Deuterated idazoxan and methods of use thereof

Abstract

Deuterated forms of idazoxan according to formula (I), and pharma- ceutically acceptable salts thereof, pharmaceutical compositions containing these compounds, and methods of treatment or prevention using these compounds or pharmaceutical compositions are described. These compounds are useful for the treatment or prevention of a disease or condition selected from psychosis, schizophrenia, schizoaffective disorder, Parkinson's disease, dementia with Lewy bodies, sleep disorders (including insomnia), agitation, mood disorders (including depression), thromboembolic disorders, autism, and attention deficit hyperactivity disorder. [Formula 1] JPEG2025506663000057.jpg42165

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 320,342, filed March 16, 2022, and U.S. Provisional Application No. 63 / 310,686, filed February 16, 2022, the contents of each of which are incorporated by reference in their entirety. [Background technology]

[0002] Idazoxan has been evaluated as both a selective α2-adrenergic receptor antagonist and an imidazoline receptor antagonist, but it suffers from the problem of being converted to one or more metabolites. Also, only about 27-28% of idazoxan reaches the systemic circulation and is cleared from the systemic circulation via urine. The major metabolites of idazoxan include hydroxylation at the 6- and / or 7-positions of the benzene ring, plus its glucuronide conjugate. Sulfate conjugates of the 7-OH metabolites may also be produced. Only small amounts of 5-OH compounds were detected. There is no evidence that the 8-OH compounds are metabolites of idazoxan. With regard to the imidazoline ring, the major metabolites arise as a result of ring cleavage. There are multiple other minor metabolites that have yet to be identified. A scheme of the metabolism of idazoxan is shown below.

[0003] [ka]

[0004] The present disclosure provides deuterated idazoxan analogs designed to improve the pharmacokinetic and metabolic properties of idazoxan. Indeed, a potentially attractive strategy for improving the metabolic properties of drugs is deuterium modification. This approach attempts to slow down the metabolism of drugs or reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive hydrogen isotope. Compared to hydrogen, deuterium forms stronger bonds with carbon.

[0005] Over the past 35 years, the effect of deuterium substitution on metabolic rate has been reported for a very small percentage of approved drugs (see, e.g., Blake, MI, et al., J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 ("Foster"); Kushner, DJ, et al., Can J Physiol Pharmacol 1999, 79-88; Fisher, MB, et al., Curr Opin Drug Discov Devel, 2006, 9: 101-09 ("Fisher")). Results have been variable and unpredictable. For some compounds, deuteration caused a decrease in metabolic clearance in vivo. For others, metabolism was unchanged. Still other compounds showed an increase in metabolic clearance. Also, variability in the effects of deuteration has led experts to question or dismiss deuteration modification as a viable drug design strategy to inhibit deleterious metabolism (see Foster, p. 35 and Fisher, p. 101). Summary of the Invention

[0006] In one aspect, the present application relates to a compound of formula (I):

[0007] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

[0008] In another aspect, the present application relates to a compound of formula (II) or formula (III):

[0009] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

[0010] In another aspect, the present application relates to a compound of formula (II-A) or formula (III-A):

[0011] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

[0012] In another aspect, the present application relates to a compound of formula (IA):

[0013] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

[0014] In another aspect, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[0015] Another aspect of the present application relates to a method of treating a neurological condition, comprising administering to a subject in need thereof a compound of the present application or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or an effective amount of a pharmaceutical composition of the present application.

[0016] Another aspect of the present application relates to a method for treating or preventing a disease caused by a neurological condition, comprising administering to a subject in need thereof a compound of the present application or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or an effective amount of a pharmaceutical composition of the present application.

[0017] Another aspect of the present application pertains to kits comprising a compound of the present application or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition of the present application.

[0018] Another aspect of the present application pertains to a compound of the present application or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition of the present application for use in the manufacture of a medicament for the treatment of a neurological condition.

[0019] Details of the disclosure are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of this application, exemplary methods and materials are now described. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features, objects, and advantages of the present disclosure will become apparent from the description and claims. In this specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0020] The contents of all cited references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are hereby expressly incorporated herein by reference in their entireties. None of the references cited herein are admitted to be prior art to this application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] In one aspect, the present application relates to a compound of formula (I):

[0022] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

[0023] In another aspect, the present application relates to a compound of formula (II) or formula (III):

[0024] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

[0025] In another aspect, the present application relates to a compound of formula (II-A) or formula (III-A):

[0026] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

[0027] In another aspect, the present application relates to a compound of formula (IA):

[0028] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

[0029] In another aspect, the present application relates to a compound of formula (IAR) or (IAS), i.e.

[0030] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

[0031] In one aspect, the present application relates to a compound of formula (IV), formula (IV-S) or formula (IV-R):

[0032] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium.

[0033] In one aspect, the present application relates to a compound of formula (V), (VS) or (VR):

[0034] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 5 , R 6 , R 7 and R 8 at least one of is independently selected from hydrogen and deuterium.

[0035] In one aspect, the present application relates to a compound of formula (VI), formula (VI-S) or formula (VI-R):

[0036] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1' , R 2 , R 2' , R5 and R 8 are each independently selected from hydrogen and deuterium.

[0037] In one aspect, the present application relates to a compound of formula (VII), formula (VII-S) or formula (VII-R), i.e.

[0038] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1' , R 2 and R 2' are each independently selected from hydrogen and deuterium.

[0039] In one aspect, the present application relates to a compound of formula (VIII), formula (VIII-S) or formula (VIII-R):

[0040] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1' , R 2 , R 2' , R 6 and R 7 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1' , R 2 , R 2' , R 6 and R 7 at least one of is independently selected from hydrogen and deuterium.

[0041] In one aspect, the present application relates to a compound of formula (IX), formula (IX-S) or formula (IX-R), i.e.

[0042] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1' , R 2 , R 2' and R 6 are each independently selected from hydrogen and deuterium.

[0043] In one aspect, the present application relates to a compound of formula (X), (XS) or (XR), i.e.

[0044] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1' , R 2 , R 2' and R 7 are each independently selected from hydrogen and deuterium.

[0045] In one aspect, the present application relates to a compound of formula (XI), formula (XI-S) or formula (XI-R):

[0046] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1' , R 2 and R 2' are each independently selected from hydrogen and deuterium.

[0047] In one aspect, the present application relates to a compound of formula (XII), formula (XII-S) or formula (XII-R):

[0048] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, 1 , R 1' , R 2 and R 2' are each independently selected from hydrogen and deuterium.

[0049] In one aspect, the present application relates to a compound of formula (I), formula (II), formula (III), formula (II-A), formula (III-A), formula (IA), formula (IAR), formula (IAS), formula (IV), formula (IV-S), formula (IV-R), formula (V), formula (VS), formula (VR), formula (VI), formula (VI-S), formula (VI-R), formula (VII), formula (VII-S), formula (VII-R), formula (VIII), formula (VIII-S), formula (VIII-R), formula (IX), formula (IX-S), formula (IX-R), formula (X), formula (XS), formula (XR), formula (XI), formula (XI-S), formula (XI-R), formula (XII), formula (XII-S) or formula (XII-R), or a pharma- ceutically acceptable salt thereof. In one aspect, the present application relates to a compound of formula (I), formula (II), formula (III), formula (II-A), formula (III-A), formula (IA), formula (IAR), formula (IAS), formula (IV), formula (IV-S), formula (IV-R), formula (V), formula (VS), formula (VR), formula (VI), formula (VI-S), formula (VI-R), formula (VII), formula (VII-S), formula (VII-R), formula (VIII), formula (VIII-S), formula (VIII-R), formula (IX), formula (IX-S), formula (IX-R), formula (X), formula (XS), formula (XR), formula (XI), formula (XI-S), formula (XI-R), formula (XII), formula (XII-S) or formula (XII-R).

[0050] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 One of them is deuterium.

[0051] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 One of them is deuterium.

[0052] In some embodiments, R 1 is deuterium.

[0053] In some embodiments, R 1 ' is deuterium.

[0054] In some embodiments, R 2 is deuterium.

[0055] In some embodiments, R 2 ' is deuterium.

[0056] In some embodiments, R 3 is deuterium.

[0057] In some embodiments, R 4 is deuterium.

[0058] In some embodiments, R 4 ' is deuterium.

[0059] In some embodiments, R 5 is deuterium.

[0060] In some embodiments, R 6 is deuterium.

[0061] In some embodiments, R 7 is deuterium.

[0062] In some embodiments, R 8 is deuterium.

[0063] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 Two of them are deuterium.

[0064] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 Two of them are deuterium.

[0065] In some embodiments, R 1 is deuterium, and R 1 ' is deuterium.

[0066] In some embodiments, R 2 is deuterium, and R 2 ' is deuterium.

[0067] In some embodiments, R 4 is deuterium, and R 4 ' is deuterium.

[0068] In some embodiments, R 5 is deuterium, and R 6 is deuterium.

[0069] In some embodiments, R 5 is deuterium, and R 7 is deuterium.

[0070] In some embodiments, R 5 is deuterium, and R 8 is deuterium.

[0071] In some embodiments, R 6 is deuterium, and R 7 is deuterium.

[0072] In some embodiments, R 6 is deuterium, and R 8 is deuterium.

[0073] In some embodiments, R 7 is deuterium, and R 8 is deuterium.

[0074] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 Three of them are deuterium.

[0075] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 Three of them are deuterium.

[0076] In some embodiments, R 1 , R 1 ' and R 5 are deuterium.

[0077] In some embodiments, R 1 , R 1 ' and R 6 are deuterium.

[0078] In some embodiments, R 1 , R 1 ' and R7 are deuterium.

[0079] In some embodiments, R 1 , R 1 ' and R 8 are deuterium.

[0080] In some embodiments, R 2 , R 2 ' and R 5 are deuterium.

[0081] In some embodiments, R 2 , R 2 ' and R 6 are deuterium.

[0082] In some embodiments, R 2 , R 2 ' and R 7 are deuterium.

[0083] In some embodiments, R 2 , R 2 ' and R 8 are deuterium.

[0084] In some embodiments, R 1 , R 5 and R 6 are deuterium.

[0085] In some embodiments, R 1 , R 5 and R 7 are deuterium.

[0086] In some embodiments, R 1 , R 5 and R 8 are deuterium.

[0087] In some embodiments, R 1 , R 6 and R 7 are deuterium.

[0088] In some embodiments, R 1 , R 6 and R 8 are deuterium.

[0089] In some embodiments, R 1 , R 7 and R 8 are deuterium.

[0090] In some embodiments, R 1 ', R 5 and R 6 are deuterium.

[0091] In some embodiments, R 1 ', R 5 and R 7 are deuterium.

[0092] In some embodiments, R 1 ', R 5 and R 8 are deuterium.

[0093] In some embodiments, R 1 ', R 6 and R 7 are deuterium.

[0094] In some embodiments, R 1 ', R 6 and R 8 are deuterium.

[0095] In some embodiments, R 1 ', R 7 and R 8 are deuterium.

[0096] In some embodiments, R 2 , R 5 and R 6 are deuterium.

[0097] In some embodiments, R 2 , R 5 and R 7 are deuterium.

[0098] In some embodiments, R 2 , R 5 and R 8 are deuterium.

[0099] In some embodiments, R 2 , R 6 and R 7 are deuterium.

[0100] In some embodiments, R 2 , R 6 and R 8 are deuterium.

[0101] In some embodiments, R 2 , R 7 and R 8 are deuterium.

[0102] In some embodiments, R 2 ', R 5 and R 6 are deuterium.

[0103] In some embodiments, R 2 ', R 5 and R 7 are deuterium.

[0104] In some embodiments, R 2 ', R 5 and R 8 are deuterium.

[0105] In some embodiments, R 2 ', R 6 and R 7 are deuterium.

[0106] In some embodiments, R 2 ', R 6 and R 8 are deuterium.

[0107] In some embodiments, R 2 ', R 7 and R 8 are deuterium.

[0108] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 Four of them are deuterium.

[0109] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 Four of them are deuterium.

[0110] In some embodiments, R 1 , R 1 ', R 5 and R 6 are deuterium.

[0111] In some embodiments, R 1 , R 1 ', R 5 and R 7 are deuterium.

[0112] In some embodiments, R 1 , R 1 ', R 5 and R 8 are deuterium.

[0113] In some embodiments, R 1 , R 1 ', R 6 and R 7 are deuterium.

[0114] In some embodiments, R 1 , R 1 ', R 6 and R 8 are deuterium.

[0115] In some embodiments, R 1 , R 1 ', R 7 and R 8 are deuterium.

[0116] In some embodiments, R 2 , R 2 ', R 5 and R 6 are deuterium.

[0117] In some embodiments, R 2 , R 2 ', R 5 and R 7 are deuterium.

[0118] In some embodiments, R 2 , R 2 ', R 5 and R 8 are deuterium.

[0119] In some embodiments, R 2 , R 2 ', R 6 and R 7 are deuterium.

[0120] In some embodiments, R 2 , R 2 ', R 6 and R 8 are deuterium.

