Deuterated compounds and uses thereof

Abstract

The present invention provides deuterium-enriched tyrosine-protein kinase 2 (TYK2) inhibitors, pharmaceutical compositions, and methods of using such deuterium-enriched tyrosine-protein kinase 2 (TYK2) inhibitors and pharmaceutical compositions to treat, prevent, or ameliorate a disease, disorder, or condition mediated by TYK2.

Description

PAT27218PCT01 DEUTERATED COMPOUNDS AND USES THEREOF TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to deuterated analogues of a tyrosine-protein kinase 2 (TYK2) inhibitor. The invention also provides pharmaceutically acceptable compositions comprising the compounds and methods of treating disorders using the same. BACKGROUND OF THE INVENTION

[0002] Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0003] In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on / off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), interleukin-12 (IL-12), interleukin-23 (IL-23), and tumor necrosis factor ^ (TNF-^)), and growth factors (e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

[0004] Many diseases are associated with abnormal cellular responses triggered by kinase- mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, some cancers, cardiovascular diseases, allergies and asthma, Alzheimer’s disease, and hormone-related diseases.

[0005] TYK2 catalyzes the phosphorylation of STAT proteins downstream of a number of cytokine receptors, including the Type I interferon receptor and the IL-12 and IL-23 receptors. 1 61651714.1PAT27218PCT01 The activation of TYK2-dependent receptors by their cytokine ligands results in the activation of STAT-dependent transcription and cellular functional responses specific for the receptors and cell types on which they are expressed. The cytokine signaling pathways regulated by TYK2 play key roles in several immune-mediated disorders. The cytokine IL-12 is essential for the development of Type 1 T-helper cells (Th1) which produce interferon-gamma, a major effector molecule in systemic autoimmune disorders such as systemic lupus erythematosus. The cytokine IL-23 is central for the expansion and survival of Th17 cells and innate lymphoid cells, both of which have been shown to play key pathogenic roles in autoimmunity. IL-23 stimulation drives the production of key proinflammatory cytokines by Th17 cells, including IL-17A, IL-17F, and IL-22, all of which are effector molecules important for pathogenesis of conditions such as psoriasis, psoriatic arthritis, and ankylosing spondylitis. Inhibition of TYK2 would be expected to impact multiple immune-mediated disorders through its effects on the IL-23 / Th17 / Th22 axis, IL-12-mediated Th1 functions, and Type I interferon-driven modulation of diverse immune pathways and cell types.

[0006] Compound 1: is a TYK2 inhibitor previouslyU.S. Patent No.11,046,698.

[0007] 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. 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 2 61651714.1PAT27218PCT01 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.

[0008] Over recent decades, 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, 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).

[0009] 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.

[0010] Finally, deuterated compounds are also useful in the quantitative analytical chemical space employing mass spectrometry. Providing deuterated versions having a different mass from their non-deuterated counterparts allowed the use of the deuterated, heavier analogue as an internal standard when quantification of a sample of the non-deuterated counterpart is needed. SUMMARY OF THE INVENTION

[0011] In one aspect, the present invention provides a compound of formula I: 3 61651714.1PAT27218PCT01 or a pharmaceutically acc1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, and R24is as defined herein.

[0012] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, and conditions, such as those mediated by TYK2. Such diseases, disorders, and conditions include those described herein. DETAILED DESCRIPTION OF THE INVENTION 1. General Description of Certain Aspects of the Invention

[0013] The present invention provides compounds, compositions, and methods for treatment, prevention, and / or reduction of a risk of diseases, disorders, or conditions such as those mediated by TYK2 or a mutant thereof. In some embodiments, such compounds include those of the formulae described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein and described in embodiments.

[0014] In one aspect, the present invention provides a compound of Formula I: 4 61651714.1PAT27218PCT01 or a pharmaceutically acc 12each of R , R , R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, and R24is 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, R22, R23, and R24is D.

[0015] In another aspect, the present invention provides a compound of Formula I’: or a pharmaceutically acceach of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R23, and R24is independently H or D; and R20, R21, and R22are H; 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, R23, and R24is D. 2. Definitions 5 61651714.1PAT27218PCT01

[0016] The term “compound” refers to a quantity of molecules that is sufficient to be weighed, tested for its structural identity, and to have a demonstrable use (e.g., a quantity that can be shown to be active in an assay, an in vitro test, or in vivo test, or a quantity that can be administered to a patient and provide a therapeutic benefit).

