Deuterated MNK inhibitors

Abstract

The present disclosure provides deuterated MNK inhibitor compounds, as well as compositions and methods of use thereof.

Description

DEUTERATED MNK INHIBITORSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 664,303, filed June 26, 2024, the contents of which are hereby incorporated by reference.STATEMENT OF GOVERNMENT INTEREST

[0002] This invention was made with government support under grant No. 1U44NS 115692 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Inadequate treatment of pain is a devastating health problem in the United States. One third of all Americans suffer from some form of chronic pain and a third of these have pain that is resistant to current medical therapies. The economic impact of pain is equally large at approximately $100 billion annually. Opioid or narcotic analgesics, typified by morphine, are the most effective treatments for acute and chronic severe pain. However, their clinical utility is often hampered by the development of analgesic tolerance which requires escalating doses to achieve equivalent pain relief. Furthermore, opioids and narcotic analgesics are often ineffective for neuropathic pain treatment, and patients using these drugs often experience worse quality of life due to the resulting drug-induced sedation, reduced physical activity, constipation, respiratory depression, high potential for addiction, and other side effects.

[0004] Inhibitors of mitogen-activated protein kinase interacting protein kinase (MNK) are a promising alternative to opioid and narcotic analgesics for treatment of neuropathic pain and other indications. Neuropathic pain often involves abnormal nociceptor sensitivity. Nociceptor sensitization may be blocked by inhibiting activity-dependent mRNA translation through mechanistic targeting of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway signals to the eukaryotic translation initiation factor (elF) 4E complex to regulate the sensitization of nociceptors. MNKs phosphorylate the eukaryotic translation initiation factor 4E (eIF4E). Inhibition of MNK has been shown to disrupt the MAPK pathway, thereby decreasing sensitization of nociceptors, which may achieve a therapeutic effect on neuropathic pain.SUMMARY

[0005] The present disclosure provides deuteri um-enriched MNK inhibitors (i.e., MNK inhibitors comprising deuterium at one or more given sites, wherein the percentage or level of deuterium incorporation is greater than its natural isotopic abundance).

[0006] In some embodiments, the present disclosure provides compounds of Formula I:I or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is as defined herein.

[0007] Provided compounds of Formula I are useful as MNK inhibitors. Accordingly, provided compounds are useful for treating MNK-associated diseases, disorders, and conditions, as described herein.

[0008] Many potential drugs suffer from poor absorption, distribution, metabolism and / or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. A potentially attractive strategy for improving a drug’s metabolic properties is deuterium enrichment. Replacing one or more hydrogen atoms with deuterium atoms may result in an improved metabolic profile and reduce unwanted degradation of the compound. In some instances, replacing one or more hydrogen atoms with deuterium atoms results in a compound that is efficacious at a lower dose and / or with less frequent administration. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms a stronger bond with carbon. In some 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 toaffect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[0009] Over recent decades, the effects of deuterium substitution on the rate of metabolism have been reported for a small percentage of approved drugs (see, e.g., Blake, M. I. et al., J Pharm Sci, 1975, 64:367-91; Foster, A. B., Adv Drug Res, 1985, 14:1-40 (“Foster”); Kushner, D. J. et al., Can J Physiol Pharmacol, 1999, 79-88; Fisher, M. B. 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).

[0010] 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. l is a graph showing results of a grimace test in a mouse model of CIPN.

[0012] FIG. 2 is a graph showing results of a von Frey test in a mouse model of CIPN.

[0013] FIG. 3 is a graph showing results of an IL-6 evoked grimace test in mice.

[0014] FIG. 4 is a graph showing results of a grimace score in a mouse migraine model.DETAILED DESCRIPTIONCompounds and Definitions

[0015] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0016] Deuterium (D or2H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes H (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art recognizes that in all chemical compounds with a H atom, the H atom actually represents a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015% should be considered unnatural and, as a result, novel, over their nonenriched counterparts.

[0017] All percentages given for the amount of deuterium present are mole percentages.

[0018] It can be quite difficult in the laboratory to achieve 100% deuteration at any one site of a lab scale amount of compound (e.g., milligram or greater). When 100% deuteration is recited or a deuterium atom is specifically shown in a structure, it is assumed that a small percentage of hydrogen may still be present.

[0019] As used herein, the terms “deuterium-enriched” or “deuterium enrichment” refer to a compound, or a particular site of said compound, which comprises deuterium in an amount that is greater than its natural isotopic abundance (0.015%). Deuterium-enrichment can be achieved by either exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials.

