WO2016109359A1

WO2016109359A1 - Cyclopropyl dihydrobenzofuran modulators of melatonin receptors

Info

Publication number: WO2016109359A1
Application number: PCT/US2015/067541
Authority: WO
Inventors: Chengzhi Zhang; Justin CHAKMA; Ralph Laufer
Original assignee: Auspex Pharmaceuticals Inc
Current assignee: Auspex Pharmaceuticals Inc
Priority date: 2014-12-29
Filing date: 2015-12-27
Publication date: 2016-07-07
Anticipated expiration: 2017-06-29
Also published as: TW201629029A; AR103317A1

Abstract

The present invention relates to new cyclopropyl dihydrobenzofuran modulators of melatonin receptors, pharmaceutical compositions thereof, and methods of use thereof.

Description

CYCLOPROPYL DIHYDROBENZOFURAN MODULATORS OF MELATONIN

RECEPTORS [0001] This application claims the benefit of priority of United States provisional Application No.62/097,450, filed December 29, 2014, the disclosure of which is hereby incorporated by reference, as if written herein, in its entirety. [0002] Disclosed herein are new cyclopropyl dihydrobenzofuran compounds and compositions and their application as pharmaceuticals for the treatment of disorders. Methods of modulation of melatonin receptor activity in a subject are also provided for the treatment of disorders such as non-24-hour sleep-wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. [0003] Tasimelteon (Hetlioz; BMS 214778; VEC 162; MA 1; CAS # 609799-22-6; (1R- trans)-N-[[2-(2,3-Dihydro-4-benzofuranyl)cyclopropyl]methyl]propanamide; N-[[(1R,2R)-2- (2,3-Dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]propanamide); (1R, 2R)-N-[2-(2,3- dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide) is a melatonin receptor MT1R and MT2R agonist. Tasimelteon is currently approved for the treatment of non-24-hour sleep- wake disorder. Tasimelteon is currently under investigation for the treatment of Smith- Magenis syndrome, major depressive disorder, and primary insomnia. Tasimelteon has also shown promise in treating circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. US 5,856,529; US 8,785,492; WO 199825606; WO 2007137244; WO

2007137247; WO 2011009102; and WO 2013173707.

Tasimelteon

[0004] Tasimelteon is subject to extensive CYP450-mediated oxidative metabolism, including hydroyxlation of the propylamide group, oxidation of the amine methylene group and/or cyclopropyl ring, CYP1A2-, CYP1A1-, and CYP3A4-mediated hydroxylation of the 3-position of the dihydrobenzofuran ring, and CYP1A2-, CYP2D6-, and CYP2C19-mediated hydroxylation/oxidation and ring-cleavage at the 2-position of the dihydrobenzofuran ring leading to active metabolites M9 and M11. Vachharajani et al., J. Pharm. Sci., 2003, 92(4), 760-772; US 8,785,492.

M11

[0005] Adverse effects associated with tasimelteon include headache, increased alanine monotransferase, nightmares or abnormal dreams, upper respiratory tract infection, and urinary tract infection. Deuterium Kinetic Isotope Effect

[0006] In order to eliminate foreign substances such as therapeutic agents, the animal body expresses various enzymes, such as the cytochrome P₄₅₀ enzymes (CYPs), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Such metabolic reactions frequently involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or a carbon-carbon (C-C) ^-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compounds. For most drugs, such oxidations are generally rapid and ultimately lead to administration of multiple or high daily doses.

[0007] The relationship between the activation energy and the rate of reaction may be quantified by the Arrhenius equation, k = Ae^-Eact/RT. The Arrhenius equation states that, at a given temperature, the rate of a chemical reaction depends exponentially on the activation energy (Eact).

[0008] The transition state in a reaction is a short lived state along the reaction pathway during which the original bonds have stretched to their limit. By definition, the activation energy E_act for a reaction is the energy required to reach the transition state of that reaction. Once the transition state is reached, the molecules can either revert to the original reactants, or form new bonds giving rise to reaction products. A catalyst facilitates a reaction process by lowering the activation energy leading to a transition state. Enzymes are examples of biological catalysts.

[0009] Carbon-hydrogen bond strength is directly proportional to the absolute value of the ground-state vibrational energy of the bond. This vibrational energy depends on the mass of the atoms that form the bond, and increases as the mass of one or both of the atoms making the bond increases. Since deuterium (D) has twice the mass of protium (¹H), a C-D bond is stronger than the corresponding C-¹H bond. If a C-¹H bond is broken during a rate- determining step in a chemical reaction (i.e. the step with the highest transition state energy), then substituting a deuterium for that protium will cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-¹H bond is broken, and the same reaction where deuterium is substituted for protium. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more.

Substitution of tritium for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects

[0010] Deuterium (²H or D) is a stable and non-radioactive isotope of hydrogen which has approximately twice the mass of protium (¹H), the most common isotope of hydrogen. Deuterium oxide (D2O or“heavy water”) looks and tastes like H2O, but has different physical properties.

[0011] When pure D₂O is given to rodents, it is readily absorbed. The quantity of deuterium required to induce toxicity is extremely high. When about 0-15% of the body water has been replaced by D₂O, animals are healthy but are unable to gain weight as fast as the control (untreated) group. When about 15-20% of the body water has been replaced with D₂O, the animals become excitable. When about 20-25% of the body water has been replaced with D2O, the animals become so excitable that they go into frequent convulsions when stimulated. Skin lesions, ulcers on the paws and muzzles, and necrosis of the tails appear. The animals also become very aggressive. When about 30% of the body water has been replaced with D₂O, the animals refuse to eat and become comatose. Their body weight drops sharply and their metabolic rates drop far below normal, with death occurring at about 30 to about 35% replacement with D₂O. The effects are reversible unless more than thirty percent of the previous body weight has been lost due to D2O. Studies have also shown that the use of D₂O can delay the growth of cancer cells and enhance the cytotoxicity of certain antineoplastic agents.

[0012] Deuteration of pharmaceuticals to improve pharmacokinetics (PK),

pharmacodynamics (PD), and toxicity profiles has been demonstrated previously with some classes of drugs. For example, the DKIE was used to decrease the hepatotoxicity of halothane, presumably by limiting the production of reactive species such as trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic switching. Metabolic switching occurs when xenogens, sequestered by Phase I enzymes, bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). Metabolic switching is enabled by the relatively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity. Such pitfalls are non-obvious and are not predictable a priori for any drug class.

[0013] Tasimelteon is a melatonin receptor modulator. The carbon-hydrogen bonds of tasimelteon contain a naturally occurring distribution of hydrogen isotopes, namely ¹H or protium (about 99.9844%), ²H or deuterium (about 0.0156%), and ³H or tritium (in the range between about 0.5 and 67 tritium atoms per 10¹⁸ protium atoms). Increased levels of deuterium incorporation may produce a detectable Deuterium Kinetic Isotope Effect (DKIE) that could affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of such tasimelteon in comparison with the compound having naturally occurring levels of deuterium.

[0014] Based on discoveries made in our laboratory, as well as considering the literature, tasimelteon is likely metabolized in humans at the 2- and 3-positions of the

dihydrobenzofuran group, the cyclopropyl ring, the amine methylene group, and the propyl amide. The current approach has the potential to prevent metabolism at these sites. Other sites on the molecule may also undergo transformations leading to metabolites with as-yet- unknown pharmacology/toxicology. Limiting the production of these metabolites has the potential to decrease the danger of the administration of such drugs and may even allow increased dosage and/or increased efficacy. All of these transformations can occur through polymorphically-expressed enzymes, exacerbating interpatient variability. Further, some disorders are best treated when the subject is medicated around the clock or for an extended period of time. For all of the foregoing reasons, a medicine with a longer half-life may result in greater efficacy and cost savings. Various deuteration patterns can be used to (a) reduce or eliminate unwanted metabolites, (b) increase the half-life of the parent drug, (c) decrease the number of doses needed to achieve a desired effect, (d) decrease the amount of a dose needed to achieve a desired effect, (e) increase the formation of active metabolites, if any are formed, (f) decrease the production of deleterious metabolites in specific tissues, and/or (g) create a more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy be intentional or not. The deuteration approach has the strong potential to slow the metabolism of tasimelteon and attenuate interpatient variability. [0015] Novel compounds and pharmaceutical compositions, certain of which have been found to modulate melatonin receptor have been discovered, together with methods of synthesizing and using the compounds, including methods for the treatment of melatonin receptor-mediated disorders in a patient by administering the compounds.

[0016] Accordingly, provided herein are compounds of structural Formula I:

or a salt thereof, wherein:

R1-R19 are independently chosen from hydrogen and deuterium; and

at least one of R1-R19 is deuterium. [0017] Also provided are enantiomers of compounds of Formula I, designated Formulas Ia, Ib, Ic, and Id:

or a salt thereof, wherein:

R1-R19 are independently chosen from hydrogen and deuterium; and

at least one of R₁-R₁₉ is deuterium.

[0019] In certain embodiments, R6 and R9-R15 are hydrogen.

[0020] In certain embodiments, R₉-R₁₅ are hydrogen.

[0021] In certain embodiments, R16 and R17 are deuterium. [0022] In certain embodiments, R18 and R19 are deuterium.

[0023] In certain embodiments, R₁₆-R₁₉ are deuterium.

[0024] In certain embodiments, R7 and R8 are deuterium.

[0025] In certain embodiments, R₇, R₈, R₁₆, and R₁₇ are deuterium.

[0026] In certain embodiments, R7, R8, R18, and R19 are deuterium.

[0027] In certain embodiments, R₇, R₈, and R₁₆-R₁₉ are deuterium.

[0028] In certain embodiments, R1-R5 are deuterium.

[0029] In certain embodiments, R₁-R₅, R₇, and R₈ are deuterium.

[0030] In certain embodiments, R1-R5, R16, and R17 are deuterium.

[0031] In certain embodiments, R₁-R₅, R₁₈, and R₁₉ are deuterium.

[0032] In certain embodiments, R1-R5 and R16-R19 are deuterium.

[0033] In certain embodiments, R1-R5, R7, R8, R16, and R17 are deuterium.

[0034] In certain embodiments, R1-R5, R7, R8, R18, and R19 are deuterium.

[0035] In certain embodiments, R1-R5, R7, R8, and R16-R19 are deuterium.

[0036] In certain embodiments, R₁-R₃ are deuterium.

[0037] In certain embodiments, R1-R3, R7, and R8 are deuterium.

[0038] In certain embodiments, R₁-R₃, R₁₆, and R₁₇ are deuterium.

[0039] In certain embodiments, R1-R3, R18, and R19 are deuterium.

[0040] In certain embodiments, R₁-R₃ and R₁₆-R₁₉ are deuterium.

[0041] In certain embodiments, R1-R3, R7, R8, R16, and R17 are deuterium.

[0042] In certain embodiments, R₁-R₃, R₇, R₈, R₁₈, and R₁₉ are deuterium.

[0043] In certain embodiments, R1-R3, R7, R8, and R16-R19 are deuterium.

[0044] In certain embodiments, R₄ and R₅ are deuterium.

[0045] In certain embodiments, R4, R5, R7, and R8 are deuterium.

[0046] In certain embodiments, R₄, R₅, R₁₆, and R₁₇ are deuterium.

[0047] In certain embodiments, R4, R5, R18, and R19 are deuterium.

[0048] In certain embodiments, R₄, R₅, and R₁₆-R₁₉ are deuterium.

[0049] In certain embodiments, R4, R5, R7, R8, R16, and R17 are deuterium.

[0050] In certain embodiments, R₄, R₅, R₇, R₈, R₁₈, and R₁₉ are deuterium.

[0051] In certain embodiments, R4, R5, R7, R8, and R16-R19 are deuterium.

[0052] Also provided are further embodiments of any of the above embodiments, wherein R₉-R₁₂ are deuterium.

[0053] In certain embodiments, R9-R12 are deuterium. [0054] Also provided herein are embodiments according to each of the embodiments above, wherein every other substituent among R₁-R₁₉ not specified as deuterium is hydrogen.

[0055] In certain embodiments are provided compounds as disclosed herein, wherein at least one of R₁-R₁₉ independently has deuterium enrichment of no less than about 1%. In certain embodiments are provided compounds as disclosed herein, wherein at least one of R1- R₁₉ independently has deuterium enrichment of no less than about 10%. In certain embodiments are provided compounds as disclosed herein, wherein at least one of R1-R19 independently has deuterium enrichment of no less than about 50%. In certain embodiments are provided compounds as disclosed herein, wherein at least one of R1-R19 independently has deuterium enrichment of no less than about 90%. In certain embodiments are provided compounds as disclosed herein, wherein at least one of R1-R19 independently has deuterium enrichment of no less than about 95%. In certain embodiments are provided compounds as disclosed herein, wherein at least one of R1-R19 independently has deuterium enrichment of no less than about 98%.

[0056] In certain embodiments of the present invention, compounds have structural Formula II:

(II)

or a salt thereof, wherein:

R₂₀-R₄₀ are independently chosen from hydrogen and deuterium; and

at least one of R20-R40 is deuterium.

[0057] In certain embodiments, R₂₅ and R₂₈-R₃₄ are hydrogen.

[0058] In certain embodiments, R28-R34 are hydrogen.

[0059] In certain embodiments, R₃₅ and R₃₆ are deuterium.

[0060] In certain embodiments, R37 and R38 are deuterium.

[0061] In certain embodiments, R₃₅-R₃₈ are deuterium.

[0062] In certain embodiments, R26 and R27 are deuterium. [0063] In certain embodiments, R26, R27, R35, and R36 are deuterium.

[0064] In certain embodiments, R₂₆, R₂₇, R₃₇, and R₃₈ are deuterium.

[0065] In certain embodiments, R26, R27, and R35-R38 are deuterium.

[0066] In certain embodiments, R₂₀-R₂₄ are deuterium.

[0067] In certain embodiments, R20-R24, R26 and R27 are deuterium.

[0068] In certain embodiments, R₂₀-R₂₄, R₃₅, and R₃₆ are deuterium.

[0069] In certain embodiments, R20-R24, R37, and R38 are deuterium.

[0070] In certain embodiments, R₂₀-R₂₄ and R₃₅-R₃₈ are deuterium.

[0071] In certain embodiments, R20-R24, R26, R27, R35, and R36 are deuterium.

[0072] In certain embodiments, R₂₀-R₂₄, R₂₆, R₂₇, R₃₇, and R₃₈ are deuterium.

[0073] In certain embodiments, R20-R24, R26, R27, and R35-R38 are deuterium.

[0074] In certain embodiments, R20-R22 are deuterium.

[0075] In certain embodiments, R20-R22, R26 and R27 are deuterium.

[0076] In certain embodiments, R20-R22, R35, and R36 are deuterium.

[0077] In certain embodiments, R₂₀-R₂₂, R₃₇, and R₃₈ are deuterium.

[0078] In certain embodiments, R20-R22 and R35-R38 are deuterium.

[0079] In certain embodiments, R₂₀-R₂₂, R₂₆, R₂₇, R₃₅, and R₃₆ are deuterium.

[0080] In certain embodiments, R20-R22, R26, R27, R37, and R38 are deuterium.

[0081] In certain embodiments, R₂₀-R₂₂, R₂₆, R₂₇, and R₃₅-R₃₈ are deuterium.

[0082] In certain embodiments, R23 and R24 are deuterium.