[0017] 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 isotopes1H (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 non- enriched counterparts.

[0018] All percentages given for the amount of deuterium present are mole percentages.

[0019] 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. 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% (i.e., the % incorporation of deuterium ranges from greater than 90% up to 100%). In certain embodiments, the incorporation of deuterium in D is from 95% to 100%, or from 97% to 100%. As used herein in the context of deuterium enrichment, the term “about” means ± 2%. In compounds provided by the present invention, any atom not designated as deuterium is present at its natural isotopic abundance, unless indicated otherwise.

[0021] The term “patient” refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like). In some embodiments, the patient is a human.

[0022] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results. An effective amount can be administered in 6 61651714.1PAT27218PCT01 one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0023] “Therapeutically effective amount” includes an amount of a compound of the invention that is effective when administered alone or in combination to treat the desired condition or disorder. “Therapeutically effective amount” includes an amount of a combination of compounds claimed that is effective to treat the desired condition or disorder. The combination of compounds can be additive and is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul.1984, 22:27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower incidence of adverse side effects and / or toxicity, increased efficacy, or some other beneficial effect of the combination compared with the individual components.

[0024] The invention provides deuterium-enriched compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of treating a disease, disorder, or condition using a deuterium-enriched compound or pharmaceutically acceptable salt thereof described herein. The deuterium-enriched compounds described herein contain deuterium enrichment at one or more positions. Deuterium enrichment at a chiral center of the compound reduces the rate at which the two enantiomers of the compound may interconvert. Further, the deuterium-enriched compounds may be provided in enantiomerically pure form. These features are contemplated to provide therapeutic agents with improved properties.

[0025] Compounds of this invention include those described generally above, 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 invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, 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. 7 61651714.1PAT27218PCT01 and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0026] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0027] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0028] In other embodiments, the compound of Formula I is freebase. In other embodiments, the compound of Formula I is not a salt.

[0029] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double 8 61651714.1PAT27218PCT01 bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. 3. Description of Exemplary Compounds

[0030] Complete deuteration, or 100% deuteration, at any one site can be difficult to achieve in the laboratory. When a deuterium atom is indicated at a given site on any compound described herein, it is understood that a small percentage of hydrogen may still be present. Such compounds are said to be enriched with deuterium. Typically, deuterium-enriched compounds are prepared via chemical synthesis utilizing appropriately enriched starting materials or by exchange of H atoms for D atoms using deuterium-containing reagents. 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%). Accordingly, in some embodiments, the present invention provides compounds comprising deuterium at a given site, wherein the percentage or level of deuterium incorporation is greater than its natural isotopic abundance.

[0031] According to one aspect, the present invention provides a compound of Formula I: or a pharmaceutically acceach of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, and R24is 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, R22, R23, and R24is D. 9 61651714.1PAT27218PCT01

[0032] In some embodiments, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R23, and R24is D.

[0033] In another aspect, the present invention provides a compound of Formula I’: or a pharmaceutically acceach of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R23, and R24is independently H or D; and R20, R21, and R22are H; 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, R23, and R24is D.

[0034] In some embodiments, the present invention provides a compound of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, I-n, or I-o: 10 61651714.161651714.11261651714.1PAT27218PCT01 I-oor a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein, either singly or in combination.

[0035] The following embodiments are applicable to each of the preceding formulae.

[0036] As defined above and described herein, R1is H or D.

[0037] 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, R23, and R24is D. In some embodiments, R1is D.

[0038] As defined above and described herein, R2is H or D.

[0039] 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, R23, and R24is D. In some embodiments, R2is D.

[0040] As defined above and described herein, R3is H or D.

[0041] 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, R23, and R24is D. In some embodiments, R3is D.

[0042] As defined above and described herein, R4is H or D.

[0043] 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, R23, and R24is D. In some embodiments, R4is D.

[0044] As defined above and described herein, R5is H or D.

[0045] 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, R23, and R24is D. In some embodiments, R5is D.

[0046] As defined above and described herein, R6is H or D. 13 61651714.1PAT27218PCT01

[0047] 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, R23, and R24is D. In some embodiments, R6is D.

[0048] As defined above and described herein, R7is H or D.

[0049] 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, R23, and R24is D. In some embodiments, R7is D.

[0050] As defined above and described herein, R8is H or D.

