Myeloperoxidase (MPO) inhibition as a treatment target for delayed cerebral injury (DCI) in aneurysmal subarachnoid hemorrhage (SAH)

Abstract

Provided herein is a method to prevent or treat cognitive dysfunction caused by delayed cerebral injury (DCI) after aneurysmal subarachnoid hemorrhage (SAH) comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO.

Description

[0001]1036.343WO1 / PROVENJ-MPO (02901-02) Myeloperoxidase (MPO) inhibition as a treatment target for Delayed Cerebral Injury (DCI) in Aneurysmal Subarachnoid Hemorrhage (SAH) Priority This application claims the benefit of the filing date of U.S. application No.63 / 482,886, filed on February 2, 2023, the disclosure of which is incorporated by reference herein. Government Funding This invention was made with government support under NS074997 awarded by the National Institutes of Health. The government has certain rights in the invention. Background Aneurysmal subarachnoid hemorrhage (SAH) occurs due to the rupture of an intracranial aneurysm (an outpouching of a blood vessel leading to the brain). Although SAH accounts for only 3% of all stroke syndromes, it accounts for 25% of the cost of lifelong stroke care (6). Unlike ischemic stroke, SAH tends to affect younger patients, including some in their 20’s and 30’s who are still in the prime of their productive lives. In addition, the disability among survivors of SAH includes both physical and cognitive disability (7-9). Because of this younger patient-age demographic and the addition of cognitive issues, patients with SAH lose more productive and meaningful work years than other stroke syndromes (10, 11). Summary Provided herein is a method to prevent or treat cognitive dysfunction caused by delayed cerebral injury (DCI) after aneurysmal subarachnoid hemorrhage (SAH) comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO. One aspect provides a method to prevent or treat cognitive dysfunction caused by delayed cerebral injury (DCI) comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO. Another aspect provides a method to prevent or treat delayed cerebral injury (DCI) comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO. One aspect provides a method to prevent infiltration of neutrophils in the meninges comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO. A further aspect provides a method to reverse late memory deficits comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO. 1036.343WO1 / PROVENJ-MPO (02901-02) In one aspect, the administration is systemic administration. In one aspect, the subject has had an aneurysmal subarachnoid hemorrhage (SAH). In one aspect, the small molecule is one or more of N-Acetyl Lysyltyrosylcysteine Amide (KYC), an N-Acetyl Lysyltyrosylcysteine Amide (KYC) and / or a thioxanthine. In one aspect, the small molecule is one or more of: . In one aspect, the small molecule is a thioxanthine. In one aspect, the thioxanthine is a compound of formula (I): 1036.343WO1 / PROVENJ-MPO (02901-02) wherein at least one of X and Y represents S, and the other represents O or S; L represents (R12)p-Q-(CR13R14)r; wherein (R12)pand (CR13R14)reach optionally contain one or two double or triple bonds; wherein Q is O, S(O)n, NR6, NR6C(O), C(O)NR6, or a bond; wherein R12is selected from Cl to 6 alkyl or Cl to 6 alkoxy, said Cl to 6 alkyl or said Cl to 6 alkoxy is optionally substituted with OH, halogen, CF3, CHF2, CFH2, CN, NR4R5, phenoxy or aryl; and wherein said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; and wherein said phenoxy optionally incorporates a carbonyl adjacent to the oxygen; and wherein said Cl to 6 alkoxy optionally incorporates a carbonyl adjacent to the oxygen; wherein R13and R14are independently selected from hydrogen, OH, halogen, CF3, CHF2, CFH2, CN, NR4R5, Cl to 6 alkyl, phenoxy and Cl to 6 alkoxy; wherein said phenoxy or Cl to 6 alkoxy optionally incorporates a carbonyl adjacent to the oxygen; and wherein said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; wherein p represents an integer 0, 1, 2, 3 or 4 and r represents an integer 0, 1, 2, 3 or 4; and wherein 1 < p+ r < 7; R represents a mono- or bicyclic heteroaromatic ring system containing one or more heteroatoms selected from N, O and S; wherein said mono- or bicyclic heteroaromatic ring system is optionally fused with one or two 5- or 6-membered saturated or partially saturated ring(s) containing one or more atoms selected from C, N, O and S, wherein said mono- or bicyclic heteroaromatic ring system alone or when fused with one or two 5- or 6- membered saturated or partially saturated ring(s) is optionally substituted with one or more substituents independently selected from halogen, CHF2, CH2F, CF3, SO(n)R9, SO(n)NR9R10, (CH2)nR3, NR4R5, OH, Cl to 7 alkyl, Cl to 7 alkoxy, phenoxy, aryl, CN, C(O)NR2R3, NR2C(O)R3, C(O)R3, a 5- or 6-membered saturated or partially saturated ring containing one or more atoms selected from C, N, O or S, and a mono- or bicyclic heteroaromatic ring system containing one or more heteroatoms selected from N3S or O; and wherein said Cl to 7 alkoxy is optionally substituted with Cl to 6 alkoxy or aryl; and wherein said Cl to 7 alkoxy or said phenoxy is optionally incorporating a carbonyl adjacent to the oxygen; and wherein said Cl to 7 alkyl is optionally substituted with hydroxy or Cl to 6 alkoxy; and wherein said Cl to 7 alkyl is optionally incorporating a carbonyl at any position in the Cl to 7 alkyl; and wherein said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; at each occurrence, R2, R3, R4, R5, R6, R9and R10are independently selected from hydrogen, Cl to 6 alkyl, Cl to 6 alkoxy, aryl and phenoxy; said Cl to 6 alkoxy or phenoxy is optionally incorporating a carbonyl adjacent to the oxygen; and said Cl to 6 alkyl is optionally substituted with halogen, Cl to 6 alkoxy, CHO, C2 to 6 alkanoyl, OH, C(O)NR7R8or 1036.343WO1 / PROVENJ-MPO (02901-02) NR7C(O)R8; and said aryl or said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; or the groups NR2R3, NR4R5and NR9R10each independently represents a 5 to 7 membered saturated azacyclic ring optionally incorporating one additional heteroatom selected from O, S and NR11, said ring being optionally further substituted with halogen, Cl to 6 alkoxy, CHO, C2 to 6 alkanoyl, OH, C(O)NR7R8or NR7C(O)R8; at each occurrence R, R and R independently represent hydrogen or Cl to 6 alkyl, or the group NR7R8represents a 5 to 7 membered saturated azacyclic ring optionally incorporating one additional heteroatom selected from O, S and NR11; n represents an integer O, 1 or 2; with the optional proviso that for R1thienyl or furyl is excluded; and with the optional proviso that when Q is O, S(O)n, NR6, NR6C(O) or C(O)NR6, then p is greater or equal to 1; as a pharmaceutically acceptable salt, solvate or solvate of a salt thereof. In one aspect, X represents S and Y represents O. In one aspect, L represents Cl to C7 alkylene. In one aspect, L represents Cl to C3 alkylene. In one aspect, L represents Cl alkylene. In one aspect, L represents C2 alkylene. In one aspect, R1represents a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S and said 5 or 6 membered heteroaromatic ring may optionally be fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S, and said ring system (said 5 or 6 membered heteroaromatic ring alone, or said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring) being optionally substituted by one or more substituents independently selected from halogen, CHF2, CH2F, CF3,SO(n)R9, SO(n)NR9R10, OH, Cl to 7 alkyl, Cl to C7 alkoxy, CN, CONR2R3, NR2COR3and COR3; said alkoxy being optionally further substituted by Cl to C6 alkoxy. In one aspect, R1represents a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S and said 5 or 6 membered heteroaromatic ring, fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S, and said ring system (said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring) being optionally substituted by one or more substituents independently selected from halogen, CHF2, CH2F, CF3, SO(n)R9, SO(n)NR9R105 OH, Cl to C7 alkyl, Cl to C7 alkoxy, CN, CONR2R3, NR2COR3and COR3; said alkoxy being optionally further substituted by Cl to C6 alkoxy, and said alkyl being optionally further substituted by hydroxy or Cl to C6 alkoxy. In one aspect, said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered 1036.343WO1 / PROVENJ-MPO (02901-02) saturated, partially saturated or unsaturated ring, is substituted with halogen. In aspect, said halogen is selected from Cl and F. In one aspect, the small molecule inhibitor is AZD5094. Brief Description of the Drawings Figures 1A-1D: A) Neutrophil percentage of inflammatory cells in the cerebral spinal fluid predicts cerebral vasospasm (CVs) by transcranial Doppler examination. The receiver operator curve suggests that 62% neutrophils is most predictive of CVs (2). B) Neutrophil depletion using the anti-neutrophil antibody (anti-Ly6G) prevents the development of vasospasm in the middle cerebral artery when administered at day 3 after hemorrhage in a murine model of SAH (red box; vessel caliber not different than Sham) (ND=neutrophil depletion). C) Spatial memory testing of mice after SAH using Barnes Maze test 5-10 days after hemorrhage and Morris water maze test in the same mice one month after hemorrhage. SAH mice take longer to find goal box than sham (upper panel) but neutrophil depletion 3 days after hemorrhage returns the performance to sham levels (lower panel, red line). The effect persists for one month. D) Slice electrophysiology at day 6 of mice with Sham, SAH or SAH with neutrophil depletion after 3 days. Neutrophil depletion normalizes long-term potentiation (red box; a surrogate for memory) (5). Figures 2A-2D: A) Barnes maze test with Sham and SAH shows that the late memory deterioration seen in WT mice is abrogated in MPO KO mice. Instillation of MPO and H2O2(lower graph) returns the late deterioration event (red line) (1). B) Although neutrophils are drivers of DCI after SAH, they are not found in the brain parenchyma 6 days after SAH when symptoms occur. The top three panels are low magnification views of the hippocampus on day 1, 3, and 6. The middle panels are high magnification views of the white box from the upper panel. The lower panels are normal brain (negative control), and two slices of EAE spinal cord (positive control) (3). C) Inhibition of the neutrophil chemoattraction by inhibition of the production of IL-17 via ROR ^^^^T (RORinh). Inhibition of IL-17 decreases microglial activation in the brain (top) and neutrophil infiltration of the meninges (bottom) (4). D) Mice deficient in