[0083] In certain embodiments, R₂₃, R₂₄, R₂₆ and R₂₇ are deuterium.

[0084] In certain embodiments, R23, R24, R35, and R36 are deuterium.

[0085] In certain embodiments, R₂₃, R₂₄, R₃₇, and R₃₈ are deuterium.

[0086] In certain embodiments, R23, R24, and R35-R38 are deuterium.

[0087] In certain embodiments, R₂₃, R₂₄, R₂₆, R₂₇, R₃₅, and R₃₆ are deuterium.

[0088] In certain embodiments, R23, R24, R26, R27, R37, and R38 are deuterium.

[0089] In certain embodiments, R₂₃, R₂₄, R₂₆, R₂₇, and R₃₅-R₃₈ are deuterium.

[0090] Also provided are further embodiments of any of the above embodiments, wherein R₂₈-R₃₁ are deuterium.

[0091] In certain embodiments, R28-R31 are deuterium.

[0092] Also provided herein are embodiments according to each of the embodiments above, wherein every other substituent among R₂₀-R₄₀ not specified as deuterium is hydrogen. [0093] In certain embodiments of the present invention, compounds have structural Formula III:

(III)

or a salt thereof, wherein:

R41-R59 are independently chosen from hydrogen and deuterium; and

at least one of R₄₁-R₅₉ is deuterium.

[0094] In certain embodiments, R46 and R49-R55 are hydrogen.

[0095] In certain embodiments, R₄₉-R₅₅ are hydrogen.

[0096] In certain embodiments, R56 and R57 are deuterium.

[0097] In certain embodiments, R47 and R48 are deuterium.

[0098] In certain embodiments, R47, R48, R56, and R57 are deuterium.

[0099] In certain embodiments, R41-R45 are deuterium.

[00100] In certain embodiments, R41-R45, R47, and R48 are deuterium.

[00101] In certain embodiments, R41-R45, R56, and R57 are deuterium.

[00102] In certain embodiments, R₄₁-R₄₅, R₄₇, R₄₈, R₅₆, and R₅₇ are deuterium.

[00103] In certain embodiments, R41-R43 are deuterium.

[00104] In certain embodiments, R₄₁-R₄₃, R₂₆ and R₂₇ are deuterium.

[00105] In certain embodiments, R41-R43, R56, and R57 are deuterium.

[00106] In certain embodiments, R₄₁-R₄₃, R₄₇, R₄₈, R₅₆, and R₅₇ are deuterium.

[00107] In certain embodiments, R44 and R45 are deuterium.

[00108] In certain embodiments, R₄₄, R₄₅, R₄₇, and R₄₈ are deuterium.

[00109] In certain embodiments, R44, R45, R56, and R57 are deuterium.

[00110] In certain embodiments, R₄₄, R₂₄, R₄₇, R₄₈, R₅₆, and R₅₇ are deuterium.

[00111] Also provided are further embodiments of any of the above embodiments, wherein R₄₉-R₅₂ are deuterium.

[00112] In certain embodiments, R49-R52 are deuterium. [00113] Also provided herein are embodiments according to each of the embodiments above, wherein every other substituent among R₄₁-R₅₉ not specified as deuterium is hydrogen.

[00114] The compounds as disclosed herein may also contain less prevalent isotopes for other elements, including, but not limited to, ¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶S for sulfur, ¹⁵N for nitrogen, and ¹⁷O or ¹⁸O for oxygen.

[00115] In certain embodiments, the compound disclosed herein may expose a patient to a maximum of about 0.000005% D₂O or about 0.00001% DHO, assuming that all of the C-D bonds in the compound as disclosed herein are metabolized and released as D2O or DHO. In certain embodiments, the levels of D₂O shown to cause toxicity in animals is much greater than even the maximum limit of exposure caused by administration of the deuterium enriched compound as disclosed herein. Thus, in certain embodiments, the deuterium-enriched compound disclosed herein should not cause any additional toxicity due to the formation of D2O or DHO upon drug metabolism.

[00116] Also provided is a compound chosen from the Examples and compounds disclosed herein.

[00117] In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 1%. In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 10%. In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 50%. In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 90%. In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 95%. In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 98%.

[00118] In certain embodiments, the deuterated compounds disclosed herein maintain the beneficial aspects of the corresponding non-isotopically enriched molecules while substantially increasing the maximum tolerated dose, decreasing toxicity, increasing the half- life (T1/2), lowering the maximum plasma concentration (Cmax) of the minimum efficacious dose (MED), lowering the efficacious dose and thus decreasing the non-mechanism-related toxicity, and/or lowering the probability of drug-drug interactions. [00119] All publications and references cited herein are expressly incorporated herein by reference in their entirety. However, with respect to any similar or identical terms found in both the incorporated publications or references and those explicitly put forth or defined in this document, then those terms definitions or meanings explicitly put forth in this document shall control in all respects.

[00120] Compounds disclosed herein possess useful melatonin receptor modulating activity, and may be used in the treatment or prophylaxis of a disorder in which melatonin receptors play an active role. Thus, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for modulating melatonin receptor. Other embodiments provide methods for treating a melatonin receptor-mediated disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or composition according to the present invention. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the prevention or treatment of a disorder ameliorated by the modulation of melatonin receptors.

[00121] Also provided is a method of treatment of a melatonin receptor-mediated disorder comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as disclosed herein to a patient in need thereof.

[00122] In certain embodiments, herein the disorder is chosen from non-24-hour sleep- wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency.

[00123] In certain embodiments, the disorder is non-24-hour sleep-wake disorder.

[00124] In certain embodiments, further comprising the administration of an additional therapeutic agent.

[00125] In certain embodiments, the additional therapeutic agent is chosen from antipsychotics, antidepressants, or medications having side effects such as sexual side effects, sleep disturbances, and daytime drowsiness. [00126] In certain embodiments, the additional therapeutic agent is an antipsychotic chosen from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, haloperidol, haloperidol decanoate, droperidol, pimozide, amisulpride, aripiprazole, bifeprunox, clozapine, melperone, norclozapine, olanzapine, risperidone, paliperidone, quetapine, symbyax, tetrabenazine, and ziprazidone.

[00127] In certain embodiments, the additional therapeutic agent is an antidepressant chosen from amitriptyline, bupropion, citalopram, clomipramine, dapoxetine, desipramine, dothiepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iofepramine, nortriptyline, paroxetine, protriptyline, sertraline, trazodone, trimipramine, and venlafaxine.

[00128] In certain embodiments, the additional therapeutic agent is a medications having a side effect chosen from sexual side effects, sleep disturbances, and daytime drowsiness.

[00129] In certain embodiments, the method of treatment further results in at least one effect chosen from:

a) decreased inter-individual variation in plasma levels of the compound or a metabolite thereof as compared to the non-isotopically enriched compound; b) increased average plasma levels of the compound per dosage unit thereof as compared to the non-isotopically enriched compound;

c) decreased average plasma levels of at least one metabolite of the compound per dosage unit thereof as compared to the non-isotopically enriched compound;

d) increased average plasma levels of at least one metabolite of the compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

e) an improved clinical effect during the treatment in the subject per dosage unit thereof as compared to the non-isotopically enriched compound.

[00130] In certain embodiments, the method further results in at least two effects chosen from:

c) decreased average plasma levels of at least one metabolite of the compound per dosage unit thereof as compared to the non-isotopically enriched compound; d) increased average plasma levels of at least one metabolite of the compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

[00131] In certain embodiments, the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P450 isoform in the subject, as compared to the corresponding non-isotopically enriched compound.

[00132] In certain embodiments, the cytochrome P₄₅₀ isoform is chosen from CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

[00133] In certain embodiments, the compound is characterized by decreased inhibition of at least one cytochrome P450 or monoamine oxidase isoform in the subject per dosage unit thereof as compared to the non-isotopically enriched compound.

[00134] In certain embodiments, the cytochrome P₄₅₀ or monoamine oxidase isoform is chosen from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO_A, and MAO_B.

[00135] In certain embodiments, the method reduces a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound.

[00136] In certain embodiments, the diagnostic hepatobiliary function endpoint is chosen from alanine aminotransferase (“ALT”), serum glutamic-pyruvic transaminase (“SGPT”), aspartate aminotransferase (“AST,”“SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “γ-GTP,”“GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5’-nucleotidase, and blood protein.

[00137] Also provided herein is a method of treating a demyelinating disease comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as recited herein to a patient in need thereof.

[00138] In certain embodiments, the demyelinating disease is multiple sclerosis. [00139] In certain embodiments, the multiple sclerosis is primary progressive multiple sclerosis.

[00140] Also provided is a method of treating a neurodegenerative disease comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as recited herein to a patient in need thereof.

[00141] In certain embodiments, the neurodegenerative disease or disorder is Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and

Huntington's disease.

[00142] In certain embodiments, the multiple sclerosis is primary progressive multiple sclerosis.

[00143] Also provided is a method of treating a mitochondrial disease comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as recited herein to a patient in need thereof.

[00144] Also provided is a method of reducing demyelination of the corpus callosum comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as recited herein to a patient in need thereof.

[00145] Also provided is a compound, or a salt thereof, as recited herein for use as a medicament.

[00146] Also provided is a compound, or a salt thereof, as recited herein for use in the manufacture of a medicament for the prevention or treatment of a melatonin receptor- mediated disorder. [00147] As used herein, the terms below have the meanings indicated.

[00148] The singular forms“a,”“an,” and“the” may refer to plural articles unless specifically stated otherwise.

[00149] The term“about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term“about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

[00150] When ranges of values are disclosed, and the notation“from n₁… to n₂” or“n₁- n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values.

[00151] The term“deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[00152] The term“is/are deuterium,” when used to describe a given position in a molecule such as R1-R59 or the symbol“D”, when used to represent a given position in a drawing of a molecular structure, means that the specified position is enriched with deuterium above the naturally occurring distribution of deuterium. In one embodiment deuterium enrichment is no less than about 1%, in another no less than about 5%, in another no less than about 10%, in another no less than about 20%, in another no less than about 50%, in another no less than about 70%, in another no less than about 80%, in another no less than about 90%, or in another no less than about 98% of deuterium at the specified position.

[00153] The term“isotopic enrichment” refers to the percentage of incorporation of a less prevalent isotope of an element at a given position in a molecule in the place of the more prevalent isotope of the element.

[00154] The term“non-isotopically enriched” refers to a molecule in which the percentages of the various isotopes are substantially the same as the naturally occurring percentages.

[00155] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols“R” or“S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[00156] The term“bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[00157] The term“disorder” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms“disease” and“condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.

[00158] A“demyelinating disease” is a disease of the nervous system in which the myelin sheath of neurons is damaged. Myelin sheaths, which cover many nerve fibers, are composed of lipoprotein layers formed in early life. Myelin formed by the oligodendroglia in the CNS differs chemically and immunologically from that formed by the Schwann cells peripherally, but both types have the same function: to promote transmission of a neural impulse along an axon. Demyelination in later life is a feature of many neurologic disorders; it can result from damage to nerves or myelin due to local injury, ischemia, toxic agents, or metabolic disorders. Extensive myelin loss is usually followed by axonal degeneration, both of which may be irreversible. However, remyelination occurs in many instances, and repair, regeneration, and complete recovery of neural function can be rapid. Recovery often occurs after the segmental demyelination that characterizes many peripheral neuropathies; this process may account for the exacerbations and remissions of multiple sclerosis (MS). Central demyelination (i.e., of the spinal cord, brain, or optic nerves) is the predominant finding in the primary demyelinating diseases. Demyelinating diseases include multiple sclerosis, optic neuritis, Guillain-Barré Syndrome, chronic inflammatory demyelinating polyneuropathy, transverse myelitis, Balo concentric sclerosis, pernicious anemia, central pontine

myelinolysis, Tabes dorsalis, neuromyelitis optica (NMO), progressive multifocal leukoencephalopathy (PML), anti-MAG (myelin-associated glycoprotein) neuropathy, hereditary motor and sensory neuropathy (Chacot-Marie-Tooth disease), cerebrotendinious xanthanomatosis, and leukodystrophies including adrenoleukodystrophy,

adrenomyeloneuropathy, metachromatic leukodystrophy, globoid cell leukodystrophy (Krabbe disease), Canavan disease, vanishing white matter disease, Alexander disease, Refsum disease, and Pelizaeus-Merzbacher disease. The most well known demyelinating disease is multiple sclerosis.

[00159] A“neurodegenerative disease” is a disease characterized by progressive nervous system dysfunction, often associated with atrophy of the affected central or peripheral structures of the nervous system. Neurodegenerative diseases include Alzheimer's Disease and other dementias, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Huntington's disease, and prion diseases such as Creutzfeldt– Jakob disease.

[00160] A“mitochondrial disease” is a disease caused by dysfunctional mitochondria, resulting in reduced cellular energy output, often resulting in one or more of poor growth, loss of muscle coordination, muscle weakness, visual or hearing problems, learning disabilities, heart disease, liver disease, kidney disease, gastrointestinal disorders, respiratory disorders, neurological problems, autonomic dysfunction and dementia. Mitochondrial diseases include mitochondrial myopathy, Leber's Hereditary Optic Neuropathy (LHON), Leigh syndrome, subacute sclerosing encephalopathy, Neuropathy, Ataxia, Retinitis Pig mentosa, and Ptosis (NARP), Myoneurogenic Gastrointestinal Encephalopathy (MNGIE), Myoclonic Epilepsy with Ragged Red Fibers (MERRF), Mitochondrial myopathy,

Encephalomyopathy, Lactic acidosis, Stroke-like symptoms (MELAS), and Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)

[00161] The terms“treat,”“treating,” and“treatment” are meant to include alleviating or abrogating a disorder or one or more of the symptoms associated with a disorder; or alleviating or eradicating the cause(s) of the disorder itself. As used herein, reference to “treatment” of a disorder is intended to include prevention. The terms“prevent,” “preventing,” and“prevention” refer to a method of delaying or precluding the onset of a disorder; and/or its attendant symptoms, barring a subject from acquiring a disorder, or reducing a subject’s risk of acquiring a disorder.

[00162] The term“therapeutically effective amount” refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder being treated. The term“therapeutically effective amount” also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[00163] The term“subject” refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, and the like. The terms“subject” and“patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human patient.

[00164] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the disorders described herein.

[00165] The term“melatonin receptor” or“MT receptor” refers to receptors which bind the hormone melatonin. For example,“melatonin receptor” or“MT receptor” would include the G-protein coupled melatonin M₁ receptor (also known as MT1R) and the G-protein coupled melatonin M2 receptor (also known as MT2R).

[00166] The term“melatonin receptor-mediated disorder,” refers to a disorder that is characterized by abnormal melatonin receptor activity or melatonin receptor activity that, when modulated, leads to the amelioration of other abnormal biological processes. A melatonin receptor-mediated disorder may be completely or partially mediated by modulating melatonin receptors. In particular, a melatonin receptor-mediated disorder is one in which modulation of melatonin receptors results in some effect on the underlying disorder e.g., administration of a melatonin receptor modulator results in some improvement in at least some of the patients being treated.

