SUBSTITUTED DIHYDROPYRAZINEDIO NE AS MODULATORS OF THE NMDA RECEPTOR CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Patent Application Serial No. 63/052,749, filed on July 16, 2020, which is incorporated herein by reference in its entirety. TECHNICAL FIELD This present application relates to compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts thereof. The present application also describes pharmaceutical composition comprising a compound of Formula (I), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions for treating neurological disorders such as schizophrenia, schizoaffective disorder, schizophreniform disorder, mild congnitive impairment, and neuropathic pain. BACKGROUND D-amino acid oxidase (DAAO) is a flavoenzyme that degrades D-amino acids via oxidative deamination. D-amino acid levels have been implicated in various physiological processes including hormone secretion, synaptic transmission, and cognition. In particular, the levels of D- serine, an endogenous co-agonist of the N-methyl-D-aspartic acid (NMDA) receptor, are regulated by DAAO. The NMDA receptor regulates a number of pathways involved in neurological function, including the positive (psychotic), negative, and cognitive symptoms of schizophrenia. Further, patients with schizophrenia exhibit increased expression and/or acivity of DAAO relative to healthy subjects. See, for example, Chumakov, et al., Proc. Natl. Acad Sci. USA, 99:13675– 13680 (2002); Burnet, et al., Mol. Psychiatry, 13:658–660 (2008); and Hashimoto, et al., Neurosci. Lett., 152:33–36 (1993). Increased levels of D-Ser are also correlated with both acute and chronic neurodegenerative diseases, such as amyotrophic lateral sclerosis, stroke, epilepsy, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. See, for example, Sacchi, et al., Amino Acids, 43, 1833–1850 (2012). Many of these neurological conditions have no currently approved therapies. For schizophrenia, standard of care therapies are treatment with typical and atypical (second generation) antipsychotic agents. While these therapies are moderately efficacious in addressing the positive symptoms, they do not address the negative symptoms and cognitive deficits observed in schizophrenics. In addition, these therapies can result in significant undesired side effects, both cognitive side effects such as flatten affect, and the development of motor disorders such as tardive dyskinesia. See, for example, Lieberman, et al., Pharmacol. Rev., 60:358–403 (2008). Thus, there remains a need for alternative approaches to modulate NMDA receptor activity, for example, by modulating levels of NMDA receptor co-agonists such as D-serine. SUMMARY Some embodiments provide a compound of the Formula (I): or a pharmaceutically acceptable salt t e eo , w e e , , , , ¹ , R ² , R ³ , n, R ^A , R ^B , R ^C , R ^D , Ring A, and Ring B, are as defined herein. Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Some embodiments provide a method of inhibiting DAAO activity, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Some embodiments provide a method of treating a neurological disorder in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein. Some embodiments provide a method of ameliorating one or more symptoms associated with a neurological disorder in a subject in thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein. Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of a neurological disorder. Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in ameliorating one or more symptoms associated with a neurological disorder. Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the inhibition of DAAO activity. Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment a neurological disorder. Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, defined herein in the manufacture of a medicament for the inhibition of DAAO activity. Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament ameliorating one or more symptoms associated with a neurological disorder. Some embodiments provide a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof obtained by a process of preparing the compound as defined herein. Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DETAILED DESCRIPTION Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. The term “tautomer,” as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer. An example of a tautomeric forms includes the following example: It will be appreciated that certain compounds provided herein may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form. The terms “halo” and “halogen” refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine. The term “C1-C6 alkyl” refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl, n-pentyl and n-hexyl. Similarly, a C1-C3 alkyl group is linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms. The term “C1-C6 haloalkyl” refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. Similarly, a C1-C3 haloalkyl group is linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms substituted with at least one halogen atom. For example, C1-C3 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, e.g., 1-chloroethyl and 2-chloroethyl, trichloroethyl e.g.1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.1-fluoromethyl and 2- fluoroethyl, trifluoroethyl e.g. 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. The term “C1-C6 hydroxyalkyl” refers to a hydrocarbon chain substituted with at least one hydroxyl (-OH) group. The hydroxyl may be present at any position on the hydrocarbon chain. Similarly, a C1-C3 hydroxyalkyl group is linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms substituted with at least one hydroxyalkyl group. For example, C1-C3 hydroxyalkyalkyl may refer to hydroxymethyl, hydroxyethyl e.g., 1-hydroxyethyl and 2- hydroxyethyl, and 2,2-dihydroxyethyl. The term “C1-C6 alkoxy” refers to a C1-C6 alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n- hexoxy. The term “C1-C6 haloalkoxy” refers to a C1-C6 alkyl group which is attached to a molecule via oxygen and where at least one hydrogen atom of the alkyl group is replaced with a halogen. This includes moieties where the alkyl part may be linear or branched, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or trifluoropropoxy. As used herein, the term “cyano” refers to a –CN radical. As used herein, the term “hydroxyl” refers to an –OH radical. As used herein, the term “amino” refers to an –NH2 radical. As used herein, the term “aryl” refers to a 6–10 all carbon mono- or fused bicyclic group wherein at least one ring in the system is aromatic. Non-limiting examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl. In bicyclic ring systems where only one ring is aromatic, the non-aromatic ring can be a cycloalkyl group, as defined herein. As used herein, the term “heteroaryl” refers to an aromatic 5–10 membered mono- or fused bicyclic group; wherein one or more carbon atoms in at least one ring in the system is/are replaced with a heteroatom independently selected from N, O, and S. The heteroaryl ring system may include one or more oxo substitutions (valence permitting) at one or more C, N, or S ring members. Non-limiting examples of heteroaryl groups include pyridyl, pyridonyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, isoindolyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, dibenzo[b,d]furan, dibenzo[b,d]thiophene, phenanthridinyl, benzimidazolyl, pyrrolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl. As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated 3–10 mono- or bicyclic hydrocarbon group; wherein bicyclic systems include fused, spiro (optionally referred to as “spirocycloalkyl” groups), and bridged ring systems. In bicyclic ring systems, one ring can be aromatic, and the other ring can be saturated or partially unsaturated, so long as the bicyclic ring system is not aromatic. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, bicyclo[1.1.1]pentyl, tetrahydronaphthalenyl, and decahydronaphthalenyl. The term “heterocyclyl” refers to a fully or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic ring system, that is not aromatic (but that can include an aromatic ring as part of a bicyclic ring system), having at least one heteroatom within the ring selected from N, O and S. Bicyclic heterocyclyl groups include fused, spiro (optionally referred to as “spiroheterocyclyl” groups), and bridged ring systems. The heterocyclyl ring system may include oxo substitution at one or more C, N, or S ring members. The heterocyclyl group may be denoted as, for example, a “5-10 membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen. In bicyclic ring systems, one ring can be aromatic, and the other ring can be saturated or partially unsaturated, so long as the bicyclic ring system is not aromatic. Exemplary heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2- dioxolanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,3-oxathiolanyl, 1,3- dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-thiazinyl, 2H-1,2-oxazinyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl, 1,4-diazabicyclo[2.2.2]octane, 1,4-diazabicyclo[3.1.1]heptane, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, 2-oxa-6-azaspiro[3,3]heptane, benzimidazolidinonyl, tetrahydroquinolinyl, and 3,4- methylenedioxyphenyl. As used herein, the term “geminal” refers to substituent atoms or groups attached to the same atom in a molecule. As used herein, the term “vicinal” refers to substituent atoms or groups attached to adjacent atoms in a molecule. The stereochemical relationship between the substituent atoms or groups can be cis, trans, undefined, or unresolved. As used herein, the term “oxo” refers to an “=O” group attached to a carbon atom. As used herein, the symbol depicts the point of attachment of an atom or moiety to the indicated atom or group in the re mainder of the molecule. It is to be understood that the ring in compounds of Formula (I) comprising groups X and Y does not contain two adjacent sulfur atoms, -S(=O) groups, -C(=O)- groups, or -S(O2)- groups. The compounds of Formula (I) include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula (I) also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) and/or for separating enantiomers of compounds of Formula (I). Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula (I) include trifluoroacetic acid and hydrochloride salts. It will further be appreciated that the compounds of Formula (I) or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention. For example, compounds of Formula (I) and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In one embodiment, the compounds of Formula (I) include the compounds of Examples 1- 306 and stereoisomers and pharmaceutically acceptable salts thereof. In one embodiment, the compounds of Examples 1-306 are in the free base form. In one embodiment, the compounds of Examples 1-306 are in the salt form. The term “pharmaceutically acceptable” indicates that the compound, or salt or composition thereof is compatible chemically and/or toxicologically with the other ingredients comprising a formulation and/or the subject being treated therewith. Protecting groups can be a temporary substituent which protects a potentially reactive functional group from undesired chemical transformations. The choice of the particular protecting group employed is well within the skill of one of ordinary skill in the art. A number of considerations can determine the choice of protecting group including, but not limited to, the functional group being protected, other functionality present in the molecule, reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, functional group tolerance to conditions required to remove the protecting group, and reaction conditions for the thermal decomposition of the compounds provided herein. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2.sup.nd ed.; Wiley: New York, 1991). A nitrogen protecting group can be any temporary substituent which protects an amine moiety from undesired chemical transformations. Examples of moieties formed when such protecting groups are bonded to an amine include, but are not limited to allylamine, benzylamines (e.g., bezylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine, and tritylamine), acetylamide, trichloroacetammide, trifluoroacetamide, pent-4-enamide, phthalimides, carbamates (e.g., methyl carbamate, t-butyl carbamate, benzyl carbamate, allyl carbamates, 2,2,2- trichloroethyl carbamate, and 9-fluorenylmethyl carbamate), imines, and sulfonamides (e.g., benzene sulfonamide, p-toluenesulfonamide, and p-nitrobenzenesulfonamide). An oxygen protecting group can be any temporary substituent which protects a hydroxyl moiety from undesired chemical transformations. Examples of moieties formed when such protecting groups are bonded to a hydroxyl include, but are not limited to esters (e.g., acetyl, t- butyl carbonyl, and benzoyl), benzyl (e.g., benzyl, p-methoxybenzyl, and 2,4-dimethoxybenzyl, and trityl), carbonates (e.g., methyl carbonate, allyl carbonate, 2,2,2-trichloroethyl carbonate and benzyl carbonate) ketals, and acetals, and ethers. Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to ¹ H, ² H, ³ H or mixtures thereof; when carbon is mentioned, it is understood to refer to ¹¹ C, ¹² C, ¹³ C, ¹⁴ C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to ¹³ N, ¹⁴ N, ¹⁵ N or mixtures thereof; when oxygen is mentioned, it is understood to refer to ¹⁴ O, ¹⁵ O, ¹⁶ O, ¹⁷ O, ¹⁸ O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to ¹⁸ F, ¹⁹ F or mixtures thereof; unless expressly noted otherwise. For example, in deuteroalkyl and deuteroalkoxy groups, where one or more hydrogen atoms are specifically replaced with deuterium ( ² H). As some of the aforementioned isotopes are radioactive, the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention. For illustrative purposes, general methods for preparing the compounds are provided herein as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. The ability of selected compounds to act as DAAO inhibitors may be demonstrated by the biological assays described herein. IC50 values are shown in Table A. Compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are useful for treating diseases and disorders which can be treated with a DAOO inhibitor, for example, neurological disorders such as schizophrenia, schizoaffective disorder, schizophreniform disorder, mild congnitive impairment, and neuropathic pain. As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean an improvement in one or more self-reported cognitive, emotional, physical, or otherwise self-assessed parameters; and/or improvement of such parameters evaluated by a medical professional such as a psychiatrist, psychologist, or neurologist. As used herein, the term “subject” refers to any animal, including mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. The term “pediatric subject” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age. In certain embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are useful for preventing neurological disorders as defined herein (for example, schizophrenia, schizoaffective disorder, schizophreniform disorder, mild congnitive impairment, or neuropathic pain). The term "preventing” as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the neurological disorders as described herein, or a symptom thereof. The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA). Provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: R ¹ is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl; X is CR ^A R ^B , -S-, -S(=O)-, -C(=O)-, -S(O2)-, or a bond; Y is CR ^C R ^D , -O-, -NH-, -S-, -S(=O)-, -C(=O)-, -S(O2)-, or a bond; wherein not more than one of X and Y is -S-, -S(=O)-, -C(=O)-, or -S(O2)-; R ^A , R ^B , R ^C , and R ^D are independently hydrogen, fluoro, or C1-C3 alkyl; or R ^A and R ^B , or R ^C and R ^D , with the carbon atom to which they are attached, together form a C3-C4 cycloalkyl; Ring A is C6-C10 aryl, C6-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl; m is 0, 1, 2, 3, or 4; R ² is halogen, cyano, hydroxyl, -SF5, -S(O2)(C1-C6 alkyl), C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, , or 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from hydroxyl and C1-C6 alkyl; Z is -O-, -NH-, -S-, or a bond; Ring B is C6-C10 aryl; n is 0, 1, 2, or 3; and R ³ is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is halogen. In some embodiments, R ¹ is fluoro. In some embodiments, R ¹ is chloro. In some embodiments, R ¹ is cyano. In some embodiments, R ¹ is C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, iso-butyl, t-butyl, pentyl, or hexyl. In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is C1-C6 haloalkyl, such as difluoromethyl or trifluoromethyl. In some embodiments, R ¹ is trifluoromethyl. In some embodiments, R ¹ is difluoromethyl. In some embodiments, R ¹ is C1-C6 hydroxyalkyl, such as 2-hydroxyethyl or hydroxymethyl. In some embodiments, R ¹ is hydroxymethyl. In some embodiments, R ¹ is 2-hydroxyethyl. In some embodiments, R ¹ is hydrogen, cyano, or chloro. In some embodiments, X is CR ^A R ^B . In some embodiments, X is -S-. In some embodiments, X is -S(=O)-. In some embodiments, X is -C(=O)-. In some embodiments, X is -S(O2)-. In some embodiments, X is a bond. In some embodiments, Y is CR ^C R ^D . In some embodiments, Y is -O-. In some embodiments, Y is -NH-. In some embodiments, Y is -S-. In some embodiments, Y is -S(=O)-. In some embodiments, Y is -C(=O)-. In some embodiments, Y is -S(O ² )-. In some embodiments, Y is a bond. In some embodiments, X is CR ^A R ^B and Y is CR ^C R ^D . In some embodiments, X is CR ^A R ^B and Y is -S-. In some embodiments, X is CR ^A R ^B and Y is -O-. In some embodiments, X is CR ^A R ^B and Y is a bond. In some embodiments, X is a bond and Y is a bond. In some embodiments, X is -S- and Y is CR ^C R ^D . In some embodiments, R ^A and R ^B are independently hydrogen, fluoro, or methyl. In some embodiments, each of R ^A and R ^B are hydrogen. In some embodiments, each of R ^A and R ^B are fluoro. In some embodiments, each of R ^A and R ^B are methyl. In some embodiments, R ^A and R ^B , with the carbon atom to which they are attached, together form a C3-C4 cycloalkyl. In some embodiments, R ^A and R ^B , with the carbon atom to which they are attached, together form a cyclopropyl. In some embodiments, R ^C and R ^D are independently hydrogen, fluoro, or methyl. In some embodiments, each of R ^C and R ^D are hydrogen. In some embodiments, each of R ^C and R ^D are fluoro. In some embodiments, each of R ^C and R ^D are methyl. In some embodiments, R ^C and R ^D , with the carbon atom to which they are attached, together form a C3-C4 cycloalkyl. In some embodiments, R ^C and R ^D , with the carbon atom to which they are attached, together form a cyclopropyl. In some embodiments, -X-Y- is -CH2-CH2-. In some embodiments, -X-Y- is -CF2-CF2-. In some embodiments, -X-Y- is -S-CH2-. In some embodiments, -X-Y- is -S-CH(CH3)-. In some embodiments, -X-Y- is -S-cyclopropyl-. In some embodiments, -X-Y- is -CH ² -S-. In some embodiments, -X-Y- is . In some embodiments, -X-Y- is -CH2-S(O2)-. In some embodiments, -X-Y- is -C . some embodiments, -X-Y- is a bond. In some embodiments, Ring A is C6-C10 aryl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is napthyl. In some embodiments, Ring A is 5-10 membered heteroaryl. In some embodiments, Ring A is 6, 9, or 10- membered heteroaryl. In some embodiments, Ring A is 6, 9, or 10- membered heteroaryl with one nitrogen atom; with one sulfur atom; with two nitrogen atoms; with two nitrogen atoms and one sulfur atom; or with three nitrogen atoms. In some embodiments, Ring A is selected from: indazolyl, pyridinyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, thiophenyl, benzothiadiazolyl, benzotriazolyl, benzoisothiazolyl, cinnolinyl, imidazo[1,2- a]pyridinyl, and benzisoxazolyl. In some embodiments, Ring A is selected from: , , , , , . , Ring A is 8-12 membered heterocyclyl. In some embodiments, Ring A is a fused bicyclic 8-12 membered heterocyclyl. In some embodiments, the one ring of the fused bicyclic heterocycle is phenyl. In some embodiments, the one ring of the fused bicyclic heterocycle is pyridyl. In some embodiments, Ring A is selected from chromanyl, tetrahydronaphthalenyl, benzo[d][1,3]dioxol- 5-yl, dihydrobenzo[b][1,4]oxathiinyl, benzopyranyl, thiochromanyl, dihydrobenzothiazinyl, dioxidothiochromanyl, dihydro-2H-benzo[b][1,4]oxazin-3-yl, dihydro-2H-pyrido[4,3- b][1,4]oxazin-3-yl, isothiochromanyl. In some embodiments, Ring A is selected from: , , In some embodiments, Ring A is attached to Y via a carbon atom of Ring A. In some embodiments, Ring A is attached to Y via a nitrogen atom of Ring A. In some embodiments, Ring A is C6-C10 cycloalkyl. In some embodiments, Ring A is 1,2,3,4-tetrahydronaphthalene. In some embodiments, Ring A is . In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 1 or 2. In some embodiments, each R ² is halogen. In some embodiments, each R ² is fluoro. In some embodiments, each R ² is independently chloro or bromo. In some embodiments, each R ² is cyano. In some embodiments, each R ² is hydroxyl. In some embodiments, each R ² is -SF ⁵ . In some embodiments, each R ² is -S(O2)(C1-C6 alkyl). In some embodiments, each R ² is - S(O2)(CH3). In some embodiments, each R ² is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, each R ² is unsubstituted C1-C6 alkyl. In some embodiments, each R ² is unsubstituted methyl. In some embodiments, each R ² is C1-C6 alkyl substituted with hydroxyl. In some embodiments, each R ² is 1-hydroxyethyl. In some embodiments, each R ² is C1-C6 haloalkyl. In some embodiments, each R ² is independently difluoromethyl or trifluoromethyl. In some embodiments, each R ² is C1-C6 alkoxy. In some embodiments, each R ² is methoxy. In some embodiments, each R ² is C1-C6 haloalkoxy. In some embodiments, each R ² is independently difluoromethoxy or trifluoromethoxy. In some embodiments, each R ² is C3-C6 cycloalkyl. In some embodiments, each R ² is cyclopropyl. In some embodiments, each R ² is 4-12 membered heterocyclyl. In some embodiments, each R ² is an oxazolidinone. In some embodiments, each R ² i In some embodiments, each R ² is 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from hydroxyl and C1-C6 alkyl. In some embodiments, each R ² is a 5-10 membered heteroaryl substituted with hydroxyl. In some embodiments, each R ² is a 5-10 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, each R ² is a 5-10 membered heteroaryl substituted with hydroxyl and C1-C6 alkyl. In some embodiments, each R ² is an unsubstituted 5-10 membered heteroaryl.In some embodiments, each R ² is selected from: pyrazole, hydroxypyrazole, methylpyrazole, N-methylpyrazole, imidazole, hydroxyimidazole, methylimidazole, and N-methylimidazole. In some embodiments, each R ² is selected from: In some embodiments, each R ² is . In some embodiments, Ring B is phenyl. In some embodiments, Ring B . embodiments, Z is -O-. In some embodiments, Z is -NH-. In some embodiments, Z is -S-. In some embodiments, Z is a bond. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, each R ³ is halogen. In some embodiments, each R ³ is cyano. In some embodiments, each R ³ is C1-C6 alkyl. In some embodiments, each R ³ is C1-C6 haloalkyl. In some embodiments, each R ³ is C1-C6 alkoxy. In some embodiments, each R ³ is C1-C6 haloalkoxy. In some embodiments, Z is -O-; Ring B is phenyl; n is 1; and R ³ is fluoro, chloro, or cyano. In some embodiments, Z is -O-; Ring B is phenyl; n is 2; and each R ³ is independently fluoro or chloro. In some embodiments, Z is a bond; Ring B is phenyl; n is 1; and R ³ is fluoro, chloro, or cyano. In some embodiments, Z is a bond; Ring B is phenyl; n is 2; and each R ³ is independently fluoro or chloro. In some embodiments, R ² is . In so ² me embodiments, R is . In some embodiments, R ² is . In some embodiments, R ² is and R ³ is halogen. In some embodiments, R ² is . In some embodiments, one R ² is at the atom connecting Ring A to Y. In some embodiments, no R ² is at the atom connecting Ring A to Y. In some embodiments m is 1 and R ² is methyl, ethyl, isopropyl, fluoro, chloro, bromo, hydroxyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, cyano, 1-hydroxyethyl, -SF5, sulfonylmethyl, cyclopropyl, an oxazolidinone, an unsubstituted pyrazole, pyrazole substituted with hydroxyl, or pyrazole substituted with methyl. In some embodiments m is 1 and R ² is methyl, fluoro, chloro, bromo, hydroxyl, difluoromethyl, trifluoromethyl, or cyano. In some embodiments, m is 2 and each R ² is independently selected from methyl, ethyl, isopropyl, fluoro, chloro, bromo, hydroxyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, cyano, 1-hydroxyethyl, -SF ⁵ , cyclopropyl, an oxazolidinone, an unsubstituted pyrazole, pyrazole substituted with hydroxyl, and pyrazole substituted with methyl. In some embodiments, m is 2 and each R ² is independently selected from methyl, fluoro, chloro, bromo, difluoromethyl, trifluoromethyl, and cyano. In some embodiments, m is 3 and each R ² is independently selected from methyl, ethyl, isopropyl, fluoro, chloro, cyano, hydroxyl, and trifluoromethyl. In some embodiments, m is 3 and each R ² is independently selected from methyl, fluoro, chloro, cyano, and trifluoromethyl. In some embodiments, m is 4 and each R ² is independently selected from methyl, ethyl, isopropyl, fluoro, chloro, cyano, hydroxyl, and trifluoromethyl. In some embodiments, m is 4 and each R ² is independently selected from methyl, fluoro, chloro, cyano, and trifluoromethyl. In some embodiments, m is 1 and R ² is halogen. In some embodiments, m is 1 and R ² is fluoro. In some embodiments, m is 1 and R ² is chloro. In some embodiments, m is 1 and R ² is -SF5. In some embodiments, m is 1 and R ² is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, m is 1 and R ² is hydroxymethyl. In some embodiments, m is 1 and R ² is C1-C6 haloalkyl. In some embodiments, m is 1 and R ² is difluoromethyl. In some embodiments, m is 1 and R ² is trifluoromethyl. In some embodiments, m is 1 and R ² is -S(O2)(C1-C6 alkyl). In some embodiments, m is 1 and R ² is -S(O2)CH3. In some embodiments, m is 1 and R ² is cyano. In some embodiments, m is 1 and R ² is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, m is 1 and R ² is methyl. In some embodiments, m is 1 and R ² is . In some embodiments, m is 1 and R ² is In some embodime ² nts, m is 1 and R is . In some embodiments, m is 1 and R ² is . In some embodiments, m is 1; R ² is and R ³ is halogen. In some embodiments, m is 1 and R ² is . In , m is 2; and each R ² is an independently selected halogen. In some embodiments, m is 2; one R ² is fluoro; and the other R ² is chloro. In some embodiments, m is 2; one R ² is halogen; and the other R ² is cyano. In some embodiments, m is 2; one R ² is fluoro; and the other R ² is cyano. In some embodiments, m is 2; one R ² is C1-C6 haloalkyl; and the other R ² is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, m is 2; one R ² is difluoromethyl; and the other R ² is methyl. In some embodiments, m is 2; one R ² is trifluoromethyl; and the other R ² is methyl. In some embodiments, m is 2; one R ² is halogen; and the other R ² is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, m is 2; one R ² is fluoro; and the other R ² is methyl. In some embodiments, m is 2; one R ² is chloro; and the other R ² is methyl. In some embodiments, m is 2; one R ² is chloro; and the other R ² is hydroxymethyl. In some embodiments, m is 2; one R ² is cyano; and the other R ² is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, m is 2; one R ² is cyano; and the other R ² is methyl. In some embodiments, m is 2; one R ² is cyano; and the other R ² is methyl. In some embodiments, m is 2; one R ² is -S(O2)CH3; and the other R ² is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, m is 2; one R ² is -S(O2)CH3; and the other R ² is methyl. In some embodiments, when an R ² group is a -S(O2)(C1-C6 alkyl), C1-C6 alkyl optionally substituted with hydroxyl, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, , or 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from hydroxyl and C1-C6 alkyl; the R ² group may be connected to Ring A via a nitrogen atom, for example, an N-methyl or N-cyclopropyl group. Some embodiments provide a compound of Formula (IA), or a pharmaceutically acceptable salt thereof: wherein: Ring A is C6-C10 aryl, C6-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl; m is 0, 1, 2, or 3; and R ² is halogen, cyano, hydroxyl, -SF5, -S(O2)(C1-C6 alkyl), C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from hydroxyl and C1-C6 alkyl. Some embodiments provide a compound of Formula (IB), or a pharmaceutically acceptable salt thereof: wherein: Ring A is C6-C10 aryl, C6-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl; m is 0, 1, 2, or 3; and R ² is halogen, cyano, hydroxyl, -SF5, -S(O2)(C1-C6 alkyl), C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from hydroxyl and C1-C6 alkyl. Some embodiments provide a compound of Formula (IC), or a pharmaceutically acceptable salt thereof: wherein: Ring A is C6-C10 aryl, C6-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl; m is 0, 1, 2, or 3; and R ² is halogen, cyano, hydroxyl, -SF5, -S(O2)(C1-C6 alkyl), C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from hydroxyl and C1-C6 alkyl. Some embodiments provide a compound of Formula (ID), or a pharmaceutically acceptable salt thereof: wherein: Ring A is C6-C10 aryl, C6-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl; m is 0, 1, 2, or 3; and R ² is halogen, cyano, hydroxyl, -SF5, -S(O2)(C1-C6 alkyl), C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from hydroxyl and C1-C6 alkyl. Some embodiments provide a compound of Formula (IE), or a pharmaceutically acceptable salt thereof: wherein: R ¹ is hydrogen, chloro, or cyano; R ^A , R ^B , R ^C , and R ^D are independently hydrogen, fluoro, or C1-C3 alkyl; or R ^A and R ^B , or R ^C and R ^D , with the carbon atom to which they are attached, together form a C3-C4 cycloalkyl; Ring A is C6-C10 cycloalkyl or 4-12 membered heterocyclyl; m1 is 0, 1, 2, or 3; R ^2A is methyl, ethyl, hydroxymethyl, difluoromethyl, or trifluoromethyl; and R ^2B is halogen, cyano, hydroxyl, -SF ⁵ , -S(O ² )(C1-C6 alkyl), C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from hydroxyl and C1-C6 alkyl. In some embodiments, the compound is a compound selected from Examples 1-306, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound selected from Examples 1-306 in the form of a pharmaceutically acceptable salt. In some embodiments, the compound is a compound selected from Examples 1-306 in the form of a free base. In some embodiments, the compound of Formula (I) is selected from the group consisting of the compounds listed in Table 1 and pharmaceutically acceptable salts thereof. Table 1.

Table 2. Compound Structure

Some embodiments provide a compound of Formula (II), or a pharmaceutically acceptable salt thereof: wherein: R ^1A is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl; X ¹ is CR ^A1 R ^B1 , -S-, -S(=O)-, -C(=O)-, -S(O2)-, a bond; Y ¹ is CR ^C1 R ^D1 , -O-, -NH-, -S-, -S(=O)-, -C(=O)-, -S(O ² )-, a bond; wherein not more than one of X and Y is -S-, -S(=O)-, -C(=O)-, or -S(O2)-; or wherein X ¹ and Y ¹ , with the atoms to which they are attached, together form , R ^A1 , R ^B1 , R ^C1 , and R ^D1 are independently hydrogen, fluoro, or C1-C3 alkyl; or R ^A1 and R ^B1 , or R ^C1 and R ^D1 , with the carbon atom to which they are attached, together form a C3-C4 cycloalkyl; Ring A1 is C6-C10 aryl, C6-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl; mA is 0, 1, 2, 3, or 4; R ^2A is halogen, cyano, hydroxyl, -SF5, -S(O2)(C1-C6 alkyl), C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, , or 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from hydroxyl and C1-C6 alkyl; Z ¹ is -O-, -NH-, -S-, or a bond; Ring B1 is C6-C10 aryl; nA is 0, 1, 2, or 3; and R ^3A is halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. Methods of Treatment Some embodiments provide a method of treating an neurological disorder (e.g., a DAAO- associated neurological disorder) in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the neurological disorder is neuropathic pain, schizophrenia, schizoaffective disorder, schizophreniform disorder, or mild cognitive impairment (MCI). In some embodiments, the neurological disorder is neuropathic pain. In some embodiments, the neurological disorder is schizophrenia. In some embodiments, the neurological disorder is mild cognitive impairment (MCI). In some embodiments, the neurological disorder is schizoaffective disorder. In some embodiments, the neurological disorder is schizophreniform disorder. In some embodiments, the subject is a human. In some embodiments, the method further comprises increasing the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, over a period of time. In some embodiments, the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is increased by about 10% to about 500%, for example, about 10% to about 100%, about 50% to about 150%, about 100% to about 200%, about 150% to about 250%, about 200% to about 300%, about 250% to about 350%, about 300% to about 400%, about 350% to about 450%, about 400% to about 500%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 125%, about 150%, about 175%, about 200%, about 225%, about 250%, about 300%, about 400%, about 450%, about 500%, or any value in between. In some embodiments of this paragraph, the period of time is about 1 week to about 6 months, for example, about 1 week to about 2 months, about 1 month to about 2.5 months, about 2 months to about 3.5 months, about 3 months to about 4.5 months, about 4 months to about 5.5 months, about 5 months to about 6 months, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 3 months, about 4 months, about 5 months, about 6 months, or any value in between. In some embodiments, the method further comprises increasing the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, a period of time after initiation of treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is increased by about 10% to about 500%, for example, about 10% to about 100%, about 50% to about 150%, about 100% to about 200%, about 150% to about 250%, about 200% to about 300%, about 250% to about 350%, about 300% to about 400%, about 350% to about 450%, about 400% to about 500%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 125%, about 150%, about 175%, about 200%, about 225%, about 250%, about 300%, about 400%, about 450%, about 500%, or any value in between. In some embodiments of this paragraph, the period of time is about 1 year to about 20 years, for example, about 1 year to about 5 years, about 3 years to about 8 years, about 5 years to about 10 years, about 8 years to about 12 years, about 10 years to about 15 years, about 12 years to about 18 years, about 15 years to about 20 years, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, about 20 years, or any value in between. Combination Therapy In some embodiments of any of the methods described herein, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with an effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic or immunomodulatory) agents. In some embodiments, the methods described herein further comprise administering one or more additional therapies selected from typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, cholinesterase inhibitors, memantine, NSAIDs, analgesics, anxiolytics, gabapentin and pregabalin. In some embodiments, the methods described herein further comprise providing cognitive behavior therapy to the subject. In some embodiments, the one or more additional therapies is a standard of care treatment for neuropathic pain. In some embodiments, the one or more additional therapies is a standard of care treatment for schizophrenia. In some embodiments, the one or more additional therapies is a standard of care treatment for MCI. In some embodiments, the one or more additional therapies is a standard of care treatment for schizoaffective disorder. In some embodiments, the one or more additional therapies is a standard of care treatment for schizophreniform disorder. In some embodiments, the one or more additional therapies is a typical antipsychotic. Representative typical antipsychotics include, but are not limited to chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopenthixol. In some embodiments, the one or more additional therapies is an atypical antipsychotic. Representative atypical antipsychotics include, but are not limited to aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone. In some embodiments, the one or more additional therapies is an antidepressant. In some embodiments, the antidepressant is an atypical antidepressant, a selective serotonin reuptake inhibitor, a selective serotonin and norepinephrine reuptake inhibitor, a monoamine oxidase inhibitor, a selective norepinephrine reuptake inhibitor, or a tricyclic antidepressant. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the one or more additional therapies are administered as separate dosages sequentially in any order. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the one or more additional therapies are administered as a single dosage form. In some embodiments, the antidepressant is an atypical antidepressant. Representative atypical antidepressants include, but are not limited to mirtazapine, mianserin, bupropion, trazodone, nefazodone, tianeptine, opipramol, agomelatine, vilazodone, and vortioxetine. In some embodiments, the antidepressant is a selective serotonin reuptake inhibitor. Representative selective serotonin reuptake inhibitors include, but are not limited to citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. In some embodiments, the antidepressant is a selective serotonin and norepinephrine reuptake inhibitor. Representative selective serotonin and norepinephrine reuptake inhibitors include, but are not limited to atomoxetine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, and venlafaxine. In some embodiments, the antidepressant is a monoamine oxidase inhibitor. Representative monoamine oxidase inhibitors include, but are not limited to moclobemide, rasagiline, selegiline, or safinamide. In some embodiments, the antidepressant is a selective norepinephrine reuptake inhibitor. Representative selective norepinephrine reuptake inhibitors include, but are not limited to reboxetine. In some embodiments, the antidepressant is a tricyclic antidepressant. Representative tricyclic antidepressants include, but are not limited to amineptine, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, norclomipramine, northiaden, nortriptyline, pipramol, protriptyline, tianeptine, and trimipramine. In some embodiments, the one or more additional therapies is a benzodiazepine. Representative benzodiazepines include, but are not limited to alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam. In some embodiments, the one or more additional therapies is a mood stabilizer. Representative mood stabilizers include, but are not limited to lithium, valproic acid, lamotrigine, or carbamazepine. In some embodiments, the one or more additional therapies is electroconvulsive therapy or transcranial magnetic stimulation. In some embodiments, the one or more additional therapies is sertraline. In some embodiments, the one or more additional therapies is venlafaxine. In some embodiments, the one or more additional therapies is a cholinesterase inhibitor. Representative cholinesterase inhibitors include, but are not limited to donepezil, galantamine, and rivastigmine. In some embodiments, the one or more additional therapies is memantine. In some embodiments, the one or more additional therapies is an NSAID. Representative NSAIDs include, but are not limited to clonixin, licofelone, salicylates (such as aspirin and diflunisal), propionic acid derivative (such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, and oxaprozin), acetic acid derivatives (such as indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, and bromfenac), and COX-2 inhibitors (such as celecoxib). In some embodiments, the one or more additional therapies is an analgesic. Representative analgesics include, but are not limited to nefopam, flupiritine, ziconotide, acetaminophen, and opioids (such as morphine, oxycodone, methadone, codeine, fentanyl, hydrocodone, and tramadol). In some embodiments, the one or more additional therapies is an anxiolytic. Representative anxiolytics include, but are not limited to alnespirone, adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, and zolazepam. In some embodiments, the one or more additional therapies is gabapentin or pregabalin. In some embodiments, the one or more additional therapies is one additional therapy. In some embodiments, the one or more additional therapies is two, three, or four additional therapies. Some embodiments provide a method of treating a neurological disorder, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional therapies selected from typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, cholinesterase inhibitors, memantine, NSAIDs, analgesics, anxiolytics, gabapentin and pregabalin, to a subject in need thereof. In some embodiments, the subject was being administered the one or more additional therapies prior to initiation of treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dose of the one or more additional therapies is decreased after initiation of treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, relative to the dose of the one or more additional therapies administered prior initiation of treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dose of the one or more additional therapies is decreased by about 10% to about 90% after initiation of treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for example, by about 10% to about 40%, about 20% to about 50%, about 30% to about 60%, about 40%, to about 70%, about 50% to about 80%, about 60% to about 90%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or any value in between. In some embodiments, the subject was being administered the one or more additional therapies prior to initiation of treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, but after treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time, the subject is no longer administered the one or more additional therapies. In some embodiments of this paragraph, the period of time is about 1 month to about 1 year, for example, about 1 month to about 5 months, about 3 months to about 8 months, about 7 months to about 1 year, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, or any value in between. In some embodiments, the amount of the one or more additional therapies is decreased during the period of time, to zero at the end of the period of time. In some embodiments, the subject has previously been administered one or more additional therapies selected from typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, cholinesterase inhibitors, memantine, NSAIDs, analgesics, anxiolytics, gabapentin, and pregabalin; wherein the subject was not responsive to the previous one or more therapies. In some embodiments, the subject has previously been administered a standard of care treatment for neuropathic pain and the subject was not responsive to the previous therapy. In some embodiments, the subject has previously been administered a standard of care treatment for schizophrenia and the subject was not responsive to the previous therapy. In some embodiments, the subject has previously been administered a standard of care treatment for schizoaffective disorder and the subject was not responsive to the previous therapy. In some embodiments, the subject has previously been administered a standard of care treatment for schizophreniform disorder and the subject was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more additional therapies selected from typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, cholinesterase inhibitors, memantine, NSAIDs, analgesics, anxiolytics, gabapentin, and pregabalin, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more typical antipsychotics such as chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopenthixol, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more atypical antipsychotics, such as aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more antidepressants and was not responsive to the previous therapy. In some embodiments, the antidepressant is an atypical antidepressant, a selective serotonin reuptake inhibitor, a selective serotonin and norepinephrine reuptake inhibitor, a monoamine oxidase inhibitor, a selective norepinephrine reuptake inhibitor, or a tricyclic antidepressant, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more atypical antidepressants, such as mirtazapine, mianserin, bupropion, trazodone, nefazodone, tianeptine, opipramol, agomelatine, vilazodone, and vortioxetine, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more selective serotonin reuptake inhibitors, such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more selective serotonin and norepinephrine reuptake inhibitors, such as atomoxetine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, and venlafaxine, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more monoamine oxidase inhibitors, such as moclobemide, rasagiline, selegiline, or safinamide, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more selective norepinephrine reuptake inhibitors, such as reboxetine, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more tricyclic antidepressants, such as amineptine, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, norclomipramine, northiaden, nortriptyline, pipramol, protriptyline, tianeptine, and trimipramine, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more benzodiazepines, such as alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more mood stabilizers, such as lithium, valproic acid, lamotrigine, or carbamazepine, and was not responsive to the previous therapy. In some embodiments, the one or more additional therapies is electroconvulsive therapy or transcranial magnetic stimulation, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered sertraline, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered venlafaxine, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more cholinesterase inhibitors such as donepezil, galantamine, or rivastigmine, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered memantine, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more NSAIDs such as clonixin, licofelone, aspirin, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, bromfenac), or celecoxib, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more analgesics such as nefopam, flupiritine, ziconotide, acetaminophen, morphine, oxycodone, methadone, codeine, fentanyl, hydrocodone, or tramadol, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered one or more anxiolytics, such as alnespirone, adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, or zolazepam, and was not responsive to the previous therapy. In some embodiments, the subject has previously been administered gabapentin or pregabalin, and was not responsive to the previous therapy. In some embodiments, the one or more additional therapies previously administered to the subject is one additional therapy. In some embodiments, the one or more additional therapies previously administered to the subject is two additional therapies. In some embodiments, the one or more additional therapies previously administered to the subject is three additional therapies. In some embodiments, the one or more additional therapies previously administered to the subject is four additional therapies. In some embodiments, the one or more additional therapies previously administered to the subject is five, six, seven, eight, nine, or ten additional therapies. Subjects that were “non-responsive” to a previous therapy includes subjects where the previous therapy lacked sufficient clinical efficacy, subjects that experienced an unacceptable number and/or severity of side effects due to the previous therapy (sufficient to require discontinuation of treatment), and subjects that experienced both of the foregoing. Side effects include, but are not limited to weight gain, flattened affect, tardive dyskinesia, drowsiness, nausea, vomiting, constipation, dry mouth, restlessness, dizziness, loss of sexual desire, erectile dysfunction, insomnia, and blurred vision. Also provided is a method for inhibiting DAAO activity in a cell, comprising contacting the cell with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a subject having a cell having DAAO activity. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is a human neural cell, such a glial cell (for example, an astrocyte) or a motor neuron. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a cell with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having a DAAO enzyme, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the DAAO enzyme. The phrase “effective amount” or “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a neurological or disorder (such as those described herein); (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular neurological disorder, such as those described herein; or (iii) delay the onset of one or more symptoms of the particular neurological disorder, such as those described herein. The amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Pharmaceutical Compositions When employed as pharmaceuticals, compounds of Formula (I), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration can include a dosage form formulated for once-daily or twice-daily (BID) administration.Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Also provided herein are pharmaceutical compositions which contain, as the active ingredient, a compound of Formula (I) or pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients. For example, a pharmaceutical composition prepared using a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi- solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as a tablet or capsule. Further provided herein are pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient can be prepared by intimately mixing the compound of Formula (I), or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition. Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be employed. Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Solid oral preparations can also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients can be added to increase solubility or preservation. Injectable suspensions or solutions can also be prepared utilizing aqueous carriers along with appropriate additives. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described herein. The compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof ) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient. In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient. In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient. The daily dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1000 mg/kg of body weight per day, or any range therein. Preferably, the range is from about 0.5 to about 500 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 250 mg/kg of body weight per day, or any range therein. More preferably, from about 0.1 to about 100 mg/kg of body weight per day, or any range therein. In an example, the range can be from about 0.1 to about 50.0 mg/kg of body weight per day, or any amount or range therein. In another example, the range can be from about 0.1 to about 15.0 mg/kg of body weight per day, or any range therein. In yet another example, the range can be from about 0.5 to about 7.5 mg/kg of body weight per day, or any amount to range therein. Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered on a regimen of 1 to 4 times per day or in a single daily dose. The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art. It will be understood, therefore, that the amount of the compound actually administered will usually be determined by a physician, and will vary according to the relevant circumstances, including the mode of administration, the actual compound administered, the strength of the preparation, the condition to be treated, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject response, age, weight, diet, time of administration and severity of the subject’s symptoms, will result in the need to adjust dosages. In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg/kg to about 100 mg/kg. In some embodiments, the compound provided herein can be administered in an amount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg. For example, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg. One skilled in the art will recognize that both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound to treat or prevent a given disorder. One skilled in the art will further recognize that human clinical trials including first-in- human, dose ranging and efficacy trials, in healthy subjects and/or those suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts. Provided herein are pharmaceutical kits useful, for example, in the treatment of neurological disorders, such as schizophrenia, schizoaffective disorder, schizophreniform disorder, mild congnitive impairment, or neuropathic pain, which include one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. EXAMPLES Materials and Methods The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1 ^st Ed., Oxford University Press, 2000; March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 ^th Ed., Wiley-Interscience Publication, 2001; and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997). The following are representative procedures for the preparation of the compounds used in the following Examples, or which can be substituted for the compounds used in the following Examples which may not be commercially available. Liquid Chromatography-Mass Spectrometry UPLC-MS was performed on a Waters Acquity I-Class with Waters Diode Array Detector coupled to a Waters SQD2 single quadrupole mass spectrometer using an Waters HSS C18 column (1.8 µm, 100 × 2.1 mm) or on a Waters DAD + Waters SQD2, single quadrupole UPLC-MS spectrometer using an Acquity UPLC BEH Shield RP181.7um 100 x 2.1mm (plus guard cartridge), maintained at 40 °C. The columns were initially held at 5% acetonitrile/water (with 0.1% formic acid or 10 mM ammonium bicarbonate in each mobile phase), followed by a linear gradient of 5-100% and then held at 100%. NMR 1H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker instrument operating at 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad. Preparative reverse-phase HPLC conditions Preparative HPLC purification was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996/2998 UV/VIS detector, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution UV directed system. The Waters 2767 liquid handler acted as both auto-sampler and fraction collector. The columns used for the preparative purification of the compounds were a Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl or Waters Xbridge Phenyl at 10 µm 19 × 150 mm or Waters CSH Phenyl Hexyl, 19 × 150, 5 µm column. Appropriate focused gradients were selected based on acetonitrile and methanol solvent systems under either acidic or basic conditions. The modifiers used under acidic/basic conditions were formic acid or trifluoroacetic acid (0.1% V/V) and ammonium bicarbonate (10 mM) respectively. The purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm, and triggered a threshold collection value at 260 nm and, when using the Fractionlynx, the presence of target molecular ion as observed under API conditions. Collected fractions were analysed by LCMS (Waters Acquity systems with Waters SQD). The diastereomeric separation of compounds was achieved by Supercritical Fluid Chromatography (SFC) using a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid handler with Stacked Injection Module). The Waters 2767 liquid handler acted as both auto-sampler and fraction collector. Appropriate isocratic methods were selected based on methanol, ethanol or isopropanol solvent systems under un-modified or basic conditions. The standard SFC method used was modifier, CO2, 100 mL/min, 120 Bar backpressure, 40 °C column temperature. The modifier used under basic conditions was diethylamine (0.1% V/V). The modifier used under acidic conditions was either formic acid (0.1% V/V) or trifluoroacetic acid (0.1% V/V). The SFC purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm and triggered at a threshold collection value, typically 260 nm. Collected fractions were analysed by SFC (Waters/Thar SFC systems with Waters SQD). The fractions that contained the desired product were concentrated by vacuum centrifugation. Supercritical Fluid Chromatography – Mass Spectrometry analytical conditions Method 1 SFC-MS was performed on a Waters/Thar SFC systems with Waters SQD using a Lux Cellulose-3 column with a 15% methyl alcohol/CO2 (with 0.5% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 °C column temperature. Method 2 SFC-MS was performed on a Waters/Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 30% (methyl alcohol /MeCN)/CO2 isocratic run at 5 mL/min, 120 Bar backpressure, 40 °C column temperature. Method 3 SFC-MS was performed on a Waters/Thar SFC systems with Waters SQD using a YMC Cellulose-C column with a 5-60% IPA (with 0.1% diethylamine)/ heptane isocratic run at 1 mL/min, 120 Bar backpressure, 40 °C column temperature. Synthesis The synthesis of the reported compounds was performed according to the following procedures. Method A 5-(4-(Trifluoromethyl)phenethyl)-1,4-dihydropyrazine-2,3-dio ne (Example 1) a) (E)-2,3-Dimethoxy-5-(4-(trifluoromethyl)styryl)pyrazine To a degassed mixture of 5-bromo-2,3-dimethoxypyrazine (1.10 g, 5.00 mmol), (E)-(4- (trifluoromethyl)styryl)boronic acid (2.16 g, 10.0 mmol) and sodium carbonate (1.59 g, 15.0 mmol) in 1,4-dioxane (30 mL) and water (10 mL) was added tetrakis(triphenylphosphine)Pd(0) (0.58 g, 0.50 mmol) and the reaction was heated to 95 °C for 4 hrs. The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL). The organics were separated and further extracted with ethyl acetate (2 x 10 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% dichloromethane in iso- hexane) to yield the title compound as a yellow solid (1.45 g, 94%). ¹ H NMR (CDCl3, 400 MHz) δ 7.65-7.60 (m, 5 H), 7.52 (d, J = 15.5 Hz, 1 H), 7.09 (d, J = 15.5 Hz, 1 H), 4.13 (s, 3H), 4.05 (s, 3 H). b) 2,3-Dimethoxy-5-(4-(trifluoromethyl)phenethyl)pyrazine To 5 g, 4.67 mmol) and 1-methyl-1,4-cyclohexadiene (10.5 mL, 93.5 mmol) in dry ethanol (80 mL) was added Pdhydroxide (20% on carbon, 1.47 g, 2.09 mmol) and the reaction was heated to reflux overnight. The reaction was cooled to room temperature and filtered through Celite ^TM under a flow of nitrogen. The filtrate was concentrated under reduced pressure and the crude material was purified by flash column chromatography (0 – 15% ethyl acetate in iso-hexane) yielding the title compound as a pale yellow oil (1.40 g, 96%). ¹ H NMR (CDCl3, 400 MHz) δ 7.51 (d, J = 8.0 Hz, 2 H), 7.36, (s, 1 H), 7.28 (d, J = 8.0 Hz.2 H), 4.00 (s, 3 H), 3.99 (s, 3 H), 3.08 (t, J = 7.5 Hz, 2 H), 2.93 (t, J = 7.5 Hz, 2 H). c) 5-(4-(Trifluoromethyl)phenethyl)-1,4-dihydropyrazine-2,3-dio ne A solution of 2,3-dimethoxy-5-(4-(trifluoromethyl)phenethyl)pyrazine (1.40 g, 4.48 mmol) in 2 M aqueous hydrochloric acid (23 mL) and 1,4-dioxane (23 mL) was heated to reflux for 16 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 20% methanol in DCM) to afford the title compound a white solid (720 mg, 57%). ¹ H NMR (DMSO-d6, 400 MHz) δ 11.40 (s, 1 H), 11.01 (s, 1 H), 7.67 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 8.0 Hz, 2 H), 6.01 (s, 1 H), 2.90 (t, J = 8.0 Hz, 2 H), 2.51 (t, J = 8.0 Hz, 2 H). MS (ESI+) m/z 285.1 (M+H) ⁺ . The following examples were prepared using an analogous method to that used to prepare 5-(4-(trifluoromethyl)phenethyl)-1,4-dihydropyrazine-2,3-dio ne (Method A) 2 5-(4- ¹H NMR (400 MHz, DMSO): δ MS 6 5-(2- ¹H NMR (400 MHz, DMSO): δ MS 5-Phenethyl-1,4-dihydropyrazine-2,3-dione (Example 7) a) 2,3-dimethoxy-5-phenethylpyra z ne 2,3-Dimethoxy-5-phenethylpyrazine was isolated as a by-product from the reduction of (E)-5-(4-chlorostyryl)-2,3-dimethoxypyrazine and deprotection of 2,3-dimethoxy-5- phenethylpyrazine following the general procedure used to prepare 5-(4- (trifluoromethyl)phenethyl)-1,4-dihydropyrazine-2,3-dione. ¹H NMR (400 MHz, DMSO) δ 11.35 (s, 1 H), 10.98 (s, 1 H), 7.32 - 7.27 (m, 2 H), 7.23 - 7.19 (m, 3 H), 5.99 (s, 1 H), 2.81 (t, J=8.0 Hz, 2 H), 2.52 - 2.45 (m, 2 H). MS (ESI-) m/z 215.1 (M-H)- Method B 5-(3,5-Dichlorophenethyl)-1,4-dihydropyrazine-2,3-dione (Example 8) a) 2,3-Dimethoxy-5-((trimethylsilyl)ethynyl)pyrazine Anhydrous T g, 20 mmol), bis(triphenylphosphine)Pd(II) dichloride (0.98 g, 1.4 mmol) and copper (I) iodide ( 0.11 g, 0.6 mmol) and degassed with a stream of nitrogen whilst being stirred at room temperature. Triethylamine (6.0 g, 60 mmol) was added followed by ethynyltrimethylsilane (2.45 g, 25 mmol) and the mixture was stirred at room temperature for 18 hrs. The mixture was partitioned between water (100 mL) and ethyl acetate (200 mL) and the aqueous layer was extracted with further portions of ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and evaporated. The crude material was purfied by flash column chromatography (0-10% ethyl actetate in cyclohexane) to elute the desired product as a yellow oil (4.7 g, 99%). ¹H NMR (400 MHz, CDCl3): δ 7.81 (s, 1 H), 4.05-4.03 (m, 6 H), 0.28-0.27 (m, 9 H). b) 5-Ethynyl-2,3-dimethoxypyrazine 2,3-Dimethoxy-5-((trimethylsilyl)ethynyl)pyrazine (4.7 g, 20 mmol), was dissolved in methanol (60 mL) and stirred at room temperature. Potassium carbonate (2.8 g, 20 mmol) was added and the mixture was stirred at room temperature for 5.5 hrs. The solution was partitioned between dichloromethane (200 mL) and water (100 mL) and the aqueous layer was extracted with further portions of dichloromethane (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and evaporated. The crude material was purified by flash column chromatography (0-10% ethyl acetate in cyclohexane) to elute the desired product as an off-white solid (2.85 g, 87%). ¹H NMR (400 MHz, CDCl3): δ 7.84 (s, 1 H), 4.04 (d, J = 3.0 Hz, 6 H), 3.16 (s, 1 H). c) 5-((3,5-Dichlorophenyl)ethynyl)-2,3-dimethoxypyrazine A solution - dichlorobenzene (0.24 g, 1.1 mmol) and triethylamine (0.3 g, 0.42 mL, 3 mmol) in DMF (12 mL) was degassed with a stream of nitrogen for 1 minute. Copper iodide (0.019 g, 0.1 mmol) and bis(triphenylphosphine)Pd(II) dichloride (0.1 g, 0.15 mmol) were added and the mixture was stirred at room temperature for 18 hrs. The mixture was diluted with ethyl acetate (30 mL) and filtered through a plug of Celite ^TM . Water (50 mL) was added to the filtrate and the organic layer extracted. The aqueous layer was extracted with further portions of ethyl acetate (2 x 30 mL). The organic layers were combined, driedover magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography (5% ethyl acetate in cyclohexane isocratic) to afford the title compound as a yellow solid (0.29 g, 94%). ¹H NMR (400 MHz, DMSO): δ 7.79 (s, 1 H), 7.65 (m, 1 H), 7.48-7.42 (m, 1 H), 7.33-7.20 (m, 1 H), 4.02 (m, 3 H), 3.94 (s, 3 H). d) 5-(3,5-Dichlorophenethyl)-2,3-dimethoxypyrazine 10% Pdhydroxide on carbon (0.1 g) was added to a solution of 5-((3,5- dichlorophenyl)ethynyl)-2,3-dimethoxypyrazine (0.28 g, 0.9 mmol) and 1-methyl-1,4- cyclohexadiene (1.7 g, 18 mmol) and the mixture stirred at 65 °C for 3 h. A further portion of 1- methyl-1,4-cyclohexadiene (1.7 g, 18 mmol) was added and the mixture was stirred at 65 °C for a further 3 hrs. The solution was then cooled and filtered through a plug of Celite ^TM . The Celite ^TM was washed with a portion of ethyl acetate (10 mL), dichoromethane (10 mL) and methanol (10 mL). The filtrate was concentrated in vacuo and the crude residue partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was washed with brine (10 mL) and the combined aqueous layers washed with ethyl acetate (2 x 10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography (0-10% ethyl acetate in cyclohexane) to afford the title compound as a pale yellow solid (0.08 g, 28%). ¹H NMR (400 MHz, DMSO): δ 7.45-7.32 (m, 2 H), 7.23 (d, J = 1.9 Hz, 2 H), 3.82-3.79 (m, 6 H), 2.94-2.81 (m, 4 H). e) 5-(3,5-Dichlorophenethyl)-1,4-dihydropyrazine-2,3-dione A solut - , - p y - , - ypy . g, . ) in 2 M aqueous hydrochloric acid (2.6 mL) and 1,4-dioxane (3 mL) was heated to reflux for 16 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to afford the title compound as a white solid (23 mg, 32%). ¹H NMR (400 MHz, DMSO): δ 11.03 (s, 2 H), 7.45 (t, J = 1.9 Hz, 1 H), 7.32 (d, J = 1.9 Hz, 2 H), 6.02 (s, 1 H), 2.82 (t, J = 8.0 Hz, 2 H), 2.49-2.47 (m, 2 H). MS (ES+) m/z 285 (M+H)+ The following examples were prepared using an analogous method to that used to prepare 5-(3,5-dichlorophenethyl)-1,4-dihydropyrazine-2,3-dione (Method B). Ex Str t r N m NMR M I n 10 5-(2- ¹H NMR (400 MHz, DMSO): δ MS (ES+) H), 2.85-2.79 (m, 2 H), 2.48- 4-(2-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)ethyl)benzoni trile (Example 15) Sodium iodide (0.14 g, 0.91 mmol) and TMSCl (0.099, 0.12 mL, 0.91 mmol) were added to a solution of 4-(2-(5,6-dimethoxypyrazin-2-yl)ethyl)benzonitrile (synthesised following general procedures a-d, Method B, used to prepare 5-(3,5-dichlorophenethyl)-1,4- dihydropyrazine-2,3-dione) (0.049 g, 0.18 mmol), in acetonitrile (1 mL) and the solution stirred at room temperature for 2 hrs. The mixture was evaporated to dryness and then dissolved in a 1:1:1 mixture of DMSO/ MeCN and water. The crude compound was purified by reverse phase preparative HPLC to afford the title compound as an off-white solid (6 mg, 14%). ¹H NMR (400 MHz, DMSO): δ 11.38-11.37 (m, 1 H), 11.01 (s, 1 H), 7.84-7.79 (m, 2 H), 7.49-7.45 (m, 2 H), 6.05-6.01 (m, 1 H), 3.34 (m, 2 H), 2.98-2.91 (m, 2 H). MS (ES+) m/z 242 (M+H)+ Example 16 (4-(2-(5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)ethyl)-2-flu orobenzonitrile) was prepared using an analogous method to that used to prepare 4-(2-(5,6-dioxo-1,4,5,6- tetrahydropyrazin-2-yl)ethyl)benzonitrile (Method B). MS (ESI+) m/z 260 (M+H)+. ¹H NMR (400 MHz, DMSO) d 11.32 (s, 1 H), 10.98 (s, 1 H), 7.86 (dd, J=7.2, 7.9 Hz, 1 H), 7.43 (dd, J=1.4, 10.8 Hz, 1 H), 7.27 (dd, J=1.4, 7.9 Hz, 1 H), 6.01 (s, 1 H), 2.95 - 2.90 (m, 2 H), 2 H obscured by DMSO peak. 5-(2-Chloro-4-(1-hydroxyethyl)phenethyl)-1,4-dihydropyrazine -2,3-dione (Example 17) a) 1-(3-Chloro-4-(2-(5,6-dimeth oxypy az n- -y e y p enyl)ethan-1-ol 1-(3-Chloro-4-(2-(5,6-dimethoxypyrazin-2-yl)ethyl)phenyl)eth an-1-one (synthesised following general procedures a-d, Method B, used prepare 5-(3,5-dichlorophenethyl)-2,3- dimethoxypyrazine) (0.15 g, 0.47 mmol) was dissolved in methanol (5 mL) and cooled to 0 °C. NaBH4 (0.027 g, 0.71 mmol) was added and the mixture stirred at 0 °C for 20 min. The mixture was concentrated and partitioned between ethyl acetate (5 mL) and and sat aq. brine (5 mL). The crude material was purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to afford the title compound as a colourless oil (0.1 g, 65%). ¹H NMR (400 MHz, CDCl3): δ 7.37 (s, 2 H), 7.15-7.12 (m, 2 H), 4.85 (d, J = 5.6 Hz, 1 H), 4.00 (s, 3 H), 3.97 (s, 3 H), 3.11 (t, J = 7.7 Hz, 2 H), 2.91 (t, J = 7.7 Hz, 2 H), 1.99-1.95 (m, 1 H), 1.50-1.45 (m, 3 H). b) 5-(2-Chloro-4-(1-hydroxyethyl)phenethyl)-1,4-dihydropyrazine -2,3-dione 5-(2-chloro-4-(1-hydroxyethyl)phenethyl)-1,4-dihydropyrazine -2,3-dione was prepared following general procedure e, Method B used to prepare 5-(3,5-dichlorophenethyl)-1,4- dihydropyrazine-2,3-dione (0.035 g, 38%). ¹H NMR (400 MHz, DMSO): δ 10.81 (s, 2 H), 7.37 (d, J = 1.4 Hz, 1 H), 7.29-7.22 (m, 2 H), 5.95 (s, 1 H), 5.24 (d, J = 4.4 Hz, 1 H), 4.73-4.66 (m, 1 H), 2.91 (t, J = 7.7 Hz, 2 H), 2.53-2.50 (m, 2 H), 1.31 (d, J = 6.5 Hz, 3 H). MS (ES+) m/z 295 (M+H)+. Racemic 5-(2-chloro-4-(1-hydroxyethyl)phenethyl)-1,4-dihydropyrazine -2,3-dione was resolved by chiral SFC to afford single enantiomers. 5-(2-Chloro-4-(1-hydroxyethyl)phenethyl)-1,4-dihydropyrazine -2,3-dione (Isomer 1) (Example 18): ¹H NMR (400 MHz, DMSO): δ 10.81 (s, 2 H), 7.37 (d, J = 1.4 Hz, 1 H), 7.29- 7.22 (m, 2 H), 5.95 (s, 1 H), 5.24 (d, J = 4.4 Hz, 1 H), 4.73-4.66 (m, 1 H), 2.91 (t, J = 7.7 Hz, 2 H), 2.53-2.50 (m, 2 H), 1.31 (d, J = 6.5 Hz, 3 H). MS (ES+) m/z 295 (M+H)+. Chiral analysis (Method 1) at 5.38 min. 5-(2-Chloro-4-(1-hydroxyethyl)phenethyl)-1,4-dihydropyrazine -2,3-dione (Isomer 2) (Example 19): ¹H NMR (400 MHz, DMSO): δ 10.81 (s, 2 H), 7.37 (d, J = 1.4 Hz, 1 H), 7.29- 7.22 (m, 2 H), 5.95 (s, 1 H), 5.24 (d, J = 4.4 Hz, 1 H), 4.73-4.66 (m, 1 H), 2.91 (t, J = 7.7 Hz, 2 H), 2.53-2.50 (m, 2 H), 1.31 (d, J = 6.5 Hz, 3 H). MS (ES+) m/z 295 (M+H)+. Chiral analysis (Method 1) at 5.91 min. Example 20 (5-(3-Fluoro-4-(1-hydroxyethyl)phenethyl)-1,4-dihydropyrazin e-2,3-dione) was prepared using an analogous method to that used to prepare 5-(2-chloro-4-(1- hydroxyethyl)phenethyl)-1,4-dihydropyrazine-2,3-dione (Method B). MS (ES+) m/z 279 (M+H)+. ¹H NMR (400 MHz, DMSO): δ 11.33-11.30 (m, 1 H), 10.98-10.95 (m, 1 H), 7.43-7.38 (m, 1 H), 6.99 (dd, J = 10.1, 17.5 Hz, 2 H), 6.02-6.00 (m, 1 H), 5.21 (d, J = 4.5 Hz, 1 H), 4.96-4.90 (m, 1 H), 2.81-2.75 (m, 2 H), 2.47-2.43 (m, 2 H), 1.30 (d, J = 6.4 Hz, 3 H). 5-(2-(4-Hydroxychroman-6-yl)ethyl)-1,4-dihydropyrazine-2,3-d ione (Example 21) a) 5-(2-(4-Hydroxychroman-6- ine-2,3-dione 5-(2- , , ng general procedures a-e, Method B used to prepare 5-(3,5-dichlorophenethyl)-1,4- dihydropyrazine-2,3-dione) (0.069 g, 0.24 mmol), was suspended in methanol (2 mL), cooled to 0 °C and degassed with a stream of nitrogen for 15 min. Sodium borohydride (14 mg, 0.362 mmol) was then added portion-wise and the mixture was stirred at 0 °C for 2 hrs. The solvent was removed under reduced pressure and the resulting brown residue was purified by reverse phase preparative HPLC to afford the title compound as a white powder (0.034 g, 49%). ¹H NMR (400 MHz, DMSO): δ 11.31 (s, 1 H), 10.98 (s, 1 H), 7.15 (d, J = 2.0 Hz, 1 H), 6.97 (dd, J = 2.2, 8.3 Hz, 1 H), 6.65 (d, J = 8.3 Hz, 1 H), 6.00 (s, 1 H), 5.29 (d, J = 5.4 Hz, 1 H), 4.59-4.53 (m, 1 H), 4.15-4.11 (m, 2 H), 2.73-2.66 (m, 2 H), 2.45-2.38 (m, 2 H), 2.01-1.92 (m, 1 H), 1.88-1.79 (m, 1 H). MS (ES+) m/z 271 (M+H)+ 5-(4-Cyclopropyl-3-fluorophenethyl)-1,4-dihydropyrazine-2,3- dione (Example 22) a) 5-((4-Cyclopropyl-3-fluorophenyl)ethynyl)-2,3-dimethoxypyraz ine 5-((4-B ng general procedures a-d, Method B used to prepare 5-(3,5-dichlorophenethyl)-2,3- dimethoxypyrazine) (0.53 g, 1.6 mmol), cyclopropyl boronic acid (0.4 g, 4.7 mmol), potassium phosphate (1.17 g, 5.5 mmol) and tricyclohexylphosphine (0.044 g, 0.16 mmol) were suspended in toluene (8 mL) and water (0.5 mL) and the solution was degassed with a stream of nitrogen for 20 min. Pdacetate (0.018 g, 0.079 mmol) was added and the mixture stirred at 110 °C for 18 hrs. The solution was cooled to room temperature and filtered through a pad of Celite ^TM . The Celite ^TM was washed with ethyl acetate (15 mL) and water (10 mL) and the filtrate concentrated under reduced pressure. Crude material was purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to afford material which was further purified by flash column chromatography (0-10% acetone in cyclohexane) to afford the title compound as an off-white solid (0.28 g, 60%). ¹H NMR (400 MHz, CDCl3) δ 7.86 (s, 1 H), 7.26 - 7.20 (m, 2 H), 6.87 - 6.82 (m, 1 H), 4.07 (s, 3 H), 4.05 (s, 3 H), 2.15 - 2.06 (m, 1 H), 1.06 - 1.00 (m, 2 H), 0.79 - 0.73 (m, 2 H). b) 5-(4-Cyclopropyl-3-fluorophenethyl)-1,4-dihydropyrazine-2,3- dione 5-(4-Cyclopropyl-3-fluorophenethyl)-1,4-dihydropyrazine-2,3- dione was synthesised from 5-((4-cyclopropyl-3-fluorophenyl)ethynyl)-2,3-dimethoxypyraz ine following general procedures c-d, Method B, used to prepare 5-(3,5-dichlorophenethyl)-1,4-dihydropyrazine-2,3- dione. ¹H NMR (400 MHz, DMSO): δ 11.29 (s, 1 H), 10.98 (s, 1 H), 6.97 (d, J = 11.4 Hz, 1 H), 6.94-6.87 (m, 2 H), 5.98 (s, 1 H), 2.78-2.72 (m, 2 H), 2.47-2.41 (m, 2 H), 2.02-1.93 (m, 1 H), 0.96-0.89 (m, 2 H), 0.70-0.64 (m, 2 H). MS (ES+) m/z 275 (M+H)+. 5-(3-Fluoro-4-(3-hydroxy-1H-pyrazol-5-yl)phenethyl)-1,4-dihy dropyrazine-2,3- dione (Example 23) a) 4-(2-(5,6-Dimethoxypyrazin-2-yl)ethyl)-2-fluorobenzoic acid T ert-butyl 4-(2-(5,6-dimethoxypyrazin-2-yl)ethyl)-2-fluorobenzoate (synthesised following general procedures a-d, Method B, used to 5-(3,5-dichlorophenethyl)-2,3- dimethoxypyrazine (0.42 g, 1.17 mmol) was stirred at room temperature in dichloromethane (15 mL) with trifluoroacetic acid (4.0 g, 2.7 mL, 35 mmol) for 3 hrs. The mixture was concentrated under reduced pressure to afford the title compound as a white solid (0.35 g, 98%). ¹H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 7.8, 7.8 Hz, 1 H), 7.38 (s, 1 H), 7.06-6.98 (m, 2 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 3.11-3.06 (m, 2 H), 2.97-2.91 (m, 2 H). Acidic OH not observed. b) Ethyl 3-(4-(2-(5,6-dimethoxypyrazin-2-yl)ethyl)-2-fluorophenyl)-3- oxopropanoate Magnesium chloride (0.1 g, 1.1 mmol) and ethyl potassium malonate (0.26 g, 1.5 mmol) were combined in dry THF (3 mL) and heated to reflux for 4 hrs.4-(2-(5,6-Dimethoxypyrazin-2- yl)ethyl)-2-fluorobenzoic acid (0.35 g, 1.14 mmol) and CDI (0.22 g, 1.4 mmol) were combined in dry THF (3 mL) and heated to reflux for 30 min. Both solutions were cooled down to room temperature and then the mixture of 4-(2-(5,6-dimethoxypyrazin-2-yl)ethyl)-2-fluorobenzoic acid and CDI was added portion-wise to the mixture of magnesium chloride and ethyl potassium malonate. The resulting suspension was stirred at room temperature for 18 hrs. The mixture was cooled to 0 °C, quenched with 1 M hydrochloric acid solution (aq) (10 mL), diluted with ethyl acetate (10 mL) and then stirred for 1 hour. The mixture was further diluted with water (10 mL) and ethyl acetate (10 mL) and the aqueous layer extracted with ethyl acetate (3 x 40 mL). The combined organic layers were then washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography (10-30% ethyl acetate in cyclohexane) to afford the title compound as a pale-yellow oil (0.35 g, 83%). ¹H NMR (400 MHz, CDCl3): δ 7.88-7.76 (m, 1 H), 7.38-7.37 (m, 1 H), 7.08-6.92 (m, 2 H), 4.24 (ddd, J = 6.5, 13.7, 20.7 Hz, 2 H), 4.01-3.98 (m, 6 H), 3.10-3.02 (m, 2 H), 2.96-2.91 (m, 2 H), 1.44-1.42 (m, 1 H), 1.34-1.24 (m, 4 H). c) 5-(3-Fluoro-4-(3-hydroxy-1H-pyrazol-5-yl)phenethyl)-1,4-dihy dropyrazine-2,3-dione Ethyl 3-(4-(2-(5,6-dimethoxypyrazin-2-yl)ethyl)-2-fluorophenyl)-3- oxopropanoate (0.35 g, 0.84 mmol) was dissolved in dry methanol (3 mL) under a nitrogen atmosphere. Glacial acetic acid (5.7 mg, 0.0054 mL, 0.094 mmol) was added followed by hydrazine hydrate (0.23 g, 0.23 mL, 4.7 mmol) and the reaction mixture was heated to reflux for 3 hrs. The mixture was cooled to room temperature and then evaporated to dryness. The crude material was purified by flash column chromatography (10-30% ethyl acetate in cyclohexane) to afford 5-(4-(2-(5,6- Dimethoxypyrazin-2-yl)ethyl)-2-fluorophenyl)-1H-pyrazol-3-ol as a white solid (0.23 g, 78%) 5-(4-(2-(5,6-Dimethoxypyrazin-2-yl)ethyl)-2-fluorophenyl)-1H -pyrazol-3-ol (0.23 g, 0.66 mmol) was used to prepare the title compound following general procedure e, Method B used to prepare 5-(3,5-dichlorophenethyl)-1,4-dihydropyrazine-2,3-dione (0.014 g, 18%). ¹H NMR (400 MHz, DMSO) δ 12.04 (s, 1 H), 11.35 (s, 1 H), 11.00 (s, 1 H), 9.72 (s, 1 H), 7.74 - 7.65 (m, 1 H), 7.15 (d, J=12.4 Hz, 1 H), 7.09 (d, J=8.0 Hz, 1 H), 6.01 (s, 1 H), 5.82 (s, 1 H), 2.87 - 2.81 (m, 2 H), (2 H obscured by DMSO peak). MS (ESI+) m/z 317 (M+H) ⁺ . 5-Methyl-6-(4-(trifluoromethyl)phenethyl)-1,4-dihydropyrazin e-2,3-dione (Example 24)

2 , . , . dissolved in DMF (3.2 mL) and N-chlorosuccinimide (0.051 g, 0.384 mmol) was added. The reaction mixture was stirred at 50 °C for 2hrs and then for 18 hrs at room temperature. The mixture was concentrated in vacuo and dissolved in ethyl acetate (5 mL) and washed with water (2 x 5 mL) and brine (5 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography (0-10% ethyl acetate in cyclohexane) to eulte the title product as a white solid (0.084 g, 76%). ¹H NMR (400 MHz, CDCl3): δ 7.55-7.51 (m, 2 H), 7.35-7.30 (m, 2 H), 4.01 (s, 3 H), 3.96 (s, 3 H), 3.09 (s, 4 H). b) 2,3-Dimethoxy-5-methyl-6-(4-(trifluoromethyl)phenethyl)pyraz ine To a stirred solution of 2-chloro-5,6-dimethoxy-3-(4-(trifluoromethyl)phenethyl)pyraz ine (0.042 g, 0.121 mmol) and Pd(dppf)2Cl2 (0.0089 g, 0.012 mmol) in toluene (1 mL) was added dimethyl zinc (0.24 mL, 2 M solution in toluene, 0.48 mmol) and the reaction mixture was heated at 80 °C for 27 hrs before a further portion of Pd(dppf)2Cl2 (0.0089 g, 0.0121 mmol) was added and the reaction was stirred at 80 °C a further 24 hrs. The mixture was cooled and water (2 mL) added. Ethyl acetate (5 mL) was added and the organic layer extracted. The aqueous layer was washed with further ethyl acetate (2 x 5 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography (0-5% ethyl acetate in cyclohexane) to afford the title compound as a pale- yellow solid (0.019 g, 48%). ¹H NMR (400 MHz, CDCl3): δ 7.53-7.50 (m, 2 H), 7.26 (s, 2 H), 3.98-3.95 (m, 6 H), 3.09-3.04 (m, 2 H), 2.96-2.92 (m, 2 H), 2.24 (s, 3 H). c) 5-Methyl-6-(4-(trifluoromethyl)phenethyl)-1,4-dihydropyrazin e-2,3-dione A sol , 019 g, 0.0582 mmol) in 2 M aqueous hydrochloric acid (2 mL) and 1,4-dioxane (0.6 mL) was heated to reflux for 2 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 20% methanol in DCM; dry load on Celite ^TM ; 80 g column) to afford the title compound a white solid (9 mg, 53%). ¹H NMR (400 MHz, DMSO): δ 11.20 (s, 1 H), 11.01 (s, 1 H), 7.68 - 7.64 (m, 2 H), 7.47 - 7.43 (m, 2 H), 2.87 - 2.81 (m, 2 H), 1.68 (s, 3 H) 2 H obscured by DMSO peak. MS (ESI+) m/z 299 (M+H)+ 5,6-Dioxo-3-(4-(trifluoromethyl)phenethyl)-1,4,5,6-tetrahydr opyrazine-2- carbonitrile (Example 25) a) 5,6-Dimethoxy-3-(4-(trifluoromethyl)phenethyl)pyrazine-2-car bonitrile A solution of 2-chloro-5,6-dimethoxy-3-(4-(trifluoromethyl)phenethyl)pyraz ine (0.05 g, 0.144 mmol), Pd(pi-cinnamyl) chloride dimer (0.0075 g, 0.0144 mmol), Xphos (0.021 g, 0.0433 mmol) and N,N-diisopropylethylamine (0.037 g, 0.288 mmol) in previously degassed 1-butanol (0.7 mL) was heated at 80 °C under a nitrogen atmosphere. Acetone cyanohydrin (0.015 g, 0.173 mmol) solubilised in 0.3 mL of 1-butanol was then added drop-wise over 4 hrs. After the addition was complete the reaction was stirred at room temperature for 18 hrs. Saturated NaHCO ³ (2 mL) was then added and the reaction mixture was stirred for 10 min. The aqueous solution was extracted with ethyl acetate (2 x 5 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (0.039 g, 80%). ¹H NMR (400 MHz, CDCl3): δ 7.56-7.52 (m, 2 H),7.34-7.31 (m, 2 H), 4.04-4.01 (m, 6 H), 3.22-3.09 (m, 4 H). b) 5,6-Dioxo-3-(4-(trifluoromethyl)phenethyl)-1,4,5,6-tetrahydr opyrazine-2- carbonitrile Sodiu m iodide (0.033 g, 0.22 mmol) and TMSCl (0.024, 0.028 mL, 0.22 mmol) were added to a solution of 5,6-dimethoxy-3-(4-(trifluoromethyl)phenethyl)pyrazine-2-car bonitrile (0.025 g, 0.074 mmol), in acetonitrile (0.4 mL) and the solution stirred at 60 °C for 2 hrs. The reaction was diluted with ethyl acetate (2 mL) and washed with water (2 mL) and brine (2 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. Crude compound was purified by reverse phase preparative HPLC to afford the title compound as an off-white solid (6 mg, 26%). ¹H NMR (400 MHz, DMSO): δ 11.97 (s, 2 H), 7.71 - 7.67 (m, 2 H), 7.47 - 7.44 (m, 2 H), 2.98 (t, J=7.6 Hz, 2 H), 2.71 (t, J=7.6 Hz, 2 H). MS (ESI-) m/z 308 (M-H)- 5-Chloro-6-(4-(trifluoromethyl)phenethyl)-1,4-dihydropyrazin e-2,3-dione (Example 26) a) 5-Chloro-6-(4-(trifluoromethyl)phenethyl)-1,4-dihydropyrazin e-2,3-dione 5-Chloro-6-(4-(trifluoromethyl)phenethyl)-1,4-dihydropyrazin e-2,3-dione was prepared following step c, Method B of the general procedure used to prepare 5-methyl-6-(4- (trifluoromethyl)phenethyl)-1,4-dihydropyrazine-2,3-dione (0.055 g, 41%). ¹H NMR (400 MHz, DMSO): δ 12.01 (s, 1 H), 11.64 (s, 1 H), 7.67 (d, J=8.0 Hz, 2 H), 7.45 (d, J=8.0 Hz, 2 H), 2.90 (dd, J=7.7, 7.7 Hz, 2 H), 2.62 (dd, J=7.5, 7.5 Hz, 2 H). MS (ESI+) m/z 319.2 (M+H)+. 5-(2-(Naphthalen-2-yl)ethyl)-1,4-dihydropyrazine-2,3-dione (Example 27) a) 2,3-Dimethoxy-5-(2-(naphthalen-2-yl)ethyl)pyrazine A mixture of 2-ethynylnaphthalene (0.33 g, 2.2 mmol), 5-bromo-2,3-dimethoxypyrazine (0.44 g, 2 mmol), Pddichloride (0.035 g, 0.2 mmol), copper iodide (0.038 g, 0.2 mmol), triphenyl phosphine (0.13 g, 0.5 mmol) and triethylamine (1.01 g, 1.4 mL, 10 mmol) in acetonitrile (10 mL) was stirred at room temperature under nitrogen for 20 hrs. The reaction mixture was filtered through Celite ^TM and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL), filtered again through Celite ^TM and the filtrate concentrated in vacuo. The crude material was purified by flash column chromatography (10-15% ethyl acetate in cyclohexane) to afford 2,3-dimethoxy-5-(naphthalen-2-ylethynyl)pyrazine as an orange powder (0.45 g, 78%). 2,3-Dimethoxy-5-(naphthalen-2-ylethynyl)pyrazine (0.28 g, 0.96 mmol) was dissolved in ethyl acetate (20 mL) and was subjected to hydrogenation using the H-cube (full H2 mode, 50 °C, Pd(OH)2/C, 1 mL/ min). The mixture was concentrated and the crude material was purified by flash column chromatography (0-10% ethyl acetate in cyclohexane) to afford the title compound as an orange solid (0.28 g, 99%). ¹H NMR (400 MHz, CDCl ³ ): δ 7.85-7.30 (m, 8 H), 4.11-3.97 (m, 6 H), 3.22-3.15 (m, 2 H), 3.05-2.98 (m, 2 H). b) 5-(2-(Naphthalen-2-yl)ethyl)-1,4-dihydropyrazine-2,3-dione 5-(2-(naphthalen-2-yl)ethyl)-1,4-dihydropyrazine-2,3-dione was prepared following following step c, Method B of the general procedure used to prepare 5-methyl-6-(4- (trifluoromethyl)phenethyl)-1,4-dihydropyrazine-2,3-dione (0.1 g, 37%). ¹H NMR (400 MHz, DMSO): δ 11.53-10.80 (m, 2 H), 7.90-7.83 (m, 3 H), 7.71 (s, 1 H), 7.52-7.40 (m, 3 H), 6.01 (s, 1 H), 3.02-2.96 (m, 2 H), 2.62-2.56 (m, 2 H). MS (ESI+) m/z 267 (M+H)+. Method C 5-(3,4-Difluorophenethyl)-1,4-dihydropyrazine-2,3-dione (Example 28) a) (E)-2,3-Dimethoxy-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol an-2-yl)vinyl)pyrazine Copper (I) chloride (0.05 g, 0.5 mmol), Xantphos (0.29 g, 0.5 mmol) and sodium tert- butoxide (0.096 g, 1 mmol) were placed in a dried flask and dry degassed THF (20 mL) was added under nitrogen and stirred for 30 min. Bis(pinacolato)diboron (2.79 g, 11 mmol) was added and the reaction mixture stirred for 10 minutes, followed by the addition of 5-ethynyl-2,3- dimethoxypyrazine (1.6 g, 10 mmol) and then methanol (0.81 mL, 20 mmol). The reaction mixture was stirred for 30 hrs. The mixture was filtered through Celite ^TM and the Celite ^TM washed with THF (3 x 10 mL). The filtrate was concentrated under reduced pressure and the resulting crude material purified by flash column chromatography (0-20% diethyl ether in cyclohexane) to afford the title compound as a pale yellow solid (2.92 g, 99%). ¹H NMR (400 MHz, CDCl3): δ 7.62 (s, 1 H), 7.29 (d, J = 3.9 Hz, 1 H), 6.63-6.58 (m, 1 H), 4.05-4.03 (m, 6 H), 1.32-1.26 (m, 12 H) b) (E)-5-(3,4-Difluorostyryl)-2,3-dimethoxypyrazine A solut on o - romo- , - uro enzene ( . g, . mmo ), ( )- , - me oxy-5-(2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrazine (0.43 mmol, 1.5 mmol) and Cs2CO3 (1.46 g, 4.5 mmol) were dissolved in dioxane (9 mL) and water (3 mL) and degassed with a stream of nitrogen for 15 min. Tetrakis(triphenylphosphine)Pd(0.17 g, 0.15 mmol) was added and the mixture was stirred at 75 °C for 2.5 hrs. The mixture was cooled to room temperature and filtered through Celite ^TM washing with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure and the resulting crude material purified by flash column chromatography (0-15% ethyl acetate in cyclohexane) to afford the title compound as a colourless solid (0.29 g, 70%). ¹H NMR (400 MHz, CDCl3): δ 7.61 (s, 1 H), 7.43-7.33 (m, 2 H), 7.25-7.22 (m, 1 H), 7.18-7.11 (m, 1 H), 6.92 (d, J = 15.6 Hz, 1 H), 4.11 (s, 3 H), 4.04 (s, 3 H). c) 5-(3,4-Difluorophenethyl)-2,3-dimethoxypyrazine To a degassed solution of (E)-5-(3,4-difluorostyryl)-2,3-dimethoxypyrazine (0.28 g, 1.0 mmol) and 1-methyl-1,4-cyclohexadiene (2.3 mL, 20.7 mmol) in dry ethanol (20 mL) was added Pdon carbon (10%, 0.15 g) and the reaction was heated to reflux overnight. The reaction was cooled to room temperature and filtered through Celite ^TM under a flow of nitrogen. The filtrate was concentrated under reduced pressure and the crude material was purified by flash column chromatography (0 – 25% ethyl acetate in iso-hexane) yielding the title compound as a colourless oil (0.2 g, 69%). ¹H NMR (400 MHz, CDCl3): δ 7.35 (s, 1 H), 7.07-6.94 (m, 2 H), 6.87-6.83 (m, 1 H), 4.00 (d, J = 11.4 Hz, 6 H), 3.00-2.86 (m, 4 H). d) 5-(3,4-Difluorophenethyl)-1,4-dihydropyrazine-2,3-dione 5-(3,4- , , analogous method to that used to prepare 5-methyl-6-(4-(trifluoromethyl)phenethyl)-1,4- dihydropyrazine-2,3-dione (0.14 g, 57%). ¹H NMR (400 MHz, DMSO): δ 11.27-10.99 (m, 2 H), 7.37-7.25 (m, 2 H), 7.05-7.00 (m, 1 H), 5.98 (s, 1 H), 2.82-2.76 (m, 2 H), 2.49-2.44 (m, 2 H). MS (ES+) m/z 253 (M+H)+. The following examples were prepared using an analogous method to that used to prepare 5-(3,4-difluorophenethyl)-1,4-dihydropyrazine-2,3-dione (Method C). Ex. Structure Name NMR Mass Ion 31 5-(2-(2-Ethyl-2H- ¹H NMR (400 MHz, DMSO): MS (ES+) m/z 5-(3-Fluoro-4-(1H-pyrazol-1-yl)phenethyl)-1,4-dihydropyrazin e-2,3-dione (Example 32) Bromo-2-fluoro-phenylhydrazine HCl (0.5 g, 2.0 mmol) was suspended in ethanol (3.5 mL) and 1,1,3,3-tetraethoxypropane (0.5 g, 2.28 mmol) and 37% HCl (0.1 mL, 1.2 mmol) were added. The mixture was stirred at 80 °C for 3 hrs. The mixture was cooled, diluted with water (10 mL), basified with saturated Na2CO3 (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated. The crude material was purfied by flash column chromatography (0-10% ethyl actetate in cyclohexane) to elute the desired product as a light yellow oil (0.47 g, 94%). ¹H NMR (400 MHz, CDCl3): δ 7.99 (t, J = 2.6 Hz, 1 H), 7.83 (t, J = 8.7 Hz, 1 H), 7.74 (d, J = 1.6 Hz, 1 H), 7.44-7.38 (m, 2 H), 6.50- 6.49 (m, 1 H). b) 5-(3-Fluoro-4-(1H-pyrazol-1-yl)phenethyl)-1,4-dihydropyrazin e-2,3-dione 5-(3-Fluoro- as synthesised from 1-(4-bromo-2-fluorophenyl)-1H-pyrazole and (E)-2,3-dimethoxy-5-(2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyrazine following general procedures a-d, Method C used to prepare 5-(3,4-difluorophenethyl)-1,4-dihydropyrazine-2,3-dione. ¹H NMR (400 MHz, DMSO): δ 11.34 (s, 1 H), 11.02 - 10.97 (m, 1 H), 8.18 - 8.16 (m, 1 H), 7.78 (d, J=1.5 Hz, 1 H), 7.71 (dd, J=8.2, 8.4 Hz, 1 H), 7.34 (dd, J=1.7, 12.7 Hz, 1 H), 7.20 (dd, J=1.7, 8.4 Hz, 1 H), 6.56 (dd, J=1.8, 2.5 Hz, 1 H), 6.05 - 6.02 (m, 1 H), 2.91 - 2.85 (m, 2 H), 2 H obscured by DMSO peak. MS (ESI+) m/z 301 (M+H)+. 5-(2-(2-Oxooxazolidin-5-yl)-4-(trifluoromethyl)phenethyl)-1, 4-dihydropyrazine-2,3- dione (Example 33) Trimethylsilyl cyanide (1.82 mL, 14.5 mmol) was added dropwise to neat 2-bromo-5- trifluoromethylbenzaldehyde (1.27 g, 5.00 mmol) under an atmosphere of nitrogen followed by the addition of zinc iodide (16 mg, 0.050 mmol) and the reaction stirred for 16 hrs. The reaction was cooled to 0 °C and lithium aluminium hydride (15 mL, 15 mmol, 1.0 M in THF) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 4 hrs. The reaction was cooled to 0 °C and quenched by the addition of saturated aqueous solution of Rochelle’s salt. The organics were extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 to 10% methanol in dichloromethane). The product containing fractions were concentrated under reduced pressure yielding the product as a pale yellow solid (1.02 g, 72%). ¹H NMR (400 MHz, CDCl3): δ 7.89-7.87 (m, 1 H), 7.65-7.62 (m, 1 H), 7.41-7.37 (m, 1 H), 4.98 (dd, J = 3.6, 7.7 Hz, 1 H), 3.20 (dd, J = 3.6, 12.8 Hz, 1 H), 2.69-2.63 (m, 1 H) (NH and OH not observed). b) 5-(2-Bromo-5-(trifluoromethyl)phenyl)oxazolidin-2-one To a solution of 2-am no- -( -bromo-5-(tr uoromet y )p eny)et an-1-ol (1.02 g, 3.59 mmol) in dichloromethane (35 mL) was added dipyridin-2yl carbonate (0.82 g, 3.8 mmol) and the reaction was stirred for 3 hrs. The reaction was quenched by addition of 2 M HCl (15 mL) and the organics separated and further extracted with dichloromethane (2 x 80 mL). The combined organics were passed through a phase separator and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-10% methanol in dichloromethane). The product containing fractions were concentrated under reduced pressure yielding the product as an off-white solid (950 mg, 85% yield). ¹H NMR (400 MHz, CDCl3): δ 7.82 (s, 1 H), 7.76-7.71 (m, 1 H), 7.53-7.48 (m, 1 H), 5.91 (t, J = 7.8 Hz, 1 H), 5.41 (s, 1 H), 4.26 (t, J = 9.0 Hz, 1 H), 3.41 (t, J = 7.8 Hz, 1 H). c) 5-(2-((5,6-Dimethoxypyrazin-2-yl)ethynyl)-5-(trifluoromethyl )phenyl)oxazolidin-2- one A degassed mixture of 5-(2-bromo-5-(trifluoromethyl)phenyl)oxazolidin-2-one (465 mg, 1.5 mmol), 5-ethynyl-2,3-dimethoxypyrazine (205 mg, 1.25 mmol), bis(triphenylphosphine)Pd(II) dichloride (88 mg, 0.12 mmol), copper (I) iodide (12 mg, 0.06 mmol) and triethylamine (0.52 mL, 3.7 mmol) in acetonitrile (10 mL) was stirred at room temperature under nitrogen for 20 hrs. The reaction mixture was filtered through Celite ^TM and the filtrate concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-75 % ethyl acetate in cyclohexane). The product containing fractions were concentrated under reduced pressure yielding the product as an orange solid (1.02 g, 72%). ¹H NMR (400 MHz, CDCl3): δ 7.90-7.84 (m, 2 H), 7.75-7.71 (m, 1 H), 7.65-7.62 (m, 1 H), 6.10 (dd, J = 7.3, 8.8 Hz, 1 H), 5.60 (s, 1 H), 4.32 (t, J = 8.9 Hz, 1 H), 4.08-4.06 (m, 6 H), 3.58 (t, J = 7.7 Hz, 1 H). f) 5-(2-(2-Oxooxazolidin-5-yl)-4-(trifluoromethyl)phenethyl)-1, 4-dihydropyrazine-2,3- dione 5-(2-((5,6-dimethoxypyrazin-2-yl)ethynyl)-5-(trifluoromethyl )phenyl)oxazolidin-2-one (0.22 g, 0.56 mmol) dissolved in ethyl acetate (12 mL) was subjected to hydrogenation using the H-cube (full H2 mode, 70 °C, Pd(OH)2/C, 1 mL/ min). The mixture was concentrated and crude material was purified by flash column chromatography (0-100% ethyl acetate in dichloromethane) to afford 5-(2-(2-(5,6-dimethoxypyrazin-2-yl)ethyl)-5- (trifluoromethyl)phenyl)oxazolidin-2-one as an orange solid.5-(2-(2-(5,6-dimethoxypyrazin-2- yl)ethyl)-5-(trifluoromethyl)phenyl)oxazolidin-2-one (60 mg, 0.15 mmol) in 2 M HCl (1.5 mL) and 1,4-dioxane (1.5 mL) was heated to reflux for 2 hrs. The reaction was allowed to cool to room temperature and and concentrated under reduced pressure. The crude material was purified by reverse-phase preparative chromatography yielding the product as an off-white solid (3.6 mg, 6%). ¹H NMR (400 MHz, DMSO): δ 11.44 (s, 1 H), 11.08 (d, J=4.0 Hz, 1 H), 7.87 (s, 1 H), 7.76 (d, J=7.6 Hz, 1 H), 7.70 (s, 1 H), 7.59 (d, J=8.1 Hz, 1 H), 6.15 (d, J=4.0 Hz, 1 H), 6.04 (dd, J=8.1, 8.1 Hz, 1 H), 4.04 (dd, J=8.8, 8.8 Hz, 1 H),, 2.92 (dd, J=7.8, 7.8 Hz, 2 H, (1 H obscured by water peak, 2 H obscured by DMSO peak), MS (ESI+) m/z 370 (M+H) ⁺ . Racemic 5-(2-(2-Oxooxazolidin-5-yl)-4-(trifluoromethyl)phenethyl)-1, 4- dihydropyrazine-2,3-dione was resolved by chiral SFC to afford single enantiomers. 5-(2-(2-Oxooxazolidin-5-yl)-4-(trifluoromethyl)phenethyl)-1, 4-dihydropyrazine-2,3- dione (Isomer 1) (Example 34): ¹H NMR (400 MHz, DMSO): δ 11.44 (s, 1 H), 11.08 (d, J=4.0 Hz, 1 H), 7.87 (s, 1 H), 7.76 (d, J=7.6 Hz, 1 H), 7.70 (s, 1 H), 7.59 (d, J=8.1 Hz, 1 H), 6.15 (d, J=4.0 Hz, 1 H), 6.04 (dd, J=8.1, 8.1 Hz, 1 H), 4.04 (dd, J=8.8, 8.8 Hz, 1 H), 2.92 (dd, J=7.8, 7.8 Hz, 2 H), (1 H obscured by water peak 2 H obscured by DMSO peak), MS (ESI+) m/z 370.3 (M+H) ⁺ . Chiral analysis (Method 2) at 3.81 min. 5-(2-(2-Oxooxazolidin-5-yl)-4-(trifluoromethyl)phenethyl)-1, 4-dihydropyrazine-2,3- dione (Isomer 2) (Example 35): ¹H NMR (400 MHz, DMSO): δ 11.44 (s, 1 H), 11.08 (d, J=4.0 Hz, 1 H), 7.87 (s, 1 H), 7.76 (d, J=7.6 Hz, 1 H), 7.70 (s, 1 H), 7.59 (d, J=8.1 Hz, 1 H), 6.15 (d, J=4.0 Hz, 1 H), 6.04 (dd, J=8.1, 8.1 Hz, 1 H), 4.04 (dd, J=8.8, 8.8 Hz, 1 H), 2.92 (dd, J=7.8, 7.8 Hz, 2 H), *1 H obscured by water peak, 2 H obscured by DMSO peak,, MS (ESI+) m/z 370.3 (M+H) ⁺ . Chiral analysis (Method 2) at 5.22 min. 5-(2-(6-(Difluoromethoxy)pyridin-3-yl)ethyl)-1,4-dihydropyra zine-2,3-dione (Example 36) a) 2,3-Bis(benzyloxy)-5-bromopyrazine To a solution of 2,3-bis(benzyloxy)pyrazine (2.5 g, 8.6 mmol) in DMF (15 mL) was added N-bromosuccinimide (1.6 g, 9 mmol) in one portion and the reaction mixture was stirred at room temperature for 48 hrs. A further portion of N-bromosuccinimide (1.6 g, 9 mmol) was added and the solution was stirred at room temperature for a further 48 hrs. The reaction mixture was concentrated under reduced pressure and the resulting crude material purified by flash column chromatography (0-30% diethyl ether in cyclohexane) to elute the desired product as a white solid (0.65 g, 21%). ¹H NMR (400 MHz, CDCl3): δ 7.70 (s, 1 H), 7.50-7.29 (m, 10 H), 5.45-5.40 (m, 4 H). b) 2,3-Bis(benzyloxy)-5-((trimethylsilyl)ethynyl)pyrazine Anhydrous T 0.65 g, 1.75 mmol), bis(triphenylphosphine)Pd(II) dichloride (0.086 g, 0.123 mmol) and copper (I) iodide ( 0.01 g, 0.0525 mmol) and degassed with a stream of nitrogen whilst being stirred room temperature. Triethylamine (0.53 g, 0.73 mL, 5.25 mmol) was added followed by ethynyltrimethylsilane (0.21 g, 2.2 mmol) and the mixture was stirred at 55 °C for 18 hrs. The mixture was filtered through a plug of silica and washed with ethyl acetate (2 x 10 mL). The filtrate was concentrated under reduced pressure and the resulting crude material purfied by flash column chromatography (0-10% ethyl actetate in cyclohexane) to elute the desired product as a pale brown solid (0.68 g, quant.). ¹H NMR (400 MHz, CDCl3): δ 7.81 (s, 1 H), 7.49-7.28 (m, 10 H), 5.47-5.45 (m, 4 H), 0.28-0.28 (m, 9 H). c) 2,3-Bis(benzyloxy)-5-ethynylpyrazine 2,3-bis(benzyloxy)-5-((trimethylsilyl)ethynyl)pyrazine (0.68 g, 1.75 mmol), was dissolved in methanol (18 mL) and stirred at room temperature. Potassium carbonate (0.24 g, 1.75 mmol) was added and the mixture was stirred at room temperature for 2.5 hrs. The solution was partitioned between dichloromethane (40 mL) and water (4 mL) and the aqueous layer was extracted with further portions of dichloromethane (2 x 10 mL). The combined organic extracts were washed with brine (100 mL), passed through a phase separator and evaporated. The crude material was purfied by flash column chromatography (0-25% diethyl ether in cyclohexane) to elute the desired product as an light brown solid (0.49 g, 88%). ¹H NMR (400 MHz, CDCl3): δ 7.84-7.83 (m, 1 H), 7.50-7.42 (m, 4 H), 7.40-7.30 (m, 6 H), 5.47-5.45 (m, 4 H), 3.16-3.14 (m, 1 H). c) 2,3-Bis(benzyloxy)-5-((6-(difluoromethoxy)pyridin-3-yl)ethyn yl)pyrazine A solutio o-2- (difluoromethoxy)pyridine (0.23 g, 1.0 mmol) and triethylamine (0.25 g, 0.34 mL, 2.5 mmol) were dissolved in acetonitrile (10 mL) and degassed with a stream of nitrogen for 1 minute. Copper iodide (0.005 g, 0.024 mmol) and bis(triphenylphosphine)Pd(II) dichloride (0.04 g, 0.06 mmol) were added and the mixture was stirred at 70 °C for 18 hrs. The mixture was diluted with ethyl acetate (10 mL) and filtered through a plug of Celite ^TM . Water (10 mL) was added to the filtrate and the organic layer extracted. The aqueous layer was washed with further portions of ethyl acetate (2 x 10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography (0- 50% dichloromethane in cyclohexane) to afford the title compound as a yellow oil (0.08 g, 21%). ¹H NMR (400 MHz, CDCl3): δ 7.72 (dd, J = 7.1, 13.4 Hz, 5 H), 7.53-7.30 (m, 10 H), 5.48 (d, J = 10.6 Hz, 4 H). d) 5-(2-(6-(Difluoromethoxy)pyridin-3-yl)ethyl)-1,4-dihydropyra zine-2,3-dione Pdhydroxide on carbon (0.02 g) was added to a solution of 2,3-bis(benzyloxy)-5-((6- (difluoromethoxy)pyridin-3-yl)ethynyl)pyrazine (0.015 g, 0.033 mmol) and 1-methyl-1,4- cyclohexadiene (0.061 g, 0.653 mmol) and the mixture stirred at 85 °C for 18 hrs. The solution was cooled and filtered through a plug of Celite ^TM . The Celite ^TM was washed with ethyl acetate (5 mL), dichoromethane (5 mL) and methanol (5 mL). The filtrate was concentrated in vacuo and the crude residue purified by reverse preparative HPLC to afford the title compound as a white solid (1 mg, 7%). ¹H NMR (400 MHz, DMSO): δ 11.34-11.33 (m, 1 H), 11.00-10.99 (m, 1 H), 8.08-8.07 (m, 1 H), 7.78-7.74 (m, 1 H), 7.67 (t, J =73.1 Hz, 1 H), 7.04-7.01 (m, 1 H), 5.98 (s, 1 H), 2.84-2.78 (m, 2 H), 2.48-2.44 (m, 2 H). MS (ES+) m/z 284 (M+H) ⁺ . 5-(4-Chlorobenzyl)-1,4-dihydropyrazine-2,3-dione (Example 37) a) 5-(4-Chlorobenzyl)-2,3-dimethoxypyrazine To a solution of 4-chlorobenzyl magnesium chloride (2.4 mL, 0.5 M soln. in THF, 1.2 mmol) in THF (1 mL) was added a zinc chloride (0.7 mL, 2 M solution in THF, 1.3 mmol) and the mixture was stirred at room temperature for 45 min. A suspension of 5-bromo-2,3- dimethoxypyrazine (0.13 g, 0.6 mmol) and bis(triphenylphosphine)Pd(II) dichloride in THF (1 mL) was added and the mixture was stirred at room temperature for 64 hrs. The mixture was filtered through Celite ^TM and washed with ethyl acetate (2 x 5 mL). The filtrate was concentrated under reduced pressure and the resulting yellow residue purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to afford the title compound as a colourless solid (0.09 g, 57%). ¹H NMR (400 MHz, CDCl3): δ 7.45-7.43 (m, 1 H), 7.25-7.19 (m, 3 H), 7.12-7.06 (m, 1 H), 3.99-3.97 (m, 6 H), 3.91-3.90 (m, 2 H). b) 5-(4-Chlorobenzyl)-1,4-dihydropyrazine-2,3-dione A solution of 5-(4-chlorobenzyl)-2,3-dimethoxypyrazine(0.09 g, 0.34 mmol) in 2 M aqueous hydrochloric acid (3.4 mL) and 1,4-dioxane (3.4 mL) was heated to reflux for 2 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford the title compound a white solid (17 mg, 22%). ¹H NMR (400 MHz, DMSO): δ 11.16 (s, 2 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.4 Hz, 2 H), 6.09 (s, 1 H), 3.52 (s, 2 H), MS (ESI+) m/z 237.2 (M+H) ⁺ . 5-(1-Phenylcyclopropyl)-1,4-dihydropyrazine-2,3-dione (Example 38) a) 2,3-Dimethoxy-5-(1-phenylcyclopropyl)pyrazine A mixture of 5 , . , . , , , , tetramethyl- 2-(1-phenylcyclopropyl)-1,3,2-dioxaborolane (0.24 g, 0.98 mmol), sodium carbonate (0.16 g, 1.49 mmol), Pdacetate (11 mg, 0.05 mmol) and XPhos (0.07 g, 0.015 mmol) were suspended in a mixture of dioxane (2.4 mL) and water (0.6 mL) and degassed with a stream of nitrogen for 15 min. The mixture was then stirred at 90 °C for 18 hrs in a sealed tube. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The aqueous layer was further extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0-10% ethyl acetate in cyclohexane) to afford the title compound as a pale-yellow oil (0.13 g, quant.). ¹H NMR (400 MHz, CDCl3): δ 7.43-7.21 (m, 2 H), 7.14-7.09 (m, 3 H), 7.04 (s, 1 H), 3.99 (s, 3 H), 3.93 (s, 3 H), 1.12-1.08 (m, 2 H), 0.92-0.89 (m, 2 H). b) 5-(1-Phenylcyclopropyl)-1,4-dihydropyrazine-2,3-dione A solution of 2,3-dimethoxy-5-(1-phenylcyclopropyl)pyrazine (0.13 g, 0.51 mmol) in 2 M aqueous hydrochloric acid (6.1 mL) and 1,4-dioxane (6 mL) was heated to reflux for 3 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford the title compound a white solid (10.7 mg, 9%). ¹H NMR (400 MHz, DMSO) δ 11.35 (s, 1 H), 11.12 (s, 1 H), 7.27 (dd, J=7.0, 7.0 Hz, 4 H), 7.22 - 7.17 (m, 1 H), 6.28 (s, 1 H), 1.22 (dd, J=4.5, 6.7 Hz, 2 H), 1.10 (dd, J=4.8, 6.8 Hz, 2 H). MS (ESI+) m/z 229 (M+H)+. 5-(2-(4-Chlorophenyl)-1,1,2,2-tetrafluoroethyl)-1,4-dihydrop yrazine-2,3-dione (Example 39) a) Ethyl 2-(5,6-dimethoxypyraz , te Coppe r powder ( .7 g, 7. mmo ) was suspended n SO (50 mL) and sonicated for 10 min. 5-Bromo-2,3-dimethoxypyrazine (2 g, 9.1 mmol) and ethyl bromodifluoroacetate (2.7 g, 13.7 mmol) were added and the mixture was heated at 50 °C for 18 hrs. The mixture was diluted with saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (20 mL) and the aqueous layer extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography (0-100% ethyl acetate in cyclohexane) to afford the title compound as a clear oil (0.7 g, 29%). ¹H NMR (400 MHz, CDCl3): δ 8.08-8.03 (m, 1 H), 4.40 (m, 2 H), 4.11- 3.97 (m, 6 H), 1.44-1.28 (m, 3 H). b) 1-(4-Chlorophenyl)-2-(5,6-dimethoxypyrazin-2-yl)-2,2-difluor oethan-1-one 1-Chloro-4-iodobenzene (0.1 g, 0.42 mmol) in diethyl ether (1.5 mL) was added to an oven dried three necked flask and cooled to -78 °C. Ethyl 2-(5,6-dimethoxypyrazin-2-yl)-2,2- difluoroacetate (0.1 g, 0.38 mmol) in diethyl ether (1.5 mL) was added to the mixture dropwise and the solution was stirred at -78 °C for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride solution (3 mL) and extracted into ethyl acetate (2 x 5 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to afford the title compound as a clear oil (0.044 g, 35%). ¹H NMR (400 MHz, CDCl3): δ 8.15 (s, 1 H), 8.07 (d, J = 8.8 Hz, 2 H), 7.46-7.43 (m, 2 H), 4.06 (s, 3 H), 3.85 (s, 3 H). c) 5-(2-(4-Chlorophenyl)-1,1,2,2-tetrafluoroethyl)-2,3-dimethox ypyrazine To a ni ent was cooled to -78 °C. (Diethylamino)sulfur trifuoride (0.043 g, 0.27 mmol) was added followed by 1-(4-chlorophenyl)-2-(5,6-dimethoxypyrazin-2-yl)-2,2-difluor oethan-1-one (0.044 g, 0.13 mmol) and the mixture was warmed to room temperature and stirred for 18 hrs. The mixture was quenched with saturated aqueous ammonium chloride solution (3 mL) and extracted into dichloromethane (2 x 5 mL). The organic layers were combined, passed through a phase separator and concentrated. The crude residue was purified by flash column chromatography (0- 80% ethyl acetate in cyclohexane) to afford the title compound as a clear oil (0.021 g, 45%). ¹H NMR (400 MHz, CDCl3): δ 7.93 (s, 1 H), 7.49-7.40 (m, 4 H), 4.07 (s, 3 H), 3.89 (s, 3 H). d) 5-(2-(4-Chlorophenyl)-1,1,2,2-tetrafluoroethyl)-1,4-dihydrop yrazine-2,3-dione Sodium iodide (0.047 g, 0.31 mmol) and TMSCl (0.034, 0.04 mL, 0.31 mmol) were added to a solution of 5-(2-(4-chlorophenyl)-1,1,2,2-tetrafluoroethyl)-2,3-dimethox ypyrazine (0.022 g, 0.63 mmol), in acetonitrile (1 mL) and the solution stirred at 60 °C for 1 hour. The mixture was evaporated to dryness and the resulting crude material purified by reverse phase preparative HPLC to afford the title compound as an off-white solid (12.4 mg, 62%). ¹H NMR (400 MHz, DMSO): δ 11.91 (s, 1 H), 11.64-11.55 (m, 1 H), 7.73-7.69 (m, 2 H), 7.64-7.60 (m, 2 H), 6.57 (s, 1 H). MS (ES+) m/z 323 (M+H)+. Method D 5-((4-(Trifluoromethyl)benzyl)thio)-1,4-dihydropyrazine-2,3- dione (Example 40) a) S-(4-(Trifluoromethyl)benzy To a solution of . , . in dry DMF (12 mL) under nitrogen was added sodium methanesulfonate (838 mg, 6.25 mmol) and the reaction mixture was stirred at room temperature for 18 hrs. The mixture was diluted with water (30 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2 x 70 mL) and the combined organic layers were washed with 10% lithium chloride solution (30 mL) and brine (40 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the title compound as a colourless oil (1.33 g, 98%). ¹ H NMR (CDCl3, 400 MHz): δ 7.65 (d, J = 8.2 Hz, 2 H), 7.54 (d, J = 8.0 Hz, 2 H), 4.42 (s, 2 H), 3.00 (s, 3 H). b) 2,3-Dichloro-5-((4-(trifluoromethyl)benzyl)thio)pyrazine To a solution of 2,3-dichloropyrazine (305 mg, 2.05 mmol) in dry THF (2 mL) under nitrogen at room temperature was added dropwise over 10 min. a solution of 2,2,6,6- tetramethylpiperidinylmagnesium chloride lithium chloride complex in THF (1.0 M, 2.3 mL, 2.26 mmol). The reaction mixture was stirred at room temperature for 30 min. before being cooled to 0 °C. A solution of S-(4-(trifluoromethyl)benzyl) methanesulfonothioate (665 mg, 2.46 mmol) in dry THF (2 mL) was added dropwise over 10 min. The reaction mixture was stirred at 0 °C for 30 minutes, allowed to warm to room temperature and stirred for 3 hrs. Saturated aqueous ammonium chloride solution (15 mL) was added followed by water (10 mL). The mixture was extracted with ethyl acetate (100 mL, 20 mL, 20 mL) and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (10 – 20% dichloromethane in cyclohexane) to yield the title compound as a yellow oil (269 mg, 39%). ¹H NMR (400 MHz, CDCl ³ ): δ 8.15 (s, 1 H), 7.60-7.53 (m, 4 H), 4.41 (s, 2 H). c) 2,3-Dimethoxy-5-((4-(trifluoromethyl)benzyl)thio)pyrazine To a su , , . dioxane (3 mL) under nitrogen at room temperature was added dry methanol (0.32 mL, 7.81 mmol) dropwise over 10 min. The reaction mixture was stirred at room temperature for 1 hour. A solution of 2,3-dichloro-5-((4-(trifluoromethyl)benzyl)thio)pyrazine (265 mg, 0.781 mmol) in dry dioxane (2 mL) was added over 5 min. and the mixture was stirred at room temperature for 18 hrs. Saturated aqueous ammonium chloride solution (15 mL) was added followed by water (10 mL). The mixture was extracted with ethyl acetate (50 mL, 20 mL, 20 mL) and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (10 – 20% dichloromethane in cyclohexane) to yield the title compound as a pale-yellow oil (138 mg, 53%). ¹H NMR (400 MHz, CDCl3): δ 7.55-7.51 (m, 3 H), 7.43 (d, J = 8.0 Hz, 2 H), 4.31 (s, 2 H), 4.01 (s, 3 H), 3.98 (s, 3 H). d) 5-((4-(Trifluoromethyl)benzyl)thio)-1,4-dihydropyrazine-2,3- dione To a solution of 2,3-dimethoxy-5-((4-(trifluoromethyl)benzyl)thio)pyrazine (138 mg, 0.418 mmol) in dioxane (10 mL) was added 2 M hydrochloric acid (10.4 mL) and the mixture was heated at 100 °C for 4 hrs. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The crude material was purified by preparative HPLC to yield the title compound as an off-white (73 mg, 58%). ¹H NMR (400 MHz, DMSO): δ 11.43 (s, 2 H), 7.71-7.67 (m, 2 H), 7.45-7.41 (m, 2 H), 6.12 (s, 1 H), 4.10 (s, 2 H). MS (ESI+) m/z 303 (M+H)+. The following examples were prepared using an analogous method to that used to prepare 5-((4-(trifluoromethyl)benzyl)thio)-1,4-dihydropyrazine-2,3- dione (Method D) Ex. Structure Name Nmr Mass Ion 45 5-((3,5- ¹H NMR (400 MHz, MS (ESI+) 49 5-((3-Fluoro-4- ¹H NMR (400 MHz, MS (ESI+) 54 5-((Chroman-6- ¹H NMR (400 MHz, MS (ESI+) 59 5-((2,4- ¹H NMR (400 MHz, MS (ESI+) 64 5-((Isoquinolin-7- ¹H NMR (400 MHz, MS (ESI+) Hz, 1 H), 6.09 (s, 1 H), 4.13 5-(((6-Fluoronaphthalen-2-yl)methyl)sulfinyl)-1,4-dihydropyr azine-2,3-dione (Racemic) (Example 70) Following steps a-d from Method D used to prepare 5-(((6-fluoronaphthalen-2- yl)methyl)thio)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (48 mg, 3% over for steps). ¹H NMR (400 MHz, DMSO): δ 9.59-9.58 (m, 2 H), 8.02 (dd, J = 5.8, 9.1 Hz, 1 H), 7.91 (d, J = 8.6 Hz, 1 H), 7.83 (s, 1 H), 7.74 (dd, J = 2.5, 10.4 Hz, 1 H), 7.48 (td, J = 2.7, 8.9 Hz, 1 H), 7.40 (d, J = 8.3 Hz, 1 H), 6.42 (s, 1 H), 4.62 (d, J = 12.6 Hz, 1 H), 4.47 (d, J = 12.6 Hz, 1 H). MS (ESI+) m/z 319 (M+H)+. 5-(((6-fluoronaphthalen-2-yl)methyl)sulfinyl)-1,4-dihydropyr azine-2,3-dione (Single Enantiomer) (Example 71) Separation of the racemic mix -yl)methyl)sulfinyl)-1,4- dihydropyrazine-2,3-dione by chiral preparative HPLC yielded the title compound as an off- white solid (10 mg, 25% yield). ¹H NMR (400 MHz, DMSO): δ 9.59-9.58 (m, 2 H), 8.02 (dd, J = 5.8, 9.1 Hz, 1 H), 7.91 (d, J = 8.6 Hz, 1 H), 7.83 (s, 1 H), 7.74 (dd, J = 2.5, 10.4 Hz, 1 H), 7.48 (td, J = 2.7, 8.9 Hz, 1 H), 7.40 (d, J = 8.3 Hz, 1 H), 6.42 (s, 1 H), 4.62 (d, J = 12.6 Hz, 1 H), 4.47 (d, J = 12.6 Hz, 1 H). MS (ESI+) m/z 319 (M+H)+. Chiral analysis (Method 3) at 9.9 min. 5-(((6-Fluoronaphthalen-2-yl)methyl)sulfonyl)-1,4-dihydropyr azine-2,3-dione (Example 72) a) 5-(((6-Fluoronaphthalen-2-yl)methyl)sulfonyl)-1,4-dihydropyr azine-2,3-dione 5-(((6-Fluoronaphthalen-2-yl)methyl)sulfinyl)-1,4-dihydropyr azine-2,3-dione (racemic) (118 mg, 0.39 mmol) was suspended in DMF (4 mL) and water (1 mL) and Oxone® (0.3 g, 0.98 mmol) was added. The mixture was stirred at room temperature for 24 hrs and then diluted with water (5 mL). The resulting solid suspension was filtered and the isolated solid purified by preparative HPLC to yield the title compound as an off-white solid (33 mg, 25%). ¹H NMR (400 MHz, DMSO): δ 12.12 (s, 1 H), 11.83-11.53 (m, 1 H), 8.05 (dd, J = 5.8, 9.0 Hz, 1 H), 7.95-7.89 (m, 2 H), 7.74 (dd, J = 2.5, 10.3 Hz, 1 H), 7.50-7.44 (m, 2 H), 6.65-6.63 (m, 1 H), 4.87 (s, 2 H). MS (ES+) m/z 335 (M+H)+ 5-(((6-Chloronaphthalen-2-yl)methyl)sulfinyl)-1,4-dihydropyr azine-2,3-dione (Racemic) (Example 73) a) 5-(((6-Chloronaphthalen-2 , ropyrazine-2,3-dione (Racemic) To a suspension of 5-(((6-chloronaphthalen-2-yl)methyl)thio)-1,4-dihydropyrazin e-2,3- dione (21 mg, 0.0659 mmol) in DMF/water (1.0 mL / 0.2 mL) was added Oxone®, monopersulfate compound (21 mg, 0.0692 mmol) and the mixture was stirred at room temperature for 2 hrs. Water (3 mL) was added and the resulting precipitate was collected by filtration. The reaction was repeated starting from 10 mg of 5-(((6-chloronaphthalen-2- yl)methyl)thio)-1,4-dihydropyrazine-2,3-dione. The crude precipitates were combined and purified by preparative HPLC to yield the title compound as an off-white solid (6 mg, 18%). ¹H NMR (400 MHz, DMSO): δ 12.02-11.41 (m, 2 H), 8.05 (d, J = 2.1 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 7.81-7.79 (m, 1 H), 7.54 (dd, J = 2.1, 8.8 Hz, 1 H), 7.39 (dd, J = 1.6, 8.5 Hz, 1 H), 6.40 (s, 1 H), 4.64-4.48 (m, 2 H). MS (ESI+) m/z 335 (M+H)+. 5-(((6-Chloronaphthalen-2-yl)methyl)sulfonyl)-1,4-dihydropyr azine-2,3-dione (Example 74) Following the method to prepare 5-(((6-fluoronaphthalen-2-yl)methyl)sulfonyl)-1,4- dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (6 mg, 12%). ¹H NMR (400 MHz, DMSO): δ 12.15 - 11.65 (m, 2H), 8.08 (d, J=2.1 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.90 - 7.89 (m, 1H), 7.57 (dd, J=2.1, 8.8 Hz, 1H), 7.48 (dd, J=1.6, 8.5 Hz, 1H), 6.64 (s, 1H), 4.86 (s, 2H). MS (ESI+) m/z 351 (M+H)+. Method E 4-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)thio)methyl)-2 -methoxybenzonitrile (Example 75) a) 4-(((5,6-Dimethoxypyrazin- y y xybenzonitrile Following s teps a-c from Method D used to prepare 5-((4-(trifluoromethyl)benzyl)thio)- 1,4-dihydropyrazine-2,3-dione yielded the title compound as a white solid (280 mg, 36% over three steps). ¹H NMR (400 MHz, CDCl3): δ 7.55 (s, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 6.96-6.93 (m, 2 H), 4.27 (s, 2 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 3.89 (s, 3 H). b) 4-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)thio)methyl)-2 -methoxybenzonitrile To a suspension of 4-(((5,6-dimethoxypyrazin-2-yl)thio)methyl)-2-methoxybenzoni trile (270 mg, 0.851 mmol) and sodium iodide (765 mg, 5.10 mmol) in dry acetonitrile (10 mL) was added chlorotrimethylsilane (0.65 mL, 5.10 mmol) and the mixture was heated at 60 °C for 2 hrs. The mixture was cooled to room temperature and saturated sodium thiosulfate solution (10 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 mL). The aqueous layer was concentrated under reduced pressure and extracted with dichloromethane (20 mL) and ethyl acetate (20 mL). The combined organic layers were concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 20% methanol in dichloromethane) to yield the title compound as an off-white solid (41 mg, 16%). ¹H NMR (400 MHz, DMSO): δ 11.65 (s, 1 H), 11.30 (s, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.11 (s, 1 H), 6.97 (d, J = 7.8 Hz, 1 H), 6.21 (s, 1 H), 4.10 (s, 2 H), 3.92 (s, 3 H). MS (ESI+) m/z 290 (M+H)+ The following examples were prepared using an analogous method to that used to prepare 4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)thio)methyl)-2 -methoxybenzonitrile (Method E) Ex. Structure Name NMR Mass Ion 5-((3,4-Difluorobenzyl)thio)-1,4-dihydropyrazine-2,3-dione (Example 78) To a solution of 3,4-difluorobenzyl mercaptan (665 mg, 4.15 mmol) in dry acetonitrile (8 mL) under nitrogen was added sodium tert-butoxide (997 mg, 10.38 mmol). The mixture was stirred at room temperature for 5 min. A solution of 2-chloro-6-methoxypyrazine (500 mg, 3.46 mmol) was added and the mixture was heated at 85 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (20 mL), passed through a phase separation and concentrated under reduced pressure. The crude material was purified by flash column chromatography (15% ethyl acetate in cyclohexane) to yield the title compound as a red oil (708 mg, 76%). ¹H NMR (400 MHz, CDCl3): δ 8.02 (s, 1 H), 7.90 (s, 1 H), 7.26-7.20 (m, 1 H), 7.12-7.06 (m, 2 H), 4.35 (s, 2 H), 3.95 (s, 3 H). b) 2-Bromo-5-((3,4-difluorobenzyl)thio)-3-methoxypyrazine To a so u on o -(( , - uoro enzy ) o)- -me oxypyraz ne ( mg, . mmol) in dry dichloromethane (8 mL) under nitrogen cooled to 0 °C was added N-bromosuccinimide (290 mg, 1.65 mmol). The reaction mixture was stirred at 0 °C for 2 hours, warmed to room temperature and stirred for 18 hrs. The reaction mixture was diluted with saturated sodium hydrogencarbonate solution (20 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-80% dichloromethane in cyclohexane) to yield the title compound as a yellow oil (350 mg, 67%). ¹H NMR (400 MHz, CDCl3): δ 7.83 (s, 1 H), 7.25-7.18 (m, 1 H), 7.15-7.06 (m, 2 H), 4.32 (s, 2 H), 4.02 (s, 3 H). c) 5-((3,4-Difluorobenzyl)thio)-1,4-dihydropyrazine-2,3-dione Following steps c-d from Method D used to prepare 5-((4-(trifluoromethyl)benzyl)thio)- 1,4-dihydropyrazine-2,3-dione yielded the title compound as an off-white solid (37 mg, 13% over two steps). ¹H NMR (400 MHz, DMSO): δ 11.32 (d, J = 115.6 Hz, 2 H), 7.33-7.21 (m, 2 H), 6.97-6.94 (m, 1 H), 6.10-6.08 (m, 1 H), 3.91 (s, 2 H). MS (ESI+) m/z 271(M+H)+. 