[0121] In some embodiments, R 2 , R 2 ', R 7 and R 8 are deuterium.

[0122] In some embodiments, R 5 , R 6 , R 7 and R 8 are deuterium.

[0123] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 Five of them are deuterium.

[0124] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 Five of them are deuterium.

[0125] In some embodiments, R 1 , R 5 , R 6 , R 7 and R 8 are deuterium.

[0126] In some embodiments, R 1 ', R 5 , R 6 , R 7 and R 8 are deuterium.

[0127] In some embodiments, R 2 , R 5 , R 6, R 7 and R 8 are deuterium.

[0128] In some embodiments, R 2 ', R 5 , R 6 , R 7 and R 8 are deuterium.

[0129] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 Six of them are deuterium.

[0130] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 Six of them are deuterium.

[0131] In some embodiments, R 1 , R 1 ', R 5 , R 6 , R 7 and R 8 are deuterium.

[0132] In some embodiments, R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 are deuterium.

[0133] In some embodiments, R 1 , R 2 , R5 , R 6 , R 7 and R 8 are deuterium.

[0134] In some embodiments, R 1 , R 2 ', R 5 , R 6 , R 7 and R 8 are deuterium.

[0135] In some embodiments, R 1 ', R 2 , R 5 , R 6 , R 7 and R 8 are deuterium.

[0136] In some embodiments, R 1 ', R 2 ', R 5 , R 6 , R 7 and R 8 are deuterium.

[0137] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 Seven of them are deuterium.

[0138] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 Seven of them are deuterium.

[0139] In some embodiments, R 1 , R 1 ', R 2 , R 5 , R 6 , R 7 and R 8 are deuterium.

[0140] In some embodiments, R 1 , R 1 ', R 2 ', R 5 , R 6 , R 7 and R 8 are deuterium.

[0141] In some embodiments, R 1 , R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 are deuterium.

[0142] In some embodiments, R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 are deuterium.

[0143] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 Eight of them are deuterium.

[0144] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 5 , R6 , R 7 and R 8 Eight of them are deuterium.

[0145] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 are deuterium.

[0146] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 At least two of the are deuterium.

[0147] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 At least three of the are deuterium.

[0148] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 At least four of the are deuterium.

[0149] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 At least five of the are deuterium.

[0150] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 At least six of these are deuterium.

[0151] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 At least seven of these are deuterium.

[0152] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 At least eight of these are deuterium.

[0153] In some embodiments, R 1 , R 1 ', R2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 At least nine of the are deuterium.

[0154] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 At least 10 of the atoms are deuterium.

[0155] In some embodiments, R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 are all deuterium.

[0156] In some embodiments, when a variable is specified as deuterium, the remaining variables are hydrogen. In some embodiments, when a variable is specified as deuterium, the remaining variables are either hydrogen or deuterium.

[0157] Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is intended to be a hydrogen or isotope thereof, such as deuterium (d, d, D or 2 H) or tritium ( 3 H).

[0158] In some embodiments, each position designated as deuterium has an abundance of deuterium at that position that is significantly greater than the natural abundance of deuterium (about 0.015%).

[0159] In some embodiments, each position designated as deuterium has at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% deuterium incorporated.

[0160] In some embodiments, each position designated as deuterium has at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% deuterium incorporated.

[0161] In some embodiments, each position specifically designated as deuterium has at least about 90% deuterium incorporated. In some embodiments, each position specifically designated as deuterium has at least about 95% deuterium incorporated. In some embodiments, each position specifically designated as deuterium has at least about 97% deuterium incorporated.

[0162] Any of the embodiments herein apply to Formula (I), Formula (II), Formula (III), Formula (II-A), Formula (III-A), Formula (IA), Formula (IAR), Formula (IAS), Formula (IV), Formula (IV-S), Formula (IV-R), Formula (V), Formula (VS), Formula (VR), Formula (VI), Formula (VI-S), Formula (VI-R), Formula (VII), Formula (VII-S), Formula (VII-R), Formula (VIII), Formula (VIII-S), Formula (VIII-R), Formula (IX), Formula (IX-S), Formula (IX-R), Formula (X), Formula (XS), Formula (XR), Formula (XI), Formula (XI-S), Formula (XI-R), Formula (XII), Formula (XII-S), Formula (XII-R) or Table 1, where applicable. 1 , R1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 Any of the groups described above for any of the groups R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 The remainder of the formula may be combined with any of the groups described above.

[0163] Representative compounds of the present application are shown in Table 1.

[0164] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

[0165] Some of the aforementioned compounds may contain one or more asymmetric centers and therefore may exist in various isomeric forms, for example, stereoisomers and / or diastereomers. Thus, the compounds of the present application may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers. In some embodiments, the compounds of the present application are enantiopure compounds. In another embodiment, a mixture of stereoisomers or diastereomers is provided.

[0166] "Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers" or optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0167] A carbon atom bonded to four nonidentical substituents is termed a "chiral center."

[0168] "Chiral isomer" means a compound having at least one chiral center. Compounds having multiple chiral centers can exist either as individual diastereomers or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center (e.g., carbon, etc.). Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Cahn, Ingold and Prelog ordering rules. (Cahn et al.,Angew. Chem. Inter. Edit.1966,5,385;errata 511;Cahn et al.,Angew. Chem. 1966,78,413;Cahn and Ingold,J. Chem. Soc. 1951(London),612;Cahn et al.,Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0169] "Geometric isomers" refers to diastereomers that exist due to hindered rotation about double bonds. These configurations are distinguished in names by the prefixes cis and trans, or Z and E, to indicate that groups are on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

[0170] Furthermore, the structures and other compounds discussed in this application include all atropisomers thereof. An "atropisomer" is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers exist due to restricted rotation caused by the prevention of rotation of large groups around a central bond. Such atropisomers usually exist as mixtures, but as a result of recent advances in chromatographic techniques, it has become possible in a few cases to separate mixtures of two atropisomers.

[0171] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solid form, one tautomer usually predominates. In solutions where tautomerization can occur, a chemical equilibrium of the tautomers is achieved. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.

[0172] Of the various types of tautomerism that can occur, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs as a result of an aldehyde group (-CHO) in a sugar molecule reacting with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (ring-shaped) form such as that exhibited by glucose. Common tautomer pairs are ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., nucleobases such as guanine, thymine, and cytosine), amine-enamine, and enamine-enamine. Compounds of the present application may also be represented in multiple tautomeric forms, and in such instances, the present application expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, and the present application expressly includes all such reaction products).

[0173] In this application, the structural formula of a compound may conveniently represent a certain isomer, but this application includes all isomers, examples of which include geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, and the like.

[0174] For example, the tautomer represented by formula (I) below can exist in both forms.

[0175] [ka]

[0176] In some embodiments, both of the above tautomers are encompassed when one or the other form is shown.

[0177] In one embodiment, an isotopically labeled compound of any of the formulas described herein contains one or more additional isotopic atoms, which may or may not be radioactive (e.g., 3 H, 14 C. 13 C. 18 F, 35 S, 32 P, 125 I and 131 I) may be incorporated into compounds that are useful in drug metabolism studies and diagnostic as well as therapeutic applications.

[0178] Also, the effectiveness of IC 50 The IC value can be measured under substantially similar conditions. 50 Compounds with low IC 50 It is more potent than compounds with higher values.

[0179] In some embodiments, the compounds of the present application are useful as therapeutic agents and thus may be useful in the treatment of diseases caused by or associated with neurological conditions.

[0180] The compounds of this application are defined herein by their chemical structure and / or chemical name. If a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0181] The recitation of a list of chemical groups in any definition of a variable herein includes a definition of that variable as any single group or combination of the listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0182] In another aspect, the present application provides a method for synthesizing the compounds disclosed herein. The synthesis of the compounds of the present application is described herein and in the Examples below. Another embodiment is a method for producing a compound of any formula described herein using any one of the reactions outlined herein, or a combination thereof. The method may include the use of one or more intermediates or chemical reagents outlined herein.

[0183] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[0184] Another aspect of the present application relates to a kit comprising a compound of the present application or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition of the present application.In another aspect, the present application provides a kit comprising a compound selected from one or more compounds disclosed herein and capable of treating a neurological condition, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, optionally in combination with a second agent and instructions for use.

[0185] In some embodiments, the compounds of the present application form one or more metabolites less than the non-deuterated analogue. In some embodiments, the compounds of the present application form one or more metabolites about 10% less, about 20% less, about 30% less, about 40% less, about 50% less, about 60% less, about 70% less, about 80% less, about 90% less, or about 100% less than the non-deuterated analogue. In some embodiments, the compounds of the present application form about 10% less, about 20% less, about 30% less, about 40% less, about 50% less, about 60% less, about 70% less, about 80% less, about 90% less, or about 100% less 6-OH metabolites than the non-deuterated analogue. In some embodiments, the compounds of the present application form about 10% less, about 20% less, about 30% less, about 40% less, about 50% less, about 60% less, about 70% less, 80% less, 90% less, or 100% less 7-OH metabolites compared to non-deuterated analogs.

[0186] In some embodiments, the compounds of the present application have improved bioavailability compared to non-deuterated analogs, hi some embodiments, the compounds of the present application have improved bioavailability that is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% greater compared to non-deuterated analogs.

[0187] In some embodiments, the compounds of the present application remain in the systemic circulation longer compared to the non-deuterated analogs, hi some embodiments, the compounds of the present application remain in the systemic circulation about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% longer compared to the non-deuterated analogs.

[0188] How to synthesize a compound The compounds of the present application can be prepared in a variety of ways by employing standard synthetic methods and procedures that are either known to those skilled in the art or will be apparent to them in light of the teachings herein, using commercially available starting materials, compounds known in the literature, or readily prepared intermediates. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Examples of such methods and procedures include, but are not limited to, any one or more of the classic texts incorporated herein by reference (Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999) are known, useful and generally accepted reference texts in organic synthesis to those skilled in the art. The following synthetic methodology descriptions are designed to illustrate the overall procedure for the preparation of the compounds of the present application, and are not limiting. These procedures generally provide the desired final compound at or near the end of the overall procedure, although in some cases it may be desirable to further convert the compound to its pharma-ceutically acceptable salt, ester, or prodrug thereof. Suitable synthetic routes are shown in the following schemes.

[0189] Those skilled in the art will recognize whether stereocenters exist in the compounds disclosed herein. Thus, the present application includes both possible stereoisomers (unless specified in the synthesis), including not only racemates but also individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-lnterscience, 1994).

[0190] The compounds of the present application can be prepared in a number of ways known to those skilled in the art of organic synthesis.As an example, the compounds of the present application can be synthesized using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or variations thereof that will be understood by those skilled in the art.Preferred methods include, but are not limited to, the methods described below.

[0191] The compounds of the present application can be synthesized according to the following steps outlined in the following schemes, which include various sequences for assembling the intermediates: Starting materials are either commercially available, described in the published literature, or prepared by known procedures as shown in the following schemes.

[0192] The compounds of the present application can be prepared as pharma- ceutically acceptable acid addition salts by reacting the free base form of the compound with a pharma- ceutically acceptable inorganic or organic acid. Alternatively, pharma-ceutically acceptable base addition salts of the compounds of the present application can be prepared by reacting the free acid form of the compound with a pharma-ceutically acceptable inorganic or organic base. The pharma-ceutically acceptable salts can include various counterions, examples of which include counterions of inorganic or organic acids, counterions of inorganic or organic bases, or counterions obtained by counterion exchange.

[0193] Acids and bases useful in the methods herein are known in the art. Acid catalysts are any acidic chemicals, which can be inorganic in nature (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate). Acids are useful in either catalytic or stoichiometric amounts to promote chemical reactions. Bases are any basic chemicals, which can be inorganic in nature (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine). Bases are useful in either catalytic or stoichiometric amounts to promote chemical reactions.

[0194] Alternatively, salt forms of the compounds of the present application can be prepared using salts of starting materials or intermediates. The free acid or free base forms of the compounds of the present application can be prepared from the corresponding base addition salt or acid addition salt form, respectively. For example, the compounds of the present application in the form of an acid addition salt can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The compounds applied in the form of a base addition salt can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0195] The compounds of the present application that contain nitrogen can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperbenzoic acid (m-CPBA) and / or hydrogen peroxide) to provide other compounds of the present application. Thus, all nitrogen-containing compounds shown and claimed may be converted to N-oxide derivatives (N→O or N) of the shown compounds and their N-oxide derivatives, where permitted by valence and structure. + -O - (which may be designated as N-hydroxy or N-alkoxy). Additionally, in other cases, nitrogens in the compounds of the present application can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine with an oxidizing agent such as m-CPBA. Additionally, all nitrogen-containing compounds shown and claimed are considered to encompass both the shown compound and its N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, where R is substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3-14 membered carbocyclic or 3-14 membered heterocyclic) derivatives, where permitted by valence and structure.