[00167] As used herein,“progressive” multiple sclerosis refers to forms of the disease which progress towards an ever-worsening disease state over a period of time. Progressive MS includes, for example, primary progressive MS, secondary progressive MS, and progressive relapsing MS. These subtypes may or may not feature episodic flare-ups of the disease, but are each associated with increased symptoms, such as increased demyelination or pain and reduced capacity for movement, over time. [00168] A modulator may activate the activity of an melatonin receptor, may activate or inhibit the activity of an melatonin receptor depending on the concentration of the compound exposed to the melatonin receptor, or may inhibit the activity of an melatonin receptor. Such activation or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and/or may be manifest only in particular cell types. The term " melatonin receptor modulator” or“modulation of melatonin receptors” also refers to altering the function of an melatonin receptor by increasing or decreasing the probability that a complex forms between an melatonin receptor and a natural binding partner. A melatonin receptor modulator may increase the probability that such a complex forms between the melatonin receptor and the natural binding partner, may increase or decrease the probability that a complex forms between the melatonin receptor and the natural binding partner depending on the concentration of the compound exposed to the melatonin receptor, and or may decrease the probability that a complex forms between the melatonin receptor and the natural binding partner. In some embodiments, modulation of the melatonin receptor may be assessed using Receptor Selection and Amplification Technology (R-SAT) as described in US 5,707,798, the disclosure of which is incorporated herein by reference in its entirety.

[00169] The term“therapeutically acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, immunogenicity, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

[00170] The term“pharmaceutically acceptable carrier,”“pharmaceutically acceptable excipient,”“physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each component must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

[00171] The terms“active ingredient,”“active compound,” and“active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients or carriers, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.

[00172] The terms“drug,”“therapeutic agent,” and“chemotherapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.

[00173] The term“release controlling excipient” refers to an excipient whose primary function is to modify the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.

[00174] The term“nonrelease controlling excipient” refers to an excipient whose primary function do not include modifying the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.

[00175] The term "prodrug" refers to a compound functional derivative of the compound as disclosed herein and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.

[00176] The compounds disclosed herein can exist as therapeutically acceptable salts. The term“therapeutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound with a suitable acid or base. Therapeutically acceptable salts include acid and basic addition salts.

[00177] Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino- salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[00178] Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H- imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[00179] While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington’s Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. The pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. [00180] The compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically salt, prodrug, or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[00181] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[00182] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[00183] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[00184] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or

triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[00185] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or

hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[00186] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[00187] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[00188] Certain compounds disclosed herein may be administered topically, that is by non- systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[00189] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.

[00190] For administration by inhalation, compounds may be delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as

dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[00191] Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[00192] Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. [00193] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[00194] The compounds can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of compound administered to a patient will be the

responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the disorder being treated. Also, the route of administration may vary depending on the disorder and its severity.

[00195] In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disorder.

[00196] In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compounds may be given continuously or temporarily suspended for a certain length of time (i.e., a“drug holiday”).

[00197] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disorder is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[00198] Disclosed herein are methods of treating a melatonin receptor-mediated disorder comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[00199] Melatonin receptor-mediated disorders, include, but are not limited to, non-24- hour sleep-wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night- time hypertension, obesity, type 2 diabetes, and testosterone insufficiency, and/or any disorder which can lessened, alleviated, or prevented by administering a melatonin receptor modulator.

[00200] Also disclosed herein are methods of treating a demyelinating disease or disorder comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[00201] In certain embodiments, the demyelinating disease is multiple sclerosis.

[00202] In certain embodiments, the multiple sclerosis is primary progressive multiple sclerosis.

[00203] Also disclosed herein are methods of treating a neurodegenerative disease or disorder comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[00204] In certain embodiments, the neurodegenerative disease or disorder is Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and

Huntington's disease.

[00205] In certain embodiments, the multiple sclerosis is primary progressive multiple sclerosis.

[00206] Also disclosed herein are methods of treating a mitochondrial disease or disorder comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[00207] Also disclosed herein are methods of reducing demyelination of the corpus callosum comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[00208] In certain embodiments, a method of treating a melatonin receptor-mediated disorder, a demyelinating disease or disorder, a neurodegenerative disease or disorder, or a mitochondrial disease or disorder comprises administering to the subject a therapeutically effective amount of a compound of as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to affect: (1) decreased inter-individual variation in plasma levels of the compound or a metabolite thereof; (2) increased average plasma levels of the compound or decreased average plasma levels of at least one metabolite of the compound per dosage unit; (3) decreased inhibition of, and/or metabolism by at least one cytochrome P450 or monoamine oxidase isoform in the subject; (4) decreased metabolism via at least one polymorphically-expressed cytochrome P450 isoform in the subject; (5) at least one statistically-significantly improved disorder-control and/or disorder-eradication endpoint; (6) an improved clinical effect during the treatment of the disorder, (7) prevention of recurrence, or delay of decline or appearance, of abnormal alimentary or hepatic parameters as the primary clinical benefit, or (8) reduction or elimination of deleterious changes in any diagnostic hepatobiliary function endpoints, as compared to the corresponding non- isotopically enriched compound.

[00209] In certain embodiments, inter-individual variation in plasma levels of the compounds as disclosed herein, or metabolites thereof, is decreased; average plasma levels of the compound as disclosed herein are increased; average plasma levels of a metabolite of the compound as disclosed herein are decreased; inhibition of a cytochrome P450 or monoamine oxidase isoform by a compound as disclosed herein is decreased; or metabolism of the compound as disclosed herein by at least one polymorphically-expressed cytochrome P₄₅₀ isoform is decreased; by greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, or by greater than about 50% as compared to the corresponding non-isotopically enriched compound.

[00210] Plasma levels of the compound as disclosed herein, or metabolites thereof, may be measured using the methods described in Vachharajani et al., J. Pharm. Sci., 2003, 92(4), 760-772 and US 8,785,492, which are hereby incorporated by reference.

[00211] Examples of cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

[00212] Examples of monoamine oxidase isoforms in a mammalian subject include, but are not limited to, MAOA, and MAOB.

[00213] The inhibition of the cytochrome P450 isoform is measured by the method of Ko et al. (British Journal of Clinical Pharmacology, 2000, 49, 343-351). The inhibition of the MAOA isoform is measured by the method of Weyler et al. (J. Biol Chem.1985, 260, 13199- 13207). The inhibition of the MAOB isoform is measured by the method of Uebelhack et al. (Pharmacopsychiatry, 1998, 31, 187-192).

[00214] Examples of polymorphically-expressed cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

[00215] The metabolic activities of liver microsomes, cytochrome P₄₅₀ isoforms, and monoamine oxidase isoforms are measured by the methods described herein.

[00216] Examples of improved disorder-control and/or disorder-eradication endpoints, or improved clinical effects include, but are not limited to, nighttime total sleep time (nTST), lower quartile of nTST (LQ-nTST), daytime total sleep duration (dTSD), upper quartile of dTSD (UQ-dTSD), clinical global impression of change (CGI-C), midpoint of sleep timing (MoST), non-24 clinical response scale, Hamilton depression rating scale (HAM-D), Arizona sexual experience scale (ASEX) and Sheehan disability scale (SDS), Columbia-suicide severity rating scale (C-SSRS). US 8,785,492.

[00217] Examples of diagnostic hepatobiliary function endpoints include, but are not limited to, alanine aminotransferase (“ALT”), serum glutamic-pyruvic transaminase

(“SGPT”), aspartate aminotransferase (“AST” or“SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,”“ ^-GTP,” or“GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5’-nucleotidase, and blood protein. Hepatobiliary endpoints are compared to the stated normal levels as given in“Diagnostic and Laboratory Test Reference”, 4^th edition, Mosby, 1999. These assays are run by accredited laboratories according to standard protocol.

[00218] Besides being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats. Combination Therapy

[00219] The compounds disclosed herein may also be combined or used in combination with other agents useful in the treatment of melatonin receptor-mediated disorders. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).

[00220] Such other agents, adjuvants, or drugs, may be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with a compound as disclosed herein. When a compound as disclosed herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound disclosed herein may be utilized, but is not required.

[00221] In certain embodiments, the compounds disclosed herein can be combined with one or more antipsychotics, antidepressants , or medications having side effects such as sexual side effects, sleep disturbances, daytime drowsiness, and the withdrawal symptoms commonly associated with antidepressant discontinuation.

[00222] In certain embodiments, the compounds disclosed herein can be combined with one or more antipsychotics chosen from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, haloperidol, haloperidol decanoate, droperidol, pimozide, amisulpride, aripiprazole, bifeprunox, clozapine, melperone, norclozapine, olanzapine, risperidone, paliperidone, quetapine, symbyax, tetrabenazine, and ziprazidone.

[00223] In certain embodiments, the compounds disclosed herein can be combined with one or more antidepressants chosen from amitriptyline, bupropion, citalopram, clomipramine, dapoxetine, desipramine, dothiepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iofepramine, nortriptyline, paroxetine, protriptyline, sertraline, trazodone, trimipramine, and venlafaxine.

[00224] In certain embodiments, the compounds disclosed herein can, when used in conjunction with other medications, may alleviate unwanted symptoms associated with the use of such medications including, but not limited to, sexual side effects, sleep disturbances, daytime drowsiness, and the withdrawal symptoms commonly associated with antidepressant discontinuation.

[00225] The compounds disclosed herein can also be administered in combination with other classes of compounds, including, but not limited to, norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as

methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepam; norepinephrine-dopamine reuptake inhibitor (NDRIs), such as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists, such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti- platelet agents, such as GPIIb/IIIa blockers (e.g., abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; Factor VIIa Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors;

vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK- 104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP

Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta-muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothlazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,

trichloromethiazide, polythiazide, benzothlazide, ethacrynic acid, tricrynafen, chlorthalidone, furosenilde, musolimine, bumetanide, triamterene, amiloride, and spironolactone;

thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g. metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors;

phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); protein tyrosine kinase inhibitors;

antiinflammatories; antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anticancer agents and cytotoxic agents (e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes); antimetabolites, such as folate antagonists, purine analogues, and pyrridine analogues; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone),

estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone- releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents, such as ecteinascidins; microtubule-stabilizing agents, such as paclitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone and dexamethasone; cytotoxic drugs, such as azathiprine and

cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunomide; and cyclooxygenase-2 (COX- 2) inhibitors, such as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin.

[00226] Thus, in another aspect, certain embodiments provide methods for treating melatonin receptor- mediated disorders in a human or animal subject in need of such treatment comprising administering to the subject an amount of a compound disclosed herein effective to reduce or prevent the disorder in the subject, in combination with at least one additional agent for the treatment of the disorder that is known in the art. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of melatonin receptor-mediated disorders.

General Synthetic Methods for Preparing Compounds

[00227] Isotopic hydrogen can be introduced into a compound as disclosed herein by synthetic techniques that employ deuterated reagents, whereby incorporation rates are predetermined; and/or by exchange techniques, wherein incorporation rates are determined by equilibrium conditions, and may be highly variable depending on the reaction conditions. Synthetic techniques, where tritium or deuterium is directly and specifically inserted by tritiated or deuterated reagents of known isotopic content, may yield high tritium or deuterium abundance, but can be limited by the chemistry required. Exchange techniques, on the other hand, may yield lower tritium or deuterium incorporation, often with the isotope being distributed over many sites on the molecule.

[00228] The compounds as disclosed herein can be prepared by methods known to one of skill in the art and routine modifications thereof, and/or following procedures similar to those described in the Example section herein and routine modifications thereof, and/or procedures found in US 5,856,529, WO 199825606, and WO 2013173707, which are hereby incorporated in their entirety, and references cited therein and routine modifications thereof. Compounds as disclosed herein can also be prepared as shown in any of the following schemes and routine modifications thereof.

[00229] The following schemes can be used to practice the present invention. Any position shown as hydrogen may optionally be replaced with deuterium. Scheme I

[00230] Compound 1 is treated with an appropriate reducing agent, such as a combination of hydrogen gas and palladium on carbon, in an appropriate solvent, such as acetic acid, to give compound 2. Compound 2 is treated with an appropriate reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at an elevated temperature, to give compound 3. Compound 3 is treated with an appropriate oxidizing agent, such as a combination of dimethyl sulfoxide and oxalyl chloride, in the presence of an appropriate base, such as triethylamine, in an appropriate solvent, such as dichloromethane, at a reduced temperature, to give compound 4. Compound 4 is reacted with malonic acid, in the presence of an appropriate base, such as pyrrolidine, in an appropriate solvent, such as pyridine, at an elevated temperature, to give compound 5. Compound 5 is treated with an appropriate activating agent, such as thionyl chloride, in an appropriate solvent, such as toluene, to give an intermediate acyl chloride, which is further reacted with (-)- camphorsultam in the presence of an appropriate base, such as sodium hydride, in an appropriate solvent, such as toluene, to give compound 6. Compound 6 is reacted with compound 7 (prepared as an ethereal solution by reacting an ethereal solution of 1-methyl-3- nitro-1-nitrosoguanidine or a deuterated analog thereof and aqueous sodium hydroxide) in the presence of an appropriate catalyst, such as palladium acetate, in an appropriate solvent, such as methylene chloride, to give compound 8. Compound 8 is treated with an appropriate reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at a reduced temperature, to give compound 9. Compound 9 is treated with an appropriate oxidizing agent, such as a combination of dimethyl sulfoxide and oxalyl chloride, in the presence of an appropriate base, such as triethylamine, in an appropriate solvent, such as dichloromethane, at a reduced temperature, to give compound 10. Compound 10 is reacted with hydroxylamine hydrochloride, in the presence of an appropriate base, such as sodium hydroxide, in an appropriate solvent, such as a mixture of ethanol and water, at an elevated temperature, to give an intermediate oxime that is then treated with an appropriate reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at a reduced temperature, to give compound 11. Compound 11 is reacted with compound 12 in the presence of an appropriate base, such as triethylamine, in an appropriate solvent, such as dichloromethane, to give a compound of formula I.

[00231] Deuterium can be incorporated to different positions synthetically, according to the synthetic procedures as shown in Scheme I, by using appropriate deuterated

intermediates. For example, to introduce deuterium at R₉, compound 1 with the

corresponding deuterium substitutions can be used. To introduce deuterium at one or more positions of R₁₃-R₁₆ and R₁₉, compound 1 with the corresponding deuterium substitutions can be used. To introduce deuterium at one or more positions of R17-R18 deuterium gas can be used. To introduce deuterium at R₇, R₈, and/or R₁₀ lithium aluminum deuteride can be used. To introduce deuterium at R8, malonic acid and/or pyrrolidine with the corresponding deuterium substitutions can be used. To introduce deuterium at one or more positions of R₁₁- R12, compound 7 with the corresponding deuterium substitutions can be used. To introduce deuterium at one or more positions of R₁-R₅, compound 12 with the corresponding deuterium substitutions can be used.

[00232] Alternatively, the compounds disclosed here can be synthesized by the synthetic route illustrated in Scheme II. Scheme II

[00233] Compound 1 is treated with an appropriate base, such as sodium hydride, in the presence of an appropriate catalyst, such as copper(I) chloride, in an appropriate solvent, such as pyridine, to effect intramolecular Friedel-Crafts alkylation to give Compound 2.

Compound 2 is treated with an appropriate vinyl tin reagent, such as tri-(tert-butyl)vinyl tin, in the presence of an appropriate palladium catalyst, such as

tris(dibenzylideneacetone)dipalladium(0), in an appropriate solvent, such as a mixture of cesium fluoride and dioxane, to give Compound 3. Compound 3 is subjected to oxidative cleavage of the olefin, with an appropriate oxidizing agent such as osmium tetroxide with sodium periodate, in an appropriate solvent such as a mixture of tetrahydrofuran and water, to give aldehyde 4. Compound 4 is reacted with malonic acid, in the presence of an appropriate base, such as pyrrolidine, in an appropriate solvent, such as pyridine, at an elevated temperature, to give compound 5. Compound 5 is treated with an appropriate activating agent, such as thionyl chloride, in an appropriate solvent, such as dichloromethane, to give an intermediate acyl chloride, which is further reacted with O-methyl N-methylhydroxylamine in the presence of an appropriate base, such as sodium carbonate, to give compound 6.

