyl (e.g. -CH3) or C2-6alkenyl (e.g. -CH2-CH=CH2). In a further example, R4and R5taken together are a monocyclic saturated C3-10carbocycle, which can be substituted or unsubstituted as defined above or herein. The unsubstituted or substituted monocyclic saturated C3-10carbocycle may be an unsubstituted or substituted cyclopentyl or cyclohexyl group. In another example, the C3-10carbocycle is substituted with one or more substituents selected from the group consisting of halogen, OH, -NO2, -NH2, -CN, -C(O)H, -C(O)OH, -C(O)NH2, alkyl, haloalkyl, alkenyl, and haloalkenyl.

[0086] In one example, the compound of Formula I is selected from the group consisting of:

[0087]

[0088] In one example, the compound of Formula I is:

[0089]

[0090] “Cyclic Glycyl-2-Allyl Proline” or “Cyclic G-2-AllylP” or “NNZ-2591” Formula la.

[0091] That is, in one example, in the compound of Formula I, X1is NH; X2is CH2; R1is -CH2CHCH2; and R2, R3, R4, and R5are each hydrogen.

[0092] In one example, the compound of Formula I is:

[0093]

[0094] “Cyclic cyclopentyl-G-2-MeP”

[0095] Formula Ib.

[0096] That is, in one example, in the compound of Formula I, X1is NH; X2is CH2; R1is CH3; R2and R3are each hydrogen; and R4and R5taken together are -CH2-(CH2)2-CH2-.

[0097] In one example, the compound of Formula I is:

[0098]

[0099] “Cyclic cyclohexyl-G-2-MeP”

[0100] Formula Ic.

[0101] That is, in one example, in the compound of Formula I, X1is NH; X2is CH2; R1is CH3; R2and R3are each hydrogen; and R4and R5taken together are -CH2-(CH2)3-CH2-. Accordingly, in one example, the compound of Formula I is selected from the group consisting of cG-2-AllylP (Formula la), Cyclic Cyclopentyl-G-2-MeP (Formula lb), and Cyclic Cyclohexyl-G-2-MeP (Formula Ic), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0102] Solvates and Hydrates

[0103] It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compound of Formula I. Those skilled in the art of organic chemistry and / or medicinal chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallised. Such complexes are referred to as “solvates”, and as used herein, the term “solvate” refers to such a complex of solute (e.g., a compound, salt of a compound) and solvent. Examples of solvents that may form pharmaceutically acceptable solvates include, but are not limited to, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine. If the solvate is water, the solvate may be conventionally referred to as a “hydrate”. In some embodiments, the pharmaceutically acceptable solvate is a pharmaceutically acceptable hydrate. The hydrate may be, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. Unless otherwise specified herein, reference to a compound of Formula I also includes solvates thereof.

[0104] Prodrugs

[0105] It may be convenient or desirable to prepare, purify, and / or handle the compound in the form of a prodrug. The term “prodrug”, as used herein, pertains to compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.

[0106] Also, as would be understood by a person skilled in the art of organic chemistry and / or medicinal chemistry, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

[0107] Methods of Treatment

[0108] In some embodiments, there is provided a method of treating Hypoxic-Ischemic Encephalopathy (HIE) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0109]

[0110] >5

[0111] Formula I;

[0112] wherein:

[0113] X1is selected from the group consisting of NR’, O, and S;

[0114] X2is selected from the group consisting of CH2, NR’, O, and S;

[0115] R1, R2, R3, R4, and R5are independently selected from the group consisting of -H, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, -alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,

[0116] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl;

[0117] wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;

[0118] or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6. In some embodiments, there is provided a proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen.

[0119] It will be appreciated that treating Hypoxic-Ischemic Encephalopathy (HIE) may include treating (e.g., reducing or alleviating) one or more symptoms associated with Hypoxic- Ischaemic Encephalopathy (HIE). In one example, the method of treatment provides treating a symptom associated with Hypoxic-Ischemic Encephalopathy (HIE). It will be appreciated that treating a symptom associated with Hypoxic-Ischaemic Encephalopathy (HIE) includes preventing and / or reducing the likelihood of occurrence of that symptom, and / or reducing the severity of that symptom.

[0120] Accordingly, in some embodiments, there is provided a method of treating a symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0121] R1

[0122]

[0123] >5

[0124] Formula I;

[0125] wherein:

[0126] X1is selected from the group consisting of NR’, O, and S;

[0127] X2is selected from the group consisting of CH2, NR’, O, and S;

[0128] R1, R2, R3, R4, and R5are independently selected from the group consisting of -H, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, -alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,

[0129] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl;

[0130] wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;

[0131] or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6. Numerous symptoms, or findings, may be associated with Hypoxic-Ischemic Encephalopathy (HIE). In some embodiments, the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is selected from the group consisting of altered level of consciousness, abnormal blood pressure, low heart rate, abnormal heart rate, heart problems, cardiac arrest, cardiorespiratory changes, bradycardia, respiratory disturbance, periodic breathing, respiratory failure, breathing problems, apnoea, birth asphyxia, poor peripheral perfusion, too much acid in body fluids (acidosis), seizures or unusual movements, epilepsy, meconium staining, low muscle tone (hypotonia), tense muscles (hypertonia), blue, pale or grey skin, fingers or lips (cyanosis), low or poor reflexes, absence of reflexes such as sucking, swallowing or grasping, weak cry, irritability, perinatal encephalopathy, perinatal asphyxia, neonatal encephalopathy, periventricular leukomalacia, cystic encephalomalacia, static encephalopathy, cerebral palsy, unusual eye motion or dilation, hearing loss, unreactive to sights or sounds, and difficulty feeding.

[0132] The symptom associated with Hypoxic-Ischaemic Encephalopathy (HIE) may be a somatic symptom (i.e., a symptom relating to the patient’s body), or otherwise an intellectual and / or neuropsychiatric symptom (i.e., a symptom relating to the patient’s mind). In one example, the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is a somatic symptom. In one example, the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is an intellectual and / or neuropsychiatric symptom.

[0133] Examples of somatic symptoms include, but are not limited to, altered level of consciousness, abnormal blood pressure, low heart rate, abnormal heart rate, heart problems, cardiac arrest, cardiorespiratory changes, bradycardia, respiratory disturbance, periodic breathing, respiratory failure, breathing problems, apnoea, birth asphyxia, poor peripheral perfusion, too much acid in body fluids (acidosis), seizures or unusual movements, epilepsy, meconium staining, low muscle tone (hypotonia), tense muscles (hypertonia), blue, pale or grey skin, fingers or lips (cyanosis), low or poor reflexes, absence of reflexes such as sucking, swallowing or grasping, weak cry, irritability, perinatal encephalopathy, perinatal asphyxia, neonatal encephalopathy, periventricular leukomalacia, cystic encephalomalacia, static encephalopathy, cerebral palsy, unusual eye motion or dilation, hearing loss, unreactive to sights or sounds, and difficulty feeding. Accordingly, in some embodiments, there is provided a method of treating a symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as described herein, wherein the symptom is selected from the group consisting of altered level of consciousness, abnormal blood pressure, low heart rate, abnormal heart rate, heart problems, cardiac arrest, cardiorespiratory changes, bradycardia, respiratory disturbance, periodic breathing, respiratory failure, breathing problems, apnoea, birth asphyxia, poor peripheral perfusion, too much acid in body fluids (acidosis), seizures or unusual movements, epilepsy, meconium staining, low muscle tone (hypotonia), tense muscles (hypertonia), blue, pale or grey skin, fingers or lips (cyanosis), low or poor reflexes, absence of reflexes such as sucking, swallowing or grasping, weak cry, irritability, perinatal encephalopathy, perinatal asphyxia, neonatal encephalopathy, periventricular leukomalacia, cystic encephalomalacia, static encephalopathy, cerebral palsy, unusual eye motion or dilation, hearing loss, unreactive to sights or sounds, and difficulty feeding. In one example, the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is respiratory disturbance (i.e., the method of treatment described herein provides a reduction in breathing difficulty associated with HIE). It will be appreciated that respiratory disturbances may encompass periodic breathing, respiratory failure, apnoea, and other breathing problems. In one example, the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is seizures (e.g., the method of treatment described herein provides a reduction in seizures associated with HIE). This reduction in seizures may be a reduction in severity and / or frequency. Accordingly, in one example, the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is seizures, and the method of treatment described herein provides a reduction in seizure severity and / or frequency. In one example, the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is low muscle tone (hypotonia) (e.g., the method of treatment described herein provides a reduction in low muscle tone (hypotonia) associated with HIE). In one example, the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is static encephalopathy.

[0134] Examples of intellectual and / or neuropsychiatric symptoms include, but are not limited to, mild to severe intellectual disabilities, mild to severe learning disabilities, cognitive impairment, neurobehavioural disorders, aberrant behaviour, attention-deficit / hyperactivity disorder, difficulty paying attention, impairment of executive function, autism spectrum disorder (ASD) or autism-like behaviours, and absent or impaired verbal or nonverbal communication. Accordingly, in some embodiments, there is provided a method of treating a symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as described herein, wherein the symptom is selected from the group consisting of mild to severe intellectual disabilities, mild to severe learning disabilities, cognitive impairment, neurob ehavioural disorders, aberrant behaviour, attention-deficit / hyperactivity disorder, difficulty paying attention, autism spectrum disorder (ASD) or autism-like behaviours, and absent or impaired verbal or nonverbal communication.

[0135] In some embodiments, a method of treating Hypoxic-Ischemic Encephalopathy (HIE) may be an improvement in a clinical outcome. Such clinical outcomes may include, for example, improved somatosensory motor function, long-term histological outcome, and reduced caspase-3 -mediated apoptosis. In one example, the method described herein provides improved somatosensory motor function. In one example, the method described herein provides improved long-term histological outcome. In one example, the method described herein provides reduced caspase-3 -mediated apoptosis.

[0136] It will be appreciated that a symptom of Hypoxic-Ischemic Encephalopathy (HIE) is infarction. Infarction describes the death of tissue that results from a failure of blood supply (i.e., during hypoxic ischemia). The resultant dead tissue is referred to as infarct, which may result in cystic encephalomalacia. Accordingly, in some embodiments, the method of treating Hypoxic-Ischemic Encephalopathy (HIE) results in reduced infarct or cystic encephalomalacia. In some embodiments, the method of treating Hypoxic-Ischemic Encephalopathy (HIE) results in reduced infarct of brain tissue. In some embodiments, the method of treating Hypoxic-Ischemic Encephalopathy (HIE) results in reduced cystic encephalomalacia.

[0137] Accordingly, in some embodiments, there is provided a method of treating a symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0138]

[0139] Formula I;

[0140] wherein:

[0141] X1is selected from the group consisting of NR’, O, and S;

[0142] X2is selected from the group consisting of CH2, NR’, O, and S;

[0143] R1, R2, R3, R4, and R5are independently selected from the group consisting of -H, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, -alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,

[0144] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl;

[0145] wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;

[0146] or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; wherein the symptom is infarct.

[0147] In some embodiments, Hypoxic-Ischemic Encephalopathy (HIE) is diagnosed and / or assessed using one or more clinical tests selected from the group consisting of APGAR score, Umbilical Artery (UA) pH, Base Excess (BE) pH, need for resuscitation and assisted ventilation, brain MRI, brain MRS (magnetic resonance spectrometry), electrocardiogram (ECG), electroencephalogram (EEG), cardiac echo, cranial ultrasound, arterial blood gas measurement, chest Xray, urinary output, hemoglobin, hematocrit, glucose, audiometry, visual evoked potential (VEP), auditory evoked potential (AEP), genetic testing, IGF-1 in serum (Total IGF-1, Free IGF-1, Bound [to IGFBPs] IGF-1); IGF-1 in cerebral spinal fluid (CSF) (Total IGF-1, Free IGF-1), IGFBPs in serum, (IGFBP-1, -2, -3, -4, -5, -6) in serum, IGFBPs in CSF, (IGFBP-1, -2, -3, -4, -5, -6) in CSF, lactate dehydrogenase (LDH), troponin-T, creatine phosphokinase (CK), serum interleukin (IL)-10, and the urine lactate / creatinine (L / C) ratio, S100B, pNF-H (Phosphorylated axonal forms of neurofilament H), and serum biomarkers of brain injury including: Neuron-Specific Biomarkers (e.g., Neuron-Specific Enolase (NSE), Ubiquitin Carb oxy -Terminal Hydrolase LI (UCH-L1), Tau protein, αII-Spectrin breakdown products (SBDP); Glial Cell Biomarkers (e.g., Glial Fibrillary Acidic Protein (GFAP), S100 Calcium-Binding Protein B (S100B), Myelin Basic Protein (MBP), Neurofilament Light Chain (NfL)); Inflammatory Biomarkers (e.g., Interleukin-6 (IL-6), Interleukin-8 (IL-8), C-Reactive Protein (CRP), Proinflammatory Cytokines); Oxidative Stress Biomarkers (e.g., Malondialdehyde (MDA), Glutathione (GSH), Superoxide Dismutase (SOD), Isoprostanes); Metabolic Biomarkers (e.g., Lactate, Glucose, Pyruvate, Amino Acids such as glutamate, and aspartate).

[0148] In some embodiments, the severity of the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is assessed using one or more clinical tests selected from the group consisting of Sarnat score, SIBEN system, the Clinical Global Impression of Severity (CGI-S), the Clinical Global Impression of Change (CGI-I), the Caregiver Global Impression of Change (CaGI-I), the Aberrant Behavior Checklist (ABC) and ABC Subscales, the Social Responsiveness Scale, the Repetitive Behavior Scale - Revised (RBS-R), Bayley Scales of Infant Development, Vineland Adaptive Behavior Scale, Mullen Scales of Early Learning, DSM-V criteria for ASD, Autism Diagnostic Observation Schedule (ADOS-2), Macarthur Bates Communicative Development Inventory, General Movement Assessment (GAM), Hammersmith Infant Neurological Examination (HINE), Gross Motor Function Classification System (GMFCS), Child Behavior Checklist (CBCL), and Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA).

[0149] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE) is diagnosed and / or assessed by determining the level(s) of one or more clinically relevant markers (e.g., biomarkers). It will be appreciated that any one or more of multiple biomarkers may be indicative of Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom, thereof. Such biomarkers include, for example, serum-based biomarkers and cell-based biomarkers. In some embodiments, the biomarker is selected from the group consisting of IGF-1, IL-1 beta, ENA-78 (CXCL5), IL- 10, IL-2, M-CSF, IP- 10 (CXCL10), IL-23, MIP-1 alpha, MCP-3, Eotaxin (CCL11), and IL-28.