5-((4-(Pentafluoro-λ ⁶ -sulfaneyl)benzyl)thio)-1,4-dihydropyrazine-2,3-dione (Example 79) Following the procedure used t nzyl)thio)-1,4- dihydropyrazine-2,3-dione yielded after purification by preparative HPLC the title compound as an off-white solid (4.6 mg, 2% over four steps). ¹H NMR (400 MHz, DMSO): δ 11.40-11.33 (m, 2 H), 7.91-7.88 (m, 2 H), 7.50-7.45 (m, 2 H), 6.19 (s, 1 H), 4.14-4.13 (m, 2 H). MS (ESI+) m/z 361 (M+H)+ 5-((3-Cyclopropylbenzyl)thio)-1,4-dihydropyrazine-2,3-dione (Example 80) a) 5-((3-Bromobenzyl)thio)-2,3-dimethoxypyrazine Following steps a-c from Method D used to prepare 5-((4-(trifluoromethyl)benzyl)thio)- 1,4-dihydropyrazine-2,3-dione yielded the title compound as an off-white solid. ¹H NMR (400 MHz, CDCl3): δ 7.55 (s, 1 H), 7.51 (s, 1 H), 7.35 (d, J = 7.9 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.14 (dd, J = 7.8, 7.8 Hz, 1 H), 4.23 (s, 2 H), 4.03 (s, 3 H), 3.98 (s, 3 H). b) 5-((3-Cyclopropylbenzyl)thio)-2,3-dimethoxypyrazine To a mixture of 5-((3-bromobenzyl)thio)-2,3-dimethoxypyrazine (63 mg, 0.185 mmol), potassium cyclopropyltrifluoroborate (33 mg, 0.222 mmol), [1,1’bis(diphenylphosphino)ferrocene]-dichloroPd(II) complex with dichloromethane (9.0 mg, 0.011 mmol) and cesium carbonate (180 mg, 0.554 mmol) under nitrogen was added degassed toluene (2.0 mL) and water (0.6 mL). The reaction mixture was heated at 75 °C for 18 hrs. More potassium cyclopropyltrifluoroborate (17 mg, 0.11 mmol) and [1,1’bis(diphenylphosphino)ferrocene]dichloroPd(II) complex with dichloromethane (1.5 mg, 0.002 mmol) were added to the reaction mixture. The mixture was heated at 75 °C for 5 hrs. The mixture was diluted with ethyl acetate (50 mL) and the organic layer was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was treated with potassium cyclopropyltrifluoroborate (33 mg, 0.222 mmol), [1,1’bis(diphenylphosphino)ferrocene]-dichloroPd(II) complex with dichloromethane (9.0 mg, 0.011 mmol) and cesium carbonate (180 mg, 0.554). To the mixture was added degassed toluene (2.0 mL) and water (0.6 mL). The reaction mixture was heated at 75 °C for 18 hrs. The mixture was diluted with ethyl acetate (50 mL) and the organic layer was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 90% ethyl acetate in cyclohexane) to yield the title compound as a colourless oil (39 mg, 69%). ¹H NMR (400 MHz, CDCl3): δ 7.54 (s, 1 H), 7.16 (dd, J = 7.5, 7.5 Hz, 1 H), 7.09 (d, J = 7.5 Hz, 1 H), 7.03 (s, 1 H), 6.92 (d, J = 7.7 Hz, 1 H), 4.24 (s, 2 H), 4.04 (s, 3 H), 3.98 (s, 3 H), 1.88-1.81 (m, 1 H), 0.96-0.91 (m, 2 H), 0.67-0.62 (m, 2 H). c) 5-((3-Cyclopropylbenzyl)thio)-1,4-dihydropyrazine-2,3-dione Following step d from Method D used to prepare 5-((4-(trifluoromethyl)benzyl)thio)- 1,4-dihydropyrazine-2,3-dione yielded the title compound as an off-white solid (13 mg, 37%). ¹H NMR (400 MHz, DMSO): δ 11.43 (s, 2 H), 7.18 (t, J = 7.7 Hz, 1 H), 6.98 (dd, J = 1.6, 7.7 Hz, 2 H), 6.86 (t, J = 1.6 Hz, 1 H), 6.11 (s, 1 H), 3.98 (s, 2 H), 1.91 - 1.83 (m, 1 H), 0.96 - 0.90 (m, 2 H), 0.62 - 0.57 (m, 2 H). MS (ESI+) m/z 275 (M+H)+. 5-((4-(Trifluoromethoxy)benzyl)thio)-1,4-dihydropyrazine-2,3 -dione (Example 81) a) 2,3-Dichloro-5-((4-(trifluor ine Following s nzyl)thio)- 1,4-dihydropyrazine-2,3-dione yielded the title compound as a yellow oil (370 mg, 42% over two steps). ¹H NMR (400 MHz, CDCl3) δ 8.12 (s, 1 H), 7.43-7.39 (m, 2 H), 7.08-7.05 (m, 2 H), 4.35 (s, 2 H). b) 2,3-Bis(benzyloxy)-5-((4-(trifluoromethoxy)benzyl)thio)pyraz ine To a suspension of sodium hydride (60% in mineral oil, 51 mg, 1.27 mmol) in dry dioxane (1 mL) under nitrogen at room temperature was added benzyl alcohol (0.13 mL, 1.27 mmol) dropwise. The reaction mixture was stirred at room temperature for 30 min. A solution of 2,3-dichloro-5-((4-(trifluoromethoxy)benzyl)thio)pyrazine (150 mg, 0.422 mmol) in dry dioxane (1.1 mL) was added over 5 min. and the mixture was stirred at room temperature for 18 hrs. Saturated aqueous ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 60% dichloromethane in cyclohexane) to yield the title compound as a colourless oil (155 mg, 73%). ¹H NMR (400 MHz, CDCl3): δ 7.52 (s, 1 H), 7.47-7.42 (m, 4 H), 7.39-7.29 (m, 6 H), 7.14 (d, J = 8.8 Hz, 2 H), 7.04 (d, J = 8.2 Hz, 2 H), 5.47 (s, 2 H), 5.42 (s, 2 H), 4.16 (s, 2 H). c) 5-((4-(Trifluoromethoxy)benzyl)thio)-1,4-dihydropyrazine-2,3 -dione To a 54 mg, 0.309 mmol) in ethanol (6 mL) under nitrogen at room temperature was added 1-methyl-1,4- cyclohexadiene (0.69 mL, 6.18 mmol) and 20% Pdhydroxide on carbon (150 mg, 0214 mmol). The reaction mixture was heated at 85 °C for 18 hrs. The reaction mixture was cooled to room temperature and the catalyst was filtered off washing with methanol. The filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC to yield the title compound as an off-white solid (21 mg, 21%). ¹H NMR (400 MHz, DMSO): δ 11.42 (s, 2 H), 7.36 - 7.31 (m, 4 H), 6.14 (s, 1 H), 4.06 (s, 2 H). MS (ESI+) m/z 319 (M+H)+. 5-((4-(Difluoromethoxy)benzyl)thio)-1,4-dihydropyrazine-2,3- dione (Example 82) Following the procedure for 5-((4-(trifluoromethoxy)benzyl)thio)-1,4-dihydropyrazine- 2,3-dione yielded the title compound as an off-white solid (15 mg, 5% over four steps). ¹H NMR (400 MHz, DMSO): δ 11.62 (s, 1 H), 11.24 (s, 1 H), 7.30 - 7.25 (m, 2 H), 7.22 (t, J = 74.2 Hz, 1 H), 7.15 - 7.10 (m, 2 H), 6.15 (s, 1 H), 4.03 (s, 2 H). MS (ESI+) m/z 301 (M+H)+. Method F 4-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)thio)methyl)-2 -fluorobenzonitrile (Example 83) a) 5-((3-Bromobenzyl)thio)-2,3-dimethoxypyrazine Following ste enzyl)thio)- 1,4-dihydropyrazine-2,3-dione yielded the title compound as a brown oil (32% over three steps). ¹H NMR (400 MHz, CDCl3): δ, 7.55 (s, 1 H), 7.45-7.41 (m, 1 H), 7.14-6.97 (m, 2 H), 4.22-4.21 (m, 2 H), 4.01 (s, 3 H), 3.98 (s, 3 H) b) 4-(((5,6-Dimethoxypyrazin-2-yl)thio)methyl)-2-fluorobenzonit rile To a deg asse so ut on o -(( - romo enzy )t o)- , - met oxypyraz ne ( mg, 0.835 mmol) in dry butanol (4 mL) was added DIPEA (0.29 mL, 1.67 mmol), Pd(pi-cinnamyl) chloride dimer (43 mg, 0.0835 mmol) and X-Phos (119 mg, 0.251 mmol). The mixture was heated at 80 °C under nitrogen before a solution of acetone cyanohydrin (0.092 mL, 1.0 mmol) in dry butanol (1 mL) was added dropwise over 90 min. The mixture was cooled to room temperature and saturated sodium hydrogencarbonate solution (10 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 30% ethyl acetate in cyclohexane) to yield the title compound as a pale-yellow oil (140 mg, 55%). ¹H NMR (400 MHz, CDCl3): δ 7.55-7.43 (m, 2 H), 7.39-7.29 (m, 2 H), 5.56 (s, 2 H), 5.51 (s, 3 H), 5.46 (s, 3 H). c) 4-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)thio)methyl)-2 -fluorobenzonitrile Following step b from Method E used to prepare 4-(((5,6-dioxo-1,4,5,6- tetrahydropyrazin-2-yl)thio)methyl)-2-methoxybenzonitrile yielded after purification by preparative HPLC the title compound as an off-white solid (61 mg, 48%). ¹H NMR (400 MHz, DMSO): δ 11.80-11.05 (m, 2 H), 7.87 (dd, J = 7.5, 7.5 Hz, 1 H), 7.42 (dd, J = 1.2, 10.5 Hz, 1 H), 7.23 (dd, J = 1.4, 8.0 Hz, 1 H), 6.17 (s, 1 H), 4.08 (s, 2 H). MS (ESI+) m/z 278 (M+H)+. The following examples were prepared using an analogous method to that used to prepare 4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)thio)methyl)-2 -fluorobenzonitrile (Method F). Ex. Structure Name NMR Mass Ion 5-((4-(Difluoromethyl)-3-fluorobenzyl)thio)-1,4-dihydropyraz ine-2,3-dione (Example 87) a) 4-(Difluoromethyl)-3-fluoro To a solution of ( -( uoromet y )- - uorop eny )met ano ( mg, .73 mmol) in dry dichloromethane (14 mL) under nitrogen cooled to 0 °C was added methanesulfonyl chloride (0.23 mL, 3.0 mmol) and triethylamine (0.46 mL, 3.27 mmol). The reaction mixture was stirred at 0 °C for 90 min. The mixture was diluted with dichloromethane (50 mL) and washed with saturated ammonium chloride solution (2 x 20 mL) and saturated sodium hydrogencarbonate solution (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield the title compound as a yellow oil (660 mg, 95%). ¹H NMR (400 MHz, CDCl3): δ 7.65 (dd, J = 7.5, 7.5 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.22 (d, J = 10.8 Hz, 1 H), 6.90 (t, J = 54.7 Hz, 1 H), 5.25 (s, 2 H), 3.03 (s, 3 H). b) 5-((4-(Difluoromethyl)-3-fluorobenzyl)thio)-1,4-dihydropyraz ine-2,3-dione Following steps a-d from Method D used to prepare 5-((4-(trifluoromethyl)benzyl)thio)- 1,4-dihydropyrazine-2,3-dione yielded the title compound as an off-white solid (44 mg, 20% over four steps). ¹H NMR (400 MHz, DMSO): δ 11.44 (s, 2 H), 7.60 - 7.55 (m, 1 H), 7.28 - 7.25 (m, 1 H), 7.18 (m, 1 H), 7.18 - 7.15 (m, 1 H), 6.18 (s, 1 H), 4.07 - 4.06 (m, 2 H). MS (ESI+) m/z 303 (M+H)+ 5-((3-Chloro-4-(difluoromethyl)benzyl)thio)-1,4-dihydropyraz ine-2,3-dione (Example 88) a) 3-Chloro-4-(difluoromethyl) To a solution of -c o o- - uo o e y e o c ac g, . mol) in dry THF (10 mL) under nitrogen was added dropwise a solution of borane dimethyl sulphide complex in THF (2.0 M, 3.8 mL, 7.52 mmol). The reaction mixture was stirred at room temperature for 18 hrs. Saturated ammonium chloride solution (10 mL) was added slowly and the organic phase was separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were washed with saturated sodium hydrogencarbonate solution (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield (3-chloro-4-(difluoromethyl)phenyl)methanol. To a solution of this alcohol (480 mg, 2.49 mmol) in dry dichloromethane (12 mL) under nitrogen cooled to 0 °C was added methanesulfonyl chloride (0.21 mL, 2.74 mmol) and triethylamine (0.42 mL, 2.99 mmol). The reaction mixture was stirred at 0 °C for 90 min. The mixture was diluted with dichloromethane (50 mL) and washed with saturated ammonium chloride solution (2 x 20 mL) and saturated sodium hydrogencarbonate solution (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield the title compound as a yellow oil (670 mg, 98% over two steps). ¹H NMR (400 MHz, CDCl ³ ): δ 7.71 (d, J = 8.0 Hz, 1 H), 7.50 (s, 1 H), 7.42 (d, J = 9.2 Hz, 1 H), 6.95 (t, J = 54.9 Hz, 1 H), 5.24 (s, 2 H), 3.03 (s, 3 H). b) 5-((3-Chloro-4-(difluoromethyl)benzyl)thio)-1,4-dihydropyraz ine-2,3-dione Followin yl)thio)- 1,4-dihydropyrazine-2,3-dione yielded the title compound as an off-white solid (35 mg, 11% over four steps). ¹H NMR (400 MHz, DMSO): δ 11.77-11.11 (m, 2 H), 7.66-7.63 (m, 1 H), 7.49- 7.47 (m, 1 H), 7.33-7.30 (m, 1 H), 7.18 (t, J = 49.8 Hz, 1 H), 6.18 (s, 1 H), 4.06 (s, 2 H). MS (ESI+) m/z 319 (M+H)+. 5-(((5,6-Dichloronaphthalen-2-yl)methyl)thio)-1,4-dihydropyr azine-2,3-dione (Example 89) a) 6-Bromo-1,2-dichloronaphthalene To a suspension of copper(II) chloride (1075 mg, 8.6 mmol) in dry acetonitrile (49 mL) under nitrogen was added dropwise tert-butyl nitrite (1.40 mL, 11.7 mmol). The mixture was heated at 60 °C and a solution of 6-bromo-1-chloronaphthalen-2-amine (2010 mg, 7.85 mmol) in dry acetonitrile (24 mL) was added dropwise. The reaction mixture was heated at 60 °C for 30 min. 2 M hydrochloric acid (30 mL) was added slowly and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with 2 M hydrochloric acid (30 mL), washed with brine (30 mL), passed through phase separation paper and concentrated under reduced pressure. The crude material was purified by flash column chromatography (100% cyclohexane) to yield the title compound as a white solid (1.58 g, 73%). ¹H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 9.0 Hz, 1 H), 8.00 (d, J = 1.8 Hz, 1 H), 7.69 (dd, J = 1.9, 9.0 Hz, 1 H), 7.61 (d, J = 8.8 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1 H). b) 5,6-Dichloro-2-naphthaldehyde To a solution of , , dry THF (35 mL) under nitrogen cooled to -78 °C was added dropwise a solution of n-butyllithium (2.5 M, 2.3 mL, 5.74 mmol). The reaction mixture was stirred at -78 °C for 15 min. A solution of dry DMF (0.74 mL, 9.57 mmol) was added dropwise and the mixture was stirred at -78 °C for 60 min. Saturated ammonium chloride solution (10 mL) was added, dropwise initially and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (2 x 20 mL), brine (20 mL), passed though phase separation paper and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-10% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (815 mg, 76%). ¹H NMR (400 MHz, CDCl3): δ 10.19 (s, 1 H), 8.40 (d, J = 8.9 Hz, 1 H), 8.34 (d, J = 1.5 Hz, 1 H), 8.09 (dd, J = 1.6, 8.9 Hz, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.8 Hz, 1 H). c) (5,6-Dichloronaphthalen-2-yl)methanol To a suspension/solution of 5,6-dichloro-2-naphthaldehyde (810 mg, 3.60 mmol) in methanol (30 mL) cooled to 0 °C was added portionwise sodium borohydride (204 mg, 5.40 mmol). The reaction mixture was stirred at 0 °C for 60 min. Water (30 mL) was added and the methanol was removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (100 mL). The organic layer was washed with water (30 mL), brine (30 mL), passed through phase separation paper and concentrated under reduced pressure to yield the title compound as a white solid (698 mg, 85%). ¹H NMR (400 MHz, CDCl ³ ): δ 8.26 (d, J = 8.7 Hz, 1 H), 7.81 (s, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.61 (dd, J = 1.7, 8.7 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 4.89 (d, J = 5.8 Hz, 2 H), 1.83 (t, J = 5.9 Hz, 1 H). d) (5,6-Dichloronaphthalen-2-yl)methyl methanesulfonate To a suspens 1.50 mmol) in dry dichloromethane (15 mL) under nitrogen cooled to 0 °C was added dropwise triethylamine (0.42 mL, 3.00 mmol) followed by mesyl chloride (0.17 mL, 2.25 mmol) again dropwise. The reaction mixture was stirred at 0 °C for 90 min. 2M hydrochloric acid (20 mL) was added and the mixture was extracted with dichloromethane (100 mL). The organic layer was washed with 2M hydrochloric acid (20 mL), passed through phase separation paper and concentrated under reduced pressure to yield the title compound as a cream solid (540 mg, quantitative). ¹H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 8.8 Hz, 1 H), 7.88 (s, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.65 (dd, J = 1.8, 8.8 Hz, 1 H), 7.56 (d, J = 8.8 Hz, 1 H), 5.41 (s, 2 H), 2.97 (s, 3 H). e) 5-(((5,6-Dichloronaphthalen-2-yl)methyl)thio)-1,4-dihydropyr azine-2,3-dione Following steps a-d from Method D used to prepare 5-((4-(trifluoromethyl)benzyl)thio)- 1,4-dihydropyrazine-2,3-dione yielded the title compound as a pale orange solid (13 mg, 3% over four steps). ¹H NMR (400 MHz, DMSO): δ 11.73-11.16 (m, 2 H), 8.18 (d, J = 8.7 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 7.80 (s, 1 H), 7.72-7.64 (m, 2 H), 6.04 (s, 1 H), 4.21 (s, 2 H). MS (ES+) m/z 353 (M+H)+. Method G 5-((Pyrazolo[1,5-a]pyridin-5-ylmethyl)thio)-1,4-dihydropyraz ine-2,3-dione (Example 90) a) Pyrazolo[1,5-a]pyridin-5-ylmethanol To a suspension/s 1.2 g, 8 mmol) in methanol (18 mL) cooled to 0 °C was added portionwise sodium borohydride (0.46 g, 12.3 mmol). The reaction mixture was stirred at 0 °C for 4 hrs. Water (30 mL) was added and the methanol was removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water (20 mL), brine (20 mL), passed through phase separation paper and concentrated under reduced pressure to yield the title compound as a colourless oil (1.18 g, quant.). ¹H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 7.2 Hz, 1 H), 7.93 (d, J = 2.3 Hz, 1 H), 7.50 (s, 1 H), 6.72 (dd, J = 1.8, 7.3 Hz, 1 H), 6.47 (d, J = 1.5 Hz, 1 H), 4.72 (d, J = 3.6 Hz, 2 H) (OH peak not observed). b) 5-(Bromomethyl)pyrazolo[1,5-a]pyridine Pyrazolo[1,5-a]pyridin-5-ylmethanol (1.18 g, 8 mmol) was dissolved in dry dichloromethane (40 mL) under nitrogen and the solution cooled to 0 °C. Phosphorous tribromide (4.3 g, 1.5 mL, 16 mmol) was added drop-wise and the reaction mixture was stirred for 45 min. The mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted into dichloromethane (3 x 20 mL). The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate (10 mL), dried with magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid (1.0 g, 63%). ¹H NMR (400 MHz, CDCl3): δ 8.46-8.43 (m, 1 H), 7.97-7.95 (m, 1 H), 7.53-7.52 (m, 1 H), 6.79-6.76 (m, 1 H), 6.53-6.52 (m, 1 H), 4.49-4.48 (m, 2 H). c) 2,3-Dimethoxy-5-((triisopropylsilyl)thio)pyrazine 5-Bromo-2,3-dimethoxypyrazine (0.14 g, 0.66 mmol), triisopropylsilanethiol (0.13 g, 0.14 mL, 0.66 mmol) and lithium bis(trimethylsilyl)amide (0.73 mL, 1 M solution in hexane, 0.73 mmol) were dissolved in toluene (1.8 mL) and the solution was degassed with a stream of nitrogen for 15 min. Pd(dppf)Cl2 (0.054 g, 0.067 mmol) was added and the mixture was then stirred at 110 °C for 1 hour. The mixture was cooled and concentrated to dryness. The crude material was purified by flash colum chromatography (0-10% ethyl acetate in cyclohexane). The isolated material was purified further by flash column chromatography (0-100% dichloromethane in cyclohexane) to afford the title compound as a white solid (0.08 g, 36%). ¹H NMR (400 MHz, CDCl3): δ 7.75 (s, 1 H), 3.99-3.98 (m, 6 H), 1.42-1.31 (m, 3 H), 1.13-1.10 (m, 18 H). d) 5-(((5,6-Dimethoxypyrazin-2-yl)thio)methyl)pyrazolo[1,5-a]py ridine T o a m xture o ,3-d met oxy-5-((tr sopropy s y )t o)pyraz ne (0.08 g, 0. mmo) and 5-(bromomethyl)pyrazolo[1,5-a]pyridine (0.057 g, 0.27 mmol) in DMF under a nitrogen atmosphere was added cesium fluoride (0.074 g, 0.49 mmol) and cesium carbonate (0.04 g, 0.12 mmol). The resulting mixture was stirred at 50 °C for 90 min. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined, dried with sodium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography (0-60% ethyl acetate in cyclohexane) to yield the title compound as a white solid (0.062 g, 84%). ¹H NMR (400 MHz, CDCl3): δ 8.38 (d, J = 7.3 Hz, 1 H), 7.91 (d, J = 2.3 Hz, 1 H), 7.57 (s, 1 H), 7.39 (d, J = 1.0 Hz, 1 H), 6.76 (dd, J = 1.9, 7.2 Hz, 1 H), 6.41 (d, J = 1.5 Hz, 1 H), 4.27 (s, 2 H), 3.99 (s, 3H), 4.01 (s, 3 H). e) 5-((Pyrazolo[1,5-a]pyridin-5-ylmethyl)thio)-1,4-dihydropyraz ine-2,3-dione Following step d from Method D used to prepare 5-((4-(trifluoromethyl)benzyl)thio)- 1,4-dihydropyrazine-2,3-dione yielded after purification by flash column chromatography (0- 15% methanol in dichloromethane) the title compound as an off-white solid (32 mg, 59% yield). ¹H NMR (400 MHz, DMSO): δ 11.63 (s, 1 H), 11.20 (s, 1 H), 8.63 (d, J=7.2 Hz, 1 H), 7.96 (d, J=2.3 Hz, 1 H), 7.42 - 7.40 (m, 1 H), 6.79 (dd, J=1.9, 7.2 Hz, 1 H), 6.55 (dd, J=0.9, 2.3 Hz, 1 H), 6.15 (s, 1 H), 4.05 (s, 2 H). MS (ESI+) m/z 275 (M+H)+. 5-((Benzo[d][1,2,3]thiadiazol-6-ylmethyl)thio)-1,4-dihydropy razine-2,3-dione (Example 91) a) 6-(Bromomethyl)benzo[d][1 , , To a solution of be nzo[ ][ , , ] a azo e- -car oxy c ac ( mg, .99 mmol) in dry THF (20 mL) under nitrogen was added dropwise a solution of borane dimethyl sulphide complex in THF (2 M, 7.5 mL, 15 mmol). The reaction mixture was stirred at room temperature for 18 hrs. Saturated ammonium chloride solution (20 mL) was added slowly and the organic phase was separated. The aqueous layer was extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were washed with saturated sodium hydrogencarbonate solution (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield benzo[d][1,2,3]thiadiazol-6-ylmethanol. The alcohol (0.34 g, 2 mmol) was dissolved in dry dichloromethane (10 mL) under nitrogen and the solution cooled to 0 °C. Phosphorous tribromide (1.12 g, 0.39 mL, 4 mmol) was added dropwise and the reaction mixture was stirred for 45 min. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with dichloromethane (3 x 20 mL). The organic layers were combined, washed with saturated sodium hydrogencarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off- white solid (0.12 g, 26%). ¹H NMR (400 MHz, CDCl3): δ 8.63-8.60 (m, 1 H), 8.11 (d, J = 1.0 Hz, 1 H), 7.67 (dd, J = 1.6, 8.7 Hz, 1 H), 4.66 (s, 2 H) b) 5-((Benzo[d][1,2,3]thiadiazol-6-ylmethyl)thio)-1,4-dihydropy razine-2,3-dione Following steps d-e from Method G used to prepare 5-((pyrazolo[1,5-a]pyridin-5- ylmethyl)thio)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (45 mg, 26% over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.60 (s, 1 H), 11.13 (s, 1 H), 8.66 (d, J=8.6 Hz, 1 H), 8.18 (d, J=1.4 Hz, 1 H), 7.63 (dd, J=1.4, 8.6 Hz, 1 H), 6.04 (s, 1 H), 4.24 (s, 2 H). MS (ESI+) m/z 293 (M+H)+. 5-(((1H-Benzo[d][1,2,3]triazol-5-yl)methyl)thio)-1,4-dihydro pyrazine-2,3-dione (Example 92) a) 6-(Chloromethyl)-1H-benzo[d][1,2,3]triazole Ethyl 1H-benzo[d][1,2,3]triazole-6-carboxylate (0.28 g, 1.5 mmol) was dissolved in dry THF (5 mL). Lithium aluminium hydride (3 mL, 1 M solution in THF, 3 mmol) was added and the mixture was refluxed under nitrogen for 18 hrs. The mixture was poured onto ice water (10 mL), adjusted to pH 2 with 2M HCl and diluted with THF (10 mL). The mixture was concentrated and extracted into ethyl acetate: THF (1:1) (3 x 10 mL), organic layers were combined, dried over magnesium sulfate, filtered and concentrated to afford (1H- benzo[d][1,2,3]triazol-6-yl)methanol. (1H-Benzo[d][1,2,3]triazol-6-yl)methanol (0.17 g, 1.14 mmol) was suspended in toluene (1 mL), thionyl chloride (1.3 g, 0.83 mL, 11.4 mmol) was added and the mixture was stirred at room temperature for 4 hrs. The mixture was filtered to isolate the title compound as a light brown solid (0.12 g, 62%). ¹H NMR (400 MHz, DMSO): δ 8.05 (s, 1 H), 7.99-7.96 (m, 1 H), 7.56 (dd, J = 1.3, 8.6 Hz, 1 H), 5.01-5.00 (m, 2 H). b) 5-(((1H-Benzo[d][1,2,3]triazol-5-yl)methyl)thio)-1,4-dihydro pyrazine-2,3-dione Following step idin-5- ylmethyl)thio)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (33 mg, 22% over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.64 (s, 1 H), 11.16 (d, J = 5.3 Hz, 1 H), 7.90-7.80 (m, 1 H), 7.67-7.62 (m, 1 H), 7.36-7.31 (m, 1 H), 6.05 (dd, J = 2.4, 5.5 Hz, 1 H), 4.20 (s, 2 H) (NH peak not observed). MS (ES+) m/z 276 (M+H)+ 5-((3-Chloro-4-(1H-pyrazol-4-yl)benzyl)thio)-1,4-dihydropyra zine-2,3-dione (Example 93) a) 5-((3-Chloro-4-(1H-pyrazol-4-yl)benzyl)thio)-2,3-dimethoxypy razine 5-((4-Bromo-3-chlorobenzyl)thio)-2,3-dimethoxypyrazine (synthesised following steps d-e from Method D used to prepare 5-((pyrazolo[1,5-a]pyridin-5-ylmethyl)thio)-1,4- dihydropyrazine-2,3-dione) (0.1 g, 0.27 mmol) was combined with N-boc-1H-pyrazole-4- boronic acid (0.056 g, 0.27 mmol), potassium carbonate (0.074 g, 0.53 mmol) and Pd(dppf)Cl2 (19 mg, 0.03 mmol) in dioxane (1 mL) and water (1 mL). The mixture was degassed with a stream of nitrogen for 10 min. and the heated at 100 °C for 5 hrs. The mixture was filtered through a pad of Celite ^TM and the filtrate concentrated under reduced pressure. Crude material was purified by flash column chromatography (0-100% ethyl acetate in cyclohexane) to yield the title compound as a white solid (0.079 g, 32%). ¹H NMR (400 MHz, CDCl3): δ 7.94-7.93 (m, 2 H), 7.57-7.57 (m, 1 H), 7.46-7.37 (m, 2 H), 7.25-7.21 (m, 1 H), 4.25 (s, 2 H), 4.05 (s, 3 H), 3.99 (s, 3 H) (NH peak not observed). b) 5-((3-Chloro-4-(1H-pyrazol-4-yl)benzyl)thio)-1,4-dihydropyra zine-2,3-dione F , , , , tetrahydropyrazin-2-yl)thio)methyl)-2-methoxybenzonitrile yielded the title compound as a white solid (0.025 g, 34%). ¹H NMR (400 MHz, DMSO): δ 11.65-11.63 (m, 1 H), 11.28 (d, J = 5.6 Hz, 1 H), 8.04-8.02 (m, 2 H), 7.57-7.54 (m, 1 H), 7.37-7.35 (m, 1 H), 7.15 (dd, J = 1.9, 8.0 Hz, 1 H), 6.21-6.17 (m, 1 H), 4.03-4.01 (m, 2 H), 3.90-3.85 (m, 1 H). MS (ES+) m/z 335 (M+H)+ 5-((3-Chloro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)thio)-1,4-di hydropyrazine-2,3- dione (Example 94) Following the procedure used to prepare 5-((3-chloro-4-(1H-pyrazol-4-yl)benzyl)thio)- 1,4-dihydropyrazine-2,3-dione yielded after purification by preparative HPLC the title compound as an off-brown solid (10 mg, 3% yield over four steps). ¹H NMR (400 MHz, DMSO): δ 11.68-11.62 (m, 1 H), 11.27-11.22 (m, 1 H), 8.17 (s, 1 H), 7.84 (s, 1 H), 7.56-7.53 (m, 1 H), 7.37 (d, J = 1.8 Hz, 1 H), 7.17 (dd, J = 1.8, 8.0 Hz, 1 H), 6.20 (s, 1 H), 4.04-4.02 (m, 2 H), 3.90 (s, 3 H). MS (ES+) m/z 349 (M+H)+ 5-(((6,7-Dichloronaphthalen-2-yl)methyl)thio)-1,4-dihydropyr azine-2,3-dione (Example 95)

. , , . , . mmol) were dissolved in toluene (10 mL) under nitrogen and heated to 80 °C. Isoamyl nitrite (0.28 g, 0.32 mL, 2.4 mmol) was added drop-wise over 10 min. The resulting red suspension was heated at 80 °C for 30 min. and then refluxed for 2 hrs. The mixture was cooled and washed with 1 M NaOH (2 x 5 mL), 5% sodium bisulfite aqueous solution (5 mL), 1 M HCl (5 mL) and brine (5 mL). Organics were dried over magnesium sulfate, filtered and concentrated. Crude material was purified by flash column chromatography (0-70% ethyl acetate in cyclohexane) to yield the title compound as a light-yellow solid (0.2 g, 41%). ¹H NMR (400 MHz, CDCl3): δ 8.51 (s, 1 H), 8.10-8.06 (m, 2 H), 8.00 (s, 1 H), 7.81-7.78 (m, 1 H), 3.99 (s, 3 H). b) 6-(Bromomethyl)-2,3-dichloronaphthalene Methyl 6,7-dichloro-2-naphthoate (0.22 g, 0.84 mmol) was dissolved in dry THF (20 mL) and cooled to 0 °C. Lithium aluminium hydride (0.88 mL, 1 M solution in THF, 0.88 mmol) was added drop-wise and the mixture was stirred at 0 °C for 1 hour. The mixture was quenched with saturated aqueous sodium sulfate solution (10 mL), stirred for 10 min. then filtered through a pad of Celite ^TM . The filtrate was concentrated to afford (6,7-dichloronaphthalen-2-yl)methanol. (6,7- dichloronaphthalen-2-yl)methanol (0.15 g, 0.68 mmol) was dissolved in dry dichloromethane (6 mL) under nitrogen and the solution cooled to 0 °C. Phosphorous tribromide (0.27 g, 0.096 mL, 1 mmol) was added drop-wise and the reaction mixture was stirred for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and extracted into dichloromethane (3 x 5 mL). The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution (5 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as a white solid (0.08 g, 24%). ¹H NMR (400 MHz, CDCl3): δ 7.93-7.91 (m, 2 H), 7.75-7.72 (m, 2 H), 7.54- 7.51 (m, 1 H), 4.62-4.62 (m, 2 H). c) 5-(((6,7-Dichloronaphthalen-2-yl)methyl)thio)-1,4-dihydropyr azine-2,3-dione Followin g p p p py , py 5- ylmethyl)thio)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an white solid. (5 mg, 5% over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.15 (s, 2H), 8.3 (s, 2 H), 8.27 (d, 1 H), 7.91 (s, 1 H), 7.51 (d, 1H), 6.05 (s, 1 H), 4.15 (s, 2 H). MS (ES+) m/z 353 (M+H)+ 5-((Benzo[c]isothiazol-5-ylmethyl)thio)-1,4-dihydropyrazine- 2,3-dione (Example 96) a) Benzo[c]isothiazol-5-ylmethanol To a solution of 5-bromobenzo[c] isothiazole (0.9 g, 4.2 mmol) in dry dioxane (32 mL) under nitrogen was added water (8 mL) followed by potassium{[2- (trimethylsilyl)ethoxy]methyl}trifluoroborate (1.2 g, 5.5 mmol) and cesium carbonate (4.1 g, 12 mmol). The reaction mixture was de-gassed with a stream of nitrogen for 10 min. before RuPhos (196 mg, 0.42 mmol), and Pdacetate (47 mg, 0.21 mmol) were added. Degassing was repeated for a further 5 min. and the reaction mixture was heated at 100 °C under nitrogen for 18 hrs. The reaction was cooled and a further portion of potassium{[2- (trimethylsilyl)ethoxy]methyl}trifluoroborate (0.4 g, 1.7 mmol) was added and the mixture was degassed with a stream of nitrogen for 10 min. Additional portions of RuPhos (196 mg, 0.42 mmol), and Pdacetate (47 mg, 0.21 mmol) were added and the mixture degassed a further 5 min. The mixture was then heated at 100 °C for a further 3 hrs. The mixture was cooled and water (30 mL) was added. The aqueous layer was extracted with ethyl acetate (150 mL) and the organic layer further washed with water (30 mL) and brine (30 mL). The organic layer was passed through phase separation paper and solvent was removed under reduced pressure. The crude material was purified by flash silica chromatography (0-10% ethyl acetate in cyclohexane) to yield 5-((2-(tetramethyl-l5-silyl)ethoxy)methyl)benzo[c]isothiazol e. 5-((2-(Tetramethyl-l5-silyl)ethoxy)methyl)benzo[c]isothiazol e (0.65 g, 2.4 mmol) was dissolved in dry dichloromethane (15 mL) and THF (7.4 g, 5 mL, 65.3 mmol) was added slowly. The reaction mixture was stirred for 18 hrs at room temperature. The solvent was removed under reduced pressure and the resulting orange oil dissolved in methanol (20 mL). Solid sodium carbonate (0.5 g) was added and the solution was stirred at room temperature for 30 min. Methanol was removed under vacuum and the residue was partitioned between ethyl acetate (100 mL) and water (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL) and passed through phase separation paper. The solvent was removed under reduced pressure and the crude material was purified by flash column chromatography (10-60% ethyl acetate in cyclohexane) to yield the title compound as a pale-yellow solid (0.25 g, 36%). ¹H NMR (400 MHz, CDCl3): δ 9.16 (s, 1 H), 7.86-7.82 (m, 1 H), 7.75 (s, 1 H), 7.44 (dd, J = 1.5, 9.1 Hz, 1 H), 4.81 (s, 2 H) (OH peak not observed). b) 5-(Chloromethyl)benzo[c]isothiazole To a suspension/solution of benzo[c]isothiazol-5-ylmethanol (285 mg, 1.7 mmol) in dry dichloromethane (10 mL) under nitrogen cooled to 0 °C was added drop-wise triethylamine (0.48 mL, 3.45 mmol) followed by methanesulfonyl chloride (0.2 mL, 2.5 mmol) drop-wise. The reaction mixture was stirred at 0 °C for 60 min. The mixture was warmed to room temperature and stirred for 2 hrs. A further portion of triethylamine (0.24 mL, 1.7 mmol) was added at 0 °C followed by methanesulfonyl chloride (0.1 mL, 1.25 mmol) and the mixture was warmed to room temperature and stirred for 64 hrs.2 M Hydrochloric acid (10 mL) was added and the mixture was extracted with dichloromethane (80 mL). The organic layer was washed with 2 M hydrochloric acid (10 mL), passed through phase separation paper and concentrated. The crude material was purified by flash column chromatography (0-10% ethyl acetate in cyclohexane) to yield the title compound as a yellow oil (0.26 g, 83%). ¹H NMR (400 MHz, CDCl3): δ 9.19 (d, J = 0.8 Hz, 1 H), 7.88-7.84 (m, 1 H), 7.77 (s, 1 H), 7.49-7.46 (m, 1 H), 4.70-4.69 (m, 2 H). c) 5-((Benzo[c]isothiazol-5-ylmethyl)thio)-1,4-dihydropyrazine- 2,3-dione Followin g p - p p - py , - py -5- ylmethyl)thio)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as a yellow solid. (38 mg, 7% over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.65 (s, 1 H), 11.16 (s, 1 H), 9.69 (s, 1 H), 7.76 (d, J = 9.2 Hz, 1 H), 7.59 (s, 1 H), 7.43 (dd, J = 1.7, 9.1 Hz, 1 H), 6.06 (d, J = 3.1 Hz, 1 H), 4.12 (s, 2 H). MS (ES+) m/z 292 (M+H)+ 5-(((7-Fluorochroman-3-yl)methyl)thio)-1,4-dihydropyrazine-2 ,3-dione (Example 97) a) (7-Fluorochroman-3-yl)methanol 7-Fluorochromane-3-carboxylic acid (0.25 g, 1.3 mmol) was dissolved in dry THF (2 mL) and cooled to 0 °C. Lithium aluminium hydride (1.9 mL, 1 M solution in THF, 1.9 mmol) was added drop-wise and the mixture was stirred under nitrogen for 3 hrs. The mixture was poured onto ice water (3 mL), and sodium hydroxide (10% aqueous solution, 3 mL) was added. The mixture was filtered, and the filtrate concentrated and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to afford the title compound as a colourless oil (0.2 g, 86%). ¹H NMR (400 MHz, MeOD) δ 7.05 (t, 1 H), 6.57 (tt, 1 H), 6.48 (dd, 1 H), 4.30 (qd, 1 H), 3.93 (dd, 1 H), 3.57 (ddd, 2 H), 2.81 (dd, 1 H), 2.54 (dd, 1 H), 2.23-2.12 (m, 1 H) (OH peak not observed). b) 5-(((7-Fluorochroman-3-yl)methyl)thio)-2,3-dimethoxypyrazine 2,3-Di y y y y . g, . d in THF (10 mL) and cesium fluoride (0.26 g, 1.7 mmol) was added and the mixture stirred at room temperature for 15 min. Tributylphosphine (0.19 g, 0.24 mL, 0.97 mmol) was added to a degassed solution of THF (5 mL) and cooled to 0 °C and diethyl azodicarboxylate (0.17 g, 0.96 mmol) was added slowly. The solution of 2,3-dimethoxy-5-((triisopropylsilyl)thio)pyrazine with cesium fluoride in THF was added to the mixture of tributylphosphine and diethyl azodicarboxylate under nitrogen and the mixture was stirred at room temperature for 18 hrs. The mixture was concentrated under vacuum and the resulting crude mixture purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to yield the title compound as a colourless oil (0.23 g, 78%). ¹H NMR (400 MHz, CDCl3): δ 7.63-7.62 (m, 1 H), 6.97-6.92 (m, 1 H), 6.59-6.49 (m, 2 H), 4.30-4.25 (m, 1 H), 4.01-3.98 (m, 6 H), 3.98-3.94 (m, 1 H), 3.14-3.11 (m, 2 H), 2.98-2.92 (m, 1 H), 2.66-2.58 (m, 1 H), 2.38-2.28 (m, 1 H). c) 5-(((7-Fluorochroman-3-yl)methyl)thio)-1,4-dihydropyrazine-2 ,3-dione Following step d from Method D used to prepare 5-((pyrazolo[1,5-a]pyridin-5- ylmethyl)thio)-1,4-dihydropyrazine-2,3-dione yielded the title compound as a white solid (0.040 g, 22%). ¹H NMR (400 MHz, DMSO): δ 11.53 (dd, J = 7.6, 18.1 Hz, 1 H), 11.33 (dd, J = 16.7, 16.7 Hz, 1 H), 7.13-7.08 (m, 1 H), 6.71-6.54 (m, 3 H), 4.30-4.25 (m, 1 H), 3.90 (dd, J = 8.2, 10.6 Hz, 1 H), 2.54-2.49 (m, 1 H (partially obscured by DMSO peak), 2.92 (dd, J = 4.9, 16.1 Hz, 1 H), 2.78 (d, J = 7.3 Hz, 2 H), 2.20-2.11 (m, 1 H). MS (ES+) m/z 309 (M+H)+. 5-(((6-Chloro-1,2,3,4-tetrahydronaphthalen-2-yl)methyl)thio) -1,4-dihydropyrazine- 2,3-dione (Example 98) a) Methyl 6-chloro-1,2,3,4-tetrahydronaphthalene-2-carboxylate 6-Chloro-3,4-dih ydronaphthalen-1(2H)-one (1 g, 5.5 mmol), dimethyl carbonate (4.99 g, 4.7 mL, 55.3 mmol) and sodium hydride (0.49 g, 60% in mineral oil, 12.2 mmol) were combined and heated at reflux for 18 hrs. The reaction was cooled to room temperature, quenched with 2 M hydrochloric acid (5 mL) and diluted with diethyl ether (10 mL). The aqueous layer was extracted with diethyl ether (2 x 20 mL), the organics combined, dried over magnesium sulfate and concentrated. The crude mixture was purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield methyl 6-chloro-1-oxo-1,2,3,4- tetrahydronaphthalene-2-carboxylate as a red solid. Methyl 6-chloro-1-oxo-1,2,3,4- tetrahydronaphthalene-2-carboxylate (0.8 g, 3.35 mmol) was dissolved in dichloromethane (15 mL) with trifluoroacetic acid (15 mL) and cooled to 0 °C, triethylsilane (0.78 g, 6.7 mmol) was added drop-wise and the reaction was warmed to room temperature and stirred for 18 hrs. The mixture was concentrated onto silica and purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as an orange oil (0.74 g, 60% over two steps). ¹H NMR (400 MHz, CDCl3): δ, 7.09-7.02 (m, 3 H), 3.72 (s, 3 H), 2.98-2.68 (m, 6 H), 2.23-2.15 (m, 1 H). b) (6-Chloro-1,2,3,4-tetrahydronaphthalen-2-yl)methanol Methyl 6-chlo mol) was dissolved in dry THF (5 mL) and cooled to 0 °C. Lithium aluminium hydride (3.3 mL, 1M solution in THF, 3.3 mmol) was added dropwise and the mixture was stirred under nitrogen for 3 hrs. The mixture was poured onto ice water (3 mL), and sodium hydroxide (10% aqueous solution, 6 mL) was added. The mixture was filtered, and the filtrate concentrated and extracted into ethyl acetate (3 x 10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to afford the title compound as a colourless oil (0.31 g, 86%). ¹H NMR (400 MHz, CDCl3): δ 7.08-6.99 (m, 3 H), 3.65-3.61 (m, 2 H), 2.89-2.76 (m, 3 H), 2.46 (dd, J = 10.7, 16.6 Hz, 1 H), 2.05-1.96 (m, 2 H), 1.49-1.36 (m, 2 H). c) 5-(((6-Chloro-1,2,3,4-tetrahydronaphthalen-2-yl)methyl)thio) -2,3-dimethoxypyrazine Following step b used to prepare 5-(((7-fluorochroman-3-yl)methyl)thio)-1,4- dihydropyrazine-2,3-dione (6-chloro-1,2,3,4-tetrahydronaphthalen-2-yl)methanol (0.22 g, 1.12 mmol) was reacted to yield the title compound as a yellow oil (0.29 g, 75%). ¹H NMR (400 MHz, CDCl3): δ 7.62-7.61 (m, 1 H), 7.07-7.03 (m, 2 H), 6.99-6.95 (m, 1 H), 4.01-3.98 (m, 6 H), 3.14-3.11 (m, 2 H), 2.96 (dd, J = 5.3, 16.4 Hz, 1 H), 2.86-2.74 (m, 2 H), 2.56-2.47 (m, 1 H), 2.12-2.01 (m, 2 H), 1.53-1.45 (m, 1 H). d) 5-(((6-Chloro-1,2,3,4-tetrahydronaphthalen-2-yl)methyl)thio) -1,4-dihydropyrazine- 2,3-dione Following step b from Method E used to prepare 4-(((5,6-dioxo-1,4,5,6- tetrahydropyrazin-2-yl)thio)methyl)-2-methoxybenzonitrile yielded after purification by preparative HPLC the title compound as a peach solid (38 mg, 41% yield). ¹H NMR (400 MHz, DMSO): δ 11.40-11.40 (m, 2 H), 7.16-7.11 (m, 3 H), 6.49 (s, 1 H), 2.99-2.72 (m, 5 H), 2.42 (dd, J = 10.4, 16.6 Hz, 1 H), 2.00-1.94 (m, 1 H), 1.91-1.83 (m, 1 H), 1.46-1.35 (m, 1 H). MS (ES+) m/z 323 (M+H)+. Method H 5-(((4-(Trifluoromethyl)phenyl)thio)methyl)-1,4-dihydropyraz ine-2,3-dione (Example 99) a) (5,6-Dimethoxypyrazin-2-yl )methanol To 5-bromo-2,3-dimethoxypyrazine (2.0 g, 9.1 mmol) in THF (25 mL) at -70 °C was added n-butyl lithium (4.0 mL, 2.5 M solution in THF, 10.0 mmol) over 15 min. The reaction was stirred at -70 °C for 1 hour and DMF (1.4 mL, 18.3 mmol) was then added over 5 min. at - 70 °C. The reaction was stirred at -70 °C for 1.5 hrs. Methanol (10 mL) and sodium borohydride (690 mg, 18.3 mmol) were added and the reaction was stirred for 0.5 hrs. The reaction was brought to -20 °C and quenched with saturated ammonium chloride solution (10 mL). The reaction was diluted with ethyl acetate (20 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 x 20 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 50% ethyl acetate in ether) to yield the title compound as a pale-yellow solid (1.31 g, 84%). ¹H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 0.8 Hz, 1 H), 4.63 (d, J = 0.8 Hz, 2 H), 4.04 (s, 3 H), 4.02 (s, 3 H), 2.41 (m, 1 H). b) 5-(Bromomethyl)-2,3-dimethoxypyrazine To (5,6-dimetho triphenylphosphine (9.6 g, 36.7 mmol) in dichloromethane at 0 °C. Carbon tetrabromide (12.2 g, 36.7 mmol) was added. The reaction was stirred at room temperature for 48 hrs. The reaction was concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 20% ethyl acetate in cyclohexane) to yield the title compound as a colourless solid (7.06 g, 82%). ¹H NMR (400 MHz, CDCl3): δ 7.69 (s, 1 H), 4.45 (s, 2 H), 4.04 (s, 3 H), 4.02 (s, 3 H). c) 2,3-Dimethoxy-5-(((4-(trifluoromethyl)phenyl)thio)methyl)pyr azine To 4-(trifl uoromethyl)thiophenol (3.36 g, 18.8 mmol) was added cesium carbonate (6.15 g, 18.8 mmol) and tetrabutylammonium iodide (6.97 g, 18.8 mmol) in DMF (85 mL), the reaction was stirred at room temperature for 1 hour. 5-(Bromomethyl)-2-3-dimethoxypyrazine (4.00 g, 17.1 mmol) was added and the reaction was stirred at room temperature for 24 hrs. The reaction was diluted with ethyl acetate (40 mL) and water (40 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 x 40 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 25% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (5.62 g, 99%). ¹H NMR (400 MHz, CDCl3): δ 7.59-7.58 (m, 1 H), 7.52-7.44 (m, 4 H), 4.15 (s, 2 H), 3.97 (d, J = 13.9 Hz, 6 H). d) 5-(((4-(Trifluoromethyl)phenyl)thio)methyl)-1,4-dihydropyraz ine-2,3-dione 2,3-Dimethoxy-5-(((4-(trifluoromethyl)phenyl)thio)methyl)pyr azine (5.60 g, 16.9 mmol) was dissolved in 1,4-dioxane (170 mL) and 2 M HCl (169.0 mL, 339.0 mmol) was added. The reaction was heated at 100 °C for 24 hrs under nitrogen. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 20% MeOH in dichloromethane), yielding the title compound as a white solid (2.82 g, 55%). ¹H NMR (400 MHz, DMSO): δ 11.38 (s, 1 H), 11.07 (d, J = 4.5 Hz, 1 H), 7.69-7.65 (m, 2 H), 7.60-7.56 (m, 2 H), 6.25 (d, J = 4.0 Hz, 1 H), 3.96 (s, 2 H). MS (ESI+) m/z 303 (M+H)+. The following examples were prepared using an analogous method to that used to prepare 5-(((4-(trifluoromethyl)phenyl)thio)methyl)-1,4-dihydropyraz ine-2,3-dione (Method H). Ex. Structure Name NMR Mass 103 5-(((4- ¹H NMR (400 MHz, MS Method I 3-Chloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methy l)thio)benzonitrile (Example 104) a) 3-Chloro-4-(((5,6-dimethoxy pyrazin-2-yl)methyl)thio)benzonitrile To 3-chloro-4-mercaptobenzonitrile (120 mg, 0.7 mmol) was added cesium carbonate (231 mg, 0.7 mmol) and tetrabutylammonium iodide (261 mg, 0.7 mmol) in DMF (3.5 mL) and the reaction was stirred at room temperature for 1 hour. 5-(Bromomethyl)-2-3- dimethoxypyrazine (150 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate (5 mL) and water (5 mL). The organics were separated and the aqueous was further extracted with ethyl acetate (5 mL). The combined organics were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 25% ethyl acetate in cyclohexane) to yield the title compound as a white solid (192 mg, 93%). ¹H NMR (400 MHz, CDCl3): δ 7.66 (s, 1 H), 7.61 (d, J = 1.8 Hz, 1 H), 7.54 (d, J = 8.3 Hz, 1 H), 7.47 (dd, J = 1.7, 8.3 Hz, 1 H), 4.20 (s, 2 H), 4.00 (s, 3 H), 3.98 (s, 3 H). b) 3-Chloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methy l)thio)benzonitrile To 3- mmol) was added sodium iodide (334 mg, 2.9 mmol) and chlorotrimethylsilane (0.37 mL, 2.9 mmol) in acetonitrile (6.0 mL) and the reaction was heated at 60 °C for 1.5 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by preparative HPLC to yield the title compound as a white solid (80 mg, 46%). ¹H NMR (400 MHz, DMSO): δ 11.22-11.15 (m, 2 H), 8.07 (d, J = 1.6 Hz, 1 H), 7.81 (dd, J = 1.8, 8.3 Hz, 1 H), 7.69-7.66 (m, 1 H), 6.42 (s, 1 H), 4.05 (s, 2 H). MS (ES+) m/z 294.1 (M+H)+. Example 105 (5-Chloro-2-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2- yl)methyl)thio)benzonitrile) was prepared using an analogous method to that used to prepare 3- chloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl) thio)benzonitrile (Method I). MS (ES+) m/z 294 (M+H)+. ¹H NMR (400 MHz, DMSO): δ 11.42-11.30 (m, 1 H), 11.03 (dd, J = 2.8, 5.4 Hz, 1 H), 8.08 (d, J = 2.3 Hz, 1 H), 7.79-7.69 (m, 2 H), 6.08 (s, 1 H), 3.90 (s, 2 H). Method J 2-Chloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methy l)thio)benzonitrile (Example 106) a) 2-Chloro-4-mercaptobenzonitrile To 2-chloro-4-fluoro m sulphide (0.27 g, 3.5 mmol) and in DMF (2.5 mL) and the reaction was stirred at room temperature for 2 hrs. 1 M Sodium hydroxide was added and the mixture washed with dichloromethane (5 mL). The aqueous layer was acidified to pH 1-2 with 1 M hydrogen chloride solution (2 mL) and extracted with dichloromethane (2 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide a crude residue. To the residue was added 10 % hydrogen chloride solution (2 mL) and the mixture was cooled with an ice-water bath. Zinc dust (2.00 g, 30.6 mmol) was added and the mixture was stirred for 1 hour. Ethyl acetate (5 mL) was added and the mixture was stirred for an additional 30 min. The organic layer was separated and washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the desired product as an orange oil (0.48 g, 88%). ¹H NMR (400 MHz, CDCl3): δ 7.52-7.46 (m, 1 H), 7.40-7.36 (m, 1 H), 7.26 (s, 1 H), 3.74 (s, 1 H). b) 4-(((5,6-Dimethoxypyrazin-2-yl)methyl)thio)phthalonitrile To 2-chloro-4-mercaptobenzonitrile (0.08 g, 0.4 mmol) was added cesium carbonate (0.15 g, 0.4 mmol) and tetrabutylammonium iodide (0.17 g, 0.4 mmol) in DMF (2.5 mL) and the reaction was stirred at room temperature for 1 hour. 5-(Bromomethyl)-2-3-dimethoxypyrazine (0.10 g, 0.4 mmol) was added at 0 °C and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane (5 mL) and water (5 mL). The organics were separated and the aqueous was extracted with dichloromethane (2 x 10 mL). The combined organics were passed through a phase separator and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 30% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (0.14 g, 98%). ¹H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 6.1 Hz, 2 H), 7.53-7.48 (m, 1 H), 7.29-7.27 (m, 1 H), 4.18 (s, 2 H), 4.01-3.98 (m, 6 H). c) 2-Chloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methy l)thio)benzonitrile To 4-(( , . , . was added sodium iodide (0.30 g, 2.0 mmol) and chlorotrimethylsilane (0.22 g, 2.0 mmol) in acetonitrile (4.0 mL) and the reaction was heated at 60 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure onto silica gel. The crude material was purified by flash column chromatography (0 – 20% MeOH in dichloromethane) to yield the title compound (53 mg, 45%). ¹H NMR (400 MHz, DMSO): δ 11.43-11.38 (m, 1 H), 11.14 (d, J = 5.1 Hz, 1 H), 7.93-7.89 (m, 1 H), 7.82-7.80 (m, 1 H), 7.55 (dd, J = 1.5, 8.3 Hz, 1 H), 6.40 (d, J = 3.3 Hz, 1 H), 4.10-4.07 (m, 2 H). MS (ESI+) m/z 294 (M+H)+. Method K 4-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)-2 -fluorobenzonitrile (Example 107) a) O-(4-Cyano-3-fluorophenyl) dimethylcarbamothioate To 2-fluoro-4-hydroxybenzonitrile (1.00 g, 7.2 mmol) was added dimethylthiocarbamoyl (1.08 g, 8.7 mmol), 4-dimethylaminopyridine (0.09 g, 0.7 mmol) and trimethylamine (3.0 mL, 21.8 mmol) in dichloromethane (20 mL) and the reaction was stirred at 40 °C for 24 hrs. The reaction was cooled to room temperature and diluted with dichloromethane (20 mL) and water (20 mL). The aqueous layer was separated and further extracted with dichloromethane (2 x 20 mL). The combined organics were passed through a phase separator and concentrated under reduced pressure. The crude solid was triturated with cyclohexane to give a white solid (1.64 g, 100%). ¹H NMR (400 MHz, CDCl ³ ): δ 7.68-7.60 (m, 1 H), 7.02-6.98 (m, 2 H), 3.45 (s, 3 H), 3.35 (s, 3 H). b) S-(4-Cyano-3-fluorophenyl) dimethylcarbamothioate O-(4-Cyano-3-f , as melted and stirred at 210 °C for 6 hrs. The reaction was cooled to room temperature. The crude material was purified by flash column chromatography (0 – 50% ethyl acetate in cyclohexane) to yield the title compound (0.92 g, 56%). ¹H NMR (400 MHz, CDCl3): δ 7.64-7.56 (m, 1 H), 7.47-7.36 (m, 2 H), 3.10 (s, 6 H). c) 2-Fluoro-4-mercaptobenzonitrile S-(4-Cyano-3-fluorophenyl) dimethylcarbamothioate (0.50 g, 2.2 mmol) was dissolved in THF (5.7 mL) and potassium hydroxide (0.23 g, 4.1 mmol) and methanol (7.7 mL) were added. The reaction was stirred at room temperature for 24 hrs. The mixture was concentrated under reduced pressure then diluted with ethyl acetate (10 mL) and 2 M hydrogen chloride (10 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the title compound (0.34 g, 100%). ¹H NMR (400 MHz, CDCl3): δ 7.49-7.41 (m, 2 H), 7.12-7.07 (m, 1 H), 2.93-2.88 (m, 1 H). d) 4-(((5,6-Dimethoxypyrazin-2-yl)methyl)thio)-2-fluorobenzonit rile To 2-fluoro-4-mercaptobenzonitrile (0.10 g, 0.7 mmol) was added cesium carbonate (0.23 g, 0.7 mmol) and tetrabutylammonium iodide (0.261 g, 0.7 mmol) in DMF (3.5 mL) and the reaction was stirred at room temperature for 1 hour. 5-(Bromomethyl)-2-3- dimethoxypyrazine (0.15 g, 0.6 mmol) was added at 0 °C and stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate (5 mL) and water (5 mL). The aqueous was separated and further extracted with ethyl acetate (2 x 5 mL). The combined organics were passed through a phase separator cartridge and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 20% ethyl acetate in cyclohexane, 12 g column) to yield the title compound as a white solid (0.135 g, 69%). ¹H NMR (400 MHz, CDCl3): δ 7.64 (s, 1 H), 7.49-7.44 (m, 1 H), 7.38-7.33 (m, 1 H), 7.19 (dd, J = 1.3, 8.3 Hz, 1 H), 4.18 (s, 2 H), 4.01-3.98 (m, 6 H). e) 4-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)-2 -fluorobenzonitrile To 4-(( (5,6-dimethoxypyrazin-2-yl)methyl)thio)-2-fluorobenzonitrile (130 mg, 0.4 mmol) was added sodium iodide (320 g, 2.1 mmol) and chlorotrimethylsilane (0.27 mL, 2.1 mmol) in acetonitrile (4.5 mL) and the reaction was heated at 60 °C for 2 hrs. The mixture was cooled to room temperature and concentrated under reduced pressure onto silica. The crude material was purified by flash column chromatography (0 – 20% MeOH in dichloromethane) and then further purified by preparative HPLC to yield the title compound as a white solid (81 mg, 67%). ¹H NMR (400 MHz, DMSO): δ 11.27 - 11.27 (m, 2 H), 7.87 (t, J=7.7 Hz, 1 H), 7.65 (dd, J=1.3, 10.7 Hz, 1 H), 7.41 (dd, J=1.3, 8.3 Hz, 1 H), 6.43 (s, 1 H), 4.07 (s, 2 H). MS (ESI+) m/z 278.1 (M+H)+. 5-((Quinolin-6-ylthio)methyl)-1,4-dihydropyrazine-2,3-dione (Example 108) a) 5-((Quinolin-6-ylthio)methyl)-1,4-dihydropyrazine-2,3-dione 5-(2-c red from 6-(((5,6-dimethoxypyrazin-2-yl)methyl)thio)quinoline (synthesised following general procedures a-d, Method K used to prepare 4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2- yl)methyl)thio)-2-fluorobenzonitrile) following general procedure c, Method J used to prepare 2-chloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methy l)thio)benzonitrile. ¹H NMR (400 MHz, DMSO): δ 11.40 (s, 1 H), 11.01 (s, 1 H), 8.87 (dd, J = 1.8, 4.1 Hz, 1 H), 8.31 (dd, J = 1.1, 8.5 Hz, 1 H), 7.99 (d, J = 2.2 Hz, 2 H), 7.74 (dd, J = 2.2, 8.8 Hz, 1 H), 7.55 (dd, J = 4.1, 8.3 Hz, 1 H), 6.16 (s, 1 H), 3.96 (s, 2 H). MS (ESI+) m/z 286.1 (M+H)+. Method L 5-(((4-(Pentafluoro-λ6-sulfaneyl)phenyl)thio)methyl)-1,4-di hydropyrazine-2,3-dione (Example 109) a) Triisopropyl((4-(pentafluoro-λ6-sulfaneyl)phenyl)thio)silan e To 1-bromo-4-(pentafluorosulfanyl)benzene (132 mg, 0.4 mmol) was added triisopropylsilanethiol (0.10 mL, 0.5 mmol) and lithium bis(trimethylsilyl)amide (0.51 mL, 0.5 mmol) in toluene (2.5 mL). The reaction was degassed for 5 min. and [1,1’- bis(diphenylphosphino)ferrocene]dichloroPd(II) complex with dichloromethane (38 mg, 0.05 mmol) was added and the reaction was stirred at 110 °C for 2 hrs. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 10% dichloromethane in cyclohexane) to yield the title compound as an orange oil (180 mg, 98%). ¹H NMR (400 MHz, CDCl3): δ 7.57-7.55 (m, 4 H), 1.31-1.23 (m, 3 H), 1.10-1.08 (m, 18 H). b) 2,3-Dimethoxy-5-(((4-(pentafluoro-λ6-sulfaneyl)phenyl)thio) methyl)pyrazine To triiso ol) was added 5-(bromomethyl)-2-3-dimethoxypyrazine (128 mg, 0.6 mmol) (prepared steps a-b, Method H), cesium fluoride (139 mg, 0.9 mmol) and cesium carbonate (74 mg, 0.23 mmol) in DMF (2.5 mL) and the reaction was stirred at 50 °C for 1.5 hrs. The reaction was diluted with ethyl acetate (5 mL) and water (5 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 x 5 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 20% ethyl acetate in cyclohexane) to yield the title compound as a pale-yellow oil (160 mg, 92%). ¹H NMR (400 MHz, CDCl3): δ 7.64 (s, 1 H), 7.61 (d, J = 6.2 Hz, 2 H), 7.45-7.41 (m, 2 H), 4.16-4.15 (s, 2 H), 4.00 (s, 3 H), 3.95 (s, 3 H). c) 5-(((4-(Pentafluoro-λ6-sulfaneyl)phenyl)thio)methyl)-1,4-di hydropyrazine-2,3-dione To 2,3-dimethoxy-5-(((4-(pentafluoro-λ6-sulfaneyl)phenyl)thio) methyl)pyrazine (155 mg, 0.4 mmol) was added sodium iodide (299 mg, 2.0 mmol) and chlorotrimethylsilane (0.25 mL, 2.0 mmol) in acetonitrile (4 mL) and the reaction was heated at 60 °C for 1 hour. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to yield the title compound as a white solid (21 mg, 15%). ¹H NMR (400 MHz, DMSO): δ 11.29-11.28 (m, 1 H), 11.00-10.96 (m, 1 H), 7.76-7.71 (m, 2 H), 7.52-7.46 (m, 2 H), 6.21 (s, 1 H), 3.25 (s, 2 H). MS (ES+) m/z 361 (M+H)+. The following examples were prepared using an analogous method to that used to prepare 5-(((4-(pentafluoro-λ6-sulfaneyl)phenyl)thio)methyl)-1,4-di hydropyrazine-2,3-dione (Method L). Ex. Structure Name NMR Mass Ion 113 5-(((4- ¹H NMR (400 MHz, DMSO): MS 117 5- ¹H NMR (400 MHz, DMSO): MS 121 5-(((5- ¹H NMR (400 MHz, DMSO): MS 125 5- ¹H NMR (400 MHz, DMSO): MS 129 5-(((4- ¹H NMR (400 MHz, DMSO): MS 133 5- ¹H NMR (400 MHz, DMSO): MS 4-((1-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)ethyl)thio)b enzonitrile (Example 136) a) 1-(5,6-Dimethoxypyrazin-2-yl)ethan-1-ol To a solution of 5-br ) in THF (20 mL) cooled to -78 °C was added n-butyllithium solution (2.50 M, hexanes) (2.50 mL, 5.02 mmol) dropwise and the mixture stirred for 45 min. Acetaldehyde (1.30 mL, 22.83 mmol) was then added slowly and the reaction allowed to slowly warm to room temperature. The reaction mixture was quenched with water (20 mL) and the organics extracted with ethyl acetate (3 × 20 mL). The organics were concentrated on to silica and purified by flash chromatography (0 – 40%, ethyl acetate in cyclohexane) to provide the desired product as a yellow oil (518 mg, 62%). ¹H NMR (400 MHz, CDCl3): δ 7.63 (s, 1 H), 4.82 (dq, J = 6.3, 6.3 Hz, 1 H), 4.04 (s, 3 H), 4.02 (s, 3 H), 2.77 (d, J = 5.6 Hz, 1 H), 1.52 (d, J = 6.5 Hz, 3 H). b) 4-((1-(3,4-Dimethoxyphenyl)ethyl)thio)benzonitrile To a solution of tributylphosphine (0.33 mL, 1.30 mmol) in THF (2.50 mL), cooled to 0 °C, was added diethylazodicarboxylate (0.21 mL, 1.30 mmol). A solution of 1-(5,6- dimethoxypyrazin-2-yl)ethan-1-ol (200 mg, 1.09 mmol) and 4-mercaptobenzonitrile (176 mg, 1.30 mmol) in THF (2.50 mL) was then added to the reaction mixture and the reaction stirred at 0 °C for 1 hour. The reaction was then concentrated directly on to silica and purified by flash chromatography (0 – 40%, ethyl acetate in cyclohexane) to give the desired product as a colourless oil (200 mg, 61%). ¹H NMR (400 MHz, CDCl3): δ 7.57 (s, 1 H), 7.51-7.49 (m, 2 H), 7.38-7.35 (m, 2 H), 4.50 (q, J = 7.0 Hz, 1 H), 4.00 (s, 3 H), 3.98 (s, 3 H), 1.71 (d, J = 7.2 Hz, 3 H). c) 4-((1-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)ethyl)thio)b enzonitrile 4-((1-(3,4-Dimethoxyphenyl)ethyl)thio)benzonitrile (200 mg, 0.66 mmol) was reacted following step c from Method L used to prepare 5-(((4-(pentafluoro-λ6- sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione, to yield the desired product as an off-white solid (33 mg, 18%). ¹H NMR (400 MHz, DMSO): δ 11.38 (s, 1 H), 11.09 (d, J = 5.3 Hz, 1 H), 7.76 (d, J = 8.5 Hz, 2 H), 7.51 (d, J = 8.5 Hz, 2 H), 6.23 (dd, J = 2.3, 5.5 Hz, 1 H), 4.42 (q, J = 7.2 Hz, 1 H), 1.52 (d, J = 7.2 Hz, 3 H). MS (ES+) m/z 274 (M+H)+ 5-(((4-(Difluoro-methyl)-2-fluoro-6-methylphenyl)thio)methyl )-1,4-dihydropyrazine-2,3- dione (Example 137) a) 5-(((4-(Difluoro-methyl)-2-fluoro-6-methylphenyl)thio)methyl )-1,4-dihydropyrazine-2,3- dione 4-Bromo-3-fluoro-5-methylbenzaldehyde was reacted following general procedures a-c, Method L used to prepare 5-(((4-(pentafluoro-λ6-sulfaneyl)phenyl)thio)methyl)-1,4- dihydropyrazine-2,3-dione) to yield 4-(((5,6-dimethoxypyrazin-2-yl)methyl)thio)-3-fluoro-5- methylbenzaldehyde.4-(((5,6-Dimethoxypyrazin-2-yl)methyl)thi o)-3-fluoro-5- methylbenzaldehyde (0.07 g, 0.21 mmol) was dissolved in toluene (4 mL) and cooled to 0 °C. Deoxo-Fluor® (0.24 mL, 0.65 mmol) was added drop-wise and the mixture stirred for 48 h. The reaction was quenched with satuarate sodium hydrogen carbonate (20 mL) and extracted with ethyl acetate (2 × 40 mL), the organics were combined, dried over magnesium sulfate, passed through a phase separator and concentrated in vacuo. The crude material was purified by flash column chromatography (0 – 15% ethyl acetate in cyclohexane) to provide 5-(((4- (difluoromethyl)-2-fluoro-6-methylphenyl)thio)methyl)-2,3-di methoxypyrazine as a pale-yellow oil (30 mg, 40%).5-(((4-(Difluoromethyl)-2-fluoro-6-methylphenyl)thio)me thyl)-2,3- dimethoxypyrazine (30 mg, 0.08 mmol) was reacted following steps c from Method L used to prepare 5-(((4-(pentafluoro-λ6-sulfaneyl)phenyl)thio)methyl)-1,4-di hydropyrazine-2,3-dione, to yield the desired product as an off-white solid (9 mg, 32%). ¹H NMR (400 MHz, DMSO): δ 10.89 (s, 2 H), 7.38 (s, 1 H), 7.33 (d, J = 9.0 Hz, 1 H), 7.02 (t, J = 55.9 Hz, 1 H), 5.77 (s, 1 H), 3.62 (s, 2 H), 2.42 (s, 3 H). MS (ES+) m/z 317 (M+H)+ Fluorobenzyl)oxy)methyl)phenyl)thio)methyl)-1,4-dihydropyraz ine-2,3-dione (Example 138) a) 1-(((4-Bromobenzyl)oxy)methyl)-3-fluorobenzene To a solution of (4-bromophenyl)methanol (200 mg, 1.07 mmol) and 1-(bromomethyl)-3- fluorbenzene (202 mg, 1.07 mmol) in THF (5 mL) cooled to 0 °C, was added sodium hydride (53 mg, 60% in mineral oil, 1.28 mmol) and the reaction stirred for 16 hrs. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2 × 15 mL), the organics were combined, dried over magnesium sulfate, passed through a phase separator and concentrated in vacuo. The crude material was purified by flash column chromatography (0 – 30% ethyl acetate in cyclohexane) to provide the desired product as a pale-yellow oil (243 mg, 77%). ¹H NMR (400 MHz, CDCl3): δ 7.50-7.47 (m, 2 H), 7.34-7.28 (m, 1 H), 7.25-7.22 (m, 2 H), 7.12-7.06 (m, 2 H), 7.01-6.96 (m, 1 H), 4.54 (s, 2 H), 4.51 (s, 2 H). b) 5-(((4-(((3-Fluorobenzyl)oxy)methyl)phenyl)thio)methyl)-1,4- dihydropyrazine-2,3-dione m Method L used to prepare 5-(((4-(pentafluoro-λ6-sulfaneyl)phenyl)thio)methyl)-1,4- dihydropyrazine-2,3-dione, to yield the desired product as an off-white solid (123 mg, 40% across 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.34 (s, 1 H), 11.00 (d, J = 5.1 Hz, 1 H), 7.43- 7.36 (m, 3 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.23-7.12 (m, 3 H), 6.07 (d, J = 5.1 Hz, 1 H), 4.56 (s, 2 H), 4.53 (s, 2 H), 3.81 (s, 2 H). MS (ES+) m/z 373 (M+H) ⁺ . Method M 5-(((6-Fluoronaphthalen-2-yl)thio)methyl)-1,4-dihydropyrazin e-2,3-dione (Example 139) a) 5-(((6-Fluoronaphthalen-2-yl)thio)methyl)-1,4-dihydropyrazin e-2,3-dione 2-Bromo-6-fluoronaphthalene was reacted following general procedures a-c, Method L used to prepare 5-(((4-(pentafluoro-λ6-sulfaneyl)phenyl)thio)methyl)-1,4-di hydropyrazine-2,3- dione) to yield 5-(((6-fluoronaphthalen-2-yl)thio)methyl)-2,3-dimethoxypyraz ine. The protected pyrazine was then reacted following general procedure d, Method H used to prepare 5-(((4- (trifluoromethyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3 -dione to give the title compound as a white solid (553 mg, 63 % over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.18 - 11.18 (m, 2 H), 8.00 - 7.95 (m, 2 H), 7.88 (d, J=8.7 Hz, 1 H), 7.71 (dd, J=2.6, 10.2 Hz, 1 H), 7.55 (dd, J=1.3, 8.7 Hz, 1 H), 7.45 (td, J=4.5, 11.5 Hz, 1 H), 6.09 (s, 1 H), 3.91 (s, 2 H). MS (ES+) m/z 303 (M+H)+. The following examples were prepared using an analogous method to that used to prepare 5-(((6-fluoronaphthalen-2-yl)thio)methyl)-1,4-dihydropyrazin e-2,3-dione (Method M). Ex. Structure Name NMR Mass