myeloperoxidase (MPO KO) do not develop neutrophil infiltration of the meninges on day 3 after SAH (neutrophils in red. white bar =25um) (1). Figures 3A-3D: A) Processed pictographs of meningeal blood vessels (red, stained with anti-CD31 Ab) and neutrophils (green, LysM-GFP) 6 days after SAH. Left panel shows SAH without treatment, middle panel shows SAH with intrathecal (into CSF) treatment with the MPO inhibitor AZD5904 at time of hemorrhage, right panel shows SAH with intraperitoneal (IP, a mouse surrogate for intravenous) treatment with the same MPO inhibitor 1036.343WO1 / PROVENJ-MPO (02901-02) at the time of hemorrhage. B) Quantification of meningeal neutrophils shows IP treatment is most effective at decreasing meningeal neutrophil infiltration. C) Ratio of neutrophils in the blood vessel and in the meningeal parenchyma shows that IP treatment is most effective in preventing neutrophils from entering meninges (unpublished data). D). Scholl analysis that investigates the percentage of neutrophils at specific distances from the blood vessel (in nm where 0 nm is inside a blood vessel) shows that IP administration of AZD5904 prevents neutrophils from leaving the blood vessel. Figure 4: Depiction of physiology of MPO action in SAH and where an MPO inhibitor impacts this physiology. MPO inhibition prevents then infiltration of neutrophils in the meninges, blocks MPO production by neutrophils in the meninges and leads to less inflammation in the brain. Administration of the MPO blocker AZD5409 is most effective when given systemically as opposed to in the CSF space. Figures 5A-5B: Meningeal cell line (Ben-Men 1 meningothelial cells) incubated with MPO (A) or neutrophils (B). LPS is a positive control and H2O2is a substrate for MPO. MPO and MPO with H2O2do not increase the secretion of IL-8, an inflammatory cytokine produced by meningothelial cells in response to stress. Neutrophils cultured with meningothelial cells do increase IL-8 more than the positive control LPS. This suggests that a non-MPO effector function of neutrophils is responsible for IL-8 production. Figures 6A-6B: Mice were randomly assigned to SAH alone or SAH plus administration of 180μg / kg MPOi (AZ5904) intraperitoneal from day 2 after SAH to day 6 (n=8 / group). Mice receiving the inhibitor had decreased latency to goal box on a spatial memory task (Barne’s maze) over the 10 days of the experiment (A). Cumulative heat maps of the entire experimental group on days 3, 5 ,7 and 9 show the mice who receive the inhibitor appear to make contralateral-hole-search errors less frequently (goal box = red circles). SAH= subarachnoid hemorrhage, MPOi = myeloperoxidase inhibitor. Description of the Invention Delayed Cerebral Injury (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits that lead to life-long disability. More than 50 years of research has failed to identify effective treatments. Neutrophil infiltration into the meninges and cerebrospinal fluid (CSF) is linked to the development of these deficits after SAH in both patients and in animal models. Mice lacking the neutrophil enzyme, myeloperoxidase (MPO) do not develop meningeal neutrophil infiltration, or the cognitive deficits associated with DCI. Importantly, the re-introduction of biologically active MPO with its substrate hydrogen peroxide (H2O2) to the CSF of MPO deficient mice at the 1036.343WO1 / PROVENJ-MPO (02901-02) time of SAH returns the cognitive deficits suggesting strongly that MPO is the critical mediator of DCI cognitive dysfunction. Blocking MPO by systemic administration of small molecule inhibitors prevents the infiltration of neutrophils in the meninges and reverses late memory deficits demonstrating that MPO inhibitors are therapies to prevent DCI. Definitions The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the recited terms have the following meanings. All other terms and phrases used in this specification have their ordinary meanings as one of skill in the art would understand. Such ordinary meanings may be obtained by reference to technical dictionaries, such as Hawley's Condensed Chemical Dictionary 14th Edition, by R.J. Lewis, John Wiley & Sons, New York, N.Y., 2001. References in the specification to "one embodiment," "an embodiment," etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described. The singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, so that a compound X includes a plurality of compounds X. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with any element described herein, and / or the recitation of claim elements or use of "negative" limitations. The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated. The phrase "one or more" is readily understood by one of skill in the art, particularly when read in context of its usage. For example, one or more substituents on a phenyl ring refers to one to five, or one to four, for example if the phenyl ring is di-substituted. As used herein, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating a listing of items, “and / or” or “or” shall be 1036.343WO1 / PROVENJ-MPO (02901-02) interpreted as being inclusive, e.g., the inclusion of at least one, but also including more than one of a number of items, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” As used herein, the terms “including,” “includes,” “having,” “has,” “with,” or variants thereof, are intended to be inclusive similar to the term “comprising.” The term "about" can refer to a variation of ± 5%, ± 10%, ± 20%, or ± 25% of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent. For integer ranges, the term "about" can include one or two integers greater than and / or less than a recited integer at each end of the range. Unless indicated otherwise herein, the term "about" is intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment. The term about can also modify the endpoints of a recited range as discuss above in this paragraph. As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements. As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. A recited range (e.g., weight percentages or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as "up to," "at least," "greater than," "less than," "more than," "or more," and the like, include 1036.343WO1 / PROVENJ-MPO (02901-02) the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation. The term "contacting" refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo. An "effective amount" refers to an amount effective to treat a disease, disorder, and / or condition, or to bring about a recited effect. For example, an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art, especially in light of the detailed disclosure provided herein. The term "effective amount" is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host. Thus, an "effective amount" generally means an amount that provides the desired effect. The terms "treating," "treat" and "treatment" include (i) preventing a disease, such as atherosclerosis, plaque buildup, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and / or (iv) diminishing symptoms associated with the disease, pathologic or medical condition. Thus, the terms "treat", "treatment", and "treating" can extend to prophylaxis and can include prevent, 1036.343WO1 / PROVENJ-MPO (02901-02) prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated. As such, the term "treatment" can include medical, therapeutic, and / or prophylactic administration, as appropriate. The terms "inhibit," "inhibiting," and "inhibition" refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, group of cells, protein or its expression. The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting. As used herein, an “effective amount” or “therapeutically effective amount” means an amount sufficient to produce a selected effect, such as alleviating symptoms of a disease or disorder. In the context of administering compounds in the form of a combination, such as multiple compounds, the amount of each compound, when administered in combination with another compound(s), may be different from when that compound is administered alone. Thus, an effective amount of a combination of compounds refers collectively to the combination as a whole, although the actual amounts of each compound may vary. The term “more effective” means that the selected effect is alleviated to a greater extent by one treatment relative to the second treatment to which it is being compared. As used herein, an “instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the peptide of the invention in the kit for effecting alleviation of the various diseases or disorders recited herein. Optionally, or alternately, the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal. The instructional material of the kit of the invention may, for example, be affixed to a container which contains the identified compound invention or be shipped together with a container which contains the identified compound. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient. The term “otherwise identical sample,” as used herein, refers to a sample similar to a first sample, that is, it is obtained in the same manner from the same subject from the same tissue or fluid, or it refers a similar sample obtained from a different subject. The term “otherwise identical sample from an unaffected subject” refers to a sample obtained from a subject not known to have the disease or disorder being examined. The sample may of course be a standard sample. By analogy, the term “otherwise identical” can also be used regarding regions or tissues in a subject or in an unaffected subject. 