CROSS-REFERENCE TO RELATED APPLICATIONS

[1] This application claims priority to U.S. Provisional Application No. 62/361,870, filed July 13, 2016; and U.S. Provisional Application No. 62/361,835, filed July 13, 2016. The entire contents of each of the aforementioned applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[2] Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the

CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect.

Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme's activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug's metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14: 1-40 ("Foster"); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9: 101-09 ("Fisher")). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher at p. 101).

[8] The effects of deuterium modification on a drug's metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

SUMMARY OF THE INVENTION

[9] This invention relates to deuterated forms of miconazole and pharmaceutically acce table salts thereof. In one aspect, the invention provides a compound of Formula I:

(I), or a pharmaceutically acceptable salt thereof, wherein each of Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is independently selected from hydrogen and deuterium; and at least one of Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and

Y 12 is deuterium. In some embodiments, the compound of Formula I does not include a compound wherein each of Y 1 , Y2 and Y 3 is deuterium and each οί Υ 4, Υ5, Υ6, Υ7, Υ8, Υ9, Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen, a compound wherein each of Y ¹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is deuterium and each of Y ² , Y ³ Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , and Y ⁹ is hydrogen, or a compound wherein each Y ¹ is deuterium, and each of Y ² , Y ³ Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen.

[10] Another aspect of this invention provides compositions comprising a compound of this invention, including pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. Another aspect of this invention provides the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering miconazole. Some exemplary embodiments include a method of treating a disease or condition selected from a fungal infection and a myelin related disorder, the method comprising the step of administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition of the present invention. Another aspect of this invention provides a method of promoting remyelination in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

[11] Miconazole, also known as l-[2-(2,4-Dichlorophenyl)-2-(2,4- dichlorobenzyloxy)ethyl]-lH-imidazole, is a known antifungal agent that acts by inhibiting lanosterol 14-a demethylase (CYP51), a cytochrome P-450 enzyme that converts lanosterol to a precursor of ergosterol. Ergosterol is an essential component of fungal cell membranes, altering the permeability and rigidity of plasma membranes much as cholesterol does in animals. Thus, inhibition of ergosterol synthesis results in increased membrane permeability and leakage of cellular contents.

[12] Miconazole is currently approved in the U.S. in topical form for the treatment of fungal infections, and, in buccal form, for the treatment of oropharyngeal candidal infection, which is more prevalent in young children, infants, HIV patients and head and neck cancer patients treated with radiation. More recently, it has been suggested that miconazole may be able to promote re-myelination in multiple sclerosis (F.J. Najm et ah, Nature, v. 522, pp. 216-220 (2015, and U.S. Patent Application No. 2016/0015707; the contents of these references are incorporated herein by reference).

[13] Other oral and parenteral forms of miconazole have not been approved. Rapid intravenous infusion of miconazole has caused cardiac abnormalities including tachycardia and cardiac arrhythmia. One fatal arrhythmia was reported in a heart transplant patient following IV miconazole (K.C. Coley and J.L. Crain, Pharmacotherapy 1997, 17, pp. 379- 82). Oral administration of miconazole had caused nausea, vomiting and diarrhea (N.S. Lima et al, Proc roy Soc Med 1977 Supplement 1, 70, pp. 35-39).

[14] Thus, despite the beneficial activities of miconazole, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.

Definitions

[15] The term "treat" means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease {e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

[16] As used herein, the term "subject" includes humans and non-human mammals. Non- limiting examples of non-human mammals include mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, apes, pigs, cows, sheep, horses, etc. [17] "Disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. The term "myelin related disorder", as used herein, can include any disease, condition (e.g. , those occurring from traumatic spinal cord injury and cerebral infarction), or disorder related to demyelination, remyelination, or dysmyelination in a subject. A myelin related disorder as used herein can arise from a myelination related disorder or demyelination resulting from a variety of neurotoxic insults. The term

"demyelination" as used herein, refers to the act of demyelinating, or the loss of the myelin sheath insulating the nerves. The term "remyelination" as used herein refers to the process of creating new myelin sheaths on demyelinatedaxons in the CNS. Examples of myelin related disorders involving demyelination include multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, optic neuritis, neuromyelitis optica (Devic' s disease), transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Zika virus infection and Guillain-Barre Syndrome.