[0051] In some embodiments, R8is D. 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, R23, and R24is D.

[0052] As defined above and described herein, R9is H or D.

[0053] In some embodiments, R9is D. 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, R23, and R24is D.

[0054] As defined above and described herein, R10is H or D.

[0055] In some embodiments, R10is D. 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, R23, and R24is D.

[0056] As defined above and described herein, R11is H or D.

[0057] In some embodiments, R11is D. 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, R23, and R24is D.

[0058] As defined above and described herein, R12is H or D.

[0059] In some embodiments, R12is D. 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, R23, and R24is D.

[0060] As defined above and described herein, R13is H or D.

[0061] In some embodiments, R13is D. 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, R23, and R24is D.

[0062] As defined above and described herein, R14is H or D.

[0063] In some embodiments, R14is D. 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, R23, and R24is D.

[0064] As defined above and described herein, R15is H or D.

[0065] In some embodiments, R15is D. 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, R23, and R24is D.

[0066] As defined above and described herein, R16is H or D.

[0067] In some embodiments, R16is D. 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, R23, and R24is D.

[0068] As defined above and described herein, R17is H or D. 14 61651714.1PAT27218PCT01

[0069] In some embodiments, R17is D. In some embodiments, R17is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18, R19, R23, and R24is D.

[0070] As defined above and described herein, R18is H or D.

[0071] In some embodiments, R18is D. 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, R23, and R24is D.

[0072] As defined above and described herein, R19is H or D.

[0073] In some embodiments, R19is D. In some embodiments, R19is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R23, and R24is D.

[0074] As defined above and described herein, R20is H or D.

[0075] In some embodiments, R20is D. 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, R22, R23, and R24is D.

[0076] As defined above and described herein, R21is H or D.

[0077] In some embodiments, R21is D. 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, R22, R23, and R24is D.

[0078] As defined above and described herein, R22is H or D.

[0079] In some embodiments, R22is D. 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, R21, R23, and R24is D.

[0080] As defined above and described herein, R23is H or D.

[0081] In some embodiments, R23is D. In some embodiments, R23is 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 R24is D.

[0082] As defined above and described herein, R24is H or D.

[0083] In some embodiments, R24is D. In some embodiments, R24is 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 R23is D.

[0084] In some embodiments, R20, R21, and R22are H.

[0085] In some embodiments, the present invention provides a compound of any one of Formulae I, I’, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, I-n, and I-o, or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, and R4is as defined above and described herein, and wherein each of R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R23, and R24is as defined in an entry set forth in Table 1, below, or a pharmaceutically acceptable salt thereof. 15 61651714.1PAT27218PCT01 Table 1. Exemplary Deuterium-Enriched Compounds. Entry R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R23R241 H H H H H H H H H H H H H H H H H 2 D D D H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H16 61651714.1PAT27218PCT01 Entry R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R23R2447 D D D D D D D D H H H H D D D H H 48 D D D D D D D D H H H H D D D H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H61651714.1PAT27218PCT01 Entry R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R23R2495 H H H D D D D D D D D D H H H D H 96 D D D D D D D D D D D D H H H D H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H61651714.1PAT27218PCT01 Entry R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R23R24143 D D D D D H H H H H H H H H H H H 144 H H H D D D D D H H H H H H H H H H H H H H H H H D D D D D D D D D D D D D D D D D D H H H H H H H H H H H H H H H H H H D D61651714.1PAT27218PCT01 Entry R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R23R24191 D D D H H H H H D D D D D D D D D 192 H H H H H D D D D D D D D D D D D D D D D D D D D D H H H H H H H H H H H H H H H H H H D D D D D D D D D D D D D D D D D D H61651714.1PAT27218PCT01 Entry R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R23R24239 D D D H H H H H H H H H D D D H H 240 D D D H H H H H H H H H D D D H H H H H H H H H H H H H H H H H D D D D D D D D D D D D D

[0086] In some embodiments, at least one of R , R , R , and R has a % deuterium incorporation of 50% or greater. In some embodiments, at least two of R1, R2, R3, and R4has a % deuterium incorporation of 50% or greater. In some embodiments, at least three of R1, R2, R3, and R4has a % deuterium incorporation of 50% or greater. In some embodiments, each of R1, R2, R3, and R4has a % deuterium incorporation of 50% or greater.