Compound 6 is reacted with the ylid generated by reacting trimethylsulfonium iodide with a suitable base, such as sodium hydride, in a suitable solvent, such as DMSO, to give cyclopropane Compound 7. Compound 7 is treated with an appropriate reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at a reduced temperature, to give compound 8. Compound 8 is treated with hydroxylamine in an appropriate solvent, such as ethanol-water, to give oxime compound 9. Compound 9 is then treated with an appropriate reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at a reduced temperature, to give compound 10. Compound 10 is reacted with compound 11 in the presence of an appropriate base, such as triethylamine, in an appropriate solvent, such as dichloromethane, to give a compound of formula I.

[00234] Deuterium can be incorporated to various positions having an exchangeable proton, such as the amine N-H, via proton-deuterium equilibrium exchange. For example, to introduce deuterium at R₆ this proton may be replaced with deuterium selectively or non- selectively through a proton-deuterium exchange method known in the art. [00235] The invention is further illustrated by the following examples. All IUPAC names were generated using CambridgeSoft’s ChemDraw 10.0. EXAMPLE 1

N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]propanamide

(tasimelteon)

Step 1

[00236] 4-chloro-2,3-dihydro-1-benzofuran: To a solution of 2-(2,6-dichlorophenyl)ethan- 1-ol (20 g, 104.68 mmol, 1.00 equiv) in pyridine (500 mL) was added sodium hydride (5.2 g, 216.67 mmol, 1.25 equiv). The resulting solution was stirred at 0 ^oC for 1 h. Then CuCl (600 mg, 6.12 mmol, 0.05 equiv) was added. The resulting solution was stirred overnight at 115 ^oC. The resulting mixture was concentrated under vacuum. The reaction was then diluted with 500 mL of H2O. The pH value of the solution was adjusted to 4 with HCl (3 M). The solids were filtered out. The resulting solution was extracted with petroleum ether. And the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by SiO2 chromatography, eluted with petroleum ether to afford 16 g (99%) of 4-chloro-2,3-dihydro-1-benzofuran as colorless oil. Step 2

[00237] 4-ethenyl-2,3-dihydro-1-benzofuran: To a solution of 4-chloro-2,3-dihydro-1- benzofuran (11.5 g, 74.39 mmol, 1.00 equiv), tri-tert-butyl(ethenyl)stannane (38.00 g, 119.48 mmol, 1.60 equiv), CsF (25 g, 164.47 mmol, 2.20 equiv), (t-Bu)3P·HBF4 (1.3 g, 4.48 mmol, 0.06 equiv) in dioxane (300 mL) was added Pd2(dba)3 (1.5 g, 1.45 mmol, 0.02 equiv) under an atmosphere of nitrogen. The resulting solution was stirred for 24 h at 110 ^oC. The reaction progress was monitored by GCMS. The resulting solution was diluted with 300 mL of ethyl acetate. Then the solids were filtered out. The organic layers were washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by SiO2 chromatography, eluted with petroleum ether to afford 5 g (46%) of 4-ethenyl-2,3-dihydro-1-benzofuran as light yellow oil. ¹H NMR (300 MHz, CDCl₃) δ: 7.09-7.00 (m, 1H), 6.98-6.96 (m, 1H), 6.74-6.70 (m, 2H), 5.68 (m, 1H), 5.30 (m, 1H), 4.62-4.52 (m, 2H), 3.27-3.04 (m, 2H). Step 3

[00238] 2,3-dihydro-1-benzofuran-4-carbaldehyde: To a solution of 4-ethenyl-2,3- dihydro-1-benzofuran (5 g, 34.20 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) and water (50 mL) was added OsO4 (440 mg, 1.73 mmol, 0.05 equiv). The resulting solution was stirred for 30 min at 20 ^oC. Then NaIO₄ (14.7 g, 68.69 mmol, 2.00 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 1 h at room temperature. The resulting solution was diluted with 100 mL of water. Then the resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5 g (99%) of 2,3-dihydro-1-benzofuran-4-carbaldehyde as light brown oil. Step 4

[00239] (2E)-3-(2,3-dihydro-1-benzofuran-4-yl)prop-2-enoic acid: A mixture of 2,3- dihydro-1-benzofuran-4-carbaldehyde (3.5 g, 23.62 mmol, 1.00 equiv), (4.9 g, 47.09 mmol, 2.00 equiv), pyrrolidine (1.4 mL), Pyridine (35 mL) was heated for 2 h at 120 ^oC. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers were combined. The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 3.7 g (82%) of (2E)-3-(2,3-dihydro-1-benzofuran-4- yl)prop-2-enoic acid as a light yellow solid. Step 5

[00240] (2E)-3-(2,3-dihydro-1- benzofuran-4-yl)-N-methoxyprop-2-enamide: A mixture of (2E)-3-(2,3-dihydro-1-benzofuran-4-yl)prop-2-enoic acid (3.7 g, 19.45 mmol, 1.00 equiv), thionyl chloride (8 mL) and dichloromethane (50 mL) was heated to reflux for 1 h. The mixture was concentrated under vacuum. Then this material was dissolved in ethyl acetate (50 mL), and a solution of N,O- dimethylhydroxylamine hydrochloride (3.8 g, 38.96 mmol, 2.00 equiv) in saturated Na2CO3 (50 mL) was added with stirring. The resulting solution was allowed to react for an additional 1 hour at room temperature. Then the mixture was diluted with 50 mL of water. The resulting solution was extracted with ethyl acetate (2 x 50 mL). And the organic layers were combined, dried over anhydrous sodium sulfate and

concentrated under vacuum to afford 3.5 g (82%) of (2E)-3-(2,3-dihydro-1- benzofuran-4-yl)- N-methoxyprop-2-enamide as brown oil. Step 6

[00241] (1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)-N-methoxy-N-methylcyclopropane-1- carboxamide: To a suspension of sodium hydride (1.8 g, 3.00 equiv) in DMSO (80 mL) was added S,S-dimethylmethanesulfinyl iodide (9.9 g, 44.99 mmol, 3.00 equiv). The resulting solution was stirred for 30 min at room temperature. Then (2E)-3-(2,3- dihydro-1- benzofuran-4-yl)-N-methoxyprop-2-enamide (3.5 g, 15.96 mmol, 1.00 equiv) in DMSO was added dropwise. The mixture solution was allowed to react, with stirring, for an additional 3 h at room temperature. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers were combined. The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by SiO₂ chromatography eluted with ethyl acetate/petroleum ether (1:4) to afford 3.3 g (84%) of (1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)-N-methoxy-N-methylcyclopropane-1- carboxamide as a light yellow solid. Step 7

[00242] (1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropane-1-carbaldehyde: To a suspension of LiAlH₄ (602 mg, 15.86 mmol, 1.20 equiv) in tetrahydrofuran (50 mL) cooled to -50 ^oC was added (1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)-N- methoxy-N- methylcyclopropane-1-carboxamide (3.3 g, 13.34 mmol, 1.00 equiv) in THF dropwise. The resulting solution was stirred for 30 min at -5 ^oC. The reaction was quenched by the addition of water. Then KHSO₄ (3.3 g, 1.70 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 10 min at 20 ^oC. The resulting solution was extracted with ethyl acetate (2 x 30 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 30 mL). The mixture was dried over anhydrous sodium sulfate and concentrate d under vacuum to afford 2.5 g (100%) of (1R,2R)-2-(2,3-dihydro-1-benzofuran- 4-yl)cyclopropane-1 -carbaldehyde as light yellow oil. Step 8

[00243] (Z)-N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4- yl)cyclopropyl]methylidene]hydroxylamine: A mixture of (1R,2R)-2-(2,3-dihydro-1- benzofuran-4-yl)cyclopropane-1- carbaldehyde (2.8 g, 14.88 mmol, 1.00 equiv), ethanol (30 mL), HONH2 (50% in H2O) (3 mL, 3.00 equiv) and water(3 mL) was stirred for 3 h at 95 ^oC. The resulting solution was diluted with DCM (2 x 20 mL). The resulting mixture was washed with brine (2 x 20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 2.7 g (89%) of (Z)-N-[[(1R,2R)-2- (2,3-dihydro-1- benzofuran-4-yl)cyclopropyl]methylidene]hydroxylamine as a light yellow solid. Step 9

[00244] [(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methanamine: To a solution of (Z)-N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]

methylidene]hydroxylamine (2.7 g, 13.28 mmol, 1.00 equiv) in THF (50 mL) was added LiAlH4 (735 mg, 19.37 mmol, 1.50 equiv). The mixture was stirred for 30 min at room temperature. Then the resulting solution was allowed to react, with stirring, for an additional 4 h while the temperature was maintained at 50 ^oC. The reaction was quenched by the addition of water and the pH value of the solution was adjusted to 1 with hydrochloric acid (1 M). The resulting solution was extracted with DCM. Then the pH value of the aqueous solution was adjusted to 10 with sodium hydroxide (3 M). The resulting solution was extracted with DCM (2 x 50 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.5 g (60%) of [(1R,2R)- 2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl] methanamine as yellow oil. Step 10

1⁰ [00245] N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]propanamide: To a solution of [(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl] methanamine (500 mg, 2.64 mmol, 1.00 equiv) and TEA (801.6 mg, 7.92 mmol, 3.00 equiv) in DCM (10 mL) was added propionyl chloride (267.7 mg, 2.89 mmol, 1.10 equiv). The mixture was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of DCM. The mixture was washed with brine (2 x 20 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 3:7). The crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO₂(75%), ethanol (25%);

Detector, UV 220 nm to afford 200 mg of N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4- yl)cyclopropyl]methyl]propanamide as a white solid.¹H NMR (300 MHz, CDCl3) δ: 7.04- 6.99 (m, 1H), 6.63-6.60 (m, 1H), 6.35-6.33 (m, 1H), 5.62 (s, 1H), 4.61-4.56 (m, 2H), 3.38- 3.18 (m, 4H), 2.26-2.18 (m, 2H), 1.77-1.71 (m, 1H), 1.37-1.26 (m, 1H), 1.19-1.14 (m, 3H), 1.00-0.85 (m, 2H). LC-MS: m/z = 246 [M+H]⁺. EXAMPLE 2

N-[[(1R,2R)-2-[2,3-dihydro(2,2-²H₂)-1-benzofuran-4-yl]cyclopropyl]methyl]propanmide

(tasimelteon-d₂)

[00246] 2-(2,6-dichlorophenyl)(1,1-²H₂)ethan-1-ol: To a 250-mL 3-necked round-bottom flask, was placed a solution of 2-(2,6-dichlorophenyl)acetic acid (15 g, 73.16 mmol, 1.00 equiv) in tetrahydrofuran (100 mL). The resulting solution was stirred at 0 ^oC. This was followed by the addition of BD₃ (in THF,1 M) (144 mL, 2.00 equiv) dropwise with stirring. The resulting solution was stirred for 20 h at room temperature. The reaction was then quenched by the addition of 50 mL of D2O. The resulting solution was extracted with ethyl acetate (3 x 100 mL). And the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to afford 14 g (99%) of 2-(2,6- dichlorophenyl)(1,1-²H₂)ethan-1-ol as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ: 7.46- 7.41 (m, 2H), 7.30-7.25 (m, 1H), 3.12-3.04 (m, 2H). Step 2

[00247] 4-chloro-2,3-dihydro(2,2-²H2)-1-benzofuran: To a solution of 2-(2,6- dichlorophenyl)(1,1-²H₂)ethan-1-ol (14 g, 72.51 mmol, 1.00 equiv) in pyridine (200 mL) was added sodium hydride (3.6 g, 150.00 mmol, 1.25 equiv), in portions. The resulting solution was stirred at 0 ^oC for 1 h. Then CuCl (350 mg, 3.57 mmol, 0.05 equiv) was added. The resulting solution was stirred overnight at 115 ^oC. The reaction was then quenched by 100 mL of D2O. The pH value of the solution was adjusted to 7 with HCl (3 M). The solids were filtered out. The resulting solution was extracted with ethyl acetate (3 x 100 mL). And the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by SiO₂ chromatography eluted with ethyl acetate/petroleum ether (1:20) to afford 6.9 g (61%) of 4-chloro-2,3-dihydro(2,2-²H2)-1 - benzofuran as light brown oil.¹H NMR (400 MHz, DMSO-d₆) δ: 7.14-7.10 (m, 1H), 6.89- 6.87 (m, 1H), 6.75-6.73 (m, 1H), 3.22-3.20 (m, 2H).

[00248] 4-ethenyl-2,3-dihydro(2,2-²H₂)-1-benzofuran: To a solution of 4-chloro-2,3- dihydro(2,2-²H2)-1-benzofuran (6.6 g, 42.14 mmol, 1.00 equiv), tri-tert- butyl(ethenyl)stannane (20.18 g, 63.64 mmol, 1.50 equiv), CsF (14.14 g, 93.03 mmol, 2.20 equiv), (t-Bu)3P (740 mg, 2.55 mmol, 0.06 equiv) in dioxane (80 mL) was added Pd2(dba)3 (870 mg, 0.84 mmol, 0.02 equiv) under an atmosphere of nitrogen. The resulting solution was stirred for 24 h at 110 ^oC. The reaction progress was monitored by GCMS. The resulting solution was diluted with 100 mL of ethyl acetate. Then the solids were filtered out. The organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by SiO2 chromatography eluted with petroleum ether to afford 4 g (64%) of 4-ethenyl-2,3-dihydro (2,2-²H₂)-1- benzofuran as light brown oil.¹H NMR (400 MHz, CDCl3) δ: 7.50-7.45 (m, 1H), 7.19-7.05 (m, 1H), 6.77-6.69 (m, 2H), 5.74 (m, 1H), 5.37 (m, 1H), 3.29-3.27 (m, 2H). Step 4

[00249] 2,3-dihydro(2,2-²H₂)-1-benzofuran-4-carbaldehyde: To a solution of 4-ethenyl- 2,3-dihydro(2,2-²H2)-1-benzofuran (4 g, 27.03 mmol, 1.00 equiv) in tetrahydrofuran (60 mL) and water (30 mL) was added OsO₄ (in tetrahydrofuran 0.2 M) (6.8 mL, 0.05 equiv). The resulting solution was stirred for 30 min at 20 ^oC. Then NaIO4 (11.57 g, 54.05 mmol, 2.00 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 1 h at room temperature. The resulting solution was diluted with 30 mL of water. Then the resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 3.2 g (79%) of 2,3-dihydro(2,2- ²H₂)-1-benzofuran-4-carbaldehyde as brown oil.¹H NMR (400 MHz, CDCl₃) δ: 10.08 (s, 1H), 7.40-7.28 (m, 2H), 7.08-7.05 (m, 1H), 3.57-3.56 (m, 2H). Step 5