[0150] In some embodiments, the method of treatment, as described herein, provides an improvement in one or more biomarkers selected from the group consisting of IGF-1, IL-1 beta, ENA-78 (CXCL5), IL-10, IL-2, M-CSF, IP-10 (CXCL10), IL-23, MIP-1 alpha, MCP-3, Eotaxin (CCL11), and IL-28. In some embodiments, the method of treatment, as described herein, provides an improvement in IGF-1 levels. In some embodiments, the method of treatment, as described herein, provides an improvement in IL-1 beta levels. In some embodiments, the method of treatment, as described herein, provides an improvement in ENA-78 (CXCL5) levels. In some embodiments, the method of treatment, as described herein, provides an improvement in IL- 10 levels. In some embodiments, the method of treatment, as described herein, provides an improvement in IL-2 levels. In some embodiments, the method of treatment, as described herein, provides an improvement in M-CSF levels. In some embodiments, the method of treatment, as described herein, provides an improvement in IP- 10 (CXCL10) levels. In some embodiments, the method of treatment, as described herein, provides an improvement in IL-23 levels. In some embodiments, the method of treatment, as described herein, provides an improvement in MIP-1 alpha levels. In some embodiments, the method of treatment, as described herein, provides an improvement in MCP-3 levels. In some embodiments, the method of treatment, as described herein, provides an improvement in Eotaxin (CCL11) levels. In some embodiments, the method of treatment, as described herein, provides an improvement in IL-28 levels. The biomarker level may be assessed at any suitable time-point following administration of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in accordance with the method of treatment described herein. In one example, the biomarker level is measured a post-natal day 51. In one example, the biomarker level is measured ay post-natal day 65. When a comparison in biomarker level is made to a non-treated subject, in one example, the comparison is made following the same time period following treatment (e.g., both subjects are assessed on postnatal day 51).

[0151] Protein biomarker levels may be measured according to any suitable means that would be understood by the person skilled in the art.

[0152] It will be appreciated that, in this context, an “improvement” refers to a shift, be it an increase or decrease, in the biomarker level toward a more normal (i.e., non-Hypoxic-Ischaemic Encephalopathy) level. For example, toward a level of a healthy subject, or for example, toward a level indicative of reduced symptoms of Hypoxic-Ischaemic Encephalopathy.

[0153] It will also be appreciated that, as used in this context, “non-treated subject” will be taken to refer to a subject diagnosed with Hypoxic-Ischaemic Encephalopathy by any suitable means, and which has not been treated with a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. It will be appreciated that a non- treated subject may have been treated with means other than a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, such as, for example, hypothermia.

[0154] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of IGF-1 (insulin-like growth factor 1) protein. It is proposed that levels of IGF-1 protein, also referred to as insulin-like growth factor 1, are reduced in brain tissue as a result of brain injury - this is postulated to be a protective response to the brain injury. Accordingly, in some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE) may be diagnosed and / or assessed by the detection of reduced IGF-1 protein levels in a subject. It has been surprisingly found that the method of treatment, as described herein, may provide an elevation in IGF-1 protein levels in subjects diagnosed with Hypoxic-Ischaemic Encephalopathy (HIE). In some embodiments, the method of treatment, as described herein, provides an elevation in IGF-1 protein levels, when compared to the equivalent non-treated subject.

[0155] In some embodiments, the method of treatment, as described herein, provides an elevation in IGF-1 protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides an elevation in IGF-1 protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides an elevation in IGF-1 protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0156] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of IL-1 beta protein. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-1 beta protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-1 beta protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-1 beta protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-1 beta protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0157] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of ENA-78 (CXCL5) protein. In some embodiments, the method of treatment, as described herein, provides a reduction in ENA-78 (CXCL5) protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in ENA-78 (CXCL5) protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in ENA-78 (CXCL5) protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in ENA-78 (CXCL5) protein levels in the subj ect of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0158] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of IL-10 protein. In some embodiments, the method of treatment, as described herein, provides a reduction in IL- 10 protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL- 10 protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL- 10 protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL- 10 protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0159] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of IL-2 protein. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-2 protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-2 protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-2 protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-2 protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0160] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of M-CSF protein. In some embodiments, the method of treatment, as described herein, provides a reduction in M-CSF protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in M-CSF protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in M-CSF protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in M-CSF protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non -treated subject.

[0161] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of IP-10 (CXCL10) protein. In some embodiments, the method of treatment, as described herein, provides a reduction in IP- 10 (CXCL10) protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IP- 10 (CXCL10) protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IP- 10 (CXCL10) protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IP-10 (CXCL10) protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0162] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of IL-23 protein. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-23 protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-23 protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-23 protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-23 protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0163] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of MIP-1 alpha protein. In some embodiments, the method of treatment, as described herein, provides a reduction in MIP-1 alpha protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in MIP-1 alpha protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in MIP-1 alpha protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in MIP-1 alpha protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0164] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of MCP-3 protein. In some embodiments, the method of treatment, as described herein, provides a reduction in MCP-3 protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in MCP-3 protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in MCP-3 protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in MCP-3 protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject. In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of Eotaxin (CCL11) protein. In some embodiments, the method of treatment, as described herein, provides a reduction in Eotaxin (CCL11) protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in Eotaxin (CCL11) protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in Eotaxin (CCL11) protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in Eotaxin (CCL11) protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0165] In some embodiments, Hypoxic-Ischaemic Encephalopathy (HIE), or a symptom thereof, is diagnosed and / or assessed by measurement of IL-28 protein. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-28 protein levels, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-28 protein levels in the subject of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-28 protein levels in the subject of between about 1% and about 60%, between about 2% and about 50%, between about 5% and about 40%, or between about 10% and about 30%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in IL-28 protein levels in the subject of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0166] Other markers that may be useful in the diagnosis and / or assessment of Hypoxic-Ischaemic Encephalopathy include, but are not limited to, neuroimaging markers, such as magnetic resonance imaging (MRI) (to undertake, for example, conventional MRI, diffusion-weighted imaging, magnetic resonance spectroscopy) and near-infrared spectroscopy (NIRS) (to undertake, for example, lactate / N-acetylaspartate (Lac / NAA) ratio, and other metabolites such as choline, creatine, and myo-inositol). Other markers may also include electrophysiologic markers, such as amplitude-integrated electroencephalography (aEEG), assessment of seizures, conventional EEG, and visual evoked potential (VEPs). Other markers may also include physiological markers, such as, for example, head circumference.

[0167] In some embodiments, the method of treatment, as described herein, provides an improvement in righting reflex of the subject. It will be appreciated that the “righting reflex” is a primitive reflex that may be assessed as a measure of early neuromotor development. The righting reflex is typically measured in time (i.e., seconds) for the subject to right itself. In some embodiments, the method of treatment, as described herein, provides a reduction in righting reflex time of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, when compared to the equivalent non -treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in righting reflex time of between about 5% and about 80%, between about 10% and about 50%, or between about 20% and about 40%, when compared to the equivalent non -treated subject. In some embodiments, the method of treatment, as described herein, provides a reduction in righting reflex time of about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, when compared to the equivalent non-treated subject.

[0168] In some embodiments, the method of treatment, as described herein, provides a reduction in OGD-driven cytotoxicity. ODG cytotoxicity, or “oxygen-glucose deprivation cytotoxicity”, refers to brain injury that results due to brain tissues being deprived of oxygenglucose. It will be appreciated that such cytotoxicity may be observed in Hypoxic-Ischaemic Encephalopathy (HIE). In some embodiments, the method of treatment, as described herein, provides a reduction in OGD-driven cytotoxicity of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, or at least about 40%, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment, as described herein, provides a dose-dependent reduction in OGD-driven cytotoxicity. In some embodiments, the method of treatment, as described herein, provides an increase in burst spike number, when compared to the equivalent non-treated subject. In some embodiments, the method of treatment as described herein, provides an improvement in any one or more of somatosensory motor function, long-term histological outcome, caspase-3 -mediated apoptosis, microglial activation, and volume of resulting infarct, when compared to the equivalent non-treated subject.

[0169] In some embodiments, there is provided a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0170]

[0171] i5

[0172] Formula I;

[0173] wherein:

[0174] X1is selected from the group consisting of NR’, O, and S;

[0175] X2is selected from the group consisting of CH2, NR’, O, and S;

[0176] R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,

[0177] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl;

[0178] wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;

[0179] or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen;

[0180] in the manufacture of a medicament for the treatment of Hypoxic-Ischemic Encephalopathy (HIE).

[0181] In some embodiments, there is provided a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0182] R1

[0183]

[0184] ,5

[0185] Formula I;

[0186] wherein:

[0187] X1is selected from the group consisting of NR’, O, and S;

[0188] X2is selected from the group consisting of CH2, NR’, O, and S;

[0189] R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,

[0190] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl;

[0191] wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;

[0192] or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen;

[0193] for use in treating Hypoxic-Ischemic Encephalopathy (HIE).

[0194] In some embodiments, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0195]

[0196] Formula I;

[0197] wherein:

[0198] X1is selected from the group consisting of NR’, O, and S;

[0199] X2is selected from the group consisting of CH2, NR’, O, and S;

[0200] R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,

[0201] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl;

[0202] wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;

[0203] or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen;

[0204] in the treatment of Hypoxic-Ischemic Encephalopathy (HIE).

[0205] Pharmaceutical Compositions

[0206] In some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in the form of a pharmaceutical composition.

[0207] In some embodiments, the pharmaceutical composition comprises the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of diluents, solvents, pH buffers, binders, carriers, additives, adjuvants, microemulsions, coarse emulsions, liquid crystals, fillers, emulsifiers, disintegrants, polymers, lubricants, oils, fats, waxes, coatings, viscosity -modifying agents, glidants, palatability agents, flavouring agents, and the like. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in the form of a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0208] Diluents may include one or more of microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, and the like. Binders may include one or more of povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like. Disintegrants may include one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like. Solvents may include one or more of ethanol, methanol, isopropanol, chloroform, acetone, methylethyl ketone, methylene chloride, water and the like. Lubricants may include one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like. A glidant may be one or more of colloidal silicon dioxide, talc or cornstarch and the like. Buffers may include phosphate buffers, borate buffers and carbonate buffers, although without limitation thereto. Fillers may include one or more gels inclusive of gelatin, starch and synthetic polymer gels, although without limitation thereto. Coatings may comprise one or more of film formers, solvents, plasticizers and the like. Suitable film formers may be one or more of hydroxypropyl methyl cellulose, methyl hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, polyethylene glycol, acrylates and the like. Suitable solvents may be one or more of water, ethanol, methanol, isopropanol, chloroform, acetone, methylethyl ketone, methylene chloride and the like. Plasticizers may be one or more of propylene glycol, castor oil, glycerin, polyethylene glycol, polysorbates, and the like.

[0209] Reference is made to the Handbook of Pharmaceutical Excipients 9th Edition, Eds. Sheskey, Hancock, Moss & Goldfarb (2020), which provides non-limiting examples of excipients which may be useful according to the present disclosure. Other pharmaceutical excipients and / or additives suitable for use in the compositions according to the present disclosure are listed in " Remington: The Science & Practice of Pharmacy", 23rdEdition, Ed. Adejare (2020), and in the " Prescribers’ Digital Reference", at www.pdr.net (2021, and in " Handbook of Pharmaceutical Excipients", Third Ed., Ed. A. H. Kibbe, Pharmaceutical Press, 2000.

[0210] It will be appreciated that the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be formulated in a pharmaceutical composition so as to facilitate administration and / or dosage. By way of example only, the composition may be in the form of a tablet, capsule, caplet, powder, an oral solution or suspension, a powder for preparing an oral solution or suspension, an injectable liquid, a suppository, a slow-release formulation, an osmotic pump formulation, intranasal formulation, or any other form that is effective and safe for administration.

[0211] Examples of pharmaceutical formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, and intraarticular), inhalation (including fine particle dusts or mists that may be generated by means of various types of metered dose pressurised aerosols), nebulisers or insufflators, rectal, intraperitoneal, intranasal, and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient. In one example, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered orally.

[0212] The pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, into association with the excipient that constitutes one or more necessary ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

[0213] In one example, in the method described herein, the pharmaceutical composition is formulated for oral administration. In some embodiments, pharmaceutical compositions of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, sachets, pills, tablets, dissolving tablets, orally disintegrating tablets, lozenges, or thin films for dissolution in the mouth, each containing a predetermined amount of the active ingredient; as a powder, effervescent powders or granules; as a solution or a suspension in an aqueous liquid or non-aqueous liquid, for example as elixirs, tinctures, suspensions or syrups / solutions; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, in the method described herein, the pharmaceutical composition is formulated as an oral solution, an oral suspension, as a powder for preparing an oral solution or oral suspension, or as a syrup / solution. In one example, the pharmaceutical composition is formulated as an oral solution. In one example, the pharmaceutical composition is formulated as an oral suspension. In one example, the pharmaceutical composition is formulated as a powder for preparing an oral solution or oral suspension. In one example, the pharmaceutical composition is formulated as a syrup / solution.

[0214] In one example, the pharmaceutical composition is an aqueous solution. Accordingly, in some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in the form of a pharmaceutical composition, wherein the pharmaceutical composition is an aqueous solution. In some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered orally to the subject in the form of a pharmaceutical composition, wherein the pharmaceutical composition is an aqueous solution.

[0215] A compound of Formula I, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, may also be presented as a bolus, electuary, or paste. In one example, a compound of Formula I, a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered as an oral tablet. In one example, a compound of Formula I, a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered as an oral capsule. A tablet may be made, for example, by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active, or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally coated or scored, and may be formulated so as to provide slow or controlled release of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. The compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising a compound of Formula I, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. A compound of Formula I, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, may also be administered liposomally.

[0216] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavouring agents and / or palatability agents.

[0217] As used herein, the term ‘flavouring agent’ will be taken to mean a pharmacologically inactive substance capable of improving the taste and / or odour of a composition. A flavouring agent will be understood to change the perceptual impression of a composition, determined primarily by the chemoreceptors of the gustatory and olfactory systems. A flavouring agent may be a ‘natural flavouring agent’ (i.e., found in nature, not made by man), a ‘nature-identical flavouring’ (i.e., a human-made substance or substances that are chemically identical to a substance found in nature), or an ‘artificial flavouring’ (i.e., synthesised from chemical substances made by man and not found in nature). In one example, the flavouring agent is a natural flavouring agent. In one example, the flavouring agent is a nature-identical flavouring agent. In one example, the flavouring agent is an artificial flavouring agent. In some embodiments, the flavouring agent is a ‘flavour enhancer’. As used herein, the term ‘flavour enhancer’ will be taken to mean a substance capable of intensifying the taste or odour of a composition. Typically, flavour enhancers are of umami taste. In one example, the flavouring agent is a flavour enhancer. The flavouring agent(s) may be employed individually or as a mixture thereof.

[0218] As used herein, the term ‘palatability agent’ will be taken to mean a substance capable of making a drug, food, or drink more agreeable to the palate. Specifically, ‘palatability agent’ is used herein to mean a substance or combination of substances capable of making an oral composition more agreeable to the palate. It will be understood that palatability can include one or more characteristics, such as taste, odour, appearance, texture, temperature, sound, and trigeminal senses. In one example, palatability, as used herein, refers to taste. In one example, palatability, as used herein, refers to odour. In one example, palatability, as used herein, refers to a combination of taste and odour.