1036.343WO1 / PROVENJ-MPO (02901-02) The term “standard,” as used herein, refers to something used for comparison. For example, it can be a known standard agent or compound which is administered and used for comparing results when administering a test compound, or it can be a standard parameter or function which is measured to obtain a control value when measuring an effect of an agent or compound on a parameter or function. Standard can also refer to an “internal standard”, such as an agent or compound which is added at known amounts to a sample and is useful in determining such things as purification or recovery rates when a sample is processed or subjected to purification or extraction procedures before a marker of interest is measured. Internal standards are often a purified marker of interest which has been labeled, such as with a radioactive isotope, allowing it to be distinguished from an endogenous marker. As used herein, a “subject in need thereof” is a patient, animal, mammal, or human, who will benefit from the method of this invention. As used herein, the term “pharmaceutically acceptable carrier” means a chemical composition with which an appropriate compound or derivative can be combined and which, following the combination, can be used to administer the appropriate compound to a subject. “Pharmaceutically acceptable” means physiologically tolerable, for either human or veterinary application. As used herein, “pharmaceutical compositions” include formulations for human and veterinary use. Methods involving conventional molecular biology techniques are described herein. Such techniques are generally known in the art and are described in detail in methodology treatises, such as Molecular Cloning: A Laboratory Manual, 2nd ed., vol.1-3, ed. Sambrook et al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989; and Current Protocols in Molecular Biology, ed. Ausubel et al., Greene Publishing and Wiley-Interscience, New York, 1992 (with periodic updates). Methods for chemical synthesis of nucleic acids are discussed, for example, in Beaucage and Carruthers, Tetra. Letts. 22: 1859-1862, 1981, and Matteucci et al., J. Am. Chem. Soc.103:3185, 1981. MPO Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene on chromosome 17 (Location: Chr 17: 58.27 – 58.28 Mb ENSG00000005381, UniProt: P05164; mRNA: NM_000250; protein: NP_000241). MPO is most abundantly expressed in neutrophils (a subtype of white blood cells) and produces hypohalous acids to carry out their antimicrobial activity, including hypochlorous acid, the sodium salt of which is the chemical in bleach. It is a lysosomal protein stored in azurophilic granules of the neutrophil and released into the extracellular space during degranulation. Neutrophil myeloperoxidase has a heme 1036.343WO1 / PROVENJ-MPO (02901-02) pigment, which causes its green color in secretions rich in neutrophils, such as mucus and sputum. The green color contributed to its outdated name verdoperoxidase. There are also non- enzymatic functions of MPO, including, but not limited to, recruitment of PMNs, evoking PMN motility, MPO playing a role in the collapse of the endothelial glycocalyx via binding with heparin sulfate and playing a role in shedding of syndecan1 in a neutrophile-dependent manner (some of these effects can be due to MPO’s positive charge / cationic charge; capacity to bind negatively charged cellular membranes) and MPO can transmigrate into various cell types (Kargapolova et al. Antioxidants.2021.10:562). The 150-kDa MPO protein is a cationic heterotetramer consisting of two 15-kDa light chains and two variable-weight glycosylated heavy chains bound to a prosthetic heme group complex with calcium ions, arranged as a homodimer of heterodimers. Both are proteolytically generated from the precursor peptide encoded by the MPO gene. The light chains are glycosylated and contain the modified iron protoporphyrin IX active site. Together, the light and heavy chains form two identical 73-kDa monomers connected by a cystine bridge at Cys153. The protein forms a deep crevice which holds the heme group at the bottom, as well as a hydrophobic pocket at the entrance to the distal heme cavity which carries out its catalytic activity. Variation in glycosylation and the identity of the heavy chain leads to variations in molecular weight within the 135-200 kDa range. In mice, three isoforms exist, differing only by the heavy chain. Treatment / MPO Inhibitors Treatment and prevention of DCI has been a goal in the field of medicine since the 1980’s. Most therapies to date have been focused on the unlikely mechanism of spastic blood vessels leading to cerebral ischemia. Currently, there is only one DCI-targeted, FDA-approved pharmaceutical, nimodipine, that has been shown to marginally improve outcome after SAH. Nimodipine was first studied as a vasodilator (to reverse arterial vasospasm). Despite failing to affect vasospasm, the drug improved patient outcome. Two related drugs were successful at reversing vasospasm but did not improve patient outcomes. Nimodipine is now felt to be a mild neuroprotective agent. Other treatment modalities have focused on dilating spasmed blood vessels with fluid expansion of the vascular space, angioplasty, or intraarterial administration of vasodilators. None of these therapies have been shown to improve patient outcomes. A CSF dialysis platform called Neuropheresis removed blood cells in the first few days after SAH. Pilot study data is published and shows promise. This technology has the disadvantage of being invasive and difficult to implement. It is not currently approved for use. 1036.343WO1 / PROVENJ-MPO (02901-02) There are currently 3 classes of MPO inhibitors used in animal studies and / or human clinical trials that work by blocking the catalytic site of MPO irreversibly. The simplest is a 3 amino acid sequence called N-Acetyl Lysyltyrosylcysteine Amide (colloquially called KYC). The second class are compounds that are N1-substituted-6-arylthiouracils. The largest class includes a group of drugs called thioxanthines (e.g., 2-thioxanthines). Provided below are examples of MPO inhibitors that can be used in the methods provided herein: Azide, 4-aminobenzoic acid hydrazide (4-ABH), Additional examples of 2-thioxanthines include: 1036.343WO1 / PROVENJ-MPO (02901-02) Additional thioxanthine compounds are provided below: A compound of Formula I: wherein at least one of X and Y represents S, and the other represents O or S; L represents (R12)p-Q-(CR13R14)r; wherein (R12)pand (CR13R14)reach optionally contain one or two double or triple bonds; wherein Q is O, S(O)n, NR6, NR6C(O), C(O)NR6, or a bond; wherein R12is selected from Cl to 6 alkyl or Cl to 6 alkoxy, said Cl to 6 alkyl or said Cl to 6 alkoxy is optionally substituted with OH, halogen, CF3, CHF2, CFH2, CN, NR4R5, phenoxy or aryl; and wherein said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; and wherein said phenoxy optionally incorporates a carbonyl adjacent to the oxygen; and wherein said Cl to 6 alkoxy optionally incorporates a carbonyl adjacent to the oxygen; wherein R13and R14are independently selected from hydrogen, OH, halogen, CF3, CHF2, CFH2, CN, NR4R5, Cl to 6 alkyl, phenoxy and Cl to 6 alkoxy; wherein said phenoxy or Cl to 6 alkoxy optionally incorporates a carbonyl adjacent to the oxygen; and wherein said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; wherein p represents an integer 0, 1, 2, 3 or 4 and r represents an integer 0, 1, 2, 3 or 4; and wherein 1 < p+ r < 7; R represents a mono- or bicyclic heteroaromatic ring system containing one or more heteroatoms selected from N, O and S; wherein said mono- or bicyclic heteroaromatic ring 1036.343WO1 / PROVENJ-MPO (02901-02) system is optionally fused with one or two 5- or 6-membered saturated or partially saturated ring(s) containing one or more atoms selected from C, N, O and S, wherein said mono- or bicyclic heteroaromatic ring system alone or when fused with one or two 5- or 6- membered saturated or partially saturated ring(s) is optionally substituted with one or more substituents independently selected from halogen, CHF2, CH2F, CF3, SO(n)R9, SO(n)NR9R10, (CH2)nR3, NR4R5, OH, Cl to 7 alkyl, Cl to 7 alkoxy, phenoxy, aryl, CN, C(O)NR2R3, NR2C(O)R3, C(O)R3, a 5- or 6-membered saturated or partially saturated ring containing one or more atoms selected from C, N, O or S, and a mono- or bicyclic heteroaromatic ring system containing one or more heteroatoms selected from N3 S or O; and wherein said Cl to 7 alkoxy is optionally substituted with Cl to 6 alkoxy or aryl; and wherein said Cl to 7 alkoxy or said phenoxy is optionally incorporating a carbonyl adjacent to the oxygen; and wherein said Cl to 7 alkyl is optionally substituted with hydroxy or Cl to 6 alkoxy; and wherein said Cl to 7 alkyl is optionally incorporating a carbonyl at any position in the Cl to 7 alkyl; and wherein said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; at each occurrence, R2, R3, R4, R5, R6, R9and R10are independently selected from hydrogen, Cl to 6 alkyl, Cl to 6 alkoxy, aryl and phenoxy; said Cl to 6 alkoxy or phenoxy is optionally incorporating a carbonyl adjacent to the oxygen; and said Cl to 6 alkyl is optionally substituted with halogen, Cl to 6 alkoxy, CHO, C2 to 6 alkanoyl, OH, C(O)NR7R8or NR7C(O)R8; and said aryl or said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; or the groups NR2R3, NR4R5and NR9R10each independently represents a 5 to 7 membered saturated azacyclic ring optionally incorporating one additional heteroatom selected from O, S and NR11, said ring being optionally further substituted with halogen, Cl to 6 alkoxy, CHO, C2 to 6 alkanoyl, OH, C(O)NR7R8or NR7C(O)R8; at each occurrence R, R and R independently represent hydrogen or Cl to 6 alkyl, or the group NR7R8represents a 5 to 7 membered saturated azacyclic ring optionally incorporating one additional heteroatom selected from O, S and NR11; n represents an integer O, 1 or 2; with the optional proviso that for R1thienyl or furyl is excluded; and with the optional proviso that when Q is O, S(O)n, NR6, NR6C(O) or C(O)NR6, then p is greater or equal to 1; as a pharmaceutically acceptable salt, solvate or solvate of a salt thereof. In one aspect of the invention, there is provided a compound of Formula (I), wherein X represents S and Y represents O. 1036.343WO1 / PROVENJ-MPO (02901-02) In another aspect of the invention, there is provided a compound of Formula (I), wherein L represents Cl to 7 alkylene. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein L represents Cl to 3 alkylene. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein L represents Cl alkylene (methylene). In yet another aspect of the invention, there is provided a compound of Formula (I), wherein L represents C2 alkylene (ethylene). In yet another aspect of the invention, there is provided a compound of Formula (I), wherein R1represents a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S and said 5 or 6 membered heteroaromatic ring may optionally be fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S, and said ring system (said 5 or 6 membered heteroaromatic ring alone, or said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring) being optionally substituted by one or more substituents independently selected from halogen, CHF2, CH2F, CF3,SO(n)R9, SO(n)NR9R10, OH, Cl to 7 alkyl, Cl to 7 alkoxy, CN, CONR2R3, NR2COR3and COR3; said alkoxy being optionally further substituted by Cl to 6 alkoxy. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein R1represents a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S and said 5 or 6 membered heteroaromatic ring, fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S, and said ring system (said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring) being optionally substituted by one or more substituents independently selected from halogen, CHF2, alky2 3 l, Cl to 7 alkoxy, CN, CONR R , NR2COR3and COR3; said alkoxy being optionally further substituted by Cl to 6 alkoxy, and said alkyl being optionally further substituted by hydroxy or Cl to 6 alkoxy. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring, is substituted with halogen. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein said halogen is selected from Cl and F. 1036.343WO1 / PROVENJ-MPO (02901-02) In yet another aspect of the invention, there is provided a compound of Formula (I), wherein said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring, is unsubstituted. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring, is selected from indolyl and benzimidazolyl. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein R1represents a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N and S, said aromatic ring being optionally substituted by one or more substituents independently selected from halogen, CHF2, CH2F, CF3, SO(n)R9, SO(n)NR9R10, OH, Cl to 7 alkyl, Cl to 7 alkoxy, CN, CONR2R3, NR2COR3and COR3; said alkoxy being optionally further substituted by Cl to 6 alkoxy, and said alkyl being optionally further substituted by hydroxy or Cl to 6 alkoxy. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein R1represents a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N and S, said aromatic ring being optionally substituted by one or more substituents independently selected from halogen, Cl to 6 alkyl and Cl to 6 alkoxy, said alkoxy being optionally further substituted by Cl to 6 alkoxy. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein R represents a five- or six-membered heteroaromatic ring containing 1 or 2 nitrogen atoms, said aromatic ring being optionally substituted by one or more substituents independently selected from halogen, CHF2, CH2F, CF3, SO(n)R9, SO(n)NR9R10, OH, Cl to 7 alkyl, Cl to 7 alkoxy, CN, CONR2R3, NR2COR3and COR3; said alkoxy being optionally further substituted by Cl to 6 alkoxy. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein said five- or six-membered heteroaromatic ring containing 1 or 2 nitrogen atoms, is substituted by one or more substituents independently selected from halogen and Cl to 7 alkyl. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein said heteroaromatic ring is selected from pyridyl and imidazolyl. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein said heteroaromatic ring is imidazolyl, substituted with halogen and Cl to 7 alkyl. The present invention also relates to a compound, said compound being selected from: 3-(pyridin-2-ylmethyl)-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-(pyridin-3 -ylmethyl)-2-thioxo- 1 ,2,3 ,7-tetrahydro-6H-purin-6-one; 1036.343WO1 / PROVENJ-MPO (02901-02) 3-(pyridin-4-ylmethyl)-2-thioxo-l,2,3,7-tetrahydro-6 / f-purin-6-one; 3-{[3-ethoxy-4-(2-ethoxyethoxy)pyridin-2-yl]methyl}-2-thioxo-l,2,3,7-tetrahydro-6H"- purin- 6-one; 3-[(5-fluoro-lH"-indol-2-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6 / i"-purin-6-one; 3-[(5-fluoro-lH-mdol-2-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-[(2-butyl-4-chloro-lH-imidazol-5-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6- one; 3-(lH'-benzimidazol-2-ylmethyl)-2-thioxo-l,2,3,7-tetrahydro-6H-purm-6-one; 3-[l-(lH-benzimidazol-2-yl)ethyl]-2-thioxo-l,2,3,7-tetrahydro-6H"-purin-6-one; 3-[(5-chloro-lH-mdol-3-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one and 3-[(4-fluoro-liϊ-indol-3-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purm-6-one; or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof. Further, the present invention also relates to a compound, said compound being selected from: 3-[2-(li7-Benzimidazol-2-yl)ethyl]-2-tliioxo-l)2,3,7-tetrahydro-6H"-purin-6-one; 3-(lH-Pyrazol-3-yhnethyl)-2-thioxo-l,2,3,7-tetrahydro-6H"-purin-6-one; 3-[(5-Methylpyrazm-2-yl)methyl)-2-thioxo-l,2,3,7-tetrahydro-6i7-purin-6-one; 3-[(3-Isopropylisoxazol-5-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6H"-purin-6-one; 3-[(4-Methyl-l,2,5-oxadiazol-3-yl)methyl]-2-thioxo-l52,3,7-tetrahydro-6H-purin-6-one; 3-[(6-Butoxypyridin-2-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6Η-purin-6-one; 3-[(4-Butoxypyridin-2-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-[(3-Butoxypyridin-2-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6H"-purm-6-one; 3-[2-(Pyridin-2-ylmethoxy)propyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-[(3,5-Dimethylisoxazol-4-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-[(l-Methyl-lH'-mdol-2-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-(2-Phenyl-2-pyridin-2-ylethyl)-2-thioxo-l,2,3,7-tetrahydro-6H'-purin-6-one; 3-(Quinolin-4-ylmethyl)-2-thioxo-l,2,3,7-tetrahydro-6i7-purin-6-one; 3 - [(6-Phenoxypyridin-3 -yl)methyl] -2-thioxo- 1 ,2,3 ,7-tetrahydro-6H-purin-6-one; 3-{2-[(Qumolin-4-ylmethyl)amino]ethyl}-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-(2-{[(l-Methyl-lHr-mdol-3-yl)methyl]amino}ethyl)-2-thioxo-l,2,3,7-tetrahydro-6H"-ρurin- 6-one; 3- {2-[Methyl(quinolin-4-ylmethyl)amino]ethyl} -2-thioxo- 1 ,2,3,7-tetrahydro-6H-purin-6- one; 3-(2-Aminopropyl)-2-thioxo-l,2,3,7-tetrahydro-6 / f-purin-6-one trifluoroacetate; 1036.343WO1 / PROVENJ-MPO (02901-02) 3-{2-[(Pyridm-2-ylmethyl)amino]propyl}-2-thioxo-l,2,3,7-tetrahydro-6H"-purin-6-one trifluoroacetate; 3-{2-[(Pyridin-3-yhnethyl)amino]propyl}-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-{2-[(Pyridin-4-yhnethyl)amino]propyl}-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-(2-{[(6-Chloropyridin-3-yl)methyl]amino}propyl)-2-thioxo-l32,3,7-tetrahydro-6H-purin- 6-one trifluoroacetate; 3-[2-({[6-(Trifluoromethyl)pyridin-3-yl]methyl}amino)propyl]- 2- thioxo-l,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate; 3 -(2- { [(4, 6-Dichloropyrimidin-5- yl)methyl] amino } propyl)-2-thioxo- 1 ,2,3 ,7-tetrahydro-6H- purin-6-one; 3-[2-({[2-(Dimethylamino)pyrimidin-5-yl]methyl}animo)propyl]-2-thioxo-l,2,3,7-tetrahydro- 6H-purin-6-one ; 3- {2-[(Quinolin-2-ylmethyl)amino]propyl} -2-thioxo- 1 ,2,3,7-tetrahydro- 6H-purin-6-one trifluoroacetate; 3-{2-[(Quinolin-3-ylmethyl)amino]propyl}-2-thioxo-l,2,3,7-tetrahydro-6H'-purin-6-one; 3-(2-{[(l-tert-Butyl-3,5-dimethyl-lH-pyrazol-4-yl)metliyl]ammo}propyl)-2-thioxo-l,2,3,7- tetrahydro-6H-purin-6-one; 3-[2-({[l-(l,l-Dioxidotetrahydro-3-thienyl)-3,5-dimethyl-lH"- pyrazol-4-yl]methyl} amino)propyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3- {2-[(lH-Benzoimidazol-2-ylmethyl)amino]propyl} -2-thioxo- 1 ,2,3,7-tetrahydro-6H-purin- 6-one; 3-[2-({[l-(Phenylsulfonyl)-lH-pyrrol-2-yl]methyl}amino]propyl]-2-thioxo-l,2,3,7- tetrahydro- 6H-purin-6-one trifluoroacetate; 3-{2-[({l-[(4-methylphenyl)sulfonyl]-lH-pyrrol-2-yl}methyl)amino]propyl}- 2-thioxo- 1 ,2,3,7-tetrahydro-6H"-purin-6-one trifluoroacetate; 3-(2- {[(1 -methyl- l / J-pyrrol-2-yl)methyl]amino}propyl)-2-thioxo- 1 ,2,3 ,7-tetrahydro-6H- purin-6-one; 3-[2-({[l-(4-5ec-Butylphenyl)-lH"-pyrrol-2-yl]methyl}amino)propyl)-2-thioxo- l,2,3,7- tetrahydro-6H-purin-6-one; 3-[2-({[l-(3-Methoxyphenyl)-l / f-pyrrol-2-yl]methyl}amino)propyl]-2-thioxo-l,2,3,7- tetrahydro-6H-purin-6-one; 3-[2-({[2,5-Dimethyl-l-(l,3-thiazol-2-yl)-lH-pyrrol-3-yl]methyl}amino)propyl]-2-thioxo- 1,2,3 ,7-tetrahydro-6H-purin-6-one; 3-[2-({[4-(3-Chlorobenzoyl)-l-methyl-lH-pyrrol-2-yl]methyl}amino)propyl]-2-thioxo- 1 ,2,3,7-tetrahydro-6H-purin-6-one; 3-{2-[(lH-Imidazol-2-ylmethyl)amino]propyl}-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-(2-{[(l-Methyl-lH-imidazol-2-yl)methyl]amino}propyl)-2-thioxo-l,2,3,7-tetrahydro-6H- purin-6-one; 1036.343WO1 / PROVENJ-MPO (02901-02) 3-(2-{[(4-Bromo-l-methyl-lHr-imidazol-5-yl)methyl]amino}propyl)-2-thioxo-l,2,3,7- tetrahydro-6H-purin-6-one; 3-(2-{[(l-Methyl-lH-indol-3-yl)methyl]amino}ρroρyl)-2-thioxo-l,2,3,7-tetrahydro-6H'-purin- 6-one; 2-TMoxo-3-{2-[(lH-l,2,3-triazol-5-ylmethyl)amino]proρyl}-l,2,3,7-tetrahydro-6H'-purin-6- one; 3-[2-({[l-(Benzyloxy)-lH-imidazol-2-yl]methyl}amino)propyl]-2-thioxo-l,2,3,7- tetrahydro- 6H-purin-6-one; 3-(2-{[(6-Bromo-2-methylimidazo[l,2-a]pyridin-3-yl)methyl]amino}propyl}-2-thioxo- 1 ,2,3 ,7-tetrahydro-6H-purin-6-one; 3-{2-[({l-[2-(2-Methoxyplienoxy)ethyl]-lH'-pyrrol-2-yl}methyl)amino]propyl]-2-thioxo-1,2,3 ,7-tetrahydro-6H-purin-6-one; iV-[l-Methyl-2-(6-oxo-2-thioxo-l,2,6,7-tetraliydro-3H-ρurin-3-yl)ethyl]pyridine-2- carboxamide; N-[l-Methyl-2-(6-oxo-2-thioxo-l,2,6,7-tetrahydro-3H'-pιirm-3-yl)ethyl]nicotinamide; TV-[I -Methyl-2-(6-oxo-2-thioxo- 1 ,2,6,7-tetrahydro-3H-purin-3 -yl)-ethyl] isonicotinamide; TV-fl-methyl^-Cό-oxo^-thioxo-l^jβ^-tetrahydro-SH-purin-S-yOethyy-l^-naphthyridine^- carboxamide; N-[l-Methyl-2-(6-oxo-2-thioxo-l,2,6,7-tetrahydro-3H-purm-3-yl)ethyl]quinolme-2- carboxamide; iV-[l-Metliyl-2-(6-oxo-2-tliioxo-l,2,657-tetraliydro-3H-purin-3- yl)etliyl]pyrimidme-2- carboxamide; and N-[l-Methyl-2-(6-oxo-2-thioxo-l,2,6,7-tetrahydro-3H-ρurin-3-yl)ethyl]-lH-imidazole-2- carboxamide trifluroaceate; or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof. The compounds of Formula (I) may exist in enantiomeric forms. Therefore, all enantiomers, diastereomers, racemates, tautomers and mixtures thereof are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallization, or ΗPLC. Alternatively, the various optical isomers may be prepared directly using optically active starting materials. The present invention includes compounds of Formula (I), in the form of salts. Suitable salts include those formed with organic or inorganic acids or organic or inorganic bases. Such salts will normally be pharmaceutically acceptable although salts of non- pharmaceutically acceptable acids or bases may be of utility in the preparation and purification of the compound in question. Thus, acid addition salts include inter alia those 1036.343WO1 / PROVENJ-MPO (02901-02) formed from hydrochloric acid or trifluoroacetic acid. Base addition salts include those in which the cation is inter alia sodium or potassium. The resultant compound of Formula (I), or another salt thereof, can where necessary be converted into a pharmaceutically acceptable salt thereof. The compounds of the invention and intermediates thereto may be isolated from their reaction mixtures and if necessary, further purified by using standard techniques. Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures. Intermediate compounds may also exist in tautomeric forms and may be used a purified tautomers or mixtures. Unless otherwise indicated, the term "Cl to 6 alkylene" or "Cl to 6 alkyl" referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, 1 -propyl, 1 -butyl, iso-butyl, tert-butyl, pentyl and hexyl. "Cl to 7 alkylene" or "Cl to 7 alkyl” are to be interpreted analogously. Unless otherwise indicated, the term "Cl to 6 alkoxy" referred to herein denotes a straight or branched chain alkoxy group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, tert-butoxy and pentoxy. The term "Cl to 7 alkoxy" is to be interpreted analogously. Unless otherwise indicated, the term "C2 to 6 alkanoyl" referred to herein denotes a straight or branched chain alkyl group having from 2 to 6 carbon atoms incorporating a carbonyl group. Examples of such groups include acetyl, propionyl and pivaloyl. Unless otherwise indicated, the term "halogen" referred to herein denotes fluoro, chloro, bromo and iodo. As used herein, "a mono- or bicyclic heteroaromatic ring system containing one or more heteroatoms selected from N, O and S" refers to a ring system containing one or more heteroatoms, however not more than 4 heteroatoms, selected from nitrogen, oxygen or sulphur. Examples, but not limiting, of such ring systems are pyrrole, oxazole, isoxazole, thiazole, imidazole, pyrazole, triazole, oxadiazole, tetrazole, pyridine, pyrazine, pyrimidine and pyridazine, indole, isoindole, benzimidazole and quinoline, naphthyridine and imidazo[l ,2- a]pyridine. As used herein, the term "5- or 6-membered saturated or partially saturated ring(s) containing one or more atoms selected from C, N, O and S" refers to a ring containing 5 to 6 atoms of which 1 to 4 ring atoms are chosen from nitrogen, sulfur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked; and wherein, unless stated otherwise, a ring 1036.343WO1 / PROVENJ-MPO (02901-02) sulphur atom is optionally oxidised to form the S-oxide(s). Examples, but not limiting, of such rings are tetrahydrofuran, pyrrolidine, piperidine, tetrahydropyridine, morpholine, piperazine, thioazolidine, dihydrothiazolidine, pyrrolidinone and piperidinone and 1,1- dioxidotetrahydrothiophene. Examples of a "5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S" include, but is not limited to, pyrrole, oxazole, isoxazole, thiazole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine and pyridazine. Examples of a "5- or 6-membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S" include, but is not limited to, cyclopentane, cyclohexane, cyclohexene, cyclopentanone, tetrahydrofuran, pyrrolidine, piperidine, tetrahydropyridine, morpholine, piperazine, pyrrolidinone and piperidinone. Examples of a "5- or 6-membered heteroaromatic ring containing one or more heteroatoms 5 selected from N, O or S" when fused with a "5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S" include, but is not limited to, indole, isoindole, benzimidazole and quinoline. Examples of a "a mono- or bicyclic heteroaromatic ring system containing one or more I0heteroatoms selected from nitrogen, oxygen and sulfur; wherein said mono- or bicyclic heteroaromatic ring system is fused with one or two 5- or 6-membered saturated or partially saturated ring(s) containing one or more atoms selected from carbon, nitrogen, oxygen and sulfur" include, but is not limited to, indole, isoindole, benzimidazole and quinoline, naphthyridine, imidazo[l,2-a]pyridine. In the definition of L, wherein L is defined to represents said (R12)pbonds to N as seen in formula (I) and said1 rbonds to R . In the definition of L, wherein L is defined to represent "Cl to 7 alkylene; said alkylene20optionally incorporating a heteroatom selected from O, S(O)nand NR6; said alkylene optionally incorporating one or two carbon-carbon double bonds", is intended to embrace a saturated or unsaturated straight or branched chain arrangement of 1 to 7 carbon atoms having two free valencies and in which any two singly bonded carbon atoms are optionally separated by a saturated carbon atom bound to O, S or NR6. The definition thus includes, 2s for example, methylene, ethylene, propylene, hexylene, ethylethylene, -CH2=CH2- , - CH2CH=CH-CH2-, -C(CH3)=CH2- -CH2=CH2-CH2O- -CH2O-, -CH2CH2O-CH2-, - CH2CH2O-CH2-CH2-, -CH2CH2S- and -CH2CH2NR6-. Examples of a 5 to 7 membered saturated azacyclic ring optionally incorporating one 30 additional heteroatom selected from O, S and NR11include pyrrolidine, piperidine, 1036.343WO1 / PROVENJ-MPO (02901-02) imindazolidine, pyrazolidine, piperazine, morpholine and thiomorpholine. A further aspect of the present invention is the use of the compounds provided herein as a medicament to treat or prevent DCI after SAH. A further aspect of the present invention is the use of a compound provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of the enzyme MPO is beneficial, including treating or preventing DCI after SAH. A further aspect of the present invention provides the use of a compound provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, for the treatment or prevention of DCI after SAH. Further, there is also provided a method of treating, or reducing the risk of, DCI after SAH in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In another aspect the present invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prophylaxis of diseases or conditions in which inhibition of the enzyme MPO is beneficial, including for the treatment or prevention of DCI after SAH. The compounds can be made by methods available to a skilled art worker (see, for example, WO2017120098, incorporated herein by reference in its entirety). Treatment / Administration The compounds described herein can be administered in a standard manner such as orally, parenterally, transmucosally (e.g., sublingually or via buccal administration), topically, transdermally, rectally, via inhalation (e.g., nasal or deep lung inhalation). Parenteral administration includes, but is not limited to intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal or via a high-pressure technique. For buccal administration, the composition can be in the form of tablets or lozenges formulated in conventional manner. For example, tablets and capsules for oral administration can contain conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (e.g., magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (e.g., potato 1036.343WO1 / PROVENJ-MPO (02901-02) starch or sodium starch glycollate), or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated according to methods well known in the art. Such preparations can also be formulated as suppositories for rectal administration, e.g., containing conventional suppository bases, such as cocoa butter or other glycerides. Compositions for inhalation typically can be provided in the form of a solution, suspension, or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant, such as dichlorodifluoromethane or trichlorofluoromethane. Typical topical and transdermal formulations comprise conventional aqueous or non-aqueous vehicles, such as eye drops, creams, ointments, lotions, and pastes, or are in the form of a medicated plaster, patch, or membrane. Additionally, compositions described herein can be formulated for parenteral administration by injection or continuous infusion. Formulations for injection can be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulation agents, such as suspending, stabilizing, and / or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use. A composition in accordance with the present invention also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the present invention can be formulated with suitable polymeric or hydrophobic materials (e.g., an emulsion in an acceptable oil), ion exchange resins, or as sparingly soluble derivatives (e.g., a sparingly soluble salt). For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may be used to form tablets. Solid compositions of a similar type are also employed as fillers in soft and hard- filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. Alternatively, the compounds / composition described herein can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example. Moreover, formulations containing these compounds can be presented as 1036.343WO1 / PROVENJ-MPO (02901-02) a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can contain conventional additives, such as suspending agents, such as sorbitol syrup, synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin, glucose / sugar syrup, gelatin, hydroxyethylcellulose, hydroxypropylmethylcellulose, aluminum stearate gel, emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol; and preservatives, such as methyl or propyl p- hydroxybenzoate and sorbic acid. The liquid forms in which the compositions described herein may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds described herein can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. The compounds described herein can also be administered in a controlled release formulation such as a slow release or a fast release formulation. Such controlled release formulations of the combinations described herein may be prepared using methods well known to those skilled in the art. The method of administration will be determined, by the attendant physician or other person skilled in the art after an evaluation of the patient's condition and requirements. The effective dose of a MPO inhibitor or a pharmaceutically acceptable salt thereof and a compound or a pharmaceutically acceptable salt thereof, which is used in the treatment and / or prevention of DCI after SAH in the combinations according to the present invention may vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder as well as the potency of the selected specific compound, the mode of administration, the age and weight of the patient, and the like. Determining a dose is within the skill of the ordinary artisan. 1036.343WO1 / PROVENJ-MPO (02901-02) The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition. Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain therapeutic effects. Typically, the effective dose of MPO inhibitors or a pharmaceutically acceptable salt thereof generally requires administering the compound in a range of from, and including, 1 to 1000 mg. According to one embodiment of the present invention, said range is from, and including, 2 to 800 mg or from, and including, 2 to 400 mg. In an alternative embodiment of the present invention the amount of MPO inhibitor or a pharmaceutically acceptable salt thereof is selected from about: 5, 10, 50, 100, 150, 200, 250, 300, 350, 400, 500, 550, 600, 700 and 800 mg. Typically, the effective dose compound or a pharmaceutically acceptable salt thereof, which is used in the treatment and / or prevention of DCI after SAH generally requires administering the compound in a range of from, and including, 1 to 1000 mg. According to one embodiment of the present invention, said range is from, and including, 2 to 800 mg or from, and including, 2 to 400 mg. In an alternative embodiment of the present invention the amount of compound or a pharmaceutically acceptable salt thereof, which is used in the treatment and / or prevention of DCI after SAH is selected from about: 5, 10, 50, 100, 150, 200, 250, 300, 350, 400, 500, 550, 600, 700 and 800 mg. The term "therapeutically effective amount" as used herein refers to a sufficient amount of the compound to treat DCI after SAH at a reasonable risk / benefit ratio applicable to any medical treatment. The term "treating" as used herein, refers to reversing, alleviating, delaying or inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of "treating" as defined herein. The term "disorder", unless stated otherwise, has the same meaning as the terms "condition" and "disease" and are used interchangeably throughout the description and claims. The term "agent" or “drug” means the compounds of the present invention. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition. Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain therapeutic effects. Example I 1036.343WO1 / PROVENJ-MPO (02901-02) Aneurysmal subarachnoid hemorrhage (SAH) occurs due to the rupture of an intracranial aneurysm (an outpouching of a blood vessel leading to the brain) and leads to long- term disability in a large proportion of survivors. Although SAH accounts for a minority of total stroke patients (only about 3% of all stroke syndromes), it carries an outsized effect on the patient’s lives and the United States economy (accounts for about 25% of the cost of lifelong stroke care (6)) for two reasons: the younger age of the patients, and the disability associated with the aneurysm rupture and subsequent damage. Unlike ischemic stroke that has an average age in the 7thdecade of life and less frequently affects young people, SAH has a broad age distribution from the teens to octogenarians with a median age in the early 50’s. SAH tends to affect younger patients, including some in their 20’s and 30’s who are still in the prime of their productive lives. In addition, the disability among survivors of SAH includes both physical and cognitive disability (7-9). Patients who develop delayed cerebral injury (DCI) experience cognitive deficits (more than strength deficits) that leave patients homebound, unable to work and needing supervision. This has ramifications for patients, their family members in the workforce, on community resource needs, and national health care costs. Further, because of this younger patient-age demographic and the addition of cognitive issues, patients with SAH lose more productive and meaningful work years than other stroke syndromes (10-11; survivors of SAH have longer expected survival which translates to more resource needs as well). Fortunately, it is commonly believed that a large part of this disability can be mitigated because the curious late complication of SAH called delayed cerebral injury (DCI) offers an opportunity to improve patient outcome after the initial hemorrhage. Some patients succumb to the initial bleeding episode either at home or early in their hospital stay. Of patients who survive the initial hemorrhage, the most prominent, potentially reversible syndrome is delayed cerebral injury (DCI) (6). The classically described syndrome of DCI occurs in approximately 50% of SAH patients. Delayed cerebral injury (DCI) is a syndrome that occurs 4-14 days after SAH and leads to long term disability. The syndrome includes alteration in mental status (with occasional focal neurological signs) which is often associated with fever, hyponatremia, and evidence of cerebral vasospasm (12). DCI was previously assumed to be due to ischemia (stroke) from arterial vasoconstriction (vasospasm), but treatment trials addressing arterial vasospasm in DCI have not improved outcomes suggesting that: 1) non-ischemic mechanisms are involved, and 2) vascular disease leading to ischemia is a small determinant of outcome. In addition, there is a growing recognition that the disability in DCI is due to cognitive deficits (cognitive testing in patients with SAH and DCI support the role of memory loss in the disability (18-20), not physical / motor impairment 1036.343WO1 / PROVENJ-MPO (02901-02) associated with stroke, despite the vascular nature of the injury. Although weakness and incoordination are known disabilities in SAH, more patients experience loss of memory, change in personality, affective disorders, and executive function disability. In an observational study of SAH patients who presented with SAH without motor or severely depressed consciousness and who made a good enough recovery from the hospital to be discharged directly home, 47% remained dependent on others for part or all their daily activities and almost half (49%) remained unemployed (including unpaid work such as caring for children or elderly adults) 18 months after SAH (13). Cognitive deficits are becoming recognized as the most important target for recovery. Patients who are hospitalized for SAH often spend 10-14 days in the hospital monitoring for the development of DCI which has both cost and patient satisfaction implications. There is clear evidence that prolonged hospital stay increases the probability of hospital acquired complications (14). In addition, resource limited hospitals find it difficult to support long hospital stays particularly for patient monitoring as opposed to therapeutic interventions. Until now, the treatment strategies for DCI have focused on the associated cerebral vasospasm. The armamentarium of treatments includes one preventative medication (nimodipine) and reactive strategies to improve cerebral blood flow by volume expansion / hypertension or by direct intraarterial vasodilation of decreased caliber arteries (12). Despite current therapies, DCI leads to long-term disability in a large proportion of survivors. The time delay between the hemorrhage and the onset of DCI is a potential window of opportunity for treatment that is not present in other types of cerebrovascular injury (15). DCI, often called Delayed Cerebral Ischemia, was previously assumed to be due to ischemia from arterial vasospasm (constriction of blood vessels) despite clinical trials of vasodilation failing to improve outcome (21-23). Controversy exists regarding the etiology of brain injury in DCI. Colloquially called “cerebral vasospasm” due to its association with arterial spasm on angiography, this association with vascular spasm has overly-simplistically led to the conclusion that ischemia is the major driver of pathology. Three human trials of vasodilators have called this into question. Administration of nimodipine, a calcium channel blocker, improves patient’s symptoms without improving vasoconstriction or decreasing strokes (24). Conversely, nicardipine, another calcium channel blocker, and clazosentan, an endothelin-1 antagonist, ameliorate vascular spasm but do not improve patient outcome (22,23,25,26). The finding that: 1) patient outcome can be improved without improving 1036.343WO1 / PROVENJ-MPO (02901-02) vasospasm and 2) that vasospasm can be improved without patient benefit makes ischemia as the driver of disability unlikely. Positron emission tomography (PET) blood flow scanning data support the findings of the clinical trials. In these studies, regional brain perfusion decreased marginally in DCI patients compared to non-DCI patients, but not to the level ischemia suggesting that ischemic cell death is not a major driver of pathology (27,28). In addition, a study in SAH patients with sequential MRI imaging of patients before and after the period of DCI found that a large proportion of strokes previously thought due to DCI are present in the first days of SAH. This suggests that the initial aneurysm rupture or subsequent aneurysm treatments may contribute to early ischemic disease (29). Other theories have been proposed to explain the delayed onset and brain injury associated with DCI. The theory of “early brain injury (EBI)” purports that damage from the initial intracranial hypertension and mechanical damage caused by the bleeding leads to poor outcome with or without DCI (30). This theory fails to recognize that between 30-40% of patients with SAH deteriorate in the time frame of DCI. The contrasting theory posits that microthromboses from platelet-leukocyte aggregates leads to arterial thrombosis and ischemia (32,32). Neither have convincingly explained the delayed onset or cognitive deficits associated with DCI. The evidence above does not exclude that ischemia is one of several mechanisms of brain damage in DCI. Studies have found that evidence of ischemic stroke after SAH is a prognostic indicator of poor outcome (33). Additionally, in patients with volume depletion (dehydration) or who are particularly susceptible to arterial spasm, ischemic stroke is an outcome (34). In animal models, in susceptible animal strains, cerebral vasospasm, EBI and micro-thromboses can lead to histological evidence of brain damage (35). The totality of the evidence does not support that these mechanisms are the major driver of long-term cognitive deficits in most patients who experience DCI after SAH. Inflammation has been identified as the mechanism most likely determinant of outcome in DCI (16,17). It is believed that inflammation plays a role in initiating DCI after SAH. Peripheral blood leukocyte counts in the first 2 days of SAH predict who will develop “cerebral vasospasm” (36,37). In animal models of SAH, several inflammatory mediators have been associated with cerebral vasospasm (fewer studies address DCI). E-selectin (CD62E) and ICAM-1(CD54), adhesion molecules that initiate endothelial transmigration of innate inflammatory cells such as neutrophils, eosinophils, and monocytes (as well as lymphocytes) into tissues, are mediators of vasospasm after SAH (38-40). Cytokine analysis of the blood of 1036.343WO1 / PROVENJ-MPO (02901-02) patients with SAH also suggests inflammation is associated with DCI, and poor outcome (41,42). Biomarker analysis shows that TNF ^^^^ levels predict poor outcome (43). The search for cellular actors in the development of DCI has implicated several cells that appear to play a role. There is evidence that endothelial cell interactions with circulating leukocytes drive the onset of DCI (40). In addition, microglia, resident