[00250] (2E)-3-[2,3-dihydro(2,2-²H2)-1-benzofuran-4-yl]prop-2-enoic acid: A mixture of 2,3-dihydro(2,2-²H₂)-1-benzofuran-4-carbaldehyde (3.2 g, 21.31 mmol, 1.00 equiv), malonic acid (4.44 g, 42.67 mmol, 2.00 equiv), pyrrolidine (1.75 mL), Pyridine (35 mL) was heated for 2 h at 120 ^oC. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers were combined. The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 3.6 g (88%) of (2E)-3- [2,3-dihydro(2,2-²H₂) -1-benzofuran-4-yl]prop-2-enoic acid as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ: 12.43 (s, 1H), 7.55-7.51 (m, 1H), 7.20-7.12 (m, 2H), 6.82-6.80 (M, 1H), 6.44-6.40 (m, 1H), 3.45-3.18 (m, 2H). Step 6

[00251] (2E)-3-[2,3-dihydro(2,2-²H₂)-1-benzofuran-4-yl]-N-methoxy-N-methylprop-2- enamide: A mixture of (2E)-3-[2,3-dihydro(2,2-²H2)-1-benzofuran-4-yl]prop-2-enoic acid (3.6 g, 18.75 mmol, 1.00 equiv), thionyl chloride (7.2 mL) and dichloromethane (40 mL) was heated to reflux for 1 h. The mixture was concentrated under vacuum. Then this material was dissolved in ethyl acetate (40 mL), and a solution of N,O- dimethylhydroxylamine hydrochloride (3.6 g, 37.11 mmol, 2.00 equiv) in saturated Na₂CO₃(36 mL) was added with stirring. The resulting solution was allowed to react for an additional 1 h at room temperature. Then the mixture was diluted with 50 mL of water. The resulting solution was extracted with ethyl acetate (2 x 50 mL). And the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 3.6 g (82%) of (2E)-3-[2,3- dihydro(2,2-²H2) -1-benzofuran-4-yl]-N-methoxy-N-methylprop-2-enamide as brown oil. LC-MS: m/z = 236 [M+H]⁺. Step 7

[00252] (1R,2R)-2-[2,3-dihydro(2,2-²H2)-1-benzofuran-4-yl]-N-methoxy-N- methylcyclopropane-1-carboxamide: To a suspension of sodium hydride (1.84 g, 3.00 equiv) in DMSO (100 mL) was added S,S-dimethylmethanesulfinyl iodide (10.12 g, 46.00 mmol, 3.00 equiv). The resulting solution was stirred for 30 min at room temperature. Then (2E)-3- [2,3-dihydro(2,2-²H2)-1-benzofuran-4-yl]-N-methoxy-N-methylprop-2-enamide (3.6 g, 15.32 mmol, 1.00 equiv) in DMSO was added dropwise. The mixture solution was allowed to react, with stirring, for an additional 3 h at room temperature. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers were combined. The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by SiO₂ chromatography eluted with ethyl acetate/petroleum ether (1:4) to afford 1.5 g (39%) of (1R,2R)-2-[2,3-dihydro(2,2-²H2)-1-benzofuran-4-yl]-N- methoxy-N-methylcyclopropane-1-carboxamide as a light yellow solid. LC-MS: m/z = 250 [M+H]⁺. Step 8

[00253] (1R,2R)-2-[2,3-dihydro(2,2-²H2)-1-benzofuran-4-yl]cyclopropane-1- carbaldehyde: To a suspension of LiAlH₄ (252 mg, 6.64 mmol, 1.10 equiv) in

tetrahydrofuran (25 mL) cooled to -50 ^oC was added (1R,2R)-2-[2,3-dihydro(2,2-²H2)-1- benzofuran-4-yl]- N-methoxy-N-methylcyclopropane-1-carboxamide (1.5 g, 6.02 mmol, 1.00 equiv) in THF dropwise. The resulting solution was stirred for 30 min at -5 ^oC. The reaction was quenched by the addition of water. Then KHSO4 (1.4 g, 1.70 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 10 min at 20 ^oC. The resulting solution was extracted with ethyl acetate (2 x 30 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 30 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.1 g (96%) of (1R,2R)-2-[2,3-dihydro(2,2-²H₂)-1-benzofuran-4-yl] cyclopropane-1-carbaldehyde as yellow oil.1H NMR (400 MHz, CDCl3) δ: 9.41-9.40 (m, 1H), 7.18-7.01 (m, 1H), 6.74-6.59 (m, 1H), 6.48-6.46 (m, 1H), 3.23 (s, 2H), 2.58-2.53 (m, 1H), 2.21-2.16 (m, 1H), 1.76-1.73 (m, 1H), 1.67-1.55 (m, 1H). Step 9

[00254] (Z)-N-[[(1R,2R)-2-[2,3-dihydro(2,2-²H2)-1-benzofuran-4- yl]cyclopropyl]methylidene]hydroxylamine: A mixture of (1R,2R)-2-[2,3-dihydro(2,2-²H2)- 1-benzofuran-4-yl]cyclopropane-1- carbaldehyde (1.14 g, 5.99 mmol, 1.00 equiv), ethanol (15 mL), HONH2 (50% in H2O) (1.2 mL, 3.00 equiv) and water(1.8 mL) was stirred for 3 h at 95 ^oC. The resulting solution was diluted with DCM (2 x 20 mL). The resulting mixture was washed with brine (2 x 20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.1 g (89%) of (Z)-N-[[(1R,2R)-2-[2,3- dihydro(2,2- ²H2)-1-benzofuran-4-yl]cyclopropyl]methylidene]hydroxylamine as a light yellow solid. LC- MS: m/z = 206 [M+H]⁺. Step 10

[00255] [(1R,2R)-2-[2,3-dihydro(2,2-²H2)-1-benzofuran-4- yl]cyclopropyl]methanamine: To a solution of (Z)-N-[[(1R,2R)-2-[2,3-dihydro(2,2-²H₂)-1- benzofuran-4-yl] cyclopropyl]methylidene]hydroxylamine (1.1 g, 5.36 mmol, 1.00 equiv) in THF (15 mL) was added LiAlH₄ (306 mg, 8.06 mmol, 1.50 equiv). The mixture was stirred for 30 min at room temperature. Then the resulting solution was allowed to react, with stirring, for an additional 4 h while the temperature was maintained at 50 ^oC. The reaction was quenched by the addition of water and the pH value of the solution was adjusted to 1 with hydrochloric acid (1 M). The resulting solution was extracted with dichloromethane. Then the pH value of the aqueous solution was adjusted to 10 with sodium hydroxide (3 M). The resulting solution was extracted with DCM (2 x 20 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 600 mg of [(1R,2R)-2-[2,3-dihydro(2,2-²H2) -1-benzofuran-4-yl]cyclopropyl]methanamine as light yellow oil. LC-MS: m/z = 192 [M+H]⁺. Step 11

[00256] N-[[(1R,2R)-2-[2,3-dihydro(2,2-²H₂)-1-benzofuran-4- yl]cyclopropyl]methyl]propanmide: To a solution of [(1R,2R)-2-[2,3-dihydro(2,2-²H2)-1- benzofuran-4-yl]cyclopropyl] methanamine (600 mg, 3.14 mmol, 1.00 equiv) and TEA (952 mg, 9.41 mmol, 3.00 equiv) in DCM (10 mL) was added propionyl chloride (318 mg, 3.44 mmol, 1.10 equiv). The mixture was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of DCM. The mixture was washed with brine (2 x 20 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 3:7). The crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO2(75%), ethanol (25%); Detector, UV 220 nm to afford 120 mg of N- [[(1R,2R)-2-[2,3-dihydro(2,2-²H₂)-1-benzofuran-4-yl]cyclopropyl]methyl]propanmide as a white solid.¹H NMR (400 MHz, CDCl3) δ: 7.04-6.99 (m, 1H), 6.63-6.60 (m, 1H), 6.34-6.32 (m, 1H), 5.65 (s, 1H), 3.38-3.32 (m, 2H), 3.29-3.22 (m, 2H), 2.23-2.18 (m, 2H), 1.77-1.70 (m, 1H), 1.37-1.30 (m, 1H), 1.26-1.19 (m, 3H), 1.00-0.89 (m, 2H). LC-MS: m/z = 248 [M+H]⁺. EXAMPLE 3

N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1-benzofuran-4- yl]cyclopropyl]methyl]propanamide (tasimelteon-d₂)

00257 As shown in the scheme Exam le 3 was s nthesized as follows:

Step 1

[00258] 2-(2,6-dichlorophenyl)( ²H₂)acetic acid: To a solution of 2-(2,6- dichlorophenyl)acetic acid (40 g, 195.09 mmol, 1.00 equiv) in D2O (200 mL) was added NaOD (78 mL, 1.25 equiv) and TBAB (125.6 mg, 0.39 mmol). The resulting solution was stirred for 40 h at 105 ^oC. The reaction mixture was cooled to 0 ^oC with a water/ice bath. The pH value of the solution was adjusted to 3 with HCl (3 M). The solids were collected by filtration. This resulted in 39 g (97%) of 2-(2,6-dichlorophenyl)(²H2)acetic acid as a white solid. Step 2

[00259] 2-(2,6-dichlorophenyl)(2,2-²H₂)ethan-1-ol: To a solution of 2-(2,6- dichlorophenyl)(2H2)acetic acid (39 g, 188.36 mmol, 1.00 equiv) in THF (60 mL) was added a solution of BD3in THF (1M) (374.4 mL, 2.00 equiv) dropwise with stirring at 0 ^oC.. The resulting solution was stirred for 20 h at room temperature. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with ethyl acetate (3 x 200 mL). And the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 35 g (96%) of 2-(2,6-dichlorophenyl)(2,2-²H2) ethan-1- ol as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ: 7.46-7.41 (m, 2H), 7.30-7.25 (m, 1H), 3.53 (s, 2H).

[00260] 4-chloro-2,3-dihydro(3,3-²H2)-1-benzofuran: A solution of 2-(2,6- dichlorophenyl)(2,2-²H₂)ethan-1-ol (35 g, 181.28 mmol, 1.00 equiv) in pyridine (350 mL) was stirred at 0 ^oC. Then sodium hydride (9.1 g, 379.17 mmol, 1.25 equiv) was added. The resulting solution was stirred at 0 ^oC for 1 h. To this was added CuCl (0.89 g, 0.05 equiv). The resulting solution was stirred overnight at 115 ^oC. The reaction mixture was cooled. The resulting solution was diluted with 300 mL of water. The pH value of the solution was adjusted to 7 with HCl (3 M). The solids were filtered out. The resulting solution was extracted with ethyl acetate (3 x 200 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). The collected fractions were combined and concentrated under vacuum to afford 18.56 g (65%) of 4-chloro-2,3- dihydro(3,3-²H2)- 1-benzofuran as light brown oil.¹H NMR (400 MHz, DMSO-d6) δ: 7.14- 7.10 (m, 1H), 6.89-6.87 (m, 1H), 6.75-6.73 (m, 1H), 4.60-4.59 (m, 2H). Step 4

[00261] 4-ethenyl-2,3-dihydro(3,3-²H₂)-1-benzofuran: To a solution of 4-chloro-2,3- dihydro(3,3-²H2)-1-benzofuran (17.5 g, 111.75 mmol, 1.00 equiv), tri-tert- butyl(ethenyl)stannane (53 mL, 1.60 equiv), CsF (37.5 g, 246.71 mmol, 2.20 equiv), (t-Bu)₃P (1.95 g, 6.72 mmol, 0.06 equiv) in dioxane (200 mL) was added Pd2(dba)3 (2.32 g, 2.24 mmol, 0.02 equiv) under an atmosphere of nitrogen. The resulting solution was stirred for 24 h at 110 ^oC. The reaction progress was monitored by GCMS. The resulting solution was diluted with 200 mL of ethyl acetate. Then the solids were filtered out. The organic layers were washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by SiO2 chromatography eluted with ethyl acetate/petroleum ether (0:1) to afford 7.5 g (45%) of 4-ethenyl-2,3-dihydro(3,3-²H₂)-1- benzofuran as light yellow oil.¹H NMR (300 MHz, Chloroform-d) δ: 7.12-7.07 (m, 1H), 7.01-6.95 (m, 1H), 6.74-6.65 (m, 2H), 5.71 (m, 1H), 5.34-5.30 (m, 1H), 4.65-4.56 (m, 2H). Step 5

[00262] 2,3-dihydro(3,3-²H2)-1-benzofuran-4-carbaldehyde: To a solution of 4-ethenyl- 2,3-dihydro(3,3-²H₂)-1-benzofuran (7.5 g, 50.61 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) and water (50 mL) was added OsO4 (in tetrahydrofuran 0.2 M) (12.7 mL, 0.05 equiv). The resulting solution was stirred for 30 min at 20^oC. Then NaIO₄ (21.69 g, 101.36 mmol, 2.00 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 1 hour at room temperature. The resulting solution was diluted with 50 mL of water. Then the resulting solution was extracted with ethyl acetate (2 x 100 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 7.5 g (99%) of 2,3- dihydro(3,3-²H₂)-1-benzofuran-4-carbaldehyde as brown oil.¹H NMR (400 MHz,

Chloroform-d) δ: 10.08 (s, 1H), 7.36-7.31 (m, 2H), 7.07-7.03 (m, 1H), 4.67 (s, 2H). Step 6

[00263] (2E)-3-[2,3-dihydro(3,3-²H2)-1-benzofuran-4-yl]prop-2-enoic acid: A mixture of 2,3-dihydro(3,3-²H₂)-1-benzofuran-4-carbaldehyde (7.5 g, 49.94 mmol, 1.00 equiv), malonic acid (10.4 g, 99.94 mmol, 2.00 equiv), pyrrolidine (4 mL), Pyridine (80 mL) was heated for 2 h at 120 ^oC. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with ethyl acetate (2 x 80 mL) and the organic layers were combined. The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 7.2 g (75%) of (2E)-3-[2,3- dihydro(3,3- ²H2)-1-benzofuran-4-yl]prop-2-enoic acid as a yellow solid.¹H NMR (400 MHz, DMSO) δ: 7.56-7.52 (m, 1H), 7.19-7.12 (m, 2H), 6.82-6.80 (m, 1H), 6.43-6.39 (m, 1H), 4.55 (s, 2H). Step 7

[00264] (2E)-3-[2,3-dihydro(3,3-²H2)-1-benzofuran-4-yl]-N-methoxy-N-methylprop-2- enamide: A mixture of (2E)-3-[2,3-dihydro(3,3-²H₂)-1-benzofuran-4-yl]prop-2-enoic acid (7.2 g, 37.46 mmol, 1.00 equiv), thionyl chloride (14 mL) and dichloromethane (70 mL) was heated to reflux for 1 hour. The mixture was concentrated under vacuum. Then this material was dissolved in ethyl acetate (70 mL), and a solution of N,O- dimethylhydroxylamine hydrochloride (7.28 g, 75.05 mmol, 2.00 equiv) in saturated Na2CO3(70 mL) was added with stirring. The resulting solution was allowed to react for an additional 1 hour at room temperature. Then the mixture was diluted with 50 mL of water. The resulting solution was extracted with ethyl acetate (2 x 100 mL). And the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 7 g (79%) of (2E)-3-[2,3- dihydro(3,3-²H₂)-1- benzofuran-4-yl]-N-methoxy-N-methylprop-2-enamide as brown oil.¹H NMR (400 MHz, CDCl3) δ 7.76-7.72 (m, 1H), 7.19-7.14 (m, 2H), 7.03-6.99 (m, 1H), 6.83- 6.81 (m, 1H), 4.64 (s, 2H), 3.79 (s, 3H), 3.34 (s, 3H). Step 8