[0196] Prodrugs of the compounds of the present application can be prepared by methods known to those skilled in the art (see, for example, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985 for further details). For example, suitable prodrugs can be prepared by reacting underivatized compounds of the present application with a suitable carbamylation agent (e.g., 1,1-acyloxyalkylcarbanochloridate, paranitrophenyl carbonate, and the like). Specifically, the central N-acetic acid moiety of the compounds of the present invention, as well as other similar carboxylic acid groups, can be modified by techniques known in the art to generate active prodrugs of the present invention.

[0197] Protected derivatives of the compounds of the present application can be prepared by means known to those skilled in the art. A detailed description of the techniques applicable to the creation and removal of protecting groups is provided in TW Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.

[0198] The compounds of the present application can be conveniently prepared, or formed during the processing of the present application, as solvates (e.g., hydrates). Hydrates of the compounds of the present application can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents such as dioxin, tetrahydrofuran or methanol.

[0199] Optical isomers may be prepared from their respective optically active precursors by the procedures described herein or by resolving racemic mixtures. Resolution can be carried out in the presence of a resolving agent, by chromatography, or by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding resolution are described in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981).

[0200] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. As one of ordinary skill in the art can appreciate, methods for further synthesizing the compounds of the formulas described herein will be apparent to one of ordinary skill in the art. Furthermore, the various synthetic steps may be carried out in an alternative order or sequence to obtain the desired compounds. Furthermore, the solvents, temperatures, reaction durations, etc. outlined herein are for illustrative purposes only, and one of ordinary skill in the art will recognize that the reaction conditions can be varied to produce the desired bridged macrocyclic products of the present application. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in the synthesis of the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0201] The compounds of the present application may be modified by adding various functionalities via any of the synthetic means outlined herein to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), those that increase oral availability, those that increase solubility to allow administration by injection, those that alter metabolism, and those that alter excretion rate.

[0202] Biological assays The biological activity of the compounds of the present application can be measured by various biochemical or cellular assays known to those skilled in the art. Non-limiting examples of methods for determining biological activity are discussed herein.

[0203] Pharmacokinetic profile of deuterated compounds The compounds of the present application can be measured for stability. In particular, the compounds of the present application can be evaluated for stability in microsomes using the protocols described herein and / or the protocols described in WO 2020 / 132461, which is incorporated by reference in its entirety.

[0204] Assessment of metabolic stability in human liver microsomes The pharmacokinetics of the compounds of the present application may be measured after a single intravenous or oral administration to one or more test subjects, including mice, rats, dogs, etc. Pharmacokinetic studies may be performed after intravenous (IV) and oral (PO) administration of the compounds of the present disclosure in three male Sprague-Dawley (SD) rats in comparison to non-deuterated compounds. Depending on the route of administration to the test subjects, various doses may be used, for example, 1 mg / kg (IV) and 10 mg / kg (PO). Test compounds may be measured in plasma, the values ​​of which are determined according to methods known in the art.

[0205] Pharmaceutical Compositions In another aspect, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound of the present application, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[0206] The compounds of the present application may be administered as pharmaceutical compositions by any conventional route, in particular enterally, for example orally, e.g. in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions, or topically, for example in the form of lotions, gels, ointments or creams, or intranasally or in the form of suppositories.

[0207] The pharmaceutical composition containing the compound of the present application in free form or in pharma-ceutically acceptable salt form, in combination with at least one pharma-ceutically acceptable carrier or diluent, may be prepared in a conventional manner by mixing, granulating or coating methods.For example, the oral composition may be a tablet or gelatin capsule, which may contain, together with the active ingredient, a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; and, in the case of tablets, c) binders, such as aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; optionally, d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fat emulsions or suspensions. The compositions can be sterilized and / or contain adjuvants, examples of which include preserving agents, stabilizing agents, wetting agents or emulsifying agents, dissolution promoters, salts for adjusting osmotic pressure and / or buffers. In addition, they can also contain other therapeutically valuable substances. Formulations suitable for transdermal administration include an effective amount of the compound of the present application together with a carrier. The carrier can include an absorbable pharmacologically acceptable solvent to assist passage through the skin of the host. For example, the transdermal device can be in the form of a dressing that includes a backing member, a reservoir that optionally contains the compound together with a carrier, optionally a rate-controlling barrier for delivering the compound to the skin of the host at a controlled, predetermined rate over an extended period of time, and a means for fixing the device to the skin. Matrix transdermal formulations can also be used. Formulations suitable for topical (e.g., to the skin and eyes) application are preferably aqueous solutions, ointments, creams or gels well known in the art. These may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0208] The pharmaceutical compositions of the present application comprise a therapeutically effective amount of the compounds of the present application formulated together with one or more pharma- ceutically acceptable carriers. As used herein, the term "pharma-ceutically acceptable carrier" refers to any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary. Some examples of materials that may serve as pharma- ceutically acceptable carriers are ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, etc.), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives (such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate); powdered tragacanth; Excipients such as malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents and perfuming agents, and preservatives and antioxidants can also be present in the composition, at the discretion of the formulator.

[0209] The pharmaceutical compositions of the present application may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powders, ointments, or drops), bucally, or as an oral or nasal spray.

[0210] Liquid dosage forms for oral administration may include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid ester sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and aromatic agents.

[0211] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be in the form of sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents (e.g., as solutions in 1,3-butanediol). Acceptable excipients and solvents that may be employed include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any brand of fixed oil may be employed, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable drugs.

[0212] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug depends upon its rate of dissolution, which in turn may depend upon the size and crystalline form of the crystals. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0213] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present application with suitable non-irritating excipients or carriers, examples of which are cocoa butter, polyethylene glycol or suppository waxes, which are solid at ordinary temperatures but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active compound.

[0214] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0215] The active compound may also be in microencapsulated form with one or more excipients as mentioned above.Solid dosage forms such as tablets, dragees, capsules, pills, granules, etc. may be prepared with coatings and shells, examples of which include enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art.In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch.According to normal practice, such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets, and pills, dosage forms may also contain buffering agents.

[0216] In some embodiments, the pharmaceutical compositions of the present disclosure are solid dosage forms formulated for immediate release (IR). In some embodiments, the pharmaceutical compositions of the present disclosure are solid dosage forms formulated for extended release (ER).

[0217] As used herein, the term "immediate release formulation" refers to a composition comprising a compound of the present application that lacks a release-modifying structural element, such as a matrix or coating.

[0218] As used herein, the term "sustained release" refers to a mode of release of an active ingredient from a pharmaceutical composition in which the timing and / or rate of release of the active ingredient is delayed or slowed. A pharmaceutical composition formulated for sustained release is a pharmaceutical composition that includes one or more structural features that have the effect of preventing the active ingredient from being released immediately after administration to a subject. For example, in a pharmaceutical composition formulated for sustained release, the active ingredient may be embedded within a matrix core that slowly degrades over time. Alternatively or additionally, the pharmaceutical composition may include a polymer coating that loses structural integrity over time, allowing the release of the active ingredient previously encapsulated by the coating.

[0219] In some embodiments, the pharmaceutical compositions of the invention comprise a racemic mixture of deuterated analogs of the (R) and (S) enantiomers of idazoxan. In some embodiments, the pharmaceutical compositions of the invention comprise a mixture of deuterated analogs of the (R) and (S) enantiomers of idazoxan enriched in the (R) enantiomer. In some embodiments, the pharmaceutical compositions of the invention comprise a deuterated analog of the (R) enantiomer of idazoxan. In some embodiments, the pharmaceutical compositions of the invention comprise a mixture of deuterated analogs of the (R) and (S) enantiomers of idazoxan enriched in the (S) enantiomer. In some embodiments, the pharmaceutical compositions of the invention comprise a deuterated analog of the (S) enantiomer of idazoxan.

[0220] Without wishing to be bound by theory, it is believed that administration of a deuterated analog of (R)-idazoxan, which is the inactive enantiomer of idazoxan, to a subject results in the formation of a deuterated analog of (R)-idazoxan in the subject's body. Over time, the depot of deuterated analog of (R)-idazoxan is believed to be converted to (S)-idazoxan. Over time, the conversion from (R) to (S) is believed to result in sustained exposure to the deuterated analog of (S)-idazoxan, for example at concentrations within the therapeutic window of idazoxan. This means that formulations of deuterated analog of (R)-idazoxan may have an improved ability to maintain the deuterated (S)-idazoxan AUC in the optimal range for desired therapeutic effect over formulations of deuterated analog of (S)-idazoxan and deuterated analog of racemic idazoxan.

[0221] Dosage forms for topical or transdermal administration of the compounds of the present application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any needed preservatives or buffers as required. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of the present application.

[0222] The ointments, pastes, creams and gels may contain, in addition to the active compounds of the present application, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0223] Powders and sprays can contain, in addition to the compounds of the present application, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons.

[0224] Transdermal patch has the additional advantage of providing controlled delivery of compound into the body.Such dosage forms can be made by dissolving or dispensing compound in appropriate medium.Also, absorption enhancers can be used to increase the flux of compound across the skin.Either by providing a rate-controlling membrane or by dispersing compound in a polymer matrix or gel, the rate can be controlled.

[0225] For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models may also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic / prophylactic efficacy and toxicity can be assessed by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (therapeutic effective dose in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0226] Dosage and administration methods are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors that may be considered include the severity of the condition, the subject's overall health, the subject's age, weight and sex, diet, timing and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0227] The amount of active ingredient (e.g., formulation of the disclosed compound or its salt, hydrate, solvate or isomer) in a unit dose of the composition is an effective amount and varies according to the particular treatment involved. Those skilled in the art will understand that it may be necessary to periodically vary the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, such as oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers or propellants that may be required.

[0228] Pharmaceutical compositions containing the active compounds of the present application may be prepared in a manner generally known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, encapsulating or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers, including excipients and / or auxiliaries that facilitate the processing of the active compounds into pharma- ceutically usable preparations. Of course, the appropriate formulation depends on the selected route of administration.

[0229] Techniques for formulation and administration of the compounds disclosed in this application are described in Remington: The Science and Practice of Pharmacy, 1999. th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharma- ceutically acceptable salts are used in pharmaceutical preparations in combination with a pharma- ceutically acceptable carrier or diluent. Suitable pharma- ceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or organic solutions. The compounds are present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0230] How to use The compounds of the present disclosure are also used for the manufacture of medicaments, in particular for the manufacture of medicaments intended for the prophylactic and / or curative treatment of disorders of the central nervous system. In some embodiments, the medicaments in the form of tablets are intended for the treatment of depression, Parkinson's disease and / or severe psychotic disorders such as schizophrenia and schizoaffective disorder.

[0231] In some embodiments, the application provides a method of treating or preventing any of the diseases, disorders, and conditions described herein, and the subject is a human. In some embodiments, the application provides a method of treatment. In some embodiments, the application provides a method of prevention.

[0232] In some embodiments, the brain disorder is selected from Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, motor neuron disease, multiple system atrophy, or progressive supranuclear palsy, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, frontal lobe dementia, or mixed dementia, migraine, tension headache, cluster headache, depression, treatment-resistant depression, postpartum depression, psychotic depression, seasonal affective disorder, major depressive disorder, persistent depressive disorder, bipolar depression, premenstrual dysphoric disorder, addiction, substance use disorder, anxiety, post-traumatic stress disorder, suicidal ideation, major depressive disorder, psychosis, schizophrenia, stroke, traumatic brain injury, generalized anxiety disorder, panic disorder, social anxiety disorder, one or more phobia-related disorders, separation anxiety disorder, substance use disorder, schizoaffective disorder, or a combination thereof.

[0233] In some embodiments, the brain disorder is schizoaffective disorder, hi some embodiments, the brain disorder is schizophrenia.

[0234] In some embodiments, the brain disorder is schizoaffective disorder, hi some embodiments, the brain disorder is a type of dementia.

[0235] In some embodiments, the brain disorder is schizoaffective disorder. In some embodiments, the brain disorder is Alzheimer's disease. In some embodiments, the pharmaceutical composition is administered in combination with a second therapeutic agent.

[0236] In some embodiments, the pharmaceutical composition is administered in combination with an antipsychotic. In some embodiments, the pharmaceutical composition is administered in combination with an antagonist of the dopamine type 2 receptor (D2 antagonist).

[0237] In some embodiments, the pharmaceutical composition is administered for a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. In some embodiments, the pharmaceutical composition is administered for a period of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In some embodiments, the pharmaceutical composition is administered for a period of 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 months, 11 years, or 12 years. In some embodiments, the pharmaceutical composition is administered for the lifetime of the subject.

[0238] In accordance with the foregoing, the present application provides a method for preventing or treating any of the diseases or disorders described herein in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the present application or an enantiomer, diastereomer, stereoisomer, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present application. In any of the above applications, the required dosage will vary depending on the mode of administration, the particular condition being treated, and the effect desired.