[0219] Accordingly, in some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is formulated as an aqueous oral solution comprising a flavouring agent and / or palatability agent.

[0220] The oral pharmaceutical composition may be administered via any suitable oral administration method, as would be understood by the person skilled in the art. In one example, the oral composition is administered via the mouth. In one example, the oral composition is administered via a gastronomy tube (G-tube). A gastronomy tube will be inserted through the belly of a subject, such that the contents of the oral composition are delivered directly to the stomach of the subject. In one example, the oral composition is administered via a gastrojejunostomy tube (GJ-tube). A gastrojejunostomy tube will be inserted through the belly of a subject and into the small intestine, such that the contents of the oral composition are delivered directly to the small intestine of the subject. In one example, the oral composition is administered via a nasogastric tube (NG-tube). A nasogastric tube will be inserted into the nose of a subject, through the oesophagus, and into the stomach, such that the contents of the oral composition are delivered directly to the stomach of the subject.

[0221] When the oral composition is provided as a syrup / solution, including as an aqueous syrup / solution, the amount of each component of the composition may be defined as a concentration.

[0222] In some embodiments, the oral composition is provided as a syrup / solution, and the concentration (mg / mL) of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 2 mg / mL and about 500 mg / mL, about 10 mg / mL and about 100 mg / mL, about 25 mg / mL and about 75 mg / mL, or about 45 mg / mL and about 55 mg / mL. In some embodiments, the oral composition is provided as a syrup / solution, and the concentration (mg / mL) of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is at least about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, or about 200 mg / mL. In some embodiments, the oral composition is provided as a syrup / solution, and the concentration (mg / mL) of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is less than about 500 mg / mL, about 300 mg / mL, about 200 mg / mL, about 100 mg / mL, about 75 mg / mL, or about 50 mg / mL. In some embodiments, the oral composition is provided as a syrup / solution, and the concentration (mg / mL) of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is about 5 mg / mL, about 10 mg / mL, about 25 mg / mL, about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, about 150 mg / mL, or about 200 mg / mL.

[0223] Dosage and Administration

[0224] It will be appreciated that, in the method of treatment described herein, a compound of Formula I may be administered at a suitable time so as to maximise its efficacy in the treatment of Hypoxic-Ischaemic Encephalopathy (HIE). The amount of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, that is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject being treated, and the renal and hepatic function of the subject, and the particular condition, disorder or disease being treated, as well as its severity. An ordinary skilled physician or clinician can readily determine and prescribe the effective amount of the drug required to prevent or treat the condition, disorder or disease.

[0225] Dosages

[0226] Dosages of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in the method described herein, may range between, for example, about 0.01 mg per kg of body weight (mg / kg) to about 1000 mg / kg. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 0.01 and 1000, 0.1 and 500, 0.1 and 200, 1 and 200, 1 and 50, 1 and 25, or 1 and 12.5 mg / kg. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 0.01 and 1000 mg / kg. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 0.1 and 200 mg / kg. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 1 and 200 mg / kg. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 1 and 50 mg / kg. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 1 and 25 mg / kg. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 1 and 12.5 mg / kg. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is greater than about 0.01, 0.1, 1, 10, 20, 50, 75, 100, 500, or 1000 mg / kg. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is less than about 5000, 1000, 75, 50, 20, 10, 1, or 0.1 mg / kg.

[0227] In some embodiments, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in an amount effective to deliver a total daily dosage of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, of between about 0.01 and about 1000 mg / kg, about 0.1 mg / kg and about 500 mg / kg, about 0.1 mg / kg and about 200 mg / kg, about 1 mg / kg and about 200 mg / kg, about 1 mg / kg and about 50 mg / kg, or about 2 mg / kg and about 25 mg / kg.

[0228] In some embodiments, the dosage of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in an amount effective to deliver a total daily dosage of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, of about 1 mg / kg, about 2 mg / kg, about 4 mg / kg, about 8 mg / kg, about 12 mg / kg, about 14 mg / kg, about 16 mg / kg, about 18 mg / kg, about 20 mg / kg, about 22 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 28 mg / kg, about 30 mg / kg, about 40 mg / kg, or about 50 mg / kg.

[0229] In one example, an oral composition comprising a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in an amount effective to deliver a starting dosage of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, of about 4 mg / kg, about 6 mg / kg, about 8 mg / kg, about 10 mg / kg, or about 12 mg / kg.

[0230] Administration

[0231] A compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may for example be administered as a single daily dose, or otherwise the total daily dosage may be administered in divided doses of two, three, or four times daily. In one example, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be dosed less frequently than once per day, for example once per two days, three days, four days, five days, six days, or once per week.

[0232] Accordingly, in some embodiments, dosages of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in the method described herein, may range between, for example, about 0.01 mg per kg of body weight per day (mg / kg / day) to about and including 1000 mg / kg / day. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 0.01 and including 1000, between 0.1 and including 500, between 0.1 and including 200, between 1 and including 200 mg / kg / day, between 1 and including 50 mg / kg / day, or between 2 and including 25 mg / kg / day. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 1 and including 50 mg / kg / day. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is between about 2 and including 25 mg / kg / day. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is greater than about 0.01, 0.1, 1, 10, 20, 50, 75, 100, 500, or 1000 mg / kg / day. In one example, the dosage of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is less than about 5000, 1000, 75, 50, 20, 10, 1, or 0.1 mg / kg / day.

[0233] In some embodiments, the dosage of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in an amount effective to deliver a total daily dosage of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, of between about 0.1 and about 3000, about 0.5 and about 1000, about 1 and about 500, about 1 and about 100, about 1 and about 50, or about 2 and about 25 mg.

[0234] In some embodiments, the oral composition is provided as syrup / solution, and comprises the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in an amount effective to deliver a total daily dosage of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, of about 150, about 200, about 250, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, or about 1500 mg.

[0235] In some embodiments, the oral composition comprising the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered to a subject that weighs between about 0.1 and about 70, about 0.2 and about 60, about 0.3 and about 50, about 0.4 and about 40, about 0.5 and about 30, about 0.6 and about 20, about 0.7 and about 10, about 0.8 and about 9, about 0.9 and about 8, 1 and about 7, about 1.1 and about 6, or about 1.2 and about 5 kg.

[0236] A compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be administered for at least 1 day, 2 days, 5 days, 10 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 200 days, 300 days, 400 days, 500 days, 600 days, 700 days, 800 days, 900 days, 1000 days, 1100 days, or 1200 days.

[0237] In some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered over a treatment period of at least 1, 2, 5, 10, 15, 30, 60, or 90 days. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered over a treatment period of at least 90 days. In some other embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered over a treatment period sufficient to provide an effective treatment of Hypoxic-Ischaemic Encephalopathy (HIE). In some other embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered over a treatment period sufficient to provide an effective reduction or alleviation in one or more symptoms associated with Hypoxic-Ischaemic Encephalopathy (HIE) as described herein. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered over a treatment period sufficient to provide an effective reduction or alleviation in respiratory disturbance. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered over a treatment period sufficient to provide an effective reduction or alleviation in seizures. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered over a treatment period sufficient to provide an effective reduction in low muscle tone (hypotonia).

[0238] In some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered orally.

[0239] In some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered parenterally. In some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered subcutaneously. In some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered intramuscularly. In some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered intravenously.

[0240] In some embodiment, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in a dosage of from about 0.001 mg / kg to and including about 1000 mg / kg.

[0241] In some embodiments, in the method described herein, the dose of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is from between about 0.01 mg per kg of body weight (mg / kg) and about 1000 mg / kg, between about 0.1 mg / kg and about 500 mg / kg, between about 0.1 mg / kg and about 200 mg / kg, between about 1 mg / kg and about 200 mg / kg, between about 1 mg / kg and about 50 mg / kg, between about 1 mg / kg and about 25 mg / kg, or between about 1 mg / kg and about 12.5 mg / kg.

[0242] It will be appreciated that, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be administered in a single dose, or otherwise administered in multiple doses. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as a single dose.

[0243] In some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with therapeutic hypothermia. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as a single dose simultaneously to therapeutic hypothermia. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as a single dose sequentially with therapeutic hypothermia. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as a single dose at the time of commencement of therapeutic hypothermia, or otherwise at any time during therapeutic hypothermia. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as a single dose following cessation of therapeutic hypothermia. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as a single dose subsequent to therapeutic hypothermia. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as a single dose at the approximate point at which the body temperature is no longer hypothermic and has returned to normal body temperature (normothermia).

[0244] In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as two, three, four, five, or more, doses. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as two, three, four, five, or more, daily doses over a treatment period.

[0245] In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as two or more doses simultaneously to therapeutic hypothermia. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as two or more doses sequentially with therapeutic hypothermia. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as two or more doses at the time of commencement of therapeutic hypothermia, or otherwise at any time during therapeutic hypothermia. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as two or more doses following cessation of therapeutic hypothermia. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as two or more doses at the approximate point at which the body temperature is no longer hypothermic and has returned to normal body temperature (normothermia).

[0246] In some embodiments, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as a single daily dose for an ongoing treatment period. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as a single daily dose over a treatment period of at least 1, 2, 5, 10, 15, 30, 60, or 90 days. In one example, in the method described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered as two daily doses over a treatment period of at least 1, 2, 5, 10, 15, 30, 60, or 90 days.

[0247] In some embodiments, in the method described herein, the subject is a mammal. In some embodiments, in the method described herein, the subject is a human being. In some embodiments, in the method described herein, the subject is a neonate. It will be understood that a “neonate” is a newborn child. Typically, a neonate is understood to be approximately four weeks or less in age. A neonate will also be understood to encompass subjects birthed pre-term. In one example, in the method described herein, the subject is a human subject birthed preterm. In some embodiments, in the method described herein, the subject is older than a neonate. In one example, in the method described herein, the subject is approximately more than four weeks in age and has been recognised as having perinatal Hypoxic-Ischemic Encephalopathy (HIE) or symptoms thereof.

[0248] In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereosiomer, or prodrug thereof, may be used as the sole active agent in a medicament, without the subject being subjected to therapeutic hypothermia. In some embodiments, in the method of treatment described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered without therapeutic hypothermia. This may be therapeutic hypothermia administered simultaneously or sequentially to the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, such that there is effectively no overlap in therapeutic efficacy of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and the therapeutic hypothermia. That is, in some embodiments, treatment with a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereosiomer, or prodrug thereof may provide a therapeutic option to an infant that has not received therapeutic hypothermia (i.e., compound I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is administered prior to therapeutic hypothermia). In some embodiments, in the method of treatment described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered to a subject that has not received therapeutic hypothermia.

[0249] Combination Therapy

[0250] Whilst a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereosiomer, or prodrug thereof, may be used as the sole active agent in a medicament, it is also possible for a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereosiomer, or prodrug thereof, to be used in combination with one or more further therapeutic agents. Accordingly, in one example, a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is used in combination with one or more further therapeutic agents. The present disclosure therefore also provides a combination of a compound of Formula I, or pharmaceutically acceptable salt, solvate, or stereoisomer, or prodrug thereof, and a further therapeutic agent. The present disclosure also provides a pharmaceutical composition comprising a combination of a compound of Formula I, or pharmaceutically acceptable salt, solvate, or stereoisomer, or prodrug thereof, a further therapeutic agent, and a pharmaceutically acceptable excipient. Such combination may be provided as a single formulation, or otherwise as separate components. Such one or more further therapeutic agents may, for example, be an antiepileptic drug (e.g., ACTH, carbamazepine, clobazam, clonazepam, clonazepam, ethosuximide, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, phenobarbitone, phenytoin, prednisolone, rufinamide, sodium valproate, topiramate, topiramate, valproic acid, vigabatrin, zonisamide), a stimulant approved for use in children (e.g., amphetamine, dexmethylphenidate, lisdexamfetamine, methylphenidate, serdexmethylphenidate, dexmethylphenidate), risperidone, a sleep medicine approved for use in children (e.g., melatonin, antihistamines such as diphenhydramine and hydroxyzine, alpha agonists such as Clonidine and guanfacine, benzodiazepines and related agents such as zolpidem, zaleplon, and eszopiclone, chloral hydrate, trazodone, doxepin), cardiovascular drugs (e.g., propranolol, digoxin, adenosine, lidocaine, lasix, spironolactone, chlorothiazide, dopamine, dobutamine, epinephrine, norepinephrine, vasopressin), pulmonary drugs (e.g., caffeine, theophylline, methylxanithine, nitric oxide, tolazoline, isoproterenol, Prostaglandin El), recombinant human growth hormone (rhGH), human growth hormone, recombinant human IGF-1 (rhIGF-1), IGF-1, IGF-2, any IGF Binding Protein (IGFBP), IGFBP-3, insulin, and any statin.

[0251] The further therapeutic agents, when employed in combination with a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be used, for example, in those amounts indicated in the Prescribers’ Digital Reference or as otherwise determined by one of ordinary skill in the art.

[0252] In some embodiments, in the method of treatment described herein, the compound of Formula I is administered in combination with a further therapeutic agent. In some embodiments, in the method described herein, the compound of Formula I is administered separately, simultaneously, or sequentially, with a further therapeutic agent. It will be appreciated that separately, simultaneously, and sequentially may be taken to mean in relation to an individual administration, or otherwise in relation to an overall dosage regimen. For example, simultaneous may merely encompass overlap in the dosage regimen of a compound of Formula I and the dosage regimen of a further therapeutic agent.

[0253] In some embodiments, the further therapeutic agent is selected from the group consisting of an antiepileptic drug (e.g., ACTH, carbamazepine, clobazam, clonazepam, clonazepam, ethosuximide, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, phenobarbitone, phenytoin, prednisolone, rufinamide, sodium valproate, topiramate, topiramate, valproic acid, vigabatrin, zonisamide), a stimulant approved for use in children (e.g., amphetamine, dexmethylphenidate, lisdexamfetamine, methylphenidate, serdexmethylphenidate, dexmethylphenidate), risperidone, a sleep medicine (e.g., melatonin, antihistamines such as diphenhydramine and hydroxyzine, alpha agonists such as Clonidine and guanfacine, benzodiazepines and related agents such as zolpidem, zaleplon, and eszopiclone, chloral hydrate, trazodone, doxepin), cardiovascular drugs (e.g., propranolol, digoxin, adenosine, lidocaine, lasix, spironolactone, chlorothiazide, dopamine, dobutamine, epinephrine, norepinephrine, vasopressin), pulmonary drugs (e.g., caffeine, theophylline, methylxanithine, nitric oxide, tolazoline, isoproterenol, Prostaglandin El), recombinant human growth hormone (rhGH), human growth hormone, recombinant human IGF-1 (rhIGF-1), IGF-1, IGF-2, any IGF Binding Protein (IGFBP), IGFBP-3, insulin, and any statin.

[0254] In one example, the further therapeutic agent is recombinant human growth hormone (rhGH).

[0255] Combination treatment with therapeutic hypothermia

[0256] In some embodiments, in the method of treatment described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered separately, simultaneously, or sequentially, with therapeutic hypothermia.

