WO2022015624A1 - Dihydropyrazinediones substituées en tant que modulateurs du récepteur nmda - Google Patents

Dihydropyrazinediones substituées en tant que modulateurs du récepteur nmda Download PDF

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WO2022015624A1
WO2022015624A1 PCT/US2021/041224 US2021041224W WO2022015624A1 WO 2022015624 A1 WO2022015624 A1 WO 2022015624A1 US 2021041224 W US2021041224 W US 2021041224W WO 2022015624 A1 WO2022015624 A1 WO 2022015624A1
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compound
mmol
methyl
ring
thio
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PCT/US2021/041224
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English (en)
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James Lewis
James Osborne
Jason Tierney
John Ellard
James Gordon
Maria PALOMERO-VAZQUEZ
Daniel Jones
Kim Hirst
Mark Sephton
Piero TARDIA
Andrew Sharpe
Haifeng Tang
Sathesh Bhat
Fiona MCROBB
Evelyne HOUANG
Markus DAHLGREN
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Schrödinger, Inc.
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Publication of WO2022015624A1 publication Critical patent/WO2022015624A1/fr

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    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • 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.
  • DAAO N-methyl-D-aspartic acid
  • the NMDA receptor regulates a number of pathways involved in neurological function, including the positive (psychotic), negative, and cognitive symptoms of schizophrenia.
  • 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.
  • 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.
  • tautomer 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.
  • 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.
  • 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.
  • a C1-C3 alkyl group is linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • C1-C3 hydroxyalkyalkyl may refer to hydroxymethyl, hydroxyethyl e.g., 1-hydroxyethyl and 2- hydroxyethyl, and 2,2-dihydroxyethyl.
  • 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.
  • 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.
  • cyano refers to a –CN radical.
  • hydroxyl refers to an –OH radical.
  • amino refers to an –NH2 radical.
  • aryl refers to a 6–10 all carbon mono- or fused bicyclic group wherein at least one ring in the system is aromatic.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl.
  • the non-aromatic ring can be a cycloalkyl group, as defined herein.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • the heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen.
  • 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, dioxopiper
  • the term “geminal” refers to substituent atoms or groups attached to the same atom in a molecule.
  • 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.
  • 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.
  • the compounds of Formula (I) include pharmaceutically acceptable salts thereof.
  • 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.
  • 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.
  • 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.
  • the compounds of Formula (I) include the compounds of Examples 1- 306 and stereoisomers and pharmaceutically acceptable salts thereof.
  • the compounds of Examples 1-306 are in the free base form.
  • the compounds of Examples 1-306 are in the salt form.
  • 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.
  • a nitrogen protecting group can be any temporary substituent which protects an amine moiety from undesired chemical transformations.
  • 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).
  • benzylamines e.g., bezy
  • An oxygen protecting group can be any temporary substituent which protects a hydroxyl moiety from undesired chemical transformations.
  • 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.
  • esters e.g., acetyl, t- butyl carbonyl, and benzoyl
  • benzyl e.g., benzyl, p-methoxybenzyl, and 2,4-dimethoxybenzyl,
  • 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.
  • 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.
  • 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.
  • neurological disorders such as schizophrenia, schizoaffective disorder, schizophreniform disorder, mild congnitive impairment, and neuropathic pain.
  • 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.
  • 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)).
  • 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).
  • 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.
  • 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).
  • preventing 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.
  • 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).
  • R 1 is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl
  • R A , R B , R C , and R D are independently hydrogen, fluoro, or C1-C3 alkyl; or R A and R B
  • 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.
  • X is a bond.
  • Y is CR C R D .
  • Y is -O-.
  • Y is -NH-.
  • Y is -S-.
  • Y is -S(O 2 )-.
  • Y is a bond.
  • X is CR A R B and Y is CR C R D .
  • X is CR A R B and Y is -S-.
  • 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 .
  • 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.
  • 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.
  • R C and R D with the carbon atom to which they are attached, together form a cyclopropyl.
  • -X-Y- is -CH2-CH2-.
  • -X-Y- is -CF2-CF2-.
  • -X-Y- is -S-CH2-.
  • -X-Y- is -S-CH(CH3)-.
  • -X-Y- is -S-cyclopropyl-.
  • -X-Y- is -CH 2 -S-.
  • -X-Y- is .
  • -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.
  • Ring A is selected from: indazolyl, pyridinyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, thiophenyl, benzothiadiazolyl, benzotriazolyl, benzoisothiazolyl, cinnolinyl, imidazo[1,2- a]pyridinyl, and benzisoxazolyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-.
  • 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.
  • 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 .
  • 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.
  • 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.
  • m is 1 and R 2 is methyl, fluoro, chloro, bromo, hydroxyl, difluoromethyl, trifluoromethyl, or cyano.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 cyano; and the other R 2 is methyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 al
  • 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.
  • R 1A is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl
  • 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.
  • the neurological disorder is neuropathic pain, schizophrenia, schizoaffective disorder, schizophreniform disorder, or mild cognitive impairment (MCI).
  • the neurological disorder is neuropathic pain.
  • the neurological disorder is schizophrenia.
  • the neurological disorder is mild cognitive impairment (MCI).
  • the neurological disorder is schizoaffective disorder.