[0239] Combination therapy may include administering the subject compound in further combination with one or more other biologically active ingredients.For example, the compounds of the present application can be used in combination with other pharma- ceutical active compounds, preferably compounds that can enhance the effect of the compounds of the present application.The compounds of the present application can be administered simultaneously (as a single preparation or separate preparations) or sequentially with other drug therapies or treatments.Combination therapy generally contemplates administering two or more drugs during a single treatment cycle or course of treatment.

[0240] The term "subject" as used herein refers to a mammal. Thus, a subject refers to, for example, a dog, a cat, a horse, a cow, a pig, a guinea pig, etc. Preferably, the subject is a human. When the subject is a human, the subject may be referred to herein as a patient.

[0241] "Treat", "treating" and "treatment" refer to a method of alleviating or alleviating a disease and / or its associated symptoms.

[0242] As used herein, "preventing" or "prevent" refers to reducing or eliminating the onset of symptoms or complications of a disease, condition or disorder.

[0243] The terms "disease(s), " "disorder(s)" and "condition(s)" are used interchangeably unless the context clearly dictates otherwise.

[0244] As used herein, the term "therapeutically effective amount" of a compound or pharmaceutical composition of the present application means an amount of the compound or pharmaceutical composition sufficient to reduce the symptoms of a disorder in a subject. As is well understood in the medical arts, a therapeutically effective amount of a compound or pharmaceutical composition of the present application will be at a reasonable benefit / risk ratio applicable to any medical treatment. However, it will be understood that the total daily usage of the compounds and compositions of the present application will be determined by the attending physician within the scope of sound medical judgment. The specific modulating (e.g., inhibiting or stimulating) dose for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration and excretion rate of the specific compound employed; the duration of treatment; drugs used in combination with or simultaneously with the specific compound employed; and similar factors well known in the medical arts.

[0245] As used herein, the phrase "pharmacologically acceptable" refers to those compounds, materials, compositions, carriers, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0246] As used herein, the term "pharmaceutical acceptable salt" refers to a salt of a compound formed by the process of the present application that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge, et al., describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the present application, or can be prepared separately by reacting a free base or free acid functional group with a suitable acid or base.

[0247] Examples of pharma- ceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, i.e., salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, maleic, tartaric, citric, succinic, or malonic acids. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobic acid, and the like. Representative salts include, but are not limited to, ionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, 7-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates, where appropriate.

[0248] As used herein, the term "pharmaceutical acceptable ester" refers to an ester of a compound formed by the process of the present application, including those that hydrolyze in vivo and are readily broken down in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutical acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, each alkyl or alkenyl moiety advantageously having 6 or fewer carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[0249] As used herein, the term "pharmaceutically acceptable prodrug" refers to prodrugs of the compounds formed by the processing of the present application, as well as zwitterionic forms (where possible) of the compounds of the present application, which prodrugs of the compounds are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and are effective for the intended use.

[0250] As used herein, "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to provide any compound outlined by the formulas of the present application. Various forms of prodrugs are known in the art and are discussed, for example, below. Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al. (ed.) ”Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

[0251] "Pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one such excipient and multiple such excipients.

[0252] The present application also encompasses pharmaceutical compositions containing pharma- ceutically acceptable prodrugs of the compounds of the present application, and methods of treating disorders by administering the prodrugs. For example, compounds of the present application having free amino, amide, hydroxy, or carboxyl groups can be converted into prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked to a free amino, hydroxy, or carboxylic acid group of a compound of the present application by an amide or ester bond. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids, commonly designated by their three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also encompassed. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxyl groups can be derivatized using groups including but not limited to hemisuccinic acid, phosphate esters, dimethylaminoacetic acid, and phosphoryloxymethyloxycarbonyl, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 1-15. Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs, sulfonate esters, and sulfate esters of hydroxyl groups. Derivatization of hydroxyl groups as (acyloxy)methyl ethers and (acyloxy)ethyl ethers is also included. Here, the acyl group can be an alkyl ester, optionally substituted with groups including but not limited to ether, amine, and carboxylic acid functional groups, or the acyl group is an amino acid ester as described herein. This type of prodrug is described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides, or phosphonamides.All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.

[0253] Combinations of substituents and variables envisioned in this application are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that have sufficient stability to permit their manufacture and maintain their compound integrity for a period of time sufficient to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0254] When any variable (e.g., R1) occurs more than once in any constituent or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with one or more R moieties, R at each occurrence is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds within the normal valences of the designated atoms.

[0255] Additionally, some of the compounds of the present application have one or more double bonds or one or more asymmetric centers. Such compounds can exist as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z-double isomeric forms, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. When compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. The configuration of any carbon-carbon double bonds found herein has been selected for convenience only, and is not intended to designate a particular configuration unless expressly stated in the text. Thus, any carbon-carbon double bond shown herein as trans may be cis, trans, or a mixture of the two in any ratio. All such isomeric forms of compounds are expressly included in the present application.

[0256] Furthermore, the compounds of the present application, such as salts of the compounds, can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0257] "Solvate" refers to a solvent addition form that contains either a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with a molecule of a substance in which the water retains its molecular state as H2O.

[0258] Treatment In some embodiments, the pharmaceutical compositions of idazoxan disclosed herein may be used to treat a disease or disorder. In some embodiments, the disease or disorder is a brain disorder. In some embodiments, the brain disorder is a neurodegenerative disorder, such as Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, motor neuron disease, multiple system atrophy, or progressive supranuclear palsy. In some embodiments, the brain disorder is dementia, such as vascular dementia, dementia with Lewy bodies, frontotemporal dementia, frontal lobe dementia, or mixed dementia.

[0259] In some embodiments, the disease or disorder is diabetes.

[0260] In some embodiments, the brain disorder is a migraine, a tension headache, or a cluster headache.

[0261] In some embodiments, the brain disorder is a psychological disorder such as depression, treatment-resistant depression, postpartum depression, psychotic depression, seasonal affective disorder, major depressive disorder, persistent depressive disorder, bipolar depression, premenstrual dysphoric disorder, addiction, substance use disorder, anxiety, post-traumatic stress disorder, suicidal ideation, major depressive disorder, psychosis, schizophrenia, stroke, traumatic brain injury, generalized anxiety disorder, panic disorder, social anxiety disorder, one or more phobia-related disorders, separation anxiety disorder or substance use disorder. In some embodiments, the brain disorder is schizophrenia.

[0262] In some embodiments, the brain disorder is schizoaffective disorder. In some embodiments, the schizoaffective disorder is bipolar schizoaffective disorder. In some embodiments, the schizoaffective disorder is depressive schizoaffective disorder. In some embodiments, the schizoaffective disorder is mixed schizoaffective disorder.

[0263] In some embodiments, the disease or disorder is a musculoskeletal pain disorder, including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, and muscle spasms.

[0264] In some embodiments, the present disclosure provides methods of treating disorders of female reproductive health, including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), postpartum depression, and menopause.

[0265] In some embodiments, pharmaceutical compositions of idazoxan may be used to treat a combination of brain disorders.

[0266] In some embodiments, pharmaceutical compositions of idazoxan have anti-addictive properties, anti-psychotic properties, anti-depressant properties, anti-anxiety properties, or combinations thereof.

[0267] The idazoxan composition of the present disclosure can be used to enhance neuroplasticity.The compounds of the present disclosure can also be used to treat any brain disorder.The compounds of the present disclosure can also be used to increase at least one of the translation, transcription or secretion of neurotrophic factors.

[0268] Combination therapy In some embodiments, the present invention relates to a modulator of serotonin receptor 2A (5-HT 2A Modulators, e.g. 5-HT 2A Serotonin receptor modulators, such as serotonin receptor agonists, are used to treat brain disorders. The pharmaceutical compositions of idazoxan disclosed herein can also be used to treat 5-HT 2ASerotonin receptor modulators useful as second therapeutic agents in the combination therapy described herein are known to those skilled in the art and include ketanserin, vorinanserin (MDL-100907), eplivanserin (SR-46349), pimavanserin (ACP-103), glemanserin (MDL-11939), ritanserin, flibanserin, nerotanserin, blonanserin, mianserin, mirtazapine, lorperiodone (CYR-101, MIN-101), quetiapine, ...ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ketanserin, ke pine, olanzapine, altanserin, acepromazine, nefazodone, risperidone, pulvanserin, AC-90179, AC-279, adatanserin, fananserin, HY10275, benanserin, butanserin, manserin, iferanserin, ridanserin, peranserin, seganserin, tropanserin, lorcaserin, ICI-169369, methysergide, trazodone, cinitapride, cyproheptadine, brexpiprazole, cariprazine, agomera Chin, Setoperone, 1-(1-naphthyl)piperazine, LY-367265, Pirenperone, Metergoline, Deramciclane, Amperozide, Cinanserin, LY-86057, GSK-215083, Cyamemazine, Mesulergine, BF-1, LY-215840, Sergolexol, Spiramide, LY-53857, Amesergide, LY-108742, Pipamperone, LY-314228, 5-I-R91150, 5-MeO-NBpBrT, 9-aminomethyl-9,1 0-Dihydroanthracene, niaprazine, SB-215505, SB-204741, SB-206553, SB-242084, LY-272015, SB-243213, SB-200646, RS-102221, zotepine, clozapine, chlorpromazine, sertindole, iloperidone, paliperidone, asenapine, amisulpride, aripiprazole, lurasidone, ziprasidone, lumateperone, perospirone, mosapramine, AMDA (9-aminomethyl-9,10-dihydroanthracene), methiothepin, zanomeline, buspirone, sustained release formulations of olanzapine (e.g., Zyprexa Relprevv), sustained release formulations of quetiapine, sustained release formulations of risperidone (e.g., Risperdal Consta), sustained release formulations of paliperidone (e.g., Invega Sustenna and Invega Trinza), sustained release formulations of fluphenazine decanoate (e.g., Prolixin Decanoate), sustained release formulations of aripiprazole lauroxyl (e.g., Aristada), sustained release formulations of aripiprazole (e.g., Abilify Maintena), 3-(2-(4-(4-fluorobenzoyl)piperazin-1-yl)ethyl)-5-methyl-5-phenylimidazolidine-2,4-dione, 3-(2-(4-benzhydrylpiperazin-1-yl)ethyl)-5-methyl-5-phenylimidazolidine-2,4-dione, 3-(3-(4-(2-fluorophenyl)piperazin-1-yl)propyl)-5-methyl-5- Phenylimidazolidine-2,4-dione, 3-(3-(4-(3-fluorophenyl)piperazin-1-yl)propyl)-5-methyl-5-phenylimidazolidine-2,4-dione, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5-methyl-5-phenylimidazolidine-2,4-dione, 3-(3-(4-(4-fluorobenzoyl)piperazin-1-yl)propyl)-5-methyl-5-phenylimidazolidine-2,4-dione 3-(2-(4-(4-fluorobenzoyl)piperazin-1-yl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione, 3-(2-(4-benzhydrylpiperazin-1-yl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione, 3-(3-(4- (2-fluorophenyl)piperazin-1-yl)propyl)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione, 3-(3-(4-(3-fluorophenyl)piperazin-1-yl)propyl)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-8-phenyl-1,Examples of serotonin receptor modulators include, but are not limited to, 3-diazaspiro[4.5]decane-2,4-dione, and 3-(3-(4-(4-fluorobenzoyl)piperazin-1-yl)propyl)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione, or a pharma- ceutically acceptable salt, solvate, metabolite, deuterated analog, derivative, prodrug, or combination thereof. In some embodiments, the serotonin receptor modulator used as the second therapeutic agent is pimavanserin or a pharma- ceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the serotonin receptor modulator is administered prior to administration of a compound disclosed herein, for example, about 3 hours or about 1 hour prior to administration of a compound disclosed herein. In some embodiments, the serotonin receptor modulator is administered up to about 1 hour prior to administration of a compound disclosed herein. Thus, in some embodiments of combination therapy using the compounds disclosed herein, the second therapeutic agent is a serotonin receptor modulator. In some embodiments, the second therapeutic agent, a serotonin receptor modulator, is provided in a dose of about 10 mg to about 350 mg. In some embodiments, the serotonin receptor modulator is provided in a dose of about 20 mg to about 200 mg. In some embodiments, the serotonin receptor modulator is provided in a dose of about 10 mg to about 100 mg. In certain such embodiments, the compound of the present application is provided in a dose of about 10 mg to about 100 mg, or about 20 mg to about 200 mg, or about 15 mg to about 300 mg, and the serotonin receptor modulator is provided in a dose of about 10 mg to about 100 mg.