[0257] As will be appreciated by the person skilled in the art, therapeutic hypothermia aims to lower body or brain structures to between 33 and 34°C, which is typically maintained for 72 hours and then gradually discontinued. Therapeutic hypothermia can be achieved either by whole body cooling or selective head cooling.

[0258] In some embodiments, in the method of treatment described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered simultaneously to therapeutic hypothermia. In some embodiments, in the method of treatment described herein, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered sequentially with therapeutic hypothermia. For example, the subject may be subjected to therapeutic hypothermia and the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be administered immediately at the time of commencement of therapeutic hypothermia, or otherwise at any time during therapeutic hypothermia. Also, as an example, the subject may be subjected to therapeutic hypothermia and the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be administered following cessation of therapeutic hypothermia. It will be appreciated that the cessation of therapeutic hypothermia may be taken to mean the immediate point at which therapeutic hypothermia is ceased, the period over which the body temperature is warming from hypothermia to normal body temperature (normothermia), and / or the approximate point at which the body temperature is no longer hypothermic and has returned to normal body temperature (normothermia). In some embodiments, the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered at least 1 day, 2 days, 3 days, 4 days, 5 days, 7 days, 8 days, 9 days, 10 days, 20 days, 30 days, 60 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years subsequent to the sentinel hypoxic-ischemic event.

[0259] Synthesis of Compounds of Formula I

[0260] Numerous synthetic routes to the compounds of Formula I, including a compound of Formula la, lb, and Ic, can be devised by any person skilled in the art and the possible synthetic routes described below are not intended to be limiting. Where appropriate, any initially produced compound of Formula I can be converted into another compound of Formula I by known methods.

[0261] Starting materials and reagents used in preparing the compounds of Formula I are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methods well known to the person of ordinary skill in the art following procedures described in such references as Fieser and Fieser’s Reagents for Organic Synthesis, vols 1-17, John Wiley and Sons, New York, N. Y., 1991; Rodd’s Chemistry of Carbon Compounds, vols. 1-5 and supplements, Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, N. Y., 1991; March J; Advanced Organic Chemistry, 4th ed. John Wiley and Sons, New York, N. Y., 1992; and Larock: Comprehensive Organic Transformations, VCH Publishers, 1989. In most instances, amino acids and their esters or amides, and protected amino acids, are widely commercially available; and the preparation of modified amino acids and their amides or esters are extensively described in the chemical and biochemical literature and thus well-known to persons of ordinary skill in the art.

[0262] Starting materials, intermediates, and final products in this disclosure may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data.

[0263] Cyclic G-2-AllylP is a cyclic dipeptide (bicyclic 2, 5 -diketopiperazine) and is a member of the class of compounds known as cyclic GPs (“cGP”). In general, cGPs and cyclic G-2-AllylP may be prepared by methods such as are already well-known to persons of ordinary skill in the art of peptide and modified peptide synthesis, following the reaction schemes set forth herein, or by following other methods well-known to those of ordinary skill in the art of the synthesis of peptides and analogues. See for example, Bodanzsky: Principles of Peptide Synthesis, Berlin, New York: Springer- Verlag 1993.

[0264] Synthesis of the diketopiperazine compounds of this disclosure may be by solution phase synthesis or via the solid-phase synthesis method exemplified by Merrifield et al. 1963 J. Amer. Chem. Soc.: 85, 2149-2156. Solid phase synthesis may be performed using commercial peptide synthesizers, such as the Applied Biosystems Model 430 A, using the protocols established for the instrument.

[0265] Specific examples of diketopiperazine synthesis can be found in Fischer, 2003, J. Peptide Science: 9: 9-35 and references therein. A person of ordinary skill in the art will have no difficulty, taking account of that skill and the knowledge available, and of this disclosure, in developing one or more suitable synthetic methods for compounds of this invention.

[0266] The choice of appropriate protecting groups for the method chosen (solid-phase or solution-phase), and of appropriate substrates if solid-phase synthesis is used, will be within the skill of a person of ordinary skill in the art. Appropriate protecting groups for peptide synthesis include t-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), Benzyl (Bzl), t-amyloxy carbonyl (Aoc), tosyl (Tos), benzyloxy carbonyl (Z or Cbz), o-bromobenzyloxycarbonyl (BrZ) and the like. Additional protecting groups are identified in Goodman M. (ed.), “Synthesis of Peptides and Peptidomimetics” in Methods of organic chemistry (Houben-Weyl) (Workbench Edition, E22a,b,c,d,e; 2004; Georg Thieme Verlag, Stuttgart, New York).

[0267] The choice of coupling agent for the method chosen will also be within the skill of a person of ordinary skill in the art. Suitable coupling agents include DCC (N, N'-Dicyclohexylcarbodiimide), Bop (Benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBop (Benzotri azol- 1 -yloxytripyrrolidinophosphonium hexafluorophosphate), BopCl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), 2-Chloro-l,3-dimethylimidazolidinium hexafluorophosphate (CIP) and the like. Other compounds may be used in the synthesis e.g. to prevent racemisation, such as HOBt (N-Hydroxybenzotriazole) and HO At (l-Hydroxy-7-azabenzotriazole).

[0268] EXAMPLES

[0269] The present disclosure is further illustrated by the following examples. These examples are offered by way of illustration only and are not intended to limit the scope of the disclosure. General: Materials and Methods

[0270] Flash chromatography was performed using Scharlau 60 (40-60 pm mesh) silica gel. Analytical thin layer chromatography was carried out on 0.20 mm pre-coated silica gel plates (ALUGRAM® SIL G / UV254) and compounds visualized using UV fluorescence, or heating of plates dipped in potassium permanganate in alkaline solution.

[0271] Melting points in degrees Celsius (°C) were determined on an Electrothermal(R)melting point apparatus and are uncorrected.

[0272] Optical rotations were measured at 20 °C on a Perkin Elmer 341 polarimeter using 10 cm path length cells and are given in units of 10-1degcm2g-1. Samples were prepared in the solvent indicated at the concentration specified (measured in g / 100 cm3). IR spectra were recorded on a Perkin Elmer Spectrum One FT-IR spectrometer. The samples were prepared as thin films on sodium chloride discs or as solids in potassium bromide discs. A broad signal indicated by br. The frequencies (u) as absorption maxima are given in wavenumbers (cm-1).

[0273] NMR spectra were recorded on a Bruker AVANCE DRX400 (XH, 400 MHz;13C, 100 MHz) or a Bruker AVANCE 300 (XH, 300 MHz;13C, 75 MHz) spectrometer at ambient temperatures. For ’H NMR data chemical shifts are described in parts per million downfield from SiMe4 and are reported consecutively as position (5H), relative integral, multiplicity (s = singlet, d = doublet, t = triplet, dd = doublet of doublets, m = multiplet, br = broad), coupling constant (J / Hz) and assignment. For13C NMR data, chemical shifts are described in parts per million relative to CDCh and are reported consecutively as position (5C), degree of hybridization as determined by DEPT experiments, and assignment. ’H NMR spectra were referenced internally using SiMe4 (50.00) or CDCh (57.26).13C NMR spectra were referenced internally using CDCh (5 77.0). When two sets of peaks arise in the NMR spectra due to different conformations around the gly cine-proline amide bond, the chemical shift for the minor cis conformer is marked with an asterisk (*).

[0274] Accurate mass measurements were recorded on a VG-70SE mass spectrometer.

[0275] Hexane and dichloromethane were distilled prior to use. Methanol was dried using magnesium turnings and iodine, and distilled under nitrogen. Triethylamine was dried over calcium hydride and distilled under nitrogen. Example 1: Synthesis of (8aS)-Methyl-hexahydropyrrolo[l,2-a]pyrazine-l, -dione (Cyclic G-2-MeP)

[0276]

[0277] Scheme 1: Reagents, conditions and yields: (i) LDA, THF, -78 °C, iodomethane, -78 -> 20-50 °C, 2 h (63%); (ii) SOCl2, CH3OH, reflux, N2, 2.5 h (98%); (iii) Et3N, BoPCl, CH2CI2, RT, N2, 20.5 h (78%); (iv) 10% Pd / C, CH3OH, RT, 15 h (98%).

[0278] ( 2R, 5 S)-4-Methyl-2 -trichlor omethyl-l-aza-3-oxabicyclo[ 3.3.0 ]octan-4-one (9)

[0279] n-BuLi (1.31 M, 4.68 cm3, 6.14 mmol) was added dropwise to a stirred solution of diisopropylamine (0.86 cm3, 6.14 mmol) in dry tetrahydrofuran (10 cm3) at -78 °C under an atmosphere of nitrogen. The solution was stirred for 5 min, warmed to 0 °C and stirred for 15 min. The solution was then added dropwise to a solution of oxazolidinone 8 (1.00 g, 4.09 mmol) in dry tetrahydrofuran (20 cm3) at -78 °C over 20 min (turned to a dark brown colour), stirred for a further 30 min then iodomethane (0.76 cm3, 12.3 mmol) was added dropwise over 5 min. The solution was warmed to -50 °C over 2 h. Water (15 cm3) was added and the solution warmed to room temperature and extracted with chloroform (3 x 40 cm3). The combined organic extracts were dried (MgSC ), filtered and evaporated to dryness in vacuo to give a dark brown semisolid. Purification of the residue by flash column chromatography (15% ethyl acetate -hexane) afforded oxazolidinone 9 (0.67 g, 63%) as a pale yellow solid: mp 55-57 °C (lit., 57-60 °C); 5H (300 MHz, CDCh) 1.53 (3H, s, CH3), 1.72-2.02 (3H, m, ProP-H and Proy-ft), 2.18-2.26 (1H, m, ProP-H), 3.15-3.22 (1H, m, Pro5-H), 3.35-3.44 (1H, m, Pro5-H) and 4.99 (1H, s, NCH). Methyl L-2-methylprolinate hydrochloride (10)

[0280] a) Using acetyl chloride

[0281] Oxazolidinone 9 (0.60 g, 2.33 mmol) was dissolved in dry methanol (15 cm3) under an atmosphere of nitrogen and acetyl chloride (0.33 cm3, 4.66 mmol) was added dropwise to the ice-cooled solution. The solution was heated under reflux for 4.5 h, then the solvent removed under reduced pressure to give a brown oil which was purified by flash column chromatography (10% CH3OH-CH2CI2) affording the hydrochloride 10 (0.2 g, 48%) as a flaky white solid: mp 107-109 °C (lit., 106-108 °C); 5H (300 MHz, CDCh) 1.81 (3H, s, CH3), 1.93-2.14 (3H, m, ProP-HAHB and Proy-H2), 2.33-2.39 (1H, m, PTOP-HAHB), 3.52-3.56 (2H, m, Pro5-H2) and 3.82 (3H, s, CO2CH3).

[0282] b) Using thionyl chloride

[0283] An ice-cooled solution of oxazolidinone 9 (53 mg, 0.21 mmol) in dry methanol (1 cm3) was treated dropwise with thionyl chloride (0.045 cm3, 0.62 mmol). The solution was heated under reflux for 2.5 h, cooled and the solvent removed under reduced pressure to yield a brown oil. The oil was dissolved in toluene (5 cm3), concentrated to dryness to remove residual thionyl chloride and methanol then purified by flash column chromatography (10% CH3OH-CH2Ch) to afford the hydrochloride 10 (16 mg, 43%) as a flaky white solid. The 'H NMR assignments were in agreement with those reported above.

[0284] Methyl-N-benzyloxycarbonyl-glycyl-L-2-methylprolinate (12)

[0285] Dry triethylamine (0.27 cm3, 1.96 mmol) was added dropwise to a solution of hydrochloride 10 (0.11 g, 0.61 mmol) and A-benzyloxycarbonyl-glycine 11 (98.5%) (0.17 g, 0.79 mmol) in dry dichloromethane (35 cm3) under an atmosphere of nitrogen at room temperature, and the reaction mixture stirred for 10 min. Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BoPCl, 97%) (0.196 g, 0.77 mmol) was added and the resultant colourless solution was stirred for 20.5 h. The solution was washed successively with 10% aqueous hydrochloric acid (30 cm3) and saturated aqueous sodium hydrogen carbonate (30 cm3), dried (MgSCh), filtered and evaporated to dryness in vacuo. Purification of the resultant residue by flash column chromatography (50-80% ethyl acetate-hexane; gradient elution) yielded dipeptide 12 (0.18 g, 92%) as a colourless oil. Amide 12 was shown to exist as a 98:2 trans:cis mixture of conformers by13C NMR analysis (the ratio was estimated from the relative intensities of the resonances at 520.8 and 23.5 assigned to the Proy-C atoms of the minor and major conformers, respectively):

[0286] [a]D- 33.0 (c 1.0 inMeOH); nmax (filmj / cm'13406, 2952, 1732, 1651, 1521, 1434, 1373, 1329, 1310, 1284, 1257, 1220, 1195, 1172, 1135, 1107, 1082, 1052, 1029, 986, 965, 907, 876, 829, 775, 738 and 699; 5H (300 MHz, CDCh) 1.49 (3H, s, CH3), 1.77-2.11 (4H, m, Prop -H2and Proy-H2), 3.43-3.48 (2H, m, Pro5-H2), 3.61 (3H, s, OCH3), 3.85-3.89 (2H, m, Glya-H2), 5.04 (2H, s, PhCH2), 5.76 (1H, br s, N-H) and 7.21-7.28 (5H, s, ArH); 5C (75 MHz, CDCh) 13.8* (CH3, Proa-CH3), 21.1 (CH3, Proa-CH3), 20.8* (CH2, Proy-C), 23.5 (CH2, Proy-C), 38.0 (CH2, ProP-C), 40.8* (CH2, ProP-C), 43.3 (CH2, Glya-C), 45.5* (CH2, Glya-C), 46.6 (CH2, Pro5-C), 48.7* (CH2, Pro5-C), 51.9* (CH3, OCH3), 52.1 (CH3, OCH3), 60.0* (quat., Proa-C), 66.0 (quat., Proa-C), 66.3 (CH2, PhCH2), 68.6* (CH2, PhCH2), 127.5 (CH, Ph), 127.6 (CH, Ph), 127.9* (CH, Ph), 128.1 (CH, Ph), 128.3* (CH, Ph), 136.2 (quat., Ph), 155.9 (quat., NCO2), 166.0 (quat., Gly-CON), 169.4* (quat., Gly-CON) and 173.6 (quat., CO2CH3); m / z (EI+) 334.1535 (M+. CI7H22N2O5requires 334.1529).