[00265] (1R,2R)-2-[2,3-dihydro(3,3-²H2)-1-benzofuran-4-yl]-N-methoxy-N- methylcyclopropane-1-carboxamide: To a suspension of sodium hydride (3.57 g, 148.75 mmol, 3.00 equiv) in DMSO (210 mL) was added S,S-dimethylmethanesulfinyl iodide (19.66 g, 89.33 mmol, 3.00 equiv). The resulting solution was stirred for 30 min at room

temperature. Then (2E)-3-[2,3-dihydro(3,3-²H2)-1-benzofuran-4-yl]-N-methoxy-N- methylprop-2-enamide (7.0 g, 29.75 mmol, 1.00 equiv) in DMSO was added dropwise. The mixture solution was allowed to react, with stirring, for an additional 3 h at room temperature. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with ethyl acetate (2 x 200 mL) and the organic layers were combined. The resulting mixture was washed with brine (2 x 200 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by SiO2 chromatography eluted with ethyl acetate/petroleum ether (1:4) to afford 6 g (81%) of (1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1-benzofuran-4-yl]-N-methoxy -N-methylcyclopropane-1- carboxamide as a light yellow solid.¹H NMR (400 MHz, CDCl3) δ 7.09-7.05 (m, 1H), 6.69- 6.66 (m, 1H), 6.49-6.47 (m, 1H), 4.60 (s, 2H), 3.75 (s, 3H), 3.27 (s, 3H), 2.46-2.41 (m, 2H), 1.65-1.60 (m, 1H), 1.36-1.29 (m, 1H). Step 9

[00266] (1R,2R)-2-[2,3-dihydro(3,3-²H2)-1-benzofuran-4-yl]cyclopropane-1- carbaldehyde: To a suspension of LiAlH₄ (671 mg, 17.68 mmol, 1.10 equiv) in

tetrahydrofuran (80 mL) cooled to -50 ^oC was added (1R,2R)-2-[2,3-dihydro(3,3-²H2)-1- benzofuran-4-yl] -N-methoxy-N-methylcyclopropane-1-carboxamide (4 g, 16.04 mmol, 1.00 equiv) in THF dropwise. The resulting solution was stirred for 30 min at -5 ^oC. The reaction was quenched by the addition of water. Then KHSO₄ (3.71 g, 1.70 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 10 min at 20 ^oC. The resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 2.9 g (95%) of (1R,2R)-2-[2,3-dihydro(3,3-²H2)-1-benzofuran-4-yl]cyclopropane-1-carbaldehyde as light yellow oil.¹H NMR (400 MHz, CDCl₃) δ: 9.40 (s, 1H), 7.10-7.06 (m, 1H), 6.71-6.69 (m, 1H), 6.48-6.46 (m, 1H), 4.61 (s, 2H), 2.58-2.52 (m, 1H), 2.21-2.16 (m, 1H), 1.76-1.72 (m, 1H), 1.60-1.55 (m, 1H). Step 10

[00267] (Z)-N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1-benzofuran-4- yl]cyclopropyl]methylidene]hydroxylamine: A mixture of (1R,2R)-2-[2,3-dihydro(3,3-²H2)- 1-benzofuran-4-yl]cyclopropane-1- carbaldehyde (2.9 g, 15.24 mmol, 1.00 equiv), ethanol (30 mL), HONH2 (50% in H2O) (3 mL, 3.00 equiv) and water (3 mL) was stirred for 3 h at 95 ^oC in an oil bath. The resulting solution was diluted with DCM (2 x 50 mL). The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 2.7 g (86%) of (Z)-N-[[(1R,2R)-2- [2,3- dihydro(3,3-²H2)-1-benzofuran-4-yl]cyclopropyl]methylidene]hydroxylamine as a light yellow solid. Step 11

[00268] [(1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1-benzofuran-4-yl]cyclopropyl]methanamine: To a solution of (Z)-N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H2)-1-benzofuran-4-yl]

cyclopropyl]methylidene]hydroxylamine (2.7 g, 13.15 mmol, 1.00 equiv) in THF (30 mL) was added LiAlH4 (751 mg, 19.79 mmol, 1.50 equiv). The mixture was stirred for 30 min at room temperature. Then the resulting solution was allowed to react, with stirring, for an additional 4 h while the temperature was maintained at 50^oC. The reaction was quenched by the addition of water and the pH value of the solution was adjusted to 1 with hydrochloric acid (1 M). The resulting solution was extracted with dichloromethane. Then the pH value of the aqueous solution was adjusted to 10 with sodium hydroxide (3 M). The resulting solution was extracted with dichloromethane (2 x 50 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.8 g (72%) of [(1R,2R)-2- [2,3-dihydro(3,3-²H₂)-1-benzofuran-4-yl]cyclopropyl]methanamine as light yellow oil.¹H NMR (400 MHz, CDCl3) δ 7.09-7.03 (m, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 4.60 (s, 2H), 2.81-2.69 (m, 2H), 1.72-1.62 (m, 1H), 1.39-1.16 (m, 1H), 0.98-0.91 (m, 1H), 0.90-0.83 (m, 1H). Step 12

[00269] N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H2)-1-benzofuran-4- yl]cyclopropyl]methyl]propanamide: To a solution of [(1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1- benzofuran-4-yl]cyclopropyl] methanamine (900 mg, 4.71 mmol, 1.00 equiv) and TEA (1.43 g, 14.13 mmol, 3.00 equiv) in DCM (10 mL) was added propionyl chloride (477 mg, 5.16 mmol, 1.10 equiv). The mixture was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 10 mL of DCM. The mixture was washed with brine (2 x 10 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 3:7). The crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20 um; mobile phase, CO₂(75%), ethanol (25%); Detector, UV 220 nm to afford 250 mg of N- [[(1R,2R)-2-[2,3-dihydro(3,3-²H2)-1-benzofuran-4-yl]cyclopropyl]methyl]propanamide as a white solid.¹H NMR (300 MHz, CDCl₃) δ: 7.05-7.00 (m, 1H), 6.63-6.61 (m, 1H), 6.36-6.33 (m, 1H), 5.69 (s, 1H), 4.58 (s, 2H), 3.39-3.24 (m, 2H), 2.26-2.19 (m, 2H), 1.77-1.71 (m, 1H), 1.37-1.23 (m, 1H), 1.20-1.14 (m, 3H), 1.00-0.87 (m, 2H). LC-MS: m/z = 248 [M+H]⁺. EXAMPLE 4

N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H₂)-1-benzofuran-4- yl]cyclopropyl]methyl]propanamide (tasimelteon-d₄)

1 ^{step 1}

2

2-(2,6-dichlorophenyl)(²H₄)ethan-1-ol: To 2-(2,6-dichlorophenyl)(²H₂)acetic acid (20 g, 96.60 mmol, 1.00 equiv), obtained, for example, by the method of Example 3, step 1, was added BD₃(in THF,1 M) (100 mL, 1.00 equiv) dropwise with stirring. The resulting solution was stirred at 0 ^oC for 3 h. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of D₂O. The resulting solution was extracted with ethyl acetate (3 x 50 mL). And the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum to afford 18 g (96%) of 2- (2,6-dichlorophenyl)(²H4)ethan-1-ol as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ: 7.49-7.39 (m, 2H), 7.29-7.25 (m, 1H), 4.82 (s, 1H). Step 2

[00270] 4-chloro-2,3-dihydro(2,2,3,3-²H4)-1-benzofuran: A solution of 2-(2,6- dichlorophenyl)(²H₄)ethan-1-ol (18 g, 92.27 mmol, 1.00 equiv) in pyridine (200 mL) was stirred at 0 ^oC. Then sodium hydride (4.62 g, 192.50 mmol, 1.25 equiv) was added. The resulting solution was stirred at 0^oC for 1 h. To this was added CuCl (450 mg, 4.59 mmol, 0.05 equiv). The resulting solution was stirred overnight at 115 ^oC. The reaction mixture was cooled down to room temperature. The resulting solution was diluted with 100 mL of D₂O. The pH value of the solution was adjusted to 7 with HCL (3 M). The solids were filtered out. The resulting solution was extracted with ethyl acetate (3 x 100 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:20). The collected fractions were combined and concentrated under vacuum to afford 8 g (55%) of 4-chloro-2,3- dihydro(2,2,3,3-²H₄)-1-benzofuran as light brown oil. Step 3

3 ^{step 3 4}

[00271] 4-ethenyl-2,3-dihydro(2,2,3,3-²H4)-1-benzofuran: To a suspension of 4-chloro- 2,3-dihydro(2,2,3,3-²H4)-1-benzofuran (8 g, 50.44 mmol, 1.00 equiv), tri-tert- butyl(ethenyl)stannane (24.15 g, 76.16 mmol, 1.50 equiv), CsF (16.93 g, 111.38 mmol, 2.20 equiv) and (t-Bu)3PHBF4 (880 mg, 3.03 mmol, 0.06 equiv) in dioxane (80 mL) was added Pd₂(dba)₃ (1.05 g, 1.01 mmol, 0.02 equiv) under an atmosphere of nitrogen. The resulting solution was stirred for 24 h at 110 ^oC. The reaction progress was monitored by GCMS. The resulting solution was diluted with 100 mL of ethyl acetate. Then the solids were filtered out. The organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by SiO₂

chromatography, eluted with petroleum ether to afford 5 g (66%) of 4-ethenyl-2,3- dihydro(2,2,3,3-²H₄)-1-benzofuran as light yellow oil.¹H NMR (400 MHz, CDCl₃) δ: 7.18- 6.97 (m, 2H), 6.95-6.66 (m, 2H), 5.78-5.64 (m, 1H), 5.39-5.36 (m, 1H). Step 4

[00272] 2,3-dihydro(2,2,3,3-²H₄)-1-benzofuran-4-carbaldehyde: To a solution of 4- ethenyl-2,3-dihydro(2,2,3,3-²H4)-1-benzofuran (6 g, 40.00 mmol, 1.00 equiv) in THF/H2O (2:1) (100 mL), was added OsO₄ (in THF 0.2 M) (10 mL, 0.05 equiv). The resulting solution was stirred for 30 min at 20 ^oC. Then NaIO4 (17.12 g, 2.00 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 1 hour at room temperature. The resulting solution was diluted with water. Then the resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5.71 g (93.9%) of 2,3-dihydro (2,2,3,3-²H₄)-1-benzofuran-4-carbaldehyde as brown oil.¹H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.37-7.30 (m, 2H), 7.13-7.01 (m, 1H). Step 5

5 6

[00273] (2E)-3-[2,3-dihydro(2,2,3,3-²H4)-1-benzofuran-4-yl]prop-2-enoic acid: A mixture of 2,3-dihydro(2,2,3,3-²H₄)-1-benzofuran-4-carbaldehyde (5.71 g, 37.52 mmol, 1.00 equiv), malonic acid (7.81 g, 75.05 mmol, 2.00 equiv), pyrrolidine (3 mL), Pyridine (60 mL) was heated for 2 h at 120 ^oC. The resulting solution was diluted with 50 mL of water. Then the resulting solution was extracted with ethyl acetate. And the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5.66 g (78%) of (2E)-3-[2,3-dihydro (2,2,3,3-²H4)-1-benzofuran-4-yl]prop-2-enoic acid as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.43 (s, 1H), 7.64-7.50 (m, 1H), 7.23-7.08 (m, 2H), 6.89- 6.80 (m, 1H), 6.44-6.40 (m, 1H). Step 6

H

[00274] A mixture of (2E)-3-[2,3-dihydro(2,2,3,3-²H4)-1-benzofuran-4-yl]prop-2-enoic acid (5.66 g, 29.14 mmol, 1.00 equiv), thionyl chloride (11.3 mL) and dichloromethane (60 mL) was heated to reflux for 1 hour. The mixture was concentrated under vacuum. Then this material was dissolved in ethyl acetate (57 mL), and a solution of N,O- dimethylhydroxylamine hydrochloride (5.66 g, 58.35 mmol, 2.00 equiv) in saturated Na2CO3(60 mL) was added with stirring. The resulting solution was allowed to react for an additional 1 hour at room temperature. Then the mixture was diluted with water. The resulting solution was extracted with ethyl acetate. And the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5.4 g (78%) of (2E)-3-[2,3-dihydro(2,2,3,3-²H4)-1-benzofuran-4-yl]-N-meth- oxy-N-methylprop-2-enamide as brown oil. LC-MS: m/z = 238 [M+H]⁺. Step 7

[00275] (1R,2R)-2-[2,3-dihydro(2,2,3,3-²H4)-1-benzofuran-4-yl]-N-methoxy-N- methylcyclopropane-1-carboxamide: To a suspension of sodium hydride (2.03 g, 84.58 mmol, 3.00 equiv) in DMSO (120 mL) was added S,S-dimethylmethanesulfinyl iodide (11.14 g, 50.62 mmol, 3.00 equiv). The resulting solution was stirred for 30 min at room

temperature. Then (2E)-3-[2,3-dihydro(2,2,3,3-²H4)-1-benzofuran-4-yl]-N-methoxy-N- methylprop-2-enamide (4 g, 16.86 mmol, 1.00 equiv) in DMSO was added dropwise. The mixture solution was allowed to react, with stirring, for an additional 3 h at room

temperature. The resulting solution was diluted with water. The resulting solution was extracted with ethyl acetate. Then the organic layers were washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by SiO₂ chromatography, eluted with ethyl acetate/petroleum ether (1:4) to afford 2.5 g (59%) of (1R,2R)-2-[2,3-dihydro(2,2,3,3-²H4)-1-benzofuran-4-yl]-N- methoxy- N-methylcyclopropane-1-carboxamide as a light yellow solid. LC-MS: m/z = 252 [M+H]⁺. Step 8

[00276] (1R,2R)-2-[2,3-dihydro(2,2,3,3-²H₄)-1-benzofuran-4-yl]cyclopropane-1- carbaldehyde: To a suspension of LiAlH4 (433 mg, 11.41 mmol, 1.10 equiv) in

tetrahydrofuran (25 mL) cooled to -50 ^oC was added (1R,2R)-2-[2,3-dihydro(2,2,3,3-²H4)-1- benzofuran -4-yl]-N-methoxy-N-methylcyclopropane-1-carboxamide (2.6 g, 10.35 mmol, 1.00 equiv) in THF dropwise. The resulting solution was stirred for 30 min at -5 ^oC. The reaction was quenched by the addition of water. Then KHSO₄ (2.4 g, 1.70 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 10 min at 20 ^oC. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.9 g (96%) of (1R,2R)-2-[2,3-dihydro(2,2,3,3-²H₄)-1- benzofuran-4-yl]cyclopropane-1-carbaldehyde as light yellow oil.¹H NMR (300 MHz, CDCl₃) δ: 9.40-9.39 (m, 1H), 7.15-7.05 (m, 1H), 6.90-6.67 (m, 1H), 6.47-6.44 (m, 1H), 2.63- 2.41 (m, 1H), 2.20-2.14 (m,1H), 1.76-1.70 (m, 1H), 1.60-1.50 (m, 1H). Step 9