142 5-(((2-Methoxy- ¹H NMR (400 MHz, DMSO): δ MS 5-(((2-(Trifluoromethyl)benzo[b]thiophen-5-yl)thio)methyl)-1 ,4-dihydropyrazine- 2,3-dione (Example 143) a) 5-Bromo-2-(trifluorometh yl)benzo[b]thiophene To (5-bromobenzo[b]thiophen-2-yl)boronic acid (514 mg, 2.0 mmol) was added sodium triflinate (936 mg, 6.0 mmol) and copper (I) chloride (198 mg, 2.0 mmol) in methanol (4 mL), dichloromethane (4 mL) and water (3.2 mL). The reaction was stirred at 0 °C. Luperox® TBH70X, tert-butyl hydroperoxide solution (70% in water, 0.970 mL, 10 mmol) was added drop-wise over 1 hour and the reaction was stirred at room temperature for 24 hrs. The reaction was diluted with diethyl ether (10 mL) and the organics were washed with saturated sodium bicarbonate solution (10 mL) and 1 M sodium thiosulfate solution (10 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 25% ethyl acetate in cyclohexane) to yield the title compound as a colourless oil (320 mg, 57%). ¹H NMR (400 MHz, CDCl3): δ 7.99-7.96 (m, 1 H), 7.74-7.69 (m, 1 H), 7.61-7.51 (m, 2 H). b) 5-(((2-(Trifluoromethyl)benzo[b]thiophen-5-yl)thio)methyl)-1 ,4-dihydropyrazine- 2,3-dione Following step a from Method M used to prepare 5-(((6-fluoronaphthalen-2- yl)thio)methyl)-1,4-dihydropyrazine-2,3-dione yielded the title compound as an off-white solid (55 mg, 13% over 3 steps). ¹ H NMR (400 MHz, DMSO): δ 11.21-11.16 (m, 2 H), 8.14 (d, J = 8.5 Hz, 1 H), 8.08 (t, J = 7.4 Hz, 2 H), 7.60-7.56 (m, 1 H), 6.01 (s, 1 H), 3.86-3.84 (m, 2 H). MS (ES+) m/z 359 (M+H)+. Method N 1-Chloro-6-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methy l)thio)-2- naphthonitrile (Example 144) To 1-chloronaphthalen-2-ol (3.00 g, 16.8 mmol) was added hydrogen bromide (48%, 2 mL, 17.6 mmol) in methanol (30 mL) and cooled to 10 °C. Hydrogen peroxide solution (50%, 1.1 mL, 17.6 mmol) was added dropwise and the reaction was stirred at room temperature for 24 hrs. The reaction was incomplete as shown by LCMS and therefore 1-chloronaphthalen-2-ol (0.9 g, 5 mmol) and hydrogen bromide (48%, 0.6 mL, 5.3 mmol) were added and stirred at room temperature for 24 hrs. The reaction was diluted with ethyl acetate (30 mL) and water (30 mL). The organics were separated and the aqueous was further extracted with ethyl acetate (2 × 30 mL). The combined organics were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 10% ethyl acetate in hexane) to yield the title compound as an off- white solid (1.8 g, 42%). ¹H NMR (400 MHz, CDCl3): δ 7.95-7.91 (m, 2 H), 7.65-7.60 (m, 2 H), 5.89-5.86 (m, 1 H) (OH peak not observed). b) (2-(((6-Bromo-1-chloronaphthalen-2-yl)oxy)methoxy)ethyl)trim ethylsilane To 6-bromo-1-c m hydride (60%, 311 mg, 7.8 mmol) in THF (40 mL) in a nitrogen flushed flask at 0 °C.2-(Trimethylsilyl) ethoxymethyl chloride (1.4 mL, 7.8 mmol) was added dropwise and the reaction was stirred at 0 °C for 1 hour. The reaction was diluted with ethyl acetate (20 mL) and hexane (20 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 × 20 mL). The combined organics were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 10% ethyl acetate in hexane) to yield the title compound as a colourless oil (800 mg, 53% yield). ¹H NMR (400 MHz, CDCl3): δ 8.12-8.09 (m, 1 H), 7.96 (d, J = 2.0 Hz, 1 H), 7.67-7.61 (m, 2 H), 7.52-7.49 (m, 1 H), 5.40 (s, 2 H), 3.89-3.84 (m, 2 H), 3.67-3.59 (m, 2 H), 0.03 (s, 9 H). c) 5-(((5-Chloro-6-((2-(trimethylsilyl)ethoxy)methoxy)naphthale n-2-yl)thio)methyl)- 2,3-dimethoxypyrazine Following steps a-b from Method L used to prepare 5-(((4-(pentafluoro-λ6- sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as a colourless oil (240 mg, 47% over two steps). ¹H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 8.9 Hz, 1 H), 7.79 (d, J = 1.8 Hz, 1 H), 7.61 (d, J = 9.0 Hz, 1 H), 7.56 (dd, J = 1.8, 9.0 Hz, 1 H), 7.50 (s, 1 H), 7.46 (d, J = 9.0 Hz, 1 H), 5.39 (s, 2 H), 4.17 (s, 2 H), 3.97 (s, 3 H), 3.95 (s, 3 H), 3.89- 3.84 (m, 2 H), 1.05 (s, 9 H), 0.99-0.94 (m, 2 H). e) 1-Chloro-6-(((5,6-dimethoxypyrazin-2-yl)methyl)thio)naphthal en-2-ol To 5-(((5-chloro-6-((2-(trimethylsilyl)ethoxy)methoxy)naphthale n-2-yl)thio)methyl)-2,3- dimethoxypyrazine (240 mg, 0.49 mmol) was added trifluoroacetic acid (5 mL) in dichloromethane (1 mL) and the reaction was stirred at room temperature for 15 min. The reaction was concentrated under reduced pressure to yield the title compound as an orange oil (177 mg, 100%). ¹H NMR (400 MHz, CDCl3): δ 7.99-7.92 (m, 3 H), 7.80-7.78 (m, 1 H), 7.61-7.53 (m, 2 H), 4.17 (s, 2 H), 4.00 (s, 3 H), 3.95 (s, 3 H) (OH peak not observed). f) 1-Chloro-6-(((5,6-dimethoxypyrazin-2-yl)methyl)thio)naphthal en-2-yl trifluoromethanesulfonate To 1-chloro-6-(((5,6-dimethoxypyrazin-2-yl)methyl)thio)naphthal en-2-ol (150 mg, 0.4 mmol) was added N-phenyl-bis(trifluoromethanesulfonamide) (148 mg, 0.4 mmol) and N,N- diisopropylethylamine (0.14 mL, 0.8 mmol) in dichloromethane (5 mL) and the reaction was stirred at room temperature for 1.2 hrs. The reaction was diluted with dichloromethane (5 mL) and water (5 mL). The organics were separated and further extracted with ethyl acetate (2 × 10 mL). The combined organics were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 30% ethyl acetate in hexane) to yield the title compound as a colourless oil which solidified on standing (140 mg, 68%). ¹H NMR (400 MHz, CDCl3): δ 8.17-8.13 (m, 1 H), 7.82-7.80 (m, 1 H), 7.68-7.59 (m, 3 H), 7.40 (d, J = 14.4 Hz, 1 H), 4.23-4.22 (s, 2 H), 3.98 (s, 3 H), 3.96 (s, 3 H). g) 1-Chloro-6-(((5,6-dimethoxypyrazin-2-yl)methyl)thio)-2-napht honitrile T trifluoromethanesulfonate (140 mg, 0.3 mmol) was added zinc cyanide (17 mg, 0.1 mmol) and tetrakis(triphenylphosphine)Pd(0) (33 mg, 0.03 mmol) in DMF (5.0 mL) and the reaction was stirred at 90 °C for 1 hour. The reaction was diluted with ethyl acetate (5 mL) and saturated sodium bicarbonate solution. (5 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 × 5 mL). The combined organics were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 50% ethyl acetate in hexane) to yield the title compound as a colourless solid (32 mg, 30%). ¹H NMR (400 MHz, CDCl3): δ 8.23-8.20 (m, 1 H), 7.83 (d, J = 1.8 Hz, 1 H), 7.69-7.56 (m, 4 H), 4.27 (s, 2 H), 3.99 (s, 3 H), 3.97 (s, 3 H). h) 1-Chloro-6-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methy l)thio)-2- naphthonitrile To 1-chloro-6-(((5,6-dimethoxypyrazin-2-yl)methyl)thio)-2-napht honitrile (31 mg, 0.08 mmol) was added sodium iodide (37 mg, 0.3 mmol) and chlorotrimethylsilane (0.03 mL, 0.3 mmol) in acetonitrile (1 mL) and the reaction was heated at 60 °C for 1 hour. The reaction was cooled to room temperature and diluted with water (1 mL). The solid formed was filtered and crude material was purified by reverse phase preparative HPLC to yield the title compound as a white solid (9.2 mg, 32%). ¹H NMR (400 MHz, DMSO): δ 11.41 (s, 1 H), 11.06-11.01 (m, 1 H), 8.22-8.19 (m, 1 H), 8.14-8.12 (m, 1 H), 8.08-8.03 (m, 1 H), 7.93-7.89 (m, 1 H), 7.80 (dd, J = 1.8, 9.0 Hz, 1 H), 6.36-6.32 (m, 1 H), 4.07-4.05 (m, 2 H). MS (ES+) m/z 344 (M+H)+. 3-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)-1 -naphthonitrile (Example 145) a) 3-Bromo-1-naphthonitrile To 3-bromo-1-nap t o c ac ( mg, . mmo ) was a e ( mg, 3.0 mmol) in THF (8.0 mL) at 0 °C. The reaction was stirred at 0 ° C for 30 min. then at room temperature for 2.5 hrs. The reaction was brought to 0 °C and ammonium hydroxide (12%, 2 mL) was added and stirred for 15 min. then stirred at room temperature for 3 hrs. The reaction was concentrated under reduced pressure to yield 3-bromo-1-naphthamide as an off white solid. To the amide (500 mg, 2 mmol) was added triethylamine (2.6 mL, 18.5 mmol) in dichloromethane (15 mL) at 0 °C. Trifluoroacetic anhydride (0.2 g, 2 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 24 hrs. The reaction was not completed therefore a further portion of triethylamine (2.6 mL, 18.5 mmol) and trifluoroacetic anhydride (1.46 g, 7 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 6 hrs. The reaction was diluted with dichloromethane (10 mL) and water (10 mL), the phases were separated with a phase separator and the organics concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 50% ethyl acetate in hexane) to yield the title compound as a colourless solid (150 mg, 32%). ¹H NMR (400 MHz, CDCl3): δ 8.25-8.20 (m, 2 H), 7.99 (s, 1 H), 7.86-7.84 (m, 1 H), 7.74-7.63 (m, 2 H). b) 3-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)-1 -naphthonitrile Following sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (12 mg, 2% over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.36 (s, 1 H), 10.92 (s, 1 H), 8.31-8.30 (m, 1 H), 8.24-8.23 (m, 1 H), 8.08-8.05 (m, 2 H), 7.79-7.69 (m, 2 H), 6.15 (s, 1 H), 3.98 (s, 2 H). MS (ES+) m/z 310 (M+H)+. 5-(((6-Chloro-5-fluoronaphthalen-2-yl)thio)methyl)-1,4-dihyd ropyrazine-2,3-dione (Example 146) To 6-bromonaphthalen-2-amine (1.00 g, 4.5 mmol) was added portionwise select-fluor® (1.75 g, 4.9 mmol) in DMF (15 mL) at room temperature. The reaction was stirred at room temperature for 24 hrs. The reaction was concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as a red solid (440 mg, 41%). ¹H NMR (400 MHz, CDCl ³ ): δ 7.87- 7.85 (m, 1 H), 7.79-7.76 (m, 1 H), 7.51 (dd, J = 1.9, 8.9 Hz, 1 H), 7.39-7.35 (m, 1 H), 7.06-7.01 (m, 1 H), 5.30-5.29 (m, 2 H). b) 6-Bromo-2-chloro-1-fluoronaphthalene To 6-bromo-1- ncentrated hydrochloric acid (1.2 mL) at 0 °C. Sodium nitrite (0.05 mL, 0.7 mmol) in water (0.2 mL) was added drop-wise and the reaction was stirred at 0 °C for 15 min. The solution was then added to a suspension of copper (II) chloride (0.1 g, 1.0 mmol) in concentrated hydrochloric acid (0.9 mL) at 0 °C and the reaction was stirred at 0 °C for 30 min. The reaction was diluted with ethyl acetate (5 mL) and water (5 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 × 10 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as a light red solid (144 mg, 90%). ¹H NMR (400 MHz, CDCl3): δ 8.00-7.92 (m, 2 H), 7.66-7.62 (m, 1 H), 7.50-7.42 (m, 2 H). c) 5-(((6-Chloro-5-fluoronaphthalen-2-yl)thio)methyl)-1,4-dihyd ropyrazine-2,3-dione Following step a from Method M used to prepare 5-(((6-fluoronaphthalen-2- yl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (15 mg, 8% over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.16 (s, 2 H), 8.07 (s, 1 H), 8.00 (d, J = 11.6 Hz, 1 H), 7.81-7.78 (m, 1 H), 7.68-7.63 (m, 2 H), 6.20 (s, 1 H), 3.98 (s, 2 H). MS (ES+) m/z 337 (M+H)+. 5-(((6-fluoro-3-methylimidazo[1,2-a]pyridin-7-yl)thio)methyl )-1,4-dihydropyrazine- 2,3-dione (Example 147) a) 6-Fluoro-7-iodo-3-methylim To 2-bromo-1,1-dieth . , . M hydrochloric acid (6.3 mL, 6.3 mmol) at room temperature. The reaction was stirred at 90 °C for 1 hour. The reaction was cooled to room temperature and neutralised with solid sodium bicarbonate.5- Fluoro-4-iodopyridin-2-amine (500 mg, 2.1 mmol) in methanol (10 mL) was added and stirred at 90 °C for 24 hrs. The solid formed was filtered and dissolved in ethyl acetate (10 mL) and then was partitioned between ethyl acetate and water (10 mL). The organic phase was washed with saturated sodium bicarbonate solution (10 mL) and the organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow solid (395 mg, 68%). ¹H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 5.8 Hz, 1 H), 7.80 (d, J = 3.3 Hz, 1 H), 7.44 (s, 1 H), 2.44 (s, 3 H). b) 5-(((6-fluoro-3-methylimidazo[1,2-a]pyridin-7-yl)thio)methyl )-1,4-dihydropyrazine- 2,3-dione Following step a from Method M used to prepare 5-(((6-fluoronaphthalen-2- yl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (49 mg, 11% over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.41-11.38 (m, 1 H), 11.03 (s, 1 H), 8.58 (d, J = 5.3 Hz, 1 H), 7.71-7.68 (m, 1 H), 7.43-7.42 (m, 1 H), 6.20 (s, 1 H), 3.92-3.90 (m, 2 H), 2.44 (s, 3 H). MS (ES+) m/z 307 (M+H)+. 5-(((2-Chlorobenzo[b]thiophen-5-yl)thio)methyl)-1,4-dihydrop yrazine-2,3-dione (Example 148) a) 5-Bromo-2-chlorobenzo[b To 5-bromobenzo[ . , . °C under nitrogen was added lithium diisopropylamide (5.8 mL, 11.6 mmol) dropwise. The reaction was stirred at -78 °C for 30 min. N-Chlorosuccinimide (2 g, 15.2 mmol) was added in three portions and the reaction was stirred at room temperature for 24 hrs. Saturated ammonium chloride solution (20 mL) was added and the product was partitioned between ethyl acetate (50 mL) and water (50 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (100% cyclohexane, isocratic) to yield the title compound which was further purified by SFC to give the title compound (287 mg, 13%). ¹H NMR (400 MHz, CDCl3): δ 7.81-7.80 (m, 1 H), 7.57-7.55 (m, 1 H), 7.44-7.40 (m, 1 H), 7.12-7.11 (m, 1 H). b) 5-(((2-Chlorobenzo[b]thiophen-5-yl)thio)methyl)-1,4-dihydrop yrazine-2,3-dione Following step a from Method M used to prepare 5-(((6-fluoronaphthalen-2- yl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (2.7 mg, 1% over 3 steps). ¹ H NMR (400 MHz, DMSO): δ 11.35 (s, 1 H), 10.95 (d, J=3.9 Hz, 1 H), 7.92 (d, J=8.5 Hz, 1 H), 7.82 (d, J=1.6 Hz, 1 H), 7.49 (s, 1 H), 7.40 (dd, J=1.9, 8.4 Hz, 1 H), 5.99 (d, J=4.1 Hz, 1 H), 3.82 (s, 2 H). MS (ES+) m/z 325 (M+H)+. 5-(((2,3-Dichlorobenzo[b]thiophen-6-yl)thio)methyl)-1,4-dihy dropyrazine-2,3-dione (Example 149) a) 5-(((2,3-Dichlorobenzo[b]thi 2,3-dimethoxypyrazine To 5-bromo benzo[b]thiophene (2.1 g, 10 mmol) in carbon tetrabromide (14 mL) was bubbled through chlorine gas. The reaction was stirred at room temperature for 2 hrs. The reaction was recharged with chlorine gas and stirred at room temperature for 2 hrs. The reaction was concentrated under reduced pressure. The crude material was triturated with dichloromethane and methanol to give crude 6-bromo-2,3-dichlorobenzo[b]thiophene. Following steps a-b from Method L used to prepare 5-(((4-(pentafluoro-λ6-sulfaneyl)phenyl)thio)methyl)- 1,4-dihydropyrazine-2,3-dione, 6-bromo-2,3-dichlorobenzo[b]thiophene was reacted to yield the title compound as a yellow oil (0.19 g, 5% over 3 steps). ¹H NMR (400 MHz, CDCl3): δ 7.75 (m, 1 H), 7.63-7.61 (m, 1 H), 7.47-7.44 (m, 2 H), 4.12 (s, 2H), 3.96 (s, 3 H), 3.88 (s, 3 H). b) 5-(((2,3-Dichlorobenzo[b]thiophen-6-yl)thio)methyl)-1,4-dihy dropyrazine-2,3-dione Following step d from Method H used to prepare 5-(((4- (trifluoromethyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3 -dione also yielded the title compound as an off-white solid (89 mg, 49%) ¹H NMR (400 MHz, DMSO): δ 11.36 (s, 1 H), 10.97 (d, J = 5.3 Hz, 1 H), 8.14 (d, J = 1.3 Hz, 1 H), 7.70 (d, J = 8.6 Hz, 1 H), 7.54 (dd, J = 1.7, 8.5 Hz, 1 H), 6.09 (dd, J = 2.2, 5.5 Hz, 1 H), 3.88 (s, 2 H). MS (ES+) m/z 359 (M+H)+. 5-(((5,6-Difluoronaphthalen-2-yl)thio)methyl)-1,4-dihydropyr azine-2,3-dione (Example 150) a) 6-Bromo-1,1-difluoronaph thalen- ( )-one To 6-bromonaphthalen-2-ol (1 g, 4.5 mmol) was added select-fluor® (1.2 mL) in acetonitrile (6 mL) and the reaction was stirred at room temperature for 1.5 hrs. The reaction was diluted with ethyl acetate (5 mL) and water (5 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 × 5 mL). The combined organics were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 20% ethyl acetate in cyclohexane) to yield the title compound as a clear oil (770 mg, 66%). ¹H NMR (400 MHz, CDCl3): δ 7.72-7.65 (m, 2 H), 7.54 (d, J = 1.0 Hz, 1 H), 7.37 (d, J = 10.1 Hz, 1 H), 6.30-6.25 (m, 1 H). b) 6-Bromo-1,2-difluoronaphthalene To 6-bromo-1,1-difluoronaphthalen-2(1H)-one (790 mg, 3 mmol) was added deoxo- fluor® (50%, 2.8 mL, 5.5 mmol) and boron trifluoride diethyl etherate (0.04 mL, 0.3 mmol) in toluene (5 mL). The reaction was stirred at 60 °C for 3.0 hrs. The reaction was diluted with ethyl acetate (5 mL) and saturated sodium bicarbonate solution (5 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 × 5 mL). The combined organics were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (100% cyclohexane, isocratic) to yield 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene. To 6-bromo-1,1,2,2- tetrafluoro-1,2-dihydronaphthalene (610 mg, 2.2 mmol) was added ammonium hydroxide (30%, 4.2 mL, 107 mmol) and zinc (1.14 g, 17.4 mmol) in THF (3.5 mL). The reaction was stirred at room temperature for 24 hrs. The reaction was diluted with cyclohexane (5 mL) and water (5 mL). The organics were separated and further extracted with cyclohexane (2 × 5 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (100% cyclohexane, isocratic) to yield the title compound as a clear oil (100 mg, 13% over two steps). ¹H NMR (400 MHz, CDCl3): δ 8.10-8.03 (m, 2 H), 7.66-7.53 (m, 2 H), 7.10-7.03 (m, 1 H). c) 5-(((5,6-Difluoronaphthalen-2-yl)thio)methyl)-1,4-dihydropyr azine-2,3-dione Following step a from Method M used to prepare 5-(((6-fluoronaphthalen-2- yl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (21 mg, 16% over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.45-11.43 (m, 1 H), 10.96 (d, J = 5.6 Hz, 1 H), 8.14-8.07 (m, 2 H), 7.83-7.76 (m, 2 H), 7.60 (dd, J = 5.6, 10.6 Hz, 1 H), 6.08 (dd, J = 2.3, 5.3 Hz, 1 H), 3.95-3.94 (m, 2 H). MS (ESI+) m/z 344 (M+H)+. 5 -(((2-fluorobenzo[b]thiophen-5-yl)thio)methyl)-1,4-dihydropy razine-2,3-dione (Example 151) a) 5-Bromo-2-fluorobenzo[b]thiophene To diisopropyl ion (5.7 mL, 13.1 mmol) in THF (20 mL) at -78 °C. The reaction was stirred at 0 °C for 30 min. At 0 °C 5- bromobenzo[b]thiophene (2.00 g, 9.4 mmol) in THF (15.0 mL) was added drop-wise and stirred for 1 hour. NFSI (2.96 g, 9.4 mmol) in THF (15.0 mL) was added drop-wise and stirred at 0 °C for 1 hour then room temperature for 3 hrs. The reaction was quenched with saturated ammonium chloride solution (10 mL) and the reaction was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic phase was separated and dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound which was further purified by SFC (621 mg, 29%). ¹H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 2.0 Hz, 1 H), 7.53-7.50 (m, 1 H), 7.40 (dd, J = 1.8, 8.6 Hz, 1 H), 6.66 (d, J = 2.3 Hz, 1 H). b) 5-(((2-fluorobenzo[b]thiophen-5-yl)thio)methyl)-1,4-dihydrop yrazine-2,3-dione Following step a from Method M used to prepare 5-(((6-fluoronaphthalen-2- yl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as a white solid (56 mg, 7% over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.33 (s, 1 H), 11.04 (s, 1 H), 7.90- 7.87 (m, 1 H), 7.77 (d, J = 1.8 Hz, 1 H), 7.37 (dd, J = 1.9, 8.5 Hz, 1 H), 7.07 (d, J = 2.6 Hz, 1 H), 6.00 (s, 1 H), 3.82 (s, 2 H). MS (ES-) m/z 307 (M-H)+. Method O 3,5-Dichloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)m ethyl)thio)benzonitrile (Example 152)

T p py . , . thium bis (trimethylsilyl)amide (0.94 mL, 0.9 mmol), the reaction was degassed for 5 min. and stirred at room temperature for 10 min. 5-(Bromomethyl)-2,3-dimethoxypyrazine (200 mg, 0.8 mmol) in THF (1 mL) was added and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 20% ethyl acetate in cyclohexane) to yield the title compound as a colourless oil (160 mg, 54%). ¹H NMR (400 MHz, CDCl3): δ 7.63 (s, 1 H), 4.02 (s, 3 H), 4.00 (s, 3 H), 3.73-3.72 (m, 2 H), 1.43-1.29 (m, 3 H), 1.17-1.14 (m, 18 H). b) 3,5-Dichloro-4-(((5,6-dimethoxypyrazin-2-yl)methyl)thio)benz onitrile To 2,3-dimethoxy-5-(((triisopropylsilyl)thio)methyl)pyrazine (140 mg, 0.4 mmol) in DMF (1.4 mL) was added 3,5-dichloro-4-fluorobenzonitrile (78 mg), cesium fluoride (124 mg, 0.8 mmol) and cesium carbonate (160 mg, 0.5 mmol). The reaction was filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 30% ethyl acetate in cyclohexane) to yield the title compound as a white solid (153 mg, 92%). ¹H NMR (400 MHz, DMSO): δ 8.18-8.17 (m, 2 H), 7.53 (s, 1 H), 4.22-4.21 (m, 2 H), 3.87 (s, 3 H), 3.65 (s, 3 H). c) 3,5-Dichloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)m ethyl)thio)benzonitrile Follow tetrahydropyrazin-2-yl)methyl)thio)benzonitrile also yielded the title compound as a cream solid (83 mg, 59%). ¹H NMR (400 MHz, DMSO): δ 11.44-11.41 (m, 1 H), 11.05-11.00 (m, 1 H), 8.27-8.26 (m, 2 H), 5.81 (dd, J = 2.1, 5.4 Hz, 1 H), 3.78 (s, 2 H). MS (ES+) m/z 328 (M+H)+. Example 153 (3-Chloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)meth yl)thio)-5- fluorobenzonitrile) was prepared using an analogous method to that used to prepare 3,5-dichloro- 4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)be nzonitrile (Method O). MS (ES+) m/z 312 (M+H)+. ¹H NMR (400 MHz, DMSO): δ 11.45-11.43 (m, 1 H), 11.13-11.08 (m, 1 H), 8.09 (t, J = 1.4 Hz, 1 H), 8.01 (dd, J = 1.6, 8.5 Hz, 1 H), 5.91 (dd, J = 2.3, 5.5 Hz, 1 H), 3.80-3.78 (m, 2 H). Example 154 (5-(((2,6-Dichloro-4-(trifluoromethyl)phenyl)thio)methyl)-1, 4- dihydropyrazine-2,3-dione) was prepared using an analogous method to that used to prepare 3,5- dichloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methy l)thio)benzonitrile (Method O). MS (ES+) m/z 371 (M+H)+. ¹H NMR (400 MHz, DMSO): δ 11.43 (s, 1 H), 11.03 (d, J = 5.1 Hz, 1 H), 8.06-8.05 (m, 2 H), 5.79 (d, J = 3.8 Hz, 1 H), 3.73 (s, 2 H). 5-(((2-Chloro-6-fluoro-4-(trifluoromethyl)phenyl)thio)methyl )-1,4-dihydropyrazine- 2,3-dione (Example 155) a) 5-(((2-Chloro-6-fluoro-4-(tr methyl)-1,4-dihydropyrazine- 2,3-dione Following step d from Method H used to prepare 5-(((4- (trifluoromethyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3 -dione also yielded the title compound as a cream solid (12 mg, 31%). ¹H NMR (400 MHz, DMSO): δ 11.38 (s, 1 H), 11.00 (d, J = 5.0 Hz, 1 H), 7.93-7.85 (m, 2 H), 5.89 (dd, J = 1.8, 5.3 Hz, 1 H), 3.75-3.73 (m, 2 H). MS (ES+) m/z 355 (M+H)+ Example 156 (5-(((2,6-Difluoro-4-(trifluoromethyl)phenyl)thio)methyl)-1, 4- dihydropyrazine-2,3-dione) was prepared using an analogous method to that used to prepare 5- (((2-chloro-6-fluoro-4-(trifluoromethyl)phenyl)thio)methyl)- 1,4-dihydropyrazine-2,3-dione. MS (ES+) m/z 356 (M+H)+. ¹ H NMR (400 MHz, DMSO): δ 11.40 (s, 1 H), 11.03-11.00 (m, 1 H), 7.76-7.73 (m, 2 H), 5.93 (d, J = 3.4 Hz, 1 H), 3.71 (s, 2 H). 4-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)-3 -(1,2,4-thiadiazol-3- yl)benzonitrile (Example 157)

T y y g, . xane (3 mL) and water (1 mL) was added 2-bromo-1,3,4-thiadiazole (300 mg, 1.8 mmol), potassium carbonate (503 mg, 3.6 mmol) and [1,1’-bis(diphenylphophino)ferrocene] dichloroPd(II) (20 mg). The reaction was stirred at 100 °C for 5 hrs. The reaction was filtered and concentrated under reduced pressure. The crude material was triturated with methanol to yield the title compound as a black solid (366 mg, 98% yield). ¹H NMR (400 MHz, DMSO): δ 10.46-10.45 (m, 1 H), 8.61 (dd, J = 2.3, 6.8 Hz, 1 H), 8.16-8.11 (m, 1 H), 7.73-7.67 (m, 1 H). b) 4-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)-3 -(1,2,4-thiadiazol-3- yl)benzonitrile Following step b-c from Method O used to prepare 3,5-dichloro-4-(((5,6-dioxo-1,4,5,6- tetrahydropyrazin-2-yl)methyl)thio)benzonitrile also yielded the title compound as an off-white solid (4.5 mg, 0.8% over 2 steps). ¹H NMR (400 MHz, DMSO): δ 11.32 (s, 1 H), 11.15-11.12 (m, 1 H), 10.43 (s, 1 H), 8.44-8.43 (m, 1 H), 7.94 (dd, J = 2.0, 8.4 Hz, 1 H), 7.80-7.77 (m, 1 H), 6.39 (d, J = 4.6 Hz, 1 H), 4.06-4.00 (m, 2 H). MS (ES+) m/z 344 (M+H)+. 4-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)-3 -(1,3,4-oxadiazol-2- yl)benzonitrile (Example 158) a) 2-(5-Bromo-2-fluorophenyl) To 5-bromo-2-fluorobe g, . y ate (5 mL) was added triethylamine (0.8 mL, 5.7 mmol), formyl hydrazine (137 mg, 2.3 mmol) and propylphosphonic anhydride solution (50%, 4.1 mL, 6.8 mmol). The reaction was stirred at 80 °C for 2 hrs. The reaction was filtered and quenched with saturated ammonium chloride solution (5 mL). The organics were separated and washed with saturated sodium bicarbonate solution (5 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (240 mg, 43% yield). ¹H NMR (400 MHz, CDCl3): δ 8.55 (s, 1 H), 8.26-8.22 (m, 1 H), 7.69-7.64 (m, 1 H), 7.20-7.15 (m, 1 H). b) 4-Fluoro-3-(1,3,4-oxadiazol-2-yl)benzonitrile To 2-(5-bromo-2-fluorophenyl)-1,3,4-oxadiazole (180 mg, 0.7 mmol) in degassed DMF (5 mL) was added zinc cyanide (87 mL, 0.7 mmol) and tetrakis(triphenylphosphine)Pd(0) (171 mg, 0.07 mmol). The reaction was degassed for 15 min. The reaction was stirred at 150 °C for 1 hour under microwave irradiation. The mixture was filtered through Celite ^TM and diluted with ethyl acetate (5 mL). The organics were separated and washed with saturated lithium chloride solution (3 × 5 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as a cream solid (90 mg, 64% yield). ¹H NMR (400 MHz, CDCl3) δ 8.61 (s, 1 H), 8.44 (dd, J=2.1, 6.7 Hz, 1 H), 7.89 - 7.84 (m, 1 H), 7.42 (dd, J=8.8, 9.6 Hz, 1 H). 5-(((5-Fluoro-6-hydroxynaphthalen-2-yl)thio)methyl)-1,4-dihy dropyrazine-2,3-dione (Example 159) a) 2-((6-Bromo-1-fluoronaph - -y y y - -pyran To a solution of 6-bromo-1-fluoronaphthalen-2-ol (0.1 g, 0.41 mmol) and 3,4-dihydro- 2H-pyran (0.174 g, 2.0 mmol) in dichloromethane (4 mL) at 0 °C was added pyridinium p- toluenesulfonate (0.01 g, 0.042 mmol). The mixture was stirred at 0 °C for 20 min. before warming to room temperature and stirring for 3 hrs. The mixture was concentrated onto silica and purified by flash column chromatography (0 – 15% ethyl acetate in cyclohexane) to yield the title compound as an off- white solid (0.113 g, 84%). ¹H NMR (400 MHz, CDCl3): δ 7.95 (t, J = 1.8 Hz, 1 H), 7.91 (d, J = 8.9 Hz, 1 H), 7.56 (dd, J = 1.9, 9.0 Hz, 1 H), 7.50-7.42 (m, 2 H), 5.56 (t, J = 3.0 Hz, 1 H), 4.05-3.98 (m, 1 H), 3.66-3.61 (m, 1 H), 2.12-1.87 (m, 3 H), 1.74-1.62 (m, 3 H). b) 5-(((5-Fluoro-6-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-2- yl)thio)methyl)-2,3- dimethoxypyrazine Following steps a-b from Method L used to prepare 5-(((4-(pentafluoro-λ6- sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione, 2-((6-Bromo-1-fluoronaphthalen- 2-yl)oxy)tetrahydro-2H-pyran was reacted to yield the title compound as a yellow gum (0.046 g, 31% over 2 steps). ¹H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.8 Hz, 1 H), 7.77 (d, J = 1.8 Hz, 1 H), 7.52-7.47 (m, 2 H), 7.46-7.38 (m, 2 H), 5.55 (dd, J = 2.9, 2.9 Hz, 1 H), 4.16 (s, 2 H), 4.05- 3.99 (m, 2 H), 3.97 (s, 3 H), 3.94 (s, 3 H), 2.11-1.88 (m, 3 H), 1.75-1.62 (m, 3 H). 5-(((5-Fluoro-6-hydroxynaphthalen-2-yl)thio)methyl)-1,4-dihy dropyrazine-2,3-dione 5-( (( - uoro- -(( e ra y ro- -pyran- -y )oxy)nap a en- -y ) o)me y )- , - dimethoxypyrazine (46 mg, 0.11 mmol) and pyridinium p-toluenesulfonate (2.7 mg, 0.011 mmol) were stirred in methanol at room temperature (1 mL) for 18 h. The mixture was concentrated and purified by flash column chromatography (0 – 30% ethyl acetate in cyclohexane) to yield 6-(((5,6-dimethoxypyrazin-2-yl)methyl)thio)-1-fluoronaphthal en-2-ol. 6-(((5,6-Dimethoxypyrazin-2-yl)methyl)thio)-1-fluoronaphthal en-2-ol was reacted following step d from Method H used to prepare 5-(((4-(trifluoromethyl)phenyl)thio)methyl)- 1,4-dihydropyrazine-2,3-dione to yield the title compound as an off-white solid (14 mg, 41% over 2 steps). ¹H NMR (400 MHz, DMSO): δ 11.35 (s, 1 H), 10.92 (s, 1 H), 10.19 (s, 1 H), 7.88- 7.86 (m, 1 H), 7.81 (d, J = 8.7 Hz, 1 H), 7.57 (d, J = 9.0 Hz, 1 H), 7.48 (dd, J = 1.8, 8.7 Hz, 1 H), 7.28-7.22 (m, 1 H), 5.99 (s, 1 H), 3.84 (s, 2 H). MS (ES+) m/z 319 (M+H)+. 6-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)-1 -fluoro-2-naphthonitrile (Example 160) a) 6-(((5,6-Dimethoxypyrazin-2-yl)methyl)thio)-1-fluoronaphthal en-2-ol A soluti as added dropwise to a suspension of sodium hydride (0.25 g, 60% in mineral oil, 6.5 mmol) in THF (20 mL) at 0 °C and the mixture was stirred for 30 min. A solution of 2- (trimethylsilyl)ethoxymethyl chloride (1.0 g, 6.5 mmol) in THF (10 mL) was added dropwise and the mixture stirred a further 30 min. at 0 °C and then warmed to room temperature and stirred for 2 hrs. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated under vacuum to yield (2-(((6-bromo-1- fluoronaphthalen-2-yl)oxy)methoxy)ethyl)trimethylsilane. (2-(((6-bromo-1-fluoronaphthalen-2- yl)oxy)methoxy)ethyl)trimethylsilane (0.8 g, 2.4 mmol) was reacted following steps a-b from Method L used to prepare 5-(((4-(pentafluoro-λ6-sulfaneyl)phenyl)thio)methyl)-1,4- dihydropyrazine-2,3-dione to yield 5-(((5-fluoro-6-((2- (trimethylsilyl)ethoxy)methoxy)naphthalen-2-yl)thio)methyl)- 2,3-dimethoxypyrazine.5-(((5- Fluoro-6-((2-(trimethylsilyl)ethoxy)methoxy)naphthalen-2-yl) thio)methyl)-2,3- dimethoxypyrazine (0.36 g, 0.77 mmol) was stirred in dichloromethane (3 mL) with trifluoroacetic acid (0.87 g, 7.70 mmol) at room temperature for 30 min. The solvent was removed in vacuo and the resulting crude material purified by flash column chromatography (0 – 40% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (0.16 g, 11% over 4 steps). ¹H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.8 Hz, 1 H), 7.79 - 7.77 (m, 1 H), 7.52 - 7.48 (m, 2 H), 7.43 (d, J=8.8 Hz, 1 H), 7.21 (dd, J=8.6, 8.6 Hz, 1 H), 5.33 - 5.29 (m, 1 H), 4.15 (s, 2 H), 3.97 (s, 3 H), 3.94 (s, 3 H). b) 6-(((5,6-Dimethoxypyrazin-2-yl)methyl)thio)-1-fluoronaphthal en-2-yl trifluoromethanesulfonate To 6-(((5,6-dimethoxypyrazin-2-yl)methyl)thio)-1-fluoronaphthal en-2-ol (134 mg, 0.4 mmol) was added DIPEA (0.17 mL, 1.0 mmol) and N-phenylbis(trifluoromethanesulfonimide (166 mg, 0.5 mmol) in dichloromethane (5.0 mL). The reaction was stirred at room temperature for 4 hrs. The reaction was concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 15% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (112 mg, 61%). ¹H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 8.9 Hz, 1 H), 7.85 (s, 1 H), 7.64-7.59 (m, 2 H), 7.55 (d, J = 9.2 Hz, 1 H), 7.37 (dd, J = 7.2, 9.0 Hz, 1 H), 4.23 (s, 2 H), 3.98 (s, 3 H), 3.96 (s, 3 H). c) 6-(((5,6-Dimethoxypyrazin-2-yl)methyl)thio)-1-fluoro-2-napht honitrile T o 5-(((6-((dioxo(trifluoromethyl)-silyl)oxy)-5-fluoronaphthale n-2-yl)thio)methyl)-1,4- dihydropyrazine-2,3-dione (112 mg, 0.2 mmol) was added zinc cyanide (33 mg, 0.3 mmol) and tetrakis(triphenylphophine)Pd(0) (27 mg, 0.02 mmol) in DMF (4.0 mL). The reaction was heated at 120 °C for 1 hour in under microwave irradiation. The reaction was diluted with ethyl acetate (5 mL) and water (5 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 × 5 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 20% ethyl acetate in cyclohexane, 12 g column) to yield the title compound (65 mg, 78% yield). ¹H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.8 Hz, 1 H), 7.84 (s, 1 H), 7.64- 7.60 (m, 2 H), 7.55-7.47 (m, 2 H), 4.27 (s, 2 H), 3.99 (s, 3 H), 3.96 (s, 3 H). d) 6-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)-1 -fluoro-2-naphthonitrile Following steps c from Method L used to prepare 5-(((4-(pentafluoro-λ6- sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as a colourless oil (1 mg, 2%). ¹H NMR (400 MHz, DMSO): δ 11.41 (s, 1 H), 11.05 (s, 1 H), 8.12- 8.07 (m, 2 H), 7.89-7.86 (m, 1 H), 7.84-7.79 (m, 1 H), 7.74-7.70 (m, 1 H), 6.34 (s, 1 H), 4.05 (s, 2 H). MS (ES+) m/z 328 (M+H)+. 5-(((6-(Difluoromethyl)naphthalen-2-yl)thio)methyl)-1,4-dihy dropyrazine-2,3-dione (Example 161) a) 5-(((6-(Difluoromethyl)n p y y , dimethoxypyrazine Follow ing steps a-b from Method L used to prepare 5-(((4-(pentafluoro-λ6- sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded 6-(((5,6- dimethoxypyrazin-2-yl)methyl)thio)-2-naphthaldehyde. To 6-(((5,6-dimethoxypyrazin-2- yl)methyl)thio)-2-naphthaldehyde (199 mg, 0.6 mmol) was added dropwise Deoxo-fluor® (0.75 mL, 1.7 mmol) in THF (15 mL) at room temperature under nitrogen. The reaction was stirred at room temperature for 48 hrs. After 48 hrs a further equivalent of Deoxo-fluor (2.25 mL, 5.1 mmol) was added and the reaction was stirred at 50 °C for 24 hrs. The reaction was poured in saturated sodium bicarbonate solution (20 mL), then diluted with ethyl acetate (20 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 × 20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% dichloromethane in cyclohexane) to yield the title compound (40 mg, 13% over 2 steps). ¹H NMR (400 MHz, CDCl3): δ 7.92-7.77 (m, 4 H), 7.60-7.50 (m, 3 H), 6.77 (t, J = 56.6 Hz, 1 H), 4.22 (s, 2 H), 3.97 (s, 3 H), 3.95 (s, 3 H). 5-(((6-(Difluoromethyl)naphthalen-2-yl)thio)methyl)-1,4-dihy dropyrazine-2,3-dione F sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as a white solid. ¹ H NMR (400 MHz, DMSO): δ 11.40 (s, 1 H), 10.99 (s, 1 H), 8.14 (s, 1 H), 8.02 (dd, J = 4.2, 8.5 Hz, 3 H), 7.69-7.66 (m, 1 H), 7.58 (dd, J = 1.8, 8.7 Hz, 1 H), 7.19 (t, J = 58.3 Hz, 1 H), 6.19 (s, 1 H), 3.99-3.97 (m, 2 H). MS (ES+) m/z 335 (M+H)+. 5-((Benzo[c]isoxazol-5-ylthio)methyl)-1,4-dihydropyrazine-2, 3-dione (Example 162) a) 5-(((5,6-Dimethoxypyrazin-2-yl)methyl)thio)-2-nitrobenzaldeh yde To 2,3-dimethoxy-5-(((triisopropylsilyl)thio)methyl)pyrazine (100 mg, 0.3 mmol) in DMF (1.4 mL) was added 5-fluoro-2-nitrobenzaldehyde (40 mg, 0.3 mmol), cesium fluoride (88 mg, 0.6 mmol) and cesium carbonate (48 mg, 0.1 mmol). The reaction was stirred at 50 °C for 2 hrs. The reaction was filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 60% ethyl acetate in cyclohexane) to yield the title compound as a white solid (58 mg, 59% yield). ¹H NMR (400 MHz, CDCl3): δ 10.45 (s, 1 H), 8.06-8.03 (m, 1 H), 7.92 (d, J = 2.3 Hz, 1 H), 7.66-7.61 (m, 2 H), 4.26-4.25 (m, 2 H), 4.12 (s, 3 H), 3.99 (s, 3 H). b) 5-(((5,6-Dimethoxypyrazin-2-yl)methyl)thio)benzo[c]isoxazole To 5 ol) in methanol (1 mL) and ethyl acetate (1 mL) was added tin (II) chloride (116 mg, 0.6 mmol). The reaction was stirred at room temperature for 48 hrs. The reaction was filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 75% ethyl acetate in cyclohexane) to yield the title compound as a yellow oil (21 mg, 40% yield). ¹H NMR (400 MHz, CDCl3): δ 9.00 (s, 1 H), 7.57-7.50 (m, 3 H), 7.29 (d, J = 19.0 Hz, 1 H), 4.11-4.10 (m, 2 H), 3.98 (s, 3 H), 3.94 (s, 3 H). c) 5-((Benzo[c]isoxazol-5-ylthio)methyl)-1,4-dihydropyrazine-2, 3-dione Following step c from Method L used to prepare 5-(((4-(pentafluoro-λ6- sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as a white solid (4.3 mg, 24%). ¹H NMR (400 MHz, DMSO): δ 11.19 (s, 2 H), 9.71 (d, J = 0.9 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.37 (dd, J = 1.6, 9.3 Hz, 1 H), 6.11 (s, 1 H), 3.85 (s, 2 H). MS (ES+) m/z 276 (M+H)+. 5-(((6,7-Dichloronaphthalen-2-yl)thio)methyl)-1,4-dihydropyr azine-2,3-dione (Example 163) a) 6,7-Dichloronaphthalen-2-ol 3,4-Dichlorobenzeneacetylchloride (1 g, 4.5 mmol) in dichloromethane (8 mL) was added dropwise to a suspension of aluminium chloride (1.20 g, 9.0 mmol) in dichloromethane (12 mL) under nitrogen at -20 °C. (Triisopropylsilyl)acetylene (3.5 mL, 15.7 mmol) was added dropwise. The reaction was stirred at -20 °C for 30 min. The reaction was poured into ice (20 mL) and Rochelle’s salt added (20 mL). The mixture was stirred at room temperature for 15 min. The organics were separated and washed with water (10 mL). The combined organics were washed with saturated sodium bicarbonate solution (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 5% ethyl acetate in cyclohexane) to yield 6,7- dichloro-3-(triisopropylsilyl)naphthalen-2-ol.6,7-dichloro-3 -(triisopropylsilyl)naphthalen-2-ol (1 g, 2.7 mmol) was dissolved in dry dioxane (15 mL) and tetrabutyl ammonium fluoride (1.06 g, 4 mmol) was added. The reaction mixture was heated to 100 °C in a sealed tube for 26 hrs. Water (30 mL) and ethyl acetate (120 mL) were added to the mixture. The organic phase was separated and washed with water (30 mL) and brine (30 mL). The organic layer was passed through phase separation paper and solvent was removed in vacuo. The crude material was purified by flash column chromatography (10 – 30% ethyl acetate in cyclohexane) to yield the title compound as a beige solid. ¹H NMR (400 MHz, CDCl3): δ 7.86 (s, 1 H), 7.78 (s, 1 H), 7.65 (d, J = 8.9 Hz, 1 H), 7.11 (dd, J = 2.5, 8.9 Hz, 1 H), 7.04 (d, J = 2.3 Hz, 1 H), 5.10 (s, 1 H). b) 6,7-Dichloronaphthalen-2-yl trifluoromethanesulfonate To a solution of 6,7-dichloronaphthalen-2-ol (0.19 g, 0.89 mmol) in dry dichloromethane (10 mL) under nitrogen at 0 °C was added drop wise pyridine (0.14 g, 0.14 mL, 1.78 mmol) and trifluoromethanesulfonic anhydride (0.37 g, 0.23 mL, 1.34 mmol) and the mixture was stirred at room temperature for 90 min. Water (10 mL) and ethyl acetate (80 mL) were added and the product was extracted into the organic phase which was further washed with 2M hydrochloric acid (20 mL), saturated aqueous sodium hydrogen carbonate (20 mL) and brine (20 mL). The organic layer was passed through phase separation paper and solvent was removed in vacuo. The crude material was purified by flash column chromatography (0– 3% ethyl acetate in cyclohexane) to yield the title compound as a pale-yellow oil (0.17 g, 57%). ¹H NMR (400 MHz, CDCl3): δ 8.02 (s, 1 H), 8.00 (s, 1 H) 7.85 (d, J = 9.0 Hz, 1 H), 7.67 (d, J = 2.5 Hz, 1 H), 7.40 (dd, J = 2.5, 9.0 Hz, 1 H). c) 5-(((6,7-Dichloronaphthalen-2-yl)thio)methyl)-1,4-dihydropyr azine-2,3-dione Follow yl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (46 mg, 27% over 3 steps). ¹H NMR (400 MHz, DMSO): δ 11.39 (s, 1 H), 10.99 (d, J = 5.1 Hz, 1 H), 8.28 (s, 1 H), 8.24 (s, 1 H), 7.94 (s, 1 H), 7.90 (d, J = 8.7 Hz, 1 H), 7.57 (dd, J = 1.8, 8.7 Hz, 1 H), 6.21 (d, J = 3.5 Hz, 1 H), 3.95 (s, 2 H). MS (ES+) m/z 353 (M+H)+. Method P 5-(1-((4-Chlorophenyl)thio)cyclopropyl)-1,4-dihydropyrazine- 2,3-dione (Example 164) a) 2,3-Dimethoxy-5-((phenylthio)methyl)pyrazine To thiophenol (260 mg, 2.4 mmol) was added cesium carbonate (769 mg, 2.4 mmol) and tetrabutylammonium iodide (872 mg, 2.4 mmol) in DMF (2.5 mL) and the reaction was stirred at room temperature for 1 hour. 5-(Bromomethyl)-2-3-dimethoxypyrazine (500 mg, 2.1 mmol) was added and the mixture was stirred at room temperature for 24 hrs. The reaction was diluted with ethyl acetate (5 mL) and water (5 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 × 5 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 50% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (410 mg, 73%). ¹H NMR (400 MHz, DMSO): δ 7.66 - 7.56 (m, 1 H), 7.42 - 7.37 (m, 2 H), 7.35 - 7.22 (m, 3 H), 3.44 (s, 6 H), 3.02 (s, 2 H). b) 2,3-Dimethoxy-5-((phenylsulfonyl)methyl)pyrazine To 2, , Oxone® monopersulfate (1.20 g, 1.9 mmol) in methanol (2.9 mL) and water (2.9 mL). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with water (5 mL) and brought to pH 10 with 10% aqueous sodium carbonate solution and a solid precipitate formed. The solid was filtered and dried in a vacuum oven to yield the title compound (384 mg, 89%). ¹H NMR (400 MHz, CDCl ³ ): δ 7.72 (d, J = 6.5 Hz, 1 H), 7.66-7.59 (m, 2 H), 7.54-7.46 (m, 3 H), 4.40-4.36 (m, 2 H), 4.03-3.99 (m, 3 H), 3.64-3.60 (m, 3 H). c) 2,3-Dimethoxy-5-(1-(phenylsulfonyl)cyclopropyl)pyrazine To tetrabutylammonium bromide (160 mg, 0.5 mmol) was added sodium hydroxide (5.53 g, 138.3 mmol).2,3-Dimethoxy-5-((phenylsulfonyl)methyl)pyrazine (740 mg, 2.5 mmol) in toluene (137 mL) was added followed by 1,2-dibromoethane (0.65 mL, 7.5 mmol) and water (7.5 mL) and the reaction was stirred at 90 °C for 24 hrs. The reaction was diluted with ethyl acetate (10 mL) and water (10 mL). The organics were separated and the aqueous further extracted with ethyl acetate (2 × 10 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 60% ethyl acetate in cyclohexane) to yield the title compound (350 mg, 43%). ¹H NMR (400 MHz, CDCl3): δ 7.78-7.78 (m, 1 H), 7.65-7.56 (m, 3 H), 7.47-7.37 (m, 2 H), 4.00-3.99 (m, 3 H), 3.59-3.59 (m, 3 H), 2.01-1.98 (m, 2 H), 1.43-1.35 (m, 2 H). d) 5-(1-((4-Chlorophenyl)thio)cyclopropyl)-1,4-dihydropyrazine- 2,3-dione To 4-chl ineral oil, 47 mg, 1.2 mmol) in DMF (1 mL) and the reaction was stirred at room temperature for 5 min. 2,3-Dimethoxy-5-(1-(phenylsulfonyl)cyclopropyl)pyrazine (120 mg, 0.4 mmol) in DMF (1 mL) was added and the reaction was heated at 140 °C for 3.5 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure onto silica gel. The crude material was purified by flash column chromatography (0 – 20% MeOH in dichloromethane) to yield the title compound (26 mg, 24%). This material was further purified by reverse phase preparative HPLC to give the title compound (10 mg, 9%). ¹H NMR (400 MHz, DMSO) δ 11.62-11.53 (m, 1 H), 11.10-11.01 (m, 1 H), 7.44-7.43 (m, 4 H), 6.07 (s, 1 H), 1.39-1.33 (m, 2 H), 1.23-1.18 (m, 2 H). MS (ES+) m/z 295 (M+H)+. Example 165 (5-(1-((4-(trifluoromethyl)phenyl)thio)cyclopropyl)-1,4-dihy dropyrazine- 2,3-dione) was prepared using an analogous method to that used to prepare 5-(1-((4- chlorophenyl)thio)cyclopropyl)-1,4-dihydropyrazine-2,3-dione (Method P). MS (ES+) m/z 329 (M+H)+. ¹H NMR (400 MHz, DMSO): δ 11.61 (d, J=1.0 Hz, 1 H), 11.13 - 11.12 (m, 1 H), 7.72 - 7.63 (m, 4 H), 6.35 (s, 1 H), 1.52 - 1.47 (m, 2 H), 1.28 - 1.24 (m, 2 H). Method Q 5-(Difluoromethyl)-6-(((4-(trifluoromethyl)phenyl)thio)methy l)-1,4- dihydropyrazine-2,3-dione (Example 166) a) 3-Bromo-5,6-dimethoxypyrazine-2-carbaldehyde To a solution of 5 L) cooled to 0 °C under nitrogen, was added N-bromosuccinimide (71.25 g, 400 mmol) in four portions over 30 min. The reaction mixture was warmed to room temperature and stirred for 72 hrs. The reaction mixture was re cooled to 0 °C and a further portion of N-bromosuccinimide (30 g, 169 mmol) added and the reaction mixture stirred for a further 24 hrs. The reaction mixture was concentrated in vacuo to two-fifths volume and then diluted with ethyl acetate (2 L), washed with saturated sodium bicarbonate solution (1 L), water (1 L), 4% lithium chloride solution (1 L) and brine (0.5 L) followed by drying over magnesium sulfate. The organics were concentrated in vacuo and purified by flash column chromatography (0-100% dichloromethane in cyclohexane) to provide 2,3-dibromo-5,6-dimethoxypyrazine. To a solution of 2,3-dibromo-5,6- dimethoxypyrazine (500 mg, 1.68 mmol) in THF (20 mL) cooled to a -78 °C, was added n-butyl lithium (0.81 ml, 2.5 M in THF, 2.01 mmol) drop-wise, and the reaction mixture stirred at room temperature for 20 min. DMF (0.65 mL, 8.39 mmol) was then added and reaction stirred for 10 min. at -78 °C before warming to room temperature. The reaction mixture was then quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL). The organics were then concentrated in vacuo and purified by flash column chromatography (0- 100% cyclohexane in ethyl acetate) to provide the desired product as a white solid (220 mg, 2% over 2 steps). ¹H NMR (400 MHz, CDCl3) δ 10.17 (s, 1 H), 4.15 (s, 3 H), 4.11 (s, 3 H). b) (3-Bromo-5,6-dimethoxypyrazin-2-yl)methanol To a solution of 3-bromo-5,6-dimethoxypyrazine-2-carbaldehyde (50 mg, 0.20 mmol) in methanol (2 mL), cooled to 0 °C, was added sodium borohydride (15 mg, 0.04 mmol) and reaction stirred for 10 min. The reaction mixture was then concentrated in vacuo and residue dissolved in ethyl acetate (5 mL) and washed with water (5 mL). The organics were then concentrated in vacuo to provide the desired product as a white solid (40 mg, 80%). ¹H NMR (400 MHz, CDCl3): δ 4.67 (d, J = 5.5 Hz, 1 H), 4.06 (s, 3 H), 4.05 (s, 3 H), 3.05 (t, J = 5.5 Hz, 1 H). c) 2-Bromo-5,6-dimethoxy-3-(((4-(trifluoromethyl)phenyl)thio)me thyl)pyrazine To a sol , rogen, cooled to 0 °C, was added diisopropyl azodicarboxylate (0.14 mL, 0.71 mmol) and the reaction was stirred at room temperature for 20 min. A solution of 2-bromo-5,6-dimethoxy-3-(((4- (trifluoromethyl)phenyl)thio)methyl)pyrazine (148 mg, 0.59 mmol) and 4-(trifluoromethyl)- thiophenol (127 mg, 0.59 mmol) in THF (3 mL) was then added and the reaction mixture stirred 16 hours, slowly warming up from 0 °C to room temperature. The mixture was then stirred for 72 hrs. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (0-100% ethyl acetate in cyclohexane) to provide the desired product as a white solid (193 mg, 79%). ¹H NMR (400 MHz, CDCl3): δ 7.56-7.48 (m, 4 H), 4.30 (s, 2 H), 4.02 (s, 3 H), 3.88 (s, 3 H). d) 2-(Difluoromethyl)-5,6-dimethoxy-3-(((4- (trifluoromethyl)phenyl)thio)methyl)pyrazine To a solution of 2-bromo-5,6-dimethoxy-3-(((4- (trifluoromethyl)phenyl)thio)methyl)pyrazine (102 mg, 0.25 mmol) and DPEPhos (27mg, 0.05 mmol) in toluene (2 mL), degassed thoroughly with nitrogen in a reaction tube, was added (1,3- bis(2,5-dissopropylphenyl)-45,-dihydro-1H-3|4-imidazol-2-yl) (difluoromethyl)silver (137 mg, 0.025 mmol) and bis(dibenzylideneacetone) Pd(0) (14 mg, 0.025 mmol) and the mixture was degassed for a further 5 min. before sealing. The reaction mixture was then heated to 80 °C for 6 hrs. The mixture was diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated in vacuo and purified by flash column chromatography (0-100% ethyl acetate in cyclohexane) followed by purification by reverse phase chromatography to provide the desired product as a white solid (19 mg, 20%). ¹H NMR (400 MHz, CDCl3): δ 7.57-7.50 (m, 4 H), 6.64 (t, J = 54.3 Hz, 1 H), 4.37 (s, 2 H), 4.03 (s, 3 H), 3.90 (s, 3 H). e) 5-(Difluoromethyl)-6-(((4-(trifluoromethyl)phenyl)thio)methy l)-1,4-dihydropyrazine- 2,3-dione Follo sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (19.9 mg, 99%) ¹H NMR (400 MHz, DMSO): δ 11.76 (s, 1 H), 11.65 (s, 1 H), 7.71 (d, J = 8.2 Hz, 2 H), 7.63 (d, J = 8.2 Hz, 2 H), 6.80 (t, J = 55.4 Hz, 1 H), 4.14 (s, 2 H). MS (ES+) m/z 353 (M+H) ⁺ . 5,6-Dioxo-3-(((4-(trifluoromethyl)phenyl)thio)methyl)-1,4,5, 6-tetrahydropyrazine-2- carbonitrile (Example 167) a) 5,6-Dimethoxy-3-(((4-(trifluoromethyl)phenyl)thio)methyl)pyr azine-2-carbonitrile To a solution of 2-bromo-5,6-dimethoxy-3-(((4- (trifluoromethyl)phenyl)thio)methyl)pyrazine (prepared following steps a-c of Method Q used to prepare 5-(difluoromethyl)-6-(((4-(trifluoromethyl)phenyl)thio)methy l)-1,4-dihydropyrazine- 2,3-dione) (75 mg, 0.18 mmol) and zinc cyanide (22 mg, 0.18 mmol) in dry degassed DMF (1 mL) was added tetrakis(triphenylphosphine) Pd(0) (11 mg, 0.01 mmol) followed by further degassing with a stream of nitrogen for 10 min. The reaction mixture was then heated to 120 °C under microwave irradiation for 30 min. Additional tetrakis(triphenylphosphine) Pd(0) (11 mg, 0.01 mmol) was added and the reaction mixture was reheated for a further 3 hrs at 120 °C, followed by another addition of tetrakis(triphenylphosphine) Pd(0) (11 mg, 0.01 mmol) and a further 2.5 hrs heating at 120 °C. The reaction mixture was then diluted with ethyl acetate (40 mL) and washed with water (4 × 10 mL) and brine (1 × 10 mL) and the organics passed through a phase separator before concentrating in vacuo. The crude material was purified by flash column chromatography (0-100% ethyl acetate in cyclohexane) to provide the desired product as an off-white solid (26 mg, 40%). ¹H NMR (400 MHz, CDCl ³ ) δ 7.54 (s, 4 H), 4.32 (s, 2 H), 4.02 (s, 3 H), 3.94 (s, 3 H). b) 5,6-Dioxo-3-(((4-(trifluoromethyl)phenyl)thio)methyl)-1,4,5, 6-tetrahydropyrazine-2- carbonitrile Follo wing step c from Method L used to prepare 5-(((4-(pentafluoro-λ6- sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (9.5 mg, 66%). ¹H NMR (400 MHz, DMSO): δ 12.13-11.94 (m, 2 H), 7.78- 7.71 (m, 4 H), 4.04 (s, 2 H). MS (ES+) m/z 328 (M+H) ⁺ . 5-(((4-Chloro-2-(difluoromethyl)phenyl)thio)methyl)-1,4-dihy dropyrazine-2,3-dione (Example 168) a) 5-(((4-Chloro-2-(difluoromethyl)phenyl)thio)methyl)-2,3-dime thoxypyrazine Following step c from Method H used to prepare 5-(((4- (trifluoromethyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3 -dione also yielded 5-(((2-bromo- 4-chlorophenyl)thio)methyl)-2,3-dimethoxypyrazine as a colourless oil (296 mg, 93%).5-(((2- bromo-4-chlorophenyl)thio)methyl)-2,3-dimethoxypyrazine was reacted following step d, Method Q used to prepare 5-(difluoromethyl)-6-(((4-(trifluoromethyl)phenyl)thio)methy l)-1,4- dihydropyrazine-2,3-dione to yield the title compound as a colourless oil (27 mg, 59%). ¹H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 2.3 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.38-7.34 (m, 1 H), 7.32 (s, 1 H), 6.99 (t, J = 55.1 Hz, 1 H), 3.99 (s, 2 H ), 3.98 (s, 3 H), 3.94 (s, 3 H). b) 5-(((4-Chloro-2-(difluoromethyl)phenyl)thio)methyl)-1,4-dihy dropyrazine-2,3-dione Follo w ng step c rom et od used to prepare 5-((( -(penta uoro-λ6- sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as an off-white solid (18.5 mg, 75%) ¹H NMR (400 MHz, DMSO): δ 11.36 (s, 1 H), 10.99 (s, 1 H), 7.66-7.64 (m, 3 H), 7.18 (t, J = 55.4 Hz, 1 H), 5.94 (s, 1 H), 3.80 (s, 2 H), MS (ES+) m/z 319 (M+H) ⁺ . Method R (R)-5-(7-(Trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxathiin- 3-yl)-1,4-dihydropyrazine-2,3- dione (Example 169) a) 2,3-Dimethoxy-5-vinylpyrazine 5-Bromo-2,3-dimethoxy vinyl trifluoroborate (612 mg, 4.57 mmol), Pd(dppf)Cl2 DCM complex (186 mg, 0.23 mmol) and triethylamine (0.95 mL, 6.85 mmol) were dissolved in 2-propanol (10 mL), degassed with nitrogen and heated to reflux for 16 hrs. The reaction mixture was allowed to cool, diluted with ethyl acetate (10 mL) and then filtered through Celite™. The filtrate was concentrated onto silica and purified by flash column chromatography (0 – 50% ethyl acetate in cyclohexane) to provide the desired product as a colourless oil (310 mg, 82%). ¹H NMR (400 MHz, CDCl3): δ 7.53 (s, 1 H), 6.66 (dd, J = 10.7, 17.0 Hz, 1 H), 6.15 (dd, J = 1.7, 17.1 Hz, 1 H), 5.35 (dd, J = 1.8, 10.7 Hz, 1 H), 4.06 (s, 3 H), 4.02 (s, 3 H). b) (S)-1-(5,6-Dimethoxypyrazin-2-yl)ethane-1,2-diol To a solution of 2,3-dimethoxy-5-vinylpyrazine (150 mg, 0.90 mmol) in a 3:1 mixture of tert-butanol (6 mL)/water (2 mL) cooled to 0 °C, was added AD mix alpha (1.40 g) and the reaction mixture was stirred for 72 hours, while being allowed to warm to room temperature. The reaction mixture was then filtered through Celite™, washing with methanol. The filtrate was concentrated directly onto silica and purified by flash column chromatography (0 – 20% methanol in DCM) to provide the desired product as a colourless oil (80 mg, 44% yield). ¹H NMR (400 MHz, CDCl3): δ 7.73-7.71 (m, 1 H), 4.75 (dd, J = 3.7, 6.8 Hz, 1 H), 4.26 (s, 1 H), 4.00 (s, 3 H), 3.99 (s, 3 H), 3.90 (dd, J = 3.7, 11.4 Hz, 1 H), 3.80 (dd, J = 6.8, 11.4 Hz, 1 H), 3.73 (s, 1 H). c) (S)-2-((tert-Butyldimethylsilyl)oxy)-1-(5,6-dimethoxypyrazin -2-yl)ethan-1-ol To a solution of (S mg, 0.45 mmol) and tert-butyldimethylsilyl chloride (81 mg, 0.54 mmol) in DCM (5 mL) cooled to 0 °C, was added imidazole (61 mg, 0.90 mmol) and the reaction mixture stirred for 4 hrs. The reaction mixture was concentrated directly onto silica and purified by flash column chromatography (0 – 40% ethyl acetate in cyclohexane) to provide the desired product as a colourless oil (90 mg, 64%). ¹H NMR (400 MHz, CDCl3): δ 7.73 (s, 1 H), 4.70-4.64 (m 1 H), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.85 (dd, J = 4.7, 10.0 Hz, 1 H), 3.80 (dd, J = 6.3, 9.9 Hz, 1 H), 3.11 (d, J = 5.5 Hz, 1 H), 0.86 (s, 9 H), 0.02 (s, 3H), 0.00 (s, 3 H). d) (R)-5-(1-((2-Bromo-4-(trifluoromethyl)phenyl)thio)-2-((tert- butyldimethylsilyl)oxy)ethyl)-2,3-dimethoxypyrazine Tributylphosphine (0.10 mL, 0.38 mmol) was dissolved in anhydrous THF (2.50 mL) and cooled to 0 °C, DIAD (0.06 mL, 0.38 mmol) was added dropwise and reaction stirred at 0 °C for 15 min. 2-bromo-4-trifluoromethylthiophenol (98 mg, 0.38 mmol) and (S)-2-((tert- butyldimethylsilyl)oxy)-1-(5,6-dimethoxypyrazin-2-yl)ethan-1 -ol (90 mg, 0.32 mmol) were dissolved in THF (2.50 mL) and added slowly to the solution of DIAD and tributyl phosphine. The reaction was allowed to warm up slowly to room temperature and left stirring for 16 hrs. The reaction mixture was concentrated directly onto silica and purified by flash column chromatography (0 – 20% ethyl acetate in cyclohexane), to give the title compound as a colourless oil (103 mg, 59%). ¹H NMR (400 MHz, CDCl3): δ 7.77 (s, 1 H), 7.70 (s, 1 H), 7.46 (s, 2 H), 4.44 (dd, J = 5.4, 7.7 Hz, 1 H), 4.19 (dd, J = 7.7, 10.2 Hz, 1 H), 4.07-4.03 (m, 4 H), 4.00 (s, 3 H), 0.81 (s, 9 H), -0.03 (s, 3 H), -0.06 (s, 3 H). e) (R)-2-((2-Bromo-4-(trifluoromethyl)phenyl)thio)-2-(5,6-dimet hoxypyrazin-2-yl)ethan-1-ol To a sol butyldimethylsilyl)oxy)ethyl)-2,3-dimethoxypyrazine (90 mg, 0.19 mmol) in THF (3 mL) cooled to 0 °C, was added tetrabutylammonium fluoride (1 M, 0.28 mL, 0.28 mmol) and stirred at 0 °C for 1 hour. The reaction was then diluted with ethyl acetate (5 mL) and washed with water (10 mL). The organics were then concentrated onto silica and purified by flash column chromatography (0 – 50% ethyl acetate in cyclohexane) to provide the desired product as a colourless oil (72 mg, 89%). ¹H NMR (400 MHz, CDCl3): δ 7.82 (s, 1 H), 7.64 (s, 1 H), 7.49-7.47 (m, 2 H), 4.50 (dd, J = 5.4, 6.4 Hz, 1 H), 4.23-4.07 (m, 2 H), 4.02 (s, 3 H), 4.00 (s, 3 H), 2.92- 2.77 (m, 1 H). f) (R)-2,3-Dimethoxy-5-(7-(trifluoromethyl)-2,3-dihydrobenzo[b] [1,4]oxathiin-3-yl)pyrazine A suspension of (R)-2-((2-bromo-4-(trifluoromethyl)phenyl)thio)-2-(5,6- dimethoxypyrazin-2-yl)ethan-1-ol (72 mg, 0.16 mmol), Pd(II) acetate (11 mg, 0.05 mmol), TrixiePhos (20 mg, 0.05 mmol) and caesium carbonate (80 mg, 0.25 mmol) in toluene (2 mL) in a microwave vial was thoroughly degassed. The reaction mixture was then heated to 150 °C for two hrs under microwave irradiation. The reaction mixture was then concentrated directly onto silica and purified by flash column chromatography (0 – 40% ethyl acetate in cyclohexane) to provide the desired product as an orange oil (22 mg, 38%). ¹H NMR (400 MHz, CDCl3): δ 7.72 (s, 1 H), 7.20 (d, J = 8.8 Hz, 1 H), 7.12 (d, J = 6.8 Hz, 2 H), 4.65 (dd, J = 2.4, 10.8 Hz, 1 H), 4.58-4.49 (m, 2 H), 4.02 (s, 3 H), 3.98 (s, 3 H). g) (R)-5-(7-(Trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxathiin- 3-yl)-1,4-dihydropyrazine-2,3- dione To a s dihydrobenzo[b][1,4]oxathiin-3-yl)pyrazine (16 mg, 0.04 mmol) in 1,4-dioxane (0.5 mL) was added hydrochloric acid (2 M, 0.45 mL) and the reaction mixture was heated to reflux for 2 hrs. The reaction mixture was then allowed to cool to room temperature and concentrated before purification via reverse phase chromatography to provide the desired product as a colourless solid (9 mg, 50%). ¹H NMR (400 MHz, DMSO): δ 11.51 (s, 1 H), 11.22 (d, J = 4.8 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.29 (d, J = 8.6 Hz, 2 H), 6.35 (d, J = 4.8 Hz, 1 H), 4.64 (dd, J = 5.9, 12.0 Hz, 1 H), 4.56 (dd, J = 2.8, 11.9 Hz, 1 H), 4.48 (dd, J = 2.4, 5.8 Hz, 1 H), MS (ES+) m/z 331 (M+H) ⁺ . The following examples were prepared using an analogous method to that used to prepare (R)-5-(7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxathiin- 3-yl)-1,4-dihydropyrazine-2,3- dione (Method R). Ex Compound Name NMR Mass Ion dihydropyrazine-2,3- H), 4.59-4.45 (m, 2 H), 4.33 Method S (R)-5-(7-(Pentafluoro-λ6-sulfaneyl)-2,3-dihydrobenzo[b][1,4 ]oxathiin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 173) a) 2-Bromo-4-(pentafluoro-λ-sulfaneyl)phenol To a solution of 4-(pentafluoro-λ6-sulfaneyl)phenol (500 mg, 2.27 mmol) and trifluoromethanesulfonic acid (0.22 mL, 2.50 mmol) in acetonitrile (10 mL) cooled to 0 °C, was added N-bromosuccinimide (445 mg, 2.50 mmol). The reaction was stirred for 16 hrs allowing it to warm up to room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organics were washed with water (2 × 10 mL) and brine (1 × 10 mL) and dried over magnesium sulfate before concentrating in vacuo and purifying by flash column chromatography (0 – 20% ethyl acetate in cyclohexane) to provide the desired product as a colourless oil (311 mg, 46%). ¹H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 2.6 Hz, 1 H), 7.64 (dd, J = 2.6, 9.0 Hz, 1 H), 7.07 (d, J = 9.0 Hz, 1 H), 5.86 (s, 1 H). b) O-(2-Bromo-4-(pentafluoro-λ-sulfaneyl)phenyl) dimethylcarbamothioate A solution of 2-bromo- , 1.00 mmol), 1,4- diazabicyclo[2,2,2]octane (225 mg, 2.01 mmol) and dimethylthiocarbomoyl chloride (186 mg, 1.50 mmol) in DMF (2 mL) was stirred at room temperature for 2 hrs. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with water (3 × 10 mL), dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to provide the desired compound as a colourless solid (190 mg, 49%). ¹H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 2.5 Hz, 1 H), 7.75 (dd, J = 2.7, 9.0 Hz, 1 H), 7.28 – 7.24 (m, 1 H), 3.48 (s, 3 H), 3.41 (s, 3 H). c) 2-Bromo-4-(pentafluoro-λ-sulfaneyl)benzenethiol O-(2-Bromo-4-(pentafluoro-λ-sulfaneyl)phenyl) dimethylcarbamothioate (160 mg, 0.41 mmol) was heated to 200 °C for 2 hrs and then allowed to cool to room temperature. A mixture of sodium hydroxide (2 M, 0.27 mL) and methanol (1 mL) was added and the reaction heated to 90 °C with stirring for 2 hrs. The reaction mixture was allowed to cool, then acidified to pH <3 with 2 M hydrochloric acid and extracted with DCM (10 mL). The organics were dried over magnesium sulfate and concentrated to provide the desired compound as a colourless oil (90 mg, 73%). ¹H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 2.3 Hz, 1 H), 7.55 (dd, J = 2.3, 8.8 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 1 H), 4.20 (s, 1 H). d) (R)-5-(7-(Pentafluoro-λ6-sulfaneyl)-2,3-dihydrobenzo[b][1,4 ]oxathiin-3-yl)-1,4- dihydropyrazine-2,3-dione Usin , yl)ethan-1-ol (prepared following steps a-c of Method R) following steps d-g from Method R yielded the title compound as a colourless solid. ¹H NMR (400 MHz, DMSO): δ 11.30 (s, 2 H), 7.49-7.42 (m, 3 H), 6.34 (s, 1 H), 4.64 (dd, J = 5.4, 11.8 Hz, 1 H), 4.56 (dd, J = 2.5, 11.8 Hz, 1 H), 4.49 (dd, J = 2.5, 5.4 Hz, 1 H), MS (ES+) m/z 389 (M+H) ⁺ . The following examples were prepared using an analogous method to that used to prepare (R)-5-(7-(pentafluoro- λ6-sulfaneyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl)-1,4- dihydropyrazine-2,3-dione (Method R). Examp Compound Name NMR Mass 175 (R)-5-(7-Chloro-6- ¹H NMR (400 MS Method T (R)-6-Chloro-3-(5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-2, 3- dihydrobenzo[b][1,4]oxathiine-7-carbonitrile (Example 176) a) 5-Bromo-2-chloro-4-mercaptobenzonitrile Following steps a-d from Method S yielded the title compound as a yellow solid (403 mg, 87%). ¹H NMR (400 MHz, CDCl3): δ 7.78 (s, 1 H), 7.48 (s, 1 H), 4.30 (s, 1 H). b) (R)-6-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[ b][1,4]oxathiine-7-carbonitrile Using intermediate (S)-2-((tert-butyldimethylsilyl)oxy)-1-(5,6-dimethoxypyrazin -2- yl)ethan-1-ol (prepared following steps a-c of Method R) following steps d-f from Method R yielded the title compound as an off white solid. ¹H NMR (400 MHz, CDCl3): δ 7.69 (s, 1 H), 7.22 (s, 1 H), 7.14 (s, 1 H), 4.66-4.60 (m, 1 H), 4.54-4.50 (m, 2 H), 4.02 (s, 3 H), 3.97 (s, 3 H). c) (R)-6-Chloro-3-(5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-2, 3- dihydrobenzo[b][1,4]oxathiine-7-carbonitrile To a suspension of sodium iodide (64 mg, 0.43 mmol) and (R)-6-chloro-3-(5,6- dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[b][1,4]oxathiine-7-c arbonitrile (30 mg, 0.09 mmol, prepared using an analogous method to that used to prepare (R)-2,3-dimethoxy-5-(7- (trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl)pyra zine (Method R steps a-f)) in acetonitrile (3.00 mL), was added TMSCl (0.05 mL, 0.43 mmol) and the reaction mixture then heated to 60 °C for 2 hrs. The reaction mixture was then allowed to cool to room temperature and concentrated, before purification via reverse phase chromatography to provide the desired product as a white solid (20 mg, 70%). ¹H NMR (400 MHz, DMSO): δ 11.46 (s, 1 H), 11.23 (s, 1 H), 7.68 (s, 1 H), 7.58 (s, 1 H), 6.30 (s, 1 H), 4.62 - 4.45 (m, 3 H) MS (ES+) m/z 322 (M+H) ⁺ . The following examples were prepared using an analogous method to that used to prepare (R)-6-chloro-3-(5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-2, 3-dihydrobenzo[b][1,4]oxathiine-7- carbonitrile (Method T) Examp Compound Name NMR Mass (dd, J = 5.8, (R)-5-(8-Chloro-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl)-1,4-d ihydropyrazine-2,3-dione (Example 179) a) 2-Bromo-3-chloroaniline To a solution of 2-bromo-1-chloro-3-nitrobenze (2.00 g, 8.46 mmol) and iron filings (1.40 g, 25.07 mmol) in ethanol (4 mL) water (4 mL) was added hydrochloric acid (37%, 0.60 mL) and the reaction heated to reflux for 2 hrs. The reaction was then allowed to cool to room temperature and filtered through Celite™, the filtrate was concentrated in vacuo to remove ethanol, and then neutralised with 2 M sodium hydroxide. The organics were extracted with ethyl acetate (3 × 10 mL), combined and concentrated before purifying by flash column chromatography (20% ethyl acetate in cyclohexane, isocratic) to provide the desired product as an off-white solid (1.30 g, 75%). ¹H NMR (400 MHz, CDCl3): δ, 7.02 (dd, J = 8.0, 8.0 Hz, 1 H), 6.84 (dd, J = 1.5, 7.9 Hz, 1 H), 6.64 (dd, J = 1.4, 8.1 Hz, 1 H), 4.25 (s, 2 H). b) S-(2-Bromo-3-chlorophenyl) O-ethyl carbonothioate To a cooled solution in hydrochloric acid (37 %, 15 mL) was added a solution of sodium nitrite (0.48 g, 6.93 mmol) in water (10 mL) dropwise. The reaction was stirred for 30 min. before heating to 60 °C and adding a solution of potassium ethyl xanthogenate (1.21 g, 7.56 mmol) in water (15 mL) dropwise. The reaction was stirred at 60 °C for 3 hrs before cooling to room temperature and decanting the organics. The organics were purified by flash column chromatography (0 – 10% ethyl acetate in cyclohexane) to provide the desired product as red oil (250 mg, 13%). ¹H NMR (400 MHz, CDCl3): δ 7.56- 7.51 (m, 1 H), 7.30 (dd, J = 7.8, 7.8 Hz, 1 H), 4.70 (q, J = 7.2 Hz, 2 H), 1.33 (t, J = 7.2 Hz, 3 H). c) 2-Bromo-3-chlorobenzenethiol S-(2-Bromo-3-chlorophenyl) O-ethyl carbonothioate (250 mg, 0.85 mmol) was dissolved in a mixture of ethanol (5mL) and water (1mL). Potassium hydroxide (450 mg, 8.50 mmol) was added and reaction stirred at reflux for 3 hrs. The reaction was then cooled to room temperature and neutralised with 2 M hydrochloric acid. Organics were extracted with ethyl acetate (3 × 10 mL), combined and then concentrated in vacuo and purified by flash column chromatography (0 – 40% ethyl acetate in cyclohexane) to provide the desired product as a white solid (70 mg, 36%). ¹H NMR (400 MHz, CDCl3): δ 7.23 (dt, J = 1.5, 8.2 Hz, 2 H), 7.09 (dd, J = 7.9, 7.9 Hz, 1 H), 4.15 (s, 1 H). d) (R)-5-(8-Chloro-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl)-1,4-d ihydropyrazine-2,3-dione Using intermediate (S)-2-((tert-butyldimethylsilyl)oxy)-1-(5,6-dimethoxypyrazin -2- yl)ethan-1-ol (prepared following steps a-c of Method R) following steps d-g from Method R provided the desired product as a white solid (0.5 mg, 3%). ¹H NMR (400 MHz, DMSO): δ 11.45 (s, 1 H), 11.24 (s, 1 H), 7.26 (dd, J = 1.5, 8.0 Hz, 1 H), 7.17 (dd, J = 1.5, 8.1 Hz, 1 H), 6.97 (dd, J = 7.8, 7.8 Hz, 1 H), 6.33 (s, 1 H), 4.66 (dd, J = 5.9, 11.6 Hz, 1 H), 4.60 (dd, J = 2.9, 11.7 Hz, 1 H), 4.45 (dd, J = 3.0, 5.8 Hz, 1 H), MS (ES+) m/z 297.1 (M+H) ⁺ . Method U (R)-5-(7-(Methylsulfonyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3 -yl)-1,4-dihydropyrazine-2,3- dione (Example 180) a) 2-Bromo-1-fluoro-4-(methylsulfonyl)benzene A solution of 1-fluoro-4-(methylsulfonyl)benzene (1.00 g, 5.74 mmol) and N- bromosuccinimide (1.12 g, 6.31 mmol) in sulfuric acid (6 mL) was heated to 50 °C, with stirring, for 16 hrs. The reaction mixture was poured over ice and the solid collected by filtration to provide the desired product as a colourless solid (1.45 g, quant.) ¹H NMR (400 MHz, CDCl3): δ 8.19 (dd, J = 2.3, 6.3 Hz, 1 H), 7.91 (ddd, J = 2.3, 4.4, 8.6 Hz, 1 H), 7.34-7.29 (m, 1 H), 3.08 (s, 3 H). b) 2-Bromo-4-(methylsulfonyl)benzenethiol 2-Bromo-1-fluoro-4- . , . , iisopropylsilanethiol (0.85 mL, 3.95 mmol) and potassium carbonate (0.82 g, 5.93 mmol) were dissolved in DMF (50.00 mL) and stirred at 50 °C for 2 hrs. The reaction mixture was then allowed to cool to room temperature and was then washed with ethyl acetate (50 mL). The aqueous layer was then acidified to pH <3 with 2 M hydrochloric acid and extracted with ethyl acetate (3 × 30 mL). The organics were combined and concentrated in vacuo, then triturated with DCM (1 × 10 mL) to give the desired product as white solid (260 mg, 25 %). ¹H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 2.0 Hz, 1 H), 7.71 (dd, J = 2.0, 8.3 Hz, 1 H), 7.52 (d, J = 8.3 Hz, 1 H), 4.31 (s, 1 H), 3.05 (s, 3 H), 2.96 (s, 6 H), 2.88 (s, 6 H), 1.05 (s, 1 H). c) (R)-5-(7-(Methylsulfonyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3 -yl)-1,4-dihydropyrazine-2,3- dione Using intermediate (S)-2-((tert-butyldimethylsilyl)oxy)-1-(5,6-dimethoxypyrazin -2- yl)ethan-1-ol (prepared following steps a-c of Method R) following steps d-g from Method R provided the desired product as an off white solid (13.3 mg, 45%). ¹H NMR (400 MHz, DMSO): δ 11.48 (s, 1 H), 11.23-11.23 (m, 1 H), 7.45-7.43 (m, 2 H), 7.39 (dd, J = 0.6, 1.6 Hz, 1 H), 6.31 (s, 1 H), 4.62 (dd, J = 5.8, 12.0 Hz, 1 H), 4.52 (dd, J = 2.7, 11.7 Hz, 1 H), 4.46 (dd, J = 2.4, 5.8 Hz, 1 H), 3.22 (s, 3 H). MS (ES+) m/z 341 (M+H) ⁺ . (R)-3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-2,3-dihydro benzo[b][1,4]oxathiine-7- carbonitrile (Example 181) a) (R)-3-(5,6-Dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[b][1,4]ox athiine-7-carbonitrile To a degassed suspension of (R)-6-chloro-3-(5,6-dimethoxypyrazin-2-yl)-2,3- dihydrobenzo[b][1,4]oxathiine-7-carbonitrile (100 mg, 0.29 mmol, prepared following steps a-b of Method T) and SPhos (47 mg, 0..11 mmol) in toluene (3 mL) was added 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (0.06 mL, 0.43 mmol) and heated to 100 °C for 16 hrs. The reaction was then allowed to cool and filtered. The solid was washed with ethyl acetate (3 × 10 mL) and the organic phases combined and concentrated in vacuo and purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to give the desired product as an off white solid (23 mg, 26%). ¹H NMR (400 MHz, DMSO): δ 11.49 (s, 1 H), 11.23 (d, J = 5.1 Hz, 1 H), 7.46 - 7.38 (m, 3 H), 6.34 (d, J = 5.1 Hz, 1 H), 4.64 - 4.47 (m, 3 H). b) (R)-3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-2,3-dihydro benzo[b][1,4]oxathiine-7- carbonitrile Following step c from Method T yielded the title compound as an off-white solid (9 mg, 0.03 mmol, 50%). ¹H NMR (400 MHz, DMSO): δ 11.49 (s, 1 H), 11.23 (d, J=5.1 Hz, 1H), 7.46 - 7.38 (m, 3 H), 6.34 (d, J = 5.1 Hz, 1 H), 4.64 - 4.47 (m, 3 H), MS (ES+) m/z 288 (M+H) ⁺ . Method V (R)-5-(7-(Hydroxymethyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3- yl)-1,4-dihydropyrazine-2,3- dione (Example 182) a) Methyl 3-bromo-4-mercaptobenzoa e Sodium sulfide (0.50 g, 6.44 mmol) was dissolved in DMF (10 mL) and stirred, methyl 3-bromo-4-fluorobenzoate (1.00 g, 4.29 mmol) was added in three portions and reaction stirred at room temperature for 2 hrs. The reaction was diluted with water (20 mL) and washed with ethyl acetate (10 mL). The aqueous layer was then acidified to pH 2 with 2 M hydrochloric acid and extracted with ethyl acetate (3 × 10 mL). The combined organics were dried over magnesium sulfate, concentrated in vacuo and purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to provide the desired product. (215 mg, 20%). ¹H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 1.9 Hz, 1 H), 7.79 (dd, J = 1.9, 8.1 Hz, 1 H), 7.37 (d, J = 8.1 Hz, 1 H), 4.21 (s, 1 H), 3.90 (s, 3 H). b) Methyl (R)-3-(5,6-dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[b][1,4]ox athiine-7-carboxylate Using intermediate (S)-2-((tert-butyldimethylsilyl)oxy)-1-(5,6-dimethoxypyrazin -2- yl)ethan-1-ol (prepared following steps a-c of Method R) following steps d-f from Method R provided the desired product. ¹H NMR (400 MHz, CDCl3): δ 7.72 (s, 1 H), 7.57-7.53 (m, 2 H), 7.15 (d, J = 8.6 Hz, 1 H), 4.67-4.61 (m, 1 H), 4.56-4.51 (m, 2 H), 4.01 (s, 3 H), 3.98 (s, 3 H), 3.89 (s, 3 H). c) (R)-(3-(5,6-Dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[b][1,4]o xathiin-7-yl)methanol To an ice cooled solution of methyl (R)-3-(5,6-dimethoxypyrazin-2-yl)-2,3- dihydrobenzo[b][1,4]oxathiine-7-carboxylate (273 mg, 0.78 mmol) in THF (8 mL) under nitrogen was added lithium borohydride solution (2 M in THF, 0.78 mL) dropwise and the reaction stirred for 16 hrs. Additional lithium borohydride solution was then added (2 M, 0.78 mL) and reaction stirred for further 48 hrs. The reaction was quenched by addition of water followed by extraction of the organics with ethyl acetate (3 × 10 mL). The organics were combined, washed with brine (1 × 10 mL) and dried over magnesium sulfate before concentrating in vacuo. The crude material was then purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to give the desired product as a off-white solid, (152 mg, 61%). ¹H NMR (400 MHz, CDCl3): δ 7.74 (s, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 6.91-6.89 (m, 2 H), 4.64-4.59 (m, 2 H), 4.56-4.47 (m, 2 H), 4.01 (s, 3 H), 4.00 (s, 3 H), 1.26 (t, J = 7.2 Hz, 1 H). d) (R)-5-(7-(Hydroxymethyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3- yl)-1,4-dihydropyrazine-2,3- dione 0.01 mmol, 22%). ¹H NMR (400 MHz, DMSO): δ 11.27-11.27 (m, 2 H), 7.06 (d, J = 7.9 Hz, 1 H), 6.89-6.85 (m, 2 H), 6.27 (s, 1 H), 5.17-5.12 (m, 1 H), 4.52 (dd, J = 5.8, 11.7 Hz, 1 H), 4.45- 4.39 (m, 3 H), 4.31 (dd, J = 2.4, 5.6 Hz, 1 H). MS (ES+) m/z 310 (M+H) ⁺ . (R)-5-(7-(((3-Fluorobenzyl)oxy)methyl)-2,3-dihydrobenzo[b][1 ,4]oxathiin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 183) a) (R)-5-(7-(((3-Fluorobenzyl)oxy)methyl)-2,3-dihydrobenzo[b][1 ,4]oxathiin-3-yl)-2,3- dimethoxypyrazine (R)-(3-(5,6-dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[b][1,4]o xathiin-7-yl)methanol (prepared following steps a-c of Method V) (125 mg, 0.39 mmol) was dissolved in THF (3 mL) and cooled to 0 °C. Sodium hydride (60% in mineral oil, 62 mg, 1.56 mmol) was then added and the solution stirred at 0 °C for 15 min. before addition of 3-fluorobenzyl bromide (0.06 mL, 0.47 mmol). The reaction was stirred at 0 °C for 3 hrs before allowing to rise to room temperature and quenching with dropwise addition of water (3 mL). The mixture was extracted with ethyl acetate (3 × 10 mL), combined and washed with brine (1 × 10 mL) and dried over magnesium sulfate before concentrating in vacuo and purifying via flash column chromatography (0 – 30% ethyl acetate in cyclohexane) to give the desired product as a yellow oil, (74 mg, 55%). ¹H NMR (400 MHz, CDCl3): δ 7.74 (s, 1 H), 7.34-7.27 (m, 1 H), 7.13-7.06 (m, 3 H), 7.01-6.94 (m, 1 H), 6.91- 6.88 (m, 2 H), 4.62 (dd, J = 2.5, 10.9 Hz, 1 H), 4.57-4.47 (m, 6 H), 4.01 (s, 3 H), 3.99 (s, 3 H). b) (R)-5-(7-(((3-Fluorobenzyl)oxy)methyl)-2,3-dihydrobenzo[b][1 ,4]oxathiin-3-yl)-1,4- dihydropyrazine-2,3-dione F , 32%). ¹H NMR (400 MHz, DMSO): δ 11.35-11.18 (m, 2 H), 7.45-7.39 (m, 1 H), 7.22-7.10 (m, 4 H), 6.95-6.89 (m, 2 H), 6.28 (s, 1 H), 4.55-4.45 (m, 6 H), 4.33 (dd, J = 2.3, 5.9 Hz, 1 H), MS (ES+) m/z 401 (M+H)+. Method W (R)-5-(7-(Difluoromethyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3 -yl)-1,4-dihydropyrazine-2,3- dione (Example 184) a) (R)-3-(5,6-Dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[b][1,4]ox athiine-7-carbaldehyde (R)-(3-(5,6-dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[b][1,4]o xathiin-7-yl)methanol (70 mg, 0.22 mmol) was dissolved in DCM (2 mL) under nitrogen and Dess Martin periodinane (102 mg, 0.24 mmol) was added. The reaction was stirred at room temperature for 2 hrs. The reaction mixture was then concentrated and purified via flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to give the desired product (55 mg, 79%). ¹H NMR (400 MHz, CDCl3): δ 9.87 (s, 1 H), 7.73 (s, 1 H), 7.41 (dd, J = 1.8, 8.0 Hz, 1 H), 7.37 (d, J = 1.6 Hz, 1 H), 7.26-7.23 (m, 1 H), 4.69-4.63 (m, 1 H), 4.58-4.54 (m, 2 H), 4.02 (s, 3 H), 3.98 (s, 3 H). b) (R)-5-(7-(Difluoromethyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3 -yl)-2,3-dimethoxypyrazine (R)- - , - ypy - -y - , - y , - - y (55 mg, 0.17 mmol) was dissolved in DCM (2 mL). (Diethylamino)sulfur trifluoride (0.14 mL, 1.04 mmol) was then added and the reaction stirred for 16 hrs. The reaction mixture was then diluted with 2 M potassium hydroxide (15 mL) and DCM (10 mL) and the organics were separated and dried through an hydrophobic frit. The organics were then concentrated and purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to give the desired product (32 mg, 54%). ¹H NMR (400 MHz, CDCl3): δ 7.73 (s, 1 H), 7.17 (d, J = 8.6 Hz, 1 H), 7.03 (d, J = 5.3 Hz, 2 H), 6.55 (t, J = 56.6 Hz, 1 H), 4.64 (dd, J = 2.3, 10.9 Hz, 1 H), 4.57- 4.48 (m, 2 H), 4.01 (s, 3 H), 3.98 (s, 3 H). c) (R)-5-(7-(Difluoromethyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3 -yl)-1,4-dihydropyrazine-2,3- dione Following step c from Method T yielded the title compound as a white solid (19 mg, 0.06 mmol). ¹H NMR (400 MHz, DMSO): δ 11.46-11.45 (m, 1 H), 11.18-11.18 (m, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.13-7.09 (m, 2 H), 6.94 (t, J = 56.1 Hz, 1 H), 6.29-6.29 (m, 1 H), 4.57 (dd, J = 5.8, 11.7 Hz, 1 H), 4.49 (dd, J = 2.7, 11.8 Hz, 1 H), 4.40 (dd, J = 2.5, 5.8 Hz, 1 H), MS (ES+) m/z 313 (M+H) ⁺ . Method X 5-(2,3-Dihydrobenzo[b][1,4]oxathiin-3-yl)-1,4-dihydropyrazin e-2,3-dione (Example 185) a) 2-((tert-Butyldimethylsilyl)oxy)-1-(5,6- y y yl)ethan-1-ol (rac) 5-Bromo-2,3-dimethoxypyrazine (2.00 g, 9.13 mmol) was dissolved in dry THF (40 mL) and cooled to -78 °C. n-Butyllithium (2.5 M in THF, 4.00 mL, 10.04 mmol) was added dropwise and the mixture stirred for 30 min. (tert-Butyldimethylsilyloxy)acetaldehyde (2.10 mL, 10.96 mmol) was dissolved in THF (2.5 mL) and added slowly. The reaction was stirred at -78 °C for 75 min. before warming to room temperature and quenching with saturated ammonium chloride solution (10 mL). The organics were separated and the aqueous extracted with ethyl acetate (3 x 20 mL). The Organics were combined and dried over sodium sulfate before concentrating and purifying by flash column chromatography (0 – 30% ethyl acetate in cyclohexane) to give 2- ((tert-butyldimethylsilyl)oxy)-1-(5,6-dimethoxypyrazin-2-yl) ethan-1-ol as a colourless oil (1.22 g, 43%). ¹H NMR (400 MHz, CDCl3): δ 7.74 (s, 1 H), 4.69 (q, J = 5.4 Hz, 1 H), 4.02 (s, 3 H), 4.02 (s, 3 H), 3.89-3.78 (m, 2 H), 3.12 (d, J = 5.5 Hz, 1 H), 0.87 (s, 9 H), 0.03 (s, 3 H), 0.01 (s, 3 H). b) 5-(2,3-Dihydrobenzo[b][1,4]oxathiin-3-yl)-1,4-dihydropyrazin e-2,3-dione Following steps d-g from Method R yielded the title compound as a colourless solid. ¹H NMR (400 MHz, DMSO): δ 11.19 (s, 2 H), 7.12 (dd, J = 1.4, 7.7 Hz, 1 H), 7.05 (ddd, J = 7.7, 7.7, 1.9 Hz, 1 H), 6.94 - 6.88 (m, 2 H), 6.29 (s, 1 H), 4.53 - 4.42 (m, 2 H), 4.35 - 4.31 (m, 1 H). MS (ES+) m/z 263 (M+H) ⁺ . 5-(5-Fluoro-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxat hiin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 186) a) 2-Bromo-6-fluoro-4-(trifluoromethyl)benzenethiol Following step a of Method V, provided the desired product as a colourless oil (190 mg, 72%). ¹H NMR (400 MHz, CDCl3): δ 7.62 (s, 1 H), 7.30 (dd, J = 1.5, 8.6 Hz, 1 H), 4.35 (d, J = 3.3 Hz, 1 H). b) 5-(5-Fluoro-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxat hiin-3-yl)-1,4-dihydropyrazine- 2,3-dione U dione (prepared following step a of Method X) Following steps d-g from Method R provided the desired product as an off white solid. ¹H NMR (400 MHz, DMSO): δ 11.29 (s, 2 H), 7.39 (dd, J = 1.4, 9.5 Hz, 1 H), 7.23 (s, 1 H), 6.35 (s, 1 H), 4.66 (dd, J = 6.3, 11.9 Hz, 1 H), 4.60 (dd, J = 2.8, 11.9 Hz, 1 H), 4.50 (dd, J = 2.9, 5.4 Hz, 1 H). MS (ES+) m/z 349 (M+H) ⁺ . 5-(2,3-dihydrobenzo[b][1,4]oxathiin-2-yl)-1,4-dihydropyrazin e-2,3-dione (Example 187) a) 2-((2-bromophenyl)thio)-1-(5,6-dimethoxypyrazin-2-yl)ethan-1 -ol To a solution of potassium tert-butoxide (0.67 g, 5.95 mmol) in DMSO (2 mL) was added trimethylsulfoxonium iodide (1.31 g, 5.95 mmol) and the solution stirred for 30 mins.5,6- dimethoxypyrazine-2-carbaldehyde (1.00 g, 5.95 mmol) in DMSO (2 mL) was then added and stirred for a further 5 min. before addition of a suspension of 2-bromothiophenol (0.71 mL, 5.95 mmol) and caesium carbonate (1.94 g, 5.95 mmol) in DMSO (2 mL). the reaction was stirred for a further 15 min. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organics were combined and concentrated in vacuo and purified by flash column chromatography (0 – 40% ethyl acetate in cyclohexane) to provide the desired product as a yellow oil (245 mg, 11%) ¹H NMR (400 MHz, CDCl3): δ 7.71 (s, 1 H), 7.54 (dd, J = 1.2, 8.0 Hz, 1 H), 7.36 (dd, J = 1.4, 7.9 Hz, 1 H), 7.21 (dt, J = 1.2, 7.6 Hz, 1 H), 7.04 (dt, J = 1.5, 7.7 Hz, 1 H), 4.81 (q, J = 6.2 Hz, 1 H), 4.01 (s, 6 H), 3.45 (dd, J = 5.4, 13.7 Hz, 1 H), 3.37 (dd, J = 6.7, 13.7 Hz, 1 H), 3.07 (d, J = 6.5 Hz, 1 H). b) 5-(2,3-Dihydrobenzo[b][1,4]oxathiin-3-yl)-2,3-dimethoxypyraz ine 2-((2-bro op e y o - - , - e o ypy a - -y e a - -o g, . mol), copper (I) iodide (1.3 mg, 0.01 mmol), cesium carbonate (88 mg, 0.27 mmol) and 8-quinolinol (2.0 mg, 0.01 mmol) were suspended in toluene (1 mL) under nitrogen in a microwave vial. The reaction was then heated to 150 °C for 48 hrs under microwave irradiation. The reaction mixture was then concentrated onto silica and purified by flash column chromatography (0 – 30% ethyl acetate in cyclohexane) to provide the desired material as a pale yellow oil (17 mg, 44%). ¹H NMR (400 MHz, CDCl3): δ 7.81 (s, 1 H), 7.11-7.02 (m, 2 H), 6.95 (dd, J = 1.3, 8.2 Hz, 1 H), 6.89 (dt, J = 1.3, 7.4 Hz, 1 H), 5.27 (ddd, J = 0.7, 2.7, 7.9 Hz, 1 H), 4.03 (s, 3 H), 4.03 (s, 3 H), 3.38 (dd, J = 8.0, 13.1 Hz, 3 H), 3.32 (dd, J = 2.6, 13.1 Hz, 3 H). c) 5-(2,3-Dihydrobenzo[b][1,4]oxathiin-2-yl)-1,4-dihydropyrazin e-2,3-dione Following steps g from Method R yielded the title compound as a white solid (4.1 mg, 30%). ¹H NMR (400 MHz, DMSO): δ 11.44 (s, 1 H), 11.32 (s, 1 H), 7.13 (dd, J = 1.6, 8.0 Hz, 1 H), 7.07-7.02 (m, 1 H), 6.92-6.89 (m, 2 H), 6.50 (s, 1 H), 4.94 (dd, J = 1.6, 9.7 Hz, 1 H), 3.54 (dd, J = 9.7, 13.1 Hz, 1 H), 3.21 (dd, J = 1.9, 13.1 Hz, 1 H). MS (ES+) m/z 263 (M+H) ⁺ . 5-(7-Chloro-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl-2,2,3-d3)- 1,4-dihydropyrazine-2,3-dione (Example 188) a) Methyl 2-(5,6-dimethoxypyrazin-2-yl)-2-oxoacetate To a solution of 5-bro mo- , - met oxypyraz ne ( . g, . mmol) in THF (15 mL) cooled to -78 °C under nitrogen was added a solution of n-butyl lithium (2.5 M, 5 mL) dropwise. The reaction was stirred at -78 °C for 30 min. before addition of a solution of dimethyl oxalate (2.70 g, 22.83 mmol) in THF (15 mL). The reaction was stirred at -78 °C for a further 30 min. The reaction mixture was allowed to warm to room temperature before quenching with saturated ammonium chloride solution (30 mL) and filtering. The filtrate was then extracted with ethyl acetate (3 × 20 mL), the organics were combined and washed with saturated ammonium chloride solution (30 mL) and brine (30 mL) and dried over magnesium sulfate. The organics were then concentrated in vacuo before purifying by flash column chromatography (0 – 40% ethyl acetate in cyclohexane) to give the desired product as a yellow solid (1.06 g, 41%). ¹H NMR (400 MHz, CDCl3): δ 8.46 (s, 1 H), 4.09 (s, 3 H), 4.01 (s, 3 H), 3.94 (s, 3 H). b) 1-(5,6-Dimethoxypyrazin-2-yl)ethane-1,2,2-d3-1,2-diol To a solution of methyl 2-(5,6-dimethoxypyrazin-2-yl)-2-oxoacetate (1.00 g, 4.42 mmol) in THF (30 mL) under nitrogen, cooled to 0 °C, was added lithium aluminium deuteride (0.74 g, 17.68 mmol). The reaction mixture was stirred at 0 °C for 30 min. before quenching with deuterium oxide (2 mL) and diluting with diethyl ether (30 mL) and 2 M sodium hydroxide (3 mL) and stirred for 15 min. Magnesium sulfate was then added and the mixture stirred for further 15 min. before filtering. The filtrate was then concentrated in vacuo to give the desired compound as a yellow oil (788 mg, 88%). ¹H NMR (400 MHz, CDCl3): δ 7.71 (s, 1 H), 4.03 (s, 6 H), 3.16 (s, 1 H), 2.48-2.42 (m, 1 H). c) 2-((tert-Butyldimethylsilyl)oxy)-1-(5,6-dimethoxypyrazin-2-y l)ethan-1,2,2-d3-1-ol To a suspensi on o -(5,6-d met oxypyraz n- -y )et ane- , , -d3- , -do (780 mg, 3.84 mmol) and imidazole (523mg, 7.68 mmol) in DCM (80 mL) at 0 °C was added tert- butyldimethylsilyl chloride (607 mg, 4.03 mmol). The reaction mixture was stirred for 1 hour then washed with saturated sodium carbonate (30 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to provide the desired product as a yellow oil (1.13 g, 93%). ¹H NMR (400 MHz, CDCl3): 7,731 (s, 1 H), 4.01 (s, 6 H), 0.86 (s, 9 H), 0.02 (s, 3H) 0.00 (s, 3 H). d) 5-(1-((2-Bromo-4-chlorophenyl)thio)-2-((tert-butyldimethylsi lyl)oxy)ethyl-1,2,2-d3)-2,3- dimethoxypyrazine Tributylphosphine (0.48 mL, 1.91 mmol) was dissolved in anhydrous THF (10 mL) and cooled to 0 °C. DIAD (0.38 mL, 1.91 mmol) was added dropwise and reaction stirred at 0 °C for 15 min. 2-Bromo-4-chlorothiophenol (357 mg, 1.60 mmol) and 2-((tert-butyldimethylsilyl)oxy)- 1-(5,6-dimethoxypyrazin-2-yl)ethan-1,2,2-d3-1-ol (506 mg, 1.60 mmol) were dissolved in THF (10 mL) and added slowly to the solution of DIAD and tributyl phosphine. The reaction was allowed to warm slowly to room temperature and left stirring for 16 hrs. The reaction mixture was concentrated directly onto silica and purified by flash column chromatography (0 – 30% ethyl acetate in cyclohexane), to provide the desired product as a colourless oil (618 mg, 74%). ¹H NMR (400 MHz, CDCl3): δ 7.59 (s, 1 H), 7.57 (d, J = 2.2 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 7.18 (dd, J = 2.3, 8.4 Hz, 1 H), 4.02 (s, 3 H), 3.99 (s, 3 H), 0.79 (s, 9 H), -0.04 (s, 3 H), -0.09 (s, 3 H). e) 2-((2-Bromo-4-chlorophenyl)thio)-2-(5,6-dimethoxypyrazin-2-y l)ethan-1,1,2-d3-1-ol 5-(1-((2-b romo-4-chlorophenyl)thio)-2-((tert-butyldimethylsilyl)oxy)et hyl)-2,3- dimethoxypyrazine (780 mg, 1.49 mmol) was dissolved in THF (15 mL) and cooled to 0 °C. Tetrabutyl ammonium fluoride (1 M in THF, 4.50 mL) was then added and the solution stirred at 0 °C for 1 hour. The reaction mixture was concentrated onto silica and purified by flash column chromatography (0 – 50% ethyl acetate in cyclohexane) to provide the desired product as a colourless oil (490 mg, 81%). ¹H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 1.8 Hz, 1 H), 7.50 (s, 1 H), 7.35 (d, J = 8.3 Hz, 1 H), 7.21 (dd, J = 2.0, 8.3 Hz, 1 H), 4.00 (s, 6 H), 2.79 (s, 1 H). f) 5-(7-Chloro-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl-2,2,3-d3)- 2,3-dimethoxypyrazine 2-((2-Bromo-4-chlorophenyl)thio)-2-(5,6-dimethoxypyrazin-2-y l)ethan-1,1,2-d3-1-ol (490 mg, 1.20 mmol), Pd(II) acetate (81 mg, 0.36 mmol), TrixiePhos (143 mg, 0.36 mmol) and caesium carbonate (586 mg, 1.80 mmol) were dissolved in toluene (6 mL) in a microwave vial and thoroughly degassed. The reaction mixture was then heated to 150 °C for two hrs under microwave irradiation. The reaction mixture was then concentrated onto silica and purified by flash column chromatography (0 – 40% ethyl acetate in cyclohexane) to give the desired product as an orange oil (145 mg, 37%). ¹H NMR (400 MHz, CDCl ³ ): δ 7.72 (s, 1 H), 7.01 (d, J = 8.3 Hz, 1 H), 6.91-6.86 (m, 2 H), 4.01 (s, 3 H), 3.99 (s, 3 H). g) 5-(7-Chloro-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl-2,2,3-d3)- 1,4-dihydropyrazine-2,3-dione 5-(7-c , y , y , , , y y ne (145 mg, 0.44 mmol) was dissolved in 1,4-dioxane (4.4 mL).2 M HCl (4.4 mL) was added and the reaction mixture heated at reflux for 2 hrs. The reaction mixture was then allowed to cool to room temperature and concentrated before purification via reverse phase chromatography to provide the desired product as a colourless solid (63 mg, 48%).¹H NMR (400 MHz, DMSO): δ 11.44 (s, 1 H), 11.19 (s, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.03 (d, J = 2.0 Hz, 1 H), 6.99 (dd, J = 2.3, 8.4 Hz, 1 H), 6.27 (s, 1 H), MS (ES+) m/z 300.1 (M+H) ⁺ . Racemic 5-(7-Chloro-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl-2,2,3-d3)- 1,4- dihydropyrazine-2,3-dione was resolved by chiral SFC to afford single enantiomers. 5-(7-Chloro-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl-2,2,3-d3)- 1,4-dihydropyrazine- 2,3-dione (Isomer 1) (Example 189): ¹H NMR (400 MHz, DMSO): δ 11.02-11.01 (m, 2 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.03-6.97 (m, 2 H), 6.27 (s, 1 H). MS (ES+) m/z 300 (M+H) ⁺ . Chiral analysis (Method 1) at 2.10 min. 5-(7-Chloro-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl-2,2,3-d3)- 1,4-dihydropyrazine- 2,3-dione (Isomer 2) (Example 190): ¹H NMR (400 MHz, DMSO): δ 10.76 (s, 2 H), 7.22 (d, J = 8.3 Hz, 1 H), 7.07-7.01 (m, 2 H), 6.31 (s, 1 H)., MS (ES+) m/z 300 (M+H) ⁺ . Chiral analysis (Method 1) at 2.90 min. Method Y 5-(3-Methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxat hiin-3-yl)-1,4-dihydropyrazine- 2,3-dione (Example 191) a) 2,3-Dimethoxy-5-(prop-1-en-2-yl)py 5-Bromo-2,3-dime y y . g, . , y ronic acid pinacol ester (2.76 g, 16.44 mmol), Pdtetrakistriphenylphosphine (0.47 g, 0.41 mmol) and sodium carbonate (4.35 g, 41.09 mmol) were dissolved in 1,4-dioxane (30.00 mL) and water (20.00 mL) and degassed. The reaction was heated to reflux for 16 hrs. The reaction mixture was allowed to cool and diluted with ethyl acetate (30 mL) and water (30 mL). The organics were separated and the aqueous layer extracted with further ethyl acetate (2 × 30 mL). The combined organics were washed with water (4 × 20 mL) and dried over magnesium sulfate before concentrating onto silica and purification by flash column chromatography (0 to 10% ethyl acetate in hexane) to give the desired compound as a colourless oil (1.89 g, 77%). ¹H NMR (400 MHz, CDCl3): δ 7.73 (s, 1 H), 5.91 (d, J = 1.4 Hz, 1 H), 5.16 (dd, J = 1.6, 1.6 Hz, 1 H), 4.05 (s, 3 H), 4.03 (s, 3 H), 2.15 (s, 3 H). b) 2,3-Dimethoxy-5-(2-methyloxiran-2-yl)pyrazine To a solution of 2,3-dimethoxy-5-(prop-1-en-2-yl)pyrazine (1.80 g, 9.99 mmol) in tert- butanol (40 mL) and water 40 mL) was added N-bromosuccinimide (2.13 g, 11.99 mmol). The reaction was heated to 60 °C for 2 hrs and then cooled to 0 °C before addition of 2 M sodium hydroxide (12.5 mL). The reaction mixture was stirred for a further 30 min. before dilution with ethyl acetate (40 mL). The organics were separated and the aqueous further extracted with ethyl acetate (3 × 40 mL) before combining and washing with brine (30 mL). The organics were then concentrated to a pink oil, which solidified on cooling, to provide the desired product (1.84 g, 94%). ¹H NMR (400 MHz, CDCl3): δ 7.71 (s, 1 H), 4.03 (s, 3 H), 4.01 (s, 3 H), 3.13 (d, J=5.9 Hz, 1 H), 2.97 (d, J=5.5 Hz, 1 H), 1.75 (s, 3 H). c) 2-((2-Bromo-4-(trifluoromethyl)phenyl)thio)-2-(5,6-dimethoxy pyrazin-2-yl)propan-1-ol To a solutio 5 mmol) and 2-bromo-4-(trifluormethyl)benzenethiol (655 mg, 2.55 mmol) in DCM (20 mL) cooled to 0 °C was added indium (III) chloride (56 mg, 0.26 mmol) and the reaction stirred for 30 min. The reaction mixture was then washed with water (2 × 15 mL) and passed through a phase separator before concentrating in vacuo and purifying by flash column chromatography (0 – 30% ethyl acetate in cyclohexane) to provide the desired product as a colourless oil (608 mg, 53%). ¹H NMR (400 MHz, CDCl3): δ 7.85 (d, J=1.3 Hz, 1 H), 7.68 (s, 1 H), 7.39 (dd, J=1.4, 8.2 Hz, 1 H), 7.32 (d, J=8.1 Hz, 1 H), 4.02 (s, 5 H), 3.86 (s, 3 H), 3.15 (dd, J=5.8, 7.8 Hz, 1 H), 1.72 (s, 3 H). d) 2,3-Dimethoxy-5-(3-methyl-7-(trifluoromethyl)-2,3-dihydroben zo[b][1,4]oxathiin-3- yl)pyrazine A suspension of 2-((2-bromo-4-(trifluoromethyl)phenyl)thio)-2-(5,6-dimethoxy pyrazin- 2-yl)propan-1-ol (600 mg, 1.32 mmol), Pd(II) acetate (89 mg, 0.40 mmol), TrixiePhos (158 mg, 0.40 mmol) and caesium carbonate (647 mg, 1.99 mmol) in toluene (6.00 mL) in a microwave vial was thoroughly degassed. The reaction mixture was then heated to 150 °C for two hrs under microwave irradiation. The reaction mixture was then concentrated onto silica and purified by flash column chromatography (0 – 40% ethyl acetate in cyclohexane) to provide the desired product as an orange oil (440 mg, 90%). ¹H NMR (400 MHz, CDCl3): δ 7.88 (s, 1 H), 7.18 (d, J = 7.9 Hz, 1 H), 7.13 - 7.08 (m, 2 H), 4.76 (d, J = 11.2 Hz, 1 H), 4.23 (d, J=11.2 Hz, 1 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 1.75 (s, 3 H). e) 5-(3-Methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxat hiin-3-yl)-1,4-dihydropyrazine- 2,3-dione Foll , 33%) ¹H NMR (400 MHz, DMSO): δ 11.42 (s, 1 H), 11.16-11.15 (m, 1 H), 7.39-7.37 (m, 1 H), 7.26-7.23 (m, 2 H), 6.27 (d, J = 4.5 Hz, 1 H), 4.88 (d, J = 12.2 Hz, 1 H), 4.17 (d, J = 12.0 Hz, 1 H), 1.64 (s, 3 H). MS (ES+) m/z 345.1 (M+H) ⁺ The following examples were prepared using an analogous method to that used to prepare 5-(3-methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxat hiin-3-yl)-1,4-dihydropyrazine- 2,3-dione (Method Y) Example Compound Name NMR Mass 193 5-(7-Fluoro-3-methyl- ¹H NMR (400 MS 5-(3-Methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxat hiin-3-yl)-1,4- dihydropyrazine-2,3-dione (Isomer 1) (Example 195) a) 2,3-Dimethoxy-5-(3-methyl-7-(tr obenzo[b][1,4]oxathiin-3- yl)pyrazine (Isomers 1 and 2) Race m c , - me oxy- -( -me y - -(r uorome y )- , - dihydrobenzo[b][1,4]oxathiin-3-yl)pyrazine (prepared via Method Y steps a-d, was resolved by chiral SFC to afford single enantiomers. 2,3-Dimethoxy-5-(3-methyl-7-(trifluoromethyl)-2,3-dihydroben zo[b][1,4]oxathiin-3- yl)pyrazine (Isomer 1), 60 mg, chiral analysis (Method 3) at 1.80 min. 2,3-Dimethoxy-5-(3-methyl-7-(trifluoromethyl)-2,3-dihydroben zo[b][1,4]oxathiin-3- yl)pyrazine (Isomer 2), 63 mg, chiral analysis (Method 3) at 2.30 min. b) 5-(3-methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxat hiin-3-yl)-1,4-dihydropyrazine- 2,3-dione (Isomer 1)(Example 196) Following step g of Method R from 2,3-Dimethoxy-5-(3-methyl-7-(trifluoromethyl)-2,3- dihydrobenzo[b][1,4]oxathiin-3-yl)pyrazine (Isomer 1) (Example 201) provided the desired product as a white solid (56 mg, 96%). ¹H NMR (400 MHz, DMSO): δ 11.41 (s, 1 H), 11.16 (d, J = 4.8 Hz, 1 H), 7.38 (d, J = 7.9 Hz, 1 H), 7.27-7.23 (m, 2 H), 6.27 (d, J = 5.0 Hz, 1 H), 4.88 (d, J = 12.0 Hz, 1 H), 4.17 (d, J = 12.2 Hz, 1 H), 1.64 (s, 3 H), MS (ES+) m/z 345 (M+H) ⁺ . Chiral analysis (Method 3) at 2.10 min. The following enantiomerically pure examples were prepared in an analogous manner to 5-(3-methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxat hiin-3-yl)-1,4-dihydropyrazine- 2,3-dione (Isomer 1) from the respective enantiomerically pure precursors. Example Compound Name NMR Mass SFC Hz, 1 H), 1.60 (s, 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-3-methyl-2,3-di hydrobenzo[b][1,4]oxathiine-7- carbonitrile (Example 199) a) 3-Bromo-4-mercaptobenzonitrile 3-Bromo-4-fluorobenzonitrile (0.75 g, 3.75 mmol) triisopropylsilanethiol (0.81 mL, 3.75 mmol) and potassium carbonate (0.77 g, 5.62 mmol) were dissolved in DMF (30 mL) and stirred at 50 °C for 3 hrs. The reaction mixture was then allowed to cool to room temperature and was then washed with ethyl acetate (30 mL). The aqueous layer was then acidified to pH <3 with 2 M hydrochloric acid and extracted with ethyl acetate (3 × 20 mL). The organics were combined and concentrated in vacuo, then triturated with DCM (10 mL) to give the desired product as a yellow solid (528 mg, 66%). ¹H NMR (400 MHz, CDCl ³ ): δ 7.80 (t, J = 1.0 Hz, 1 H), 7.44-7.43 (m, 2 H), 4.27 (s, 1 H). b) 3-(5,6-Dimethoxypyrazin-2-yl)-3-methyl-2,3-dihydrobenzo[b][1 ,4]oxathiine-7-carbonitrile U g , y y y py p p g steps a-b Method Y) following steps c-d of Method Y provided the desired compound as an orange oil (172 mg, 37% over two steps). ¹H NMR (400 MHz, CDCl ³ ) δ 7.85 (s, 1 H), 7.16 - 7.14 (m, 2 H), 7.10 (d, J = 1.5 Hz, 1 H), 4.75 (d, J = 11.2 Hz, 1 H), 4.23 (d, J = 11.2 Hz, 1 H), 4.01 (s, 3 H), 4.00 (s, 3 H), 1.76 (s, 3 H). c) 3-(5,6-Dimethoxypyrazin-2-yl)-3-methyl-2,3-dihydrobenzo[b][1 ,4]oxathiine-7-carbonitrile (Isomers 1 and 2) Racemic 3-(5,6-dimethoxypyrazin-2-yl)-3-methyl-2,3-dihydrobenzo[b][1 ,4]oxathiine-7- carbonitrile (prepared via Method Y steps a-d, was resolved by chiral SFC to afford single enantiomers. 3-(5,6-dimethoxypyrazin-2-yl)-3-methyl-2,3-dihydrobenzo[b][1 ,4]oxathiine-7- carbonitrile (Isomer 1), white solid, (38 mg, 0.21 mmol), chiral analysis (Method 2) at 6.00 min. 3-(5,6-dimethoxypyrazin-2-yl)-3-methyl-2,3-dihydrobenzo[b][1 ,4]oxathiine-7- carbonitrile (Isomer 2), white solid, (39 mg, 0.21 mmol), chiral analysis (Method 2) at 5.00 min. d) 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-3-methyl-2,3-di hydrobenzo[b][1,4]oxathiine-7- carbonitrile (Racemic) (Example 199) Follo thyl- 2,3-dihydrobenzo[b][1,4]oxathiine-7-carbonitrile (racemic) provided the desired product as a colourless solid (3 mg, 0.01 mmol, 6%), ¹H NMR (400 MHz, DMSO) d 11.46 - 11.22 (m, 2 H), 7.45 (s, 1 H), 7.39 (s, 2 H), 6.30 (s, 1 H), 4.89 (d, J = 12.1 Hz, 1 H), 4.20 (d, J = 12.1 Hz, 1 H), 1.67 (s, 3 H). The following enantiomerically pure examples were prepared in an analogous manner to the racemic 3-(5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-3-methyl-2,3- dihydrobenzo[b][1,4]oxathiine-7-carbonitrile (step c Method T) using the enantiomerically pure intermediates. Examp Compound Name NMR Mass 201 3-(5,6-Dioxo- ¹H NMR (400 MS 5-(3-Methyl-7-(methylsulfonyl)-2,3-dihydrobenzo[b][1,4]oxath iin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 202) a) 5-(3-Methyl-7-(methylsulfonyl)-2,3-dihydrobenzo[b][1,4]oxath iin-3-yl)-1,4-dihydropyrazine- 2,3-dione Using intermediates 2,3-dimethoxy-5-(2-methyloxiran-2-yl)pyrazine (prepared following Method Y steps a-b) and 2-bromo-4-(methylsulfonyl)benzenethiol (prepared following Method U steps a-b), following steps c-e of Method Y provided the desired product as an off white solid (21 mg, 34%). ¹H NMR (400 MHz, DMSO): δ 11.41 (s, 1 H), 11.18 (s, 1 H), 7.43-7.38 (m, 3 H), 6.30-6.28 (m, 1 H), 4.92-4.87 (m, 1 H), 4.21-4.16 (m, 1 H), 3.21 (s, 3 H), 1.64 (s, 3 H). MS (ES+) m/z 355.0 (M+H) ⁺ . Racemic 5-(3-Methyl-7-(methylsulfonyl)-2,3-dihydrobenzo[b][1,4]oxath iin-3-yl)-1,4- dihydropyrazine-2,3-dione was resolved by chiral SFC to afford single enantiomers. 5-(3-Methyl-7-(methylsulfonyl)-2,3-dihydrobenzo[b][1,4]oxath iin-3-yl)-1,4- dihydropyrazine-2,3-dione (Isomer 1) (Example 203): ¹H NMR (400 MHz, DMSO): δ 11.06 (s, 2 H), 7.47 (s, 2 H), 7.43 (s, 1 H), 6.33 (s, 1 H), 4.93 (d, J = 12.1 Hz, 1 H), 4.22 (d, J = 12.1 Hz, 1 H), 3.25 (s, 3 H), 1.68 (s, 3 H), MS (ES+) m/z 355 (M+H) ⁺ . Chiral analysis (Method 1) at 3.26 min. 5-(3-Methyl-7-(methylsulfonyl)-2,3-dihydrobenzo[b][1,4]oxath iin-3-yl)-1,4- dihydropyrazine-2,3-dione (Isomer 2) (Example 204): ¹H NMR (400 MHz, DMSO): δ 11.18 (s(b), 2 H), 7.43 (d, J = 1.1 Hz, 2 H), 7.39 (t, J = 1.1 Hz, 1 H), 6.29 (s, 1 H), 4.89 (d, J = 12.2 Hz, 1 H), 4.19 (d, J = 12.2 Hz, 1 H), 3.21 (s, 3 H), 1.64 (s, 3 H). MS (ES+) m/z 355 (M+H) ⁺ . Chiral analysis (Method 1) at 4.91 min. 5-(7-(Difluoromethyl)-3-methyl-2,3-dihydrobenzo[b][1,4]oxath iin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 205) a) Methyl 3-(5,6-dimethoxypyrazin-2-yl)-3-methyl-2,3-dihydrobenzo[b][1 ,4]oxathiine-7- carboxylate Using intermediates 2,3-dimethoxy-5-(2-methyloxiran-2-yl)pyrazine (prepared following steps a-b Method Y) and methyl 3-bromo-4-mercaptobenzoate (prepared following step a from Method V), following steps c-d from Method Y provided the desired compound as a yellow oil (180 mg, 16% over two steps). ¹H NMR (400 MHz, CDCl3): δ 7.88 (s, 1 H), 7.56-7.50 (m, 2 H), 7.13 (d, J = 8.1 Hz, 1 H), 4.73 (d, J = 11.1 Hz, 1 H), 4.23 (d, J = 11.1 Hz, 1 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 3.87 (s, 3 H), 1.76 (s, 3 H). b) (3-(5,6-Dimethoxypyrazin-2-yl)-3-methyl-2,3-dihydrobenzo[b][ 1,4]oxathiin-7-yl)methanol , .. (400 MHz, CDCl3): δ 7.91 (s, 1 H), 7.07 (d, J = 7.9 Hz, 1 H), 6.91-6.87 (m, 1 H), 6.86 (s, 1 H), 4.73 (d, J = 11.0 Hz, 1 H), 4.58 (s, 2 H), 4.21 (d, J = 10.9 Hz, 1 H), 4.02 (s, 3 H), 3.98 (s, 3 H), 1.73 (s, 3 H), (OH peak not observed). c) 5-(7-(Difluoromethyl)-3-methyl-2,3-dihydrobenzo[b][1,4]oxath iin-3-yl)-1,4-dihydropyrazine- 2,3-dione Following Method W gave the desired product as an off-white solid (7 mg, 8%). ¹H NMR (400 MHz, DMSO): δ 11.39 (s, 1 H), 11.17-11.14 (m, 1 H), 7.29-7.26 (m, 1 H), 7.12-7.08 (m, 3 H), 6.27 (d, J = 5.0 Hz, 1 H), 4.85 (d, J = 12.2 Hz, 1 H), 4.14 (d, J = 12.0 Hz, 1 H), 1.62 (s, 3 H). MS (ES+) m/z 327 (M+H) ⁺ . 5-(7-chloro-3-(difluoromethyl)-2,3-dihydrobenzo[b][1,4]oxath iin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 206) a) 2,3-Dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyrazine To a degassed ol), bis(pinacolate)diboron (3.48 g, 13.70 mmol) and potassium acetate (2.69 g, 27.39 mmol) in dioxane (40 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloroPd(II) complex with DCM (0.75 g, 0.91 mmol) and the reaction was heated to 80 °C for 16 hrs. The reaction was cooled to room temperature, diluted with ethyl acetate (60 mL) and filtered over Celite ^TM . The filtrare was concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 to 50% ethyl acetate in cyclohexane) to yield the title compound as off white solid (2.24 g, 92%). ¹H NMR (400 MHz, CDCl3): δ 8.09 (s, 1 H), 4.10 (s, 3 H), 4.04 (s, 3 H), 1.37 (s, 12 H). b) 2-(5,6-Dimethoxypyrazin-2-yl)prop-2-en-1-ol To a degassed mixture of 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazine (2.24 g, 8.42 mmol), 2-bromoallyl alcohol (1.27 g, 0.77 ml, 9.26 mmol) and potassium phosphate tribasic (3.57 g, 16.84 mmol) in tetrahydrofuran (58 mL) was added XPhos Pd G1 (0.62 g, 0.84 mmol) and the reaction was heated to 80 °C for 3.5 hrs. The reaction was cooled to room temperature, diluted with ethyl acetate (80 mL) and filtered over Celite ^TM . The filtrate was washed with brine (40 mL), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash column chromatography (0 to 70% ethyl acetate in cyclohexane) to yield the title compound as an off white solid (1.33 g, 81%). ¹H NMR (400 MHz, CDCl3): δ 7.90 (s, 1 H), 5.82 (d, J=0.7 Hz, 1 H), 5.42 - 5.40 (m, 1 H), 4.56 (dd, J=1.1, 6.4 Hz, 2 H), 4.04 (s, 3 H), 4.03 (s, 3 H), 2.68 (t, J=6.4 Hz, 1 H). c) 2-(5,6-Dimethoxypyrazin-2-yl)allyl acetate At 0 °C, to a solution of 2-(5,6-dimethoxypyrazin-2-yl)prop-2-en-1-ol (1.33 g, 6.79 mmol) and triethylamine (1.37 g, 1.9 ml, 13.59 mmol) in tetrahydrofuran (68 mL) was added acetyl chloride (0.8 g, 0.72 ml, 10.19 mmol) and the reaction was stirred for 2 hrs. The reaction was diluted with ethyl acetate (70 mL) and washed with saturated aqueous ammonium chloride solution (2 × 30 mL) and saturated sodium hydrogencarbonate solution (30 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure yielding the title compound as yellow oil (1.54 g, 95%). ¹H NMR (400 MHz, CDCl3): δ 7.79 (s, 1 H), 6.02 (d, J=0.9 Hz, 1 H), 5.46 - 5.45 (m, 1 H), 5.04 (d, J=0.9 Hz, 2 H), 4.04 (s, 3 H), 4.03 (s, 3 H), 2.10 (s, 3 H). d) (2-(5,6-Dimethoxypyrazin-2-yl)oxiran-2-yl)methyl acetate 2-(5,6-Dime t oxypyraz n- -y )a y acetate ( .5 g, 6. 6 mmo ) and N- bromosuccinimide (1.38 g, 7.76 mmol) were dissolved in a 1:1 tert-butanol/water mixture (30 mL) and the reaction was heated to 50 °C for 1.5 hrs. The reaction was then cooled to 0 °C and a 2 M solution of sodium hydroxide (6.5 mL, 12.93 mmol) was added. The mixture was stirred for additional 30 min. and then diluted with ethyl acetate (60 mL). The aqueous phase was separated and back extracted with ethyl acetate (10 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated yielding the desired product as colourless oil (1.51 g, 92%). ¹H NMR (400 MHz, CDCl ³ ): δ 7.71 (s, 1 H), 4.93 (d, J=12.2 Hz, 1 H), 4.38 (d, J=12.2 Hz, 1 H), 4.02 (s, 3 H), 4.01 (s, 3 H), 3.16 (d, J=5.4 Hz, 1 H), 3.03 (d, J=5.4 Hz, 1 H), 2.05 (s, 3 H). e) 2-((2-Bromo-4-chlorophenyl)thio)-2-(5,6-dimethoxypyrazin-2-y l)-3-hydroxypropyl acetate At 0 °C, to a solution of (2-(5,6-dimethoxypyrazin-2-yl)oxiran-2-yl)methyl acetate (1.5 g, 5.90 mmol) and 2-bromo-4-chlorobenzenethiol (1.58 g, 7.08 mmol) in DCM (59 mL) under nitrogen atmosphere was added copper (II) trifluoromethansulfonate (0.21 g, 0.59 mmol) and the mixture was stirred for 30 min. The reaction was then diluted with DCM (60 mL) and washed with water (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 to 80% ethyl acetate in cyclohexane) yielding the title compound as a brown oil (1.05 g, 37%). ¹H NMR (400 MHz, CDCl3): δ 7.60 (d, J=2.2 Hz, 1 H), 7.52 (s, 1 H), 7.21 (d, J=8.3 Hz, 1 H), 7.13 (dd, J=2.2, 8.3 Hz, 1 H), 4.78 (d, J=11.7 Hz, 1 H), 4.68 (d, J=11.7 Hz, 1 H), 4.24 - 4.19 (m, 1 H), 4.15 - 4.09 (m, 1 H), 4.01 (s, 3 H), 3.90 (s, 3 H), 3.22 - 3.18 (m, 1 H), 2.03 (s, 3 H). f) (7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[b][ 1,4]oxathiin-3- yl)methyl acetate A degassed mixture of Pd(II) acetate (0.15 g, 0.66 mmol), trixiePhos (0.26 g, 0.66 mmol) and caesium carbonate (1.07 g, 3.3 mmol) in toluene (22 mL) in a microwave vial was stirred at room temperature for 30 min. and then 2-((2-bromo-4-chlorophenyl)thio)-2-(5,6- dimethoxypyrazin-2-yl)-3-hydroxypropyl acetate (1.05 g, 2.2 mmol) was added. The reaction mixture was then heated to 100 °C for 2 hrs under microwave irradiation. The reaction was cooled to room temperature, diluted with ethyl acetate (40 mL) and filtered over Celite ^TM . The filtrare was washed with brine (15 mL), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash column chromatography (0 to 35% ethyl acetate in cyclohexane) to yield the title compound as a brown oil (0.51 g, 55%). ¹H NMR (400 MHz, CDCl ³ ): δ 7.76 (s, 1 H), 6.99 (d, J=8.3 Hz, 1 H), 6.92 - 6.88 (m, 2 H), 4.72 - 4.64 (m, 2 H), 4.59 - 4.51 (m, 2 H), 4.03 (s, 3 H), 4.02 (s, 3 H), 2.00 (s, 3 H). g) (7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[b][ 1,4]oxathiin-3- yl)methanol To a solution of (7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-2,3- dihydrobenzo[b][1,4]oxathiin-3-yl)methyl acetate (0.51 g, 1.29 mmol) in methanol (13 mL) was added sodium methoxide (25% in methanol, 0.42 g, 1.93 mmol, 0.44 mL) and the reaction was stirred at room temperature for 1 hour. Acetic acid was then added (0.4 mL) and the reaction mixture was concentrated under reduced pressure. Ethyl acetate (40 mL) was added to the residue and the resulting suspension was washed with water (10 mL) and brine (10 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated yielding the the title compound as brown oil (0.45 g, 99%). ¹H NMR (400 MHz, CDCl3): δ d 7.87 (s, 1 H), 7.02 (d, J=8.3 Hz, 1 H), 6.95 (d, J=2.1 Hz, 1 H), 6.90 (dd, J=2.1, 8.4 Hz, 1 H), 4.70 (d, J=11.4 Hz, 1 H), 4.42 (d, J=11.4 Hz, 1 H), 4.17 - 4.12 (m, 1 H), 4.07 - 4.02 (m, 7 H), 3.03 (s, 1 H). h) 7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-2,3-dihydrobenzo[b][1 ,4]oxathiine-3- carbaldehyde To a solution of (7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-2,3- dihydrobenzo[b][1,4]oxathiin-3-yl)methanol (0.15 g, 0.42 mmol) in DCM (4.9 mL) was addeed Dess-Martin periodinane (0.20 g, 0.47 mmol) and the mixture was stirred at room temperature for 2.5 hrs. The reaction was concentrated under reduced pressure and the crude material was purified by flash column chromatography (0 to 50% ethyl acetate in cyclohexane) to yield the title compound as a colourless oil (0.07 g, 47%). ¹H NMR (400 MHz, CDCl3): δ 9.56 (d, J=1.1 Hz, 1 H), 7.79 (s, 1 H), 7.09 (d, J=8.4 Hz, 1 H), 6.96 - 6.90 (m, 2 H), 5.07 (d, J=11.6 Hz, 1 H), 4.47 (dd, J=1.1, 11.6 Hz, 1 H), 4.04 (s, 3 H), 4.03 (s, 3 H). i) 5-(7-Chloro-3-(difluoromethyl)-2,3-dihydrobenzo[b][1,4]oxath iin-3-yl)-1,4- dihydropyrazine-2,3-dione To a sol dihydrobenzo[b][1,4]oxathiine-3-carbaldehyde (0.07 g, 0.19 mmol) in DCM (2 mL) was added (diethylamino)sulfur trifluoride (0.12 g, 0.1 mL, 0.76 mmol) and the mixture was stirred at room temperature overnight. Satured sodium hydrogencarbonate solution (1 mL) was added and the mixture was passed trough a phase separator. The organic layer was concentrated under reduced pressure and the crude material was purified by flash column chromatography (0 to 30% ethyl acetate in cyclohexane) to yield 5-(7-chloro-3-(difluoromethyl)-2,3- dihydrobenzo[b][1,4]oxathiin-3-yl)-2,3-dimethoxypyrazine. Sodium iodide (0.02 g, 0.13 mmol) and TMSCl (0.01 g, 0.02 mL, 0.13 mmol) were added to a solution of 5-(7-chloro-3- (difluoromethyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl)-2,3- dimethoxypyrazine (0.016 g, 0.04 mmol), in acetonitrile (0.4 mL) and the solution was stirred at 60 °C for 1.5 hrs. The reaction was concentrated to dryness. The crude material was purified by reverse phase preparative HPLC to afford the title compound as an off-white solid (8.1 mg, 12% over two steps). ¹H NMR (400 MHz, DMSO): δ 11.38 (s, 2 H), 7.31 (d, J=8.5 Hz, 1 H), 7.09 (d, J=2.5 Hz, 1 H), 7.06 (dd, J=2.5, 8.5 Hz, 1 H), 6.71 - 6.44 (m, 2 H), 4.98 - 4.92 (m, 1 H), 4.52 - 4.48 (m, 1 H). MS (ESI+) m/z 327 (M+H) ⁺ . 5-(7-chloro-3-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]oxathi in-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 207) a) 5-(7-Chloro-3-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]oxathi in-3-yl)-1,4- dihydropyrazine-2,3-dione Sodium re added to a solution of (7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-2,3- dihydrobenzo[b][1,4]oxathiin-3-yl)methanol (0.056 g, 0.16 mmol), in acetonitrile (1.6 mL) and the solution was stirred at 60 °C for 1.5 hrs. The reaction was concentrated to dryness. The crude material was purified by reverse phase preparative HPLC to afford the title compound as an off- white solid (6.7 mg, 13%). ¹H NMR (400 MHz, DMSO): δ 11.17 - 11.17 (m, 2 H), 7.18 (d, J=8.3 Hz, 1 H), 7.01 - 6.96 (m, 2 H), 6.27 (s, 1 H), 5.46 (s, 1 H), 4.79 (d, J=12.0 Hz, 1 H), 4.23 (d, J=12.0 Hz, 1 H), 3.83 - 3.74 (m, 2 H). MS (ESI+) m/z 327 (M+H) ⁺ . Method Z 5-(7-Fluorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione (Example 208) a) 3-(5,6-Dimethoxypyrazin-2-yl)-7-fluorochroman-4-one A mixture of 4-fluoro-2-hydroxybenzaldehyde (0.7 g, 5 mmol), 5-ethynyl-2,3- dimethoxypyrazine (0.8 g, 5 mmol), gold cyanide (0.056 g, 0.25 mmol) and tributylphosphine (0.25 g, 1.25 mmol) in toluene (10 mL) were heated under microwave irradiation at 200 °C for 10 min. The reaction mixture was concentrated onto silica and purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane followed by 0-5% methanol in dichloromethane) to elute the title compound as a cream solid (0.11 g, 8%). ¹H NMR (400 MHz, CDCl3): δ 7.99 (dd, J = 6.6, 8.8 Hz, 1 H), 7.58-7.58 (m, 1 H), 6.77 (ddd, J = 8.5, 8.5, 2.5 Hz, 1 H), 6.69 (dd, J = 2.4, 9.7 Hz, 1 H), 4.90 (dd, J = 9.9, 11.4 Hz, 1 H), 4.71 (dd, J = 4.9, 11.5 Hz, 1 H), 4.01-4.00 (m, 4 H), 3.92 (s, 3 H). b) 3-(5,6-Dimethoxypyrazin-2-yl)-7-fluorochroman-4-ol To a mmol) in methanol (4 mL) at 0 °C was added sodium borohydride (0.04 g, 1.1 mmol). The resulting mixture was warmed to room temperature and stirred for 3.5 hrs. The mixture was quenched with dichloromethane (5 mL) and water (5 mL) and the product extracted into dichloromethane (2 x 5 mL). The combined organic layers were passed through a phase separator and concentrated to afford the title compound as an orange oil (0.12 g, quant.) ¹H NMR (400 MHz, CDCl3): δ 7.66 (s, 1 H), 7.29 (dd, J = 6.6, 8.6 Hz, 1 H), 6.72-6.55 (m, 2 H), 5.05 (s, 1 H), 4.62 (t, J = 11.1 Hz, 1 H), 4.47 (d, J = 2.1 Hz, 1 H), 4.29 (ddd, J = 1.1, 3.8, 10.7 Hz, 1 H), 4.03 (s, 3 H), 4.00 (s, 3 H), 3.39-3.34 (m, 1 H). c) 5-(7-Fluoro-2H-chromen-3-yl)-2,3-dimethoxypyrazine 3-(5,6-Dimethoxypyrazin-2-yl)-7-fluorochroman-4-ol (0.11 g, 0.38 mmol) was dissolved in THF (2.5 mL) and cooled to 0 °C. Triethylamine (0.38 g, 0.52 mL, 3.75 mmol) and methane sulfonic anhydride (0.13 g, 0.75 mmol) were added and the reaction was allowed to warm to room temperature and stirred for 18 hrs. The mixture was diluted with dichloromethane (5 mL) and water (5 mL) and the product extracted into dichloromethane (2 x 5 mL). Combined organic layers were passed through a phase separator and concentrated. The crude material was purified by flash column chromatography (0-50% ethyl acetate in cyclohexane gradient) to elute the title compound as a white solid (0.047 g, 44%). ¹H NMR (400 MHz, CDCl3): δ 7.73-7.73 (m, 1 H), 7.15 (s, 1 H), 7.07 (dd, J = 6.6, 8.3 Hz, 1 H), 6.66-6.57 (m, 2 H), 5.22 (d, J = 1.3 Hz, 2 H), 4.07 (s, 3 H), 4.04 (s, 3 H). d) 5-(7-Fluorochroman-3-yl)-2,3-dimethoxypyrazine Pdon carbon (12 mg) was added to 5-(7-fluoro-2H-chromen-3-yl)-2,3-dimethoxypyrazine (0.047 g, 0.16 mmol) in ethanol (3 mL) and ethyl acetate (3 mL) and the mixture was stirred under an atmospheric pressure of hydrogen for 18 hrs. The mixture was filtered through a pad of silica and washed with several portions of ethanol and ethyl acetate. The solvent was concentrated yielding the title compound as a crude orange oil (0.037 mg, 79%). ¹H NMR (400 MHz, CDCl3): δ 7.56 (s, 1 H), 7.03 (t, J = 7.3 Hz, 1 H), 6.63-6.55 (m, 2 H), 4.41-4.36 (m, 1 H), 4.17 (t, J = 10.1 Hz, 1 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 3.31-3.13 (m, 2 H), 2.94 (dd, J = 3.8, 15.4 Hz, 1 H). e) 5-(7-Fluorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione Sodium iodide (0.096 g, 0.64 mmol) and chlorotrimethylsilane (0.069 g, 0.08 mL, 0.64 mmol) was added to a solution of 5-(7-fluorochroman-3-yl)-2,3-dimethoxypyrazine (0.037 g, 0.13 mmol) in acetonitrile (2 mL) and the mixture was heated at 60 °C for 1.5 hrs. The mixture was concentrated and purified by preparative HPLC to afford the title compound as a white solid (19 mg, 58%). ¹H NMR (400 MHz, DMSO): δ 11.30-11.24 (m, 1 H), 11.09-11.01 (m, 1 H), 7.06 (dd, J = 6.8, 8.3 Hz, 1 H), 6.66-6.55 (m, 2 H), 5.98 (s, 1 H), 4.25-4.21 (m, 1 H), 3.99-3.93 (m, 1 H), 2.85-2.81 (m, 3 H). MS (ES+) m/z 263 (M+H)+. Racemic 5-(7-Fluorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione was resolved by chiral SFC to yield the two enantiomers. 5-(7-Fluorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione (Isomer 1) (Example 209): ¹H NMR (400 MHz, DMSO): δ 11.40-11.38 (m, 1 H), 11.18-11.13 (m, 1 H), 7.19 (dd, J = 7.1, 8.3 Hz, 1 H), 6.79-6.68 (m, 2 H), 6.10 (s, 1 H), 4.38-4.33 (m, 1 H), 4.12-4.05 (m, 1 H), 2.97-2.93 (m, 3 H). MS (ES+) m/z 263 (M+H)+. Chiral analysis (Method 1) at 4.7 min. 5-(7-Fluorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione (Isomer 2) (Example 210): ¹H NMR (400 MHz, DMSO): δ 11.40 (s, 1 H), 11.17 (d, J = 5.6 Hz, 1 H), 7.19 (dd, J = 6.8, 8.3 Hz, 1 H), 6.78-6.68 (m, 2 H), 6.10 (d, J = 4.0 Hz, 1 H), 4.38-4.33 (m, 1 H), 4.11-4.05 (m, 1 H), 2.97-2.93 (m, 3 H). MS (ES+) m/z 263 (M+H)+. Chiral analysis (Method 1) at 5.8 min. 5-(7-Fluoro-2H-chromen-3-yl)-1,4-dihydropyrazine-2,3-dione (Example 211) 5-(7-Fluorochroman-3-yl)-2,3-di ypy ynthesised from 3-(5,6- dimethoxypyrazin-2-yl)-7-fluorochroman-4-ol (0.03 g, 0.098 mmol) following step e, Method Z used the synthesis of 5-(7-fluorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione. The crude material was purified by preparative HPLC to afford the title compound as a white solid (5 mg, 20%). ¹H NMR (400 MHz, DMSO): δ 11.60 (d, J = 5.1 Hz, 1 H), 11.32-11.31 (m, 1 H), 7.16- 7.12 (m, 2 H), 6.86-6.77 (m, 2 H), 6.59-6.55 (m, 1 H), 4.97 (s, 2 H). MS (ES+) m/z 261 (M+H)+. 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)chromane-7-carbo nitrile (Example 212) a) 3-(5,6-Dimethoxypyrazin-2-yl)chroman-7-ol 5-(7-(Benzyloxy)-2H-chromen-3-yl)-2,3-dimethoxypyrazine (synthesised following steps a-c, Method Z used for the synthesis of 5-(7-fluoro-2H-chromen-3-yl)-2,3-dimethoxypyrazine) (0.05 g, 0.13 mmol) was dissolved in a 1:1 mixture of methanol and ethyl acetate (5 mL). Pdon carbon (14 mg, 0.13 mmol) was added and the mixture stirred under an atmospheric pressure of hydrogen for 18 hrs. The mixture was filtered through a pad of silica and washed with several portions of methanol and ethyl acetate. The solvent was concentrated yielding the title compound as a clear oil (0.037 mg, 97%). ¹H NMR (400 MHz, CDCl ³ ): δ 7.55 (s, 1 H), 6.94 (d, J = 8.3 Hz, 1 H), 6.43-6.34 (m, 2 H), 4.38-4.33 (m, 1 H), 4.15 (t, J = 10.1 Hz, 1 H), 4.00 (s, 3 H), 3.99 (s, 3 H), 3.83 (s, 1 H), 3.30-3.19 (m, 1 H), 3.13 (dd, J = 10.4, 15.7 Hz, 1 H), 2.94-2.86 (m, 1 H). b) 3-(5,6-Dimethoxypyrazin-2-yl)chroman-7-yl methanesulfonate 3-(5 , y y y . g, . dichloromethane (2 mL) and cooled to 0 °C. Pyridine (0.02 g, 0.26 mmol) and trifluromethanesulfonic anhydride (0.043 g, 0.15 mmol) were added and the mixture was stirred at 0 °C for 2 hrs. The mixture was quenched with ice water (2 mL) and extracted into ethyl acetate (2 x 5 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to yield the title compound as a yellow oil (0.054 g, 100%). ¹H NMR (400 MHz, CDCl3): δ 7.57 (s, 1 H), 7.15 (d, J = 9.3 Hz, 1 H), 6.81-6.79 (m, 2 H), 4.44-4.39 (m, 1 H), 4.20 (t, J = 11.2 Hz, 1 H), 4.02 (s, 3 H), 3.97 (s, 3 H), 3.33-3.19 (m, 2 H), 3.02-2.96 (m, 1 H). c) 3-(5,6-Dimethoxypyrazin-2-yl)chromane-7-carbonitrile 3-(5,6-Dimethoxypyrazin-2-yl)chroman-7-yl methanesulfonate (0.054 g, 0.13 mmol) was dissolved in DMF (1 mL) and the mixture degassed with a stream of nitrogen for 5 min. Zinc cyanide (0.015 g, 0.13 mmol), Pd2(dba)3 (3.5 mg, 0.004 mmol) and dppf (4.3 mg, 0.008 mmol) were added and the mixture heated at 120 °C under nitrogen for 45 min. The mixture was diluted with brine (2 mL) and water (2 mL) and extracted into ethyl acetate (2 x 5 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography (0-50% ethyl acetate, cyclohexane gradient) to elute the title compound as an off-white solid (22 mg, 58%). ¹H NMR (400 MHz, CDCl3): δ 7.57 (s, 1 H), 7.20-7.13 (m, 3 H), 4.45-4.40 (m, 1 H), 4.23-4.17 (m, 1 H), 4.01 (s, 3 H), 3.97 (s, 3 H), 3.31-3.23 (m, 2 H), 3.06-2.97 (m, 1 H). d) 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)chromane-7-carbo nitrile 3-(5, , , , d from 3-(5,6-dimethoxypyrazin-2-yl)chromane-7-carbonitrile (22 mg, 0.074 mmol) following step e, Method Z used for the synthesis of 5-(7-fluorochroman-3-yl)-1,4-dihydropyrazine-2,3- dione. The crude material was purified by preparative HPLC to afford the title compound as a white solid (14 mg, 70%). ¹H NMR (400 MHz, DMSO): δ 11.39 (s, 1 H), 11.22-11.16 (m, 1 H), 7.40-7.33 (m, 3 H), 6.11 (s, 1 H), 4.40 (dd, J = 2.4, 10.7 Hz, 1 H), 4.14 (dd, J = 8.8, 10.6 Hz, 1 H), 3.10-2.96 (m, 3 H). MS (ES+) m/z 270 (M+H)+ Racemic 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)chromane-7-carbo nitrile was resolved by chiral SFC to yield the two enantiomers. 