[0287] ( 8aS)-Methyl-hexahydropyrrolo[ 1, 2 -a ]pyrazine-l, 4-dione ( Cyclic G-2MeP)

[0288] To a solution of dipeptide 12 (0.167 g, 0.51 mmol) in methanol (8.0 cm3) was added 10% Pd on activated charcoal (8.1 mg, 0.076 mmol) and the vessel flushed with hydrogen gas. The resulting suspension was stirred vigorously under an atmosphere of hydrogen for 15 h. The mixture was then filtered through a Celite pad then a short plug of silica gel with methanol, and the solvent removed under reduced pressure to produce cyclic G-2MeP (83 mg, 98%) as a yellow solid: mp 133-135 °C; [a]D-128.1 (c 0.52 in MeOH); 5H (300 MHz, CDCh) 1.36 (3H, s, CH3), 1.87-2.01 (3H, m, ProP-ZMfe and Proy-H2), 2.07-2.21 (1H, m, PTOP-HAHB), 3.45-3.64 (2H, m, Pro5-H2), 3.82 (1H, dd, J 17.1 and 4.1, CZMfeNH), 3.99 (1H, d, J 17.1, CHAHBNH) and 7.66 (1H, br s, N-H); 5C (75 MHz, CDCh) 20.2 (CH2, Proy-C), 23.2 (CH3, Proa-CH3), 35.0 (CH2, ProP-C), 44.7 (CH2, Pro5-C), 45.9 (CH2, CH2NH), 63.8 (quat., Proa-C), 163.3 (quat., NCO) and 173.3 (quat., CONH); m / z (EI+) 168.08986 (M+. CSHI2N2O2requires 168.08988). Example 2: Synthesis of (8aS)-Methyl-spiro[cyclohexane-l,3(4H)-tetrahydropyrrolo[l,2-a]pyrazine]-l,4(2H)-dione (Cyclic cyclohexyl-G-2-MeP) Formula Ic

[0289]

[0290] Scheme 2: Reagents, conditions and yields: (i) BnChCCl, Na2CCh, IbO-dioxane (3:1), 19 h, 96%; (ii) Et3N, HO At, CIP, 1,2-dichloroethane, reflux, N2, 19 h (23%); (iii) 10% Pd / C, CH3OH, RT, 17 h (65%).

[0291] N-benzyloxycarbonyl-1 -aminocyclohexane- 1 -carboxylic acid (14)

[0292] To a suspension of 1 -aminocyclohexanecarboxylic acid 13 (0.72 g, 5.02 mmol) and sodium carbonate (1.6 g, 15.1 mmol) were dissolved in water-dioxane (21 cm3, 3:1) was added benzyl chloroformate (0.79 cm3, 5.52 mmol) was added dropwise and the solution was stirred at room temperature for 19.5 h. The aqueous layer was washed with diethyl ether (60 cm3), acidified with 2 M HC1 and extracted with ethyl acetate (2 x 60 cm3). The organic layers were combined, dried (MgSC ), filtered and evaporated under reduced pressure to produce a colourless oil, which solidified on standing to crude carbamate 14 (1.23 g, 88%) as a white solid: mp 152-154 °C (lit., 148-150 °C); 5H (400 MHz, CDCh) 1.27-1.56 (3H, m, 3 x cyclohexyl-H), 1.59-1.73 (3H, m, 3 x cyclohexyl-H), 1.85-1.91 (2H, m, 2 x cyclopentyl-H), 2.05-2.09 (2H, m, 2 x cyclopentyl-H), 5.02 (1H, br s, N-H), 5.12 (2H, s, OC / APh) and 7.27- 7.36 (5H, s, Ph); 5C (100 MHz, CDCh) 21.1 (CH2, 2 x cyclohexyl-C), 25.1 (CH2, 2 x cyclohexyl-C), 32.3 (CH2, cyclohexyl-C), 5 59.0 (quat.,l-C), 67.1 (CH2, OCH2Ph), 128.1 (CH, Ph), 128.2 (CH, Ph), 128.5 (CH, Ph), 136.1 (quat., Ph), 155.7 (quat., NCO2) and 178.7 (quat., CO2H).

[0293] Methyl-N-benzyloxycarbonyl-cyclohexyl-glycyl-L-2-methylprolinate (15)

[0294] Dry triethylamine (0.21 cm3, 1.5 mmol) was added dropwise to a solution of hydrochloride 10 (84.0 mg, 0.47 mmol), carboxylic acid 14 (0.17 g, 0.61 mmol) and 1 -hydroxy -7-azabenzotriazole (16 mg, 0.12 mmol) in dry 1,2-di chloroethane (26 cm3) under an atmosphere of nitrogen at room temperature, and the reaction mixture stirred for 10 min. 2-Chloro-l,3-dimethylimidazolidinium hexafluorophosphate (0.13 g, 0.47 mmol) was added and the resultant solution heated under reflux for 21 h, then washed successively with 10% aqueous hydrochloric acid (30 cm3) and saturated aqueous sodium hydrogen carbonate (30 cm3), dried (MgSCh), filtered and evaporated to dryness in vacuo. Purification of the resultant residue by flash column chromatography (40-50% ethyl acetate-hexane; gradient elution) yielded amide 15 (16 mg, 9%) as a white solid. Amide 15 was shown to exist as a 11: 1 trans:cis mixture of conformers by13C NMR analysis (the ratio was estimated from the relative intensities of the resonances at 541.3 and 48.2 assigned to the Pro5-C atoms of the minor and major conformers, respectively): mp 219-222 °C; [a]D-44.9 (c 1.31 in CH2C12); nmax (filmj / cm'13239, 2927, 1736, 1707, 1617, 1530, 1450, 1403, 1371, 1281, 1241, 1208, 1194, 1165, 1150, 1132, 1089, 1071, 1028, 984, 912, 25 796, 749, 739 and 699; 5H (400 MHz, CDCh) 1.24-2.10 (17H, m, Proa-CH3, ProP-H2, Proy-H2and 5 x cyclohexyl-H2), 3.25-3.48 (1H, br m, Prod-T / iHe), 3.61-3.87 (4H, br m, OCH3and Pro6-HA7 / «), 4.92-5.19 (3H, m, N-H and OC / CPh) and 7.35-7.37 (5H, s, Ph); 5C (100 MHz, CDCh) 21.26 (CH2, cyclohexyl-C), 21.33 (CH2, cyclohexyl-C), 21.7 (CH3, Proa-CH3), 24.8 (CH2, cyclohexyl-C), 25.0 (CH2, Proy-C), 29.4* (CH2, cyclohexyl-C), 29.7* (CH2, cyclohexyl-C), 31.1 (CH2, cyclohexyl-C), 31.6 (CH2, cyclohexyl-C), 31.9* (CH2, cyclohexyl-C), 32.2* (CH2, cyclohexyl-C), 32.8* (CH2, cyclohexyl-C), 37.3 (CH2, ProP-C), 41.4* (CH2, Pro5-C), 48.2 (CH2, Pro5-C), 52.1 (CH3, OCH3), 59.1 (quat., Glya-C), 66.7 (CH2, OCH2Ph), 67.3* (CH2, OCH2Ph), 67.4 (quat., Proa-C), 128.0* (CH, Ph), 128.1* (CH, Ph), 128.3 (CH, Ph), 128.5 (CH, Ph), 128.7 (CH, Ph), 136.6 (quat., Ph), 153.7 (quat., NCO2), 171.0 (quat., Gly-CO) and 174.8 (quat., CO2CH3); m / z (EI+) 402.2151 (M+C22H30N2O5requires 402.2155). (8aS)-Methyl-spiro[cyclohexane-l,3(4H)-tetrahydropyrrolo[ 1, 2-a]pyrazine ]-l, 4(2H)-dione (Cyclic cyclohexyl-G-2MeP) (Formula Ic) To a solution of amide 15 (40 mg, 0.01 mmol) in methanol (3.3 cm3) was added 10% Pd on activated charcoal (1.6 mg, 0.015 mmol) and the vessel flushed with hydrogen gas. The resulting suspension was stirred vigorously under an atmosphere of hydrogen for 61.5 h, then filtered through a Celite™ pad with methanol (15 cm3). The filtrate was concentrated to dryness under reduced pressure to produce a yellow semi-solid which was purified by reverse-phase C18 flash column chromatography (0-10% CH3CN / H2O; gradient elution) to produce cyclic cyclohexyl-G-2MeP (19 mg, 81%) as a white solid: mp 174-177 °C; [a]o -63.8 (c 1.13 in CH2CI2); nmax (film) / cm'13215, 2925, 2854, 1667, 1646, 1463, 1427, 1276, 1232, 1171, 1085, 1014, 900, 868, 818, 783, 726 and 715; 5H (400 MHz, CDCk) 1.31-1.89 (12H, m, 9 x cyclohexyl-H and 8a-CH3), 1.94-2.15 (4H, m, 7-H2 and 8-H2), 2.26 (1H, td, J 13.7 and 4.5, 1 x cyclohexyl-H), 3.44-3.51 (1H, m, 6- 4HB), 3.79-3.86 (1H, m, 6-HAHB) and 6.40 (1H, br s, N-H); 5C (100 MHz, CDCh) 19.5 (CH2, 7-C), 20.6 (CH2, cyclohexyl-C), 20.8 (CH2, cyclohexyl-C), 24.5 (CH2, cyclohexyl-C), 25.0 (CH3, 8a-CH3), 33.7 (CH2, cyclohexyl-C), 36.3 (CH2, 8-C), 36.5 (CH2, cyclohexyl-C), 44.7 (CH2, 6-C), 59.5 (quat., 8a-C), 64.0 (quat., 3-C), 168.1 (quat., 4-C) and 171.6 (quat., 1-C); m / z (EI+) 236.15246 (M+C13H20N2O2 requires 236.15248).

[0295] Example 3: Synthesis of (8aS)-Allyl-hexahydropyrrolo[l,2-a]pyrazine-l, 4-dione (Cyclic G- 2-AllylP)

[0296]

[0297] Scheme 3: Reagents, conditions and yields: (i) LDA, THF, -78 °C, allyl bromide, -78->-30°C, N2, 4 h (60%); (ii) acetyl chloride, CH3OH, reflux, N2, 24 h (63%); (iii) Et3N, BoPCl, CH2Ch, RT, N2, 19.5 h (45%); (iv) TFA, CH2C12, 1 h, then EfeN, CH2C12, 23 h (37%).

[0298] (2R,5S)-4-Allyl-2-trichloromethyl-l-aza-3-oxabicyclo[3.3.0]octan-4-one (17)

[0299] n-BuLi (1.31 M, 9.93 cm3, 13.0 mmol) was added dropwise to a stirred solution of diisopropylamine (1.82 cm3, 13.0 mmol) in dry tetrahydrofuran (20 cm3) at -78 °C under an atmosphere of nitrogen. The solution was stirred for 5 min, warmed to 0 °C, stirred for 15 min then added dropwise to a solution of pro-oxazolidinone 16 (2.12 g, 8.68 mmol) in dry tetrahydrofuran (40 cm3) at -78 °C over 20 min and the reaction mixture was stirred for a further 30 min then allyl bromide (2.25 cm3, 26.0 mmol) was added dropwise over 5 min. The solution was warmed slowly to -30 °C over 4 h, quenched with H2O (30 cm3) and the mixture warmed to room temperature and extracted with chloroform (3 x 80 cm3). The combined organic extracts were dried (MgSCh), filtered and evaporated to dryness in vacuo to produce a dark brown semisolid which was purified by flash column chromatography (10-20% ethyl acetate-hexane; gradient elution) to produce oxazolidinone 17 (1.48 g, 60%) as an orange oil which solidified at 0 °C, for which the nmr data were in agreement with that reported in the literature: 5H (400 MHz, CDCh) 1.58-1.92 (2H, m, Proy-H2), 1.96-2.14 (2H, m, ProP-H2), 2.50-2.63 (2H, m, Pro5-H2), 3.12-3.23 (2H, m, CH2-CH=CH2), 4.97 (1H, s, NCH), 5.13-5.18 (2H, m, CH=CH2) and 5.82-5.92 (1H, m, CH=CH2); 5C (100 MHz, CDCh) 25.1 (CH2, Proy-C), 35.1 (CH2, ProP-C), 41.5 (CH2, Pro5-C), 58.3 (CH2, CH2CH=CH2), 71.2 (quat., Proa-C), 100.4 (quat., CCh), 102.3 (CH, NCH), 119.8 (CH2, CH2CH=CH2), 131.9 (CH, CH2CH=CH2) and 176.1 (quat., C=O); m / z (CI+) 284.0009 [(M+H)+. CioHi3ChN02requires 284.0012], 285.9980 [(M+H)+. CioHi335Cl37ChN02requires 285.9982], 287.9951 [(M+H)+. CIOHI335C137C12N02requires 287.9953] and 289.9932 [(M+H)+. CIOHI337C13N02requires 289.9923],

[0300] Methyl L-2-allylprolinate hydrochloride (18)

[0301] An ice-cooled solution of oxazolidinone 17 (0.64 g, 2.24 mmol) in dry methanol (15 cm3) was treated dropwise with a solution of acetyl chloride (0.36 cm3, 5.0 mmol) in methanol (5 cm3). The solution was heated under reflux for 24 h, then cooled and the solvent removed under reduced pressure. The resultant brown oil was dissolved in toluene (40 cm3) and concentrated to dryness to remove residual thionyl chloride and methanol, then purified by flash column chromatography (5-10% CH3OH-CH2Ch; gradient elution) to afford hydrochloride 18 (0.29 g, 63%) as a green solid for which the NMR data were in agreement with that reported in the literature: 5H (300 MHz, CDCh) 1.72-2.25 (3H, m, ProP-ZMfe and Proy-H2), 2.32-2.52 (1H, m, PTOP-HAHB), 2.72-3.10 (2H, m, Pro5-H2), 3.31-3.78 (2H, m, C / / 2CHCH2), 3.84 (3H, s, CO2CH3), 5.20-5.33 (2H, m, CH=C / / 2), 5.75-5.98 (1H, m, C / / =CH2) and 8.06 (1H, br s, N-H); m / z (CI+) 170.1183 [(M+H)+. C9Hi6NO2requires 170.1181],

[0302] Methyl-N-tert-butyloxycarbonyl-glycyl-L-2-allylprolinate (20)

[0303] Dry triethylamine (0.28 cm3, 2.02 mmol) was added dropwise to a solution of hydrochloride 18 (0.13 g, 0.63 mmol) and A-Zc / V-butyloxycarbonyl-glycine 19 (0.14 g, 0.82 mmol) in dry di chloromethane (35 cm3) under an atmosphere of nitrogen at room temperature, and the reaction mixture was stirred for 10 min. Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BoPCl, 97%) (0.20 g, 0.80 mmol) was added and the solution stirred for 19.5 h, then washed successively with 10% aqueous hydrochloric acid (35 cm3) and saturated aqueous sodium hydrogen carbonate (35 cm3), dried (MgSCh), filtered and evaporated to dryness in vacuo. Purification of the resultant residue by flash column chromatography (40% ethyl acetatehexane) yielded dipeptide 20 (0.09 g, 45%) as a light yellow oil: [a]o +33.8 (c 0.83 in CH2C12); nmax (filmVcm'13419, 5 3075, 2977, 2930, 2874, 1739, 1715, 1656, 1499, 1434, 1392, 1366, 1332, 1268, 1248, 1212, 1168, 1122, 1051, 1026, 1003, 943, 919, 867, 830, 779, 739, 699 and 679; 5H (300 MHz, CDCh) 1.42 [9H, s, C(CH3)3], 1.93-2.08 (4H, m, ProP-H2and Proy-H2), 2.59-2.67 (1H, m, C 4HBCH=CH2), 3.09-3.16 (1H, m, CHAHBCH=CH2), 3.35-3.44 (1H, m, Pro8- 4HB), 3.56-3.62 (1H, m, PTOS-HAHB), 3.70 (3H, s, OCH3), 3.89 (2H, d, J4.2, Glya-H2), 5.06-5.11 (2H, m, CH=C / / 2), 5.42 (1H, br s, Gly-NH) and 5.58-5.72 (1H, m, C =CH2); 5C (75 MHz, CDCh) 23.7 (CH2, Proy-C), 28.3 [CH3, C(CH3)3], 35.0 (CH2, ProP-C), 37.6 (CH2, CH2CH=CH2), 43.3 (CH2, Glya-C), 47.5 (CH2, Pro5-C), 52.5 (CH3, OCH3), 68.8 (quat., Proa-C), 79.5 [quat., C(CH3)3], 119.4 (CH2, CH=CH2), 132.9 (CH, CH=CH2), 155.7 (quat., NCO2), 166.9 (quat., Gly-CON) and 173.8 (quat., CO2CH3); m / z (EI+) 326.1845 (M+. Ci6H26N2O5requires 326.1842).