  • the neurological disorder is schizophreniform disorder.
  • the subject is a human.
  • the method further comprises increasing the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, over a period of time.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the methods described herein further comprise providing cognitive behavior therapy to the subject.
  • the one or more additional therapies is a standard of care treatment for neuropathic pain.
  • the one or more additional therapies is a standard of care treatment for schizophrenia.
  • the one or more additional therapies is a standard of care treatment for MCI.
  • the one or more additional therapies is a standard of care treatment for schizoaffective disorder.
  • the one or more additional therapies is a standard of care treatment for schizophreniform disorder.
  • 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.
  • 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.
  • the one or more additional therapies is an antidepressant.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the antidepressant is a monoamine oxidase inhibitor.
  • Representative monoamine oxidase inhibitors include, but are not limited to moclobemide, rasagiline, selegiline, or safinamide.
  • the antidepressant is a selective norepinephrine reuptake inhibitor.
  • Representative selective norepinephrine reuptake inhibitors include, but are not limited to reboxetine.
  • the antidepressant is a tricyclic antidepressant.
  • 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.
  • 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.
  • 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.
  • the one or more additional therapies is electroconvulsive therapy or transcranial magnetic stimulation.
  • the one or more additional therapies is sertraline.
  • 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.
  • 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).
  • clonixin such as aspirin and diflunisal
  • salicylates such as aspirin and diflunisal
  • propionic acid derivative such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dex
  • 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).
  • opioids such as morphine, oxycodone, methadone, codeine, fentanyl, hydrocodone, and tramadol.
  • the one or more additional therapies is an anxiolytic.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the subject has previously been administered a standard of care treatment for neuropathic pain and the subject was not responsive to the previous therapy.
  • 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.
  • 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.
  • 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.
  • 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.
  • typical antipsychotics such as chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorpera
  • 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.
  • atypical antipsychotics such as aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the subject has previously been administered one or more selective norepinephrine reuptake inhibitors, such as reboxetine, and was not responsive to the previous therapy.
  • 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.
  • tricyclic antidepressants such as amineptine, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin, imipramine, iprin
  • 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.
  • 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.
  • the one or more additional therapies is electroconvulsive therapy or transcranial magnetic stimulation, and was not responsive to the previous therapy.
  • 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.
  • 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.
  • NSAIDs such as clonixin, licofelone, aspirin, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, indomethacin, tolmetin, sulind
  • 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.
  • analgesics such as nefopam, flupiritine, ziconotide, acetaminophen, morphine, oxycodone, methadone, codeine, fentanyl, hydrocodone, or tramadol
  • 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.
  • anxiolytics
  • the subject has previously been administered gabapentin or pregabalin, and was not responsive to the previous therapy.
  • the one or more additional therapies previously administered to the subject is one additional therapy.
  • the one or more additional therapies previously administered to the subject is two additional therapies.
  • the one or more additional therapies previously administered to the subject is three additional therapies.
  • the one or more additional therapies previously administered to the subject is four additional therapies.
  • 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.
  • 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.
  • 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.
  • 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.
  • the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting 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.
  • phrases “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.
  • 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.
  • 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 intranas
  • 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.
  • 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.
  • a pharmaceutical composition prepared using a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the composition is suitable for topical administration.
  • 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.
  • 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.
  • 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.
  • the composition is formulated for oral administration.
  • the composition is a solid oral formulation.
  • the composition is formulated as a tablet or capsule.
  • compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier 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).
  • 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.
  • 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.
  • any of the usual pharmaceutical media can be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • 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.
  • the carrier will usually consist of sterile water and other ingredients can be added to increase solubility or preservation.
  • 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.
  • 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.
  • 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.
  • active material i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof
  • the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient.
  • compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • kits can also be included in the kit.
  • 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.
  • 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.