[0020] Unless indicated otherwise, when a D is specifically recited at a position or is shown in a formula, this D represents a mixture of hydrogen and deuterium where the amount (incorporation, abundance, or enrichment) of deuterium is about 50% or greater. In some embodiments, the amount (incorporation, abundance, or enrichment) of deuterium is about 100%. In some embodiments, the incorporation of deuterium is from greater than about 90% up to about 100%. In some embodiments, the incorporation of deuterium is from about 95% to about 100%, or from about 97% to about 100%. As used herein in the context of deuterium enrichment, theterm “about” means ± 2%. Tn compounds provided by the present disclosure, any atom not designated as deuterium is present at its natural isotopic abundance, unless indicated otherwise.

[0021] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19(1977).

[0022] As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0023] As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition.Provided Compounds

[0024] In some embodiments, the present disclosure provides compounds of Formula I:or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is independently H or D, provided that at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D.

[0025] In some embodiments, the present disclosure provides a compound of Formula I-a:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R3, R6, R7, R8, R9, R10, R11, R12, R13, R17, R18, R19, R20, R21, and R22are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.

[0026] In some embodiments, the present disclosure provides a compound of Formula I-b:Lb or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.

[0027] In some embodiments, the present disclosure provides a compound of Formula Lc:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R13, R16, R17, R18, R20, R21, and R22are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.

[0028] In some embodiments, the present disclosure provides a compound of Formula Ld:I-d or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R21, and R22are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.

[0029] In some embodiments, the present disclosure provides a compound of Formula Le:I-e or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18, R19. R20, R21, and R22are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.

[0030] In some embodiments of any Formulae described herein, R1is H or D. In some embodiments, R1is H. In some embodiments, R1is H and at least one of R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R1is D.

[0031] In some embodiments of any Formulae described herein, R2is H or D. In some embodiments, R2is H. In some embodiments, R2is H and at least one of R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R2is D.

[0032] In some embodiments of any Formulae described herein, R3is H or D. In some embodiments, R3is H. In some embodiments, R3is H and at least one of R1, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R3is D.

[0033] In some embodiments of any Formulae described herein, R4is H or D. In some embodiments, R4is H. In some embodiments, R4is H and at least one of R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R4is D.

[0034] In some embodiments of any Formulae described herein, R5is H or D. In some embodiments, R5is H. In some embodiments, R5is H and at least one of R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R5is D.

[0035] In some embodiments of any Formulae described herein, R6is H or D. In some embodiments, R6is H. In some embodiments, R6is H and at least one of R1, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R6is D.

[0036] In some embodiments of any Formulae described herein, R7is H or D. In some embodiments, R7is H. In some embodiments, R7is H and at least one of R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R7is D.

[0037] In some embodiments of any Formulae described herein, R8is H or D. In some embodiments, R8is H. In some embodiments, R8is H and at least one of R1, R2, R3, R4, R5, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R8is D.

[0038] In some embodiments of any Formulae described herein, R9is H or D. In some embodiments, R9is H. In some embodiments, R9is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R9is D.

[0039] In some embodiments of any Formulae described herein, R10is H or D. In some embodiments, R10is H. In some embodiments, R10is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R10is D.

[0040] In some embodiments of any Formulae described herein, R11is H or D. In some embodiments, R11is H. In some embodiments, R11is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R11is D.

[0041] In some embodiments of any Formulae described herein, R12is H or D. In some embodiments, R12is H. In some embodiments, R12is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R12is D.

[0042] In some embodiments of any Formulae described herein, R13is H or D. In some embodiments, R13is H. In some embodiments, R13is H and at least one of R1, R2, R3, R4, R5, R6,R7, R8, R9, R10, R11, R12, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R13is D.

[0043] In some embodiments of any Formulae described herein, R14is H or D. In some embodiments, R14is H. In some embodiments, R14is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R15, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R14is D.

[0044] In some embodiments of any Formulae described herein, R15is H or D. In some embodiments, R15is H. In some embodiments, R15is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R16, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R15is D.

[0045] In some embodiments of any Formulae described herein, R16is H or D. In some embodiments, R16is H. In some embodiments, R16is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R17, R18, R19, R20, R21, and R22is D. In some embodiments, R16is D.