[18] It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of miconazole will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada, E et ah , Seikagaku, 1994, 66: 15; Gannes, LZ et ah , Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[19] In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. In some embodiments, when a position is designated specifically as "H" or "hydrogen", the position has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% hydrogen. In some embodiments, when a position is designated specifically as "H" or "hydrogen", the position incorporates <20% deuterium, <10% deuterium, <5% deuterium, <4% deuterium, <3% deuterium, <2% deuterium, or <1% deuterium. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium", the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e. , at least 50.1% incorporation of deuterium). [20] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[21] In other embodiments, a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[22] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 52.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 60%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 67.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 75%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 82.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 90%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 95%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 97.5%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 99%. In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of at least 99.5%.

[23] The term "isotopologue" refers to a species in which the chemical structure differs from a specific compound of this invention only in the isotopic composition thereof.

[24] The term "compound," when referring to a compound of this invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.

[25] The invention also provides salts of the compounds of the invention.

[26] A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to one embodiment, the compound is a pharmaceutically acceptable acid addition salt. In one embodiment the acid addition salt may be a deuterated acid addition salt.

[27] The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

[28] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. In one embodiment, the acids commonly employed to form pharmaceutically acceptable salts include the above-listed inorganic acids, wherein at least one hydrogen is replaced with deuterium.

[29] In some embodiments, the pharmaceutically acceptable salt is a mononitrate salt. In some embodiments the pharmaceutically acceptable salt is a subsalicylate salt.

[30] The compounds of the present invention (e.g. , compounds of Formula I), may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise. As such, compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers. Accordingly, a compound of the present invention may exist as either a racemic mixture or a scalemic mixture, or as individual respective stereoisomers that are substantially free from another possible stereoisomer. "Stereoisomer" refers to both enantiomers and diastereomers. The term "substantially free of other stereoisomers" as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers are present. Methods of obtaining or synthesizing an individual enantiomer for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.

[31] Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[32] The term "stable compounds," as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g. , formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).

[33] "D" and "d" both refer to deuterium. "Tert" and "t-" each refer to tertiary. "US" refers to the United States of America.

[34] "Substituted with deuterium" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms. [35] Throughout this specification, a variable may be referred to generally (e.g. , "each R")

1 2 3

or may be referred to specifically (e.g. , R , R , R , etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.

Therapeutic Compounds

[36] Certain aspects of the present invention provide a compound of Formula I:

(I), or a pharmaceutically acceptable salt thereof, wherein each of Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is independently selected from hydrogen and deuterium, and at least one of Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and

12

Y is deuterium. In some embodiments, the compound of Formula I does not include a

1 2 3 4 5 6 7 8 9 compound wherein each of Y , Y and Y is deuterium and each οί Υ , Υ , Υ , Υ , Υ , Υ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen, a compound wherein each of Y ¹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is deuterium and each of Y ² , Y ³ Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , and Y ⁹ is hydrogen, or a compound wherein each Y ¹ is deuterium, and each of Y ² , Y ³ Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen.

[37] In some embodiments of Formula I, the compound is of Formula la:

(la), or a pharmaceutically acceptable salt thereof, wherein the compound or salt is substantially free of other stereoisomers. In some embodiments, each of Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is independently selected from hydrogen and deuterium, and at least one of Y 1 ,

Y ¹⁰ , Y ¹¹ , and Y ¹² is deuterium. In some embodiments, the compound of Formula la does not include a compound wherein each of Y 1 , Y2 and Y 3 is deuterium and each of Y 4 , Y 5 , Y 6 , Y 7 , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen, a compound wherein each of Y ¹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is deuterium and each of Y ² , Y ³ Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , and Y ⁹ is hydrogen, or a compound wherein each Y ¹ is deuterium, and each of Y ² , Y ³ Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen.

[38] In some embodiments of Formula I, the compound is of Formula lb:

(ib) , or a pharmaceutically acceptable salt thereof, wherein the compound or salt is substantially free of other stereoisomers. In some embodiments, each of Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is independently selected from hydrogen and deuterium, and at least one of Y 1 ,

Y ¹⁰ , Y ¹¹ , and Y ¹² is deuterium. In some embodiments, the compound of Formula Ib does not include a compound wherein each of Y 1 , Y 2 and Y 3 is deuterium and each of Y 4 , Y 5 , Y 6 , Y 7 , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen, a compound wherein each of Y ¹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is deuterium and each of Y ² , Y ³ Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , and Y ⁹ is hydrogen, or a compound wherein each Y ¹ is deuterium, and each of Y ² , Y ³ Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen.