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)chromane-7-carbo nitrile (Isomer 1) (Example 213): ¹H NMR (400 MHz, DMSO): δ 11.24 (s, 2 H), 7.40-7.33 (m, 3 H), 6.11 (s, 1 H), 4.41 (dd, J = 2.7, 10.5 Hz, 1 H), 4.13 (dd, J = 8.8, 10.6 Hz, 1 H), 3.10-2.96 (m, 3 H). MS (ES+) m/z 270 (M+H)+. Chiral analysis (Method 2) at 2.3 min. 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)chromane-7-carbo nitrile (Isomer 2) (Example 214): ¹H NMR (400 MHz, DMSO): δ 11.24 (s, 2 H), 7.40-7.33 (m, 3 H), 6.11 (s, 1 H), 4.40 (dd, J = 2.5, 10.6 Hz, 1 H), 4.14 (dd, J = 8.8, 10.6 Hz, 1 H), 3.10-2.96 (m, 3 H). MS (ES+) m/z 270 (M+H)+. Chiral analysis (Method 2) at 3.2 min. Method AA 5-(7-Chlorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione (Example 215) a) 5-(7-Chloro-2H-chromen-3-yl)-2,3-dimethoxypyrazine T chromanone (1.46 g, 8 mmol) and potassium carbonate (0.8 g, 8 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was added Pd2dba3 (0.009 g, 0.1 mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.11 g, 0.4 mmol) and the reaction was heated at 80 °C under nitrogen for 3 hrs. The mixture was cooled to room temperature, filtered and the filtrate concentrated under reduced pressure. The crude material was purified by flash column chromatography (10-15% ethyl acetate in cyclohexane gradient) to elute 5-(7-chloro-2H-chromen-3-yl)-2,3- dimethoxypyrazine as an off-white solid. To a solution of 5-(7-chloro-2H-chromen-3-yl)-2,3- dimethoxypyrazine (0.19 g, 15%) in methanol (5 mL) at 0 °C was added sodium borohydride (0.065 g, 1.8 mmol). The resulting mixture was warmed to room temperature and stirred for 3.5 hrs. The mixture was quenched with dichloromethane (5 mL) and water (5 mL) and the product extracted into dichloromethane (2 x 5 mL). Combined organic layers were passed through a phase separator cartridge and concentrated. Crude 7-chloro-3-(5,6-dimethoxypyrazin-2- yl)chroman-4-ol was dissolved in THF (5 mL) and cooled to 0 °C. Triethylamine (0.06 g, 0.84 mL, 6.02 mmol) and methane sulfonic anhydride (0.2 g, 1.2 mmol) were added and the reaction was warmed to room temperature and stirred for 18 hrs. The mixture was diluted with dichloromethane (5 mL) and water (5 mL) and the product extracted into dichloromethane (2 x 5 mL). Combined organic layers were passed through a phase separator cartridge and concentrated. The crude material was purified by flash column chromatography (0-40% ethyl acetate in cyclohexane gradient) to elute the title compound as a white solid (0.093 g, 44%). ¹H NMR (400 MHz, CDCl3): δ 7.74 (s, 1 H), 7.15 (s, 1 H), 7.04 (d, J = 7.8 Hz, 1 H), 6.91-6.86 (m, 2 H), 5.23- 5.22 (m, 2 H), 4.07 (s, 3 H), 4.05 (s, 3 H). b) 5-(7-Chlorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione Pdon carbon (30 mg) was added to 5-(7-chlorochroman-3-yl)-2,3-dimethoxypyrazine (85 mg, 0.86 mmol) in methanol (3.5 mL) and ethyl acetate (4 mL) and the mixture was stirred under an atmospheric pressure of hydrogen for 18 hrs. The mixture was filtered through a pad of silica and washed with several portions of methanol and ethyl acetate. The solvent was concentrated yielding crude 5-(7-chlorochroman-3-yl)-2,3-dimethoxypyrazine. The mixture was dissolved in acetonitrile (2 mL) and sodium iodide (0.15 g, 1.0 mmol) and chlorotrimethylsilane (0.11 g, 0.13 mL, 1.0 mmol) were added and the mixture was heated at 60 °C for 2 hrs. The mixture was concentrated and purified by preparative HPLC to afford the title compound as a white solid (27 mg, 26%). ¹H NMR (400 MHz, DMSO) δ 11.39 (s, 1 H), 11.18 (s, 1 H), 7.21 - 7.17 (m, 1 H), 6.98 - 6.91 (m, 2 H), 6.11 - 6.09 (m, 1 H), 4.37 - 4.33 (m, 1 H), 4.12 - 4.06 (m, 1 H), 2.98 - 2.92 (m, 3 H). MS (ES+) m/z 279 (M+H)+ Racemic 5-(7-Chlorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione was resolved by chiral SFC to yield the two enantiomers. 5-(7-Chlorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione (Isomer 1) (Example 216): ¹H NMR (400 MHz, DMSO) δ 11.39 (s, 1 H), 11.18 (s, 1 H), 7.21 - 7.17 (m, 1 H), 6.98 - 6.91 (m, 2 H), 6.11 - 6.09 (m, 1 H), 4.37 - 4.33 (m, 1 H), 4.12 - 4.06 (m, 1 H), 2.98 - 2.92 (m, 3 H). MS (ES+) m/z 279 (M+H)+. Chiral analysis (Method 2) at 2.2 min. 5-(7-Chlorochroman-3-yl)-1,4-dihydropyrazine-2,3-dione (Isomer 2) (Example 217): ¹H NMR (400 MHz, DMSO) δ 11.39 (s, 1 H), 11.18 (s, 1 H), 7.21 - 7.17 (m, 1 H), 6.98 - 6.91 (m, 2 H), 6.11 - 6.09 (m, 1 H), 4.37 - 4.33 (m, 1 H), 4.12 - 4.06 (m, 1 H), 2.98 - 2.92 (m, 3 H). MS (ES+) m/z 279 (M+H)+. Chiral analysis (Method 2) at 3.1 min. 5-(Chroman-3-yl)-1,4-dihydropyrazine-2,3-dione (Example 218) a) 5-(Chroman-3-yl)-1,4-dihydropyrazine-2,3-dione 5-(Ch by- product in step b, Method AA used to synthesise 5-(7-chlorochroman-3-yl)-1,4- dihydropyrazine-2,3-dione (15 mg, 47%). ¹H NMR (400 MHz, DMSO) δ 11.40 (s, 1 H), 11.17 (s, 1 H), 7.17 - 7.12 (m, 2 H), 6.93 - 6.81 (m, 2 H), 6.11 (s, 1 H), 4.33 (dd, J=1.9, 11.0 Hz, 1 H), 4.09 - 4.03 (m, 1 H), 3.00 - 2.94 (m, 3 H). MS (ES+) m/z 245 (M+H)+. Method AB 5-(7-(Pentafluoro-λ6-sulfaneyl)chroman-3-yl)-1,4-dihydropyr azine-2,3-dione (Example 219) a) Pentafluoro(3-(prop-2-yn-1-yloxy)phenyl)- -sulfane Potassium carbonate (1.63 g, 11.8 mmol) was added to 3- hydroxyphenylsulphutoentafluoride (1.3 g, 5.9 mmol) in DMF (24 mL) followed by propargyl bromide (80% solution in toluene) (1.32 g, 0.95 mL, 8.86 mmol) and the reaction was stirred for 3.5 hrs at room temperature. The mixture was diluted with brine (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to afford the title compound as an orange oil (1.4 g, 92%). ¹H NMR (400 MHz, CDCl3): δ 7.41-7.38 (m, 3 H), 7.16-7.11 (m, 1 H), 4.74 (d, J = 2.3 Hz, 2 H), 2.57-2.55 (t, J = 2.4 Hz, 1 H). b) 3-Iodo-7-(pentafluoro-λ6-sulfaneyl)-2H-chromene To a suspension of pentafluoro(3-(prop-2-yn-1-yloxy)phenyl)- -sulfane (0.5 g, 1.94 mmol) and silver nitrate (0.033 g, 0.194 mmol) in acetone (10 mL) was added N- iodosuccinimide (0.5 g, 1.15 mmol) and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-50% diethyl ether in cyclohexane gradient) to elute pentafluoro(3-((3-iodoprop-2-yn-1-yl)oxy)phenyl)- -sulfane as a pale- yellow oil (0.68 g, 91%). To a degassed solution of pentafluoro(3-((3-iodoprop-2-yn-1- yl)oxy)phenyl)- -sulfane (200 mg, 0.521 mmol) in 1,4-dioxane (3.5 mL) was added [1,3- bis(2,6-diisopropylphenyl)imidazol-2-ylidene] [bis(trifluoromethanesulfonyl)imide]gold(I) (0.5 g, 1.15 mmol) and the mixture heated to 90 °C and stirred for 16 hrs. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography (10-100% diethyl ether in cyclohexane gradient) to elute the title compound as a pale-yellow oil that solidified on standing (181 mg, 91%). ¹H NMR (400 MHz, CDCl3): δ 7.42 (t, J = 8.0 Hz, 1 H), 7.26 -7.15 (m, 3 H), 4.74 (d, J = 2.3 Hz, 2 H). d) 2,3-Dimethoxy-5-(7-(pentafluoro-λ6-sulfaneyl)-2H-chromen-3- yl)pyrazine To a degassed solution of 3-iodo-7-(pentafluoro-λ6-sulfaneyl)-2H-chromene (180 mg, 0.469 mmol), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyrazine (137 mg, 0.515 mmol) and potassium carbonate (194 mg, 1.41 mmol) in THF (5 mL) and water (0.5 mL) was added tetrakis(triphenylphosphine)Pd(0) (54 mg, 0.047 mmol) and the mixture heated to 80 °C and stirred at this temperature for 3 hrs. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography (10-50% ethyl acetate in cyclohexane gradient) to elute the title compound as a pale yellow solid (181 mg, 91%). ¹H NMR (400 MHz, CDCl3): δ 7.78 (s, 1 H), 7.29 (dd, J = 2.3, 8.6 Hz, 1 H), 7.24 (d, J = 2.3 Hz, 1 H), 7.19-7.14 (m, 2 H), 5.29 (d, J = 1.5 Hz, 2 H), 4.08 (s, 3 H), 4.06 (s, 3 H). e) 2,3-Dimethoxy-5-(7-(pentafluoro-λ6-sulfaneyl)chroman-3-yl)p yrazine Pd sulfaneyl)-2H-chromen-3-yl)pyrazine (90 mg, 0.227 mmol) in methanol (7.5 mL) and ethyl acetate (7.5 mL) and the mixture was stirred under atmospheric pressure of hydrogen for 18 hrs. The mixture was filtered through a pad of Celite ^TM and washed with several portions of methanol and ethyl acetate. The solvent was concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-25% ethyl acetate in cyclohexane) to elute the title compound as a colourless viscous oil (50 mg, 56%). ¹H NMR (400 MHz, CDCl3): δ 7.57 (s, 1 H), 7.25-7.23 (m, 2 H), 7.19-7.15 (m, 1 H), 4.43 (dd, J = 3.4, 10.7 Hz, 1 H), 4.24-4.18 (m, 1 H), 4.01 (s, 3 H), 3.97 (s, 3 H), 3.33-3.21 (m, 2 H), 3.07-2.99 (m, 1 H). f) 5-(7-(Pentafluoro-λ6-sulfaneyl)chroman-3-yl)-1,4-dihydropyr azine-2,3-dione To a mixture of sodium iodide (94 mg, 0.628 mmo) and 2,3-dimethoxy-5-(7- (pentafluoro-λ6-sulfaneyl)chroman-3-yl)pyrazine (50 mg, 0.126 mmol) in acetonitrile (6 mL) was added chlorotrimethylsilane (0.080 mL, 68 mg, 0.628 mmol) and the mixture was heated at 60 °C for 2 hrs. The mixture was concentrated and purified by preparative HPLC to afford the title compound as a white solid (27 mg, 59%). ¹H NMR (400 MHz, DMSO): δ 11.40 (s, 1 H), 11.13 (d, J=5.1 Hz, 1 H), 7.38 (d, J=1.9 Hz, 2 H), 7.30 (d, J=1.4 Hz, 1 H), 6.07 (dd, J=1.9, 5.3 Hz, 1 H), 4.41 - 4.36 (m, 1 H), 4.12 (dd, J=8.7, 10.5 Hz, 1 H), 3.07 - 2.93 (m, 3 H). MS (ES+) m/z 371 (M+H)+ Racemic 5-(7-(Pentafluoro-λ6-sulfaneyl)chroman-3-yl)-1,4-dihydropyr azine-2,3-dione was resolved by chiral SFC to yield the two enantiomers. 5-(7-(Pentafluoro-λ6-sulfaneyl)chroman-3-yl)-1,4-dihydropyr azine-2,3-dione (Isomer 1) (Example 220): ¹H NMR (400 MHz, DMSO): δ 10.97-10.88 (m, 2 H), 7.37-7.35 (m, 2 H), 7.28-7.27 (m, 1 H), 6.05 (s, 1 H), 4.39-4.35 (m, 1 H), 4.11 (dd, J = 8.6, 10.6 Hz, 1 H), 3.05- 2.92 (m, 3 H). MS (ES+) m/z 371.5 (M+H)+. Chiral analysis (Method 2) at 3.3 min 5-(7-(Pentafluoro-λ6-sulfaneyl)chroman-3-yl)-1,4-dihydropyr azine-2,3-dione (Isomer 2) (Example 221): ¹H NMR (400 MHz, DMSO): δ 11.14-11.08 (m, 2 H), 7.37-7.35 (m, 2 H), 7.28-7.27 (m, 1 H), 6.05 (s, 1 H), 4.39-4.35 (m, 1 H), 4.11 (dd, J = 8.7, 10.5 Hz, 1 H), 3.05- 2.92 (m, 3 H). MS (ES+) m/z 371.5 (M+H)+. Chiral analysis (Method 2) at 3.9 min. 5-(7-(Trifluoromethyl)chroman-3-yl)-1,4-dihydropyrazine-2,3- dione (Example 222) Following steps a-f, Method A y 7-(pentafluoro-λ6- sulfaneyl)chroman-3-yl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as a white solid. ¹H NMR (400 MHz, DMSO): δ 11.43 (s, 1 H), 11.17 (s, 1 H), 7.41 (d, J = 5.5 Hz, 1 H), 7.25 (d, J = 7.4 Hz, 1 H), 7.15 (s, 1 H), 6.11 (s, 1 H), 4.43-4.40 (m, 1 H), 4.18-4.12 (m, 1 H), 3.08-2.99 (m, 3 H). MS (ES+) m/z 313 (M+H)+. Racemic 5-(7-(Trifluoromethyl)chroman-3-yl)-1,4-dihydropyrazine-2,3- dione was resolved by chiral SFC to yield the two enantiomers. 5-(7-(Trifluoromethyl)chroman-3-yl)-1,4-dihydropyrazine-2,3- dione (Isomer 1) (Example 223): ¹H NMR (400 MHz, DMSO): δ 11.43 (s, 1 H), 11.17 (s, 1 H), 7.41 (d, J = 5.5 Hz, 1 H), 7.25 (d, J = 7.4 Hz, 1 H), 7.15 (s, 1 H), 6.11 (s, 1 H), 4.43-4.40 (m, 1 H), 4.18-4.12 (m, 1 H), 3.08-2.99 (m, 3 H). MS (ES+) m/z 313 (M+H)+. Chiral analysis (Method 2) at 2.7 min. 5-(7-(Trifluoromethyl)chroman-3-yl)-1,4-dihydropyrazine-2,3- dione (Isomer 2) (Example 224): ¹H NMR (400 MHz, DMSO): δ 11.43 (s, 1 H), 11.17 (s, 1 H), 7.41 (d, J = 5.5 Hz, 1 H), 7.25 (d, J = 7.4 Hz, 1 H), 7.15 (s, 1 H), 6.11 (s, 1 H), 4.43-4.40 (m, 1 H), 4.18-4.12 (m, 1 H), 3.08-2.99 (m, 3 H). MS (ES+) m/z 313 (M+H)+. Chiral analysis (Method 2) at 3.5 min. 5-(7-(Difluoromethyl)chroman-3-yl)-1,4-dihydropyrazine-2,3-d ione (Example 225) a) 3-(Prop-2-yn-1-yloxy)benzaldehyde yde (0.76 g, 6.19 mmol) in DMF (20 mL) followed by propargyl bromide (80% solution in toluene) (1.38 g, 1.00 mL, 9.28 mmol) and the reaction was stirred for 16 hrs at room temperature. The mixture was diluted with brine (20 mL) and extracted into ethyl acetate (2 x 20 mL). Organic layers were combined, washed with brine (20 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure. The crude material was purified by flash column chromatography (0-100% dichloromethane in cyclohexane gradient) to elute the title compound as a pale-yellow oil (938 mg, 95%). ¹H NMR (400 MHz, CDCl3): δ 10.00 (s, 1 H), 7.54-7.46 (m, 3 H), 7.28-7.24 (m, 1 H), 4.77 (d, J = 1.5 Hz, 2 H), 2.55 (t, J = 2.5 Hz, 1 H). b) 3-((3-Iodoprop-2-yn-1-yl)oxy)benzaldehyde To a mixture of 3-(prop-2-yn-1-yloxy)benzaldehyde (641 mg, 4.00 mmol) and silver nitrate (68 mg, 0.40 mmol) in acetone (20 mL) was added N-iodosuccinimide (1035 mg, 4.60 mmol) and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-100% dichloromethane in cyclohexane gradient) to elute the title compound as a colourless solid (586 mg, 51%). ¹H NMR (400 MHz, CDCl3): δ 9.99 (s, 1 H), 7.54-7.44 (m, 3 H), 7.26-7.22 (m, 1 H), 4.90 (s, 2 H). c) 3-Iodo-2H-chromene-7-carbaldehyde A mixture of 3-((3-iodoprop-2-yn-1-yl)oxy)benzaldehyde (586 mg, 2.05 mmol) and [1,3- Bis(2,6-diisopropylphenyl)imidazol-2-ylidene] [bis(trifluoromethanesulfonyl)imide]gold(I) (53 mg, 0.0615 mmol) in 1,4-dioxane (14 mL) was heated to 90 °C and stirred at this temperature for 4 hrs. The reaction mixture was cooled to room temperature and was concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-100% dichloromethane in cyclohexane gradient) to elute the title compound as a yellow oil (303 mg, 52%). ¹H NMR (400 MHz, CDCl3): δ 9.89 (s, 1 H), 7.41 (t, J = 5.2 Hz, 1 H), 7.26-7.25 (m, 1 H), 7.10-7.02 (m, 2 H), 4.97 (s, 2 H). d) 3-(5,6-Dimethoxypyrazin-2-yl)-2H-chromene-7-carbaldehyde To a dega - - - - - y g, . mol), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyrazine (310 mg, 1.17 mmol) and potassium carbonate (439 mg, 3.18 mmol) in 1,4-dioxane (4 mL) and water (0.5 mL) was added tetrakis(triphenylphosphine)Pd(0) (122 mg, 0.11 mmol) and the mixture heated to 80 °C and stirred at this temperature for 2 hrs. The reaction mixture was cooled to room temperature and diluted with water (30 mL) and extracted into ethyl acetate (30 mL). Organic layers were combined, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude material was purified by flash column chromatography (0-100% ethyl acetate in cyclohexane gradient) to elute the title compound (230 mg, 73%). ¹H NMR (400 MHz, CDCl3): δ 9.91 (s, 1 H), 7.80 (s, 1 H), 7.44 (dd, J = 2.7, 8.4 Hz, 2 H), 7.34 (s, 1 H), 7.28-7.24 (m, 1 H overlapping with CHCl3 peak), 5.30 (d, J = 1.6 Hz, 2 H), 4.09 (s, 3 H), 4.06 (s, 3 H). d) 5-(7-(Difluoromethyl)-2H-chromen-3-yl)-2,3-dimethoxypyrazine To a pre-cooled 0 °C (ice/water bath) solution of 3-(5,6-dimethoxypyrazin-2-yl)-2H- chromene-7-carbaldehyde (230 mg, 0.771 mmol) in dichloromethane (5 mL) was added (diethylamino)sulfur trifluoride (621 mg, 0.51 mL, 3.86 mmol) and the mixture was allowed to warm slowly to room temperature and stirred for 3 days. The reaction mixture was quenched with saturated aqueous potassium carbonate solution (30 mL) and extracted into ethyl acetate (2 x 30 mL). Organic layers were combined, washed with brine (25 mL), dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude material was purified by flash column chromatography (0-40% ethyl acetate in cyclohexane gradient) to elute the title compound as a light yellow solid (116 mg, 47%). ¹H NMR (400 MHz, CDCl3): δ 7.76 (s, 1 H), 7.21-6.98 (m, 4 H), 6.58 (t, J = 56.8 Hz, 1 H), 5.27 (s, 2 H), 4.09 (s, 3 H), 4.06 (s, 3 H). e) 5-(7-(Difluoromethyl)chroman-3-yl)-1,4-dihydropyrazine-2,3-d ione Pdhy rox e on car on ( , mg, . mmo ) was a e o -( -( uorome yl)- 2H-chromen-3-yl)-2,3-dimethoxypyrazine (115 mg, 0.359 mmol) in methanol (4 mL) and ethyl acetate (4 mL) and the mixture was stirred under atmospheric pressure of hydrogen for 5 days. The mixture was filtered through a pad of celite and washed with several portions of methanol and ethyl acetate. The solvent was concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-30% ethyl acetate in cyclohexane gradient) to elute 5-(7-(difluoromethyl)chroman-3-yl)-2,3-dimethoxypyrazine. To a mixture of sodium iodide (140 mg, 0.931 mmo) and 5-(7-(difluoromethyl)chroman-3-yl)-2,3-dimethoxypyrazine (60 mg, 0.186 mmol) in acetonitrile (3 mL) was added chlorotrimethylsilane (101 mg, 120 L, 0.931 mmol) and the mixture was heated at 60 °C for 2 hrs. The mixture was concentrated and purified by preparative HPLC to afford the title compound as a white solid (6 mg, 11%). ¹H NMR (400 MHz, DMSO): δ 11.31 (s, 1 H), 11.05 (s, 1 H), 7.20 (d, J = 9.1 Hz, 1 H), 7.00-6.86 (m, 3 H), 5.99 (s, 1 H), 4.28-4.23 (m, 1 H), 4.03-3.96 (m, 1 H), 2.94-2.84 (m, 3 H). 5-(4-Oxo-6-(trifluoromethyl)thiochroman-2-yl)-1,4-dihydropyr azine-2,3-dione (Example 226) a) O-(2-Acetyl-4-(trifluoromethyl)phenyl) dimethylcarbamothioate A mixture of 1-(2-H 00 g, 9.8 mmol) and 1,4-Diazabicyclo[2.2.2]octane (2.20 g, 19.6 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 10 min. Dimethylthiocarbamoyl chloride (1.82 g, 14.7 mmol) was then added in one portion and stirred overnight. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL), the organic phase was washed with brine (50 mL), dried over magnesium sulphate and concentrated under reduced pressure. The crude material was concentrated onto silica and purified by flash column chromatography (0-40% ethyl acetate in cyclohexane) to yield the title compound as a yellow oil (2.23 g, 78%). ¹H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 2.1 Hz, 1 H), 7.78 (dd, J = 1.8, 8.4 Hz, 1 H), 7.24 (d, J = 8.7 Hz, 1 H), 3.47 (s, 3 H), 3.42 (s, 3 H), 2.59 (s, 3 H). b) 1-(2-Mercapto-5-(trifluoromethyl)phenyl)ethan-1-one O-(2-Acetyl-4-(trifluoromethyl)phenyl) dimethylcarbamothioate (2.23 g, 7.6 mmol) was stirred at 200 °C for 4 hrs then cooled to room temperature. The residue was then dissolved in methanol (10 mL) and 2 M aqueous sodium hydroxide (10 mL) and stirred at 90 °C for 2 hrs. The reaction mixture was then cooled to room temperature, acidified to pH 2 with 1 M aqueous hydrochloric acid and partitioned into ethyl acetate (50 mL). The organic phase was separated, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was concentrated onto silica and purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to yield the title compound as a red solid (1.05 g, 62%). ¹H NMR (400 MHz, CDCl3): δ 8.09 (s, 1 H), 7.54 (dd, J = 1.5, 8.4 Hz, 1 H), 7.45-7.42 (m, 1 H), 4.69 (s, 1 H), 2.68 (s, 3 H). c) 2-(5,6-Dimethoxypyrazin-2-yl)-6-(trifluoromethyl)thiochroman -4-one A , mmol) and pyrrolidine (32 mg, 0.454 mmol) in methanol (5 mL) was stirred at reflux for 10 min. 5,6-dimethoxypyrazine-2-carbaldehyde (76 mg, 0.454 mmol) was then added in one portion and stirred at reflux for a further 10 min. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate (20 mL) and water (20 mL), the organic phase was washed with brine (20 mL), dried over magnesium sulphate and the solvent removed under reduced pressure. The crude material was concentrated onto silica and purified by flash column chromatography (0-40% ethyl acetate in cyclohexane) to yield the title compound as an orange solid (0.12 g, 69%). ¹H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 1.3 Hz, 1 H), 7.65 (s, 1 H), 7.58 (dd, J = 2.0, 8.4 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 4.68-4.64 (m, 1 H), 3.99 (s, 3 H), 3.73 (s, 3 H), 3.42 (dd, J = 6.8, 16.4 Hz, 1 H), 3.32 (dd, J = 4.5, 16.4 Hz, 1 H). d) 5-(4-Oxo-6-(trifluoromethyl)thiochroman-2-yl)-1,4-dihydropyr azine-2,3-dione A solution of 2-(5,6-dimethoxypyrazin-2-yl)-6-(trifluoromethyl)thiochroman -4-one (40 mg, 0.108 mmol) in dioxane (1 mL) and 2 M aqueous hydrochloric acid (1 mL) was stirred at reflux for 2 hrs. The reaction was cooled to room temperature, the solvent removed under reduced pressure and the residue purified by preparative HPLC to yield the title compound as an off-white solid (10 mg, 27%). ¹H NMR (400 MHz, DMSO): δ 11.53-11.07 (m, 2 H), 8.19-8.17 (m, 1 H), 7.86 (dd, J = 2.1, 8.4 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 6.17 (s, 1 H), 4.70 (dd, J = 3.6, 9.8 Hz, 1 H), 3.44 (dd, J = 9.8, 16.7 Hz, 1 H), 3.21 (dd, J = 3.6, 16.7 Hz, 1 H). LCMS: MS (ES+) m/z 343 (M+H)+. 5-(6-(Trifluoromethyl)thiochroman-2-yl)-1,4-dihydropyrazine- 2,3-dione (Example 227) a) A solution of 2-(5,6-dimethoxypyrazin-2-yl)-6-(trifluoromethyl)thiochroman -4-one (334 mg, 0.902 mmol) and sodium borohydride (41 mg, 1.08 mmol) in methanol (10 mL) was stirred at 0 °C for 30 min. The solvent was removed under reduced pressure, the residue was subsequently azeotroped from methanol (10 mL) and partitioned between ethyl acetate (10 mL) and water (10 mL). The organic phase was washed with brine (10 mL), dried over magnesium sulphate and the solvent was removed under reduced pressure to yield the title compound as an off-white solid (266 mg, 79%). ¹H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 1.4 Hz, 1 H), 7.65 (s, 1 H), 7.40 (dd, J = 2.0, 8.3 Hz, 1 H), 7.22 (d, J = 8.3 Hz, 1 H), 5.00-4.93 (m, 1 H), 4.69 (dd, J = 5.3, 8.3 Hz, 1 H), 4.02 (s, 3 H), 3.94 (s, 3 H), 3.40 (d, J = 8.3 Hz, 1 H), 2.70-2.56 (m, 2 H). b) 5-(4-Bromo-6-(trifluoromethyl)thiochroman-2-yl)-2,3-dimethox ypyrazine A solution of 2-(5,6-dimethoxypyrazin-2-yl)-6-(trifluoromethyl)thiochroman -4-ol (266 mg, 0.714 mmol), triphenylphosphine (225 mg, 0.857 mmol) and carbon tetrabromide (284 mg, 0.857 mmol) in dichloromethane (10 mL) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated on silica and purified by flash column chromatography (0-40% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (233 mg, 75%). ¹H NMR (400 MHz, CDCl ³ ): δ 7.72 (s, 1 H), 7.57 (d, J = 1.6 Hz, 1 H), 7.38 (dd, J = 1.5, 8.3 Hz, 1 H), 7.19 (d, J = 8.3 Hz, 1 H), 5.65 (t, J = 3.2 Hz, 1 H), 5.16 (dd, J = 4.2, 10.7 Hz, 1 H), 4.04 (s, 3 H), 4.02 (s, 3 H), 2.85-2.80 (m, 2 H). c) 2,3-Dimethoxy-5-(6-(trifluoromethyl)thiochroman-2-yl)pyrazin e A solut - - - - y - -y - , - ypy e (233 mg, 0.535 mmol) and 10% Pdon carbon (50 mg) was stirred under a hydrogen atmosphere at room temperature for 18 hrs. The reaction mixture was purged of hydrogen, placed under a nitrogen atmosphere, filtered through Celite ^TM , washing with ethyl acetate (20 mL), concentrated onto silica and purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (96 mg, 50%). ¹H NMR (400 MHz, CDCl3): δ 7.69 (s, 1 H), 7.33-7.30 (m, 2 H), 7.21 (d, J = 8.6 Hz, 1 H), 4.52 (dd, J = 4.9, 8.2 Hz, 1 H), 4.02 (s, 3 H), 3.98 (s, 3 H), 3.01-2.95 (m, 2 H), 2.45-2.38 (m, 2 H). d) 5-(6-(Trifluoromethyl)thiochroman-2-yl)-1,4-dihydropyrazine- 2,3-dione A solution of 2,3-dimethoxy-5-(6-(trifluoromethyl)thiochroman-2-yl)pyrazin e (96 mg, 0.269 mmol) in dioxane (3 mL) and 2 M aqueous hydrochloric acid (3 mL) was stirred at reflux for 2 hrs. The reaction mixture was cooled to room temperature, the solvent removed under reduced pressure and the crude material concentrated onto silica gel and purified by flash column chromatography (0-10% methanol in dichloromethane) to yield the title compound as an off- white solid (58 mg, 63%). ¹H NMR (400 MHz, DMSO): δ 11.40 (s, 1 H), 11.17-11.16 (m, 1 H), 7.51-7.49 (m, 1 H), 7.44-7.41 (m, 1 H), 7.33-7.29 (m, 1 H), 6.32-6.29 (m, 1 H), 4.41-4.36 (m, 1 H), 3.01-2.94 (m, 1 H), 2.85-2.77 (m, 1 H), 2.23-2.19 (m, 2 H). MS (ES+) m/z 329 (M+H)+. 2-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-4-oxothiochroma ne-6-carbonitrile (Example 228) a mx ure o -( - romo- - y roxyp eny )e an- -one ( . g, . mmol) and 1,4- diazabicyclo[2.2.2]octane (8.60 g, 69.6 mmol) in N,N-dimethylformamide (120 mL) was stirred at room temperature for 10 min. Dimethylthiocarbamoyl chloride (10.5 g, 93.2 mmol) was then added in one portion and stirred overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude material was concentrated and purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as a pale green oil (14.1 g, 100%). ¹H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 2.4 Hz, 1 H), 7.63 (dd, J = 2.5, 8.7 Hz, 1 H), 6.98 (d, J = 8.7 Hz, 1 H), 3.45 (s, 3 H), 3.39 (s, 3 H), 2.53 (s, 3 H). b) 1-(5-Bromo-2-merca to hen l)ethan-1-one O-(2-Acetyl-4-bromophenyl) dimethylcarbamothioate (14.1 g, 46.7 mmol) was stirred at 200 °C for 4 hrs then cooled to room temperature. The residue was then dissolved in methanol (20 mL) and 2 M aqueous sodium hydroxide (20 mL) and stirred at 90 °C for 2 hrs. The reaction mixture was then cooled to room temperature, acidified to pH 2 with 1 M aqueous hydrochloric acid and partitioned into ethyl acetate. The organic phase was separated, dried over magnesium sulfate and the solvent removed under reduced pressure. The crude material was concentrated and purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to yield the title compound as a red oil (1.05 g, 62%). ¹H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 2.3 Hz, 1 H), 7.42 (dd, J = 2.1, 8.5 Hz, 1 H), 7.19 (d, J = 8.3 Hz, 1 H), 4.50 (s, 1 H), 2.62 (s, 3 H). c) 6-Bromo-2-(5,6-dimethoxypyrazin-2-yl)thiochroman-4-one A p p y . g, . pyrrolidine (437 mg, 6.1 mmol) in methanol (25 mL) was stirred at reflux for 10 min. 5,6- Dimethoxypyrazine-2-carbaldehyde (1.0 g, 6.1 mmol) was then added in one portion and stirred at reflux for a further 10 min. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase was washed with brine (100 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The crude material was purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to yield the title compound as a pale brown solid (1.360 g, 59%). ¹H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 2.3 Hz, 1 H), 7.65 (s, 1 H), 7.47 (dd, J = 2.3, 8.3 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 1 H), 4.63 (dd, J = 4.2, 7.2 Hz, 1 H), 3.99 (s, 3 H), 3.78 (s, 3 H), 3.38 (dd, J = 7.2, 16.5 Hz, 1 H), 3.27 (dd, J = 4.3, 16.7 Hz, 1 H). d) 2-(5,6-Dimethoxypyrazin-2-yl)-4-oxothiochromane-6-carbonitri le A solution of 6-bromo-2-(5,6-dimethoxypyrazin-2-yl)thiochroman-4-one (1.35 g, 3.5 mmol) in N,N-dimethylformamide (10 mL) was degassed with nitrogen for 5 min. Zinc cyanide (416 mg, 3.5 mmol) and tetrakis(triphenylphosphine)Pd(0) (208 mg, 0.18 mmol) were sequentially added and stirred at 100 °C under microwave irradiation. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through Celite ^TM , washed with ethyl acetate (100 mL) and the solvent removed under reduced pressure. The crude material was purified by flash column chromatography (0-40% ethyl acetate in cyclohexane) to yield the title compound as a pale orange solid (1.03 g, 89%). ¹H NMR (400 MHz, CDCl ³ ): δ 8.39 (d, J = 1.5 Hz, 1 H), 7.64 (s, 1 H), 7.57 (dd, J = 2.0, 8.3 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 4.67 (dd, J = 4.5, 6.6 Hz, 1 H), 3.99 (s, 3 H), 3.72 (s, 3 H), 3.40 (dd, J = 6.6, 16.4 Hz, 1 H), 3.31 (dd, J = 4.3, 16.4 Hz, 1 H). e) 2-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-4-hydroxythioch romane-6-carbonitrile A solut on o -( , - me oxypyraz n- -y )- -oxo oc romane- -car on r e ( 7 mg, 1.0 mmol) in acetonitrile was degassed with nitrogen for 5 min. Sodium iodide (749 mg, 5.0 mmol) and chlorotrimethylsilane (543 mg, 5.0 mmol) were then added sequentially and the reaction mixture stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The crude material was purified by flash column chromatography (0-20% methanol in dichloromethane) to yield the title compound as a pale brown solid (10 mg, 3%). ¹H NMR (400 MHz, DMSO): δ 11.54 (d, J = 1.5 Hz, 1 H), 11.24 (d, J = 5.3 Hz, 1 H), 8.34 (d, J = 1.8 Hz, 1 H), 7.98 (dd, J = 2.0, 8.3 Hz, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 6.23 (dd, J = 2.0, 5.6 Hz, 1 H), 4.78 (dd, J = 3.5, 9.9 Hz, 1 H), 3.49 (dd, J = 10.0, 16.8 Hz, 1 H), 3.26 (dd, J = 3.7, 16.8 Hz, 1 H). MS (ES+) m/z 300 (M+H)+. 2-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-4-hydroxythioch romane-6-carbonitrile (Example 229) a) 2-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-4-hydroxythioch romane-6-carbonitrile A solu -6- carbonitrile (300 mg, 1.0 mmol) and sodium borohydride (82 mg, 2.2 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, concentrated onto silica and purified by flash column chromatography (20-50% methanol in dichloromethane) to yield the title compound as a mixture of diastereomers as a yellow solid (140 mg, 46%). ¹H NMR (400 MHz, DMSO): δ 11.29-11.18 (m, 2 H), 7.86- 7.84 (m, 1 H), 7.59 (dd, J = 1.7, 8.1 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 1 H), 6.39 (s, 1 H), 4.69-4.63 (m, 2 H), 2.36-2.22 (m, 2 H) (OH peak not observed) MS (ES+) m/z 302 (M+H)+. 2-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-4-fluorothiochr omane-6-carbonitrile (Example 230) a) 2-(5,6-Dimethoxypyrazin-2-yl)-4-hydroxythiochromane-6-carbon itrile A solution of 2-(5,6-dimethoxypyrazin-2-yl)-4-oxothiochromane-6-carbonitri le (190 mg, 0.58 mmol) and sodium borohydride (24 mg, 0.63 mmol) in methanol (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (0-75% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (140 mg, 73%). ¹H NMR (400 MHz, CDCl3): δ 7.88-7.86 (m, 1 H), 7.64 (s, 1 H), 7.40 (dd, J = 1.6, 8.5 Hz, 1 H), 7.19 (d, J = 8.3 Hz, 1 H), 4.93 (dt, J = 4.5, 8.3 Hz, 1 H), 4.70 (dd, J = 5.2, 8.7 Hz, 1 H), 4.02 (s, 3 H), 3.95 (s, 3 H), 3.38 (d, J = 7.8 Hz, 1 H), 2.68-2.54 (m, 2 H). b) 2-(5,6-Dimethoxypyrazin-2-yl)-4-fluorothiochromane-6-carboni trile A solut , e (140 mg, 0.42 mmol) in dichloromethane (7 mL) was cooled to -78 °C and a 50% solution of Deoxo- Fluor® in tetrahydrofuran (0.22 mL, 0.51 mmol) was added dropwise. The reaction mixture stirred at -78 °C for 30 min. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL), warmed to room temperature and phases separated. The aqueous phase was washed with dichloromethane (20 mL) and the combined organic phases were dried through a phase separator and the solvent removed under reduced pressure. The crude material was purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (31 mg, 22%). ¹H NMR (400 MHz, CDCl3): δ 7.71-7.69 (m, 2 H), 7.50 (td, J = 1.8, 8.3 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 5.70 (ddd, J = 2.4, 4.2, 49.1 Hz, 1 H), 4.74 (dd, J = 2.5, 12.3 Hz, 1 H), 4.04 (s, 3 H), 4.02 (s, 3 H), 2.84-2.74 (m, 1 H), 2.67-2.49 (m, 1 H). c) 2-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-4-fluorothiochr omane-6-carbonitrile A solution of 2-(5,6-dimethoxypyrazin-2-yl)-4-fluorothiochromane-6-carboni trile (31 mg, 0.09 mmol) and sodium iodide (70 mg, 0.47 mmol) in acetonitrile was degassed with nitrogen for 5 min. Chlorotrimethylsilane (51 mg, 0.47 mmol) was then added and the reaction mixture was stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite ^TM . The solvent was removed under reduced pressure. The crude material was purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) and purified further by preparative HPLC to yield the title compound as a yellow solid (11 mg, 39%). ¹H NMR (400 MHz, DMSO): δ 11.27-11.23 (m, 2 H), 8.35 (s, 1 H), 7.94 (dd, J = 2.0, 2.0 Hz, 1 H), 7.70-7.66 (m, 1 H), 7.38 (d, J = 8.1 Hz, 1 H), 6.50 (s, 1 H), 5.86- 5.70 (m, 1 H), 4.49-4.43 (m, 1 H) 2.93- 2.79 (m, 2 H). MS (ES+) m/z 304 (M+H)+. 2-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)thiochromane-6-c arbonitrile (Example 231) a) 4-Bromo-2-(5,6-dimethoxypyrazin - -y oc omane- -ca onitrile A solution of 2-(5,6-dimethoxypyrazin-2-yl)-4-hydroxythiochromane-6-carbon itrile (225 mg, 0.68 mmol), triphenylphosphine (197 mg, 0.75 mmol) and carbon tetrabromide (249 mg, 0.75 mmol) in dichloromethane (15 mL) was stirred at room temperature for 90 min. The reaction mixture was recharged with triphenyl phosphine (65 mg, 0.25 mmol) and carbon tetrabromide (83 mg, 0.25 mmol) and stirred for a further 18 hrs. The reaction mixture was concentrated and purified by flash column chromatography (0-70% ethyl acetate in cyclohexane) to yield the title compound as an orange gum (153 mg, 57%). ¹H NMR (400 MHz, CDCl3): δ 7.71 (s, 1 H), 7.60 (d, J = 1.8 Hz, 1 H), 7.38 (dd, J = 1.8, 8.3 Hz, 1 H), 7.18 (d, J = 8.3 Hz, 1 H), 5.61-5.58 (m, 1 H), 5.14 (dd, J = 4.2, 10.7 Hz, 1 H), 4.04 (s, 3 H), 4.02 (s, 3 H), 2.83-2.78 (m, 2 H). b) 2-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)thiochromane-6-c arbonitrile A solution of 4-bromo-2-(5,6-dimethoxypyrazin-2-yl)thiochromane-6-carbonit rile (153 mg, 0.39 mmol) and 10% Pdon carbon (70 mg) in a 1:1 mixture of methanol and ethyl acetate (20 mL) was stirred under a hydrogen atmosphere for 18 hrs. The reaction mixture was filtered through Celite ^TM and the solvent removed under reduced pressure to yield 2-(5,6- Dimethoxypyrazin-2-yl)thiochromane-6-carbonitrile as an orange solid (120 mg, 99%). A solution of 2-(5,6-dimethoxypyrazin-2-yl)thiochromane-6-carbonitrile (120 mg, 0.38 mmol) and sodium iodide (287 mg, 1.9 mmol) in acetonitrile was degassed with nitrogen for 5 min. Chlorotrimethylsilane (208 mg, 1.9 mmol) was then added and the reaction mixture was stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature, concentrated and purified by flash column chromatography (0-20% methanol in DCM) and then further purified by preparative HPLC to yield the title compound as a pale pink solid (23 mg, 21%). ¹H NMR (400 MHz, DMSO): δ 11.41 (s, 1 H), 11.19 (s, 1 H), 7.63 (s, 1 H), 7.54 (dd, J = 1.8, 8.1 Hz, 1 H), 7.32 (d, J = 8.3 Hz, 1 H), 6.33 (d, J = 3.5 Hz, 1 H), 4.43 (dd, J = 6.9, 6.9 Hz, 1 H), 3.00-2.91 (m, 1 H), 2.86-2.75 (m, 1 H), 2.27-2.19 (m, 2 H). MS (ES+) m/z 286 (M+H)+. 5-(6,8-Difluoro-4-oxothiochroman-2-yl)-1,4-dihydropyrazine-2 ,3-dione (Example 232) a) O-(2-Acetyl-4,6-difluorophenyl) dimethylcarbamothioate A mixture of 1-(3,5-difluoro-2-hydroxyphenyl)ethan-1-one (2.00 g, 11.6 mmol) and 1,4- diazabicyclo[2.2.2]octane (2.15 g, 17.4 mmol) in N,N-dimethylformamide (25 mL) was stirred at room temperature for 10 min. Dimethylthiocarbamoyl chloride (2.61 g, 23.3 mmol) was then added in one portion and stirred overnight. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL), the organic phase was washed with brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude material was concentrated and purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (1.88 g, 62%). ¹H NMR (400 MHz, CDCl3): δ 7.34- 7.30 (m, 1 H), 7.11-7.05 (m, 1 H), 3.47-3.41 (m, 6 H), 2.55 (s, 3 H). b) 2-(5,6-Dimethoxypyrazin-2-yl)-6,8-difluorothiochroman-4-one - - y - , - p y y . g, . was stirred at 200 °C for 4 hrs then cooled to room temperature. The residue was then dissolved in methanol (5 mL) and 2 M aqueous sodium hydroxide (5 mL) and stirred at 90 °C for 2 hrs. The reaction mixture was then cooled to room temperature, acidified to pH 2 with 1 M aqueous hydrochloric acid and partitioned into ethyl acetate (100 mL). The organic phase was separated, dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude material was purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to yield 1-(3,5- Difluoro-2-mercaptophenyl)ethan-1-one as a pale yellow solid (880 mg, 65%). A solution of 1- (3,5-difluoro-2-mercaptophenyl)ethan-1-one (1.4 g, 6.1 mmol) and pyrrolidine (375 mg, 2.0 mmol) in methanol (5 mL) was stirred at reflux for 10 min. 5,6-Dimethoxypyrazine-2- carbaldehyde (335 mg, 2.0 mmol) was then added in one portion and stirred at reflux for a further 10 min. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate (50 mL) and water (50 mL), the organic phase was washed with brine (50 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The crude material was purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to yield the title compound as pale yellow solid (296 mg, 44%). ¹H NMR (400 MHz, CDCl3): δ 7.70 (ddd, J = 1.4, 2.8, 9.0 Hz, 1 H), 7.67 (s, 1 H), 6.98 (ddd, J = 2.8, 8.0, 9.2 Hz, 1 H), 4.67-4.63 (m, 1 H), 3.99 (s, 3 H), 3.77 (s, 3 H), 3.44-3.38 (m, 1 H), 3.33-3.27 (m, 1 H). c) 5-(6,8-Difluoro-4-oxothiochroman-2-yl)-1,4-dihydropyrazine-2 ,3-dione A solut g, 0.15mmol) in dioxane (2 mL) and 2 M aqueous hydrochloric acid (2 mL) was stirred at reflux for 2 hrs. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure and the crude material was purified by trituration from methanol to yield the title compound as a pale brown solid (18 mg, 39%). ¹H NMR (400 MHz, DMSO) d 11.52 (s, 1 H), 11.24 (d, J=5.3 Hz, 1 H), 7.77 (ddd, J=2.8, 8.5, 9.7 Hz, 1 H), 7.71 - 7.67 (m, 1 H), 6.27 - 6.23 (m, 1 H), 4.75 (dd, J=3.2, 10.2 Hz, 1 H), 3.51 (dd, J=10.4, 16.9 Hz, 1 H), 3.29 - 3.22 (m, 1 H). MS (ES+) m/z 311 (M+H)+. 6-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-5,6,7,8-tetrahy dronaphthalene-2- carbonitrile (Example 233) To a degassed suspension of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8- dihydronaphthalene-2-carbonitrile (562 mg, 2.00 mmol, synthesised according to WO 2013149362), 5-bromo-2,3-dimethoxypyrazine (438 mg, 2.00 mmol) and cesium carbonate (1.95 g, 6.00 mmol) was added tetrakis(triphenylphosphine)Pd(0) (462 mg, 0.4 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) and the reaction was heated to 80 °C under nitrogen for 1.5 hrs. The reaction was allowed to cool to room temperature and the organics separated from the aqueous. The organics were filtered through celite and the filtrate concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-100% DCM in iso-hexane) yielding the desired product as a pale yellow solid (510 mg, 87% yield). ¹ H NMR (CDCl3, 400 MHz) δ 7.88 (s, 1 H), 7.47 (dd, J = 1.4, 7.8 Hz, 1 H), 7.44-7.36 (m, 2 H), 7.26-7.23 (m, 1 H), 4.11 (s, 3 H), 4.06 (s, 3 H), 2.99 (t, J = 8.1 Hz, 2 H), 2.81 (t, J = 8.2 Hz, 2 H). b) 6-(5,6-dimethoxypyrazin-2-yl)-5,6,7,8-tetrahydronaphthalene- 2-carbonitrile A deg , , carbonitrile (300 mg, 1.02 mmol) and Pdon carbon (10 wt %, 109 mg, 1.02 mmol) in methanol (20 mL) was placed under an atmosphere of hydrogen and stirred for 16 hrs. The catalyst and hydrogen atmosphere were recharged and the mixture stirred for a further 72 hrs. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to give the desired product as an off-white solid (30 mg, 10% yield). ¹H NMR (400 MHz, CDCl3): δ 7.52 (s, 1 H), 7.44-7.36 (m, 2 H), 7.19 (d, J = 8.1 Hz, 1 H), 4.01 (s, 3 H), 3.98 (s, 3 H), 3.16-2.92 (m, 4 H), 2.84-2.79 (m, 1 H), 2.17-1.99 (m, 2 H). c) 6-(5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-5,6,7,8-tetrahy dronaphthalene-2- carbonitrile To a suspension of 6-(5,6-dimethoxypyrazin-2-yl)-5,6,7,8-tetrahydronaphthalene- 2- carbonitrile (30 mg, 0.102 mmol) and sodium iodide (76 mg, 0.51 mmol) in acetontrile (1.0 mL) was added chlorotrimethylsilane (0.064 mL, 0.51 mmol) dropwise and the reaction was heated to 60 °C and stirred for 2 hrs. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC purification. The product containing fractions were concentrated under reduced pressure yielding the product as a white solid (5 mg, 19% yield). ¹ H NMR (CDCl3, 400 MHz) δ 11.35-11.30 (m, 1 H), 11.13 (s, 1 H), 7.65-7.58 (m, 2 H), 7.37-7.34 (m, 1 H), 6.06 (s, 1 H), 3.22 (d, J = 4.5 Hz, 1 H), 3.11-3.05 (m, 1 H), 2.96-2.85 (m, 2 H), 2.74-2.68 (m, 1 H), 2.05 (dd, J = 2.4, 12.8 Hz, 1 H), 1.88-1.76 (m, 1 H). MS (ESI-) m/z 266 [M-H]-. 5-(3,4-Dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-dihydropyra zine-2,3-dione (Example 234) a) 3-(5,6-Dimethoxypyrazin-2-yl) - , - y o- - enzo[b][1,4]thiazine To a solution of 2-bromo-1-(5,6-dimethoxypyrazin-2-yl)ethan-1-one (137 mg, 0.525 mmol) and 2-aminothiophenol (66 mg, 0.525 mmol) in N,N-dimethylformamide (1.5 mL) was added acetic acid (105 mg, 1.75 mmol) and the mixture stirred at room temperature for 5 min. After this time sodium cyanoborohydride (33 mg, 0.525 mmol) was added and stirring continued at room temperature for a further 2.5 hrs. The mixture was diluted with ethyl acetate (20 mL) and washed sequentially with 1 M aqueous HCl (10 mL), saturated aqueous sodium bicarbonate (15 mL) and brine (10 mL). The organic layer was dried with magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure and the residue was purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to give the desired product as a viscous yellow oil (113 mg, 74%); ¹H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 0.7 Hz, 1 H), 7.05 (dd, J = 1.4, 7.8 Hz, 1 H), 6.96 (ddd, J = 1.5, 7.3, 8.0 Hz, 1 H), 6.67 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H), 6.60 (dd, J = 1.1, 8.0 Hz, 1 H), 4.80-4.75 (m, 1 H), 4.41 (s, 1 H), 4.02 (s, 3 H), 4.02 (s, 3 H), 3.25 (dd, J = 7.0, 12.4 Hz, 1 H), 3.15 (dd, J = 3.1, 12.5 Hz, 1 H). b) 5-(3,4-Dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-dihydropyra zine-2,3-dione To a solution of 3-(5, iazine (63 mg, 0.218 mmol) in acetonitrile (4 mL) was added sodium iodide (98 mg, 0.653 mmol) followed by chlorotrimethylsilane (71 mg, 0.653 mmol) at room temperature. The mixture was then heated and stirred at 60 °C for 3 hrs. The mixture was concentrated under reduced pressure to give a residue, which was purified using preparative HPLC to give the desired product as a brown amorphous solid (21 mg, 37%); ¹H NMR (400 MHz, DMSO): δ 11.28 (s, 1 H), 11.15 (d, J = 3.1 Hz, 1 H), 6.92-6.85 (m, 2 H), 6.64 (dd, J = 1.1, 8.1 Hz, 1 H), 6.54-6.49 (m, 1 H), 6.37 (d, J = 2.4 Hz, 1 H), 6.10 (d, J = 3.8 Hz, 1 H), 4.44-4.39 (m, 1 H), 3.21 (dd, J = 6.5, 12.8 Hz, 1 H), 2.98 (dd, J = 2.8, 12.7 Hz, 1 H).; MS (ES+) m/z 262 (M+H)+. 5-(4-Methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3- dione (Example 235) a) 3-(5,6-Dimethoxypyrazin-2-yl)-4-methyl-3,4-dihydro-2H-benzo[ b][1,4]thiazine To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]th iazine (50 mg, 0.173 mmol) in acetic acid (1 mL) was added formaldehyde (37% aqueous solution, 0.13 mL, 1.73 mmol) then stirred at room temperature for 5 minutes, followed by addition of sodium cyanoborohydride (52 mg, 0.829 mmol). The mixture was then heated and stirred at 20 °C for 16 hrs. The mixture was neutralised with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure to give the desired product as an off-white solid (58.3 mg, >100% mass recovery), which was used directly in the next step without further purification; ¹H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 0.8 Hz, 1 H), 7.14-7.07 (m, 2 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.66 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H), 4.82 (dt, J = 0.8, 3.7 Hz, 1 H), 3.99 (s, 6 H), 3.22-3.20 (m, 2 H), 3.05 (s, 3 H). b) 5-(4-Methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3- dione To a solution of 3-(5, ypy y y , y o[b][1,4]thiazine (52 mg, 0.171 mmol) in acetonitrile (2.5 mL) was added sodium iodide (77 mg, 0.514 mmol) followed by chlorotrimethylsilane (56 mg, 0.514 mmol) at room temperature. The mixture was then heated and stirred at 60 °C for 90 min. The mixture was concentrated under reduced pressure to give a residue, which was purified using preparative HPLC to give the desired product as an off-white amorphous solid (7 mg, 13%); ¹H NMR (400 MHz, DMSO): δ 11.27 (s, 1 H), 11.05 (s, 1 H), 7.05 (ddd, J = 1.5, 7.1, 8.4 Hz, 1 H), 7.00 (dd, J = 1.6, 7.6 Hz, 1 H), 6.76 (dd, J = 1.0, 8.4 Hz, 1 H), 6.61 (ddd, J = 7.4, 7.4, 1.1 Hz, 1 H), 5.66 (s, 1 H), 4.58 (dd, J = 2.6, 3.6 Hz, 1 H), 3.21 (dd, J = 3.6, 13.5 Hz, 1 H), 3.05 (dd, J = 3.5, 13.5 Hz, 1 H), 2.97-2.96 (m, 3 H); MS (ES+) m/z 276 (M+H)+. 5-(3-Methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3- dione (Example 236) a) 3-(5,6-Dimethoxypyrazin-2-yl)-3-methyl-3,4-dihydro-2H-benzo[ b][1,4]thiazine To a mixture of sodium iodide (17 mg, 0.111 mmol) in acetonitrile (8 mL) was added 2,3- dimethoxy-5-(prop-1-en-2-yl)pyrazine (200 mg, 1.11 mmol) and 2-aminothiophenol (132 mg, 1.05 mmol) followed by potassium peroxodisulfate (150 mg, 0.555 mmol) at room temperature. The reaction was heated to 80 °C and stirring continued for a further 20 hrs. The reaction was quenched with saturated aqueous sodium bicarbonate (8 mL) and the mixture was further diluted with ethyl acetate (10 mL) and washed with 20 % aqueous sodium thiosulfate soltution (10 mL). The layers were separated, the aqueous extracted with ethyl acetate (2 × 6 mL). The combined organic extracts were dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure and the residue was purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to give the desired product as a viscous pink oil (77 mg, 23%); ¹H NMR (400 MHz, CDCl3): δ 7.68 (s, 1 H), 6.99-6.93 (m, 2 H), 6.65-6.57 (m, 2 H), 4.32 (s, 1 H), 4.01 (s, 3 H), 3.98 (d, J = 7.4 Hz, 3 H), 3.37 (dd, J = 1.0, 12.3 Hz, 1 H), 2.97 (d, J = 12.3 Hz, 1 H), 1.65 (s, 3 H). b) 5-(3-Methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3- dione To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-3-methyl-3,4-dihydro-2H-benzo[ b][1,4]thiazine (100 mg, 0.330 mmol) in acetonitrile (5 mL) was added sodium iodide (148 mg, 0.989 mmol) followed by chlorotrimethylsilane (107 mg, 0.989 mmol) at room temperature. The mixture was then heated and stirred at 60 °C for 3 hrs. The mixture was concentrated under reduced pressure to give a residue, which was purified using preparative HPLC to give the desired product as a brown amorphous solid (47 mg, 52%); ¹H NMR (400 MHz, DMSO): δ 11.15 (s, 1 H), 11.03 (s, 1 H), 6.91-6.84 (m, 2 H), 6.68 (dd, J = 1.1, 8.0 Hz, 1 H), 6.51 (dt, J = 1.1, 7.5 Hz, 1 H), 6.45 (s, 1 H), 5.85 (s, 1 H), 3.46 (d, J = 13.4 Hz, 1 H), 3.29 (s, 1 H), 2.80 (d, J = 13.3 Hz, 1 H), 1.51 (s, 3 H).; MS (ES+) m/z 276 (M+H)+. 5-(7-Chloro-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3- dione (Example 237)

To a sol , ypy y g, . ol) and 5-chloro-2-aminothiophenol (101 mg, 0.632 mmol) in N,N-dimehtylformamide (2 mL) was added acetic acid (126 mg, 2.10 mmol) and the mixture stirred at 20 °C for 5 min. After this time sodium cyanoborohydride (40 mg, 0.632 mmol) was added and stirring continued at 20 °C for a further 2.5 hrs. The mixture was diluted with ethyl acetate (25 mL) and washed sequentially with 1 M aqueous HCl (15 mL), saturated aqueous sodium bicarbonate (20 mL) and brine (15 mL). The organic layer was separated, dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure and the residue was purified by flash column chromatography (0-40% ethyl acetate in cyclohexane) to give the desired product as a pale yellow solid (193 mg, 94%); ¹H NMR (400 MHz, CDCl3): δ 7.66 (s, 1 H), 7.03 (d, J = 2.4 Hz, 1 H), 6.90 (dd, J = 2.4, 8.5 Hz, 1 H), 6.52 (d, J = 8.5 Hz, 1 H), 4.77-4.73 (m, 1 H), 4.43 (s, 1 H), 4.02-4.01 (m, 6 H), 3.23 (dd, J = 7.0, 12.4 Hz, 1 H), 3.13 (dd, J = 3.1, 12.5 Hz, 1 H). b) 5-(7-Chloro-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3- dione To a solution of 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo[ b][1,4]thiazine (150 mg, 0.463 mmol) in acetonitrile (10 mL) was added sodium iodide (208 mg, 1.39 mmol) followed by chlorotrimethylsilane (151 mg, 1.39 mmol) at room temperature. The mixture was then heated and stirred at 60 °C for 2 hrs. The mixture was concentrated under reduced pressure to give a residue, which was purified using preparative HPLC to give the desired product as a off- white amorphous solid (91 mg, 66%); ¹H NMR (400 MHz, DMSO): δ 11.27-11.15 (m, 2 H), 6.98 (d, J = 2.5 Hz, 1 H), 6.91 (dd, J = 2.5, 8.6 Hz, 1 H), 6.64 (d, J = 8.7 Hz, 1 H), 6.58 (d, J = 2.3 Hz, 1 H), 6.12 (s, 1 H), 4.44-4.39 (m, 1 H), 3.23 (dd, J = 6.7, 12.8 Hz, 1 H), 3.02-2.97 (m, 1 H).; MS (ES+) m/z 296 (M+H)+ Racemic 5-(7-Chloro-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3-dione was separated by chiral SFC to yield the two enantiomers. 5-(7-Chloro-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3-dione (Isomer 1) (Example 238): off-white solid (14 mg, e.e. 100%, 10%), ¹H NMR (400 MHz, DMSO): δ 11.24-11.12 (m, 2 H), 6.98 (d, J = 2.4 Hz, 1 H), 6.91 (dd, J = 2.5, 8.7 Hz, 1 H), 6.64 (d, J = 8.7 Hz, 1 H), 6.58 (d, J = 2.3 Hz, 1 H), 6.11 (s, 1 H), 4.44-4.39 (m, 1 H), 3.23 (dd, J = 6.9, 12.7 Hz, 1 H), 3.00 (dd, J = 2.8, 12.8 Hz, 1 H). MS (ES+) m/z 294 (M+H)+. Chiral analysis (Method 2) at 4.25 min. 5-(7-Chloro-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3-dione (Isomer 2) (Example 239): off-white solid (11 mg, e.e.100%, 8%). ¹H NMR (400 MHz, DMSO): δ 11.20-11.12 (m, 2 H), 6.98 (d, J = 2.5 Hz, 1 H), 6.91 (dd, J = 2.5, 8.7 Hz, 1 H), 6.64 (d, J = 8.7 Hz, 1 H), 6.58 (d, J = 2.3 Hz, 1 H), 6.11 (s, 1 H), 4.44-4.39 (m, 1 H), 3.23 (dd, J = 6.8, 12.7 Hz, 1 H), 2.99 (dd, J = 2.8, 12.8 Hz, 1 H). MS (ES+) m/z 294 (M+H)+. Chiral analysis (Method 2) at 6.56 min. 5-(7-Chloro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione (Example 240) a) 7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-4-methyl-3,4-dihydro- 2H- benzo[b][1,4]thiazine To a solution o ]thiazine (50 mg, 0.154 mmol) in acetic acid (1 mL) was added formaldehyde (37% aqueous solution, 0.11 mL, 1.54 mmol) then stirred at room temperature for 5 minutes, followed by addition of sodium cyanoborohydride (47 mg, 0.741 mmol). The mixture was then heated and stirred at 20 °C for 16 hrs. The mixture was neutralised with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure to give the desired product as a colourless solid (49.4 mg, 95%), which was used directly in the next step without further purification. ¹H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 0.8 Hz, 1 H), 7.07- 7.02 (m, 2 H), 6.66 (d, J = 8.8 Hz, 1 H), 4.81 (dt, J = 0.7, 3.7 Hz, 1 H), 3.99 (s, 3 H), 3.98 (s, 3 H), 3.22-3.20 (d, J = 3.7 Hz, 2 H), 3.03 (s, 3 H). b) 5-(7-Chloro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione To a solution of 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-4-methyl-3,4-dihydro- 2H- benzo[b][1,4]thiazine (52 mg, 0.154 mmol) in acetonitrile (2.5 mL) was added sodium iodide (69 mg, 0.462 mmol) followed by chlorotrimethylsilane (50 mg, 0.462 mmol) at room temperature. The mixture was then heated and stirred at 60 °C for 90 min. The mixture was concentrated under reduced pressure to give a residue, which was purified using preparative HPLC to give the desired product as a light brown solid (3.5 mg, 7%); ¹H NMR (400 MHz, DMSO): δ 11.27 (s, 1 H), 11.07 (s, 1 H), 7.09-7.05 (m, 2 H), 6.75 (d, J = 10.0 Hz, 1 H), 5.65 (s, 1 H), 4.61-4.57 (m, 1 H), 3.24 (dd, J = 3.6, 13.6 Hz, 1 H), 3.06 (dd, J = 3.5, 13.6 Hz, 1 H), 2.96 (s, 3 H); MS (ES+) m/z 310 (M+H)+. 5-(7-Chloro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione (Example 241) a) 7-Chloro-3-(5,6-dimethoxyp dihydro-2H- benzo[b][1,4]thiazine To a mixture o g, . . ed 2,3- dimethoxy-5-(prop-1-en-2-yl)pyrazine (130 mg, 0.721 mmol) and 2-amino-5-chlorobenzenethiol (138 mg, 0.866 mmol) followed by potassium peroxodisulfate (195 mg, 0.721 mmol) at room temperature. The reaction was heated to 80 °C and stirring continued for a further 20 hrs. The reaction was quenched with saturated aqueous sodium bicarbonate (8 mL) and the mixture was further diluted with ethyl acetate (10 mL) and washed with 20 % aqueous sodium thiosulfate solution (10 mL). The layers were separated and the aqueous further extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure and the residue was purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to give the desired product as a viscous yellow oil (70 mg, 29%); ¹H NMR (400 MHz, CDCl3): δ 7.62 (s, 1 H), 6.95 (d, J = 2.4 Hz, 1 H), 6.90 (dd, J = 2.4, 8.5 Hz, 1 H), 6.54 (d, J = 8.5 Hz, 1 H), 4.35 (s, 1 H), 4.09 (d, J = 1.6 Hz, 1 H), 4.00 (s, 3 H), 3.98 (s, 3 H), 3.37 (d, J = 12.3 Hz, 1 H), 2.94 (d, J = 12.4 Hz, 1 H). b) 5-(7-Chloro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione To a solution of 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-3-methyl-3,4-dihydro- 2H- benzo[b][1,4]thiazine (62 mg, 0.184 mmol) in acetonitrile (4.0 mL) was added sodium iodide (83 mg, 0.551 mmol) followed by chlorotrimethylsilane (60 mg, 0.551 mmol) at room temperature. The mixture was then heated and stirred at 60 °C for 3 hrs. The mixture was concentrated under reduced pressure to give a residue, which was purified using preparative HPLC to give the desired product as a yellow amorphous solid (30 mg, 53%); ¹H NMR (400 MHz, DMSO): δ 11.16 (s, 1 H), 11.04 (d, J = 5.3 Hz, 1 H), 6.95-6.91 (m, 2 H), 6.70-6.64 (m, 2 H), 5.82 (d, J = 5.3 Hz, 1 H), 3.48 (d, J = 13.3 Hz, 1 H), 2.81 (d, J = 13.3 Hz, 1 H), 1.52-1.51 (m, 3 H); MS (ES+) m/z 310 (M+H)+. 5-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3- dione (Example 242) a) 3-(5,6-Dimethoxypyrazin-2-yl )-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]thiazine To a solution of 2-bromo-1-(5,6-dimethoxypyrazin-2-yl)ethan-1-one (200 mg, 0.766 mmol) and 5-fluoro-2-aminothiophenol (110 mg, 0.766 mmol) in N,N-dimethylformamide (2 mL) was added acetic acid (153 mg, 2.55 mmol) and the mixture stirred at room temperature for 5 min. After this time sodium cyanoborohydride (48 mg, 0.766 mmol) was added and stirring continued at room temperature for a further 2 hrs. The mixture was diluted with ethyl acetate (30 mL) and washed sequentially with 1 M aqueous HCl (20 mL), saturated aqueous sodium bicarbonate (30 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure and the residue was purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to give the desired product as a pale yellow solid (234 mg, 100%); ¹H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 0.7 Hz, 1 H), 6.79 (dd, J = 2.8, 8.8 Hz, 1 H), 6.68 (ddd, J = 8.4, 8.4, 2.9 Hz, 1 H), 6.54 (dd, J = 4.9, 8.8 Hz, 1 H), 4.71 (dd, J = 2.7, 7.1 Hz, 1 H), 4.02 (s, 3 H), 4.02 (s, 3 H), 3.26 (dd, J = 7.3, 12.4 Hz, 1 H), 3.14 (dd, J = 2.9, 12.4 Hz, 1 H), (NH peak not observed). b) 5-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-1,4-di hydropyrazine-2,3- dione To a solution of , , ,4]thiazine (100 mg, 0.325 mmol) in acetonitrile (5 mL) was added sodium iodide (146 mg, 0.976 mmol) followed by chlorotrimethylsilane (106 mg, 0.976 mmol) at room temperature. The mixture was then heated and stirred at 60 °C for 90 min. The mixture was concentrated under reduced pressure to give a residue, which was purified using preparative HPLC to give the desired product as an off-white amorphous solid (57.6 mg, 63%); ¹H NMR (400 MHz, DMSO): δ 11.27 (s, 1 H), 11.15 (d, J = 5.0 Hz, 1 H), 6.82 (dd, J = 3.0, 9.2 Hz, 1 H), 6.75 (dt, J = 2.9, 8.7 Hz, 1 H), 6.63 (dd, J = 5.1, 8.9 Hz, 1 H), 6.31 (d, J = 2.1 Hz, 1 H), 6.12 (d, J = 5.1 Hz, 1 H), 4.38-4.36 (m, 1 H), 3.24 (dd, J = 6.8, 12.7 Hz, 1 H), 3.01 (dd, J = 2.6, 12.7 Hz, 1 H).; MS (ES+) m/z 280 (M+H)+; 99.7%. 5-(7-Fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione (Example 243) a) 3-(5,6-Dimethoxypyrazin-2-yl)-7-fluoro-4-methyl-3,4-dihydro- 2H- benzo[b][1,4]thiazine To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-7-fluoro-3,4-dihydro-2H-benzo[ b][1,4]thiazine (130 mg, 0.423 mmol) in acetic acid (2.0 mL) was added formaldehyde (37% aqueous solution, 0.31 mL, 4.23 mmol) then stirred at room temperature for 5 minutes, followed by addition of sodium cyanoborohydride (128 mg, 2.03 mmol). The mixture was then heated and stirred at room temperature for 5 days. The mixture was neutralised with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 × 35 mL). The combined organic extracts were dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure to give the desired product as a light brown solid (110 mg, 81%), which was used directly in the next step without further purification; ¹H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 0.8 Hz, 1 H), 6.86- 6.78 (m, 2 H), 6.67 (dd, J = 4.7, 9.0 Hz, 1 H), 4.80-4.78 (m, 1 H), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.24- 3.22 (m, 2 H), 3.03-3.02 (m, 3 H). b) 5-(7-Fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione To a solutio n of 3-(5,6-dimethoxypyrazin-2-yl)-7-fluoro-4-methyl-3,4-dihydro- 2H- benzo[b][1,4]thiazine (110 mg, 0.342 mmol) in acetonitrile (5.0 mL) was added sodium iodide (154 mg, 1.03 mmol) followed by chlorotrimethylsilane (112 mg, 1.03 mmol) at room temperature. The mixture was then heated and stirred at 60 °C for 90 min. The mixture was concentrated under reduced pressure to give a residue, which was purified using preparative HPLC to give the desired product as an off-white amorphous solid (43 mg, 43%); ¹H NMR (400 MHz, DMSO): δ 11.27 (s, 1 H), 11.06 (d, J = 4.1 Hz, 1 H), 6.96-6.87 (m, 2 H), 6.74 (dd, J = 4.9, 9.0 Hz, 1 H), 5.66 (d, J = 4.9 Hz, 1 H), 4.55 (dd, J = 2.7, 3.6 Hz, 1 H), 3.24 (dd, J = 3.7, 13.5 Hz, 1 H), 3.07 (dd, J = 3.5, 13.5 Hz, 1 H), 2.94 (s, 3 H); MS (ES+) m/z 294 (M+H)+. Racemic 5-(7-Fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4-dihydropyrazine- 2,3-dione was resolved by chiral SFC to yield the two enantiomers. 