[00277] (Z)-N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H₄)-1-benzofuran-4- yl]cyclopropyl]methylidene]hydroxylamine: A mixture of (1R,2R)-2-[2,3-dihydro(2,2,3,3- ²H₄)-1-benzofuran-4-yl]cyclopropane -1-carbaldehyde (1.9 g, 9.88 mmol, 1.00 equiv), ethanol (20 mL), HONH2 (50% in H2O) (1.96 mL, 3.00 equiv) and water(2.0 mL) was stirred for 3 h at 95 ^oC. The resulting solution was diluted with DCM. Then the mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.7 g (83%) of (Z)-N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H4)-1-benzofuran-4-yl]cyclopropyl] methylidene]hydroxylamine as a light yellow solid. LC-MS: m/z = 208 [M+H]⁺. Step 10

[00278] [(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H₄)-1-benzofuran-4- yl]cyclopropyl]methanamine: To a solution of (Z)-N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H4)- 1-benzofuran-4-yl] cyclopropyl]methylidene]hydroxylamine (1.7 g, 8.20 mmol, 1.00 equiv) in THF (20 mL) was added LiAlH4 (468 mg, 12.33 mmol, 1.50 equiv). The mixture was stirred for 30 min at room temperature. Then the resulting solution was allowed to react, with stirring, for an additional 4 h while the temperature was maintained at 50 ^oC. The reaction was quenched by the addition of water and the pH value of the solution was adjusted to 1 with hydrochloric acid (1 M). The resulting solution was extracted with dichloromethane. Then the pH value of the aqueous solution was adjusted to 10 with sodium hydroxide (3 M). The resulting solution was extracted with dichloromethane. And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 950 mg (60%) of [(1R,2R)-2-[2,3-dihydro (2,2,3,3-²H₄)-1-benzofuran-4- yl]cyclopropyl]methanamine as light yellow oil. LC-MS: m/z = 194 [M+H]⁺. Step 11

[00279] N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H2)-1-benzofuran-4- yl]cyclopropyl]methyl]propanamide: To a solution of [(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H₂)- 1-benzofuran-4-yl]cyclopropyl] methanamine (550 mg, 2.85 mmol, 1.00 equiv), and TEA (863 mg, 8.53 mmol, 3.00 equiv) in DCM (8 mL) was added propionyl chloride (289 mg, 3.12 mmol, 1.10 equiv). The mixture was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 10 mL of DCM. The mixture was washed with brine (2 x 20 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 3:7). The crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO2(75%), ethanol (25%); Detector, UV 220 nm to afford 160 mg of N- [[(1R,2R)-2-[2,3-dihydro(2,2,3,3- ²H₄)-1-benzofuran-4-yl]cyclopropyl]methyl]propanamide as a white solid.¹H NMR (300 MHz, CDCl3) δ: 7.03-6.99 (m, 1H), 6.63-6.60 (m, 1H), 6.35- 6.32 (m, 1H), 5.73 (s, 1H), 3.35-3.24 (m, 2H), 2.26-2.17 (m, 2H), 1.76-1.70 (m, 1H), 1.34- 1.21 (m, 1H), 1.19-1.14 (m, 3H), 0.99-0.87 (m, 2H). LC-MS: m/z = 250 [M+H]⁺. EXAMPLE 5

N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl](²H₂)methyl]propanamide

(tasimelteon-d2)

00280 As shown in the scheme Exam le 5 was s nthesized as follows:

Step 1

2

[00281] [(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl](²H)formaldehyde: To a suspension of LiAlD₄ (599 mg, 14.27 mmol, 1.10 equiv) in tetrahydrofuran (50 mL) cooled to -50 ^oC was added (1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)-N- methoxy-N- methylcyclopropane-1-carboxamide, obtained, for example, as the product of step 6 of

Example 1, (3.2 g, 12.94 mmol, 1.00 equiv) in THF dropwise. The resulting solution was stirred for 30 min at -5 ^oC. The reaction was quenched by the addition of water. Then KHSO₄ (3.2 g, 1.70 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 10 min at 20 ^oC. The resulting solution was extracted with ethyl acetate (2 x 30 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 30 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 2.4 g (98%) of [(1R,2R)-2-(2,3-dihydro-1-benzofuran-4- yl)cyclopropyl](²H)formaldehyde as light yellow oil. Step 2

[00282] (Z)-N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4- yl)cyclopropyl](²H)methylidene]hydroxylamine: A mixture of [(1R,2R)-2-(2,3-dihydro-1- benzofuran-4-yl)cyclopropyl](²H) formaldehyde (2.75 g, 14.53 mmol, 1.00 equiv), ethanol (30 mL), HONH2 (50% in H2O) (2.9 mL, 3.00 equiv) and water (3 mL) was stirred for 3 h at 95 ^oC. The resulting solution was diluted with DCM (2 x 20 mL). The resulting mixture was washed with brine (2 x 20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 2.6 g (88%) of (Z)-N-[[(1R,2R)-2- (2,3-dihydro-1- benzofuran-4-yl)cyclopropyl](²H)methylidene]hydroxylamine as a light yellow solid. Step 3

[00283] [(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl](²H2)methanamine: To a solution of (Z)-N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl](²H)

methylidene]hydroxylamine (2.6 g, 12.73 mmol, 1.00 equiv) in THF (50 mL) was added LiAlD4 (726 mg, 17.29 mmol, 1.50 equiv). The mixture was stirred for 30 min at room temperature. Then the resulting solution was allowed to react, with stirring, for an additional 4 h while the temperature was maintained at 50 ^oC. The reaction was quenched by the addition of water and the pH value of the solution was adjusted to 1 with hydrochloric acid (1 M). The resulting solution was extracted with DCM. Then the pH value of the aqueous solution was adjusted to 10 with sodium hydroxide (3 M). The resulting solution was extracted with DCM (2 x 20 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.9 g (78%) of [(1R,2R)- 2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl](²H2) methanamine as yellow oil. Step 4

4

[00284] N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4- yl)cyclopropyl](²H2)methyl]propanamide: To a solution of [(1R,2R)-2-(2,3-dihydro-1- benzofuran-4-yl)cyclopropyl](²H₂) methanamine (800 mg, 4.18 mmol, 1.00 equiv) and TEA (1.3 g, 12.85 mmol, 3.00 equiv) in DCM (10 mL) was added propionyl chloride (424 mg, 4.58 mmol, 1.10 equiv). The mixture was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of DCM. The mixture was washed with brine (2 x 20 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 3:7). The crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO2(75%), ethanol (25%); Detector, UV 220 nm to afford 250 mg (24%) of N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4- yl)cyclopropyl](²H2)methyl]propanamide as a white solid.¹H NMR (300 MHz, CDCl3) δ: 7.04-6.99 (m, 1H), 6.63-6.60 (m, 1H), 6.35-6.33 (m, 1H), 5.61 (s, 1H), 4.62-4.56 (m, 2H), 3.49-3.15 (m, 2H), 2.26-2.18 (m, 2H), 1.77-1.71 (m, 1H), 1.33-1.27 (m, 1H), 1.22-1.14 (m, 3H), 1.00-0.89 (m, 2H). LC-MS: m/z = 248 [M+H]⁺. EXAMPLE 6

N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H2)-1-benzofuran-4- yl]cyclopropyl](²H₂)methyl]propanamide (tasimelteon-d₄)

As shown in the scheme, PH-APX-SD-1084 was synthesized as follows:

Step 1

[00285] [(1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1-benzofuran-4- yl]cyclopropyl](²H)formaldehyde: To a suspension of LiAlD4 (371 mg, 1.10 equiv) in tetrahydrofuran (40 mL) cooled to -50 ^oC was added (1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1- benzofuran-4-yl]-N-methoxy-N- methylcyclopropane-1-carboxamide, obtained, for example, as the product of step 8 of Example 3, (2 g, 8.02 mmol, 1.00 equiv) in THF dropwise. The resulting solution was stirred for 30 min at -5 ^oC. The reaction was quenched by the addition of water. Then KHSO₄ (1.86 g, 1.70 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 10 min at 20 ^oC. The resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.5 g (98%) of [(1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1- benzofuran-4-yl]cyclopropyl](²H)form- aldehyde as light yellow oil. Step 2

[00286] (Z)-N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H2)-1-benzofuran-4- yl]cyclopropyl](²H)methylidene]hydroxylamine: A mixture of [(1R,2R)-2-[2,3-dihydro(3,3- ²H2)-1-benzofuran-4-yl]cyclopropyl](²H) formaldehyde (1.5 g, 7.84 mmol, 1.00 equiv), ethanol (20 mL), HONH2 (50% in H2O) (1.6 mL, 3.00 equiv) and water (2 mL) was stirred for 3 h at 95 ^oC. The resulting solution was diluted with DCM. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.48 g (91%) of (Z)-N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H2)-1- benzofuran-4-yl]cyclopropyl](²H)methylidene]hydroxylamine as a light yellow solid. Step 3

[00287] [(1R,2R)-2-[2,3-dihydro(3,3-²H2)-1-benzofuran-4- yl]cyclopropyl](²H₂)methanamine: To a solution of Z)-N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H₂)- 1-benzofuran-4-yl] cyclopropyl](²H)methylidene]hydroxylamine (1.48 g, 7.18 mmol, 1.00 equiv) in THF (30 mL) was added LiAlD₄ (410 mg, 1.50 equiv). The mixture was stirred for 30 min at room temperature. Then the resulting solution was allowed to react, with stirring, for an additional 4 h while the temperature was maintained at 50 ^oC. The reaction was quenched by the addition of water and the pH value of the solution was adjusted to 1 with hydrochloric acid (1 M). The resulting solution was extracted with dichloromethane. Then the pH value of the aqueous solution was adjusted to 10 with sodium hydroxide (3 M). The resulting solution was extracted with dichloromethane. And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.1 g (79%) of [(1R,2R)-2-[2,3-dihydro (3,3-²H2)-1-benzofuran-4-yl]cyclopropyl](²H2)methanamine as light yellow oil.

[00288] N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1-benzofuran-4- yl]cyclopropyl](²H₂)methyl]propanamide: To a solution of [(1R,2R)-2-[2,3-dihydro(3,3- ²H2)-1-benzofuran-4-yl]cyclopropyl] (²H2)methanamine (1.1 g, 5.69 mmol, 1.00 equiv) and TEA (1.73 g, 17.10 mmol, 3.00 equiv) in DCM (15 mL) was added propionyl chloride (577 mg, 6.24 mmol, 1.10 equiv). The mixture was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 10 mL of DCM. The mixture was washed with brine (2 x 10 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 3:7). The crude product was purified by Prep-SFC with the f following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO2(75%), ethanol (25%); Detector, UV 220 nm to afford 260 mg of N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1-benzofuran-4- yl]cyclopropyl](²H2)methyl]propanamide as a white solid.¹H NMR (300 MHz, CDCl3) δ: 7.05-6.99 (m, 1H), 6.62-6.60 (m, 1H), 6.35-6.32 (m, 1H), 5.67 (s, 1H), 4.57 (s, 2H), 2.25- 2.18 (m, 2H), 1.76-1.70 (m, 1H), 1.40-1.29 (m, 1H), 1.27-1.14 (m, 3H), 1.03-0.89 (m, 2H). LC-MS: m/z = 250 [M+H]⁺. EXAMPLE 7

N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H₄)-1-benzofuran-4- yl]cyclopropyl]methyl](²H₅)propanamide (tasimelteon-d₉)

1^{0 step 1} [00289] N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H₄)-1-benzofuran-4- yl]cyclopropyl]methyl](²H5)propanamide: To a solution of [(1R,2R)-2-[2,3-dihydro(2,2,3,3- ²H₄)-1-benzofuran-4-yl]cyclopropyl] methanamine, obtained, for example, as the product of step 10 of Example 4, (500 mg, 2.59 mmol, 1.00 equiv), BOP (1.72 g, 1.50 equiv) and TEA (785 mg, 7.76 mmol, 3.00 equiv) in DCM (8 mL) was added (²H₅)propan(²H)oic acid (249 mg, 3.11 mmol, 1.20 equiv). The resulting solution was stirred overnight at room

temperature. The resulting solution was diluted with 20 mL of DCM. The mixture was washed with brine (2 x 20 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 3:7). The crude product was purified by Prep-SFC with the following conditions following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO2(75%), ethanol (25%); Detector, UV 220 nm to afford 160 mg of N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H₄) -1-benzofuran-4- yl]cyclopropyl]methyl](²H5)propanamide as a white solid.¹H NMR (300 MHz, CDCl3) δ: 7.05-7.00 (m, 1H), 6.63-6.60 (m, 1H), 6.37-6.33 (m, 1H), 5.72 (s, 1H), 3.39-3.32 (m, 2H), 1.77-1.71 (m, 1H), 1.37-1.27 (m, 1H), 1.00-0.97 (m, 2H). LC-MS: m/z = 255 [M+H]⁺. EXAMPLE 8

N-[[(1R,2R)-2-[2,3-dihydro(3,3-²H₂)-1-benzofuran-4- yl]cyclopropyl]methyl](²H₅)propanamide (tasimelteon-d₇)

[00290] N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3-²H4)-1-benzofuran-4- yl]cyclopropyl]methyl](²H5)propanamide: To a solution of [(1R,2R)-2-[2,3-dihydro(3,3- ²H₂)-1-benzofuran-4-yl]cyclopropyl] methanamine, obtained, for example, as the product of step 11 of Example 3, (850 mg, 4.44 mmol, 1.00 equiv), BOP (2.95 g, 1.50 equiv) and TEA (1.35 g, 13.34 mmol, 3.00 equiv) in DCM (10 mL) was added (²H2)propan(²H)oic acid (427 mg, 5.33 mmol, 1.30 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of DCM. The mixture was washed with brine (2 x 20 mL). And the organic layers was combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 3:7). The crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO₂(75%), ethanol (25%); Detector, UV 220 nm to afford 180 mg of N-[[(1R,2R)-2- [2,3-dihydro(3,3-²H2)-1-benzofuran -4-yl]cyclopropyl]methyl](²H5)propanamide as a white solid.¹H NMR (300 MHz, CDCl₃) δ: 7.04-6.99 (m, 1H), 6.62-6.60 (m, 1H), 6.35-6.32 (m, 1H), 5.65 (s, 1H), 4.57 (s, 2H), 3.38-3.33 (m, 2H), 1.77-1.70 (m, 1H), 1.36-1.26 (m, 1H), 1.00-0.95 (m, 2H). LC-MS: m/z = 253 [M+H]⁺. [00291] The following compounds can generally be made using the methods described above. It is expected that these compounds when made will have activity similar to those described in the examples above.

Attorney Docket No. APX0262-401-PC

Attorney Docket No. APX0262-401-PC

,

, ,

[00292] Changes in the metabolic properties of the compounds disclosed herein as compared to their non-isotopically enriched analogs can be shown using the following assays. Compounds listed above which have not yet been made and/or tested are predicted to have changed metabolic properties as shown by one or more of these assays as well. Biological Activity Assays In vitro Liver Microsomal Stability Assay

[00293] Human liver microsomal stability assays are conducted at 0.5 mg per mL liver microsome protein with NADPH (2mM, pH 7.4). Test compounds are typically prepared as solutions in acetonitrile with 5% DMSO and added to the assay mixture (1uM, final concentration in incubation) to be incubated at 37 ºC. Reactions are initiated with the addition of NADPH cofactor and are stopped at 0, 15, 30, 45 or 60 min after cofactor addition with stop reagent, acetonitrile. After quenching, plates containing samples are vibrated for 10 min (600 rpm/min) and then centrifuged at 5594 g for 15 min. Supernatant fractions are analyzed by LC-MS/MS to determine the percent remaining and estimate the degradation half-life of the test compounds. Results are given below.