[39] In some embodiments of each of Formulae I, la, and Ib, at least one of Y 1 ¹ , and Y 3 ³ is hydrogen. In some embodiments, at least one of Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ ,

Y 11 , and Y 12 is hydrogen.

[40] In some embodiments of each of Formulae I, la, and Ib, each Y ¹ is the same; and each

Y 2" is the same. In some embodiments each Y 1 is deuterium and each Y2 is hydrogen. In some embodiments, each Y 1 is hydrogen and each Y 2 is deuterium. In some embodiments, each Y 1 is deuterium; and each Y2 is deuterium. In some embodiments, each Y 1 is hydrogen, each Y is hydrogen, and Y is deuterium. In some embodiments, each Y , each Y , and Y

1 2 3

are the same. In some embodiments, each Y , each Y , and Y are hydrogen. In other embodiments, each Y ¹ , each Y ² , and Y ³ are deuterium. In some embodiments, Y ⁴ , Y ⁵ , and Y ⁶ are the same. In some embodiments, Y ⁴ , Y ⁵ , and Y ⁶ are each hydrogen. In other

embodiments, Y ⁴ , Y ⁵ , and Y ⁶ are each deuterium. In some embodiments, Y ⁷ , Y ⁸ , and Y ⁹ are the same. In some embodiments, Y ¹⁰ , Y ¹¹ , and Y ¹² are the same. In some embodiments, Y , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² are the same.

[41] In some embodiments, each Y ¹ is the same; each Y ² is the same; each of Y ⁴ , Y ⁵ , Y ⁶ ,

7 8 9 10 11 12

Y , Y , Y , Y , Y , and Y is hydrogen; and the compound is selected from any one of the compounds set forth in Table 1 (below):

Table 1 : Exemplary Embodiments of Formula I, la, and lb ¹

or a pharmaceutically acceptable salt thereof.

1 3

Y atoms depicted with a wedged bond indicate an enantiomer of a compound of Formula I

3 3

(i.e. , a compound of Formula la) with (R) (wedged Y ) orientation. Y atoms depicted with a dashed bond indicate an enantiomer of a compound of Formula I (i.e. , a compound of Formula lb) with (S) (dashed Y ) orientation. [42] In some embodiments, each Y ¹ is the same; each Y ² is the same; each of Y ⁴ , Y ⁵ , Y ⁶ ,

7 8 9 10 11 12

Y , Y , Y , Y , Y , and Y is deuterium; and the compound is selected from any one of the compounds set forth in Table 2 (below):

Table 2: Exemplary Embodiments of Formula I, la, lb ¹

or a pharmaceutically acceptable salt thereof.

[43] In some embodiments, each Y ¹ is the same; each Y ² is the same; each of Y ⁴ , Y ⁵ , and Y ⁶ is deuterium and each of Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen; and the compound is selected from any one of the compounds set forth in Table 3 (below):

Table 3: Exemplary Embodiments of Formula I, la, and lb

2 3

Y atoms depicted with a wedged bond indicate an enantiomer of a compound of Formula I

3 3

(i.e. , a compound of Formula la) with (R) (wedged Y ) orientation. Y atoms depicted with a dashed bond indicate an enantiomer of a compound of Formula I (i.e. , a compound of Formula lb) with (S) (dashed Y ) orientation. Compound Y Y Y ^J

301-R D H -^D

301-S D H I D

302 H D D

302-R H D -^D

302-S H D ^• " H I D

303 D D H

303-R D D

303-S D D H

304 D H H

304-R D H -^H

304-S D H H

305 H D H

305-R H D -^H

305-S H D H

306 D D D

306-R D D -^D

306-S D D ^• " H I D or a pharmaceutically acceptable salt thereof.

[44] In some embodiments, each Y ¹ is the same; each Y ² is the same; each of Y ⁴ , Y ⁵ , and Y ⁶ is hydrogen and each of Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is deuterium; and the compound is selected from any one of the compounds set forth in Table 4 (below):

Table 4: Exemplary Embodiments of Formula I, la, and lb

or a pharmaceutically acceptable salt thereof.