[0087] In some embodiments, at least one of R1, R2, R3, and R4has a % deuterium incorporation of 70% or greater. In some embodiments, at least two of R1, R2, R3, and R4has a % deuterium incorporation of 70% or greater. In some embodiments, at least three of R1, R2, R3, and R4has a % deuterium incorporation of 70% or greater. In some embodiments, each of R1, R2, R3, and R4has a % deuterium incorporation of 70% or greater. 21 61651714.1PAT27218PCT01

[0088] In some embodiments, at least one of R1, R2, R3, and R4has a % deuterium incorporation of 80% or greater. In some embodiments, at least two of R1, R2, R3, and R4has a % deuterium incorporation of 80% or greater. In some embodiments, at least three of R1, R2, R3, and R4has a % deuterium incorporation of 80% or greater. In some embodiments, each of R1, R2, R3, and R4has a % deuterium incorporation of 80% or greater.

[0089] In some embodiments, at least one of R1, R2, R3, and R4has a % deuterium incorporation of 90% or greater. In some embodiments, at least two of R1, R2, R3, and R4has a % deuterium incorporation of 90% or greater. In some embodiments, at least three of R1, R2, R3, and R4has a % deuterium incorporation of 90% or greater. In some embodiments, each of R1, R2, R3, and R4has a % deuterium incorporation of 90% or greater.

[0090] In some embodiments, at least one of R1, R2, R3, and R4has a % deuterium incorporation of 95% or greater. In some embodiments, at least two of R1, R2, R3, and R4has a % deuterium incorporation of 95% or greater. In some embodiments, at least three of R1, R2, R3, and R4has a % deuterium incorporation of 95% or greater. In some embodiments, each of R1, R2, R3, and R4has a % deuterium incorporation of 95% or greater.

[0091] In some embodiments, the present invention provides a deuterium-enriched compound or pharmaceutically acceptable salt thereof of Formula I, I’, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, or I-o, wherein a variable indicated as D in Table 1, has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater; or about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 99.5% or greater.

[0092] In some embodiments, the present invention provides a compound selected from those recited in Table 1, or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the present invention provides a compound of Formula II- a, II-b, II-c, II-d, II-e, II-f, or II-g: 22 61651714.1PAT27218PCT0123 61651714.1PAT27218PCT01 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein, either singly or in combination.

[0094] The following embodiments are applicable to each of the preceding formulae.

[0095] As defined above and described herein, R1is H or D.

[0096] 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, R23, and R24is D. In some embodiments, R1is D.

[0097] As defined above and described herein, R2is H or D.

[0098] 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, R23, and R24is D. In some embodiments, R2is D.

[0099] As defined above and described herein, R3is H or D.

[0100] 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, R23, and R24is D. In some embodiments, R3is D.

[0101] As defined above and described herein, R4is H or D.

[0102] 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, R23, and R24is D. In some embodiments, R4is D.

[0103] As defined above and described herein, R5is H or D.

[0104] 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, R23, and R24is D. In some embodiments, R5is D.

[0105] As defined above and described herein, R6is H or D.

[0106] 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, R23, and R24is D. In some embodiments, R6is D.

[0107] As defined above and described herein, R7is H or D.

[0108] 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, R23, and R24is D. In some embodiments, R7is D.

[0109] As defined above and described herein, R8is H or D.

[0110] In some embodiments, R8is D. 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, R23, and R24is D.

[0111] As defined above and described herein, R9is H or D.

[0112] In some embodiments, R9is D. 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, R23, and R24is D.

[0113] As defined above and described herein, R10is H or D.

[0114] In some embodiments, R10is D. 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, R23, and R24is D.

[0115] As defined above and described herein, R11is H or D. 24 61651714.1PAT27218PCT01

[0116] In some embodiments, R11is D. 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, R23, and R24is D.

[0117] As defined above and described herein, R12is H or D.

[0118] In some embodiments, R12is D. 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, R23, and R24is D.

[0119] As defined above and described herein, R13is H or D.

[0120] In some embodiments, R13is D. 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, R23, and R24is D.

[0121] As defined above and described herein, R14is H or D.

[0122] In some embodiments, R14is D. 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, R23, and R24is D.

[0123] As defined above and described herein, R15is H or D.

[0124] In some embodiments, R15is D. 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, R23, and R24is D.

[0125] As defined above and described herein, R16is H or D.