5-(7-Fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione (Isomer 1) (Example 244): off-white solid (18 mg, e.e.100%, 18%), ¹H NMR (400 MHz, DMSO): δ 11.24 (s, 1 H), 11.05 (s, 1 H), 6.95-6.87 (m, 2 H), 6.76- 6.72 (m, 1 H), 5.67 (s, 1 H), 4.57-4.53 (m, 1 H), 3.28-3.21 (m, 1 H), 3.10-3.04 (m, 1 H), 2.94 (s, 3 H). Chiral analysis (Method 2) at 2.83 min. 5-(7-Fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4-dihydropyrazine-2,3- dione (Isomer 2) (Example 245): off-white solid (18 mg, e.e.97%, 18%), ¹H NMR (400 MHz, DMSO): δ 11.10-11.09 (m, 2 H), 6.95-6.87 (m, 2 H), 6.76-6.72 (m, 1 H), 5.66 (s, 1 H), 4.57-4.53 (m, 1 H), 3.28-3.21 (m, 1 H), 3.10-3.04 (m, 1 H), 2.94 (s, 3 H). Chiral analysis (Method 2) at 3.93 min. 5-(7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione (Example 246) a) 3-(5,6-Dimethoxypyrazin-2-yl )- -f uoro- -met y - , -dihydro-2H- benzo[b][1,4]thiazine To a mixture of sodium iodide (67 mg, 0.444 mmol) in acetonitrile (15.0 mL) was added 2,3- dimethoxy-5-(prop-1-en-2-yl)pyrazine (400 mg, 2.22 mmol) and 2-amino-5-fluorobenzenethiol (381 mg, 2.66 mmol) followed by potassium peroxodisulfate (600 mg, 2.22 mmol) at room temperature. The reaction was heated to 80 °C and stirring continued for a further 20 hrs. The reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and the mixture was further diluted with ethyl acetate (40 mL) and washed with 20 % aqueous sodium thiosulfate solution (40 mL). The layers were separated and the aqueous further extracted with ethyl acetate (2 × 40 mL). The combined organic extracts were dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure and the residue was purified by flash column chromatography (0-30% ethyl acetate in cyclohexane7:3) to give the desired product as a viscous brown oil (380 mg, 53%); ¹H NMR (400 MHz, CDCl3): δ 7.65-7.64 (m, 1 H), 6.72-6.64 (m, 2 H), 6.55 (dd, J = 4.6, 8.7 Hz, 1 H), 4.27 (s, 1 H), 4.00 (s, 3 H), 3.98 (s, 3 H), 3.39 (d, J = 12.3 Hz, 1 H), 2.96 (d, J = 12.3 Hz, 1 H), 1.63 (s, 3 H). b) 5-(7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione To a soluti ydro-2H- benzo[b][1,4]thiazine (200 mg, 0.622 mmol) in acetonitrile (10 mL) was added sodium iodide (280 mg, 1.87 mmol) followed by chlorotrimethylsilane (203 mg, 1.87 mmol) at room temperature. The mixture was then heated and stirred at 60 °C for 3 hrs. The mixture was concentrated under reduced pressure to give a residue, which was purified using preparative HPLC to give the desired product as a yellow amorphous solid (102 mg, 56%); ¹H NMR (400 MHz, DMSO): δ 11.15 (d, J = 1.9 Hz, 1 H), 11.03 (d, J = 5.5 Hz, 1 H), 6.80-6.73 (m, 2 H), 6.67 (dd, J = 5.1, 8.7 Hz, 1 H), 6.42 (s, 1 H), 5.85 (dd, J = 2.6, 5.6 Hz, 1 H), 3.48 (d, J = 13.4 Hz, 1 H), 2.82 (d, J = 13.3 Hz, 1 H), 1.50 (s, 3 H); MS (ES+) m/z 294 (M+H)+ Racemic 5-(7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione was resolved by chiral SFC to yield the two enantiomers. 5-(7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione (Isomer 1) (Example 247): off-white solid (39 mg, e.e.100%, 21%), ¹H NMR (400 MHz, DMSO): δ 10.96-10.96 (m, 2 H), 6.80-6.73 (m, 2 H), 6.67 (dd, J = 5.2, 8.6 Hz, 1 H), 6.42 (s, 1 H), 5.85 (s, 1 H), 3.47 (d, J = 13.3 Hz, 1 H), 2.82 (d, J = 13.3 Hz, 1 H), 1.50 (s, 3 H). Chiral analysis (Method 2) at 1.79 min. 5-(7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-y l)-1,4- dihydropyrazine-2,3-dione (Isomer 2) (Example 248): off-white solid (41 mg, e.e.99%, 22%), ¹H NMR (400 MHz, DMSO): δ 10.99 (s, 2 H), 6.80-6.73 (m, 2 H), 6.67 (dd, J = 5.1, 8.7 Hz, 1 H), 6.42 (s, 1 H), 5.85 (s, 1 H), 3.48 (d, J = 13.3 Hz, 1 H), 2.82 (d, J = 13.4 Hz, 1 H), 1.50 (s, 3 H). Chiral analysis (Method 2) at 2.65 min. 5-(7-Fluoro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]thiazin -3-yl)-1,4- dihydropyrazine-2,3-dione (Example 249) a) 3-(5,6-Dimethoxypyrazin-2-yl -3,4-dihydro-2H- benzo[b][1,4]thiazine To a solution of , y y y y , y H-benzo[b]- [1,4]thiazine (160 mg, 0.498 mmol) in acetic acid (2 mL) was added formaldehyde (37% aqueous solution, 0.37 mL, 4.98 mmol) then stirred at room temperature for 5 minutes, followed by addition of sodium cyanoborohydride (150 mg, 2.39 mmol). The mixture was then heated and stirred at room temperature for 3 days. The mixture was neutralised with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 × 35 mL). The combined organic extracts were dried with magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure to give the desired product as a beige solid (164 mg, 98%), which was used directly in the next step without further purification. ¹H NMR (400 MHz, CDCl3): δ 7.66 (s, 1 H), 6.90 (dd, J = 3.0, 8.4 Hz, 1 H), 6.83 (dt, J = 3.0, 8.5 Hz, 1 H), 6.69 (dd, J = 4.8, 9.0 Hz, 1 H), 4.01 (s, 3 H), 3.95 (s, 3 H), 3.15 (d, J = 13.1 Hz, 1 H), 2.87 (d, J = 13.1 Hz, 1 H), 2.81 (s, 3 H), 1.79 (s, 3 H). b) 5-(7-Fluoro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]thiazin -3-yl)-1,4- dihydropyrazine-2,3-dione To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-7-fluoro-3,4-dimethyl-3,4-dihy dro-2H- benzo[b][1,4]thiazine (164 mg, 0.489 mmol) in acetonitrile (8 mL) was added sodium iodide (220 mg, 1.47 mmol) followed by chlorotrimethylsilane (159 mg, 1.47 mmol) at room temperature. The mixture was then heated and stirred at 60 °C for 3.5 hrs. The mixture was concentrated under reduced pressure to give a residue, which was purified using preparative HPLC to give the desired product as an off white amorphous solid (20 mg, 13%). ¹H NMR (400 MHz, DMSO): δ 11.20 (s, 1 H), 10.87 (s, 1 H), 6.96-6.87 (m, 2 H), 6.78 (dd, J = 4.9, 9.2 Hz, 1 H), 6.08-6.06 (m, 1 H), 3.42 (d, J = 13.3 Hz, 1 H), 2.79 (d, J = 13.4 Hz, 1 H), 2.76 (s, 3 H), 1.58 (s, 3 H); MS (ES+) m/z 308 (M+H)+. 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-3,4-dihydro-2H- benzo[b][1,4]thiazine- 7-carbonitrile (Example 250) a) 7-Bromo-3-(5,6-dimethoxypy az n- -y - , - y o- H-benzo[b][1,4]thiazine To a solution of 2-bromo-1-(5,6-dimethoxypyrazin-2-yl)ethan-1-one (500 mg, 1.92 mmol) and 5-bromo-2-aminothiophenol (391 mg, 1.92 mmol) in N,N-dimethylformamide (6.0 mL) was added acetic acid (383 mg, 6.38 mmol) and the mixture stirred at room temperature for 5 min. After this time sodium cyanoborohydride (120 mg, 1.92 mmol) was added and stirring continued at room temperature for a further 2 hrs. The mixture was diluted with ethyl acetate (30 mL) and washed sequentially with 1 M aqueous HCl (20 mL), saturated aqueous sodium bicarbonate (30 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated under reduced pressure and the residue was purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to give the desired product as a gummy yellow solid (638 mg, 90%). ¹H NMR (400 MHz, CDCl3): δ 7.65 (s, 1 H), 7.16 (d, J = 2.3 Hz, 1 H), 7.03 (dd, J = 2.3, 8.5 Hz, 1 H), 6.47 (d, J = 8.5 Hz, 1 H), 4.75 (dd, J = 2.9, 6.8 Hz, 1 H), 4.44 (s, 1 H), 4.02-4.01 (m, 6 H), 3.25-3.10 (m, 2 H). b) 3-(5,6-Dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]th iazine-7-carbonitrile A solution of 7 ]thiazine (150 mg, 0.407 mmol) and copper(I) cyanide (96 mg, 0.815 mmol) in 1-methylpyrrolidin-2-one (3 mL) was stirred at 200 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered through Celite™ and washed with ethyl acetate (10 mL). The organic phase was washed with brine (3 × 10 mL), the combined aquous phase was extracted further with ethyl acetate (5 mL), the combined organic phases were dried over magnesium sulfate and the solvent removed under reduced pressure. The crude residue was concentrated onto silica and purified by flash column chromatography (0-100% ethyl acetate in cyclohexane) to yield the title compound as a pale brown solid (45 mg, 35%). ¹H NMR (400 MHz, CDCl3): δ 7.67 (s, 1 H), 7.38 (d, J = 1.9 Hz, 1 H), 7.26 (dd, J = 1.9, 8.4 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 4.98-4.95 (m, 1 H), 4.93-4.89 (m, 1 H), 4.06 (s, 3 H), 4.05 (s, 3 H), 3.28-3.15 (m, 2 H). c) 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-3,4-dihydro-2H- benzo[b][1,4]thiazine- 7-carbonitrile To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]th iazine-7- carbonitrile (80 mg, 0.254 mmol) and sodium iodide (191 mg, 1.27 mmol) in acetonitrile (3 mL) was added chlorotrimethylsilane (138 mg, 1.27 mmol) and stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with acetonitrile (5 mL), filtered through Celite™, washed with acetonitrile (10 mL) and solvent removed under reduced pressure. The crude residue was purified by preparative HPLC to yield the title compound as an off-white solid (2.7 mg, 4%). ¹H NMR (400 MHz, DMSO): δ 11.31 (s, 1 H), 11.19 (s, 1 H), 7.41-7.36 (m, 2 H), 7.29 (dd, J = 1.9, 8.5 Hz, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 6.12 (s, 1 H), 4.56-4.51 (m, 1 H), 3.22 (dd, J = 6.7, 13.0 Hz, 1 H), 3.01 (dd, J = 3.0, 12.9 Hz, 1 H). MS (ES+) m/z 287 (M+H) ⁺ . 3-(5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-3-methyl-3,4-di hydro-2H- benzo[b][1,4]thiazine-7-carbonitrile (Example 251) a) 7-bromo-3-(5,6-dimethox ,4-dihydro-2H- benzo[b][1,4]thiazine To a mixtu re o so um o e ( mg, . mmo ) n ace on r e ( . m ) was added 2,3- dimethoxy-5-(prop-1-en-2-yl)pyrazine (400 mg, 2.22 mmol) and 2-amino-5-bromobenzenethiol (544 mg, 2.66 mmol) followed by potassium peroxodisulfate (600 mg, 2.22 mmol) at room temperature. The reaction was heated to 80 °C and stirring continued for a further 20 hrs. The reaction was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (30 mL) and the mixture was further diluted with ethyl acetate (40 mL) and washed with 20 % aqueous sodium thiosulfate solution (40 mL). The layers were separated and the aqueous extracted with ethyl acetate (2 × 40 mL). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure and purified by flash column chromatography (0-40% ethyl acetate in cyclohexane) to yield the desired product as a gummy brown solid (411 mg, 48%). ¹H NMR (400 MHz, CDCl3): δ 7.62 (s, 1 H), 7.09 (d, J = 2.3 Hz, 1 H), 7.03 (dd, J = 2.3, 8.5 Hz, 1 H), 6.50 (d, J = 8.5 Hz, 1 H), 4.35 (s, 1 H), 4.00 (s, 3 H), 3.98 (s, 3 H), 3.37 (dd, J = 1.0, 12.4 Hz, 1 H), 2.94 (d, J = 12.3 Hz, 1 H), 1.64 (s, 3 H). b) 3-(5,6-Dimethoxypyrazin-2-yl)-3-methyl-3,4-dihydro-2H-benzo[ b][1,4]thiazine-7- carbonitrile A solution of 7-bromo-3-(5,6-dimethoxypyrazin-2-yl)-3-methyl-3,4-dihydro-2 H- benzo[b][1,4]thiazine (150 mg, 0.392 mmol) and copper(I) cyanide (92 mg, 0.785 mmol) in 1- methylpyrrolidin-2-one (3 mL) was stirred at 200 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered through Celite™ and washed with ethyl acetate (10 mL). The organic phase was washed with brine (3 × 10 mL), the combined aqueous phases were further extracted with ethyl acetate (5 mL), the combined organic phases were dried over magnesium sulfate and the solvent removed under reduced pressure. The crude residue was concentrated onto silica and purified by flash column chromatography (0-100% ethyl acetate in cyclohexane) to yield the title compound as a pale brown solid (35 mg, 27%). ¹H NMR (400 MHz, CDCl3): δ 7.58 (s, 1 H), 7.27 (d, J = 1.8 Hz, 1 H), 7.22 (dd, J = 1.9, 8.3 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 4.86 (s, 1 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 3.38 (dd, J = 1.0, 12.5 Hz, 1 H), 2.92 (d, J = 12.5 Hz, 1 H), 1.70 (s, 3 H). c) 3-(5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-3-methyl-3,4-di hydro-2H- benzo[b][1,4]thiazine-7-carbonitrile To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-3-methyl-3,4-dihydro-2H- benzo[b][1,4]thiazine-7-carbonitrile (66 mg, 0.201 mmol) and sodium iodide (151 mg, 1.00 mmol) in acetonitrile (3 mL) was added chlorotrimethylsilane (109 mg, 1.00 mmol) and stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with acetonitrile (5 mL), filtered through Celite™, washed with acetonitrile (10 mL) and solvent removed under reduced pressure. The crude residue was purified by preparative HPLC to yield the title compound as an off-white solid (17 mg, 28%). ¹H NMR (400 MHz, DMSO): δ 11.23 (s, 1 H), 11.05 (d, J = 4.1 Hz, 1 H), 7.41-7.37 (m, 2 H), 7.31 (dd, J = 1.9, 8.5 Hz, 1 H), 6.77 (d, J = 8.4 Hz, 1 H), 5.79 (d, J = 4.5 Hz, 1 H), 3.49 (d, J = 13.4 Hz, 1 H), 2.81 (d, J = 13.4 Hz, 1 H), 1.56 (s, 3 H). MS (ES+) m/z 301 (M+H) ⁺ . 5-(Thiochroman-3-yl)-1,4-dihydropyrazine-2,3-dione (Example 252) a) 3-(5,6-Dimethoxypyrazin-2-yl)t To a solution o , , . y THF (10 mL) under nitrogen cooled to -78 °C was added dropwise a solution of n-buthyllithium (2.5 M in hexanes, 1.2 mL, 3.0 mmol). The mixture was stirred at -78 °C for 45 min. A solution of thiochroman-3-one (500 mg, 3.0 mmol) in dry THF (10 mL) was added dropwise and the mixture was stirred at -78 °C for 45 min. Saturated ammonium chloride solution (10 mL) was added dropwise and the mixture was warmed to room temperature. The reaction was repeated on the same scale and the combined mixtures were extracted with ethyl acetate (200 mL). The organic layer was washed with water (2 x 20 mL) and brine (20 mL), passed through phase separation paper and concentrated under reduced pressure. The crude material was purified by flash column chromatography (5 – 20% ethyl acetate in cyclohexane) to yield the title compound as an orange gum (252 mg, 16%). ¹H NMR (400 MHz, CDCl3): δ 7.96 (s, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.16-7.09 (m, 1 H), 7.09-7.06 (m, 2 H), 4.04 (s, 3 H), 4.01 (s, 3 H), 3.58-3.48 (m, 2 H), 3.44 (s, 1 H), 3.02-2.93 (m, 2 H). b) 2,3-Dimethoxy-5-(2H-thiochromen-3-yl)pyrazine To a solution of 3-(5,6-dimethoxypyrazin-2-yl)thiochroman-3-ol (150 mg, 0.49 mmol) in dry dichloromethane (9 mL) under nitrogen cooled to 0 °C was added dropwise triethylamine (0.14 mL, 0.98 mmol) followed by mesyl chloride (0.57 mL, 0.74 mmol) dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred for 18 hrs. The mixture was re-cooled to 0 °C and triethylamine (0.07 mL, 0.49 mmol) and mesyl chloride (0.03 mL, 0.37 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 4 hrs. Water (10 mL) was added and the mixture was extracted with dichloromethane (60 mL). The organic layer was washed with 2 M hydrochloric acid (10 mL), passed through a phase separator and concentrated under reduced pressure. The crude material was purified by flash column chromatography (4 – 8% ethyl acetate in cyclohexane) to yield the title compound as a yellow viscous oil (94 mg, 67% ). ¹H NMR (400 MHz, CDCl3): δ 7.92 (s, 1 H), 7.30-7.27 (m, 2 H), 7.23-7.20 (m, 1 H), 7.15-7.12 (m, 2 H), 4.09 (s, 3 H), 4.05 (s, 3 H), 3.92 (d, J = 1.1 Hz, 2 H). c) 2,3-Dimethoxy-5-(thiochroman-3-yl)pyrazine To a solutio , y y py g, . 1 mmol) in ethyl acetate (10 mL) was added Pdhydroxide on carbon (36 mg) and the mixture was stirred under an atmosphere of hydrogen for 3 days. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (4 – 8% ethyl acetate in cyclohexane) to yield the title compound as a colourless viscous oil (38 mg, 42%). ¹H NMR (400 MHz, CDCl3): δ 7.55 (s, 1 H), 7.14 (d, J = 6.8 Hz, 1 H), 7.11-7.05 (m, 2 H), 7.02-6.98 (m, 1 H), 4.01 (s, 3 H), 4.01 (s, 3 H), 3.40-3.16 (m, 3 H), 3.09-2.98 (m, 2 H). d) 5-(Thiochroman-3-yl)-1,4-dihydropyrazine-2,3-dione To a solution of 2,3-dimethoxy-5-(thiochroman-3-yl)pyrazine (38 mg, 0.13 mmol) in dioxane (2 mL) was added dropwise 2 M hydrochloric acid (2 mL) and the mixture was heated at 110 °C in a sealed tube for 2.5 hrs. The mixture was cooled to room temperature and the resulting precipitate was filtered off, washed with water (10 mL) and dichloromethane (10 mL) and dried under reduced pressure to yield the title compound as an off-white solid (25 mg, 74%). ¹ H NMR (DMSO, 400 MHz) δ 11.33 (s, 1 H), 11.15 (s, 1 H), 7.14-7.07 (m, 3 H), 7.04-6.98 (m, 1 H), 6.12 (d, J = 3.6 Hz, 1 H), 3.25-3.17 (m, 1 H), 3.12-3.05 (m, 1 H), 3.00-2.90 (m, 3 H). MS (ESI+) m/z 261 (M+H)+. 5-(2,2-Difluorothiochroman-3-yl)-1,4-dihydropyrazine-2,3-dio ne (Example 253) a) 5-(2,2-Difluorovinyl)-2,3-dimethoxy To a solution , , . and triphenylphosphine (1.17 g, 4.5 mmol) in DMF (7.5 mL) at room temperature was added a solution of sodium chlorodifluoroacetate (544 mg, 3.6 mmol) in DMF (2.5 mL) and stirred at 110 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash column chromatography (5-60% dichloromethane in cyclohexane) to yield the title compound as a yellow solid (477 mg, 79%). ¹H NMR (400 MHz, CDCl3) δ 7.65 (s, 1 H), 5.31 (dd, J=3.4, 25.1 Hz, 1 H), 4.02 (s, 3 H), 4.01 (s, 3 H). b) 2-Mercaptobenzaldehyde To a solution of 2-bromobenzaldehyde (1.00 g, 5.4 mmol) and triisopropylsilanethiol (1.03 g, 5.4 mmol) in toluene (15 mL) was added lithium bis(trimethylsilyl)amide solution (1 M in toluene, 5.9 mL, 5.95 mmol) and stirred at room temperature for 10 min. [1,1’bis(diphenylphosphino)ferrocene]dichloroPd(II) complex with dichloromethane (441 mg, 0.54 mmol) was added and stirred at 110 °C for 45 min. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude was purified by flash column chromatography (0-50% dichloromethane in cyclohexane) to yield the title compound as an orange oil (250 mg, 34%). ¹H NMR (400 MHz, CDCl3) δ 10.06 (s, 1 H), 7.73 (dd, J=1.5, 7.7 Hz, 1 H), 7.42 - 7.37 (m, 1 H), 7.33 - 7.27 (m, 2 H), 5.53 (s, 1 H). c) 3-(5,6-Dimethoxypyrazin-2-yl)-2,2-difluorothiochroman-4-ol To a solutio uorovinyl)- 2,3-dimethoxypyrazine (366 mg, 1.8 mmol) in dry DMF (1.8 mL) under nitrogen was added 1,8- diazabicyclo[5.4.0]undec-7-ene (0.14 mL, 0.90 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (5 – 40% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (230 mg, 37%). The compound was obtained as mixture of diastereoisomers (ratio 6:4). ¹H NMR (400 MHz, CDCl3) δ 7.74 - 7.71 (m, 2 H), 7.68 (s, 1 H), 7.55 (dd, J=1.4, 7.5 Hz, 1 H), 7.31 - 7.25 (m, 3 H, partially obscured by chloroform), 7.24 - 7.16 (m, 2 H), 7.12 (dd, J=1.6, 7.5 Hz, 1 H), 5.53 - 5.48 (m, 1 H), 5.29 (dd, J=4.1, 9.9 Hz, 1 H), 4.41 (d, J=6.0 Hz, 1 H), 4.04 (s, 3 H), 4.02 (s, 3 H), 3.94 (s, 3 H), 3.93 - 3.86 (m, 1 H), 3.82 - 3.72 (m, 4 H), 2.79 (d, J=5.6 Hz, 1 H). d) 5-(2,2-Difluorothiochroman-3-yl)-2,3-dimethoxypyrazine To a suspension of 3-(5,6-dimethoxypyrazin-2-yl)-2,2-difluorothiochroman-4-ol (115 mg, 0.33 mmol) in ethanol (1.1 mL) was added triethylsilane (1.1 mL, 6.76 mmol) followed by Pd(II) chloride (60 mg, 0.33 mmol). The reaction mixture was heated at 65 °C for 3 hrs. More triethylsilane (1.1 mL, 6.76 mmol) and Pd(II) chloride (60 mg, 0.33 mmol) were added and the reaction mixture was heated at 65 °C for 18 hrs. More triethylsilane (1.1 mL, 6.76 mmol) and Pd(II) chloride (60 mg, 0.33 mmol) were added and the reaction mixture was heated at 65 °C for 2 hrs. The mixture was cooled to room temperature and filtered through Celite™. The filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 10% ethyl acetate in cyclohexane) to yield the title compound as a pale yellow oil (18 mg, 16%). ¹H NMR (400 MHz, CDCl3) δ 7.65 (s, 1 H), 7.21 - 7.15 (m, 2 H), 7.14 - 7.08 (m, 2 H), 4.01 (s, 3 H), 3.86 (s, 3 H), 3.78 - 3.57 (m, 2 H), 3.29 - 3.21 (m, 1 H). e) 5-(2,2-Difluorothiochroman-3-yl)-1,4-dihydropyrazine-2,3-dio ne To a suspens (18 mg, 0.04 mmol) and sodium iodide (19 mg, 0.12 mmol) in dry acetonitrile (10 mL) was added dropwise chlorotrimethylsilane (0.016 mL, 0.12 mmol) and the mixture was heated at 60 °C for 2 hrs. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by preparative HPLC to yield the title compound as a white solid (9 mg, 75%). ¹H NMR (400 MHz, DMSO): δ 11.34 (s, 2 H), 7.36-7.33 (m, 1 H), 7.31-7.20 (m, 3 H), 6.35 (s, 1 H), 3.63-3.48 (m, 2 H), 3.21-3.13 (m, 1 H). MS (ES+) m/z 297 (M+H)+. 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)thiochromane-7-c arbonitrile (Example 254) a) (4-Bromo-2-mercaptophenyl)methanol To a solution of 4-bromo-2-mercaptobenzoic acid (940 mg, 4.0 mmol) in THF (15 mL) at 0 °C was added dropwise a solution of lithium aluminium hydride (1 M in THF, 6.1 mL, 6.1 mmol) and stirred at 0 °C then warming to room temperature 1 hour. The reaction mixture was quenched with water (15 mL) and diluted with ethyl acetate (15 mL), the organic phase was separated. The aqueous phase was acidified to pH 2 with 2 M hydrogen chloride (10 mL) and extracted with ethyl acetate (15 mL), the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as a colourless oil (550 mg, 62%). ¹H NMR (400 MHz, CDCl3) δ 7.48 (d, J=2.0 Hz, 1 H), 7.31 (dd, J=2.0, 8.1 Hz, 1 H), 7.22 (d, J=8.1 Hz, 1 H), 4.68 (s, 2 H), 3.75 (s, 1 H), (OH peak not observed). b) 5-Bromo-2-((bromotriphenyl-l5-phosphaneyl)methyl)benzenethio l A solut , triphenylphosphine hydrobromide (783 mg, 2.3 mmol) in acetonitrile (15 mL) was stirred at 85 °C for 3 hrs. The reaction mixture was cooled to room temperature and left to stand for 18 hrs. The resulting precipitate was filtered to yield 5-bromo-2-((bromotriphenyl-l5- phosphaneyl)methyl)benzenethiol as a colourless solid (610 mg), which was taken crude onto the next step. To a solution of 2-bromo-1-(5,6-dimethoxypyrazin-2-yl)ethan-1-one (281 mg, 0.86 mmol) and potassium tert-butoxide (97 mg, 0.86 mmol) in THF (8 mL) at room temperature was added 5-bromo-2-((bromotriphenyl-l5-phosphaneyl)methyl)benzenethio l (610 mg, 1.1 mmol) and the mixture was stirred at room temperature for 30 min. The reaction mixture was recharged with potassium tert-butoxide (97 mg, 0.86 mmol) and stirred at 80 °C for 2 hrs. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (15 mL) and 1 M hydrogen chloride (10 mL). The organic phase was washed with brine (10 mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (88 mg, 28%). ¹H NMR (400 MHz, CDCl3) δ 7.89 (s, 1 H), 7.40 (d, J=1.9 Hz, 1 H), 7.23 - 7.20 (m, 2 H), 7.04 (d, J=8.0 Hz, 1 H), 4.07 (s, 3 H), 4.05 (s, 3 H), 3.90 (d, J=1.1 Hz, 2 H). c) 3-(5,6-Dimethoxypyrazin-2-yl)-2H-thiochromene-7-carbonitrile A solution of 5-(7-bromo-2H-thiochromen-3-yl)-2,3-dimethoxypyrazine (70 mg, 0.19 mmol), zinc cyanide (23 mg, 0.19 mmol) and tetrakis(triphenylphosphine)Pd(0) (22 mg, 0.02 mmol) in DMF (1 mL) in a 1 mL microwave vial was heated to 200 °C in a Biotage® Initiator microwave for 10 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and water (10 mL) and the phases were separated. The aqueous phase was washed with ethyl acetate (2 × 10 mL), the combined organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (12 mg, 20%). ¹H NMR (400 MHz, CDCl3) δ 7.95 (s, 1 H), 7.55 - 7.52 (m, 1 H), 7.37 (dd, J=1.6, 7.9 Hz, 1 H), 7.30 - 7.27 (m, 1 H), 7.26 (d, J=7.9 Hz, 1 H, partially obscured by CDCl3), 4.09 (s, 3 H), 4.07 (s, 3 H), 3.95 (d, J=1.3 Hz, 2 H). d) 3-(5,6-Dimethoxypyrazin-2-yl)thiochromane-7-carbonitrile To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-2H-thiochromene-7-carbonitrile (20 mg, 0.06 mmol) in ethanol (10 mL) was added 10% Pdhydroxide on carbon (9 mg, 0.006 mmol), placed under a hydrogen atmosphere at atmospheric pressure and stirred at room temperature for 18 hrs. The reaction mixture was purged with nitrogen, recharged with 10% Pdhydroxide on carbon (9 mg, 0.006 mmol), placed under a hydrogen atmosphere at atmospheric pressure and stirred at room temperature for another night. The reaction mixture was purged with nitrogen, filtered over Celite® and washed with methanol (10 mL) and ethyl acetate (10 mL) and concentrated under reduced pressure to yield the title compound as a colourless solid (20 mg, 95%). ¹H NMR (400 MHz, CDCl3): δ 7.54 (s, 1 H), 7.43-7.41 (m, 1 H), 7.29-7.24 (m, 1 H), 7.14 (d, J = 7.9 Hz, 1 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 3.42-3.19 (m, 3 H), 3.12-3.03 (m, 2 H). e) 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)thiochromane-7-c arbonitrile A solution of sodium iodide (29 mg, 0.19 mmol) and chlorotrimethylsilane (21 mg, 0.19 mmol) in acetonitrile (1 mL) was stirred at room temperature for 10 min. A solution of 3-(5,6- dimethoxypyrazin-2-yl)thiochromane-7-carbonitrile (20 mg, 0.06 mmol) in acetonitrile (1 mL) was added and the reaction mixture stirred at 85 °C for 45 min. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified by preparative HPLC to yield the title compound as an off-white solid (5 mg, 28%). ¹H NMR (400 MHz, DMSO-d6 ): δ 11.35 (s, 1 H), 11.16-11.16 (m, 1 H), 7.64 (d, J = 1.6 Hz, 1 H), 7.46 (dd, J = 1.8, 7.9 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 6.11 (s, 1 H), 3.26 (dd, J = 10.2, 12.2 Hz, 1 H), 3.15 (dd, J = 2.3, 12.4 Hz, 1 H), 3.08-3.03 (m, 2 H), 2.96-2.89 (m, 1 H). MS (ES+) m/z 286.1 (M+H)+. 5-(7-Chlorothiochroman-3-yl)-1,4-dihydropyrazine-2,3-dione (Example 255) a) Methyl 4-chloro-2-hydroxybenzoate To a solution of 4-chloro-2-hydroxybenzoic acid (5.00 g, 29.0 mmol) in methanol (150 mL) was added dropwise thionyl chloride (14.2 g, 119 mmol) at room temperature. The reaction mixture was heated to 75 °C and stirred for 18 hrs. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography (0-100% ethyl acetate in cyclohexane) to yield the title compound as a pale oil (4.5 g, 83%). ¹H NMR (400 MHz, CDCl3): δ 10.85 (s, 1 H), 7.75 (d, J = 8.6 Hz, 1 H), 7.00 (d, J = 2.0 Hz, 1 H), 6.86 (dd, J = 2.0, 8.6 Hz, 1 H), 3.94 (s, 3 H). b) Methyl 4-chloro-2-((dimethylcarbamothioyl)oxy)benzoate To a solution of methyl 4-chloro-2-hydroxybenzoate (3.00 g, 17.4 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (5.29 g, 34.8 mmol) in DMF (20 mL) was added dimethylthiocarbamoyl chloride (3.22 g, 26.1 mmol) and heated to 60 °C overnight. The reaction was extracted into ethyl acetate (40 mL) and water (100 mL), the aqueous phase was washed with ethyl acetate (2 × 40 mL), the combined organics were dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0-100% ethyl acetate in cyclohexane) to yield the title compound as a white solid (3.88 g, 82%). ¹H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.6 Hz, 1 H), 7.29 (dd, J = 2.0, 8.5 Hz, 1 H), 7.15 (d, J = 2.0 Hz, 1 H), 3.84 (s, 3 H), 3.46 (s, 3 H), 3.39 (s, 3 H). c) Methyl 4-chloro-2-((dimethylcarbamoyl)thio)benzoate Methyl 4-chloro-2- e y ca a o oy o y e oa e . g, . mmol) was stirred at 190 °C for 5 hrs. The reaction mixture was cooled to room temperature, concentrated and purified by flash column chromatography (0-80% ethyl acetate in cyclohexane) to yield the title compound as a pale yellow oil (3.0 g, 78%). ¹H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.3 Hz, 1 H), 7.63 (d, J = 2.0 Hz, 1 H), 7.39 (dd, J = 2.1, 8.5 Hz, 1 H), 3.88 (s, 3 H), 3.13 (s, 3 H), 3.01 (s, 3 H). d) Methyl 4-chloro-2-mercaptobenzoate To a solution of methyl 4-chloro-2-((dimethylcarbamoyl)thio)benzoate (3.00 g, 11.0 mmol) in methanol (90 mL) was added sodium methoxide (1.78 g, 32.9 mmol) and stirred at 65 °C for 1 hour. The reaction mixture was extracted into ethyl acetate (50 mL) and water (50 mL), the aqueous phase was acidified to pH 2 with hydrochloric acid solution (1 M in water) (70 mL), combined aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined organic phase was dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as a waxy off-white solid (2.22 g, 95%). ¹H NMR (400 MHz, CDCl3): δ, 7.97-7.93 (m, 1 H), 7.33-7.31 (m, 1 H), 7.14-7.10 (m, 1 H), 4.88-4.87 (m, 1 H), 3.92 (s, 3 H). e) (4-Chloro-2-mercaptophenyl)methanol To a solution of me mol) in THF (40 mL) was added lithium aluminium hydride solution (1 M in THF) (20.6 mL, 20.6 mmol) dropwise at 0 °C and stirred for 30 min. The reaction mixture was quenched with water (20 mL), acidified to pH 2 with hydrochloric acid solution (1 M in water) (50 mL), extracted into ethyl acetate (2 × 40 mL), dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as a pale yellow oil (1.91 g, 95%). ¹H NMR (400 MHz, CDCl3) d 7.32 (d, J=2.0 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.14 (dd, J=2.0, 8.3 Hz, 1H), 4.68 (s, 2H), 3.75 (s, 1H), (OH peak not observed). f) 5-(7-Chloro-2H-thiochromen-3-yl)-2,3-dimethoxypyrazine A solution of (4 -chloro-2-mercaptophenyl)methanol (200 mg, 1.15 mmol) and triphenylphosphine hydrobromide (393 mg, 1.15 mmol) in acetonitrile (7 mL) was stirred at 85 °C for 18 hrs. The reaction mixture was concentrated under reduced pressure to yield 2- ((bromotriphenyl-l5-phosphaneyl)methyl)-5-chlorobenzenethiol as a cream solid. The crude residue was used for further chemistry with no further purification or analysis. A solution of 2- ((bromotriphenyl-l5-phosphaneyl)methyl)-5-chlorobenzenethiol (490 mg, 0.98 mmol) and potassium tert-butoxide (86 mg, 0.76 mmol) in THF (10 mL) was stirred at room temperature for 10 min. 2-Bromo-1-(5,6-dimethoxypyrazin-2-yl)ethan-1-one (200 mg, 0.76 mmol) was then added and the reaction mixture stirred at 80 °C for 30 min. The reaction mixture was recharged with potassium tert-butoxide (86 mg, 0.76 mmol) and stirred at 80 °C for a further 90 min. The reaction mixture was extracted into ethyl acetate (20 mL) and water (10 mL), the aqueous phase was acidified to pH 2 with hydrochloric acid solution (1 M in water), (20 mL), washed with ethyl acetate (2 × 15 mL), combined organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (193 mg, 78%). ¹H NMR (400 MHz, CDCl3): δ 7.90 (s, 1 H), 7.27 (d, J = 2.0 Hz, 1 H), 7.23 (s, 1 H), 7.14-7.11 (m, 1 H), 7.09-7.06 (m, 1 H), 4.08 (s, 3 H), 4.05 (s, 3 H), 3.91 (d, J = 1.3 Hz, 2 H). g) 5-(7-Chlorothiochroman-3-yl)-2,3-dimethoxypyrazine To a , , 0.31 mmol) in methanol (20 mL) was added 10% Pdhydroxide on Carbon (40 mg) and stirred under an atmosphere of hydrogen at atmospheric pressure at room temperature for 18 hrs. The reaction mixture was purged with nitrogen, filtered over Celite™ washing with ethyl acetate (2 × 10 mL) methanol (2 × 10 mL) and concentrated under reduced pressure. The crude residue was taken up in methanol (20 mL), charged with 10% Pdhydroxide on carbon (40 mg) and stirred under an atmosphere of hydrogen at atmospheric pressure at room temperature for 18 hrs. The reaction mixture was purged with nitrogen, filtered over Celite™ washing with ethyl acetate (2 × 10 mL) methanol (2 × 10 mL) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as a pale oil (57 mg, 44%). ¹H NMR (400 MHz, CDCl3): δ 7.54 (s, 1 H), 7.14-7.13 (m, 1 H), 6.98-6.96 (m, 2 H), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.38-3.32 (m, 1 H), 3.29-3.21 (m, 1 H), 3.18-3.10 (m, 1 H), 3.08-3.03 (m, 1 H), 2.99-2.94 (m, 1 H). h) 5-(7-Chlorothiochroman-3-yl)-1,4-dihydropyrazine-2,3-dione A solution of 5-(7-chlorothiochroman-3-yl)-2,3-dimethoxypyrazine (57 mg, 0.18 mmol), sodium iodide (132 mg, 0.88 mmol) and chlorotrimethylsilane (96 mg, 0.88 mmol) in acetonitrile was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to yield the title compound as an orange solid (17 mg, 33%). ¹H NMR (400 MHz, DMSO): δ 11.36 (s, 1 H), 11.17 (d, J = 5.3 Hz, 1 H), 7.23 (d, J = 2.3 Hz, 1 H), 7.18 (d, J = 8.1 Hz, 1 H), 7.11 (dd, J = 2.1, 8.2 Hz, 1 H), 6.15 (dd, J = 2.3, 5.6 Hz, 1 H), 3.29-3.23 (m, 1 H), 3.18-3.13 (m, 1 H), 3.02-2.92 (m, 3 H). MS (ES+) m/z 295 (M+H)+. 5-(7-(Difluoromethyl)thiochroman-3-yl)-1,4-dihydropyrazine-2 ,3-dione (Example 256) a) 5-(7-(Difluoromethyl)-2H-thiochr , yrazine To a so ut on o ( , - s( , - sopropy p eny ) m azo n- - ylidene)(difluoromethyl)silver (531 mg, 0.966 mmol), (2-dicyclohexylphosphino-2′,4′,6′- triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl) ]Pd(II) methanesulfonate (57 mg, 0.067 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (32 mg, 0.067 mmol) in toluene (5 mL) was added 5-(7-chloro-2H-thiochromen-3-yl)-2,3-dimethoxypyrazine (310 mg, 0.96 mmol) and stirred at 100 °C for 12 hrs. The reaction mixture was cooled to room temperature, filtered over Celite™, washed with ethyl acetate (2 × 10 mL) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0- 50% ethyl acetate in cyclohexane) to yield the title compound as a yellow oil (92 mg, 28%). ¹H NMR (400 MHz, CDCl3): δ, 7.93 (s, 1 H), 7.42 (s, 1 H), 7.31-7.27 (m, 3 H), 6.58 (t, J = 56.4 Hz, 1 H), 4.09 (s, 3 H), 4.06 (s, 3 H), 3.94 (d, J = 0.6 Hz, 2 H). b) 5-(7-(Difluoromethyl)thiochroman-3-yl)-2,3-dimethoxypyrazine To a solution of 5-(7-(difluoromethyl)-2H-thiochromen-3-yl)-2,3-dimethoxypyra zine (90 mg, 0.26 mmol) in methanol (10 mL) and ethyl acetate (5 mL) was added 10% Pdhydroxide on carbon (40 mg) and stirred under an atmosphere of hydrogen at atmospheric pressure at room temperature for 18 hrs. The reaction mixture was purged with nitrogen, filtered over Celite™ washing with ethyl acetate (2 × 10 mL) methanol (2 × 10 mL) and concentrated under reduced pressure to yield the title compound as an orange oil (15 mg, 16%). ¹H NMR (400 MHz, CDCl3): δ 7.55 (s, 1 H), 7.31-7.27 (m, 2 H), 7.14 (s, 1 H), 6.73-6.41 (m, 1 H), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.42-3.18 (m, 3 H), 3.11-3.01 (m, 2 H). c) 5-(7-(Difluoromethyl)thiochroman-3-yl)-1,4-dihydropyrazine-2 ,3-dione To a so u o o - - uo o e y oc o a - -y - , - e o ypy a e mg, 0.044 mmol) and sodium iodide (33 mg, 0.22 mmol) in acetonitrile (1 mL) was added chlorotrimethylsilane (24 mg, 0.22 mmol) and stirred at 60 °C for 30 min. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to yield the title compound as a white solid (3 mg, 21%). ¹H NMR (400 MHz, DMSO): δ 11.38 (s, 1 H), 11.17 (d, J = 5.1 Hz, 1 H), 7.34-7.23 (m, 3 H), 6.98 (t, J = 56.2 Hz, 1 H), 6.16-6.14 (m, 1 H), 3.33-3.26 (m, 1 H), 3.18 (dd, J = 2.5, 12.4 Hz, 1 H), 3.06 (d, J = 6.3 Hz, 2 H), 3.01-2.95 (m, 1 H). MS (ES-) m/z 309 (M-H)-. 5-(7-(Trifluoromethyl)thiochroman-3-yl)-1,4-dihydropyrazine- 2,3-dione (Example 257) a To a solution of 2-fluoro-4-(trifluoromethyl)benzonitrile (1.00 g, 5.29 mmol) and triisopropylsilanethiol (1.11 g, 5.82 mmol) in DMF (50 mL) was added potassium carbonate (1.10 g, 7.93 mmol) and stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, poured into 0.5 M hydrochloric acid (100 mL) and extracted with ethyl acetate (3 × 30 mL), the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as an off-white oil (1.07 g, 95%). ¹H NMR (400 MHz, CDCl3): δ 8.02 (s, 1 H), 7.74 (d, J = 8.3 Hz, 1 H), 7.48 (d, J = 8.8 Hz, 1 H), (SH peak not observed). b) 2-Mercapto-4-(trifluoromethyl)benzoic acid A solution of 2- p - - y . g, . ol) in 5 M sodium hydroxide (16 mL) was stirred at 80 °C for 18 hrs. The reaction mixture was cooled to room temperature, acidified to pH 2 with 2 M hydrochloric acid solution (60 mL), extracted with ethyl acetate (3 × 30 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0-10% methanol in dichloromethane) to yield the title compound as a yellow solid (752 mg, 64%). ¹H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 8.2 Hz, 1 H), 7.60 (s, 1 H), 7.45 (d, J = 8.3 Hz, 1 H), 4.85-4.78 (m, 1 H), (COOH peak not observed). c) (2-Mercapto-4-(trifluoromethyl)phenyl)methanol To a solution of 2-mercapto-4-(trifluoromethyl)benzoic acid (750 mg, 3.38 mmol) in THF (10 mL) at 0 °C was added lithium aluminium hydride solution (1 M in THF), (6.8 mL, 6.75 mmol) dropwise and stirred at 0 °C for 1 hour. The reaction mixture was quenched by addition of hydrochloric acid (2 M in water) (20 mL), extracted into ethyl acetate (3 × 30 mL), dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a yellow oil (643 mg, 91%). ¹H NMR (400 MHz, CDCl3): δ 7.58 (s, 1 H), 7.52 (d, J = 8.1 Hz, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 4.78 (s, 2 H), 3.77 (s, 1 H), 1.93-1.88 (m, 1 H). d) 2,3-Dimethoxy-5-(7-(trifluoromethyl)-2H-thiochromen-3-yl)pyr azine A soluti ol) and triphenylphosphine hydrobromide (577 mg, 1.68 mmol) in acetonitrile (9 mL) was stirred at 80 °C for 28 hrs. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to yield 2-((bromotriphenyl-l5-phosphaneyl)methyl)-5- (trifluoromethyl)benzenethiol as an off-white solid. The crude residue was used directly without further purification or analysis. A solution of 2-((bromotriphenyl-l5-phosphaneyl)methyl)-5- (trifluoromethyl)benzenethiol (897 mg, 1.68 mmol) and potassium tert-butoxide (188 mg, 1.68 mmol) in THF (7 mL) was stirred at room temperature for 20 min. 2-Bromo-1-(5,6- dimethoxypyrazin-2-yl)ethan-1-one (338 mg, 1.29 mmol) was then added and the reaction mixture was stirred at 80 °C for 30 min. The reaction mixture was recharged with potassium tert-butoxide (188 mg, 1.68 mmol) and stirred at 80 °C for a further 3 hrs. The reaction mixture was cooled to room temperature, acidified to pH 2 with1 M hydrochloric acid (6 mL), extracted into ethyl acetate (3 × 5 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0-10% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (236 mg, 52%). ¹H NMR (400 MHz, CDCl3): δ 7.94 (s, 1 H), 7.52 (s, 1 H), 7.37-7.33 (m, 1 H), 7.31-7.26 (m, 2 H), 4.09 (s, 3 H), 4.06 (s, 3 H), 3.96-3.95 (m, 2 H). e) 2,3-Dimethoxy-5-(7-(trifluoromethyl)thiochroman-3-yl)pyrazin e To a solution of 2,3-dimethoxy-5-(7-(trifluoromethyl)-2H-thiochromen-3-yl)pyr azine (234 mg, 0.66 mmol) in methanol (7 mL) and ethyl acetate (7 mL) was added 20% Pdhydroxide on carbon (234 mg, 0.33 mmol) and stirred under an atmosphere of hydrogen at atmospheric pressure at room temperature for 18 hrs. The reaction mixture was purged with nitrogen, filtered over Celite™ washing with ethyl acetate (2 × 10 mL) and methanol (2 × 10 mL) and concentrated under reduced pressure. The crude residue was dissolved in methanol (7 mL) and ethyl acetate (7 mL), 20% Pdhydroxide on carbon (234 mg, 0.33 mmol) was added and the reaction mixture was stirred under an atmosphere of hydrogen at atmospheric pressure at room temperature for 18 hrs. The reaction mixture was purged with nitrogen, filtered over Celite™ washing with ethyl acetate (2 × 10 mL) and methanol (2 × 10 mL) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (205 mg, 87%). ¹H NMR (400 MHz, CDCl3): δ 7.55 (s, 1 H), 7.39 (s, 1 H), 7.25-7.21 (m, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.42-3.19 (m, 3 H), 3.12-3.02 (m, 2 H). f) 5-(7-(Trifluoromethyl)thiochroman-3-yl)-1,4-dihydropyrazine- 2,3-dione To a so ut on o ,3-dmet oxy-5-(7-(tr uoromet y )t oc roman-3-y )pyraz ne ( 00 mg, 0.56 mmol) and sodium iodide (252 mg, 1.68 mmol) in acetonitrile (6 mL) was added chlorotrimethylsilane (183 mg, 0.56 mmol) at room temperature and subsequently stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified by preparative HPLC to yield the title compound as a white solid (22 mg, 12%). ¹H NMR (400 MHz, DMSO-d6): δ 11.36-11.34 (m, 1 H), 11.17-11.13 (m, 1 H), 7.46 (s, 1 H), 7.35-7.35 (m, 2 H), 6.12 (d, J = 3.9 Hz, 1 H), 3.31-3.23 (m, 1 H), 3.19-2.92 (m, 4 H). MS (ES+) m/z 329.1 (M+H)+. 5-(7-(Trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)-1,4- dihydropyrazine-2,3-dione (Example 258) a) 2-Bromo-1-(5,6-dimethoxypyrazin-2-yl)ethan-1-one To a solution of tributyl(1- ethoxyvinyl)tin (15.1 g, 41.9 mmol) in 1,4-dioxane (100 mL) at room temperature was added bis(triphenylphosphine)Pd(II) dichloride (577 mg, 0.822 mmol) and stirred at 100 °C for 90 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL) and saturated potassium fluoride solution (80 mL) and stirred at room temperature for 90 min. The resulting mixture was filtered through Celite™, washing with ethyl acetate (50 mL), the phases were separated, and the organic phase washed with sodium hydrogen carbonate solution (50 mL) and the combined aqueous phases were further extracted with ethyl acetate (50 mL). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to yield a brown oil. The crude residue was dissolved in tetrahydrofuran (60 mL) and water (15 mL) and colled to 0 °C. N-bromosuccinimide (7.01 g, 39.4 mmol) was added and the mixture stirred at 0 °C warming to room temperature for 90 min. The reaction mixture was extracted with ethyl acetate (80 mL) and washed with sodium hydrogen carbonate solution (80 mL), the aqueous phase was further extracted with ethyl acetate (2 × 30 mL), the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was concentrated onto silica and purified by flash column chromatography (5-30% ethyl acetate in cyclohexane) to yield the title compound as a white solid (7.66 g, 74%). ¹H NMR (400 MHz, CDCl3): δ 8.48 (s, 1 H), 4.64 (s, 2 H), 4.12 (s, 3 H), 4.10 (s, 3 H). b) 3-(5,6-Dimethoxypyrazin-2-yl)-7-(trifluoromethyl)-2H-benzo[b ][1,4]oxazine To a solution of 2-amino-5-(trifluoromethyl)phenol (102 mg, 0.575 mmol) and 2-bromo- 1-(5,6-dimethoxypyrazin-2-yl)ethan-1-one (150 mg, 0.575 mmol) in acetonitrile (5 mL) was added cesium carbonate (187 mg, 0.575 mmol) and stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, concentrated onto silica and purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (140 mg, 72%). ¹H NMR (400 MHz, CDCl3): δ 8.70 (s, 1 H), 7.48 (d, J = 8.3 Hz, 1 H), 7.28-7.25 (m, 1 H), 7.16 (d, J = 1.5 Hz, 1 H), 5.24 (s, 2 H), 4.11 (s, 3 H), 4.07 (s, 3 H). c) 3-(5,6-Dimethoxypyrazin-2-yl)-7-(trifluoromethyl)-3,4-dihydr o-2H- benzo[b][1,4]oxazine To a , benzo[b][1,4]oxazine (130mg, 0.383 mmol) in ethanol (1.0 mL) and water (0.3 mL) at room temperature was added sodium borohydride (29 mg, 0.766 mmol). The reaction mixture was heated to 90 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and water (10 mL) and extracted twice with ethyl acetate (2 × 10 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the title compound as an off-white solid (83 mg, 63%). ¹H NMR (400 MHz, CDCl3): δ 7.66 (s, 1 H), 7.09-7.06 (m, 2 H), 6.75-6.71 (m, 1 H), 4.59-4.56 (m, 1 H), 4.54-4.49 (m, 1 H), 4.41 (dd, J = 2.8, 10.6 Hz, 1 H), 4.26 (dd, J = 6.4, 10.5 Hz, 1 H), 4.01 (s, 3 H), 4.01 (s, 3 H). d) 5-(7-(Trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3- yl)-1,4- dihydropyrazine-2,3-dione To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-7-(trifluoromethyl)-3,4-dihydr o-2H- benzo[b][1,4]oxazine (32 mg, 0.0938 mmol) and sodium iodide (70 mg, 0.469 mmol) in acetonitrile (2 mL) at room temperature was added chlorotrimethylsilane (51 mg, 0.469 mmol) and stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC to yield the title compound as a white solid (17 mg, 59%). ¹H NMR (400 MHz, DMSO): δ 11.35-11.16 (m, 2 H), 7.08 (dd, J = 1.5, 8.4 Hz, 1 H), 6.98 (d, J = 2.0 Hz, 1 H), 6.95 (d, J = 1.1 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H), 6.11 (s, 1 H), 4.31-4.26 (m, 1 H), 4.20 (d, J = 4.3 Hz, 2 H). MS (ESI+) m/z 314 (M+H)+. 5-(4-Methyl-7-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 259) a) 3-(5,6-Dimethoxypyrazin-2-yl)-4-m 3,4-dihydro-2H- benzo[b][1,4]oxazine A solu on o -( , - me oxypyraz n- -y )- -( r uorome y )- , - y ro- - benzo[b][1,4]oxazine (50 mg, 0.147 mmol), formaldehyde solution (37% in water, 0.087 mL, 1.17 mmol) and sodium cyanoborohydride (55 mg, 0.879 mmol) in methanol (1.7 mL), water (0.2 mL) and acetic acid (0.04 mL) was stirred at room temperature for 1 hour. The reaction mixture was recharged with formaldehyde solution (37% in water), (0.044 mL, 0.585 mmol), sodium cyanoborohydride (28 mg, 0.440 mmol) and acetic acid (0.04 mL) and stirred at room temperature for a further 18 hrs. The reaction mixture was extracted into ethyl acetate (10 mL) and sodium hydrogen carbonate solution (10 mL), the aqueous phase was extracted further with ethyl acetate (2 × 10 mL), the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as an off-white solid (80 mg, >95%). ¹¹H NMR (400 MHz, CDCl3): δ 7.37 (s, 1 H), 7.16 (dd, J = 1.3, 8.6 Hz, 1 H), 7.00 (d, J = 1.8 Hz, 1 H), 6.71 (d, J = 8.3 Hz, 1 H), 4.50 (dd, J = 2.9, 10.6 Hz, 1 H), 4.45-4.42 (m, 1 H), 4.29 (dd, J = 2.8, 10.6 Hz, 1 H), 3.98 (s, 3 H), 3.94 (s, 3 H), 3.02 (s, 3 H). b) 5-(4-Methyl-7-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-3-yl)-1,4- dihydropyrazine-2,3-dione To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-4-methyl-7-(trifluoromethyl)-3 ,4- dihydro-2H-benzo[b][1,4]oxazine (52 mg, 0.147 mmol) and sodium iodide (110 mg, 0.735 mmol) in acetonitrile (2 mL) at room temperature was added chlorotrimethylsilane (80 mg, 0.735 mmol) and stirred at 60 °C for 90 min. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC to yield the title compound as a white solid (25 mg, 52%). ¹H NMR (400 MHz, DMSO): δ 11.35 (s, 1 H), 11.05 (s, 1 H), 7.21- 7.18 (m, 1 H), 7.00 (d, J = 1.9 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 5.75 (s, 1 H), 4.40 (dd, J = 3.5, 11.2 Hz, 1 H), 4.32-4.29 (m, 1 H), 4.12 (dd, J = 2.8, 11.2 Hz, 1 H), 2.97 (s, 3 H). MS (ESI+) m/z 328 (M+H)+. 5-(7-Chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1,4-dih ydropyrazine-2,3- dione (Example 260) a) 7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-2H-benzo[b][1,4]oxazi ne To a solution of 2-amino-5-chlorophenol (110 mg, 0.766 mmol) and 2-bromo-1-(5,6- dimethoxypyrazin-2-yl)ethan-1-one (200 mg, 0.766 mg) in acetonitrile (3 mL) was added cesium carbonate (250 mg, 0.766 mmol) and stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, concentrated onto silica gel and purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as a pink solid (117 mg, 43%). ¹H NMR (400 MHz, CDCl3): δ 8.65 (s, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 6.98 (dd, J = 2.1, 8.2 Hz, 1 H), 6.92 (d, J = 2.3 Hz, 1 H), 5.18 (s, 2 H), 4.10 (s, 3 H), 4.06 (s, 3 H). b) 7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo[ b][1,4]oxazine To a zine (117 mg, 0.383 mmol) in ethanol (4 mL) and water (0.3 mL) at room temperature was added sodium borohydride (29 mg, 0.766 mmol) and stirred at 90 °C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous phase was extracted further with ethyl acetate (2 × 10 mL), the combined organics were dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as a yellow solid (89 mg, 75%). ¹H NMR (400 MHz, CDCl3): δ 7.67-7.67 (m, 1 H), 6.83 (d, J = 2.3 Hz, 1 H), 6.78 (dd, J = 2.3, 8.3 Hz, 1 H), 6.64 (d, J = 8.6 Hz, 1 H), 4.50 (dd, J = 2.7, 6.7 Hz, 1 H), 4.38 (dd, J = 2.8, 10.6 Hz, 1 H), 4.23-4.17 (m, 2 H), 4.01 (s, 3 H), 4.01 (s, 3 H). c) 5-(7-Chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1,4-dih ydropyrazine-2,3-dione To a solution of 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazine (40 mg, 0.130 mmol) and sodium iodide (97 mg, 0.650 mmol) in acetonitrile (2 mL) was added chlorotrimethylsilane (71 mg, 0.650 mmol) and stirred at 60 °C for 45 min. The reaction mixture was concentrated under reduced pressure and the crude residue purified by preparative HPLC to yield the title compound as a white solid (27 mg, 75%). ¹H NMR (400 MHz, DMSO) d 11.34 (s, 1H), 11.22 (s, 1H), 6.83 - 6.80 (m, 2H), 6.73 - 6.70 (m, 1H), 6.41 (s, 1H), 6.15 (s, 1H), 4.24 - 4.16 (m, 3H). MS (ESI+) m/z 280 (M+H)+. Racemic 5-(7-Chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1,4-dih ydropyrazine- 2,3-dione was resolved by chiral SFC to afford the two single enantiomers: 5-(7-Chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1,4-dih ydropyrazine-2,3- dione (Isomer 1) (Example 261): off-white solid (6 mg, e.e.100 %, 17 %). ¹H NMR (400 MHz, DMSO) d 11.30 - 11.21 (m, 2H), 6.83 - 6.80 (m, 2H), 6.73 - 6.70 (m, 1H), 6.40 (s, 1H), 6.15 (s, 1H), 4.24 - 4.16 (m, 3H)., MS (ESI+) m/z 280 (M+H)+. Chiral analysis (Method 2) at 2.95 min. 5-(7-Chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1,4-dih ydropyrazine-2,3- dione (Isomer 2) (Example 262): off-white solid (6 mg, e.e.100 %, 17 %). ¹H NMR (400 MHz, DMSO) 11.30 - 11.19 (2H, m), 6.83 - 6.79 (2H, m), 6.73 - 6.69 (1H, m), 6.41 (1H, s), 6.15 (1H, s), 4.25 - 4.16 (3H, m);, MS (ESI+) m/z 280 (M+H)+. Chiral analysis (Method 2) at 4.37 min. 5-(7-Chloro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (Example 263) a) 7-Chloro-3-(5,6-dimethoxypyrazin- 2-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine A solution of 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazine (45 mg, 0.146 mmol), formaldehyde solution (37% in water, 0.086 mL, 1.17 mmol) and sodium cyanoborohydride (55 mg, 0.877 mmol) in methanol (1.7 mL), water (0.2 mL) and acetic acid (0.04 mL) was stirred at room temperature for 90 min. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (10 mL) and sodium hydrogen carbonate solution (10 mL). The aqueous phase was extracted further with ethyl acetate (2 × 10 mL), dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as an off-white solid (50 mg, >95%). ¹H NMR (400 MHz, CDCl3): δ 7.39 (s, 1 H), 6.86 (dd, J = 2.5, 8.6 Hz, 1 H), 6.78 (d, J = 2.5 Hz, 1 H), 6.61 (d, J = 8.8 Hz, 1 H), 4.46 (dd, J = 3.0, 10.6 Hz, 1 H), 4.38-4.35 (m, 1 H), 4.28 (dd, J = 2.8, 10.6 Hz, 1 H), 3.98 (s, 3 H), 3.95 (s, 3 H), 2.94 (s, 3 H). b) 5-(7-Chloro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4-dihydropyrazine-2,3- dione To a so benzo[b][1,4]oxazine (50 mg, 0.155 mmol) and sodium iodide (116 mg, 0.777 mmol) in acetonitrile (2 mL) at room temperature was added chlorotrimethylsilane (84 mg, 0.777 mmol) and stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the crude residue purified by preparative HPLC to yield the title compound as a white solid (25 mg, 54%). ¹H NMR (400 MHz, DMSO): δ 11.18 (s, 1 H), 10.97 (s, 1 H), 6.79 (dd, J = 2.5, 8.6 Hz, 1 H), 6.69 (d, J = 2.5 Hz, 1 H), 6.65 (d, J = 8.8 Hz, 1 H), 5.69 (s, 1 H), 4.26 (dd, J = 3.9, 11.0 Hz, 1 H), 4.07 (dd, J = 3.1, 3.1 Hz, 1 H), 4.02 (dd, J = 3.1, 11.0 Hz, 1 H), 2.77 (s, 3 H). MS (ESI+) m/z 294 (M+H)+. Racemic 5-(7-Chloro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione was resolved by chiral SFC to afford the two single enantiomers: 5-(7-Chloro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (Isomer 1) (Example 264): off-white solid (7 mg, e.e.100%, 15%); ¹H NMR (400 MHz, DMSO): δ 11.28 (s, 1 H), 11.06 (s, 1 H), 6.89 (dd, J = 2.4, 8.6 Hz, 1 H), 6.80 (d, J = 2.5 Hz, 1 H), 6.75 (d, J = 8.8 Hz, 1 H), 5.79 (s, 1 H), 4.36 (dd, J = 3.9, 11.0 Hz, 1 H), 4.19-4.09 (m, 2 H), 2.87 (s, 3 H). MS (ESI+) m/z 294 (M+H)+. Chiral analysis (Method 2) at 4.62 min. 5-(7-Chloro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (Isomer 2) (Example 265): off-white solid (7 mg, e.e.96.8%, 15%); ¹H NMR (400 MHz, DMSO): δ 11.26 (s, 1 H), 11.07 (s, 1 H), 6.89 (dd, J = 2.4, 8.6 Hz, 1 H), 6.80 (d, J = 2.5 Hz, 1 H), 6.75 (d, J = 8.8 Hz, 1 H), 5.79 (s, 1 H), 4.36 (dd, J = 3.9, 11.0 Hz, 1 H), 4.19-4.10 (m, 2 H), 2.87 (s, 3 H). MS (ESI+) m/z 294 (M+H)+. Chiral analysis (Method 2) at 6.43 min. 5-(7-Chloro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (Example 266) a) 7-Chloro-3-(5,6-dimethoxypyrazin o-2H-benzo[b][1,4]oxazine To a s , , 130 mg, 0.425 mmol) in tetrahydrofuran (10 mL) at 0 °C was added dropwise methyllithium solution (1.6 M in diethyl ether, 0.80 mL, 1.27 mmol) and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with ammonium chloride solution (10 mL) and extracted into ethyl acetate (30 mL). The organic phase was washed with brine (20 mL), passed through a phase separator and concentrated under reduced pressure. The crude residue was concentrated onto silica and purified by flash column chromatography (0-20% ethyl acetate in cyclohexane) to yield the title compound as an orange gum (35 mg, 26%). ¹H NMR (400 MHz, CDCl3): δ, 7.67 (s, 1 H), 6.76-6.74 (m, 2 H), 6.63-6.61 (m, 1 H), 4.56-4.51 (m, 1 H), 4.22-4.19 (m, 1 H), 4.09 (d, J = 12.9 Hz, 1 H), 4.01 (s, 3 H), 3.98 (s, 3 H), 1.51 (s, 3 H). b) 5-(7-Chloro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4-dihydropyrazine-2,3- dione A solution of 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-3-methyl-3,4-dihydro- 2H- benzo[b][1,4]oxazine (87 mg, 0.27 mmol) in acetonitrile (5 mL) was degassed with nitrogen for 5 min. Sodium iodide (203 mg, 1.35 mmol) and chlorotrimethylsilane (147 mg, 1.35 mmol) were then added sequentially and the reaction mixture was stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The crude residue was purified by preparative HPLC to yield the title compound as an off-white solid (11 mg, 14%). ¹H NMR (400 MHz, DMSO): δ 11.25 (s, 1 H), 11.07 (d, J = 3.0 Hz, 1 H), 6.78 (dd, J = 2.4, 8.4 Hz, 1 H), 6.72 (d, J = 2.4 Hz, 1 H), 6.65 (d, J = 8.5 Hz, 1 H), 6.53 (s, 1 H), 5.93 (d, J = 3.5 Hz, 1 H), 4.56 (dd, J = 1.2, 11.1 Hz, 1 H), 3.70 (d, J = 11.0 Hz, 1 H), 1.36 (s, 3 H). MS (ESI+) m/z 294 (M+H)+. Racemic 5-(7-Chloro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione was resolved by chiral SFC to afford the two single enantiomers: 5-(7-Chloro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (Isomer 1) (Example 267): off-white solid (9 mg, e.e.100%, 11%); ¹H NMR (400 MHz, DMSO): δ 11.25-11.25 (m, 1 H), 11.07-11.07 (m, 1 H), 6.78 (dd, J = 2.4, 8.5 Hz, 1 H), 6.72 (d, J = 2.4 Hz, 1 H), 6.65 (d, J = 8.4 Hz, 1 H), 6.52 (s, 1 H), 5.94-5.90 (m, 1 H), 4.55 (d, J = 10.4 Hz, 1 H), 3.70 (d, J = 11.2 Hz, 1 H), 1.36 (s, 3 H). MS (ESI-) m/z 292 (M-H)-. Chiral analysis (Method 2) at 4.65 min. 5-(7-Chloro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (Isomer 2) (Example 268): off-white solid (9 mg, e.e.100%, 11%); ¹H NMR (400 MHz, DMSO): δ 6.78 (dd, J = 2.4, 8.4 Hz, 1 H), 6.72 (d, J = 2.4 Hz, 1 H), 6.65 (d, J = 8.4 Hz, 1 H), 6.52 (s, 1 H), 5.92 (s, 1 H), 4.57-4.53 (m, 1 H), 3.70 (d, J = 11.0 Hz, 1 H), 1.36 (s, 3 H). (2 × NH 1H not observed) MS (ESI-) m/z 292 (M-H)-. Chiral analysis (Method 2 at 6.75 min. 5-(7-Chloro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)-1,4- dihydropyrazine-2,3-dione (Example 269) a) 7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-3,4-dimethyl-3,4-dihy dro-2H-benzo[b][1,4]oxazine To a solution of 5-(7-chloro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (75 mg, 0.233 mmol) in methanol (3 mL) were added sequentially water (0.5 mL), acetic acid (0.1 mL), formaldehyde solution (37% in water, 0.14 mL, 1.86 mmol) and sodium cyanoborohydride (88 mg, 1.40 mmol) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate (20 mL) and sodium hydrogen carbonate solution (5 mL), the organic phase was washed with brine (5 mL), dried through a phase separator and concentrated under reduced pressure to yield the title compound as a green gummy solid (98 mg, >95%). ¹H NMR (400 MHz, CDCl3) d 7.47 (s, 1 H), 6.87 (dd, J=2.5, 8.6 Hz, 1 H), 6.77 (d, J=2.5 Hz, 1 H), 6.62 (d, J=8.8 Hz, 1 H), 4.38 (s, 3 H), 4.29 (d, J=10.6 Hz, 1 H), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.95 (d, J=10.6 Hz, 1 H), 2.83 (s, 3 H). b) 5-(7-Chloro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)-1,4-dihydropyrazine- 2,3-dione To a so lution of 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-3,4-dimethyl-3,4-dihy dro-2H- benzo[b][1,4]oxazine (78 mg, 0.232 mmol) and sodium iodide (174 mg, 1.16 mmol) in acetonitrile (3 mL) at room temperature was added chlorotrimethylsilane (126 mg, 1.16 mmol) and the reaction mixture was stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (5 mL) and water (5 mL). The organic phase was washed with brine (5 mL), dried through a phase separator and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to yield the title compound as a white solid (26 mg, 36%). ¹H NMR (400 MHz, CDCl3): ¹H NMR (400 MHz, DMSO): δ 11.01-11.01 (m, 2 H), 6.89 (dd, J = 2.5, 8.7 Hz, 1 H), 6.81 (d, J = 2.5 Hz, 1 H), 6.75 (d, J = 8.8 Hz, 1 H), 6.04 (s, 1 H), 4.34 (d, J = 10.8 Hz, 1 H), 3.87 (d, J = 10.8 Hz, 1 H), 2.69 (s, 3 H), 1.38 (s, 3 H). MS (ESI+) m/z 308 (M+H)+. Racemic 5-(7-Chloro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)-1,4- dihydropyrazine-2,3-dione was resolved by chiral SFC to afford the two single enantiomers: 5-(7-Chloro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)-1,4- dihydropyrazine-2,3-dione (Isomer 1) (Example 270): off-white solid (9 mg, e.e.100%, 13%) ; ¹H NMR (400 MHz, DMSO): δ 11.19-11.19 (m, 1 H), 10.97-10.97 (m, 1 H), 6.89 (dd, J = 2.5, 8.7 Hz, 1 H), 6.81 (d, J = 2.5 Hz, 1 H), 6.75 (d, J = 8.8 Hz, 1 H), 6.04 (s, 1 H), 4.34 (d, J = 10.8 Hz, 1 H), 3.86 (d, J = 10.8 Hz, 1 H), 2.69 (s, 3 H), 1.37 (s, 3 H). MS (ESI+) m/z 308 (M+H)+. Chiral analysis (Method 2) at 3.40 min. 5-(7-Chloro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)-1,4- dihydropyrazine-2,3-dione (Isomer 2) (Example 271): off-white solid (9 mg, e.e.99% 13%); ¹H NMR (400 MHz, DMSO) d 11.21 - 10.87 (m, 2H), 6.89 (dd, J=2.5, 8.7 Hz, 1H), 6.81 (d, J=2.5 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.04 (s, 1H), 4.34 (d, J=10.8 Hz, 1H), 3.87 (d, J=10.8 Hz, 1H), 2.69 (s, 3H), 1.38 (s, 3H). MS (ESI+) m/z 308 (M+H)+. Chiral analysis (Method 2) at 4.62 min. 5-(7-Chloro-3-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) -1,4-dihydropyrazine- 2,3-dione (Example 272) a) 7-Chloro-3-(5,6-dimethoxypyrazin- 2-yl)-3-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine To a solution of 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-2H-benzo[b][1,4]oxazi ne (500 mg, 1.64 mmol) and bis(cyclopentadienyl)zirconium(IV) dichloride (48 mg, 0.164 mmol) in tetrahydrofuran (20 mL) at room temperature was added ethylmagnesium bromide solution (1 M in tetrahydrofuran,3.3 mL, 3.27 mmol) and stirred at room temperature for 2 hrs. The reaction mixture was quenched with 2 M sodium hydroxide solution (10 mL), diluted with water (10 mL) and extracted with ethyl acetate (15 mL). The aqueous phase was extracted further with ethyl acetate (2 × 15 mL), the combined organics were dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was concentrated onto silica and purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to yield the title compound as a viscous red oil (210 mg, 38%). ¹H NMR (400 MHz, CDCl3): δ 7.63 (s, 1 H), 6.78-6.71 (m, 2 H), 6.66-6.62 (m, 1 H), 4.56-4.51 (m, 1 H), 4.32 (s, 1 H), 4.01-3.95 (m, 7 H), 2.05-1.95 (m, 1 H), 1.86-1.75 (m, 1 H), 0.82-0.77 (m, 3 H). b) 5-(7-Chloro-3-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl) -1,4-dihydropyrazine-2,3- dione A solut benzo[b][1,4]oxazine (20 mg, 0.0596 mmol) in 1,4-dioxane (0.6 mL) and 2 M hydrochloric acid (0.60 mL) was stirred at 100 °C for 2 hrs. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the crude residue was purified by preparative HPLC to yield the title compound as an off-white solid (1.7 mg, 9%). ¹H NMR (400 MHz, DMSO): δ 11.12-11.12 (m, 2 H), 6.77-6.75 (m, 2 H), 6.74-6.71 (m, 1 H), 6.36 (s, 1 H), 5.92 (s, 1 H), 4.57- 4.52 (m, 1 H), 3.77-3.73 (m, 1 H), 1.87-1.79 (m, 1 H), 1.62-1.52 (m, 1 H), 0.85-0.80 (m, 3 H). MS (ESI+) m/z 308 (M+H)+. 