[0046] In some embodiments of any Formulae described herein, R17is H or D. In some embodiments, R17is H. In some embodiments, R17is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R13, R16, R18, R19, R20, R21, and R22is D. In some embodiments, R17is D.

[0047] In some embodiments of any Formulae described herein, R18is H or D. In some embodiments, R18is H. In some embodiments, R18is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R19, R20, R21, and R22is D. In some embodiments, R18is D.

[0048] In some embodiments of any Formulae described herein, R19is H or D. In some embodiments, R19is H. In some embodiments, R19is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R13, R16, R17, R18, R20, R21, and R22is D. In some embodiments, R19is D.

[0049] In some embodiments of any Formulae described herein, R20is H or D. In some embodiments, R20is H. In some embodiments, R20is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R21, and R22is D. In some embodiments, R20is D.

[0050] In some embodiments of any Formulae described herein, R21is H or D. In some embodiments, R21is H. In some embodiments, R21is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R22is D. In some embodiments, R21is D.

[0051] In some embodiments of any Formulae described herein, R22is H or D. In some embodiments, R22is H. In some embodiments, R22is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21is D. In some embodiments, R22is D.

[0052] In some embodiments of any Formulae described herein, R21and R22are H, and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20is D.

[0053] In some embodiments of any Formulae described herein, R18, R21, and R22are H, and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R19, and R20is D.

[0054] In some embodiments of any Formulae described herein, R13, R21, and R22are H, and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R14, R15, R16, R17, R18, R19, and R20is D.

[0055] In some embodiments of any Formulae described herein, R13, R18, R21, and R22are H, and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R14, R15, R16, R17, R19, and R20is D.

[0056] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is as defined in an entry set forth in Table 1 below.Table 1. Exemplary Deuterium-Enriched Compounds

[0057] In some embodiments, the present disclosure provides a compound of Formula I-a, or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R17, R18, R19, R20, R21, and R22is as defined in an entry set forth in Table 2 below.Table 2. Exemplary Deuterium-Enriched Compounds

[0058] In some embodiments, the present disclosure provides a compound of Formula I-b, or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is as defined in an entry set forth in Table 3 below.Table 3. Exemplary Deuterium-Enriched Compounds

[0059] In some embodiments, the present disclosure provides a compound of Formula I-c, or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R\ R6, R7, R8, R9, R10,R11, R12, R13, R14, R13, R16, R17, R18, R20, R21, and R22is as defined in an entry set forth in Table 4 below.Table 4. Exemplary Deuterium-Enriched Compounds

[0060] In some embodiments, the present disclosure provides a compound of Formula I-d, or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R3, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R21, and R22is as defined in an entry set forth in Table 5 below.Table 5. Exemplary Deuterium-Enriched Compounds

[0061] In some embodiments, the present disclosure provides a compound of Formula I-e, or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R3, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18, R19, R20, R21, and R22is as defined in an entry set forth in Table 6 below.Table 6. Exemplary Deuterium-Enriched Compounds

[0062] In some embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, selected from Table 7.Table 7. Exemplary Deuterium-Enriched Compounds

[0063] In some embodiments, the present disclosure provides any compound described herein, wherein the compound comprises one, two, three, four, five, six, seven, eight, nine, ten, or more deuterium atoms (i.e., one or more variables in a Formula depicted herein having deuterium enrichment).

[0064] In some embodiments, each position comprising deuterium has a % deuterium incorporation in an amount of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, about 99.5%, or about 100%. In some embodiments, one, two, three, four, five, six, seven, eight, nine, ten, or more positions of deuterium enrichment each independently has a % deuterium incorporation in an amount of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, about 99.5%, or about 100%.

[0065] In some embodiments, each position comprising deuterium has a % deuterium incorporation in an amount of about 5% to about 99%, about 10% to about 95%, about 15% to about 90%, about 20% to about 85%, about 25% to about 80%, about 30% to about 80%, about 35% to about 75%, about 40% to about 70%, about 30% to about 99%, about 30% to about 95%, about 30% to about 90%, about 50% to about 75%, about 50% to about 99%, about 50% to about 95%, about 50% to about 90%, about 60% to about 99%, about 60% to about 95%, about 60% to about 90%, about 70% to about 99%, about 70% to about 95%, about 70% to about 90%, about 80% to about 99%, about 80% to about 95%, about 80% to about 90%, about 90% to about 99%, or about 90% to about 95%.