[45] In some embodiments, any atom not designated as deuterium in any of the

embodiments set forth herein is present at its natural isotopic abundance.

[46] In some embodiments of a compound of this invention, when each Y ¹ is deuterium, the level of deuterium incorporation at each Y ¹ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[47] In some embodiments of a compound of this invention, when each Y is deuterium, the level of deuterium incorporation at each Y is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[48] In some embodiments of a compound of this invention, when Y is deuterium, the level of deuterium incorporation at Y is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[49] In some embodiments of a compound of this invention, when Y ⁴ is deuterium, the level of deuterium incorporation at Y ⁴ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[50] In some embodiments of a compound of this invention, when Y ⁵ is deuterium, the level of deuterium incorporation at Y ⁵ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[51] In some embodiments of a compound of this invention, when Y ⁶ is deuterium, the level of deuterium incorporation at Y ⁶ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[52] In some embodiments of a compound of this invention, when Y is deuterium, the level of deuterium incorporation at Y is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[53] In some embodiments of a compound of this invention, when Y is deuterium, the level of deuterium incorporation at Y is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[54] In some embodiments of a compound of this invention, when Y ⁹ is deuterium, the level of deuterium incorporation at Y ⁹ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%. [55] In some embodiments of a compound of this invention, when Y is deuterium, the level of deuterium incorporation at Y ¹⁰ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[56] In some embodiments of a compound of this invention, when Y ¹¹ is deuterium, the level of deuterium incorporation at Y ¹¹ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[57] In some embodiments of a compound of this invention, when Y 12 is deuterium, the level of deuterium incorporation at Y 12 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[58] In some embodiments of a compound of this invention, deuterium incorporation at each designated deuterium atom is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[59] In some embodiments of a compound of this invention, at least one of Y 1 , Y2 , Y 3 , Y 4 , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen.

[60] The synthesis of compounds of Formula I, Formula la, and Formula lb may be readily achieved by synthetic chemists of ordinary skill by reference to the Exemplary Synthesis and Examples disclosed herein. Relevant procedures analogous to those of use for the preparation of compounds of Formula I and intermediates thereof are disclosed, for instance in DE 1940388 and by Godefroi, E. et ah, Journal of Medicinal

Chemistry (1969), 12(5), 784-91.

[61] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

Exemplary Synthesis

[62] A convenient method for synthesizing compounds of Formula I is depicted in Scheme I, below. Scheme 1: General S nthesis of Compounds of Formula I

(S)-Formula lb (i?)-Formula la

Reagents and conditions: (a) 0°C; (b) NaBH ₄ or NaBD ₄ ; (c) NaH; (d) chiral resolution

[63] In a manner analogous to a procedure described by Godefroi, E. et ah, Journal of Medicinal Chemistry (1969), 12(5), 784-91, excess of appropriately deuterated imidazole (2) is condensed with appropriately deuterated bromoacetophenone intermediate (1) at low temperature to furnish appropriately deuterated imidazolylacetophenone (3). Subsequent reduction of keto moiety in (3) using sodium borohydride or sodium borodeuteride affords correspondingly and appropriately deuterated racemic alcohol intermediate (4). Finally, treatment of sodium salt of (4) with appropriately deuterated benzyl halide intermediate (5) using sodium hydride as base produces appropriately deuterated racemic compounds of Formula (I).

[64] By analogy to a procedure described in DE 1940388 or by Chen, J. et ah , Chirality, 23(3), 228-236; 2011, chiral resolution of compounds of Formula (I) produces appropriately deuterated (S) and (R) enantiomeric compounds of Formula I.

[65] Pharmaceutically acceptable salts of compounds of Formula I may be prepared by adjusting the pH to 1-2 with concentrated acids. For instance, concentrated nitric acid will produce nitrate salts of appropriately deuterated compounds of Formula (I).

[66] Using commercially available reagents and deuterated reagents that can be readily prepared by known methods, compounds of Formula I can be prepared with greater than 90%, greater than 95%, greater than 97%, greater than 98%, or greater than 99% deuterium incorporation at each position designated as D (see below for details).

[67] Appropriately deuterated intermediate (1), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 2.