brain inflammatory cells, have been implicated in promoting inflammation after SAH (44). In addition to cells local to the brain, systemic inflammatory cells have been associated with DCI. Interestingly, the late onset of DCI would suggest a role for the adaptive immune system (T cells and B cells), but research suggests that cells of the innate immune system play a larger role. Monocytes and macrophages increase over the first few days in animal models of SAH and, when sequestered away from the brain, appear to confer benefit to the development of inflammation after SAH (45). Provided herein is the role of another inflammatory cell, the neutrophil and a protein produced by neutrophils, Myeloperoxidase (MPO). This cell, and its effector molecules, are targets for drug development. Neutrophils are part of the innate immune system. In infection, they are an early actor in inflammation, and make up more than 90% of cells found in pus. However, neutrophils appear to act differently in sterile injuries (where there is no infection but inflammation) than in bacterial infections. In sterile diseases outside the nervous system (in arthritis and other autoimmune disorders,) neutrophils play a delayed role (46-48). In the setting of SAH, patients who go on to develop DCI show an increase in neutrophils in the CSF three (3) days after hemorrhage (Figure 1A) (2). This correlates well with studies of cytokines and adhesion factors that consistently show that those that act on neutrophils are predictive of DCI (49). Inhibition of the neutrophil activation factors CD11b / CD18 and depletion of neutrophils rescue aspects of DCI (50). In addition, depletion of blood borne neutrophils improves both the vascular spasm and spatial memory deficits analogous to those seen in patients with DCI (Figure 1B, C, and D) (5). Interestingly, the timing of depletion sheds light on the time course of action of neutrophils in SAH. Depletion of neutrophils prior to the hemorrhage is protective, but after hemorrhage, there is a period around three days in mice that affords the most protection. This agrees with histological data that neutrophil accumulation in the central nervous system (CNS) becomes evident at the same three-day timepoint (DCI in mice develops reliably around day 6 whereas in patients is more variable). Neutrophils have a variety of effector molecules that are studied in the setting of infection. Their role in sterile injuries is less well understood (51). In SAH, myeloperoxidase 1036.343WO1 / PROVENJ-MPO (02901-02) (MPO), an enzyme largely restricted to neutrophils and immature monocytes that catalyzes the reaction between halogens and superoxide to make a bleach (most commonly the chlorinated bleach HOCl.; catalyzes the hydroxylation of chloride ions into hypochlorite (a form of bleach)), but also has important nonenzymatic functions including activating neutrophils and promoting neutrophil accumulation in the central nervous system (52). As provided herein, MPO is an intermediary in this neutrophil-mediated brain damage after SAH (Figure 4). In the mouse model of SAH, neutrophil depletion / inactivation and MPO inhibition prevent the development of DCI and its downstream cognitive consequences. The conclusion that neutrophils and MPO play a role in the development of DCI is based on both human and animal model data. Neutrophils, as a percentage of leukocytes, found in the cerebral spinal fluid (CSF) of patients with SAH three days after the hemorrhage is a predictor of arterial vasospasm (a biomarker for DCI). In the mouse model, depletion of neutrophils throughout the entire body protects the animals from developing arterial vasospasm (biomarker) and the cognitive damage associated with DCI. In mice that have neutrophils that lack MPO (MPO knockout (KO)), vasospasm and the cognitive damage associated with DCI does not develop. Instillation of MPO (and its substrate H2O2) into the CSF of MPO KO mice after SAH reverses the protection leading to the development of cognitive deficits (demonstrating that MPO mediates the DCI event; Figure 2)). Finally, blocking MPO in genetically normal mice after SAH prevents the infiltration of neutrophils into the meninges (where the CSF resides) and improve performance o delayed spatial memory tasks. Based on this data, MPO inhibition can prevent DCI after SAH. The meninges have been long characterized as the “coverings of the brain”. In the last 10 years, with the advent of RNA sequencing data and better flow cytometric techniques, the meninges have been found to have a rich landscape of immune cells, and more recently, functional consequences for the brain (reviewed in 53). For example, interferon gamma (INF ^^^^) produced from T cells in the meninges affects sociability behavior in mice (54). Meningeal lymphatic channels play a role in immune surveillance and coordinate with the brain glymphatic system to monitor brain solutes for infection, inflammation, and abnormal cells (55,56). The role of meningeal neutrophils is an active area of investigation. Neutrophils make up the largest proportion of inflammatory cells in the meninges (27%) (57). In SAH, few neutrophils enter the brain. Instead, neutrophils accumulate in the perivascular spaces and in the meninges (Figure 2B). The time course of neutrophil infiltration in mice correlates with the critical period of neutrophil depletion (1,5). Prevention of neutrophil infiltration into the 1036.343WO1 / PROVENJ-MPO (02901-02) meninges by blocking RoR ^^^^T, a transcription factor for IL-17, a potent homing agent for neutrophils into tissues, decreases inflammation in the brain and neutrophil infiltration of the meninges (Figure 2C) (4). In addition, MPO KO mice do not develop meningeal infiltration by neutrophils suggesting that MPO also plays a role in homing of neutrophils into the meninges (Figure 2D) (1). The data suggests that neutrophil infiltration into the meninges is a step in the late development of brain inflammation days after the hemorrhage which leads to inflammation in the brain and the development of DCI and cerebral vasospasm. In an animal model of subarachnoid hemorrhage, MPO inhibition was tested with the MPO inhibitor (AZ5904) administered via the intraperitoneal route in SAH versus SAH alone and it was found that, like in the MPO KO mice, the inhibitor improved spatial memory in the period of DCI (day 5-10) (Figure 6A). The data reveals that data reveals that MPO inhibition improves outcome. For example, mice receiving the inhibitor had decreased latency to goal box on a spatial memory task (Barne’s maze) over the 10 days of the experiment (top panel). Cumulative heat maps of the entire experimental group on days 3, 5 ,7 and 9 show the mice who receive the inhibitor make contralateral-hole-search errors less frequently. A series of cell culture experiments where MPO or activated neutrophils were co- cultured with cells of the meninges showed that neutrophils, but not MPO alone, lead to the release of signaling molecules (particularly, the cytokine IL-8) that are implicated in the development of DCI. This shows that MPO is not a downstream actor in development of cognitive deficits after SAH (Figure 5). Because the meninges are outside the blood brain barrier, administration of MPO inhibitors outside the nervous system appears to be sufficient to prevent meningeal infiltration. In fact, administration of the MPO inhibitor AZD5094 prevents the infiltration of neutrophils into the meninges. Interestingly, intraperitoneal administration (a surrogate for intravenous administration) decreases infiltration of neutrophils in the meninges more effectively than intrathecal administration (directly into the CSF space) suggesting that systemic administration of MPO inhibition is the preferred route (Figure 3A and B). All the data taken together suggests that peripheral administration of an MPO inhibitor after SAH decreases neutrophil infiltration of the meninges, decreases brain inflammation and reverses late cognitive memory deficits by preventing DCI (Figure 4). 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Conserved meningeal lymphatic drainage circuits in mice and humans. J Exp Med. Aug 12022;219(8)doi:10.1084 / jem.20220035 61. DeSisto J, O'Rourke R, Jones HE, et al. Single-Cell Transcriptomic Analyses of the Developing Meninges Reveal Meningeal Fibroblast Diversity and Function. Dev Cell. Jul 6 2020;54(1):43-59 e4. doi:10.1016 / j.devcel.2020.06.009 Subarachnoid hemorrhage (Outcomes, cognitive problems and cost) Modi, S., et al., Cost of hospitalization for aneurysmal subarachnoid hemorrhage in the United States.Clin Neurol Neurosurg, 2019.182: p.167-170. Al-Khindi, T., R.L. Macdonald, and T.A. Schweizer, Cognitive and functional outcome after 1036.343WO1 / PROVENJ-MPO (02901-02) aneurysmal subarachnoid hemorrhage. Stroke, 2010.41(8): p. e519-36. Powell, J., et al., Psychosocial outcomes at 18 months after good neurological recovery from aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry, 2004.75(8): p.1119- 24. Treatments van Gijn, J. and G.J. Rinkel, Subarachnoid haemorrhage: diagnosis, causes and management. Brain, 2001.124(Pt 2): p.249-78. Philippon, J., et al., Prevention of vasospasm in subarachnoid haemorrhage. A controlled study with nimodipine. Acta Neurochir (Wien), 1986.82(3-4): p.110-4. Inflammation in SAH and DCI Stein, S.C., et al., Vasospasm as the sole cause of cerebral ischemia: how strong is the evidence? Neurosurg Focus, 2006.21(3): p. E2. Ahn, S.H., et al., Inflammation in delayed ischemia and functional outcomes after subarachnoid hemorrhage. J Neuroinflammation, 2019.16(1): p.213. Neutrophils and MPO van der Veen, B.S., M.P. de Winther, and P. Heeringa, Myeloperoxidase: molecular mechanisms of action and their relevance to human health and disease. Antioxid Redox Signal, 2009.11(11): p.2899-937. Provencio, J.J., et al., CSF neutrophils are implicated in the development of vasospasm in subarachnoid hemorrhage. Neurocrit Care, 2010.12(2): p.244-51. 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Stroke, 2021. 52(10): p. 3374- 1036.343WO1 / PROVENJ-MPO (02901-02) All publications, patents, and patent applications, Genbank sequences, websites and other published materials referred to throughout the disclosure herein are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application, Genbank sequences, websites and other published materials was specifically and individually indicated to be incorporated by reference. In the event that the definition of a term incorporated by reference conflicts with a term defined herein, this specification shall control.