[0066] In some embodiments of any Formulae described herein, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22has a % deuterium incorporation of 50% or greater.

[0067] In some embodiments of any Formulae described herein, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22has a % deuterium incorporation of 60% or greater.

[0068] In some embodiments of any Formulae described herein, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22has a % deuterium incorporation of 70% or greater.

[0069] In some embodiments of any Formulae described herein, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22has a % deuterium incorporation of 80% or greater.

[0070] In some embodiments of any Formulae described herein, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22has a % deuterium incorporation of 90% or greater.

[0071] In some embodiments of any Formulae described herein, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22has a % deuterium incorporation of 95% or greater.

[0072] In some embodiments, the present disclosure provides a deuteri um-enriched compound of Formulae I-a or pharmaceutically acceptable salt thereof, wherein a variable indicated as D hasa deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater. In some embodiments, the % deuterium incorporation is about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% or greater.

[0073] In some embodiments, the present disclosure provides a deuterium-enriched compound of Formulae I-b or pharmaceutically acceptable salt thereof, wherein a variable indicated as D has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater. In some embodiments, the % deuterium incorporation is about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% or greater.

[0074] In some embodiments, the present disclosure provides a deuterium-enriched compound of Formulae I-c or pharmaceutically acceptable salt thereof, wherein a variable indicated as D has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater. In some embodiments, the % deuterium incorporation is about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% or greater.

[0075] In some embodiments, the present disclosure provides a deuterium-enriched compound of Formulae I-d or pharmaceutically acceptable salt thereof, wherein a variable indicated as D has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater. In some embodiments, the % deuterium incorporation is about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% or greater.

[0076] In some embodiments, the present disclosure provides a deuterium-enriched compound of Formulae I-e or pharmaceutically acceptable salt thereof, wherein a variable indicated as D has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater. In some embodiments, the % deuterium incorporation is about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% or greater.

[0077] In some embodiments, the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds (such as non-deuterated analogs of the compounds described herein). For example, in some embodiments, provided compounds may perform better in one or more assays described in the Examples herein than, e.g., a non-deuterated analog of the compounds described herein. In some embodiments, provided compounds have improved exposure (e.g., when measured by AUC or Cmax), relative to a non-deuterated analog of the compound. In some embodiments, provided compounds have improved microsomal stability, relative to a non-deuterated analog of the compound. In some embodiments, provided compounds have improved oral bioavailability, relative to a non-deuterated analog of the compound. In some embodiments, provided compounds have an improved plasma half-life, relative to a non-deuterated analog of the compound. In some embodiments, provided compounds are efficacious at a lower dose and / or at a lower dosing frequency, relative to a non-deuterated analog of the compound.Compositions

[0078] The present disclosure also provides compositions that comprise or deliver a compound as provided herein. In some embodiments, the present disclosure provides compositions comprising a compound provided herein with one or more other components.

[0079] In some embodiments, provided compositions comprise and / or deliver a compound described herein (e.g., compounds of Formulae I, I-a, I-b, I-c, I-d, and I-e).

[0080] In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a compound provided herein (e.g., compounds of Formulae I, I-a, I-b, I-c, I-d, and I-e) and further comprises a pharmaceutically acceptable carrier.

[0081] Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and / or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms,suppository, nasal spray and / or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions.

[0082] Provided pharmaceutical compositions can be prepared with any appropriate available technologies.

[0083] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0084] Provided compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that is (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and / or decreasing incidence and / or intensity of) a disease or disorder, for example as described herein.

[0085] The present disclosure also provides methods of preparing pharmaceutical compositions provided herein. In some embodiments, provided methods comprise (i) providing a provided compound or a pharmaceutically acceptable salt thereof; and (ii) formulating the compound with suitable excipients to give a pharmaceutical composition.Uses

[0086] The present disclosure also encompasses uses of provided compounds. In some embodiments, provided compounds are useful in methods of treating MNK-associated diseases, disorders, or conditions.

[0087] In some embodiments, the present disclosure provides methods of administering provided compounds to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds to a subject suffering from or susceptible to a disease, disorder, or condition associated with MNK.

[0088] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with MNK, comprising administering a provided compound to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition, comprising administering a provided compound to a subject in need thereof.

[0089] In some embodiments, provided methods are for treating neuropathic pain. In some embodiments, the present disclosure provides a method of treating neuropathic pain, the method comprising administering a provided compound to a subject in need thereof.