[0269] In some embodiments, dopamine receptor modulators, such as modulators of dopamine receptor type 2 (D2 modulators, e.g., D2 agonists), are used to treat brain disorders. The pharmaceutical compositions of idazoxan disclosed herein may be used in combination with a second therapeutic agent that is also a D2 modulator. In such cases, the second therapeutic agent can be an agonist or an antagonist. Dopamine receptor modulators useful as the second therapeutic agent in the combination therapies described herein are known to those of skill in the art and include, but are not limited to, rolperiodone (CYR-101, MIN-101), quetiapine, olanzapine, altanserin, acepromazine, nefazodone, risperidone, trazodone, brexpiprazole, cariprazine, agomelatine, setoperone, zotepine, clozapine, chlorpromazine, sertindole, iloperidone, paliperidone, asenapine, amisulpride, aripiprazole, lurasidone, ziprasidone, lumateperone, perospirone, mosapramine, zanomeline, buspirone, sustained release formulations of olanzapine (e.g., ZYPREXA RELPREVV), sustained release formulations of quetiapine, sustained release formulations of risperidone (e.g., Risperdal Consta), sustained release formulations of paliperidone (e.g., Invega Sustenna and Invega Trinza), sustained release formulations of fluphenazine decanoate, including Prolixin Decanoate, sustained release formulations of aripiprazole lauroxyl, including Aristada, sustained release formulations of aripiprazole, including Abilify Maintena, or pharma- ceutically acceptable salts, solvates, metabolites, deuterated analogs, derivatives, prodrugs, or combinations thereof. In some embodiments, the dopamine receptor modulator is administered prior to administration of the compounds disclosed herein, for example, about 3 hours or about 1 hour prior to administration of the compounds disclosed herein. In some embodiments, the dopamine receptor modulator is administered up to about 1 hour prior to administration of the compounds disclosed herein.Thus, in some embodiments of combination therapy using the compounds disclosed herein, the second therapeutic agent is a dopamine receptor modulator. In some embodiments, the second therapeutic agent, a dopamine receptor modulator, is provided in a dose of about 10 mg to about 350 mg. In some embodiments, the dopamine receptor modulator is provided in a dose of about 20 mg to about 200 mg. In some embodiments, the dopamine receptor modulator is provided in a dose of about 10 mg to about 100 mg. In certain such embodiments, the compound of the present application is provided in a dose of about 10 mg to about 100 mg, or about 20 mg to about 200 mg, or about 15 mg to about 300 mg, and the dopamine receptor modulator is provided in a dose of about 10 mg to about 100 mg.

[0270] US Patent Application Publication No. 20060281735 and US Pat. No. 5,663,167 disclose combinations of idazoxan and D2 antagonists and are hereby incorporated by reference.

[0271] In some embodiments, the pharmaceutical composition of idazoxan may be used in combination with a second agent to treat Alzheimer's disease. In some embodiments, the pharmaceutical composition of idazoxan is used in combination with a cholinesterase inhibitor and / or an NMDA receptor antagonist. Exemplary and non-limiting agents for the treatment of Alzheimer's disease that may be administered in combination with the pharmaceutical composition of idazoxan include Rekembi (Recanemab-Irumbu), Donepezil (Aricept), Galantamine (Razadyne), Rivastigmine (Exelon), Memantine (Namenda), Memantine (Namzalic), Ginkgo biloba extract, Aducanumab, 3APS, 3TC, AAB-001 , AADvac1, AAV2-BDNF Gene Therapy, ABBV-8E12, ABBV-552, ABBV-916, ABT-089, ABT-126, ABT-288, ABT-384, ABvac40, AC-1204, AC-3933, AC-OLE-01-VA, ACC-001, Acetyl-L-Carnitine, ACI-24.060, ACI-35.030, Acitretin, Active tPBM, ACU193, Accumore XL, AD-35, Adenosine Triphosphate, Adrarity, Aducanumab, Aduherm, AGB101, Acufa E, AL001, AL002, Albumin 5%, Albumin 20%, Arfoatirin, Allogeneic MSC, allopregnanolone, ALN-APP, ALZ-101, Aljok, ALZT-OP1a, ALZT-OP1b, amlodipine, AMX0035, AN-1792, ANAVEX2-73, APH-1105, APNmAb005, Aquagem-E, Aquasol E, AQW051, AR1001, ARB, Aricept, Aricept ODT, Aripiprazole, Amodafinil, Astaxanthin, Astrostem, Atabese Stat, ATH-1017, atomoxetine hydrochloride, atorvastatin, atorvastatin calcium, atropine, AV-1959D, avagacestat, AVE1625, AVP-786, AVP-923-30, AXS-05 (dextromethorphan-bupropion), AZD0530, AZD1446, AZD3480, AZD3480, AZD5213, azeliragon, BAC, bapinezumab, baricitinib, Belsomra,Benfotiamine, Bepranemab, Bexarotene, BI 409306, BI 425809, Bifeprunox, BIIB080, BIIB092, BMS-708163, BPDO-1603, BPN14770, Brexpiprazole, Bromocriptine, Bryostatin, Bryostatin 1, Buntanetap, Buprenorphine, C-11 ER-176, CAD106 Immunotherapy, Canakinumab, Caprylic Triglyceride, Caprylidene, Carvedilol, CB-AC-02, CCB, Celecoxib (Celebrex), CERE-110, Celebrolysin, CHF 5074, choline alfosserate, cholinergic antagonist, cholinesterase inhibitor, cilostazol, circadin, citalopram, CMS121, CNP520, COR388, CORT108297, CPC-201, crenezumab, CT1812, CX516, CY6463, DAOI-A, DAOI-B, DAOI-C, dapagliflozin, daratumumab injection, dasatinib, DCB-AD1, deferiprone, delta-9-tetrahydrocannabinol Binol, dexmethylphenidate, dextroamphetamine, DHP1401, dimebon, divalproex, divalproex ER, dl-α-tocopherol, docosahexaenoic acid, donanemab, donepezil, donepezil / memantine, donepezil HCL, dronabinol, DSPE-DOTA-Gd liposome injection, E-400 Clear, E-600, E-Gem, E2020, E2609, E2814, Ebicom, Ebixa, EGb761, EHT 0202 etazolate, elenbecestat (E2609), ELND005, elontril, empagliflozin, emtriba capsule, ENA713, Eferol, epigallocatechin gallate, ergoloid mesylate, escitalopram, escitalopram oxalate, estrogen, etanercept, ethosuximide, EVP-0962, EVP-6124, EX039, Exelon, Exendin-4 SC, Explus, filgrastim, FK962, florbetaben (BAY94-9172), flosgossyptiflavonoids, flutemetamol, formoterol A, gabapentin enacarbil, galantamine, galantamine hydrobromide, Garcia XL, gantenerumab,Gastric retentive zinc cysteine, Gatalin XL, Gonadorelin acetate, GRF6019, GSK239512, Guanfacine, GV-971, GV1001, Haloperidol, HB-adMSC, HF0220, Human mesenchymal stem cells and lactated Ringer's solution, Huperzine A, Hydergine, Hydralazine hydrochloride, Hydrocodone / APAP, Hydroxypropyl-β-cyclodextrin, IBC-Ab002, Icosapent ethyl, ID1201, Idalopirdine, IGC-AD1, Idalopirdine, Immunoglobulin intravenous injection (human), Immunoglobulin, Indomethacin, Insulin, Insulin glulisine, IONIS MAPTRx, Isotretinoin, ITI-007, JACI-35.054, JNJ-54861911, JNJ-63733657, KarXT. Prazosin, L-arginine, L-serine, ladostigil hemitartrate, lanabecestat, lecanemab, lecozotan SR, lemborexant, lenalidomide, lequenvi, leuprolide acetate, levetiracetam, levodopa, liraglutide, lithium, lithium carbonate, LM11A-31-BHS, LMTM, long-chain triglycerides, lornoxicam, losartan, lovostatin, Lu AE58054, Lu AF87908, LX1001, LY450139, LY450139 dihydrate, LY451395, LY2062430, LY2886721, LY3154207, LY3202626, LY3372689, LY3372993, MABT5102A, masitinib, maspiridine, MEDI1814 (anti-amyloid beta mAb), medroxyprogesterone, MEM 1003, MEM 3454, memantine, memantine hydrochloride, metformin, methylene blue, methylphenidate, MIB-626, mifepristone, minocycline, mirtazapine, MK-1942, MK-2214, MK-7622, ​​MK0249, MK0677, MK0952, MLC601, MLC901, modafinil, montelukast, montelukast buccal film, MPC-7869, MSDC-0160, MT-4666, MW150, nabilone, Namenda XR, Namenda, Namzalic, NanoLithium NP03, naproxen, naproxen sodium (Aleve), NE3107, nefiracetam, nefrapimod,Nelotanserin, Nemdatine, Neramexane, NuGam 10% IVIG, NGP 555, NIC5-15, Nicotinamide Riboside, Nilotinib, Nilotinib BE, Nilvadipine, NIO752, NP031112, NPT2042, NS 2330, Nuedexta, Ovicetrapib, Octagam 10%, Octaplasma, Octohydroaminoacridine succinate, Olanzapine, Omega-3 PUFA, ONO-2506PO, ORM-12741, ORY-2001, Paracetamol, PBT2, Pepinemab, Perindopril, Perphenazine, PF-01913539, PF-04360365, PF-04447943, PF-04494700, PF-05212377, PF-06648671, Pimavanserin, Pimava tartrate, pioglitazone, piracetam, piromelatine, PM012, posiphen, PPI-1019, PQ912, prednisone, probucol, proleukin, PRX-03140, PTI-125, PXT00864, ​​PYM50028, QS-21, quercetin, quetiapine, quetiapine fumarate, raloxifene, ramelteon, ramipril, rapamycin, rasagiline, razadyne, razadyne ER, RB-ADSC, regulatory T cells REM0046127, reminiscence ole, lemternetag, reserpine, resveratrol, rifaximin, rilapladib, riluzole, risperidone, rivastigmine, rivastigmine patch, RO4602522, RO5313534, RO7126209, rofecoxib, rosiglitazone, rosiglitazone XR, rotigotine transdermal patch, RPh201, RVT-101, S-equol, S47445, SAGE-718, SAM-531, SAR110894, sargramostim, SB-742457, SCI- 110, seltrexant, semagacestat, semaglutide, semolinemab, senicapoq, sertraline, SGS742, SHR-1707, simufilam, simvastatin, SK-PC-B70M, SLS-005, SNK01, sodium oligomannuranate, sodium oligomanganate, sodium oxybate, solanezumab, solifenacin, spironolactone, SR57667B, SRA-333, SSR180711C, ST101, sulbutiamine, SUVN-502,Suvorexant, T-817MA, T-817MA-H, T-817MA-L, T2:C100, T3D-959, tacrine, tacrolimus, talsaclidine, tamibarotene, tandospirone citrate, taumab, TB006, telmisartan, tetrahydrobiopterin, TH9507 human growth hormone releasing hormone, thalidomide, thiethylperazine, tideglusib, tirabonemab, TPI287 (next generation taxane), tramiprosate, traneurosin, transdermal estradiol including: valcyclovir, transdermal methylphenidate, trazodone, tricaprylin, troliluzole, TRx0014, TRx0237, tryptophan, TW001, UB-311, UCMSC, valacyclovir / valaciclovir, valproic acid, varenicline, venlafaxine, verubecestat, VI-1121, vitamin E, VP4896, VT301, VX-745, xaliproden (SR57746A), xanamem, XPro1595, zagotenemab, zolpidem, zoplicone, zydena,

[0272] In some embodiments, monoclonal or polyclonal antibodies, such as antibodies against beta amyloid, are used to treat brain disorders.The pharmaceutical compositions of idazoxan disclosed herein may be used in combination with a second therapeutic agent that is also a monoclonal or polyclonal antibody.For example, the pharmaceutical compositions of idazoxan disclosed herein may be used in combination with aducanumab or rekembi (recanemab-irmb). EXAMPLES

[0273] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are not intended to impose any limitations on the scope of the present disclosure. It should be further understood that various other embodiments, modifications thereof, and equivalents that may themselves suggest to those skilled in the art can be employed without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0274] NMR analysis Analyzed on a 400 MHz NMR spectrometer using deuterated chloroform, deuterated methanol or deuterated dimethyl sulfoxide as solvent ( 1 H, 13 C and 19 F NMR was performed. Chemical shifts (d) of each signal are measured in parts per million (ppm) relative to the residual solvent peak, and multiplicities are reported along with associated coupling constants (J) when applicable. Data are reported as (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet).

[0275] Agilent LC-MS analysis method Instrument: Agilent 1260 infinity HPLC with Agilent 6130 single quadrupole mass spectrometer. Column: Phenomenex Kinetex XB-C 18 , 50×4.6mm, 2.6μm

[0276] [Table 2]

[0277] Flow rate: 2 mL / min; Detector wavelength: 225 ± 50 nm bandwidth; Column temperature: 40 °C; Injection volume: 1 μl; Mass Spectrometry parameters: Scan with ES+ / - and APCI over 70-1000 m / z; Needle wash: MeOH wash in vial 4, autosampler set to do 5 needle washes (to clean the outside of the needle before injecting sample); Sample preparation: 0.5-1.0 mg / ml in either acetonitrile or DMSO depending on the nature of the sample in terms of solubility.