5-(7-Chloro-3-ethyl-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxa zin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 273) a) 7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-3-ethyl-4-methyl-3,4- dihydro-2H- benzo[b][1,4]oxazine To a solution of 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-3-ethyl-3,4-dihydro-2 H- benzo[b][1,4]oxazine (150 mg, 0.447 mmol) in methanol (6 mL) was added sequentially water (1 mL), acetic acid (0.2 mL), formaldehyde solution (37% in water, 0.27 mL, 3.57 mmol) and sodium cyanoborohydride (168 mg, 2.68 mmol) and stirred at room temperature for 3 hrs. The reaction mixture was partitioned between ethyl acetate (15 mL) and sodium hydrogen carbonate solution (5 mL) and diluted with water (10 mL). The organic phase was extracted with ethyl acetate (3 × 15 mL), the combined organic phases were passed through a phase separator and concentrated under reduced pressure. The crude residue was concentrated onto silica and purified by flash column chromatography (0-30% ethyl acetate in cyclohexane) to yield the title compound as a colourless oil (96 mg, 62%). ¹H NMR (400 MHz, CDCl3): δ 7.38 (s, 1 H), 6.86 (dd, J = 2.4, 8.7 Hz, 1 H), 6.74 (d, J = 2.5 Hz, 1 H), 6.62 (d, J = 8.6 Hz, 1 H), 4.36-4.32 (m, 1 H), 4.17-4.11 (m, 1 H), 3.97 (s, 3 H), 3.96 (s, 3 H), 2.90-2.89 (m, 3 H), 2.36-2.25 (m, 1 H), 2.05-1.95 (m, 1 H), 1.03-0.98 (m, 3 H). b) 7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-3-ethyl-4-methyl-3,4- dihydro-2H- benzo[b][1,4]oxazine To a so lution of sodium iodide (123 mg, 0.823 mmol) in acetonitrile (2.5 mL) was added chlorotrimethylsilane (89 mg, 0.823 mmol) and stirred at 50 °C for 10 min. A solution of 7- chloro-3-(5,6-dimethoxypyrazin-2-yl)-3-ethyl-4-methyl-3,4-di hydro-2H-benzo[b][1,4]oxazine (96 mg, 0.274 mmol) in acetonitrile (2.5 mL) was then added and the reaction mixture was stirred at 80 °C for 6 hrs. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC to yield the title compound as an off-white solid (23 mg, 26%). ¹H NMR (400 MHz, DMSO): δ 11.12 (s, 1 H), 10.99 (s, 1 H), 6.89 (dd, J = 2.5, 8.7 Hz, 1 H), 6.78 (d, J = 2.4 Hz, 1 H), 6.73 (d, J = 8.8 Hz, 1 H), 5.81-5.77 (m, 1 H), 4.36 (d, J = 11.2 Hz, 1 H), 3.98 (d, J = 11.2 Hz, 1 H), 2.79 (s, 3 H), 2.16-2.07 (m, 1 H), 1.92-1.83 (m, 1 H), 0.90-0.85 (m, 3 H). MS (ESI+) m/z 322 (M+H)+. 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazine- 7-carbonitrile (Example 274) a) 7-Bromo-3-(5,6-dimethoxypyrazin-2-yl)-2H-benzo[b][1,4]oxazin e T dimethoxypyrazin-2-yl)ethan-1-one (3.00 g, 11.5 mmol) in acetonitrile (40 mL) was added cesium carbonate (3.74 g, 11.5 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated onto silica and purified by flash column chromatography (0-10% ethyl acetate in dichloromethane) to yield the title compound as an orange solid (1.84 g, 46%). ¹H NMR (400 MHz, CDCl3): δ 8.66 (s, 1 H), 7.27-7.25 (m, 1 H), 7.15-7.12 (m, 1 H), 7.07 (d, J = 2.0 Hz, 1 H), 5.18 (s, 2 H), 4.10 (s, 3 H), 4.06 (s, 3 H). b) 3-(5,6-Dimethoxypyrazin-2-yl)-2H-benzo[b][1,4]oxazine-7-carb onitrile To a solution of 7-bromo-3-(5,6-dimethoxypyrazin-2-yl)-2H-benzo[b][1,4]oxazin e (50 mg, 0.143 mmol) and zinc cyanide (12 mg, 0.100 mmol) in N,N-dimethylformamide (2 mL) under a nitrogen atmosphere was added tetrakis(triphenylphosphine)Pd(0) (12 mg, 0.0100 mmol) and stirred at 85 °C for 18 hrs. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and partitioned between ethyl acetate (5 mL) and water (5 mL). The organic phase was dried over magnesium sulfate, concentrated onto silica and purified by flash column chromatography (10-30% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (35 mg, 83%). ¹H NMR (400 MHz, CDCl3): δ 8.71 (s, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.30 (dd, J = 1.8, 8.1 Hz, 1 H), 7.18 (d, J = 1.8 Hz, 1 H), 5.24 (s, 2 H), 4.12 (s, 3 H), 4.07 (s, 3 H). c) 3-(5,6-Dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]ox azine-7-carbonitrile To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-2H-benzo[b][1,4]oxazine-7-carb onitrile (35 mg, 0.118 mmol) in a mixture of methanol (2 mL) and tetrahydrofuran (2 mL) at 0 °C was added sodium borohydride (5.4 mg, 0.142 mmol) in one portion and stirred at 0 °C warming to room temperature over 90 min. The reaction mixture was partitioned between ethyl acetate (5 mL) and sodium hydrogen carbonate solution (5 mL), the organic phase was washed with brine (5 mL), the combined aqueous phases were extracted further with ethyl acetate (5 mL) and the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was concentrated onto silica and purified by flash column chromatography (0-80% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (21 mg, 60%). ¹H NMR (400 MHz, CDCl3): δ 7.63 (s, 1 H), 7.13-7.07 (m, 2 H), 6.68 (d, J = 8.3 Hz, 1 H), 4.72 (s, 1 H), 4.63-4.59 (m, 1 H), 4.39 (dd, J = 3.4, 10.7 Hz, 1 H), 4.25 (dd, J = 6.0, 10.7 Hz, 1 H), 4.01 (d, J = 6.0 Hz, 6 H). d) 3-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-7- carbonitrile To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]ox azine-7- carbonitrile (21 mg, 0.0704 mmol) and sodium iodide (53 mg, 0.352 mmol) in acetonitrile (2 mL) at room temperature was added chlorotrimethylsilane (38 mg, 0.352 mmol) and stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the crude residue was purified by preparative HPLC to yield the title compound as an off-white solid (6 mg, 32%). ¹H NMR (400 MHz, DMSO): δ 11.24-11.24 (m, 2 H), 7.26 (s, 1 H), 7.18 (dd, J = 1.9, 8.3 Hz, 1 H), 7.12 (d, J = 1.8 Hz, 1 H), 6.76 (d, J = 8.2 Hz, 1 H), 6.11 (s, 1 H), 4.33-4.31 (m, 1 H), 4.19-4.16 (m, 2 H). MS (ESI+) m/z 271 (M+H)+. 5-(7-(Trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxaz in-3-yl)-1,4- dihydropyrazine-2,3-dione (Isomer 1) (Example 275) a) 3-(5,6-Dimethoxypyrazin-2-yl)-7-(trifluoromethyl)-3,4-dihydr o-2H-pyrido[4,3- b][1,4]oxazine A (5,6-dimethoxypyrazin-2-yl)ethan-1-one (586 mg, 2.25 mmol) and cesium carbonate (732 mg, 2.25 mmol) in acetonitrile (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated onto silica and purified by flash column chromatography (0-100% ethyl acetate in dichloromethane) to yield the title compound as part of a mixture as a gummy yellow solid (536 mg, 70%). To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-7- (trifluoromethyl)-2H-pyrido[4,3-b][1,4]oxazine (200 mg, 0.588 mmol) in ethanol (7 mL) and water (2.1 mL) at room temperature was added sodium borohydride (44 mg, 1.18 mmol) and stirred at 90 °C for 90 min. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, concentrated onto silica and purified by flash column chromatography (0-40% 3:1 ethyl acetate and ethanol in cyclohexane) to yield the title compound as a yellow solid (136 mg, 67%). ¹H NMR (400 MHz, CDCl3): δ 8.09 (s, 1 H), 7.66 (s, 1 H), 7.12 (s, 1 H), 4.60-4.49 (m, 3 H), 4.35-4.30 (m, 1 H), 4.02 (s, 3 H), 4.00 (s, 3 H). Racemic 3-(5,6-Dimethoxypyrazin-2-yl)-7-(trifluoromethyl)-3,4-dihydr o-2H-pyrido[4,3- b][1,4]oxazine was resolved by chiral SFC to afford the two single enantiomers: 3-(5,6-Dimethoxypyrazin-2-yl)-7-(trifluoromethyl)-3,4-dihydr o-2H-pyrido[4,3- b][1,4]oxazine (Isomer 1): off-white solid (51 mg, e.e.100%, 25%). Chiral analysis (Method 2) at 3.30 min. 3-(5,6-Dimethoxypyrazin-2-yl)-7-(trifluoromethyl)-3,4-dihydr o-2H-pyrido[4,3- b][1,4]oxazine (Isomer 2): off-white solid (55 mg, e.e.100%, 27%). Chiral analysis (Method 2) at 4.70 min Both isomers were used for further chemistry without further analysis. b) 5-(7-(Trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxaz in-3-yl)-1,4-dihydropyrazine- 2,3-dione (Isomer 1) (Example 275) To a so - pyrido[4,3-b][1,4]oxazine (Isomer 1) (51 mg, 0.149 mmol) and sodium iodide (112 mg, 0.745 mmol) in acetonitrile (1 mL) at room temperature was added chlorotrimethylsilane (81 mg, 0.745 mmol) and stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to yield the title compound as an off-white solid (11 mg, e.e.100%, 23%). ¹H NMR (400 MHz, DMSO): δ 11.36 (s, 1 H), 11.18 (s, 1 H), 8.05 (s, 1 H), 7.20 (s, 1 H), 7.11 (s, 1 H), 6.16 (s, 1 H), 4.34-4.26 (m, 3 H). MS (ESI+) m/z 315 (M+H)+. Chiral analysis (Method 2) at 1.86 min. c) 5-(7-(Trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxaz in-3-yl)-1,4-dihydropyrazine- 2,3-dione (Isomer 2) (Example 276) To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-7-(trifluoromethyl)-3,4-dihydr o-2H- pyrido[4,3-b][1,4]oxazine (Isomer 2) (55 mg, 0.161 mmol) and sodium iodide (120 mg, 0.803 mmol) in acetonitrile (1 mL) at room temperature was added chlorotrimethylsilane (87 mg, 0.803 mmol) and stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to yield the title compound as an off-white solid (39 mg, e.e.99%, 78%). ¹H NMR (400 MHz, DMSO): δ 11.33-11.20 (m, 2 H), 8.05 (s, 1 H), 7.20 (s, 1 H), 7.11 (s, 1 H), 6.16 (s, 1 H), 4.34-4.26 (m, 3 H). MS (ESI+) m/z 315 (M+H)+. Chiral analysis (Method 2) at 2.73 min. 5-(7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (Example 277) a . , . , dimethoxypyrazin-2-yl)ethan-1-one (1.30 g, 4.98 mmol) in acetonitrile (20 mL) was added cesium carbonate (1.62 g, 4.98 mmol) and stirred at room temperature for 18 hrs. The reaction mixture was concentrated onto silica and purified by flash column chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (440 mg, 31%). ¹H NMR (400 MHz, CDCl3): δ 8.64 (s, 1 H), 7.36 (dd, J = 6.1, 8.7 Hz, 1 H), 6.72 (ddd, J = 8.5, 8.5, 2.8 Hz, 1 H), 6.64 (dd, J = 2.8, 9.3 Hz, 1 H), 5.18 (s, 2 H), 4.10 (s, 3 H), 4.07 (s, 3 H). b) 3-(5,6-Dimethoxypyrazin-2-yl)-7-fluoro-3-methyl-3,4-dihydro- 2H-benzo[b][1,4]oxazine To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-7-fluoro-2H-benzo[b][1,4]oxazi ne (440 mg, 1.52 mmol) in tetrahydrofuran (28 mL) at 0 °C was added dropwise methyllithium solution (1.6 M in diethyl ether, 1.9 mL, 3.04 mmol) and stirred at 0 °C for 30 min. The reaction mixture was quenched by addition of ammonium chloride solution (10 mL) and partitioned between ethyl acetate (20 mL) and water (20 mL), the organic phase was passed through a phase separator and concentrated under reduced pressure. The crude residue was concentrated onto silica gel and purified by flash column chromatography (0-60% ethyl acetate in cyclohexane) to yield the title compound as a brown oil (170 mg, 37%). ¹H NMR (400 MHz, CDCl3): δ 7.69 (s, 1 H), 6.63 (dd, J = 5.6, 8.6 Hz, 1 H), 6.56-6.48 (m, 2 H), 4.55 (d, J = 10.4 Hz, 1 H), 4.09 (s, 1 H), 4.01 (s, 3 H), 3.97 (s, 3 H), 3.95 (d, J = 10.5 Hz, 1 H), 1.50 (s, 3 H). c) 5-(7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4-dihydropyrazine-2,3- dione To a sol - benzo[b][1,4]oxazine (305 mg, 0.999 mmol) and sodium iodide (749 mg, 4.99 mmol) in acetonitrile (6 mL) was added chlorotrimethylsilane (543 mg, 4.99 mmol) and the reaction mixture was stirred at 60 °C for 1 hour. Then, the reaction mixture was diluted with a 1:1 mixture of ethyl acetate and dichloromethane (15 mL), filtered through Celite™ and washed with a 1:1 mixture of ethyl acetate and dichloromethane (15 mL). The solvent was removed under reduced pressure and the crude residue purified by preparative HPLC to yield the title compound as an off-white solid (150 mg, 54%). ¹H NMR (400 MHz, CDCl3): ¹H NMR (400 MHz, DMSO): δ 11.22 (s, 1 H), 11.07 (s, 1 H), 6.66-6.54 (m, 3 H), 6.25 (s, 1 H), 5.95 (s, 1 H), 4.58-4.53 (m, 1 H), 3.71 (d, J = 11.2 Hz, 1 H), 1.35 (s, 3 H). Racemic 5-(7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione was resolved by chiral SFC to afford the two single enantiomers: 5-(7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (Isomer 1) (Example 278): off-white solid (55 mg). ¹H NMR (400 MHz, DMSO): δ 11.09-11.09 (d, J = 68.6 Hz, 2 H), 6.66-6.54 (m, 3 H), 6.25 (s, 1 H), 5.95 (s, 1 H), 4.55 (d, J = 10.9 Hz, 1 H), 3.71 (d, J = 11.0 Hz, 1 H), 1.35 (s, 3 H). Chiral analysis (Method 2) at 7.40 min. 5-(7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (Isomer 2) (Example 279): off-white solid (55 mg). ¹H NMR (400 MHz, DMSO): δ 11.15 (d, J = 68.7 Hz, 2 H), 6.66-6.54 (m, 3 H), 6.25 (s, 1 H), 5.95 (s, 1 H), 4.55 (d, J = 10.9 Hz, 1 H), 3.71 (d, J = 11.0 Hz, 1 H), 1.35 (s, 3 H). Chiral analysis (Method 2) at 11.20 min. 5-(7-Fluoro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)-1,4- dihydropyrazine-2,3-dione (Example 280) a) 3-(5,6-Dimethoxypyrazin-2-yl)-7-fl hydro-2H-benzo[b][1,4]oxazine To a so , , - benzo[b][1,4]oxazine (85 mg, 0.278 mmol) in methanol (3 mL) were added sequentially water (0.5 mL), acetic acid (0.1 mL), formaldehyde solution (37% in water, 0.17 mL, 2.23 mmol) and sodium cyanoborohydride (105 mg, 1.67 mmol) and the reaction was stirred at room temperature for 18 hrs. The reaction mixture was quenched by addition of sodium hydrogen carbonate solution (5 mL) and extracted with ethyl acetate (2 × 5 mL), the combined organic phases were passed through a phase separator and concentrated under reduced pressure to yield the title compound as a yellow oil (52 mg, 58%). ¹H NMR (400 MHz, CDCl3): δ 7.50 (s, 1 H), 6.64-6.61 (m, 2 H), 6.57-6.53 (m, 1 H), 4.30 (d, J = 10.5 Hz, 1 H), 3.99 (s, 3 H), 3.98-3.95 (m, 4 H), 2.82 (s, 3 H), 1.59 (s, 3 H). b) 5-(7-Fluoro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)-1,4-dihydropyrazine- 2,3-dione A solution of 3-(5,6-dimethoxypyrazin-2-yl)-7-fluoro-3,4-dimethyl-3,4-dihy dro-2H- benzo[b][1,4]oxazine (52 mg, 0.163 mmol), sodium iodide (122 mg, 0.814 mmol) and chlorotrimethylsilane (88 mg, 0.814 mmol) in acetonitrile (3 mL) was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the crude residue was purified by preparative HPLC to yield the title compound as a white solid (18 mg, 38%). ¹H NMR (400 MHz, DMSO): δ 11.21-11.21 (m, 1 H), 10.89-10.87 (m, 1 H), 6.76-6.64 (m, 3 H), 6.07-6.07 (m, 1 H), 4.36 (d, J = 10.8 Hz, 1 H), 3.87 (d, J = 10.7 Hz, 1 H), 2.67 (s, 3 H), 1.35 (s, 3 H). MS (ESI+) m/z 292 (M+H)+. Racemic 5-(7-Fluoro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)-1,4- dihydropyrazine-2,3-dione was resolved by chiral SFC to afford the two single enantiomers: 5-(7-Fluoro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)-1,4- dihydropyrazine-2,3-dione (Isomer 1) (Example 281): off-white solid (5 mg, e.e., 100%, 11%), ¹H NMR (400 MHz, DMSO): δ 11.21 (s, 1 H), 10.89 (s, 1 H), 6.76-6.64 (m, 3 H), 6.07 (s, 1 H), 4.36 (d, J = 10.8 Hz, 1 H), 3.87 (d, J = 10.8 Hz, 1 H), 2.67 (s, 3 H), 1.35 (s, 3 H). MS (ESI+) m/z 292 (M+H)+. Chiral analysis (Method 2) at 4.51 min. 5-(7-Fluoro-3,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 3-yl)-1,4- dihydropyrazine-2,3-dione (Isomer 2) (Example 282): off-white solid (5 mg, e.e., 100%, 11%) ¹H NMR (400 MHz, DMSO): δ 11.21 (s, 1 H), 10.89 (s, 1 H), 6.76-6.64 (m, 3 H), 6.07 (s, 1 H), 4.36 (d, J = 10.7 Hz, 1 H), 3.87 (d, J = 10.7 Hz, 1 H), 2.67 (s, 3 H), 1.35 (s, 3 H). MS (ESI+) m/z 292 (M+H)+. Chiral analysis (Method 2) at 5.93 min. 5-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1,4-dih ydropyrazine-2,3- dione (Example 283) a) 3-(5,6-Dimethoxypyrazin-2-yl)-7-fluoro-3,4-dihydro-2H-benzo[ b][1,4]oxazine To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-7-fluoro-2H-benzo[b][1,4]oxazi ne (250 mg, 0.864 mmol) in tetrahydrofuran (2 mL) and water (0.1 mL) was added sodium borohydride and stirred at 65 °C for 18 hrs. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (5 mL) and water (5 mL). The aqueous phase was extracted further with ethyl acetate (5 mL) and the combined organic phases were passed through a phase separator and concentrated under reduced pressure to yield the title compound as an off-white solid (215 mg, 85%). ¹H NMR (400 MHz, CDCl3): δ 7.69 (s, 1 H), 6.66 (dd, J = 5.6, 8.6 Hz, 1 H), 6.61-6.52 (m, 2 H), 4.48-4.37 (m, 2 H), 4.19 (dd, J = 7.1, 10.4 Hz, 1 H), 4.02-4.01 (m, 7 H). b) 5-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-1,4-dih ydropyrazine-2,3-dione A solutio , , benzo[b][1,4]oxazine (115 mg, 0.395 mmol), sodium iodide (296 mg, 0.97 mmol) and chlorotrimethylsilane (214 mg, 1.97 mmol) in acetonitrile (2 mL) was stirred at 60 °C for 1 hour The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to yield the title compound as a yellow solid (40 mg, 38%). ¹H NMR (400 MHz, DMSO): δ 11.31-11.31 (m, 1 H), 11.16-11.16 (m, 1 H), 6.66-6.57 (m, 3 H), 6.13-6.11 (m, 1 H), 6.09 (s, 1 H), 4.23-4.10 (m, 3 H). MS (ESI+) m/z 264 (M+H)+. 5-(7-Fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4- dihydropyrazine-2,3-dione (Example 284) a) 5-(7-Fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl )-1,4-dihydropyrazine-2,3- dione To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-7-fluoro-3,4-dihydro-2H- benzo[b][1,4]oxazine (115 mg, 0.395 mmol) in methanol (3 mL) were added sequentially water (0.5 mL), acetic acid (0.1 mL), formaldehyde solution (37% in water, 0.23 mL, 3.16 mmol) and sodium cyanoborohydride (149 mg, 2.37 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was quenched by addition of sodium hydrogen carbonate solution (5 mL) and extracted twice into ethyl acetate (2 × 5 mL), the combined organic phases were passed through a phase separator and concentrated under reduced pressure to afford 3-(5,6- dimethoxypyrazin-2-yl)-7-fluoro-4-methyl-3,4-dihydro-2H-benz o[b][1,4]oxazine, which was used for the following step without further purification. 3-(5,6-dimethoxypyrazin-2-yl)-7-fluoro- 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, sodium iodide (297 mg, 1.98 mmol) and chlorotrimethylsilane (215 mg, 1.98 mmol) in acetonitrile (2 mL) were stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the crude residue purified by preparative HPLC to yield the title compound as an off-white solid (37 mg, 34%). ¹H NMR (400 MHz, DMSO): δ 11.27-11.27 (m, 1 H), 11.07- 11.07 (m, 1 H), 6.77-6.63 (m, 3 H), 5.84 (s, 1 H), 4.37 (dd, J = 4.4, 10.9 Hz, 1 H), 4.17-4.09 (m, 2 H), 2.85 (s, 3 H). MS (ESI+) m/z 278 (M+H)+. 5-(7-(2,4-Difluorophenethyl)-3,4-dihydro-2H-benzo[b][1,4]oxa zin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 285) a) (E)-7-(2,4-Difluorostyryl)-3-(5,6-dimethoxypyrazin-2-yl)-2H- benzo[b][1,4]oxazine To a solution of 7-bromo-3-(5,6-dimethoxypyrazin-2-yl)-2H-benzo[b][1,4]oxazin e (50 mg, 0.143 mmol), 2,4-difluorostyrene (40 mg, 0.286 mmol), 1,2,3,4,5-Pentaphenyl-1′-(di-tert- butylphosphino)ferrocene (15 mg, 0.0214 mmol) and N,N-diisopropylethylamine (55 mg, 0.428 mmol) in tetrahydrofuran (1.5 mL) was added Pd(II) acetate (1.6 mg, 0.00714 mmol) at room temperature and the reaction mixture stirred at 65 °C for 16 hrs. The reaction mixture was cooled to room temperature, concentrated onto silica and purified by flash column chromatography (0-20% ethyl acetate in dichloromethane) to yield the title compound as a yellow solid (60 mg, >95%). ¹H NMR (400 MHz, CDCl3): δ 8.68 (s, 1 H), 7.60-7.52 (m, 1 H), 7.39 (d, J = 8.1 Hz, 1 H), 7.19-7.15 (m, 2 H), 7.10-7.02 (m, 2 H), 6.92-6.81 (m, 2 H), 5.21 (s, 2 H), 4.10 (s, 3 H), 4.08 (s, 3 H). b) 7-(2,4-Difluorophenethyl)-3-(5,6-dimethoxypyrazin-2-yl)-3,4- dihydro-2H- benzo[b][1,4]oxazine T - - , - y y - - , - ypy - -y - - benzo[b][1,4]oxazine (54 mg, 0.132 mmol) in ethanol (2 mL) was added 10% Pdon charcoal (6 mg) and stirred under a hydrogen atmosphere at room temperature for 18 hrs. The reaction mixture was purged with nitrogen, filtered over a fibreglass filter washing with ethyl acetate and concentrated under reduced pressure to yield the title compound as a gummy orange solid (56 mg, >95%). ¹H NMR (400 MHz, CDCl3): δ 7.70 (s, 1 H), 7.10-7.04 (m, 2 H), 6.79-6.74 (m, 2 H), 6.68-6.62 (m, 3 H), 4.50 (dd, J = 2.7, 6.8 Hz, 1 H), 4.39 (dd, J = 2.9, 10.5 Hz, 1 H), 4.22-4.19 (m, 1 H), 4.02 (s, 3 H), 4.01 (s, 3 H), 2.88-2.82 (m, 2 H), 2.78-2.72 (m, 2 H). c) 5-(7-(2,4-Difluorophenethyl)-3,4-dihydro-2H-benzo[b][1,4]oxa zin-3-yl)-1,4- dihydropyrazine-2,3-dione To a solution of 7-(2,4-difluorophenethyl)-3-(5,6-dimethoxypyrazin-2-yl)-3,4- dihydro- 2H-benzo[b][1,4]oxazine (55 mg, 0.133 mmol) in acetonitrile (3 mL) were added sequentially sodium iodide (100 mg, 0.665 mmol) and chlorotrimethylsilane (72 mg, 0.665 mmol) and stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (10 mL) and water (5 mL). The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by preparative HPLC to yield the title compound as a yellow solid (22 mg, 43%). ¹H NMR (400 MHz, DMSO): δ 11.31 (d, J = 1.6 Hz, 1 H), 11.15 (d, J = 5.6 Hz, 1 H), 7.35-7.28 (m, 1 H), 7.19-7.13 (m, 1 H), 7.03-6.98 (m, 1 H), 6.57-6.55 (m, 3 H), 6.12-6.09 (m, 1 H), 6.01 (s, 1 H), 4.17-4.07 (m, 3 H), 2.83-2.77 (m, 2 H), 2.70-2.64 (m, 2 H). MS (ESI+) m/z 386 (M+H)+. 5-(7-chloro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-yl)-1, 4-dihydropyrazine-2,3- dione (Example 286) a) 7-Chloro-3-(5,6-dimethoxypyrazin- -y - , - y o- -py ido[3,2-b][1,4]oxazine To a solution of 2-amino-5-chloropyridin-3-ol (277 mg, 1.92 mmol) and 2-bromo-1-(5,6- dimethoxypyrazin-2-yl)ethan-1-one (500 mg, 1.92 mmol) in acetonitrile (5 mL) was added cesium carbonate (624 mg, 1.92 mmol) and stirred at room temperature for 90 min. The reaction mixture was concentrated onto silica and purified by flash column chromatography (0- 100% ethyl acetate in dichloromethane) to yield 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-2H- pyrido[3,2-b][1,4]oxazine as a brown solid (310 mg, 53%), which was used for the following step without further purification. To a solution of 7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-2H- pyrido[3,2-b][1,4]oxazine (310 mg, 1.01 mmol) in ethanol (3.0 mL) and water (0.9 mL) was added sodium borohydride (76 mg, 2.02 mmol) and the reaction mixture was stirred at 90 °C for 90 min. The reaction mixture was cooled to room temperature, concentrated onto silica and purified by flash column chromatography (5-80% 3:1 ethanol in ethyl acetate in cyclohexane) to yield the title compound as a white solid (110 mg, 35%). ¹H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 2.1 Hz, 1 H), 7.65 (s, 1 H), 7.04 (d, J = 2.1 Hz, 1 H), 5.27 (s, 1 H), 4.70-4.67 (m, 1 H), 4.40 (d, J = 15.9 Hz, 1 H), 4.26 (dd, J = 6.1, 10.8 Hz, 1 H), 4.02 (s, 3 H), 3.99 (s, 3 H). b) 5-(7-Chloro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-yl)-1, 4-dihydropyrazine-2,3-dione To a sol ,2- b][1,4]oxazine (110 mg, 0.356 mmol) and sodium iodide (267 mg, 1.78 mmol) in acetonitrile (3 mL) was added chlorotrimethylsilane (194 mg, 1.78 mmol) and stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with a 9:1 mixture of ethyl acetate and methanol (15 mL), filtered through Celite™ washed with a 9:1 mixture of ethyl acetate and methanol (15 mL) and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to yield the title compound as an off-white solid (40 mg, 40%). ¹¹H NMR (400 MHz, DMSO): δ 11.32-11.12 (m, 2 H), 7.67 (d, J = 2.3 Hz, 1 H), 7.38 (d, J = 1.9 Hz, 1 H), 7.18 (d, J = 2.5 Hz, 1 H), 6.06 (s, 1 H), 4.36 (dd, J = 2.4, 5.0 Hz, 1 H), 4.26-4.14 (m, 2 H). Racemic 5-(7-Chloro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-yl)-1, 4- dihydropyrazine-2,3-dione was resolved by chiral SFC to afford the two single enantiomers: 5-(7-Chloro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-yl)-1, 4-dihydropyrazine-2,3- dione (Isomer 1) (Example 287): off-white solid (10 mg, e.e.100%, 10%); ¹H NMR (400 MHz, DMSO) d 10.94 - 10.94 (m, 2H), 7.67 (d, J=2.3 Hz, 1H), 7.39 - 7.37 (m, 1H), 7.17 (dd, J=0.6, 2.3 Hz, 1H), 6.06 (s, 1H), 4.37 - 4.35 (m, 1H), 4.26 - 4.14 (m, 2H). MS (ESI+) m/z 281 (M+H)+. Chiral analysis (Method 2) at 6.76 min. 5-(7-Chloro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-yl)-1, 4-dihydropyrazine-2,3- dione (Isomer 2) (Example 288): off-white solid (9 mg, e.e.100%, 9%); ¹H NMR (400 MHz, DMSO): δ 11.07-11.07 (m, 2 H), 7.59 (d, J = 2.3 Hz, 1 H), 7.31-7.28 (m, 1 H), 7.09 (dd, J = 0.5, 2.2 Hz, 1 H), 5.97 (s, 1 H), 4.29-4.26 (m, 1 H), 4.17-4.05 (m, 2 H). MS (ESI+) m/z 281 (M+H)+. Chiral analysis (Method 2) at 10.50 min. 5-(3-Methyl-7-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b] [1,4]oxazin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 289) a) 3-(5,6-Dimethoxypyrazin-2-yl)-3-methyl-7-(trifluoromethyl)-3 ,4-dihydro-2H-pyrido[4,3- b][1,4]oxazine To a s b][1,4]oxazine (200 mg, 0.588 mmol) in tetrahydrofuran (10 mL) at -10 °C was added dropwise methyllithium solution (1.6 M in diethyl ether, 0.44 mL, 0.705 mmol) and stirred at -10 °C to room temperature for 45 min. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (3 × 5 mL). the combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. The crude residue was concentrated onto silica and purified by flash column chromatography (5-80% 3:1 ethyl acetate and ethanol in cyclohexane) to yield the title compound as an orange solid (47 mg, 22%). ¹H NMR (400 MHz, CDCl3): δ 8.10-8.08 (m, 1 H), 7.64 (s, 1 H), 7.04 (s, 1 H), 4.68-4.62 (m, 2 H), 4.08-4.04 (m, 1 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 1.57 (s, 3 H). b) 5-(3-Methyl-7-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b] [1,4]oxazin-3-yl)-1,4- dihydropyrazine-2,3-dione To a solution of 3-(5,6-dimethoxypyrazin-2-yl)-3-methyl-7-(trifluoromethyl)-3 ,4- dihydro-2H-pyrido[4,3-b][1,4]oxazine (46 mg, 0.129 mmol) and sodium iodide (97 mg, 0.646 mmol) in acetonitrile (1 mL) was added chlorotrimethylsilane (70 mg, 0.646 mmol) and the reaction mixture was stirred at 60 °C for 90 min. The reaction mixture was cooled to room temperature and purified by preparative HPLC to yield the title compound as a white solid (10 mg, 23%). ¹H NMR (400 MHz, DMSO): δ 11.31-11.31 (m, 1 H), 11.07-11.07 (m, 1 H), 8.05 (s, 1 H), 7.26 (s, 1 H), 7.18 (s, 1 H), 5.95 (s, 1 H), 4.68 (d, J = 11.3 Hz, 1 H), 3.86 (d, J = 11.3 Hz, 1 H), 1.43 (s, 3 H). MS (ESI+) m/z 329 (M+H)+. 5-(7-Chloro-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]ox azin-3-yl)-1,4- dihydropyrazine-2,3-dione (Example 290) a) 2-((2-Bromo-4-chlorophenyl)amin n-2-yl)-3-hydroxypropyl acetate so ut on o ( -( , - met oxypyraz n- -y )ox ran- -y )met y acetate ( mg, . mmol), 2-bromo-4-chloroaniline (586 mg, 2.84 mmol) and copper(II) triflate (85 mg, 0.236 mmol) in dichloromethane (20 mL) was stirred at 0 °C to room temperature for 18 hrs. Water (15 mL) was added, the organic phase was passed through a phase separator and the solvent removed under reduced pressure. The crude residue was concentrated onto silica and purified by silica gel chromatography (0-40% ethyl acetate in cyclohexane) to yield the title compound as an orange gummy solid (140 mg, 13%). ¹H NMR (400 MHz, CDCl3): δ 7.75 (s, 1 H), 7.45 (d, J = 2.4 Hz, 1 H), 6.89 (dd, J = 2.4, 8.8 Hz, 1 H), 6.15 (d, J = 8.9 Hz, 1 H), 5.32 (s, 1 H), 4.74 (d, J = 11.7 Hz, 1 H), 4.57 (d, J = 11.5 Hz, 1 H), 4.31-4.26 (m, 1 H), 4.02 (s, 3 H), 4.02 (s, 3 H), 3.95- 3.89 (m, 1 H), 3.04-3.00 (m, 1 H), 2.10 (s, 3 H). b) (7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-3-yl)methyl acetate A solution of 2-((2-bromo-4-chlorophenyl)amino)-2-(5,6-dimethoxypyrazin-2- yl)-3- hydroxypropyl acetate (140 mg, 0.304 mmol), Pd(II) acetate (20 mg, 0.0912 mmol), TrixiePhos (36 mg, 0.0912 mmol) and cesium carbonate (149 mg, 0.456 mmol) in toluene (2 mL) was stirred at 120 °C under microwave irradiation for 2 hrs. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The crude residue was concentrated onto silica and purified by silica gel chromatography (0-50% ethyl acetate in cyclohexane) to yield the title compound as an orange oil (90 mg, 78%). ¹H NMR (400 MHz, CDCl3): δ 7.72 (s, 1 H), 6.82-6.78 (m, 2 H), 6.67 (d, J = 8.5 Hz, 1 H), 4.65-4.56 (m, 2 H), 4.43- 4.40 (m, 1 H), 4.27-4.19 (m, 2 H), 4.02 (s, 3 H), 4.00 (s, 3 H), 2.01 (s, 3 H). c) (7-Chloro-3-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-3- yl)methanol A solu t on o ( -c oro- -( , - met oxypyraz n- -y )- , - y ro- - benzo[b][1,4]oxazin-3-yl)methyl acetate (90 mg, 0.237 mmol) and potassium carbonate (39 mg, 0.284 mmol) in methanol (3 mL) and water (3 mL) was stirred at room temperature for 20 min. The reaction mixture was diluted with ethyl acetate (15 mL) and water (10 mL), phases were separated, the organic phase was dried over magnesium sulfate and the solvent removed under reduced pressure to yield the title compound as an orange residue (80 mg, >95%). ¹H NMR (400 MHz, CDCl3): δ, 7.76 (s, 1 H), 6.81-6.78 (m, 2 H), 6.68-6.65 (m, 1 H), 4.57 (s, 1 H), 4.37-4.33 (m, 1 H), 4.26-4.22 (m, 1 H), 4.04-3.98 (m, 7 H), 3.83-3.80 (m, 1 H). d) 5-(7-Chloro-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]ox azin-3-yl)-1,4- dihydropyrazine-2,3-dione To a solution of sodium iodide (107 mg, 0.711 mmol) and chlorotrimethylsilane (77 mg, 0.711 mmol) in acetonitrile was added (7-chloro-3-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-3-yl)methanol (80 mg, 0.237 mmol) and stirred at 50 °C for 3 hrs. The reaction mixture was cooled to room temperature and solvent removed under reduced pressure. The crude residue was purified by preparative HPLC to yield the title compound as an off-white solid (12 mg, 16%). ¹H NMR (400 MHz, DMSO): δ 11.10 (s, 2 H), 6.77-6.76 (m, 2 H), 6.73-6.71 (m, 1 H), 6.39 (s, 1 H), 6.05 (s, 1 H), 5.15 (s, 1 H), 4.54 (d, J = 11.0 Hz, 1 H), 3.86 (d, J = 11.2 Hz, 1 H), 3.66 (d, J = 11.2 Hz, 1 H), 3.45 (d, J = 11.1 Hz, 1 H). MS (ES+) m/z 310 (M+H) ⁺ . Method AC 5-(7-(Trifluoromethyl)isothiochroman-3-yl)-1,4-dihydropyrazi ne-2,3-dione (Example 291) a) (2-((5,6-Dimethoxypyrazin-2 -y e yny - - f uo omethyl)phenyl)methanol To a degassed mixture of 5-ethynyl-2,3-dimethoxypyrazine (0.5 g, 1.66 mmol), (2-iodo- 5-(trifluoromethyl)phenyl)methanol (0.33 g, 1.99 mmol), diisopropylamine (0.67 g, 6.62 mmol) and copper (I) iodide (0.01 g, 0.06 mmol) in DMF (5.9 mL) was added bis(triphenylphosphine)Pd(II) dichloride (0.12 g, 0.17 mmol) and the reaction was heated to 70 °C for 2.5 hrs. The reaction was cooled to room temperature, diluted with water (90 mL) and extracted with a mixture 8:2 DCM/methanol (3 × 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude material was purified by flash column chromatography (5 – 35% ethyl acetate in cyclohexane) to yield the title compound as yellow solid (0.51 g, 92%). ¹H NMR (400 MHz, CDCl3): δ 7.90 (s, 1 H), 7.82 (s, 1 H), 7.68 (d, J=8.0 Hz, 1 H), 7.55 (d, J=8.0 Hz, 1 H), 4.99 (d, J=6.3 Hz, 2 H), 4.08 (s, 3 H), 4.07 (s, 3H), 2.16 (dd, J=6.3, 6.3 Hz, 1 H). MS (ESI+) m/z 339 (M+H) ⁺ . b) 5-((2-(Bromomethyl)-4-(trifluoromethyl)phenyl)ethynyl)-2,3-d imethoxypyrazine (2- 1.18 mmol), triphenylphosphine (0.37 g, 1.42 mmol) and tetrabromomethane (0.47 g, 1.42 mmol) were dissolved in DCM (12 mL) and the reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the crude material was purified by flash column chromatography (0 – 20% ethyl acetate in cyclohexane) yielding the title compound as light yellow solid (0.37 g, 78%). ¹H NMR (400 MHz, CDCl3): δ 7.98 (s, 1 H), 7.73 - 7.69 (m, 2 H), 7.57 (d, J=8.2 Hz, 1 H), 4.75 (s, 2 H), 4.09 (s, 3 H), 4.07 (s, 3 H). MS (ESI+) m/z 401 (M+H) ⁺ . c) 2,3-Dimethoxy-5-(7-(trifluoromethyl)-1H-isothiochromen-3-yl) pyrazine To a degassed mixture of 5-((2-(bromomethyl)-4-(trifluoromethyl)phenyl)ethynyl)-2,3- dimethoxypyrazine (0.37 g, 0.92 mmol), thiourea (0.14 g, 1.84 mmol) and potassium carbonate (0.26 g, 1.84 mmol) in DMSO (3 mL) was added [1,1’- Bis(diphenylphosphino)ferrocene]dichloroPd(II) (0.007 g, 0.01 mmol) and the reaction was stirred at room temperature 24 hrs. The reaction was diluted with water (45 mL) and extracted with DCM (3 × 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude material was purified by flash column chromatography (5 – 35% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (0.277 g, 85%). ¹H NMR (400 MHz, CDCl3): δ 7.83 (d, J=8.3 Hz, 1 H), 7.73 (s, 1 H), 7.65 (s, 1 H), 7.60 (d, J=8.3 Hz, 1 H), 7.12 (s, 1 H), 4.45 (s, 2 H), 4.25 (s, 3 H), 4.05 (s, 3 H). MS (ESI+) m/z 355 (M+H) ⁺ . d) 2,3-Dimethoxy-5-(7-(trifluoromethyl)isothiochroman-3-yl)pyra zine A deg -3- yl)pyrazine (0.2 g, 0.56 mmol) and Pdhydroxyde on carbon (20 wt %, 0.05 g, 0.07 mmol) in a mixture 1:1 methanol/ethyl acetate (5.6 mL) was placed under an atmosphere of hydrogen and stirred for 60 hrs. The reaction mixture was filtered over Celite ^TM and the filtrate concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 to 20% ethyl acetate in cyclohexane) yielding the title compound as light yellow oil (0.145 g, 72%). ¹H NMR (400 MHz, CDCl3): δ 7.51 - 7.46 (m, 3 H), 7.30 (d, J=8.5 Hz, 1 H), 5.18 - 5.14 (m, 1 H), 4.21 - 4.13 (m, 2 H), 4.02 (s, 3 H), 3.96 (s, 3 H), 3.35 - 3.29 (m, 1 H), 3.08 - 3.02 (m, 1 H). MS (ESI+) m/z 357 (M+H) ⁺ . e) 5-(7-(Trifluoromethyl)isothiochroman-3-yl)-1,4-dihydropyrazi ne-2,3-dione Sodium iodide (0.11 g, 0.72 mmol) and TMSCl (0.078 g, 0.09 mL, 0.72 mmol) were added to a solution of 2,3-dimethoxy-5-(7-(trifluoromethyl)isothiochroman-3-yl)pyra zine (0.085 g, 0.24 mmol), in acetonitrile (2.4 mL) and the solution was stirred at 60 °C for 1.5 hrs. The reaction was concentrated to dryness. The crude material was purified by reverse phase preparative HPLC to afford the title compound as an off-white solid (50 mg, 64%). ¹H NMR (400 MHz, DMSO): δ 11.36 (s, 1 H), 11.09 (s, 1 H), 7.71 (s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 6.07 (s, 1 H), 4.97-4.92 (m, 1 H), 4.32 (dd, J = 1.6, 15.1 Hz, 1 H), 4.21 (d, J = 14.8 Hz, 1 H), 2.96 (dd, J = 4.8, 14.3 Hz, 1 H), 2.58-2.54 (m, 1 H). MS (ESI+) m/z 329 (M+H) ⁺ . Racemic 5-(7-(trifluoromethyl)isothiochroman-3-yl)-1,4-dihydropyrazi ne-2,3-dione was resolved by chiral SFC to afford single enantiomers. 5-(7-(trifluoromethyl)isothiochroman-3-yl)-1,4-dihydropyrazi ne-2,3-dione (Isomer 1) (Example 292): ¹H NMR (400 MHz, DMSO): δ 11.36 (s, 1 H), 11.10 (s, 1 H), 7.71 (s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 6.07 (s, 1 H), 4.97-4.92 (m, 1 H), 4.32 (dd, J = 1.6, 14.9 Hz, 1 H), 4.21 (d, J = 14.9 Hz, 1 H), 2.97 (dd, J = 4.7, 14.2 Hz, 1 H), 2.58-2.54 (m, 1 H). MS (ES+) m/z 329 (M+H)+; Chiral analysis (Method 1) at 2.36 min. 5-(7-(trifluoromethyl)isothiochroman-3-yl)-1,4-dihydropyrazi ne-2,3-dione (Isomer 2) (Example 293): ¹H NMR (400 MHz, DMSO): δ 11.10-11.10 (m, 2 H), 7.71 (s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 6.07 (s, 1 H), 4.95-4.92 (m, 1 H), 4.32 (dd, J = 1.7, 14.9 Hz, 1 H), 4.21 (d, J = 14.9 Hz, 1 H), 2.97 (dd, J = 4.7, 14.4 Hz, 1 H), 2.58-2.53 (m, 1 H). MS (ES+) m/z 329 (M+H)+; Chiral analysis (Method 1) at 3.18 min. 5-(Isothiochroman-3-yl)-1,4-dihydropyrazine-2,3-dione (Exmaple 294) Example 294 was prepared using a n ana ogous me o to that used to prepare 5-(7- (trifluoromethyl)isothiochroman-3-yl)-1,4-dihydropyrazine-2, 3-dione (Method AC). ¹H NMR (400 MHz, DMSO) δ 11.36 (s, 1 H), 11.09 (d, J=4.8 Hz, 1 H), 7.33 - 7.25 (m, 4 H), 6.08 - 6.04 (m, 1 H), 4.91 - 4.86 (m, 1 H), 4.27 - 4.11 (m, 2 H), 3.00 - 2.94 (m, 1 H), 2.50 - 2.45 (m, 1 H). MS (ESI+) m/z 261 (M+H)+ Method AD 5-(3,4-Dihydro-2H-benzo[b][1,4]thiazin-2-yl)-1,4-dihydropyra zine-2,3-dione (Example 295) a) Methyl 2-(5,6-dimethoxypyrazin-2-yl)-2-oxoacetate A solution of 5-bromo-2,3-dimethoxypyrazine (2 g, 9.13 mmol) in dry THF (15 mL) under nitrogen was cooled to -78 °C. A solution of n-butyllithium (2.5 mL in hexanes, 4 mL, 10 mmol) was added dropwise over 10 min. The resulting solution was stirred at -78 °C for 30 min. before being added in small portions via syringe to a solution of dimethyloxalate (2.05 g, 17.4 mmol) in dry THF (15 mL) under nitrogen at -78 °C. After the addition was complete, the reaction mixture was stirred at -78 °C for 15 min. before being allowed to warm to room temperature. The mixture was quenched with a saturated aqueous solution of ammonium chloride (20 mL). The organic solvent was evaporated under reduced pressure and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as a pale orange solid (1.16 g, 56% yield). ¹H NMR (400 MHz, CDCl3): δ 8.51 (s, 1 H), 4.12 (s, 3 H), 4.04 (s, 3 H), 3.96 (s, 3 H). b) Methyl 2-(5,6-dimethoxypyrazin-2-yl)-2-hydroxyacetate To a solu tion of methyl 2-(5,6-dimethoxypyrazin-2-yl)-2-oxoacetate (1.06 g, 5.1 mmol) in dry methanol (20 mL) under nitrogen at 0 °C, sodium borohydride (160 mg, 4.1 mmol) was added in portions over 5 min. The reaction mixture was stirred at 0 °C for 30 min. before being diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous was washed with ethyl acetate (20 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (280 mg, 28% yield). ¹H NMR (400 MHz, CDCl3): δ 7.73 (s, 1 H), 5.15 (d, J = 7.8 Hz, 1 H), 4.03 (s, 3 H), 4.02 (s, 3 H), 3.78 (s, 3 H), (OH peak not observed). c) Methyl 2-bromo-2-(5,6-dimethoxypyrazin-2-yl)acetate To a solution of methyl 2-(5,6-dimethoxypyrazin-2-yl)-2-hydroxyacetate (280 mg, 1.2 mmol) in dry dichloromethane (15 mL) under nitrogen were added carbon tetrabromide (431 mg, 1.35 mmol) and subsequently triphenylphosphine (341 mg, 1.35 mmol). The reaction mixture was stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure and the crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as a pale-yellow oil (180 mg, 51% yield). ¹H NMR (400 MHz, CDCl3): δ 7.89 (s, 1 H), 5.44 (s, 1 H), 4.04 (s, 3 H), 4.01 (s, 3 H), 3.82 (s, 3 H). d) 2-(5,6-Dimethoxypyrazin-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)- one A solutio y , ypy y g, . 3 mmol) and 2-aminobenzenethiol (15 μL, 0.14 mmol) in DMF (0.5 mL) was stirred at room temperature for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (15 mL) and 5% lithium chloride aqueous solution (5 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as a white solid (32 mg, 76% yield). ¹H NMR (400 MHz, CDCl3): δ 8.59 (s, 1 H), 7.64-7.63 (m, 1 H), 7.18-7.13 (m, 1 H), 7.02-6.97 (m, 1 H), 6.87 (dd, J = 1.1, 8.0 Hz, 1 H), 4.64 (s, 1 H), 3.96 (s, 3 H), 3.59 (s, 3 H), (NH peak not observed). e) 2-(5,6-Dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]th iazine To a suspension of 2-(5,6-dimethoxypyrazin-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)- one (52 mg, 0.17 mmol) in dry THF (1 mL) under nitrogen at 0 °C was added dropwise a solution of borane THF complex (1 M in THF, 2.6 mL, 2.6 mmol). The reaction mixture was stirred at room temperature for 18 hrs then quenched with water and diluted with ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (2 x 30 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 40% ethyl acetate in cyclohexane) to yield the title compound (23 mg, 48% yield). ¹H NMR (400 MHz, CDCl3): δ 7.74-7.73 (m, 1 H), 7.04 (dd, J = 1.4, 7.8 Hz, 1 H), 6.94-6.90 (m, 1 H), 6.68-6.63 (m, 1 H), 6.53 (dd, J = 1.1, 8.0 Hz, 1 H), 4.38 (t, J = 5.2 Hz, 1 H), 4.00 (s, 3 H), 3.99 (s, 3 H), 3.85-3.83 (m, 2 H), (NH peak not observed). f) 5-(3,4-Dihydro-2H-benzo[b][1,4]thiazin-2-yl)-1,4-dihydropyra zine-2,3-dione To a sol , , , zine (32 mg, 0.11 mmol) in dry acetonitrile (1.1 mL) under nitrogen was added sodium iodide (50 mg, 0.33 mmol) and subsequently chlorotrimethylsilane (42 μL, 0.33 mmol) at room temperature and the reaction mixture was stirred at 60 °C for 1 hour. The mixture was diluted with water (30 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL) and a 4:1 mixture of dichloromethane and methanol (20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to yield the title compound as a light yellow solid (9.1 mg, 31%). ¹H NMR (400 MHz, DMSO): δ 11.36 (s, 1H), 11.14 - 11.13 (m, 1H), 6.92 - 6.85 (m, 2H), 6.57 (dd, J=1.1, 8.1 Hz, 1H), 6.54 - 6.49 (m, 1H), 6.27 - 6.21 (m, 2H), 4.07 - 4.04 (m, 1H), 3.62 - 3.59 (m, 2H). MS (ESI+) m/z 262 (M+H)+. 5-(3-Oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)-1,4-dihyd ropyrazine-2,3-dione (Example 296) Following step f from Method AD yielded the title compound as an off-white solid. ¹H NMR (400 MHz, DMSO): δ 11.43 (s, 1 H), 11.06 (s, 1 H), 10.98 (s, 1 H), 7.34 (q, J = 3.0 Hz, 1 H), 7.27-7.22 (m, 1 H), 7.05 (d, J = 7.5 Hz, 1 H), 7.02 (q, J = 3.0 Hz, 1 H), 5.91 (s, 1 H), 4.57 (s, 1 H). MS (ES+) m/z 276 (M+H)+. 5-(4-Methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)-1,4-di hydropyrazine-2,3- dione (Example 297) a) 2-(5,6-Dimethoxypyrazin-2-yl)-4-me thiazin-3(4H)-one To a solu on o -( , - me oxypyraz n- -y )- - enzo[ ][ , ] az n- ( )-one (175 mg, 0.58 mmol) in dry THF (2 mL) under nitrogen was added sodium hydride (60% in mineral oil, 25 mg, 0.64 mmol) in one portion at 0 °C. After 20 min. stirring at 0 °C, methyl iodide (0.043 mL, 0.69 mmol) was added, the reaction mixture was stirred at room temperature for two hrs and then quenched by addition of water (10 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 70% ethyl acetate in cyclohexane) to yield the title compound (80 mg, 44% yield). ¹H NMR (400 MHz, CDCl3) δ 7.57 (s, 1 H), 7.34 - 7.22 (m, 2 H), 7.13 - 7.08 (m, 1 H), 7.03 - 6.97 (m, 1 H), 4.69 (s, 1 H), 3.95 (s, 3 H), 3.66 (s, 3 H), 3.54 (s, 3 H). b) 5-(4-Methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)-1,4-di hydropyrazine-2,3- dione Following steps e-f from Method AD yielded the title compound as an off-white solid. ¹H NMR (400 MHz, DMSO) δ 11.39 (s, 1 H), 11.19 - 11.14 (m, 1 H), 7.08 - 7.02 (m, 2 H), 6.80 (d, J=7.3 Hz, 1 H), 6.71 - 6.66 (m, 1 H), 6.24 - 6.20 (m, 1 H), 4.28 (dd, J=3.3, 6.8 Hz, 1 H), 3.73 - 3.59 (m, 2 H), 2.97 (s, 3 H). MS (ES+) m/z 276 (M+H)+. Method AE 5-(6-Chloro-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)-1,4-di hydropyrazine-2,3- dione (Example 298) a) 1-(5,6-Dimethoxypyrazin-2-y - - - - To a solution of 5 ,6-dimethoxypyrazine-2-carbaldehyde (2 g, 11.9 mmol) in dry THF (40 mL) under nitrogen was added potassium carbonate (1.88 g, 14.2 mmol) and nitromethane (0.7 mL, 13.0 mmol) and the reaction mixture was stirred at room temperature for 18 hrs. The mixture was diluted with water (50 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were washed with brine (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (25 – 55% ethyl acetate in cyclohexane) to yield the title compound as a white solid (1.93 g, 71% yield). ¹H NMR (400 MHz, CDCl3): δ 7.79 (s, 1 H), 5.41-5.36 (m, 1 H), 4.76-4.73 (m, 2 H), 4.04 (s, 3 H), 4.02 (s, 3 H), 3.21 (d, J = 6.8 Hz, 1 H). b) tert-Butyl (2-(5,6-dimethoxypyrazin-2-yl)-2-hydroxyethyl)carbamate To a solution of 1-(5,6-dimethoxypyrazin-2-yl)-2-nitroethan-1-ol (1.92, 8.37 mmol) in a 1:1 mixture of methanol and saturated ammonium chloride solution (80 mL), zinc (5.47 g, 83.8 mmol) was added in small portions at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. before adding di-tert-butyl dicarbonate (2.19 g, 10.04 mmol). The reaction mixture was allowed to warm to room temperature and stirred for two hrs. The crude mixture was filtered through a pad of Celite ^TM , which was washed with ethyl acetate, and the filtrate was diluted with ethyl acetate (200 mL) and washed with brine (40 mL). The aqueous layer was extracted with ethyl acetate (100 mL) and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (10 – 100% ethyl acetate in cyclohexane) to yield the title compound as a colourless oil (1.16 mg, 46% yield). ¹H NMR (400 MHz, CDCl3): δ 7.74- 7.70 (m, 1 H), 5.01-4.97 (m, 1 H), 4.79-4.72 (m, 1 H), 4.03 (s, 3 H), 4.02 (s, 3 H), 3.63-3.51 (m, 2 H), 3.43-3.34 (m, 1 H), 1.43 (s, 9 H). c) tert-Butyl (2-((2-bromo-4-chlorophenyl)thio)-2-(5,6-dimethoxypyrazin-2- yl)ethyl)carbamate To a solution of tributylphophine (0.21 mL, 0.84 mmol) in dry THF (2.5 mL) under nitrogen was added diisopropyl azodicarboxylate (0.17 mL, 0.84 mmol) and the resulting mixture was stirred at 0 °C for 20 min. A solution of tert-butyl (2-(5,6-dimethoxypyrazin-2-yl)- 2-hydroxyethyl)carbamate (210 mg, 0.7 mmol) and 2-bromo-4-chlorobenzenethiol (156 mg, 0.7 mmol) in dry THF (2.5 mL) was added dropwise over 10 min. and the reaction mixture was stirred at room temperature for 18 hours, then concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as a colourless oil (287 mg, 81% yield). ¹ H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 1.8 Hz, 1 H), 7.51-7.50 (m, 1 H), 7.45 (d, J = 9.6 Hz, 1 H), 7.26-7.22 (m, 1 H), 4.98 (s, 1 H), 4.49-4.40 (m, 1 H), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.71 (t, J = 6.3 Hz, 2 H), 1.42 (s, 9 H). d) 2-((2-Bromo-4-chlorophenyl)thio)-2-(5,6-dimethoxypyrazin-2-y l)ethan-1-amine (287 mg, 0.57 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.87 mL, 11.4 mmol) and the mixture was stirred at room temperature for 2 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the title compound as a light yellow oil (230 mg, 100% yield). ¹H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 2.3 Hz, 1 H), 7.51-7.51 (m, 1 H), 7.29 (d, J = 8.6 Hz, 1 H), 7.18 (dd, J = 2.3, 8.6 Hz, 1 H), 4.25 (dd, J = 6.1, 7.1 Hz, 1 H), 4.00 (s, 3 H), 3.99 (3, 3 H), 3.36 (dd, J = 7.3, 13.4 Hz, 1 H), 3.35 (bs, 2 H), 3.24 (dd, J = 5.8, 13.4 Hz, 1 H). e) 6-Chloro-2-(5,6-dimethoxypyrazin-2-yl)-3,4-dihydro-2H-benzo[ b][1,4]thiazine To a degassed solution of 2-((2-bromo-4-chlorophenyl)thio)-2-(5,6-dimethoxypyrazin-2- yl)ethan-1-amine (210 mg, 0.52 mmol), (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (33 mg, 0.05 mmol) and sodium tert-butoxide (76 mg, 0.79 mmol) in dry toluene (4 mL) was added tris(dibenzylideneacetone)diPd(0) (24 mg, 0.02 mmol) and the reaction was heated to 100 °C under nitrogen for 18 hrs. The reaction was allowed to cool to room temperature and ethyl acetate (50 mL) and water (10 mL) were added. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as a light yellow oil (87 mg, 52% yield). ¹H NMR (400 MHz, CDCl3): δ 7.71-7.70 (m, 1 H), 6.96-6.93 (m, 1 H), 6.63-6.60 (m, 1 H), 6.52 (d, J = 2.3 Hz, 1 H), 4.32 (dd, J = 4.3, 6.1 Hz, 1 H), 4.15 (s, 1 H), 4.01 (s, 3 H), 3.98 (s, 3 H), 3.86-3.82 (m, 2 H). f) 5-(6-Chloro-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)-1,4-di hydropyrazine-2,3- dione To a s , y y y , y benzo[b][1,4]thiazine (60 mg, 0.18 mmol) in dioxane (2.5 mL) was added 2 M hydrochloric acid (2.3 mL) and the mixture was heated at 100 °C for 4 hrs. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The crude material was purified by preparative HPLC to yield the title compound as a white solid (22 mg, 40%). ¹H NMR (400 MHz, DMSO): δ 11.37 (t, J = 15.3 Hz, 1 H), 11.20-11.19 (m, 1 H), 6.94-6.91 (m, 1 H), 6.62-6.51 (m, 3 H), 6.20 (s, 1 H), 4.05 (t, J = 4.5 Hz, 1 H), 3.65-3.61 (m, 2 H). MS (ES+) m/z 296 (M+H)+. 5-(6-(Trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-2 -yl)-1,4- dihydropyrazine-2,3-dione (Example 299) Following steps a-f from Method AE yielded the title compound as a white solid. ¹H NMR (400 MHz, DMSO): δ 11.39 (bs, 1 H), 11.19 (bs, 1 H), 7.15-7.12 (m, 1 H), 6.88 (d, J = 1.5 Hz, 1 H), 6.81-6.72 (m, 2 H), 6.23 (s, 1 H), 4.13 (t, J = 4.5 Hz, 1 H), 3.68-3.64 (m, 2 H). MS (ES+) m/z 330 (M+H)+. 5-(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-y l)-1,4- dihydropyrazine-2,3-dione (Example 300) Method AF a) 6-chloro-2-(5,6-dimethoxypyrazin-2-yl)-4-methyl-3,4-dihydro- 2H- benzo[b][1,4]thiazine To a s o u on o -c oro- -( , - me oxypyraz n- -y )- , - y ro- - benzo[b][1,4]thiazine (86 mg, 0.26 mmol) in acetic acid (1 mL) was added formaldehyde (37% aqueous solution, 0.2 mL, 2.66 mmol). The reaction mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (80 mg, 1.27 mmol) was added. After stirring at room temperature for 1 hour, the crude mixture was carefully poured into ice-cold 6 M aqueous sodium hydroxide solution (5 mL), then extracted with dichloromethane (3 x 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 – 100% ethyl acetate in cyclohexane) to yield the title compound as a light yellow oil (55 mg, 61% yield). ¹H NMR (400 MHz, CDCl3): δ 7.69 (s, 1 H), 7.00-6.97 (m, 1 H), 6.66-6.61 (m, 2 H), 4.36 (dd, J = 3.3, 7.8 Hz, 1 H), 4.00 (s, 3 H), 3.99 (s, 3 H), 3.87 (dd, J = 8.0, 12.0 Hz, 1 H), 3.75 (dd, J = 3.7, 12.0 Hz, 1 H), 2.98-2.97 (m, 3 H). b) 5-(6-Chloro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-y l)-1,4- dihydropyrazine-2,3-dione Following step f from Method AE yielded the title compound as a white solid. ¹H NMR (400 MHz, DMSO): δ 11.32 (s, 1 H), 11.11 (s, 1 H), 7.03-7.00 (m, 1 H), 6.74 (d, J = 2.1 Hz, 1 H), 6.66 (dd, J = 2.1, 8.3 Hz, 1 H), 6.14 (s, 1 H), 4.22 (dd, J = 3.3, 6.7 Hz, 1 H), 3.74-3.61 (m, 2 H), 2.95 (s, 3 H). MS (ES+) m/z 310 (M+H)+. 5-(4-Methyl-6-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4] thiazin-2-yl)-1,4- dihydropyrazine-2,3-dione (Example 301) Following steps a-b from Meth o ye e e e compound as a white solid. ¹H NMR (400 MHz, DMSO): δ 11.39 (s, 1 H), 11.12 (s, 1 H), 7.23 (d, J = 7.7 Hz, 1 H), 6.93 (d, J = 10.2 Hz, 2 H), 6.19 (s, 1 H), 4.32 (dd, J = 3.3, 6.8 Hz, 1 H), 3.77-3.63 (m, 2 H), 3.00 (s, 3 H). MS (ES+) m/z 344 (M+H)+. Biological Assays The D-amino acid oxidase (DAO) assays are fluorescence-based assays, in which the hydrogen peroxide (H2O2) generated from the reaction of D-serine with DAO and Flavine Adenine Dinucleotide (FAD), is linked to oxidation of Amplex Red in the presence of horseradish peroxidase (HRP). The Amplex Red reagent reacts with H2O2 in a 1:1 stoichiometry to produce the red-fluorescent oxidation product, resorufin, which is measured fluorometrically. Preparation of Assay Ready Plates 100-fold concentrated, 12-point serial dilutions of test compounds (250 nL) in duplicate were prepared using DMSO in 384 well black plates (262260, Nunc) using the Echo555 Acoustic Dispenser (Labcyte). These assay ready plates were employed in the biochemical and cellular screening assays described below. Human DAO Biochemical Assay The human DAO biochemical assay was performed using reagents at the following final assay concentrations: 1 nM recombinant full-length human DAO protein, D-Serine at Km concentration (10 mM), 50 µM FAD (excess), 50 µM Amplex Red and 0.1 U/mL HRP in the presence of compound or DMSO vehicle (1%). All reagents were made up in assay buffer containing 20 mM Tris, pH 7.4 + 0.1% BSA. The final assay volume was 25 µL/well. Briefly, 10 µL of a working solution containing 2.5 nM hDAO (TECC-1280-14AA, Takeda) and 125 µM FAD (F6625, Sigma) in assay buffer was added to all the wells in the assay ready plate (containing 250 nL compound / DMSO vehicle per well) except for the negative control wells. 10 µL of 125 µM FAD (working solution) was added to the negative control wells containing 250 nL of DMSO vehicle. The plates were incubated at 25˚C for 20 minutes (pre- incubation of compound with human DAO). 10 µL of a working solution containing 125 µM Amplex Red and 0.25 U/mL HRP (A22188, ThermoFisher Scientific) in assay buffer was then added to all the wells. The reaction was initiated by the addition of 5 µL of 50 mM D-Serine (S4250, Sigma-Aldrich) to all the wells. The plate was incubated for 4 hours in the dark at 25˚C before measuring fluorescence in each well using the Envision plate reader with excitation at 530 nm and emission at 595 nm. Concentration response curves were generated using ActivityBase (IDBS). IC50 values were determined by plotting % Inhibition vs Log10 compound concentration using a sigmoidal fit with a variable slope (four parameter fit). Horseradish Peroxidase (HRP) Counter Screen The HRP counter screen was routinely performed using reagents at the following final assay concentrations: D-Serine (10 mM), FAD (50 µM), Amplex Red (50 µM), HRP (0.1 U/mL) and hydrogen peroxide (H2O2) (2 µM) in the presence of compound or DMSO vehicle (1%). All reagents were made up in assay buffer containing 20 mM Tris, pH7.4 + 0.1% BSA. The final assay volume was 25 µL/well. Briefly, 5 µL of 250 µM FAD and 5µL of 50mM D-Serine were added to all the wells in the assay ready plate (containing 250 nL compound / DMSO vehicle per well). 5 µL of a working solution containing 250 µM Amplex Red and 0.5 U/mL HRP was added to all the wells except for the negative control wells. 5 µL of 250 µM Amplex Red was added to the negative control wells containing 250 nL of DMSO vehicle. 10 µL of 5 µM H2O2 was added to all the wells. The plate was incubated for 10 minutes in the dark at 25˚C before measuring fluorescence in each well using the Envision plate reader with excitation at 530 nm and emission at 595 nm. Dose response curves were generated using ActivityBase (IDBS). IC50 values were determined by plotting % Inhibition vs Log10 compound concentration using a sigmoidal fit with a variable slope (four parameter fit). Human DAO Cell Assay The human DAO cell assay routinely employed a CHO-K1 clone, which was stably transfected with a mammalian expression plasmid containing the human DAO nucleotide encoding the full-length human DAO protein. This cell line was originally generated as described in Howley et al, 2017 (Supplementary Information). The human DAO CHO-K1 stable cell line was routinely cultured in Gibco Ham's F-12 Nutrient Mix (31765-027, ThermoFisher Scientific) containing 10% FBS (10082-147, ThermoFisher Scientific) and 500 µg/mL Geneticin™ Selective Antibiotic (10131-027, ThermoFisher Scientific). The human DAO cell assay was performed using the following final assay conditions: 25,000 human DAO CHO-K1 stable cells/well, 50 mM D-Serine, 50 µM Amplex Red and 0.125 U/mL HRP. All cells and reagents were made up in 10 mM HEPES buffer (15630-056, ThermoFisher Scientific). The final assay volume was 25 µL/well. The human DAO CHO-K1 stable cells were trypsinised, resuspended in complete medium and centrifuged at 1200 rpm for 4 minutes at room temperature. The cell pellet was then washed in 10 mM HEPES buffer and centrifuged at 1200 rpm for 4 minutes at room temperature. The resulting cell pellet was resuspended in 10 mM HEPES buffer at 1.25x10 ⁶ cells/mL. 25,000 human DAO CHO-K1 stable cells (20 µL in 10 mM HEPES buffer) were added to all the wells in the assay ready plate (containing 250 nL compound / DMSO vehicle per well). 5µl of a working solution containing 250 mM D-Serine, 250 µM Amplex Red and 0.625 U/mL HRP in assay buffer was added to all the wells except for the negative control wells. 5 µL of a working solution of 250 µM Amplex Red and 0.625 U/mL HRP in assay buffer was added to the negative control wells. The plate was incubated for 30 minutes in the dark at 25˚C before measuring fluorescence in each well using the Envision plate reader with excitation at 530 nm and emission at 595 nm. Dose response curves were generated using ActivityBase (IDBS). IC50 (Point of Inflection) values were determined by plotting % Inhibition vs Log10 compound concentration using a sigmoidal fit with a variable slope (four parameter fit). Mouse DAO Cell Assay The mouse DAO cell assay routinely employed CHO-K1 cells, which were transiently transfected with an expression plasmid containing the mouse DAO nucleotide encoding the full- length mouse DAO protein. The CHO-K1 cell line was routinely cultured in Gibco Ham's F-12 Nutrient Mix containing 10% FBS. The mouse DAO cell assay was performed using the following final assay conditions: 35,000 CHO-K1 cells transiently transfected with mouse DAO/ pcDNA3.1+C_(K)-DYK expression plasmid, 50 mM D-Serine, 50 µM Amplex Red and 0.125 U/mL HRP. All cells and reagents were made up in 10 mM HEPES buffer. The final assay volume was 25 µL/well. Briefly, 5x10 ⁶ CHO-K1 cells were seeded into two T175 flasks, in Gibco Ham's F-12 Nutrient Mix containing 10% FBS and incubated for 24 hours at 37 °C/5% CO2. The T175 flasks, which were seeded with CHO-K1 cells were transfected with mouse DAO/ pcDNA3.1+C_(K)-DYK expression plasmid as follows. A transfection mix for each T175 flask was made up containing 43.75 µL mouse DAO/ pcDNA3.1+C_(K)-DYK expression plasmid (OMu05394D_pcDNA3.1+ C_(K)-DYK endotoxin free (maxi-prep, 1 mg/mL, Genscript), 8575 µL of Optimem (31985-062, ThermoFisher Scientific) and 131.25 µL of Lipofectamine LTX (15338-100, ThermoFisher Scientific). The transfection mix was incubated at room temperature for 25 minutes. During this incubation period the complete growth medium was removed by aspiration from the CHO-K1 cells, which were seeded 24 hours previously and replaced with 35ml of fresh Gibco Ham's F-12 Nutrient Mix containing 10% FBS. The transfection mix was then added to each flask containing CHO-K1 cells and incubated for a further 24 hours at 37 °C/5% CO2. The mouse DAO transiently transfected CHO-K1 cells were trypsinised, resuspended in complete medium and centrifuged at 1200 rpm for 4 minutes at room temperature. The cell pellet was then washed in 10mM HEPES buffer and centrifuged at 1200 rpm for 4 minutes at room temperature. The resulting cell pellet was resuspended in 10 mM HEPES buffer at 1.75x10 ⁶ cells/mL. 35,000 mouse DAO CHO-K1 transiently transfected cells (20 µL in 10 mM HEPES buffer) were added to all the wells in the assay ready plate (containing 250 nL compound / DMSO vehicle per well). 5 µL of a working solution containing 250 mM D-Serine, 250 µM Amplex Red and 0.625 U/mL HRP in assay buffer was added to all the wells except for the negative control wells. 5 µL of a working solution of 250 µM Amplex Red and 0.625 U/mL HRP in assay buffer was added to the negative control wells. The plate was incubated for 30 minutes in the dark at 25˚C before measuring fluorescence in each well using the Envision plate reader with excitation at 530 nm and emission at 595 nm. Dose response curves were generated using ActivityBase (IDBS). IC50 (Point of Inflection) values were determined by plotting % Inhibition vs Log10 compound concentration using a sigmoidal fit with a variable slope (four parameter fit). Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the disclosure are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The disclosure is not restricted to the details of any foregoing embodiments. The disclosure extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. All documents cited or referred to in this specification, and the contents of all such documents are incorporated herein by reference in their entireties. Table A. Human DAAO Biochemical Inhibition (A ≤ 100 nM; 100 nM < B ≤ 1 µM; 1 µM < C < 10 µM) 24 C 165 B 247 A 103 A 214 A 295 B Table B. Human and mouse DAAO cell-based inhibition (A ≤ 100 nM; 100 nM < B ≤ 1 µM; 1 µM < C < 10 µM) E _{xample #} ^{hDAAO cell} mDAAO cell Example # hDAAO cell mDAAO cell 84 B B 239 C B 191 B B 300 B B