[0090] Neuropathic pain typically develops over time and may benefit from therapies that interfere with pathways involved in its development and / or continuation. Disease or damage causing neuropathic pain may affect the central nervous system (CNS), the peripheral nervous system, or both (as opposed to causes of nociceptive pain, which affect the peripheral nervous system only). Common causes of neuropathic pain include spinal cord injury, multiple sclerosis, central nervous system ischemia, spinal nerve disease, diabetes, other metabolic disorders, herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders, physical trauma to a nerve trunk such as during surgery, peripheral ischemia, peripheral nerve lesions, nerve compression, chemotherapy or other drug-induced nerve damage, radiation injury, arthritis, autoimmune disease, and infection in an area near the affected nerves.

[0091] Neuropathic pain often involves abnormal nociceptor sensitivity. Nociceptors are specialized neurons that detect pain. Nociceptor sensitivity is not fixed; it can change over time. Some causes of neuropathic pain affect nociceptor sensitivity by inducing “peripheral sensitization.” Peripheral sensitization includes spontaneous pathological activity, abnormal excitability, heightened sensitivity to chemical stimuli, heightened sensitivity to thermal stimuli, heightened sensitivity to mechanical stimuli, and any combinations of these. Disruption of peripheral sensitization, either by reducing or preventing such peripheral sensitization in the first place or by reducing the degree of already-developed peripheral sensitization, may therefore treatneuropathic pain. Although the disclosure is not limited to one mechanism of action, MNK inhibitors as disclosed herein (e.g., compounds of Formula I) may disrupt peripheral sensitization.

[0092] MNKs phosphorylate the eukaryotic translation initiation factor 4E (eIF4E). MNKs are a subfamily of Ser / Thr kinases, phylogenetically considered Ca2+ / calmodulin-dependent kinases (CaMKs). MNKs are activated through phosphorylation by the growth factor-stimulated Ras / extracellular signal -regulated kinase pathway and the stress-induced p38 pathway. Nociceptor sensitization may be blocked by inhibiting activity-dependent mRNA translation through mechanistic targeting of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway signal to the eukaryotic translation initiation factor (elF) 4E complex to regulate the sensitization of nociceptors.

[0093] In some embodiments, provided methods are for treating migraine. In some embodiments, the present disclosure provides a method of treating migraine, the method comprising administering a provided compound to a subject in need thereof.

[0094] In some embodiments, provided methods are for treating or preventing pain associated with rheumatoid arthritis. In some embodiments, the present disclosure provides a method of treating or preventing pain associated with rheumatoid arthritis, the method comprising administering a provided compound to a subject in need thereof.

[0095] In some embodiments, provided methods are for treating a disease, disorder, or condition selected from viral infection-induced pain, lupus, COVID-19-related acute respiratory distress syndrome (ARDS), Alzheimer's disease, Huntingdon’s disease, high fat-induced obesity, non-alcoholic fatty liver disease (NAFLD), and Fragile X syndrome. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition selected from viral infection-induced pain, lupus, COVID-19-related acute respiratory distress syndrome (ARDS), Alzheimer's disease, Huntingdon’s disease, high fat-induced obesity, non-alcoholic fatty liver disease (NAFLD), and Fragile X syndrome, the method comprising administering a provided compound to a subject in need thereof.

[0096] In some embodiments, provided compositions are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound of Formula I, I-a, I-b, I-c, I-d, or I-e) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single doseof the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for a solid pharmaceutical composition (e.g., a capsule or a tablet) containing a predetermined amount of an active agent (e g., a compound of Formula I, I-a, I-b, I-c, I-d, or I-e).

[0097] Provided compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and / or decreasing incidence and / or intensity of) a disease or disorder, for example, as described herein.