[0126] In some embodiments, R16is D. 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, R23, and R24is D.

[0127] As defined above and described herein, R17is H or D.

[0128] In some embodiments, R17is D. In some embodiments, R17is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18, R19, R23, and R24is D.

[0129] As defined above and described herein, R18is H or D.

[0130] In some embodiments, R18is D. 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, R23, and R24is D.

[0131] As defined above and described herein, R19is H or D.

[0132] In some embodiments, R19is D. In some embodiments, R19is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R23, and R24is D.

[0133] As defined above and described herein, R20is H or D.

[0134] In some embodiments, R20is D. 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, R22, R23, and R24is D.

[0135] As defined above and described herein, R21is H or D.

[0136] In some embodiments, R21is D. 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, R22, R23, and R24is D. 25 61651714.1PAT27218PCT01

[0137] As defined above and described herein, R22is H or D.

[0138] In some embodiments, R22is D. 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, R21, R23, and R24is D.

[0139] As defined above and described herein, R23is H or D.

[0140] In some embodiments, R23is D. In some embodiments, R23is 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 R24is D.

[0141] As defined above and described herein, R24is H or D.

[0142] In some embodiments, R24is D. In some embodiments, R24is 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 R23is D.

[0143] In some embodiments, the present invention provides a compound of any one of Formulae II-a, II-b, II-c, II-d, II-e, II-f, and II-g, or a pharmaceutically acceptable salt thereof, wherein each of R5, R6, and R7is as defined above and described herein, and wherein each of R1, R2, R3, R4, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R23, and R24is as defined in an entry set forth in Table 2, below.

[0144] In some embodiments, present invention provides a compound of Formula I or I’ selected from these depicted in Table 2, below, or a pharmaceutically acceptable salt thereof. Table 2. Exemplary Deuterium-Enriched Compounds. Entry R1R2R3R4R8R9R10R11R12R13R14R15R16R17R18R19R23R241 H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H26 61651714.1PAT27218PCT01 Entry R1R2R3R4R8R9R10R11R12R13R14R15R16R17R18R19R23R2423 H H H H H H D D D H H H H D D D H H 24 H H H H D D D D D H H H H D D D H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H D D61651714.1PAT27218PCT01 Entry R1R2R3R4R8R9R10R11R12R13R14R15R16R17R18R19R23R2475 D D D D D D H H H D D D D H H H D D 76 D D D D H H D D D D D D D H H H D D D D D D H H H H H H H H D D D D D D D D H H H H H H H H D D D D D D D D H H H H H H H H D D D D D D61651714.1PAT27218PCT01 Entry R1R2R3R4R8R9R10R11R12R13R14R15R16R17R18R19R23R24127 H H H H H H D D D D D D D D D D D D 128 H H H H D D D D D D D D D D D D D D [0014euterium incorporation of 50% or greater. In some embodiments, at least two of R5, R6, and R7has a % deuterium incorporation of 50% or greater. In some embodiments, each of R5, R6, and R7has a % deuterium incorporation of 50% or greater.

[0146] In some embodiments, at least one of R5, R6, and R7has a % deuterium incorporation of 70% or greater. In some embodiments, at least two of R5, R6, and R7has a % deuterium incorporation of 70% or greater. In some embodiments, each of R5, R6, and R7has a % deuterium incorporation of 70% or greater.

[0147] In some embodiments, at least one of R5, R6, and R7has a % deuterium incorporation of 80% or greater. In some embodiments, at least two of R5, R6, and R7has a % deuterium incorporation of 80% or greater. In some embodiments, each of R5, R6, and R7has a % deuterium incorporation of 80% or greater.

[0148] In some embodiments, at least one of R5, R6, and R7has a % deuterium incorporation of 90% or greater. In some embodiments, at least two of R5, R6, and R7has a % deuterium incorporation of 90% or greater. In some embodiments, each of R5, R6, and R7has a % deuterium incorporation of 90% or greater.

[0149] In some embodiments, at least one of R5, R6, and R7has a % deuterium incorporation of 95% or greater. In some embodiments, at least two of R5, R6, and R7has a % deuterium incorporation of 95% or greater. In some embodiments, each of R5, R6, and R7has a % deuterium incorporation of 95% or greater.

[0150] In some embodiments, the present invention provides a deuterium-enriched compound or pharmaceutically acceptable salt thereof of Formula II-a, II-b, II-c, II-d, II-e, II-f, or II-g, wherein a variable indicated as D in Table 2, has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater; or about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 99.5% or greater.