[0278] Waters Alliance LC-MS analysis method Acid method (named Formic_8min) Instrumentation: Waters 2795 Alliance HPLC system equipped with a 2996 PDA detector and a Micromass ZQ mass spectrometer detector. Column: Gemini C18, 5 μm, 110 Å, 50 × 4.6 mm ID Mobile phase A: 0.1% formic acid in water Mobile phase B: 100% acetonitrile

[0279] [Table 3] Flow rate: 1 ml / min; injection volume: 10 μl; column oven temperature: 40 °C; detector: PDA UV (190-400 nm), also with λ fixed at 225 nm; mass spectrometry parameters: MS scan (ES+, ES-, M / Z range 100-1000); purge solvent involved in injection.

[0280] Example 1: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-5,6,7,8-d4)-4,5-dihydro-1H-imidazole (compound 4)

[0281] [ka]

[0282] Step 1: (3,4,5,6-d4)-Benzene-1,2-diol To a suspension of benzene-1,2-diol (1.00 g, 9.08 mmol) in deuterated water (20.0 mL, 1108 mmol) in a 10-20 mL Biotage microwave vial was added potassium tert-butoxide (510 mg, 4.54 mmol) in one portion with stirring. The vial was placed under a N2 atmosphere, sealed, and then heated to 140 °C for 15 h (Biotage Initiator microwave). The mixture was extracted with EtOAc (5 x 50 mL) and the combined organic layers were concentrated under reduced pressure to give an oil on standing. This oil solidified on standing. The crude product was triturated with hexanes, isolated by filtration, and washed with hexanes to give the title compound (600 mg, 57%) as a solid. Retention time 1.079 min; m / z = [MH] + Calculated for C6H2D4O2: 113.0; Observed: 113.0; 1 H NMR (400 MHz, CDCl3) δ 5.14 (2H, s). Deuterium incorporation in this compound was determined to be 97% by quantitative NMR using maleic acid as the reference standard.

[0283] Step 2: 2,3-Dihydrobenzo[b][1,4]dioxine-2-carbonitrile-5,6,7,8-d4 To a solution of (3,4,5,6-d4)-benzene-1,2-diol (600 mg, 5.26 mmol) and K2CO3 (1.45 g, 10.5 mmol) in acetone (12 ml) was added 2-chloroprop-2-enenitrile (460 mg, 5.26 mmol) in one portion. The mixture was heated to 50 °C and stirred for 18 h. The mixture was concentrated under reduced pressure and the brown viscous residue was partitioned between H2O (100 mL) and Et2O (100 mL). The organic layer was dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was dry loaded onto silica gel and then purified by column chromatography on silica gel (10 g Biotage HC cartridge) using a gradient of DCM (CH2Cl2) in hexanes (1:9 to 4:6) as eluent to give the title compound (450 mg, 51%) as a viscous oil. Retention time 1.570 minutes; 1H NMR (400 MHz, CDCl3) δ 5.10 (1H, dd, J = 4.0 Hz and 2.8 Hz), 4.42 (1H, dd, J = 12.0 Hz and 4.0 Hz), 4.35 (1H, dd, J = 11.6 Hz and 2.8 Hz).

[0284] Step 3: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-5,6,7,8-d4)-4,5-dihydro-1H-imidazole To a solution of 2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile-5,6,7,8-d4 (144 mg, 0.87 mmol) in dry MeOH (3 mL) stirred with ice bath cooling (0-5 °C) under N2 atmosphere was added NaOMe (1.88 mg, 0.035 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 6 h, then cooled in an ice bath and ethane-1,2-diamine (64 μL, 0.96 mmol) was added in one portion. After 5 min, HCl in MeOH (1.25 M; 767 μL, 0.96 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using 2M ammonia in MeOH / DCM (CH2Cl2) (1:9) as eluent to give the title compound (72 mg, 39%) as a solid. Retention time 0.994 min; m / z=[M+H] + C 11 Calculated for H8D4N2O2: 209.1; Observed: 209.2; 1 H NMR (400 MHz, CDCl3) δ 5.06 (1H, br s), 4.89 (1H, dd, J = 7.6 Hz and 2.4 Hz), 4.54 (1H, dd, J = 11.6 Hz and 2.8 Hz), 4.18 (1H, dd, J = 7.6 Hz and 11.2 Hz), 4.10-3.25 (4H, br m). 1 It was determined to be 96.3% by measuring the integral of the residual aromatic protons in 1 H NMR.

[0285] Example 2: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-5,6,7,8-d4)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 (Compound 52)

[0286] [ka] To a solution of 5,6,7,8-tetradeuterio-2,3-dihydro-1,4-benzodioxine-3-carbonitrile (139 mg, 0.84 mmol) in dry methanol (3 mL) stirred with ice bath cooling (0-5 °C) under a N2 atmosphere was added sodium methoxide (25.0 wt% solution in MeOH, 7.70 μL, 0.034 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 6 h, then cooled in an ice bath and 1,1,2,2-tetradeuterioethane-1,2-diamine (61.8 μL, 0.93 mmol) was added in one portion. After 5 min, HCl in MeOH (1.25 M in MeOH, 741 μL, 0.93 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight, then H2O (40 mL) was added, basified with 33-34% aqueous NH3 (5 mL) and extracted with CHCl3 (2 x 20 mL). The combined organic layers were concentrated under reduced pressure to give the title compound (155 mg, 77%) as a solid. Retention time 0.957 min; m / z = [M+H] + C 11 H4D8N2O2 calculated: 213.1; observed: 213.2; 1 H NMR (400 MHz, CDCl3) δ 5.03 (1H, br s), 4.89 (1H, dd, J = 8.0 Hz and 2.8 Hz), 4.54 (1H, dd, J = 11.6 Hz and 2.8 Hz), 4.18 (1H, dd, J = 11.2 Hz and 7.6 Hz).

[0287] Example 3: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-6-d)-4,5-dihydro-1H-imidazole (Compound 1)

[0288] [ka]

[0289] Step 1: 6-Bromo-2,3-dihydro-1,4-benzodioxine-2-carboxamide To a stirred suspension of 6-bromo-2,3-dihydro-1,4-benzodioxine-2-carboxylic acid (250 mg, 0.97 mmol) in toluene (5 mL) was added thionyl chloride (141 μL, 1.93 mmol) in one portion. The suspension was heated to 100 °C and stirred for 2 h, then the toluene was removed under reduced pressure. The residue was co-evaporated with toluene (2 × 10 mL) to remove excess thionyl chloride. The residue was suspended in 1,4-dioxane (5 mL) and this mixture was added dropwise over 5 min to a stirred solution of 33-34% aq. NH3 (5 mL) with ice bath cooling. The ice bath was removed and the mixture was allowed to warm to room temperature and stirred for 30 min, then H2O (40 mL) was added. The resulting precipitate was collected by filtration and air-dried at 40 °C to give the title compound (224 mg, 89%) as a solid. Retention time 1.510 min; 1 H NMR (400MHz, DMSO-d6) δ 7.53 (1H, br. s), 7.48 (1H, br. s), 7.07 (1H, d, J=2.4Hz), 7.03 (1H, dd, J=8.4Hz, 2.4Hz), 6.92 (1H, d, J=8.8Hz), 4.79-4.47 (1H, m), 4.36-4.24 (2H, m).

[0290] Step 2: 6-Bromo-2,3-dihydro-1,4-benzodioxine-2-carbonitrile To a suspension of 6-bromo-2,3-dihydro-1,4-benzodioxin-2-carboxamide (170 mg, 0.66 mmol) in DMF (4 mL) stirred at room temperature was added 2,4,6-trichloro-1,3,5-triazine (46 mg, 0.26 mmol) in portions over 2 min. The mixture was stirred at room temperature for 18 h, then a further portion of 2,4,6-trichloro-1,3,5-triazine (46 mg, 0.26 mmol) was added in one portion and the mixture was stirred at room temperature overnight. The mixture was combined with a smaller validation batch (50 mg scale) and then poured into H2O (50 mL) and extracted with Et2O (4 x 20 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (Biotage Isolera system, 5 g HC silica cartridge) using a gradient of EtOAc in hexanes (1:9 to 4:6) as eluent to give the title compound (176 mg, 85%) as a solid. Retention time 1.171 min; 1 H NMR (400MHz, CDCl3) δ 7.12 (1H, J=2.0Hz), 7.04 (1H, dd, J=8.8Hz and 2.4Hz), 6.84 (1H, J=8.4Hz), 5.13-5.09 (1H, m), 4.49-4.30 (2H, m).

[0291] Step 3: 2-(6-bromo-2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole To a solution of 6-bromo-2,3-dihydro-1,4-benzodioxine-2-carbonitrile (175 mg, 0.73 mmol) in dry methanol (4 mL) stirred with ice-bath cooling (0-5 °C) under N2 atmosphere was added NaOMe (25 wt% solution in MeOH, 6.67 μL, 0.029 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 6 h, at which point TLC analysis (eluent 1:1 hexane-CH2Cl2) indicated that essentially all of the starting nitrile had been converted to the imidate. The mixture was cooled in an ice bath and ethane-1,2-diamine (53.5 μL, 0.80 mmol) was added in one portion. After 5 min, HCl in MeOH (1.25 M; 642 μL, 0.80 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight, then H2O (40 mL) was added and the mixture was basified with 33-34% aqueous NH3 (5 mL) and extracted with DCM (CH2Cl2) (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (169 mg, 81%) as a solid. Retention time 1.172 min; m / z = [M+H] + C 11 H 11 BrN2O2 calculated: 283.0; Observed: 283.0; 1 H NMR (400 MHz, CDCl3) δ 7.06 (1H, d, J = 2.0 Hz), 6.97 (1H, dd, J = 8.8 Hz and 2.4 Hz), 6.78 (1H, J = 8.8 Hz), 5.29 (1H, br s), 4.85 (1H, dd, J = 7.6 Hz and 2.4 Hz), 4.53 (1H, dd, J = 11.6 Hz and 2.4 Hz), 4.22-4.13 (1H, m), 3.97-3.81 (2H, br m), 3.57-3.38 (2H, br m).

[0292] Step 4: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-6-d)-4,5-dihydro-1H-imidazole A mixture of 2-(6-bromo-2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole (135 mg, 0.48 mmol) and 10% Pd / C (45 mg, 0.042 mmol) in MeOH-d4 (3.5 mL) was stirred at room temperature under deuterium atmosphere (ca. 20 psi) for 2 h. The reaction mixture was filtered to remove the Pd / C catalyst and combined with the reaction mixture from the validation batch (30 mg scale). The reaction mixture was added to water (40 mL), basified with 33-34% aqueous NH3 (5 mL) and extracted with CHCl3 (2 x 20 mL). The combined organic layers were concentrated under reduced pressure and the crude residue was purified by column chromatography on silica gel using 2M NH3 in MeOH / DCM (CH2Cl2) (1:9) as eluent to give the title compound (60 mg, 50%) as a viscous oil. Retention time 0.959 min; m / z=[M+H] + C 11 H 11 DN2O2 calculated: 206.1; observed: 206.2; 1 H NMR (400 MHz, CDCl3) δ 6.99-6.86 (3H, m), 4.94 (0.65H, dd, J = 7.2 Hz and 2.4 Hz due to partial deuteration at this position), 4.58-4.51 (1H, m), 4.27-4.19 (1H, m), 3.69 (4H, s).

[0293] Example 4: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-7-d)-4,5-dihydro-1H-imidazole (Compound 2)

[0294] [ka]

[0295] Step 1: 7-Bromo-2,3-dihydro-1,4-benzodioxine-2-carbonitrile To a solution of 4-bromobenzene-1,2-diol (1.0 g, 5.29 mmol) and K2CO3 (1.46 g, 10.6 mmol) in acetone (20 mL) was added 2-chloroprop-2-enenitrile (463 mg, 5.29 mmol) in one portion. The mixture was heated to 85 °C under microwave irradiation (Biotage Initiator microwave) and stirred for 12 h. The mixture was concentrated under reduced pressure and the residue was partitioned between H2O (100 mL) and EtOAc (100 mL). The organic layer was concentrated under reduced pressure and the residue was combined with the crude product of a validation batch (1 g scale) and then purified by column chromatography on silica gel (Biotage Isolera system, 10 g HC silica cartridge) using DCM (CH2Cl2) / hexanes (1:9 to 4:6 gradient) as eluent to give the title compound (703 mg, 27%) as a solid. Retention time 1.711 minutes; 1 H NMR (400MHz, CDCl3) δ 7.12 (1H, d, J = 2.4Hz), 7.10-7.01 (1H, m), 6.84 (1H, d, J = 8.8Hz), 5.12-5.06 (1H, m), 4.42 (1H, dd, J = 11.6Hz and 3.6Hz), 4.39-4.30 (1H, m).