  • 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 ⁇ m, 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.
  • 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 ( ⁇ ) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g.
  • 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 ⁇ m 19 ⁇ 150 mm or Waters CSH Phenyl Hexyl, 19 ⁇ 150, 5 ⁇ m 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.
  • SFC Supercritical Fluid Chromatography
  • 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 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%).
  • 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 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.
  • Example 20 (5-(3-Fluoro-4-(1-hydroxyethyl)phenethyl)-1,4-dihydropyrazine-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)+.
  • 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%).
  • 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.
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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: ⁇ 7.70 (s, 1 H), 7.50-7.29 (m, 10 H), 5.45-5.40 (m, 4 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).
  • 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 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%).
  • 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%).
  • 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%).
  • 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.
  • 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]isothiazole.
  • 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).
  • 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%).
  • 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%).
  • 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)+.
  • 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 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%).
  • step c) 4-((1-(5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)ethyl)thio)benzonitrile 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- ⁇ 6- sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione, to yield the desired product as an off-white solid (33 mg, 18%).
  • 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 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%).
  • Method M 5-(((6-Fluoronaphthalen-2-yl)thio)methyl)-1,4-dihydropyrazine-2,3-dione (Example 139) a) 5-(((6-Fluoronaphthalen-2-yl)thio)methyl)-1,4-dihydropyrazine-2,3-dione 2-Bromo-6-fluoronaphthalene was reacted following general procedures a-c, Method L used to prepare 5-(((4-(pentafluoro- ⁇ 6-sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3- dione) to yield 5-(((6-fluoronaphthalen-2-yl)thio)methyl)-2,3-dimethoxypyrazine.
  • 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 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%).
  • 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).
  • 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%).
  • Example 153 (3-Chloro-4-(((5,6-dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)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)benzonitrile (Method O). MS (ES+) m/z 312 (M+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)methyl)thio)benzonitrile (Method O). MS (ES+) m/z 371 (M+H)+.
  • step b-c 4-(((5,6-Dioxo-1,4,5,6-tetrahydropyrazin-2-yl)methyl)thio)-3-(1,2,4-thiadiazol-3- yl)benzonitrile
  • 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).
  • Example 160 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-fluoronaphthalen-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.
  • sodium hydride (0.25 g, 60% in mineral oil, 6.5 mmol
  • 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).
  • step c 5-((Benzo[c]isoxazol-5-ylthio)methyl)-1,4-dihydropyrazine-2,3-dione
  • step c from Method L used to prepare 5-(((4-(pentafluoro- ⁇ 6- sulfaneyl)phenyl)thio)methyl)-1,4-dihydropyrazine-2,3-dione also yielded the title compound as a white solid (4.3 mg, 24%).
  • 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 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%).
  • Example 165 (5-(1-((4-(trifluoromethyl)phenyl)thio)cyclopropyl)-1,4-dihydropyrazine- 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)+.
  • 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.
  • 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 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%).
  • reaction was then allowed to cool to room temperature and filtered through CeliteTM, 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%).
  • 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 %).
  • 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%).
  • 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%).
  • 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.
  • 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.
  • 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).
  • 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%).
  • Racemic 5-(3-Methyl-7-(methylsulfonyl)-2,3-dihydrobenzo[b][1,4]oxathiin-3-yl)-1,4- dihydropyrazine-2,3-dione was resolved by chiral SFC to afford single enantiomers.
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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.
  • sodium iodide 140 mg, 0.931 mmo
  • 5-(7-(difluoromethyl)chroman-3-yl)-2,3-dimethoxypyrazine 60 mg, 0.186 mmol
  • chlorotrimethylsilane 101 mg, 120 L, 0.931 mmol
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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%).
  • 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 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 reaction mixture was cooled to room temperature, diluted with acetonitrile (5 mL), filtered through CeliteTM, 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%).
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered through CeliteTM 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%).
  • reaction mixture was cooled to room temperature, diluted with acetonitrile (5 mL), filtered through CeliteTM, 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%).
  • 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).
  • 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%).
  • 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%).
  • 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%).

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Abstract

La présente invention concerne des composés de Formule (I), tels que définis dans la description, et des sels pharmaceutiquement acceptables de ceux-ci. La présente invention concerne également une composition pharmaceutique comprenant un composé de formule (I) et des sels pharmaceutiquement acceptables de ceux-ci, ainsi que des procédés d'utilisation des composés et des compositions pour traiter des troubles neurologiques tels que la schizophrénie, un trouble cognitif léger et une douleur neuropathique chronique.
PCT/US2021/041224 2020-07-16 2021-07-12 Dihydropyrazinediones substituées en tant que modulateurs du récepteur nmda WO2022015624A1 (fr)

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