Scheme 2: Preparation of Intermediate (1)

(6) (8) (1)

Reagents and conditions: (a) A1C1 ₃ , HC1; (b) Br ₂ , Na ₂ C0 ₃

[68] By analogy to a procedure described in CN 102974280, Friedel-Crafts acylation of appropriately deuterated halobenzene intermediate (6) with appropriately deuterated acetyl halide intermediate (7) using a Lewis acid such as aluminum chloride, furnishes appropriately deuterated acetophenone intermediate (8), which is subsequently brominated with bromine in a manner analogous to a procedure described in WO2000069842 or DE 1940388 to produce appropriately deuterated bromoacetophenone intermediate (1). [69] l,3-Dichlorobenzene-d ₄ (98 atom %D) (6a) and Acetyl-d ₃ chloride (99 atom %D) (7a) are commercially available.

[70] Use of appropriately deuterated reagents allows deuterium incorporation at the Y 2 , Y 7 ,

Y 8 , Y 9 positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90,

95, 97, 98, or 99% deuterium incorporation at any Y 2 , Y 7 , Y 8 , and / or Y 9.

[71] Appropriately deuterated intermediate (2) may be prepared according to known procedures: lH-Imidazole-4,5-d2 (2b) and lH-Imidazole-2-d (2c) may be prepared according to a procedure described by Proniewicz, L. et ah, Journal of the American Chemical Society, 111(18), 7050-6; 1989; lH-Imidazole-2,4-d ₂ (2d), by a procedure described by Bruha, A. et al, Journal of the American Chemical Society (1988), 110(18), 6006-14. Imidazole-d ₄ (98 atom %D) intermediate (2a) is commercially available.

[72] Use of appropriately deuterated reagents allows deuterium incorporation at the Y ⁴ , Y ⁵ , Y ⁶ positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90, 95, 97, 98%, or 99% deuterium incorporation at any Y ⁴ , Y ⁵ , and/ or Y ⁶ .

[73] Appropriately deuterated intermediate (5), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 3.

Scheme 3: Pre aration of Intermediate (5)

(6) (9) (5)

[74] In a manner analogous to a procedure described in BE 1005988, chloromethylation of appropriately deuterated halobenzene intermediate (6) with appropriately deuterated chloromethyl carbonate intermediate (9) under Friedel-Crafts alkylation conditions using a Lewis acid such as stannic chloride (SnCl ₄ ) produces appropriately deuterated benzyl halide intermediate (5).

[75] l,3-Dichlorobenzene-d ₄ (98 atom %D) (6a) is commercially available.

[76] Intermediate (9a) is prepared by analogy to a procedure described in CN 103922938 by photochemical reaction of commercially available Dimethyl-d6 carbonate (99 atom %D) with chlorine gas using a photoinitiator such as azobisisobutyronitrile (AIBN). [77] Use of appropriately deuterated reagents allows deuterium incorporation at the Y , Y ¹⁰ , Y ¹¹ , and/or Y ¹² positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90, 95, 97, 98%, or 99% deuterium incorporation at any Y ¹ , Y ¹⁰ , Y ¹¹ , and /or Y ¹² .

[78] The specific approaches and compounds shown above are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name (i.e.,

R 1 , R2 , R 3 , etc.) or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound is within the knowledge of one of ordinary skill in the art.

[79] Additional methods of synthesizing compounds of Formula I and their synthetic precursors, including those within routes not explicitly shown in schemes herein, are within the means of chemists of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene, TW et al, Protective Groups in Organic Synthesis, 3 Ed., John Wiley and Sons (1999); Fieser, L et al., Fieser and Fieser' s Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette, L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[80] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

Pharmaceutical Compositions

[81] Certain aspects of the present invention provide pharmaceutical compositions comprising an effective amount of a compound of Formula I, la, or lb, or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier. In some embodiments, the compound of Formula I, la, or lb does not include a compound wherein each of Y ¹ , Y ² and Y ³ is deuterium and each of Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen, or a compound wherein each of Y ¹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is deuterium and each of Y ² , or a pharmaceutically acceptable salt thereof. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament. [82] Pharmaceutically acceptable carriers, adjuvants, excipients, and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates (e.g. , phosphate-buffered saline, etc.), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[83] If required, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See "Oral Lipid- Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)," David J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006.

[84] Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502.

[85] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g. , using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g. , tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins,

Baltimore, MD (20th ed. 2000).

[86] Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[87] In certain embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In a particular embodiment, the compound is formulated in lipid nanoparticles (see, e.g. , Int J Nanomedicine. 2016; 11 : 441- 447).