[0098] In some embodiments, provided compositions are administered orally.EXAMPLESExample 1. Synthesis of Compound 1

[0099] Compound 1 was prepared according to the following scheme:

[0100] A 10 mL microwave reaction vial was charged with Int-1, described in WO2023 / 014943, (0.019 g 0.049 mmol), deuterated methyl boronic acid Int-2 (0.009 g, 0.147 mmol),Pd(OAc)2 (0.001 g, 0.005 mmol), tricyclohexylphosphine tetrafluoroboroate salt (0.004 g, 0.010 mmol), K3PO4 (0.031 g, 0.147 mmol) and 1,4-di oxane: water (9: 1; 3.2 mL). The mixture was degassed and then sealed under N2 and irradiated (30 min, 140 °C, Anton Paar Monowave 300). Water (10 mL) and chloroform :isopropanol (3: 1; 20 mL) were added to the reaction mixture. The layers were separated and the aqueous layer was extracted with additional chlorofornrisopropanol (3:1; 2 x 20 mL). The organic layers were combined and concentrated in vacuo to about 10 mL. The 10 mL solution was divided among 10 prep plates (SiCL, 20 cm x 20 cm, 1000 micron thickness) that were eluted with chloroform:0.25M NH3 in MeOH (19: 1) to afford Compound 1(9.2 mg, 50%). ‘H NMR (400 MHz, DMSO) 8 10.05 (s, 1H), 8.63 (s, 1H), 8.40 (s, 1H), 8.18 (s, 1H), 6.51 (s, 2H), 6.15 (s, 1H), 3.30 - 3.18 (m, 1H), 2.23 - 2.09 (m, 2H), 1.51 - 1.32 (m, 2H), 0.97 - 0.84 (m, 2H), 0.47 - 0.36 (m, 2H), 0.36 - 0.27 (m, 2H). HPLC-MS (ESI): m / z 370.5 [M+H]+.Example 2. Biological Evaluation of Compound 1

[0101] Compound 1 had an IC50 value of 114 nM against MNK1 and 4.9 nM against MNK2 in the following assay, measuring inhibition of MNK: Recombinant full-length human kinase MNK1 or MNK2 was expressed in insect cells. In a radiometric activity assay, the test compound was incubated with MNK1 or MNK2 kinase, substrate, cofactors, and radioisotope-labeled ATP, and % kinase activity determined based upon the extent of substrate phosphorylation.

[0102] Compound 1 had an IC50 value of 6.5 nM in the following HEK cell assay: The ability of Compound 1 to inhibit eIF4E phosphorylation at Serine 209 in the human embryonic kidney (HEK) 293 cell line was tested by exposing the cells to compound for 2 hours and then measuring eIF4E phosphorylation with a phosphorylation-specific antibody in a fluorescent plate reader. These experiments were done with HEK-293 cells plated on 96 well plates. Following treatment, cells were fixed with ice cold methanol for 10 min and then washed in IX phosphate buffered saline (PBS) and the permeabilized with 0.02% Triton X-100 in 10% normal goat serum made up in PBS. Primary antibody was applied overnight at a concentration dilution of 1 :2000 (p-eIF4E antibody from Cell Signaling ab76256). Following washing, cells were then exposed to secondary antibody conjugated to alexa-fluor 488 and then visualized on a Syngergy HTX plate reader. Fluorescence for p-eIF4E was measured and normalized to total DAPI fluorescence to determine the percentage of eIF4E phosphorylation in each well. Data were plotted in Graphpad Prism V8 to determine concentration-response effects and calculate IC50 values.Example 3. Pharmacokinetic Studies of Compound 1

[0103] A pharmacokinetic study of Compound 1 was conducted in nine Sprague-Dawley rats, using two oral dosing groups (Groups 1 and 2) and one IV dosing group (Group 3). Three rats per group were used. Groups 1 and 2 were dosed with Compound 1 (1.0 mg / kg; 0.11 mg / mL) as a suspension in deionized water with 0.5% (w / v) hydroxypropyl methylcellulose (HPMC). Prior to dosing, the pH of the suspension was adjusted to approximately pH = 5 using 1 N HC1. Group 3 was dosed with Compound 1 (0.5 mg / kg; 0.11 mg / mL) as a solution in 10% dimethyl isosorbide,15% ethanol, 35% propylene glycol and 40% normal saline. Plasma was collected at time-points 0.03 (IV only), 0.08 (PO only), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hr post-dose and was analyzed for concentrations of Compound 1.

[0104] Results of PK studies in rats are summarized in Table 3.1.Table 3.1.