[0151] In some embodiments, the present invention provides a compound selected from those recited in Table 2, or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the present invention provides a compound of Formula III- a, III-b, or III-c: 29 61651714.1PAT27218PCT01or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein, either singly or in combination.

[0153] The following embodiments are applicable to each of the preceding formulae.

[0154] As defined above and described herein, R1is H or D.

[0155] 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, R23, and R24is D. In some embodiments, R1is D.

[0156] As defined above and described herein, R2is H or D.

[0157] 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, R23, and R24is D. In some embodiments, R2is D.

[0158] As defined above and described herein, R3is H or D.

[0159] 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, R23, and R24is D. In some embodiments, R3is D.

[0160] As defined above and described herein, R4is H or D.

[0161] 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, R23, and R24is D. In some embodiments, R4is D.

[0162] As defined above and described herein, R5is H or D.

[0163] 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, R23, and R24is D. In some embodiments, R5is D. 30 61651714.1PAT27218PCT01

[0164] As defined above and described herein, R6is H or D.

[0165] 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, R23, and R24is D. In some embodiments, R6is D.

[0166] As defined above and described herein, R7is H or D.

[0167] 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, R23, and R24is D. In some embodiments, R7is D.

[0168] As defined above and described herein, R8is H or D.

[0169] In some embodiments, R8is D. 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, R23, and R24is D.

[0170] As defined above and described herein, R9is H or D.

[0171] In some embodiments, R9is D. 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, R23, and R24is D.

[0172] As defined above and described herein, R10is H or D.

[0173] In some embodiments, R10is D. 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, R23, and R24is D.

[0174] As defined above and described herein, R11is H or D.

[0175] In some embodiments, R11is D. 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, R23, and R24is D.

[0176] As defined above and described herein, R12is H or D.

[0177] In some embodiments, R12is D. 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, R23, and R24is D.

[0178] As defined above and described herein, R13is H or D.

[0179] In some embodiments, R13is D. 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, R23, and R24is D.

[0180] As defined above and described herein, R14is H or D.

[0181] In some embodiments, R14is D. 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, R23, and R24is D.

[0182] As defined above and described herein, R15is H or D.

[0183] In some embodiments, R15is D. 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, R23, and R24is D.

[0184] As defined above and described herein, R16is H or D.

[0185] In some embodiments, R16is D. 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, R23, and R24is D.

[0186] As defined above and described herein, R17is H or D. 31 61651714.1PAT27218PCT01

[0187] In some embodiments, R17is D. In some embodiments, R17is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18, R19, R23, and R24is D.

[0188] As defined above and described herein, R18is H or D.

[0189] In some embodiments, R18is D. 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, R23, and R24is D.

[0190] As defined above and described herein, R19is H or D.

[0191] In some embodiments, R19is D. In some embodiments, R19is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R23, and R24is D.

[0192] As defined above and described herein, R20is H or D.

[0193] In some embodiments, R20is D. 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, R22, R23, and R24is D.

[0194] As defined above and described herein, R21is H or D.

[0195] In some embodiments, R21is D. 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, R22, R23, and R24is D.

[0196] As defined above and described herein, R22is H or D.

[0197] In some embodiments, R22is D. 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, R21, R23, and R24is D.

[0198] As defined above and described herein, R23is H or D.

[0199] In some embodiments, R23is D. In some embodiments, R23is 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 R24is D.

[0200] As defined above and described herein, R24is H or D.

[0201] In some embodiments, R24is D. In some embodiments, R24is 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 R23is D.

[0202] In some embodiments, the present invention provides a compound of any one of Formulae III-a, III-b, and III-c, or a pharmaceutically acceptable salt thereof, wherein each of R8and R9is as defined above and described herein, and wherein each of R1, R2, R3, R4, R5, R6, R7, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R23, and R24is as defined in an entry set forth in Table 3, below.