[0304] (8aS)-Allyl-hexahydropyrrolo [ 1,2-a]pyrazine-l,4-dione (Cyclic G-2AllylP) Formula la To a solution of dipeptide 20 (0.09 g, 0.28 mmol) in dichloromethane (9 cm3) at room temperature was added trifluoroacetic acid (1 cm3, 0.013 mmol) dropwise and the reaction mixture was stirred for 1 h under an atmosphere of nitrogen. The solution was evaporated under reduced pressure to give a colorless oil which was dissolved in di chloromethane (10 cm3), dry tri ethylamine (0.096 cm3, 0.69 mmol) was added and the reaction mixture stirred for 4.5 h, after which further triethylamine (0.096 cm3, 0.69 mmol) was added. The reaction mixture was stirred overnight, concentrated to dryness to give a green oil which was purified by flash column chromatography (10% CH3OH-CH2CI2) to produce cyclic G-2AllylP (20 mg, 37%) as an off-white solid: mp 106-109 °C; [a]D-102.7 (c 0.95 in CH2CI2); nmax (CH2C12) / cm-l 3456, 3226, 2920, 1666, 1454, 1325, 1306, 1299, 1210, 1133, 1109, 1028, 1010, 949, 928, 882, 793, 761 and 733; 5H (400 MHz, CDCh) 1.92-2.01 (2H, m, Proy-H2), 2.09-2.16 (2H, m, ProP-H2), 2.39-2.56 (2H, m, C / / 2CH2CH2), 3.46-3.53 (1H, m, ProS-^Hn), 3.78-3.87 (2H, m, Pro6-HA / / « and Glya- 4HB), 4.09 (1H, d, J 17.2, Glya-HA / ffi), 5.16-5.20 (2H, m, CH=C / / 2), 5.73-5.84 (1H, m, C7 / =CH2) and 7.17 (1H, br s, N-H); 5C (100 MHz, CDCh) 20.1 (CH2, Proy-C), 34.1 (CH2, ProP-C), 41.7 (CH2, CH2CH2=CH2), 44.9 (CH2, Pro5-C), 46.4 (CH2, Glya-C), 67.2 (quat., Proa-C), 120.9 (CH2, CH=CH2), 131.0 (CH, CH=CH2), 163.4 (quat., NCO) and 171.7 (quat., CONH); m / z (EI+) 195.1132 (M+. C10H15N2O2 requires 5 195.1134).

[0305] Example 4: Synthesis of (8aS)-Methyl-spiro[cyclopentane-l,3(4H)-tetrahydropyrrolo[l,2-a]pyrazine]-l,4(2H)-dione (Cyclic Cyclopentyl-G-2-MeP) Formula lb

[0306]

[0307] Scheme 4: Reagents, conditions and yields: (i) EtsN, HO At, CIP, 1,2-di chloroethane, 83 °C, N2, 19 h (23%); (ii) 10% Pd / C, CH3OH, RT, 17 h (65%). N-Benzyloxycarbonyl-l-aminocyclopentane-l-carboxylic acid (21)

[0308] A solution of benzyl chloroformate (0.29 g, 1.1 mmol) in dioxane 5 (2.5 cm3) was added dropwise to a solution of 1 -aminocyclopentanecarboxylic acid (Fluka) (0.20 g, 1.54 mmol) and sodium carbonate (0.49 g, 4.64 mmol) in water (5 cm3) at 0 °C. Stirring was continued at room temperature overnight and the reaction mixture washed with ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate, dried (Na2SO4), filtered and the solvent removed to afford carbamate 21 (0.253 g, 62%) as an oil which solidified on standing. Carbamate 21 was shown to be a 70:30 mixture of conformers by1H NMR analysis (the ratio was estimated from the integration of the resonances at 55.31 and 7.29-7.40, assigned to the N-H protons of the major and minor conformers, respectively): mp 70-80 °C (lit.l 82-86 °C, ethyl acetate, petroleum ether); 5H (400 MHz; CDCh; Me4Si) 1.83 (4H, br s, 2 x cyclopentyl-H2), 2.04 (2H, br s, cyclopentyl-H2), 2.20-2.40 (2H, m, cyclopentyl-H2), 5.13 (2H, br s, OC / hPh), 5.31 (0.7H, br s, N-H) and 7.29-7.40 (5.3H, m, Ph and N-H*); 5C (100 MHz; CDCh) 24.6 (CH2, cyclopentyl-C), 37.5 (CH2, cyclopentyl-C), 66.0 (quat., cyclopentyl-C), 66.8 (CH2, OCH2PI1), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.4 (CH, Ph), 136.1 (quat, Ph), 155.8 (quat., NCO2) and 179.5 (quat., CO2H).

[0309] Methyl N-benzyloxycarbonyl cyclopentyl-glycyl-L-2-methylprolinate (22)

[0310] Dry triethylamine (0.19 cm3, 1.4 mmol) was added dropwise to a solution of hydrochloride 10 (78 mg, 0.43 mmol), carboxylic acid 21 (0.15 g, 0.56 mmol) and 1-hydroxy-7-azabenzotriazole (Acros) (15 mg, 0.11 mmol) in dry 1,2-di chloroethane (24 cm3) under an atmosphere of nitrogen at room temperature, and the reaction mixture stirred for 10 min. 2-Chloro-l,3-dimethylimidazolidinium hexafluorophosphate (CIP) (Aldrich) (0.12 g, 0.43 mmol) was added and the resultant solution heated under reflux for 19 h, then washed successively with 10% aqueous hydrochloric acid (30 cm3) and saturated aqueous sodium hydrogen carbonate (30 cm3), dried (MgSCh), filtered and evaporated to dryness in vacuo. Purification of the resultant residue by flash column chromatography (60% ethyl acetate -hexane) yielded amide 22 (39 mg, 23%) as a white solid. Amide 22 was shown to exist as a 3: 1 trans:cis mixture of carbamate conformers by13C NMR analysis (the ratio was estimated from the relative intensities of the resonances at 5 154.1 and 155.7 assigned to the carbamate carbonyl-C atoms of the major and minor conformers, respectively): mp 200-203 °C; [a]o -54.5 (c 1.52 in CH2CI2); nmax (filmj / cm'13432, 3239, 5 3042, 2953, 1736, 1712, 1627, 1540, 1455, 1417, 1439, 1374, 1282, 1256, 1216, 1194, 1171, 1156, 1136, 1100, 1081, 1042, 1020, 107, 953, 917, 876, 756 and 701; 5H (400 MHz, CDCh) 1.33-1.53 (3H, br m, Proa-CH3), 1.62-2.20 (11H, m, ProP-H2, Proy-H2 and 7 x cyclopentyl-H), 2.59-2.71 (1H, br m, 1 x cyclopentyl-H), 3.31-3.42 (1H, br m, Prod-ZMfe), 3.58-3.79 (4H, br m, OCH3and Pro6-HA / / «), 4.92-5.17 (3H, m, N-H and OCTCPh) and 7.27-7.42 (5H, s, Ph); 5C (100 MHz, CDCh) 21.7 (CH3, Proa-CH3), 24.1* (CH2, cyclopentyl-C), 24.2 (CH2, cyclopentyl-C), 24.4 (CH2, Proy-C), 24.5 (CH2, cyclopentyl-C), 36.4 (CH2, cyclopentyl-C), 37.1 (CH2, cyclopentyl-C), 37.2* (CH2, cyclopentyl-C), 37.7 (CH2, ProP-C), 38.2* (CH2, cyclopentyl-C), 48.5 (CH2, Pro5-C), 52.1 (CH3, OCH3), 66.6 (CH2, OCH2Ph), 66.9 (quat., Proa-C), 67.2 (quat., Glya-C), 127.8 (CH, Ph), 128.2 (CH, Ph), 128.4 (CH, Ph), 136.6 (quat., Ph), 154.1 (quat., NCO2), 155.7* (quat., NCO2), 170.5 (quat., Gly-CO) and 174.7 (quat., CO2CH3); m / z (EI+) 388.1991 (M+. C21H28N2O5 requires 388.1998).

[0311] (8aS)-Methyl-spiro[cyclopentane-l,3(4H)-tetrahydropyrrolo[ 1,2 -a] pyrazine ]-l, 4(2H)-dione (Cyclic cyclopentyl-G-2MeP) (Formula lb)

[0312] To a solution of amide 22 (54 mg, 0.14 mmol) in methanol (4.6 cm3) was added 10% Pd on activated charcoal (2.2 mg, 0.021 mmol) and the vessel flushed with hydrogen gas. The resulting suspension was stirred vigorously under an atmosphere of hydrogen for 17 h, then filtered through a Celite™ pad with methanol (15 cm3). The filtrate was concentrated to dryness under reduced pressure to give a yellow semi-solid which was purified by reverse-phase Cl 8 flash column chromatography (0-10% CH3CN / H2O; gradient elution) to afford cyclic cyclopentyl-G-2MeP (20 mg, 65%) as a yellow solid: mp 160-163 °C; [a]o -97.9 (c 1.61 in CH2CI2); nmax (filmVcm'13429, 2956, 2928, 2856, 1667, 1643, 1463, 1432, 1373, 1339, 1254, 1224, 1175, 1086, 1048, 976, 835, 774 and 730; 5H (300 MHz, CDCh) 1.47 (3H, brs, 8a-CH3), 1.56-2.19 (11H, m, 8-H2, 7-H2 and 7 x cyclopentyl), 2.58-2.67 (1H, br m, 1 x cyclopentyl), 3.48-3.56 (1H, m, 6-ZMHB), 3.72-3.82 (1H, m, 6-HAHB) and 6.56 (1H, br s, N-H); 5C (75 MHz, CDCh) 19.9 (CH2, 7-C), 24.6 (CH2, cyclopentyl), 24.92 (CH3, 8a-CH3), 24.93 (CH2, cyclopentyl), 36.0 (CH2, 8-C), 38.7 (CH2, cyclopentyl), 41.9 (CH2, cyclopentyl), 44.8 (CH2, 6-C), 64.3 (quat., 8a-C), 66.8 (quat., 3-C), 168.3 (quat., 4-C) and 172.2 (quat., 1-C); m / z (EI+) 222.1369 (M+. C12H18N2O2 requires 222.1368).

[0313] Example 5: Delivery of cG2-AllylP (Formula la) into the Brain After Oral Administration

[0314] In an in vivo study, male Sprague Dawley rats (aged 14 weeks) received a single dose of cG-2-AllylP, either 100 mg / kg or 200 mg / kg, by oral gavage. Cerebrospinal fluid (CSF) and whole blood were collected at 1.5 and 4 hours post-dose, and brain tissue was collected at 4 hours post-dose to evaluate cG-2-AllylP exposure. Table 1 below shows the concentration of cG-2-AllylP in blood, CSF, and the brain 1.5 hours after dosing. Table 1

[0315] Concentration of cG-2-AllylP in CSF, Blood, and the Brain in Wild Type Rats

[0316] Mean Test Article Exposure

[0317] Dose 100 mg / kg 200 mg / kg 200:100 mg / kg 1.5 h post-dose

[0318] CSF 40.4 μg / ml 82.2 μg / ml 2.03:1

[0319] Blood 58.5 μg / ml 116.0 μg / ml 1.98:1

[0320] 4 h post-dose

[0321] CSF 11.0 μg / ml 24.7 μg / ml 2.25:1

[0322] Blood 15.6 μg / ml 34.2 μg / ml 2.19:1

[0323] Brain 22.6 μg / ml 37.0 μg / ml 1.63:1

[0324]

[0325] CSF = cerebrospinal fluid.

[0326] There was an approximately proportional increase in the concentration of cG-2-AllylP in blood and CSF at 1.5 hours following a single, oral dose. There was also an approximately proportional increase in the concentration of cG-2-AllylP in blood, CSF, and the brain at 4 hours (when the animals were sacrificed) following a single, oral dose. At 4 hours post-dose, the concentration of cG-2-AllylP in blood and brain tissue was approximately equivalent.

[0327] Example 6: Oxygen-glucose deprivation in vitro model

[0328] Hypoxic-ischemic events can result in ischemic necrosis within minutes for the brain tissue exposed to the most drastic blood flow reduction; this irreversibly damaged brain tissue is known as the ischemic core. Surrounding the ischemic core is the ischemic penumbra, which contains cells that are less severely affected and that are potentially salvageable from a lethal fate. However, without improved perfusion or therapeutic intervention to increase the resistance of cells to injury, the ischemic cascade occurring in the penumbra will result in secondary cerebral damage thereby expanding the infarct core several hours to days after the onset of the HIE-induced brain injury.

[0329] A therapeutically relevant in vitro model of ischemic brain injury should mimic the conditions of the ischemic penumbra (i.e., where cells are functionally silent but initially viable). To study ischemic brain injury in vitro, ischemia-like conditions can be achieved by ‘oxygen-glucose deprivation’ or OGD. To this end, human iPSC-derived tricultures of glutamatergic neurons, GABAergic neurons, and astrocytes were cultured for 3 weeks until maturation. Cell cultures were then placed in glucose-free medium and incubated in 1% O2, 5% CO2, and 94% N2 for 24 h at 37 °C before returning them to medium containing glucose and normal oxygenation. Cyclic G-2-AllylP reduced the amount of OGD-driven cytotoxicity in a concentration-dependent manner (Figure 2A). Multielectrode array recordings of cultures revealed that OGD resulted in a significant decrease in burst spike number that was prevented by treatment with Cyclic G-2-AllylP (Figure 2B).