[88] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[89] Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[90] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, 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. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[91] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[92] In certain embodiments, injection solutions may be formulated for bolus injection or intravenous infusions.

[93] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[94] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance

bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g. : Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.

[95] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.

Topically-transdermal patches and iontophoretic administration are also included in this invention.

[96] In certain embodiments, topical preparations are formulated as a lotion or cream. In other embodiments, topical preparations are formulated for buccal administration for either immediate or prolonged release (see, e.g., United States patents 6,916,485, 7,651,698 and 8,518,442).

[97] In another embodiment, a composition of this invention further comprises one or more additional therapeutic agents. The additional therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as Miconazole.

[98] Preferably, the additional therapeutic agent is an agent useful in the treatment of a disease or condition selected from a fungal infection or a demyelination disease such as multiple sclerosis.

[99] In some embodiments, the one or more additional therapeutic agents is selected from interferon beta- la, interferon beta- lb, glatiramer acetate, peginterferon beta- la,

teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, natalizumab, and any combination thereof.

[100] In another embodiment, the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described additional therapeutic agents, wherein the compound and additional therapeutic agent(s) are associated with one another. The term "associated with one another" as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).

[101] In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.

[102] The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al., Cancer Chemother. Rep, 1966, 50: 219. Body surface area may be approximately determined from height and weight of the subject. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.

[103] In some embodiments, an effective amount of a compound of this invention can range from 50 mg-3 g, administered 1, 2, or 3 times per day. In one aspect of these embodiments, an effective amount of a compound of this invention for buccal dosing is between 10-100 mg/day. In another aspect of these embodiments, an effective amount of a compound of this invention for oral dosing is between 100-1000 mg, 200-700 mg, or 300-500 mg, dosed one, two, or three times a day. In still another aspect of these embodiments, an effective amount of a compound of this invention for intravenous dosing is between 50-1200 mg, 100-2000 mg, 300-1500 mg, 500- 1000 mg, or 700-2800 mg, dosed one, two, or three times a day. In some embodiments, an effective amount of a compound of this invention for intravenous dosing is 10-40 mg per kg of body weight.

[104] Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for Miconazole.

[105] For pharmaceutical compositions that comprise one or more additional therapeutic agents, an effective amount of the additional therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent.

Preferably, an effective amount is between about 70% and 100% of the normal

monotherapeutic dose. The normal monotherapeutic dosages of these additional therapeutic agents are well known in the art. See, e.g., Wells et ah, eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.

[106] Some of the additional therapeutic agents referenced above will act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the additional therapeutic agent and/or the compound of this invention to be reduced from that required in a monotherapy. This may have the advantage of minimizing toxic side effects of either the additional therapeutic agent of a compound of this invention, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound preparation or formulation. Methods of Treatment

[107] According to another aspect, the invention provides a method of treating a disease or condition that is beneficially treated by miconazole in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound or a composition of this invention. In some embodiments, the compound of Formula I, Formula la, or Formula lb does not include a compound wherein each of Y 1 , Y2 and Y 3 is deuterium and each of Y 4 , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen, or a compound wherein each of Y ¹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is deuterium and each of Y ² , Y ³ Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , and Y ⁹ is hydrogen, or a pharmaceutically acceptable salt thereof. In one embodiment the subject is a patient in need of such treatment. Such diseases include, but are not limited to, fungal infections and myelin related disorders such as myelin related disorders involving demyelination include multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, optic neuritis, neuromyelitis optica (Devic's disease), transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Zika virus infection, and Guillain-Barre Syndrome. In another embodiment, the invention provides a method of treating conditions related to phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2).

[108] According to another aspect, the invention provides a method of treating a disease or condition that is beneficially treated by miconazole in a subject in need thereof, comprising the step of administering to the subject an effective amount of (R)-miconazole (i.e., non- deuterated (R)-miconazole, substantially free of other stereoisomers). According to another aspect, the invention provides a method of treating a disease or condition that is beneficially treated by miconazole in a subject in need thereof, comprising the step of administering to the subject an effective amount of (S) -miconazole (i.e., non-deuterated (S)-miconazole, substantially free of other stereoisomers).

[109] In certain particular embodiments, the method of this invention is used to treat a myelin related disorder selected from multiple sclerosis, Zika virus infection, and Guillain- Barre Syndrome in a subject in need thereof.