[0105] Microsomal stability in mouse and liver microsomes was assessed for Compound 1. A sample of Compound 1 at a final concentration of 1 pM was prepared in 25 mM potassium phosphate buffer with mouse and human liver microsomes at a final concentration of 0.5 mg / mL. The enzyme reaction was initiated by the addition of NADPH reagent at a final concentration of 1 mM. For negative control samples, NADPH reagent was not added. All samples were incubated at 37 °C on a 50-RPM orbital shaker, and an aliquot was removed at pre-determined timepoints (0, 5, 10, 15, 30, and 60 minutes). Samples were precipitated with three volumes of acetonitrile containing propranolol as internal standard, and centrifuged for 10 min at 2000 g before LC / MS / MS analysis of the supernatant solutions. Percent parent compound remaining was determined relative to 0-minute incubation samples for each replicate, from which the eliminationhalf-life was calculated based on the natural log of % compound remaining vs. time plot. The following parameters were calculated to estimate the compound’s in vitro metabolic stability:1. CmP= concentration of microsomal proteins (mg / mL)2. TI / 2 = the half-life (min), where T1 / 2 is equal to 0.693 / slope3. CLmt = the intrinsic hepatic clearance (uL / min / mg), where CLint is equal to 0.693 / (Ti / 2 XCmp)

[0106] Results of liver microsome studies are summarized in Table 3.2.Table 3.2.

[0107] The brain-to-plasma ratio of Compound 1 in male Sprague Dawley rats was approximately 0.17 (six hours after administering a 1 mg / kg PO dose). Data are summarized in Table 3.3. Plasma and brain LLOQ = 1.826 ng / mL.Table 3.3.Example 4. Chemotherapy Induced Peripheral Neuropathy (CIPN) Mouse Model

[0108] Compound 1 was screened for efficacy in relieving chemotherapy induced peripheral neuropathy (CIPN) by measuring nociceptive behaviors using von Frey testing and the mouse grimace scale. Paclitaxel was provided as a powder (Sigma-Aldrich cat# Y0000698) and reconstituted at 8 mg / mL in 1 : 1 Kollipher:Ethanol (Kolliphor EL, Millipore Sigma cat# C5135). The solution was diluted in IX DPBS, no calcium, no magnesium (Gibco cat# 14190235) at time of injection. Working solution was prepared fresh at time of injections at a concentration of 0.8 mg / mL for an injection volume 5 times the animal’s weight in grams. ICR (CD-I) mice were bred in-house or sourced from Envigo or Charles River, housed on a 12 hr light / dark cycle and had access to food and water ad libitum. Experiments were performed only during the light cycle. 8-16-week-old animals were used. Animals were administered 4 mg / kg paclitaxel intraperitoneally every other day for a total of 4 doses (16 mg / kg cumulative). Tactile hypersensitivity was confirmed on Day 0, after CIPN had been established. On Days 0 - 6, animals were given an oral injection of drug (10 mg / kg) or vehicle daily. Animals were habituated to Plexiglas chambers with wire mesh bottoms for at least one hour prior to any testing. Baseline scores were taken for von Frey testing using the up-down method as described by Chaplan et al., 1994. Von Frey testing was done on Day 0 (30 days after the start of paclitaxel injections) to confirm CIPN. Additional von Frey testing was done on days 2 - 4, 6 and 7. On Day 0, animals were also scored on the Mouse Grimace Scale as described by Langford et al., 2010 (2), as well as on days 2 - 4 and 7. All behavioral testing was done blinded.

[0109] Results of the grimace test are shown in FIG. 1, and results of the von Frey test are shown in FIG. 2.Example 5. IL-6 Evoked Grimace Test

[0110] Compound 1 was screened for affective pain-relief in a high throughput mouse behavioral model using grimace scoring. Grimace scoring was performed as described in Langford, et al., 2010 (1). Mice were habituated to Plexiglas chambers with wire mesh bottoms for at least thirty minutes prior to any behavioral testing. Baseline scores were taken up to one week prior to experiment. At time of experiment, vehicle or drug was administered orally (PO) via flexible plastic feeding tubes (Instech Laboratories cat# FTB-20-38). Animals were returned to their home cages after vehicle / drug injections. After one hour, all animals were given a 20 pL intraplantar injection of recombinant human IL-6 protein (0.1 ng dose, R&D Systems cat# 206- IL-050) in the left hind paw using a microliter syringe (Hamilton cat# 80501 or 80401) and 30G needle (BD cat# 305106). Animals were then placed back into the Plexiglass chambers for scoring at 1 and 3 hours post IL-6 injection by blinded scorers. IL-6 was prepared according to manufacturer's instructions and diluted to 5 ng / mL in sterile saline (Teknova cat# S5819) at time of experiment. The working solution was kept on ice until time of injection. Animals were aged 8 to 16 weeks. CD-I wild-type mice were purchased from Envigo, Charles River, or bred in house. All animals were housed on a 12-hour light / dark cycle and had access to food and water ad libitum, with experiments performed only during the light cycle. Grimace score was calculated by averaging the score of each category and from all scorers. Animals with a baseline score higherthan 1 .0 were excluded from experiments. Grimace scores were analyzed via two-way ANOVA with Sidak’s multiple comparisons test. Effect size was calculated as the cumulative difference from baseline for each time point. Statistical analysis was done using unpaired t test.