[0330] Example 7: Excitotoxicity in vitro models

[0331] Given that excitotoxicity is a key outcome of hypoxic-ischemic injury, the ability of cyclic G-2-AllylP to be neuroprotective was explored in two separate in vitro cytotoxicity experiments. In the first experiment, a combination of 3 -nitropropionic acid and glutamate was utilized to induce a neuronal insult to P8 cerebellar explants from mice. At concentrations as low as 100 pM, cyclic G-2-AllylP significantly reduced cell death resulting from excitotoxic / oxi dative damage (Figure 3).

[0332] In the second experiment, human iPSC-derived tricultures of glutamatergic neurons, GABAergic neurons, and astrocytes were utilised. Following maturation (28 days in culture), cells were treated with 100 pM glutamic acid to elicit excitotoxicity with and without MK801, IGF-1, and cG-2-AllylP for 1 h.

[0333] Animal Model and Clinical Studies

[0334] The following pharmacological studies described below demonstrate efficacy of cyclic G-2-AllylP in attenuation of symptoms of HIE. All of the following experiments were carried out using protocols developed under guidelines approved by the University of Auckland Animal Ethics Committee or comparable regulatory bodies.

[0335] Example 8: Effects of cG-2-AllylP in Rat Model of Hypoxic-Ischemic Encephalopathy

[0336] A) In a rat model of hypoxic-ischemic brain injury induced by transient ligation of the right carotid artery followed by 10 minutes of hypoxia (6% O2), treatment with cG-2-AllylP for 5 days improved somatosensory motor function (p<0.05), long-term histological outcome (p<0.0001), and reduced caspase-3 -mediated apoptosis. Additionally, cG-2-AllylP significantly (p<0.001) decreased microglial activation as measured by isolectin B-4 positive immunohistochemical staining (Figure 4). B) In a separate study in rats in which transient ischemia was induced by middle cerebral artery occlusion (MCAO), a single oral dose of cG-2-AllylP significantly reduced the volume of the resulting infarct (Figure 5).

[0337] Example 9: Effects of cG-2-AllylP in a Mouse Model of Hypoxic-Ischemic Encephalopathy (HIE)

[0338] To explore whether chronic administration of cG-2-AllylP showed benefit, an in vivo mouse model of hypoxic-ischemic encephalopathy (HIE) in which there is unilateral ligation of common carotid artery (using the Rice-Vannucci model) followed by 30 min of hypoxia (8% Ch), while maintained at normothermia throughout, was utilised. Treatment with cG-2-AllylP (200 mg / kg / day; PO) was conducted over a 6-week period, beginning on Day 3 (20 animals: 10 euthanized at P51, and 10 at P65). Biochemical and behavioral assays were conducted at postnatal days 51 and 65.

[0339] Four groups of evenly sexed (1 / 2F, 1 / 2M) CD1 at postnatal day 9:

[0340] • Group 1: no HIE, no treatment

[0341] 20 animals; 10 euthanized at P51, and 10 at P65

[0342] • Group 2: no HIE, 6 weeks treatment with cG-2-AllylP (200 mg / kg / day; PO) beginning on Day 3

[0343] 20 animals: 10 euthanized at P51, and 10 at P65

[0344] • Group 3: HIE, no treatment

[0345] 20 animals; 10 euthanized at P51, and 10 at P65

[0346] • Group 4: HIE, 6 weeks treatment with cG-2-AllylP (200 mg / kg / day; PO) beginning on Day 3

[0347] 20 animals: 10 euthanized at P51, and 10 at P65.

[0348] Measurements:

[0349] • Weight was obtained the day of injury, daily for the first week after injury, and then weekly until euthanasia.

[0350] • Behavioural testing was undertaken in accordance with that disclosed in Diaz et al. (Diaz, J., et al., “Therapeutic Hypothermia Provides a Variable Protection Against Behavioural Deficits After Neonatal Hypoxia-Ischemia: A Potential Role for Brain-Derived Neurotrophic Factor”, DevNeurosci, 2017, 39(1 -4):257- 272). • Day 3 (Post-natal day 12): Neuromotor behaviors: righting reflex and negative geotaxis.

[0351] o At this point, it was considered whether any of the HIE animals with normal negative geotaxis (<3 sec) will be excluded from the study. • Day 10 (Post-natal day 19): Neuromotor behaviors: righting reflex and negative geotaxis.

[0352] • Day 42 (Post-natal day 51) Completion of treatment for treated groups.

[0353] o 10 mice / group euthanized:

[0354] ■ 4 mice / group sent for spatial transcriptomics. 6 mice / group assessed for IGF-1 protein levels through use of ELISA (can also add on PCR, etc. to the homogenate depending on spatial transcriptomics results)

[0355] o Remaining 10 mice / group had behavioral assessments. These were done in sequence over 10-14 days so as to not exhaust the animals by performing too many in one day:

[0356] ■ Motor coordination and balance: beam walking and gait analysis ■ Phenotypic assessments: hyperactivity and anxiety-like behavior (open field), memory and learning (Y maze), episodic memory (object-place context recognition), sensorimotor function (adhesive removal)

[0357] • Day 56 (Post-natal day 65):

[0358] o 10 mice / group assessed for IGF-1 protein levels through use of ELISA or other biochemical assays based on results of day 42 assessments (PCR, IHC, etc)

[0359] IGF-1 protein levels were reduced in the ipsilateral brain tissue at post-natal day 65 (P65) in animals that underwent Hypoxic-Ischemic (HI) injury (Figure 7; note that there is a trend at post-natal day 51 in Figure 6). Treatment with cG-2-AllylP in animals that underwent Hypoxic-Ischemic (HI) injury restored the IGF-1 protein levels to sham levels at both postnatal days 51 and 65.

[0360] IL-1β and CXCL5 Neuroinflammatory markers, IL-1β and CXCL5, were elevated in mice that received the Hypoxic-Ischemic (HI) brain injury (Figure 8). Importantly, treatment with cG-2-AllylP reduced levels of both IL-1β and CXCL5 proteins (Figure 8).

[0361] Additional neuroinflammatory markers

[0362] Other neuroinflammatory markers, including IL-10, IL-28, TNFa, and CCL11, were significantly altered in mice receiving the Hypoxic-Ischemic (HI) injury, and appeared to be improved by treatment with cG-2-AllylP treatment (Figure 9).

[0363] Righting reflex

[0364] The righting reflex is a primitive reflex that is assessed as a measure of early neuromotor development. In rodent models of Hypoxic-Ischaemic Encephalopathy (HIE), the righting reflex is typically adversely affected. In this study, the time to return to a supine position after being placed on their backs in PND12 mice was evaluated. In mice in which the Hypoxic-Ischaemic (HI) injury was induced, time to righting was significantly lower in animals treated with cG-2-AllylP compared to those animals that received vehicle (Figure 10).

[0365] Example 10: Effects of cG-2-AllylP in Neonates and Infants Following Moderate to Severe Hypoxic Ischemic Encephalopathy and Therapeutic Hypothermia

[0366] Neonates and infants with gestational age at birth > 36 weeks and diagnosed with moderate to severe Hypoxic-Ischemic Encephalopathy (HIE) who received 72 hours of therapeutic hypothermia (TH) beginning within 6 hours of birth will be enrolled in the study within four days after completion of TH and return to normothermia. Participants (n=84) will be randomized 1:1 for active treatment vs. placebo. Study medicine (cG-2-AllylP ) or placebo will be administered orally or via nasogastric tube twice daily for 12 months at an age-based dose predicted to result in a median area under the plasma concentration curve (AUC) exposure of approximately 350 mcg.h / mL. Primary and key secondary endpoints will be assessed at 12 months following completion of dosing, or earlier, depending on the age appropriateness of the measure.

[0367] Inclusion and exclusion criteria will be designed to ensure both that the study population comprises infants and neonates that have been treated with TH as a part of their standard of care treatment and, due to the extent of their neurologic insult, were most likely to benefit from treatment. Primary and key secondary endpoints will include: • Safety (deaths and incidence of treatment-emergent adverse events [TEAEs], abnormal laboratory values, ECGs and seizures)

[0368] • Primary endpoint

[0369] o Bayley Scales of Infant and Toddler Development Version 4 (Bayley -4) at 24 months of age (e.g. cognitive scale, language scale, motor scale, social- emotional scale, adaptive behaviour scale)

[0370] • Key Secondary endpoints

[0371] o Age at which independent sitting is achieved as assessed by Bayley-4 item 18 on the Gross Motor Subtest

[0372] o Gross Motor Function Classification System, Expanded and Revised (GMFCS) at 24 months. ITEMIZED LIST OF EMBODIMENTS

[0373] Item 1. A method of treating Hypoxic-Ischemic Encephalopathy (HIE) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0374]

[0375] >5

[0376] Formula I;

[0377] wherein:

[0378] X1is selected from the group consisting of NR’, O, and S;

[0379] X2is selected from the group consisting of CH2, NR’, O, and S;

[0380] R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,

[0381] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl;

[0382] wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;

[0383] or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen. Item 2. The method of item 1, wherein R1is selected from the group consisting of hydrogen, -CH3, and -CH2CHCH2.

[0384] Item 3. The method of item 1 or item 2, wherein R2is selected from the group consisting of hydrogen and -CH3.

[0385] Item 4. The method of any one of items 1 to 3, wherein R3is selected from the group consisting of hydrogen and -CH3.

[0386] Item 5. The method of any one of items 1 to 4, wherein X1is NH.

[0387] Item 6. The method of any one of items 1 to 5, wherein X2is selected from the group consisting of CH2 and S.

[0388] Item 7. The method of any one of items 1 to 6, wherein R4and R5are each hydrogen, or taken together are selected from the group consisting of -CH2-(CH2)3-CH2- and -CH2-(CH2)2-CH2-.

[0389] Item 8. The method of any one of items 1 to 7, wherein the compound of Formula I is selected from the group consisting of:

[0390]

[0391] Formula Ia; Formula Ib; and Formula Ic.

[0392] Item 9. The method of any one of items 1 to 8, wherein the compound of Formula I is:

[0393]

[0394] Formula Ib.

[0395] Item 10. The method of any one of items 1 to 9, wherein the treatment comprises treating a symptom associated with Hypoxic-Ischemic Encephalopathy (HIE). Item 11. The method of any one of items 1 to 10, wherein Hypoxic-Ischemic Encephalopathy (HIE) is assessed using one or more clinical tests selected from the group consisting of APGAR score, Umbilical Artery (UA) pH, Base Excess (BE) pH, need for resuscitation and assisted ventilation, brain MRI, brain MRS (magnetic resonance spectrometry), electrocardiogram (ECG), electroencephalogram (EEG), cardiac echo, cranial ultrasound, arterial blood gas measurement, chest Xray, urinary output, hemoglobin, hematocrit, glucose, audiometry, visual evoked potential (VEP), auditory evoked potential (AEP), genetic testing, IGF-1 in serum (Total IGF-1, Free IGF-1, Bound [to IGFBPs] IGF-1); IGF-1 in cerebral spinal fluid (CSF) (Total IGF-1, Free IGF-1), IGFBPs in serum, (IGFBP-1, -2, -3, -4, -5, -6) in serum, IGFBPs in CSF, (IGFBP-1, -2, -3, -4, -5, -6) in CSF, lactate dehydrogenase (LDH), troponin-T, creatine phosphokinase (CK), serum interleukin (IL)- 10, and the urine lactate / creatinine (L / C) ratio, S100B, pNF-H (Phosphorylated axonal forms of neurofilament H), and serum biomarkers of brain injury including: Neuron-Specific Biomarkers (e.g., Neuron-Specific Enolase (NSE), Ubiquitin Carboxy-Terminal Hydrolase LI (UCH-L1), Tau protein, αII-Spectrin breakdown products (SBDP); Glial Cell Biomarkers (e.g., Glial Fibrillary Acidic Protein (GFAP), SI 00 Calcium -Binding Protein B (S100B), Myelin Basic Protein (MBP), Neurofilament Light Chain (NfL)); Inflammatory Biomarkers (e.g., Interleukin-6 (IL-6), Interleukin-8 (IL-8), C-Reactive Protein (CRP), Proinflammatory Cytokines); Oxidative Stress Biomarkers (e.g., Malondialdehyde (MDA), Glutathione (GSH), Superoxide Dismutase (SOD), Isoprostanes); Metabolic Biomarkers (e.g., Lactate, Glucose, Pyruvate, Amino Acids such as glutamate, and aspartate).

[0396] Item 12. The method of item 10 or item 11, wherein the severity of the symptom associated with Hypoxic-Ischaemic Encephalopathy (HIE) is assessed using one or more clinical tests selected from the group consisting of the Sarnat score, SIBEN system, the Clinical Global Impression of Severity (CGI-S), the Clinical Global Impression of Change (CGI-I), the Caregiver Global Impression of Change (CaGI-I), the Aberrant Behavior Checklist (ABC) and ABC Subscales, the Social Responsiveness Scale, the Repetitive Behavior Scale - Revised (RBS-R), Bayley Scales of Infant Development, Vineland Adaptive Behavior Scale, Mullen Scales of Early Learning, DSM-V criteria for ASD, Autism Diagnostic Observation Schedule (ADOS-2), Macarthur Bates Communicative Development Inventory, General Movement Assessment (GAM), Hammersmith Infant Neurological Examination (HINE), Gross Motor Function Classification System (GMFCS), Child Behavior Checklist (CBCL), and Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA). Item 13. The method of any one of items 10 to 12, wherein the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is selected from the group consisting of altered level of consciousness, abnormal blood pressure, low heart rate, abnormal heart rate, heart problems, cardiac arrest, cardiorespiratory changes, bradycardia, respiratory disturbance, periodic breathing, respiratory failure, breathing problems, apnoea, birth asphyxia, poor peripheral perfusion, too much acid in body fluids (acidosis), seizures or unusual movements, epilepsy, meconium staining, low muscle tone (hypotonia), tense muscles (hypertonia), blue, pale or grey skin, fingers or lips (cyanosis), low or poor reflexes, absence of reflexes such as sucking, swallowing or grasping, weak cry, irritability, perinatal encephalopathy, perinatal asphyxia, neonatal encephalopathy, periventricular leukomalacia, cystic encephalomalacia, static encephalopathy, cerebral palsy, unusual eye motion or dilation, hearing loss, unreactive to sights or sounds, difficulty feeding, mild to severe intellectual disabilities, mild to severe learning disabilities, cognitive impairment, neurob ehavioural disorders, aberrant behaviour, attention-deficit / hyperactivity disorder, difficulty paying attention, impaired executive function, autism spectrum disorder (ASD) or autism-like behaviours, and absent or impaired verbal or nonverbal communication.

[0397] Item 14. The method of any one of items 1 to 13, wherein the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is selected from the group consisting of respiratory disturbance, seizures, and low muscle tone (hypotonia).

[0398] Item 15. The method of any one of items 1 to 14, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with a further therapeutic agent.