[00294] Other compounds disclosed herein are expected to have activity similar to or greater than the compounds disclosed above. In vitro metabolism using human cytochrome P450 enzymes

[00295] Compounds disclosed herein were tested in the following assay. Recombinant CYP1A2 stability assays are conducted at an enzyme concentration of 40 pmol per mL with NADPH (2mM, pH 7.4). Test compounds are typically prepared as acetonitrile with 5% DMSO and added to the assay mixture (1uM, final concentration in incubation) to be incubated at 37 ºC. Reactions are initiated with the addition of NADPH cofactor and are stopped at 0, 30, 60, 90 or 120 min after cofactor addition with stop reagent, acetonitrile. After quenching, plates containing samples are vibrated for 10 min (600 rpm/min) and then centrifuged at 5594 g for 15 min. Supernatant fractions are analyzed by LC-MS/MS to determine the percent remaining and estimate the degradation half-life of the test compounds. Results are given below.

[00296] Other compounds disclosed herein are expected to have activity similar to or greater than the compounds disclosed above.

[00297] Compounds disclosed herein may be tested in variations of the assay above, for metabolic activity by other CYP enzymes. Alternatively, the compounds may be tested as follows. Cytochrome P450 enzymes may be expressed from the corresponding human cDNA using a baculovirus expression system (BD Biosciences, San Jose, CA). A 0.25 milliliter reaction mixture containing 0.8 milligrams per milliliter protein, 1.3 millimolar NADP⁺, 3.3 millimolar glucose-6-phosphate, 0.4 U/mL glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesium chloride and 0.2 millimolar of a compound of Formula I, the corresponding non-isotopically enriched compound or standard or control in 100 millimolar potassium phosphate (pH 7.4) may be incubated at 37 °C for 20 min. After incubation, the reaction is stopped by the addition of an appropriate solvent (e.g., acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial acetic acid) and centrifuged (10,000 g) for 3 min. The supernatant is analyzed by HPLC/MS/MS. Compounds disclosed herein are expected to have activity in this assay as demonstrated by reduced metabolism by one or more cytochrome P₄₅₀ enzymes of deuterated compound as compared to the non-isotopically enriched compound.

In vitro Human Liver Microsomal Metabolite ID Assay

[00298] In vitro metabolite identification was conducted after incubating compounds (parent compound, final concentration 10 µM) with human liver microsomes (0.5 mg/mL) at 37 ^C in 100 mM potassium phosphate buffer containing 5 mM Mg²⁺(K/Mg-Buffer) in the presence of NADPH or without NADPH (w/o). Samples taken at 0 min and 60 min were quenched by using acetonitrile and analyzed using UPLC-UV-G2-S Q-Tof . The major metabolites of the example compounds in terms of the UV absorbance and mass spectrometry response were identified by comparison of the LC-UV and LC-MS total ion chromatograms (TIC) of T₀, T_60-w/o, T₆₀ samples in full scan mode using MassLynx and MetaboLynx. The tandem mass spectra or MSMS data of the parent compounds and the metabolites were obtained by using product ion scanning during positive and negative ion electrospray. The possible chemical structures of the metabolites were deduced based on their MSMS spectra.

[00299] Approximately 10 metabolites were identified by MS with putative structure assignment, including phase I biotransformations of mono- and di-hydroxylation and ketone formation. A subset of at least 3 of these metabolites could be detected by UV. The pattern of metabolite abundance relative to the unmetabolized compound for deuterium-substituted structures was compared to that of the parent. In general, deuterium substitution on dihydrofuran ring reduced formation of metabolites arising from its hydroxylation and further ring opening. Deuterium substitution on the ethyl group of amide moiety reduced formation of metabolites arising from hydroxylation at this site. In contrast, hydroxylation of the aromatic ring was not altered by deuterium substitution in any example. Monoamine Oxidase A Inhibition and Oxidative Turnover

[00300] The procedure is carried out using the methods described by Weyler, Journal of Biological Chemistry 1985, 260, 13199-13207, which is hereby incorporated by reference in its entirety. Monoamine oxidase A activity is measured spectrophotometrically by monitoring the increase in absorbance at 314 nm on oxidation of kynuramine with formation of 4-hydroxyquinoline. The measurements are carried out, at 30 °C, in 50mM NaPi buffer, pH 7.2, containing 0.2% Triton X-100 (monoamine oxidase assay buffer), plus 1 mM kynuramine, and the desired amount of enzyme in 1 mL total volume. Monoamine Oxidase B Inhibition and Oxidative Turnover

[00301] The procedure is carried out as described in Uebelhack, Pharmacopsychiatry 1998, 31(5), 187-192, which is hereby incorporated by reference in its entirety. In vitro Human Liver Microsomal Metabolite ID Assay

[00302] In vitro metabolite identification is conducted after incubating compounds (parent compound, final concentration between 1 and 10 µM) with human liver microsomes at 37 ^C in 100 mM potassium phosphate buffer containing 1 mM EDTA in the presence of NADPH or without NADPH (w/o). Samples taken at 0 min and 120 min are quenched by using acetonitrile and analyzed using Xevo G2-S QTof system with positive-ion electrospray ionization. LC-UV-MS extract ion chromatograms (EIC) of the T120min and T0min are compared to identify the major putative metabolites. The MS/MS spectra of compounds were also obtained to facilitate metabolite structure elucidation. Human Pharmacokinetic Study of Tasimelteon and Metabolites

[00303] The procedure is carried out as described in US 8,785,492, which is hereby incorporated by reference in its entirety. Compounds disclosed herein are expected to have pharmacokinetic activity at least as favorable as tasimelteon. Melatonergic Receptor Binding Activity

[00304] The procedure is carried out as described in US 5,856,529, which is hereby incorporated by reference in its entirety. Compounds disclosed herein are expected to bind the melatonin receptor, and more specifically to demonstrate activity as agonists of the melatonin MTi and MT2 receptors.

In Vivo Pharmacokinetic Study of Tasimelteon and Metabolites

[00305] The procedure is carried out as described in Vachharajani et al, J. Pharm. Sci., 2003, 92(4), 760-772, which is hereby incorporated by reference in its entirety. Compounds disclosed herein are expected to have pharmacokinetic activity at least as favorable as tasimelteon.

[00306] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

CLAIMS What is claimed is:

1. A compound of structural Formula Ia

(Ia)

or a salt thereof, wherein:

R₁-R₁₉ are independently chosen from hydrogen and deuterium; and

at least one of R1-R19 is deuterium.

2. The compound, or a salt thereof, as recited in claim 1, wherein R₆ and R₉-R₁₅ are hydrogen.

3. The compound, or a salt thereof, as recited in claim 2, wherein R₉-R₁₅ are hydrogen.

4. The compound, or a salt thereof, as recited in claim 2, wherein R16 and R17 are deuterium.

5. The compound, or a salt thereof, as recited in claim 2, wherein R₁₈ and R₁₉ are deuterium.

6. The compound, or a salt thereof, as recited in claim 2, wherein R16-R19 are deuterium.

7. The compound, or a salt thereof, as recited in claim 2, wherein R₇ and R₈ are deuterium.

8. The compound, or a salt thereof, as recited in claim 2, wherein R7, R8, R16, and R17 are deuterium.

9. The compound, or a salt thereof, as recited in claim 2, wherein R₇, R₈, R₁₈, and R₁₉ are deuterium.

10. The compound, or a salt thereof, as recited in claim 2, wherein R₇, R₈, and R₁₆-R₁₉ are deuterium.

11. The compound, or a salt thereof, as recited in claim 2, wherein R₁-R₅ are deuterium.

12. The compound, or a salt thereof, as recited in claim 2, wherein R1-R5, R7, and R8 are deuterium.

13. The compound, or a salt thereof, as recited in claim 2, wherein R1-R5, R16, and R17 are deuterium.

14. The compound, or a salt thereof, as recited in claim 2, wherein R1-R5, R18, and R19 are deuterium.

15. The compound, or a salt thereof, as recited in claim 2, wherein R₁-R₅ and R₁₆-R₁₉ are deuterium.

16. The compound, or a salt thereof, as recited in claim 2, wherein R₁-R₅, R₇, R₈, R₁₆, and R₁₇ are deuterium.

17. The compound, or a salt thereof, as recited in claim 2, wherein R₁-R₅, R₇, R₈, R₁₈, and R₁₉ are deuterium.

18. The compound, or a salt thereof, as recited in claim 2, wherein R₁-R₅, R₇, R₈, and R₁₆-R₁₉ are deuterium.

19. The compound, or a salt thereof, as recited in any one of claims 1-18, wherein at least one of R1-R19 independently has deuterium enrichment of no less than about 10%.

20. The compound, or a salt thereof, as recited in any one of claims 1-18, wherein at least one of R1-R19 independently has deuterium enrichment of no less than about 50%.

21. The compound, or a salt thereof, as recited in any one of claims 1-18, wherein at least one of R₁-R₁₉ independently has deuterium enrichment of no less than about 90%.

22. The compound, or a salt thereof, as recited in any one of claims 1-18, wherein at least one of R₁-R₁₉ independently has deuterium enrichment of no less than about 98%.

23. The compound as recited in Claim 1 wherein the compound has a structural formula chosen from

Attorney Docket No. APX0262-401-PC

Attorney Docket No. APX0262-401-PC

Attorney Docket No. APX0262-401-PC

Attorney Docket No. APX0262-401-PC

Attorney Docket No. APX0262-401-PC

Attorney Docket No. APX0262-401-PC

,

24. The compound as recited in Claim 1 wherein the compound has a structural formula chosen from

25. The compound as recited in claim 1 wherein the compound has a structural formula chosen from

26. The compound as recited in claim 1 wherein the compound has a structural formula chosen from

, or a salt thereof.

27. The compound as recited in any of claims 23-26, wherein each position represented as D has deuterium enrichment of no less than about 10%.

28. The compound as recited in any of claims 23-26, wherein each position represented as D has deuterium enrichment of no less than about 50%.

29. The compound as recited in any of claims 23-2625, wherein each position represented as D has deuterium enrichment of no less than about 90%.

30. The compound as recited in any of claims 23-26, wherein each position represented as D has deuterium enrichment of no less than about 98%.

31. A pharmaceutical composition comprising a compound, or a salt thereof, as recited any one of claims 1-30, together with a pharmaceutically acceptable carrier.

32. A method of treatment of a melatonin receptor-mediated disorder comprising the

administration of a therapeutically effective amount of a compound, or a salt thereof, as recited any one of claims 1-30 to a patient in need thereof.

33. The method as recited in claim 32 wherein the disorder is chosen from non-24-hour sleep- wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency.

34. The method as recited in claim 32 wherein the disorder is non-24-hour sleep-wake

disorder.

35. The method as recited in claim 32 further comprising the administration of an additional therapeutic agent.

36. The method as recited in claim 35 wherein the additional therapeutic agent is chosen from antipsychotics, antidepressants , or medications having side effects such as sexual side effects, sleep disturbances, and daytime drowsiness.

37. The method as recited in claim 36 wherein the additional therapeutic agent is an

antipsychotic chosen from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, haloperidol, haloperidol decanoate, droperidol, pimozide, amisulpride, aripiprazole, bifeprunox, clozapine, melperone, norclozapine, olanzapine, risperidone, paliperidone, quetapine, symbyax, tetrabenazine, and ziprazidone.

38. The method as recited in claim 36 wherein the additional therapeutic agent is an

antidepressant chosen from amitriptyline, bupropion, citalopram, clomipramine, dapoxetine, desipramine, dothiepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iofepramine, nortriptyline, paroxetine, protriptyline, sertraline, trazodone, trimipramine, and venlafaxine.

39. The method as recited in claim 36 wherein the additional therapeutic agent is a

medications having a side effect chosen from sexual side effects, sleep disturbances, and daytime drowsiness .

40. The method as recited in claim 32, further resulting in at least one effect chosen from:

a. decreased inter-individual variation in plasma levels of the compound or a metabolite thereof as compared to the non-isotopically enriched compound; b. increased average plasma levels of the compound per dosage unit thereof as compared to the non-isotopically enriched compound; c. decreased average plasma levels of at least one metabolite of the compound per dosage unit thereof as compared to the non-isotopically enriched compound;

d. increased average plasma levels of at least one metabolite of the compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

e. an improved clinical effect during the treatment in the subject per dosage unit thereof as compared to the non-isotopically enriched compound.

41. The method as recited in claim 32, further resulting in at least two effects chosen from:

a. decreased inter-individual variation in plasma levels of the compound or a metabolite thereof as compared to the non-isotopically enriched compound; b. increased average plasma levels of the compound per dosage unit thereof as compared to the non-isotopically enriched compound;

c. decreased average plasma levels of at least one metabolite of the compound per dosage unit thereof as compared to the non-isotopically enriched compound;

42. The method as recited in claim 32, wherein the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P450 isoform in the subject, as compared to the corresponding non- isotopically enriched compound.

43. The method as recited in claim 42, wherein the cytochrome P450 isoform is chosen from CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

44. The method as recited in claim 32, wherein the compound is characterized by decreased inhibition of at least one cytochrome P₄₅₀ or monoamine oxidase isoform in the subject per dosage unit thereof as compared to the non-isotopically enriched compound.

45. The method as recited in claim 44, wherein the cytochrome P450 or monoamine oxidase isoform is chosen from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO_A, and MAO_B.

46. The method as recited in claim 32, wherein the method reduces a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non- isotopically enriched compound.

47. The method as recited in claim 46, wherein the diagnostic hepatobiliary function endpoint is chosen from alanine aminotransferase (“ALT”), serum glutamic-pyruvic transaminase (“SGPT”), aspartate aminotransferase (“AST,”“SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,”“γ-GTP,”“GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5’-nucleotidase, and blood protein.

48. A method of treating a demyelinating disease comprising the administration of a

therapeutically effective amount of a compound, or a salt thereof, as recited in any one of claims 1-30 to a patient in need thereof.

49. The method of claim 48, wherein the demyelinating disease is multiple sclerosis.

50. The method of claim 49, wherein the multiple sclerosis is primary progressive multiple sclerosis.

51. A method of treating a neurodegenerative disease comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as recited in any one of claims 1-30 to a patient in need thereof.

52. The method of claim 51, wherein the neurodegenerative disease or disorder is

Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease.

53. The method of claim 52, wherein the multiple sclerosis is primary progressive multiple sclerosis.

54. A method of treating a mitochondrial disease comprising the administration of a

55. A method of reducing demyelination of the corpus callosum comprising the

administration of a therapeutically effective amount of a compound, or a salt thereof, as recited in any one of claims 1-30 to a patient in need thereof.

56. A compound, or a salt thereof, as recited in any one of claims 1-30 for use as a medicament.

57. A compound, or a salt thereof, as recited in any one of claims 1-30 for use in the manufacture of a medicament for the prevention or treatment of a melatonin receptor- mediated disorder.

58. A compound of structural Formula II

(II)

or a salt thereof, wherein:

R20-R40 are independently chosen from hydrogen and deuterium; and

at least one of R₂₀-R₄₀ is deuterium.

59. A compound of structural Formula III

(III)

or a salt thereof, wherein:

R41-R59 are independently chosen from hydrogen and deuterium; and

at least one of R41-R59 is deuterium.