[0296] Step 2: 2-(7-Bromo-2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole To a solution of 7-bromo-2,3-dihydro-1,4-benzodioxine-2-carbonitrile (505 mg, 2.10 mmol) in dry MeOH (10 mL) stirred with ice-bath cooling (0-5 °C) under N2 atmosphere was added NaOMe (4.55 mg, 0.084 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 6 h, then cooled in an ice bath and ethane-1,2-diamine (0.155 mL, 2.31 mmol) was added in one portion. After 5 min, HCl in MeOH (1.25 M; 1.85 mL, 2.31 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight, then H2O (100 mL) was added, basified with 33-34% aqueous NH3 (10 mL) and extracted with DCM (CH2Cl2) (3 x 40 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure and combined with the filtrate from the validation batch (200 mg scale). The crude residue was purified by column chromatography on silica gel using 2M ammonia in MeOH / DCM (CH2Cl2) (1:9) as eluent to give the title compound (331 mg, 39%) as a solid. Retention time 1.169 min; m / z=[M+H] + C 11 H 11 BrN2O2 calculated: 283.0; Observed: 283.0; 1 H NMR (400MHz, CD3OD) δ 7.12(1H, d, J=2.4Hz), 6.97(1H, dd, J=8.8Hz and 2.4Hz), 6.80(1H, d, J=8.4H z), 4.92-4.86(1H, m), 4.45-4.38(1H, m), 4.20-4.12(1H, m), 3.63(4H, s).

[0297] Step 3: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-7-d)-4,5-dihydro-1H-imidazole A mixture (0.75 mL) of 2-(7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole (30 mg, 0.11 mmol) and 10% Pd / C (10 mg) in MeOH-d4 (0.75 mL) at room temperature was stirred under a deuterium atmosphere (ca. 20 psi) for 2 h. The mixture was filtered to remove the Pd / C and the filtrate was loaded directly onto silica wetted with 2M NH3 in MeOH / DCM (CHCl) (1:9) and purified by column chromatography on silica gel using 2M NH3 in MeOH / DCM (CHCl) (1:9) as eluent to give the desired product (18 mg, 82%) as a viscous oil. Retention time 0.986 min; m / z=[M+H] + C 11 H 11 DN2O2 calculated: 206.0; observed: 206.2; 1 H NMR (400 MHz, CD3OD) δ 6.94 (1H, br s), 6.85 (2H, br s), 4.91-4.87 (1H, m, partially obscured by water peak), 4.46-4.38 (1H, m), 4.20-4.10 (1H, m), 3.64 (4H, s).

[0298] Example 5: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-6,7-d2)-4,5-dihydro-1H-imidazole (compound 3)

[0299] [ka]

[0300] Step 1: 6,7-Dibromo-2,3-dihydro-1,4-benzodioxine-2-carbonitrile To a stirred solution of 4,5-dibromobenzene-1,2-diol (1.53 g, 5.71 mmol) in acetone (30 mL) was added 2-chloroprop-2-enenitrile (0.50 g, 5.71 mmol) in one portion. The mixture was heated to 50 °C and stirred overnight, then concentrated under reduced pressure and the residue partitioned between H2O (150 mL) and EtOAc (150 mL). The organic layer was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (10 g Biotage HC cartridge) using DCM (CHCl2) in hexanes (2:8 to 4:6) as eluent to give the title compound (1.06 g, 58%) as a solid. Retention time 1.765 min; m / z = [M+H] + Calculated for C9H5Br2NO2: 317.8; Observed: 317.8; 1 H NMR (400 MHz, CDCl3) δ 7.15-7.08 (2H, m), 5.24 (1H, dd, J = 3.6 Hz and 2.4 Hz), 4.56 (1H, dd, J = 12.0 Hz and 3.6 Hz), 4.43 (1H, dd, J = 12.0 Hz and 2.4 Hz).

[0301] Step 2: 2-(6,7-dibromo-2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole To a solution of 6,7-dibromo-2,3-dihydro-1,4-benzodioxine-2-carbonitrile (420 mg, 1.32 mmol) in dry MeOH (16 mL) stirred with ice bath cooling (0-5 °C) under N2 atmosphere was added sodium methoxide (25 wt% solution in MeOH, 12 μL, 0.053 mmol) in one portion. The mixture was warmed to room temperature and stirred for 6 h, then cooled in an ice bath and ethane-1,2-diamine (96.7 μL, 1.45 mmol) was added in one portion. After 5 min, 1.25 M HCl in MeOH (1.16 mL, 1.45 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. The precipitate was isolated by filtration, washed with cold MeOH (1 mL) and air-dried to give the title compound (312 mg, 62%) as a solid. Retention time 1.213 minutes; m / z=[M+H] + C 11 H 10Br2N2O2 calculated: 362.9; Observed: 362.8; 1 H NMR (400MHz, DMSO-d6) δ 7.14-7.08(2H, m), 6.50(1H, br. s), 5.03(1H, dd, J=6.4, 2.4Hz), 4.52(1H, dd, J=11.6, 2.8Hz), 4.34(1H, dd, J=11.6, 6.4Hz), 3.80-3.20(4H, br. s).

[0302] Step 3: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-6,7-d2)-4,5-dihydro-1H-imidazole A solution of 2-(6,7-dibromo-2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole (303 mg, 0.84 mmol) and 10% Pd / C (79 mg, 0.74 mmol) in MeOH-d4 (6 mL) was stirred at room temperature under D2 atmosphere (ca. 20 psi) for 24 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 2M NH3 in MeOH / DCM (CH2Cl2) (5:95 to 15:85) as eluent to give the title compound (126 mg, 73%) as a viscous oil. Retention time 0.753 min; m / z=[M+H] + C 11 H 10 Calculated D2N2O2: 207.1; Observed: 207.2; 1 H NMR (400MHz, CD3OD) δ 6.93-6.85(2H, m), 5.42(1H, dd, J=5.6, 2.4Hz), 4.47(1H, dd, J=12.0, 2.8Hz), 4.38(1H, dd, J=12.0, 5.6Hz), 4.00(4H, s).

[0303] Example 6: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-6-d)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 (Compound 49)

[0304] [ka]

[0305] Step 1: 2-(6-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 To a mixture of 6-bromo-2,3-dihydro-1,4-benzodioxine-2-carbonitrile (170 mg, 0.71 mmol) in dry MeOH (4 ml) stirred with ice bath cooling (0-5 °C) under N2 atmosphere was added sodium methanolate (25 wt% solution in MeOH, 6.5 μL, 0.028 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 7 h, then cooled in an ice bath and 1,1,2,2-tetradeuterioethane-1,2-diamine (48.9 μL, 0.78 mmol) was added in one portion. After 5 min, hydrogen chloride (1.25 M in MeOH) (623 μL, 0.78 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight, then poured into H2O (40 mL), basified with 33-34% aqueous NH3 (5 mL), and the resulting precipitate was isolated by filtration to give the title compound (134 mg, 64%) as a solid after air drying. Retention time 2.850 min; m / z=[M+H] + C 11 Calculated for H7D4BrN2O2: 287.0; Observed: 287.0; 1 H NMR (400MHz, CDCl3) δ 7.06 (1H, d, J=2.4Hz), 6.97 (1H, dd, J=8.4, 2.4Hz), 6.78 (1H, J=8.4Hz), 4.98 (1H, br. s), 4.85 (1H, dd, J=7.6, 2.4Hz), 4.53 (1H, dd, J=11.6, 2.8Hz), 4.17 (1H, dd, J=11.6, 8.0Hz).

[0306] Step 2: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-6-d)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 2-(6-bromo-2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro(4,4,5,5- 2H4) A mixture of 1H-imidazole (130 mg, 0.45 mmol) and 10% Pd / C (42.7 mg, 0.04 mmol) was stirred at room temperature under D2 atmosphere (ca. 20 psi) for 2 h. The mixture was filtered, poured into H2O (40 mL), basified with 33-34% aqueous NH3 (5 mL), and extracted with CHCl3 (2 x 20 mL). The combined organic layers were concentrated under reduced pressure and the crude residue was purified by column chromatography on silica gel using 2M NH3 in MeOH / DCM (CH2Cl2) (1:9) as eluent to give the title compound (78 mg, 82%) as a viscous oil. Retention time 0.779 min; m / z = [M+H] + C 11 Calculated for H7D5N2O2: 210.1; Observed: 210.2; 1 H NMR (400 MHz, CDCl3) δ 7.00-6.84 (3H, m), 4.90 (0.57H, dd, J = 8.0, 2.8 Hz due to partial deuteration at this position), 4.57-4.50 (1H, m), 4.22-4.13 (1H, m).

[0307] Example 7: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-7-d)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 (Compound 50)

[0308] [ka]

[0309] Step 1: 2-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 To a mixture of 7-bromo-2,3-dihydro-1,4-benzodioxine-2-carbonitrile (200 mg, 0.88 mmol) in dry MeOH (4 mL) with ice-bath cooling (0-5 °C) under N2 atmosphere was added a solution of sodium methoxide in MeOH (25 wt%, 7.6 μL, 0.033 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 6 h, then cooled in an ice bath and 1,1,2,2-tetradeuterioethane-1,2-diamine (57.5 μL, 0.92 mmol) was added in one portion. After 5 min, 1.25 M HCl in MeOH (0.73 mL, 0.92 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight, then diluted with H2O (40 mL), basified with 33-34% aqueous NH3 (5 mL) and extracted with DCM (CH2Cl2) (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (210 mg, 87%) as a solid. Retention time 1.169 min; m / z = [M+H] + C 11 Calculated for H7D4BrN2O2: 287.0; Observed: 287.0; 1 H NMR (400MHz, DMSO-d6) δ 7.12-7.08(1H, m), 7.05-6.98(1H, m), 6.90-6.81(1H, m), 4.92-4.86(1H, m), 4.46-4.37(1H, m), 4.26-4.15(1H, m).

[0310] Step 2: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-7-d)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 A mixture of 2-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 (205 mg, 0.71 mmol) and 10% Pd / C (67 mg) in MeOH-d4 (4 mL) was stirred at room temperature under D2 atmosphere (ca. 20 psi) for 2 h. The mixture was filtered and the filtrate was loaded directly onto silica wetted with 2M NH3 in MeOH / DCM(CHCl) (1:9). The mixture was purified by column chromatography on silica gel using 2M NH3 in MeOH / DCM(CHCl) (1:9) as eluent to give the title product (86 mg, 57%) as a viscous oil. Retention time 0.981 min; m / z=[M+H] + C 11 Calculated for H7D5N2O2: 210.1; Observed: 210.2; 1 H NMR (400 MHz, CDCl3) δ 6.96-6.82 (3H, m), 5.02 (1H, br. s), 4.88 (0.62H, dd, J = 8.0, 5.2 Hz due to partial deuteration at this position), 4.57-4.50 (1H, m), 4.21-4.11 (1H, m).

[0311] Example 8: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-6,7-d2)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 (Compound 51)

[0312] [ka]

[0313] Step 1: 2-(6,7-dibromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 To a solution of 6,7-dibromo-2,3-dihydro-1,4-benzodioxine-3-carbonitrile (86 mg, 0.27 mmol) in dry MeOH (4 mL) stirred with ice / water bath cooling under N2 atmosphere was added sodium methoxide (25% wt in MeOH, 2.5 μL, 0.011 mmol). The mixture was warmed to room temperature and stirred for 18 h, then cooled in an ice bath and 1,1,2,2-tetradeuterioethane-1,2-diamine (18.6 μL, 0.30 mmol) was added in one portion. After 5 min, 1.25 M HCl in MeOH (237 μL, 0.30 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 24 h, then added to ice water (30 mL) containing 33-34% aqueous NH3 (5 mL). The mixture was stirred for 5 min and the resulting precipitate was isolated by filtration and air-dried to give the title compound (32 mg, 32%) as a solid. Retention time 1.192 min; m / z=[M+H] + C 11 Calculated for H6Br2D4N2O2: 366.9; Observed: 366.9; 1 H NMR (400MHz, DMSO-d6) δ 7.17-7.08(2H, m), 5.04(1H, dd, J=6.8, 2.8Hz), 4.53(1H, dd, J=11.6, 2.8Hz), 4.35(1H, dd, J=11.6, 6.8Hz).

[0314] Step 2: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl-6,7-d2)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 To a stirred mixture of 2-(6,7-dibromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 (30 mg, 0.082 mmol) and 10% Pd / C (15 mg, 0.014 mmol) in MeOH-d4 (2.5 ml) was added N-ethyl-N-isopropyl-propan-2-amine (28 mL, 0.16 mmol). The mixture was stirred at room temperature under D2 atmosphere (ca. 20 psi) for 24 h and then filtered through a pad of Celite. The filtrate was diluted with H2O (40 mL), basified with 33-34% aqueous NH3 (5 mL) and extracted with CHCl3 (2 x 20 ml). The combined organic layers were concentrated under reduced pressure to give the title compound (11 mg, 63%) as a viscous oil. Retention time 0.935 min; m / z=[M+H] + C 11 Calculated for H6D6N2O2: 211.1; Observed: 211.2; 1 H NMR (400MHz, CDCl3) δ 6.92-6.85(2H, m), 5.02(1H, br. s), 4.88(ca. 0.25H, dd, J=7.6, 2.4Hz), 4.58-4.49(1H, m), 4.22-4.14(1H, m).

[0315] NOTE: LCMS and NMR show that the CHα of the imidazoline ring is approximately 75% deuterated.