Claims

1036.343WO1 / PROVENJ-MPO (02901-02) WHAT IS CLAIMED:

1. A method to prevent or treat cognitive dysfunction caused by delayed cerebral injury (DCI) comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO.

2. A method to prevent or treat delayed cerebral injury (DCI) comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO.

3. A method to prevent infiltration of neutrophils in the meninges comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO.

4. A method to reverse late memory deficits comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO.

5. The method of any one of claims 1 to 4, wherein the administration is systemic administration.

6. The method of any one of claims 1 or 5, wherein the subject has had an aneurysmal subarachnoid hemorrhage (SAH).

7. The method of any one of claims 1 to 6, wherein the small molecule is one or more of N-Acetyl Lysyltyrosylcysteine Amide (KYC), an N-Acetyl Lysyltyrosylcysteine Amide (KYC) and / or a thioxanthine.

8. The method any one of claims 1 to 6, wherein the small molecule is selected from1036.343WO1 / PROVENJ-MPO (02901-02)9. The method of any one of claims 1 to 8, wherein the small molecule is a thioxanthine.

10. The method of claim 7 or 9, wherein the thioxanthine is a compound of formula (I):wherein at least one of X and Y represents S, and the other represents O or S;1036.343WO1 / PROVENJ-MPO (02901-02) L represents (R12)p-Q-(CR13R14)r; whereineach optionally contain one or two double or triple bonds; wherein Q is O, S(O)n, NR6, NR6C(O), C(O)NR6, or a bond; wherein R12is selected from Cl to 6 alkyl or Cl to 6 alkoxy, said Cl to 6 alkyl or said Cl to 6 alkoxy is optionally substituted with OH, halogen, CF3, CHF2, CFH2, CN, NR4R5, phenoxy or aryl; and wherein said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; and wherein said phenoxy optionally incorporates a carbonyl adjacent to the oxygen; and wherein said Cl to 6 alkoxy optionally incorporates a carbonyl adjacent to the oxygen; wherein R13and R14are independently selected from hydrogen, OH, halogen, CF3, CHF2, CFH2, CN, NR4R5, Cl to 6 alkyl, phenoxy and Cl to 6 alkoxy; wherein said phenoxy or Cl to 6 alkoxy optionally incorporates a carbonyl adjacent to the oxygen; and wherein said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; wherein p represents an integer 0, 1, 2, 3 or 4 and r represents an integer 0, 1, 2, 3 or 4; and wherein 1 < p+ r < 7; R represents a mono- or bicyclic heteroaromatic ring system containing one or more heteroatoms selected from N, O and S; wherein said mono- or bicyclic heteroaromatic ring system is optionally fused with one or two 5- or 6-membered saturated or partially saturated ring(s) containing one or more atoms selected from C, N, O and S, wherein said mono- or bicyclic heteroaromatic ring system alone or when fused with one or two 5- or 6- membered saturated or partially saturated ring(s) is optionally substituted with one or more substituents independently selected from halogen, CHF2, CH2F, CF3, SO(n)R9, SO(n)NR9R10, (CH2)nR3, NR4R5, OH, Cl to 7 alkyl, Cl to 7 alkoxy, phenoxy, aryl, CN, C(O)NR2R3, NR2C(O)R3, C(O)R3, a 5- or 6-membered saturated or partially saturated ring containing one or more atoms selected from C, N, O or S, and a mono- or bicyclic heteroaromatic ring system containing one or more heteroatoms selected from N3S or O; and wherein said Cl to 7 alkoxy is optionally substituted with Cl to 6 alkoxy or aryl; and wherein said Cl to 7 alkoxy or said phenoxy is optionally incorporating a carbonyl adjacent to the oxygen; and wherein said Cl to 7 alkyl is optionally substituted with hydroxy or Cl to 6 alkoxy; and wherein said Cl to 7 alkyl is optionally incorporating a carbonyl at any position in the Cl to 7 alkyl; and wherein said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; at each occurrence, R2, R3, R4, R5, R6, R9and R10are independently selected from hydrogen, Cl to 6 alkyl, Cl to 6 alkoxy, aryl and phenoxy; said Cl to 6 alkoxy or phenoxy is optionally incorporating a carbonyl adjacent to the oxygen; and said Cl to 6 alkyl is optionally substituted with halogen, Cl to 6 alkoxy, CHO, C2 to 6 alkanoyl, OH, C(O)NR7R8or1036.343WO1 / PROVENJ-MPO (02901-02) NR7C(O)R8; and said aryl or said phenoxy is optionally substituted with Cl to 6 alkyl, halogen or Cl to 6 alkoxy; or the groups NR2R3, NR4R5and NR9R10each independently represents a 5 to 7 membered saturated azacyclic ring optionally incorporating one additional heteroatom selected from O, S and NR11, said ring being optionally further substituted with halogen, Cl to 6 alkoxy, CHO, C2 to 6 alkanoyl, OH, C(O)NR7R8or NR7C(O)R8; at each occurrence R, R and R independently represent hydrogen or Cl to 6 alkyl, or the group NR7R8represents a 5 to 7 membered saturated azacyclic ring optionally incorporating one additional heteroatom selected from O, S and NR11; n represents an integer O, 1 or 2; with the optional proviso that for R1thienyl or furyl is excluded; and with the optional proviso that when Q is O, S(O)n, NR6, NR6C(O) or C(O)NR6, then p is greater or equal to 1; as a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.

11. The method of any one of claims 1 to 7, wherein the small molecule inhibitor is AZD5094.

12. The method of claim 10, wherein X represents S and Y represents O.

13. The method of claim 10 or 12, wherein L represents Cl to C7 alkylene.

14. The method of any one of claims 10 or 12-13, wherein L represents Cl to C3 alkylene.

15. The method of any one of claims 10 to 12-14, wherein L represents Cl alkylene.

16. The method of any one of claims 10 to 12-15, wherein L represents C2 alkylene.

17. The method of any one of claims 10 or 12-16, wherein R1represents a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S and said 5 or 6 membered heteroaromatic ring may optionally be fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S, and said ring system (said 5 or 6 membered heteroaromatic ring alone, or said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring) being optionally substituted by one or more1036.343WO1 / PROVENJ-MPO (02901-02) substituents independently selected from halogen, CHF2, CH2F, CF3,SO(n)R9, SO(n)NR9R10, OH, Cl to 7 alkyl, Cl to C7 alkoxy, CN, CONR2R3, NR2COR3and COR3; said alkoxy being optionally further substituted by Cl to C6 alkoxy.

18. The method of any one of claims 10 or 12-16, wherein R1represents a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S and said 5 or 6 membered heteroaromatic ring, fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S, and said ring system (said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring) being optionally substituted by one or more substituents independently selected from halogen, CHF2, CH2F, CF3, SO(n)R9, SO(n)NR9R105 OH, Cl to C7 alkyl, Cl to C7 alkoxy, CN, CONR2R3, NR2COR3and COR3; said alkoxy being optionally further substituted by Cl to C6 alkoxy, and said alkyl being optionally further substituted by hydroxy or Cl to C6 alkoxy.

19. The method of any one of claims 10 or 12-18, wherein said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring, is substituted with halogen.

20. The method of any one of claims 10 or 12-19, wherein said halogen is selected from Cl and F.

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