[0399] Item 16. The method of item 15, wherein the further therapeutic agent is selected from the group consisting of an antiepileptic drug (e.g., ACTH, carbamazepine, clobazam, clonazepam, clonazepam, ethosuximide, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, phenobarbitone, phenytoin, prednisolone, rufinamide, sodium valproate, topiramate, topiramate, valproic acid, vigabatrin, zonisamide), a stimulant approved for use in children (e.g., amphetamine, dexmethylphenidate, lisdexamfetamine, methylphenidate, serdexmethylphenidate, dexmethylphenidate), risperidone, any sleep medicine, (e.g., melatonin, antihistamines such as diphenhydramine and hydroxyzine, alpha agonists such as Clonidine and guanfacine, benzodiazepines and related agents such as zolpidem, zaleplon, and eszopiclone, chloral hydrate, trazodone, doxepin), recombinant human growth hormone (rhGH), human growth hormone, recombinant human IGF-1 (rhIGF-1), IGF-1, IGF-2, any IGF Binding Protein (IGFBP), IGFBP-3, insulin, any statin, and caffeine.

[0400] Item 17. The method of any of items 1 to 16, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with therapeutic hypothermia.

[0401] Item 18. The method of any one of items 1 to 17, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered subsequent to therapeutic hypothermia.

[0402] Item 19. The method of any of items 1 to 18, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered for at least 90 days.

[0403] Item 20. The method of any one of items 1 to 19, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered orally.

[0404] Item 21. The method of any one of items 1 to 20, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in a dosage of from about 0.001 mg / kg to and including about 1000 mg / kg.

[0405] Item 22. The method of any of items 1 to 21, wherein the dose of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is about 0.01, or 0.1, or 1, or 10, or 20, or 50, or 75, or 100, or 500, or 1000, or 5000 mg / kg. Item 23. The method of any one of items 1 to 22, wherein the subject is a human being. Item 24. The method of any one of items 1 to 23, wherein the subject is a neonate.

[0406] Item 25. The method of any one of items 1 to 24, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable excipient. Item 26. The method of item 25, wherein the pharmaceutically acceptable excipient is selected from the group consisting of binders, carriers, additives, adjuvants, microemulsions, coarse emulsions, palatability agents, flavouring agents, and liquid crystals. Item 27. The method of item 25 or item 26, wherein the pharmaceutical composition is formulated as an oral solution, an oral suspension, or as a powder for preparing an oral solution or oral suspension.

[0407] Item 28. The method of any of items 1 to 27, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is cG-2-AllylP (Formula la), or Cyclic Cyclopentyl-G-2-MeP (Formula lb), or Cyclic Cyclohexyl-G-2-MeP (Formula Ic).

[0408] Item 29. The method of any of items 1 to 28, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is formulated as an aqueous solution.

[0409] Item 30. Use of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0410]

[0411] Formula I;

[0412] wherein:

[0413] X1is selected from the group consisting of NR’, O, and S;

[0414] X2is selected from the group consisting of CH2, NR’, O, and S;

[0415] R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,

[0416] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;

[0417] or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen;

[0418] in the manufacture of a medicament for the treatment of Hypoxic-Ischemic Encephalopathy (HIE).

[0419] Item 31. A compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0420]

[0421] Formula I;

[0422] wherein:

[0423] X1is selected from the group consisting of NR’, O, and S;

[0424] X2is selected from the group consisting of CH2, NR’, O, and S;

[0425] R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,

[0426] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;

[0427] or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen;

[0428] for use in treating Hypoxic-Ischemic Encephalopathy (HIE).

[0429] Item 32. The use of item 30, or the compound of item 31, wherein said subject is a human being.

[0430] Item 33. The use or compound of item 32, wherein said subject is a neonate.

[0431] Item 34. The use of item 30, or compound of item 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is cG-2-AllylP (Formula la), or Cyclic Cyclopentyl-G-2-MeP (Formula lb), or Cyclic Cyclohexyl-G-2-MeP (Formula Ic).

[0432] Item 35. The use of item 30, or compound of item 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is formulated as an aqueous solution.

[0433] Item 36. The use of item 30, or compound of item 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with therapeutic hypothermia.

[0434] Item 37. The use of item 30, or compound of item 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered subsequent to therapeutic hypothermia

[0435] Item 38. The use of item 30, or compound of item 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered for at least 90 days. Item 39. The use of item 30, or compound of item 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered orally.

[0436] Item 40. The method of treating Hypoxic-Ischameic Encephalopathy (HIE), or the use of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for treating a subject having Hypoxic-Ischemic Encephalopathy, substantially as described herein.

Claims

Claims1. A method of treating Hypoxic-Ischemic Encephalopathy (HIE) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:Formula I;wherein:X1is selected from the group consisting of NR’, O, and S;X2is selected from the group consisting of CH2, NR’, O, and S;R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl;wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen.

2. The method of claim 1, wherein R1is selected from the group consisting of hydrogen, -CH3, and -CH2CHCH2.

3. The method of claim 1 or claim 2, wherein R2is selected from the group consisting of hydrogen and -CH3.

4. The method of any one of claims 1 to 3, wherein R3is selected from the group consisting of hydrogen and -CH3.

5. The method of any one of claims 1 to 4, wherein X1is NH.

6. The method of any one of claims 1 to 5, wherein X2is selected from the group consisting of CH2 and S.

7. The method of any one of claims 1 to 6, wherein R4and R5are each hydrogen, or taken together are selected from the group consisting of -CH2-(CH2)3-CH2- and -CH2-(CH2)2-CH2-.

8. The method of any one of claims 1 to 7, wherein the compound of Formula I is selected from the group consisting of:Formula Ia; Formula Ib; and Formula Ic.

9. The method of any one of claims 1 to 8, wherein the compound of Formula I is:Formula Ib.

10. The method of any one of claims 1 to 9, wherein the treatment comprises treating a symptom associated with Hypoxic-Ischemic Encephalopathy (HIE).

11. The method of any one of claims 1 to 10, wherein Hypoxic-Ischemic Encephalopathy (HIE) is assessed using one or more clinical tests selected from the group consisting of APGARscore, Umbilical Artery (UA) pH, Base Excess (BE) pH, need for resuscitation and assisted ventilation, brain MRI, brain MRS (magnetic resonance spectrometry), electrocardiogram (ECG), electroencephalogram (EEG), cardiac echo, cranial ultrasound, arterial blood gas measurement, chest Xray, urinary output, hemoglobin, hematocrit, glucose, audiometry, visual evoked potential (VEP), auditory evoked potential (AEP), genetic testing, IGF-1 in serum (Total IGF-1, Free IGF-1, Bound [to IGFBPs] IGF-1); IGF-1 in cerebral spinal fluid (CSF) (Total IGF-1, Free IGF-1), IGFBPs in serum, (IGFBP-1, -2, -3, -4, -5, -6) in serum, IGFBPs in CSF, (IGFBP-1, -2, -3, -4, -5, -6) in CSF, lactate dehydrogenase (LDH), troponin-T, creatine phosphokinase (CK), serum interleukin (IL)-IO, and the urine lactate / creatinine (L / C) ratio, S100B, pNF-H (Phosphorylated axonal forms of neurofilament H), and serum biomarkers of brain injury including: Neuron-Specific Biomarkers (e.g., Neuron-Specific Enolase (NSE), Ubiquitin Carb oxy -Terminal Hydrolase LI (UCH-L1), Tau protein, αII-Spectrin breakdown products (SBDP); Glial Cell Biomarkers (e.g., Glial Fibrillary Acidic Protein (GFAP), SI 00 Calcium -Binding Protein B (S100B), Myelin Basic Protein (MBP), Neurofilament Light Chain (NfL)); Inflammatory Biomarkers (e.g., Interleukin-6 (IL-6), Interleukin-8 (IL-8), C-Reactive Protein (CRP), Proinflammatory Cytokines); Oxidative Stress Biomarkers (e.g., Malondialdehyde (MDA), Glutathione (GSH), Superoxide Dismutase (SOD), Isoprostanes); Metabolic Biomarkers (e.g., Lactate, Glucose, Pyruvate, Amino Acids such as glutamate, and aspartate).

12. The method of claim 10 or claim 11, wherein the severity of the symptom associated with Hypoxic-Ischaemic Encephalopathy (HIE) is assessed using one or more clinical tests selected from the group consisting of the Sarnat score, SIBEN system, the Clinical Global Impression of Severity (CGI-S), the Clinical Global Impression of Change (CGI-I), the Caregiver Global Impression of Change (CaGI-I), the Aberrant Behavior Checklist (ABC) and ABC Subscales, the Social Responsiveness Scale, the Repetitive Behavior Scale - Revised (RBS-R), Bayley Scales of Infant Development, Vineland Adaptive Behavior Scale, Mullen Scales of Early Learning, DSM-V criteria for ASD, Autism Diagnostic Observation Schedule (ADOS-2), Macarthur Bates Communicative Development Inventory, General Movement Assessment (GAM), Hammersmith Infant Neurological Examination (HINE), Gross Motor Function Classification System (GMFCS), Child Behavior Checklist (CBCL), and Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA).

13. The method of any one of claims 10 to 12, wherein the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is selected from the group consisting of altered levelof consciousness, abnormal blood pressure, low heart rate, abnormal heart rate, heart problems, cardiac arrest, cardiorespiratory changes, bradycardia, respiratory disturbance, periodic breathing, respiratory failure, breathing problems, apnoea, birth asphyxia, poor peripheral perfusion, too much acid in body fluids (acidosis), seizures or unusual movements, epilepsy, meconium staining, low muscle tone (hypotonia), tense muscles (hypertonia), blue, pale or grey skin, fingers or lips (cyanosis), low or poor reflexes, absence of reflexes such as sucking, swallowing or grasping, weak cry, irritability, perinatal encephalopathy, perinatal asphyxia, neonatal encephalopathy, periventricular leukomalacia, cystic encephalomalacia, static encephalopathy, cerebral palsy, unusual eye motion or dilation, hearing loss, unreactive to sights or sounds, difficulty feeding, mild to severe intellectual disabilities, mild to severe learning disabilities, cognitive impairment, neurob ehavioural disorders, aberrant behaviour, attention-deficit / hyperactivity disorder, difficulty paying attention, impaired executive function, autism spectrum disorder (ASD) or autism-like behaviours, and absent or impaired verbal or nonverbal communication.

14. The method of any one of claims 1 to 13, wherein the symptom associated with Hypoxic-Ischemic Encephalopathy (HIE) is selected from the group consisting of respiratory disturbance, seizures, and low muscle tone (hypotonia).

15. The method of any one of claims 1 to 14, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with a further therapeutic agent.

16. The method of claim 15, wherein the further therapeutic agent is selected from the group consisting of an antiepileptic drug (e.g., ACTH, carbamazepine, clobazam, clonazepam, clonazepam, ethosuximide, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, phenobarbitone, phenytoin, prednisolone, rufinamide, sodium valproate, topiramate, topiramate, valproic acid, vigabatrin, zonisamide), a stimulant approved for use in children (e.g., amphetamine, dexmethylphenidate, lisdexamfetamine, methylphenidate, serdexmethylphenidate, dexmethylphenidate), risperidone, any sleep medicine, (e.g., melatonin, antihistamines such as diphenhydramine and hydroxyzine, alpha agonists such as Clonidine and guanfacine, benzodiazepines and related agents such as zolpidem, zaleplon, and eszopiclone, chloral hydrate, trazodone, doxepin), recombinant human growth hormone (rhGH), human growth hormone, recombinant human IGF-1 (rhIGF-1), IGF-1, IGF-2, any IGF Binding Protein (IGFBP), IGFBP-3, insulin, any statin, and caffeine.

17. The method of any of claims 1 to 16, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with therapeutic hypothermia.

18. The method of any one of claims 1 to 17, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered subsequent to therapeutic hypothermia.

19. The method of any of claims 1 to 18, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered for at least 90 days.

20. The method of any one of claims 1 to 19, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered orally.

21. The method of any one of claims 1 to 20, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in a dosage of from about 0.001 mg / kg to and including about 1000 mg / kg.

22. The method of any of claims 1 to 21, wherein the dose of the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is about 0.01, or 0.1, or 1, or 10, or 20, or 50, or 75, or 100, or 500, or 1000, or 5000 mg / kg.

23. The method of any one of claims 1 to 22, wherein the subject is a human being.

24. The method of any one of claims 1 to 23, wherein the subject is a neonate.

25. The method of any one of claims 1 to 24, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable excipient.

26. The method of claim 25, wherein the pharmaceutically acceptable excipient is selected from the group consisting of binders, carriers, additives, adjuvants, microemulsions, coarse emulsions, palatability agents, flavouring agents, and liquid crystals.

27. The method of claim 25 or claim 26, wherein the pharmaceutical composition is formulated as an oral solution, an oral suspension, or as a powder for preparing an oral solution or oral suspension.

28. The method of any of claims 1 to 27, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is cG-2-AllylP (Formula la), or Cyclic Cyclopentyl-G-2-MeP (Formula lb), or Cyclic Cyclohexyl-G-2-MeP (Formula Ic).

29. The method of any of claims 1 to 28, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is formulated as an aqueous solution.

30. Use of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:>5Formula I;wherein:X1is selected from the group consisting of NR’, O, and S;X2is selected from the group consisting of CH2, NR’, O, and S;R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl;wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen;in the manufacture of a medicament for the treatment of Hypoxic-Ischemic Encephalopathy (HIE).

31. A compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:Formula I;wherein:X1is selected from the group consisting of NR’, O, and S;X2is selected from the group consisting of CH2, NR’, O, and S;R1, R2, R3, R4, and R5are independently selected from the group consisting of hydrogen, halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle,wherein each alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10-membered heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -OR’, -SR’, -NR’R’, -NO2, -CN, -C(O)R’, -C(O)OR’, -C(O)NR’R’, -C(NR’)NR’R’, alkyl, heteroalkyl, alkenyl, and alkynyl;wherein each R’ is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10-membered carbocycle, and 3-10- membered heterocycle;or R4and R5taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; or R2and R3taken together are -CH2-(CH2)n-CH2- where n is an integer from 0-6; with the proviso that when R1is CH3, R2is hydrogen, R3is hydrogen, and R4is hydrogen, then R5is not benzyl; and when R1is hydrogen, then at least one of R2and R3is not hydrogen;for use in treating Hypoxic-Ischemic Encephalopathy (HIE).

32. The use of claim 30, or the compound of claim 31, wherein said subject is a human being.

33. The use or compound of claim 32, wherein said subject is a neonate.

34. The use of claim 30, or compound of claim 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is cG-2-AllylP (Formula la), or Cyclic Cyclopentyl-G-2-MeP (Formula lb), or Cyclic Cyclohexyl-G-2-MeP (Formula Ic).

35. The use of claim 30, or compound of claim 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is formulated as an aqueous solution.

36. The use of claim 30, or compound of claim 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with therapeutic hypothermia.

37. The use of claim 30, or compound of claim 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered subsequent to therapeutic hypothermia38. The use of claim 30, or compound of claim 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered for at least 90 days.

39. The use of claim 30, or compound of claim 31, wherein the compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered orally.

40. The method of treating Hypoxic-Ischameic Encephalopathy (HIE), or the use of a compound of Formula I, or pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for treating a subject having Hypoxic-Ischemic Encephalopathy, substantially as described herein.

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