[0316] Example 9: 2-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole-4,4,5,5-d4 (Compound 64)

[0317] [ka] To a mixture of 2,3-dihydro-1,4-benzodioxine-2-carbonitrile (120 mg, 0.75 mmol) in dry MeOH (2.5 mL) stirred with ice / water bath cooling (0-5 °C) under N2 atmosphere was added sodium methoxide (25% by weight in MeOH) (6.8 μL, 0.03 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 6 h, then cooled in an ice bath and 1,1,2,2-tetradeuterioethane-1,2-diamine (51 μL, 0.82 mmol) was added in one portion. After 5 min, 1.25 M HCl in MeOH (655 μL, 0.82 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight, then diluted with H2O (50 mL), basified with 33-34% aqueous NH3 (3 mL) and extracted with DCM (CH2Cl2) (3 x 40 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (143 mg, 92%) as a solid. Retention time 0.982 min; m / z = [M+H] + C 11 Calculated for H8D4N2O2: 209.1; Observed: 209.2; 1 H NMR (400MHz, CDCl3) δ 6.98-6.85(4H, m), 5.03(1H, br. s), 4.89(1H, dd, J=8.0, 2.8Hz), 4.54(1H, dd, J=11.6, 2.8Hz), 4.18(1H, dd, J=11.6, 8.0Hz).

[0318] Example 10: Enantiomerically enriched compounds Compounds of the present disclosure (e.g., compounds 1, 2, 3, 4, 49, 50, 51, 52, and 64) can be obtained as single enantiomers (e.g., as shown in the table below) by, for example, resolution of the racemic deuterated compounds with (+) or (-) tartaric acid or by chiral HPLC.

[0319] [Table 4-1] [Table 4-2] [Table 4-3]

[0320] Biological Example 1: Pharmacokinetic Profiles of Deuterated Compounds Microsomal stability can be assessed using the protocol described in WO2020 / 132461, which is incorporated herein by reference in its entirety. Microsomal stability was assessed using the protocol described below.

[0321] Assessment of metabolic stability in human liver microsomes Protocol Overview Test compounds (1 μM) were incubated with pooled liver microsomes for 45 minutes at five time points over the course of the assay and analyzed by LC-MS / MS.

[0322] the purpose The stability of the test compound in the presence of liver microsomes is determined.

[0323] Customer requirements Compound identifier, molecular weight and / or molecular formula. · 50 μL of 10 mM test compound in DMSO per species per assay condition.

[0324] Experimental procedure Pooled liver microsomes were purchased from a reputable commercial supplier and were stored at -80°C prior to use. Microsomes (final protein concentration 0.5 mg / mL), 0.1 M phosphate buffer pH 7.4 and test compound (final substrate concentration 1 μM, final DMSO concentration 0.25%) were pre-incubated at 37°C before adding NADPH (final concentration 1 mM) to initiate the reaction. For each compound tested, a minus cofactor control incubation was included, in which 0.1 M phosphate buffer pH 7.4 was added instead of NADPH (minus NADPH). Two control compounds were included for each species. All incubations were performed alone for each test compound. Each compound was incubated for 0, 5, 15, 30, or 45 minutes. Controls (minus NADPH) were incubated for 45 minutes only. Reactions were stopped at the appropriate time points by transferring the incubations to acetonitrile in a 1:3 ratio. Termination plates were centrifuged at 3,000 rpm for 20 minutes at 4°C to precipitate proteins.

[0325] quantitative analysis After protein precipitation, sample supernatants were combined into cassettes of up to four compounds, internal standards were added, and samples were analyzed using generic LCMS / MS conditions. Optionally, if metabolite profiling was requested after the stability assay, a second assay was performed, where compounds were incubated in quadruplicate and the four resulting incubations were pooled to generate a higher sample concentration for analysis. Timepoints where 30-70% of the parent substance was degraded were then investigated with three different levels of metabolite profiling and / or identification.

[0326] Data analysis The ln peak area ratio (compound peak area / internal standard peak area) was plotted against time and the slope of the line was determined. The half-life and intrinsic clearance were then calculated using the following formulas: Elimination rate constant (k) = (-slope) Half-life (t 1 / 2)(min)=0.693 / k Intrinsic clearance (CLint) (μL / min / mg protein) = (V × 0.693) / t 1 / 2 Where V = incubation volume (µL) / microsomal protein (mg) Relevant control compounds were evaluated to ensure that intrinsic clearance values ​​were within specified limits (where available). Any that failed were rejected and the assay was repeated. Intrinsic clearance (CLint) and standard error (SE CLint), t 1 / 2 and n (the number of time points used to calculate CLint) is returned. In these experiments, values ​​with a ≥15% increase in half-life were considered to be significantly different, and apparent intrinsic clearance ratios (deuterated compound / idazoxan) greater than 1.15 or less than 0.85 were considered to be significantly differentiated. An alternative protocol is described in WO2020 / 132461 (herein incorporated by reference in its entirety) and is briefly described below.

[0327] Microsomal assay: Human liver microsomes (20 mg / mL) were obtained from Xenotech, LLC (Lenexa, KS). β-Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl2) and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich.

[0328] Measurement of metabolic stability: Prepare a 7.5 mM stock solution of each compound or its pharma- ceutically acceptable salt in DMSO. Dilute the 7.5 mM stock solution to 12.5-50 μM with acetonitrile (ACN). Dilute 20 mg / mL human liver microsomes to 0.625 mg / mL with 0.1 M potassium phosphate buffer (pH 7.4) containing 3 mM MgCl2. Add the diluted microsomes to wells of a 96-well deep-well polypropylene plate in triplicate. Add a 10 pL aliquot of the test compound (12.5-50 μM) to the microsomes and pre-warm the mixture for 10 min. The reaction is initiated by adding pre-warmed NADPH solution. The final reaction volume is 0.5 mL and contains 4.0 mg / mL human liver microsomes, 0.25 μM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer (pH 7.4) and 3 mM MgCl2. The reaction mixture is incubated at 37 °C and 50 pL aliquots are taken at 0, 5, 10, 20, and 30 min and added to a shallow-well 96-well plate. The plate contains 50 pL of ice-cold ACN (acetonitrile) with an internal standard to stop the reaction. The plate is stored at 4 °C for 20 min, after which 100 pL of water is added to the wells of the plate before centrifugation to pellet the precipitated proteins. The supernatant is transferred to another 96-well plate and analyzed for the amount of parent material remaining by LC-MS / MS using an Applied Bio-systems API 4000 mass spectrometer. The same procedure is followed for the non-deuterated counterpart and the positive control 7-ethoxycoumarin (1 μM). The test will be conducted three times.

[0329] Data Analysis: In Vitro Test Compounds 1 / 2 was calculated from the slope of the linear regression of the percentage of parent compound remaining (In) versus incubation time. In vitro T 1 / 2 =0.693 / k k = -[slope of linear regression of fraction of parent compound remaining (In) vs. incubation time]

[0330] The apparent intrinsic clearance is calculated using the following formula: CL int (mL / min / kg) = (0.693 / in vitro T) (incubation volume / mg microsomes) (45 mg of microsomes / gram of liver) (20 gm of liver / kg body weight) Data analysis was performed using Microsoft Excel software.

[0331] Assessment of metabolic stability in human liver microsomes - Results Test compound concentration = 3 μM Microsome concentration = 0.5mg / mL Time points = 0, 5, 15, 30, 45 min Cofactor=NADPH Final DMSO concentration=0.25% Control = 0 μM (blank); positive control compound with known activity Analysis method=LC-MS / MS

[0332] [Table 5] Based on the results in Table 2, compounds 1, 2, 3, 4, 49, 50, 51, 52 and 64 showed significant differences in in vitro clearance and half-life compared to idazoxan.

[0333] Biological Example 2: Oral Bioavailability in Rats The pharmacokinetics of the test compound is measured after a single intravenous or oral dose in rats. Pharmacokinetic (PK) studies are performed in three male Sprague-Dawley (SD) rats after intravenous (IV) and oral (PO) dosing of idazoxan or a deuterated idazoxan analog of the present disclosure at 1 mg / kg (IV) and 10 mg / kg (PO). The test compound, i.e., idazoxan, is measured in plasma.

[0334] Rat strains Rats used in these studies were supplied by Charles River (Margate, UK) and were specific pathogen-free. The rat strain was Sprague Dawley. Male rats were 175-225 g upon receipt and were allowed to acclimate for 5-7 days.

[0335] Animal Containment Rats were group-housed in sterile, individually ventilated cages and exposed to sterile HEPA-filtered air at all times. Animals had free access to food and water (sterile) and were provided with sterile aspen chip bedding (at least weekly).

[0336] The room temperature is 22°C ± 1°C, the relative humidity is 60%, and the maximum background noise is 56 dB. Rats are exposed to a 12-hour light-dark cycle.

[0337] treatment Each test compound is diluted in 10% v / v DMSO, 40% v / v PEG-400, 50% v / v water. Each test compound is administered at a dose volume of 2 mL / kg for the intravenous (IV) route of administration and 5 mL / kg for the oral route of administration (PO).

[0338] Single IV / PO dose pharmacokinetic study in rats Each test compound is administered by one IV bolus (via a lateral tail vein) or one oral gavage to a cohort of three rats per route of administration. After dose administration, 100 μL whole blood samples (EDTA) are collected via the tail vein at the time points listed in Table 3. The blood is centrifuged to separate the plasma. Approximately 40 μL of plasma per rat per time point is aliquoted into 96-well plates and frozen until analysis. Bioanalysis is performed on the plasma samples.

[0339] [Table 6]

[0340] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein which are intended to be encompassed within the scope of this application.

[0341] All patents, patent applications and references cited herein are hereby expressly incorporated by reference.

Claims

1. Formula (I), 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

2. Formula (II) or Formula (III), 【Chemistry 2】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

3. Formula (II-A) or Formula (III-A), 【Chemistry 3】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 4 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

4. R 5 , R 6 , R 7 and R 8 The compound according to claims 1 to 3, wherein at least one of is deuterium.

5. R 5 , R 6 , R 7 and R 8 The compound according to claims 1 to 4, wherein at least two of are deuterium.

6. R 5 , R 6 , R 7 and R 8 The compound according to claims 1 to 4, wherein at least three of are deuterium.

7. R 5 , R 6 , R 7 and R 8 The compound according to claims 1 to 4, wherein all of are deuterium.

8. R 1 , R 1 ', R 2 , R 2 8. The compound according to claim 1, wherein at least one of is deuterium.

9. R 1 , R 1 ', R 2 , R 2 8. The compound according to claim 1, wherein at least two of are deuterium.

10. R 1 , R 1 ', R 2 , R 2 8. The compound according to claim 1, wherein at least three of are deuterium.

11. R 1 , R 1 ', R 2 , R 2 8. The compound of claim 1, wherein all of are deuterium.

12. Formula (IA), 【Chemistry 4】 The compound according to any one of claims 1 to 2, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen and deuterium, with the proviso that R 1 , R 1 ', R 2 , R 2 ', R 5 , R 6 , R 7 and R 8 at least one of which is deuterium).

13. R 1 , R 1 ', R 2 , R 2 13. The compound of claim 12, wherein at least one of is deuterium.

14. R 1 and R 2 The compound according to any one of claims 12 to 13, wherein at least one of is deuterium.

15. R 5 , R 6 , R 7 and R 8 The compound according to any one of claims 12 to 14, wherein at least one of is deuterium.

16. R 6 and R 7 The compound according to any one of claims 12 to 14, wherein at least one of is deuterium.

17. 【Chemical 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 A compound according to any one of claims 1 to 3 or 12, selected from the list consisting of or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

18. 【Chemical 6】 13. The compound of any one of claims 1 to 3 or 12, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, selected from the list consisting of:

19. 2. A compound according to any one of the preceding claims, wherein at least 90% deuterium is incorporated at each position specifically designated as deuterium.

20. 2. A compound according to any one of the preceding claims, wherein at least 95% deuterium is incorporated at each position specifically designated as deuterium.

21. 2. A compound according to any one of the preceding claims, having at least 97% deuterium incorporated at each position specifically designated as deuterium.

22. 10. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharma- ceutically acceptable excipient.

23. 23. A method for treating or preventing a disease or condition selected from psychosis, schizophrenia, schizoaffective disorder, Parkinson's disease, dementia with Lewy bodies, sleep disorders, agitation, mood disorders, thromboembolic disorders, autism, attention deficit hyperactivity disorder, and any combination thereof in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 21, or a pharmaceutical composition according to claim 22.

24. 22. Use of a compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a disease or condition selected from psychosis, schizophrenia, schizoaffective disorder, Parkinson's disease, dementia with Lewy bodies, sleep disorders, agitation, mood disorders, thromboembolic disorders, autism, attention deficit hyperactivity disorder, and any combination thereof.

25. A kit comprising a compound according to any one of claims 1 to 21, or a pharmaceutical composition according to claim 22, together with instructions for its use.

Images