[0111] Results of the IL-6 evoked grimace test are shown in FIG. 3.Example 6. Mouse Migraine Model

[0112] Compound 1 was screened for affective pain relief in a mouse migraine model using grimace scoring. Compound 1 was efficacious in alleviating grimacing as compared to vehicle group back to the level of baseline scores. Grimace scoring was performed as described in Langford, et al., 2010. Animals were habituated to Plexiglas chambers with wire mesh bottoms for at least thirty minutes prior to any behavioral testing. Baseline scores were taken up to one week prior to experiment. At time of experiment, vehicle or drug was administered orally (PO) via flexible feeding tubes (Instech Laboratories cat# FTB-20-38). Animals were returned to their home cages after vehicle / drug injections. After one hour, all animals were given a 5 pL dural injection of alpha-rat calcitonin gene-related peptide (CGRP) (1.0 pg dose, Bachem cat# 4025897.0500). Animals were then placed back into the Plexiglass chambers for scoring at 1 and 3 hours post CGRP injection by blinded scorers. Mouse dural injections were performed as previously described. Mice were anesthetized under isoflurane for <2 min <2.5%-3% isoflurane. While anesthetized, drugs were injected in a volume of 5 pL in a modified internal cannula (Invivol, part #8IC313ISPCXC, Internal Cannula, standard, 28 gauge, fit to 0.5 mm). The inner projection of the cannula was used to inject through the soft tissue at the intersection of the lambdoidal and sagittal sutures. The length of the projection was adjusted, using calipers, to be 0.6 mm as to not puncture the dura. CGRP stock solution was prepared in ddELO (1 mg / mL) and then diluted to 0.2 pg / pL in synthetic interstitial fluid (SLF) consisting of 135 mm NaCl, 5 mm KC1, 10 mm HEPES, 2 mm CaCL, 10 mm glucose, 1 mm MgCh (pH 7.4, 310 mOsm) at time of experiment. The working solution was kept on ice until time of experiment. Female mice aged 6-8 weeks were used in the experiment. ICR (CD-I) wild-type mice were purchased from Envigo, Charles River, or bred in house. All animals were housed on a 12-hour light / dark cycle and had access to food and water ad libitum, with experiments performed only during the light cycle.

[0113] Results of the grimace score in the mouse migraine model are shown in FIG. 4.

[0114] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is independently H or D, provided that at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22is D.

2. The compound of claim 1, wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R14, R15, R16, R17, R19, and R20is D.

3. The compound of claim 1 or 2, wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22has a % deuterium incorporation of about 50% or greater.

4. The compound of claim 1 or 2, wherein at least one of R1, R2, R3, R4, R , R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22has a % deuterium incorporation of about 80% or greater.

5. The compound of claim 1 or 2, wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22has a % deuterium incorporation of about 90% or greater.

6. The compound of claim 1 or 2, wherein at least one of R1, R2, R3, R4, R , R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, and R22has a % deuterium incorporation of about 95% or greater.

7. The compound of claim 1, wherein the compound is a compound of Formula La:I-a or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein the compound is compound of Formula b:Lb or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein the compound is compound of Formula I-c:I-c or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein the compound is compound of Formula I-d:I-d or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein the compound is compound of Formula I-e:or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein the compound is selected from Table 7, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, wherein the compound is:or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 7-13, wherein each position indicated as “D” has a % deuterium incorporation of about 50% or greater.

15. The compound of any one of claims 7-13, wherein each position indicated as “D” has a % deuterium incorporation of about 80% or greater.

16. The compound of any one of claims 7-13, wherein each position indicated as “D” has a % deuterium incorporation of about 90% or greater.

17. The compound of any one of claims 7-13, wherein each position indicated as “D” has a % deuterium incorporation of about 95% or greater.

18. A pharmaceutical composition comprising the compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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