[110] In certain particular embodiments, the method of this invention is used to treat multiple sclerosis in a subject in need thereof.

[Ill] In other embodiments, the method of this invention is used to treat a fungal infection in a subject in need thereof.

[112] According to another aspect, the invention provides a method of promoting remyelination in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound or a composition of this invention. In some embodiments, the compound of Formula I, Formula la, or Formula lb does not include a

1 2 3 4 5 6 7 8 9 compound wherein each of Y , Y and Y is deuterium and each οί Υ , Υ , Υ , Υ , Υ , Υ , Y ¹⁰ , Y ¹¹ , and Y ¹² is hydrogen, or a compound wherein each of Y ¹ , Y ¹⁰ , Y ¹¹ , and Y ¹² is deuterium and each of Y ² , Y ³ Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ , and Y ⁹ is hydrogen, or a pharmaceutically acceptable salt thereof.

[113] According to another aspect, the invention provides a method of promoting remyelination in a subject in need thereof, comprising the step of administering to the subject an effective amount of (R)-miconazole (i.e. , non-deuterated (R)-miconazole, substantially free of other stereoisomers). According to another aspect, the invention provides a method of promoting remyelination in a subject in need thereof, comprising the step of administering to the subject an effective amount of (S)-miconazole (i.e. , non-deuterated (S)-miconazole, substantially free of other stereoisomers).

[114] Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).

[115] In another set of embodiments, any of the above methods of treatment comprises the further step of co-administering to the subject in need thereof one or more additional therapeutic agents. In one aspect of these embodiments, the choice of additional therapeutic agent may be made from any additional therapeutic agent known to be useful for coadministration with miconazole. In another aspect of these embodiments, the choice of additional therapeutic agent may be made from any additional therapeutic agent known to be useful for the treatment of multiple sclerosis. Examples of additional therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and an additional therapeutic agent.

[116] The term "co-administered" as used herein means that the additional therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an additional therapeutic agent as described above) or as separate, multiple dosage forms.

Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the additional therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention, comprising both a compound of the invention and an additional therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other additional therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.

[117] Effective amounts of these additional therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et ah, eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan's purview to determine the additional therapeutic agent's optimal effective- amount range.

[118] In one embodiment of the invention, where an additional therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the additional therapeutic agent is not administered. In another embodiment, the effective amount of the additional therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.

[119] In yet another aspect, the invention provides the use of a compound of Formula I, Formula la, or Formula lb alone or together with one or more of the above-described additional therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment in a subject of a disease, disorder or symptom set forth above. Another aspect of the invention is a compound of Formula I, Formula la, or Formula lb for use in the treatment in a subject of a disease, disorder or symptom thereof delineated herein.

Example 1. Evaluation of Metabolic Stability

[120] Microsomal Assay : Human liver microsomes (20 mg/mL) are obtained from

Xenotech, LLC (Lenexa, KS). β -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl ₂ ), and dimethyl sulfoxide (DMSO) are purchased from Sigma- Aldrich. [121] Determination of Metabolic Stability: 7.5 niM stock solutions of test compounds are prepared in DMSO. The 7.5 mM stock solutions are diluted to 12.5-50 μΜ in acetonitrile (ACN). The 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl ₂ . The diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate. A 10 \L aliquot of the 12.5-50 μΜ test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution. The final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 μΜ test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl ₂ . The reaction mixtures are incubated at 37 °C, and 50 \L aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 \L of ice- cold ACN with internal standard to stop the reactions. The plates are stored at 4 °C for 20 minutes after which 100 lL of water is added to the wells of the plate before centrifugation to pellet precipitated proteins. Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio-systems API 4000 mass spectrometer. The same procedure is followed for the non-deuterated counterpart of the compound of Formula I and the positive control, 7-ethoxycoumarin (1 μΜ). Testing is done in triplicate.

[122] Data analysis: The in vitro ti _/2 s for test compounds are calculated from the slopes of the linear regression of % parent remaining (In) vs incubation time relationship.

in vitro t _½ = 0.693/k

k = -[slope of linear regression of % parent remaining (In) vs incubation time]

[123] Data analysis is performed using Microsoft Excel Software.

[124] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative examples, make and utilize the

compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention. The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.