[0203] In some embodiments, present invention provides a compound of Formula I or I’ selected from these depicted in Table 3, below, or a pharmaceutically acceptable salt thereof. 32 61651714.1PAT27218PCT01 Table 3. Exemplary Deuterium-Enriched Compounds. EntryR1 R2 R3 R4 R5 R6 R7 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R23 R241 H H H H H H H H H H H H H H H H H H H 2 D D D D H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H33 61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R10R11R12R13R14R15R16R17R18R19R23R2451 D D D D D D D H H H H H H H D D D H H 52 H H H H D D D H H H H H H H D D D H H H H H H H H H H H H H H H H H H H H H H D D D D D D D D H H H H H H H H D D D D D D D D H H H H H H61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R10R11R12R13R14R15R16R17R18R19R23R24103 D D D D D D D D D D H H H H H H H H H 104 H H H H D D D D D D H H H H H H H H H D D D D D D D D H H H H H H H H D D D D D D D D

[002] n some em o ments, at east one o an as a euter um ncorporation of 50% or greater. In some embodiments, each of R8and R9has a % deuterium incorporation of 50% or greater.

[0205] In some embodiments, at least one of R8and R9has a % deuterium incorporation of 70% or greater. In some embodiments, each of R8and R9has a % deuterium incorporation of 70% or greater.

[0206] In some embodiments, at least one of R8and R9has a % deuterium incorporation of 80% or greater. In some embodiments, each of R8and R9has a % deuterium incorporation of 80% or greater.

[0207] In some embodiments, at least one of R8and R9has a % deuterium incorporation of 90% or greater. In some embodiments, each of R8and R9has a % deuterium incorporation of 90% or greater.

[0208] In some embodiments, at least one of R8and R9has a % deuterium incorporation of 95% or greater. In some embodiments, each of R8and R9has a % deuterium incorporation of 95% or greater. 35 61651714.1PAT27218PCT01

[0209] In some embodiments, the present invention provides a deuterium-enriched compound or pharmaceutically acceptable salt thereof of Formula III-a, III-b, and III-c, wherein a variable indicated as D in Table 3, has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater; or about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 99.5% or greater.

[0210] In some embodiments, the present invention provides a compound selected from those recited in Table 3, or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the present invention provides a compound of Formula IV- a, IV-b, and IV-c:ther singly or in combination.

[0212] The following embodiments are applicable to each of the preceding formulae.

[0213] As defined above and described herein, R1is H or D.

[0214] 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, R23, and R24is D. In some embodiments, R1is D.

[0215] As defined above and described herein, R2is H or D.

[0216] 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, R23, and R24is D. In some embodiments, R2is D. 36 61651714.1PAT27218PCT01

[0217] As defined above and described herein, R3is H or D.

[0218] 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, R23, and R24is D. In some embodiments, R3is D.

[0219] As defined above and described herein, R4is H or D.

[0220] 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, R23, and R24is D. In some embodiments, R4is D.

[0221] As defined above and described herein, R5is H or D.

[0222] 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, R23, and R24is D. In some embodiments, R5is D.

[0223] As defined above and described herein, R6is H or D.

[0224] 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, R23, and R24is D. In some embodiments, R6is D.

[0225] As defined above and described herein, R7is H or D.

[0226] 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, R23, and R24is D. In some embodiments, R7is D.

[0227] As defined above and described herein, R8is H or D.

[0228] In some embodiments, R8is D. 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, R23, and R24is D.

[0229] As defined above and described herein, R9is H or D.

[0230] In some embodiments, R9is D. 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, R23, and R24is D.

[0231] As defined above and described herein, R10is H or D.

[0232] In some embodiments, R10is D. 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, R23, and R24is D.

[0233] As defined above and described herein, R11is H or D.

[0234] In some embodiments, R11is D. 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, R23, and R24is D.

[0235] As defined above and described herein, R12is H or D.

[0236] In some embodiments, R12is D. 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, R23, and R24is D.

[0237] As defined above and described herein, R13is H or D.

[0238] In some embodiments, R13is D. 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, R23, and R24is D.

[0239] As defined above and described herein, R14is H or D. 37 61651714.1PAT27218PCT01

[0240] In some embodiments, R14is D. 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, R23, and R24is D.

[0241] As defined above and described herein, R15is H or D.

[0242] In some embodiments, R15is D. 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, R23, and R24is D.

[0243] As defined above and described herein, R16is H or D.

[0244] In some embodiments, R16is D. 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, R23, and R24is D.

[0245] As defined above and described herein, R17is H or D.

[0246] In some embodiments, R17is D. In some embodiments, R17is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18, R19, R23, and R24is D.

[0247] As defined above and described herein, R18is H or D.

[0248] In some embodiments, R18is D. 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, R23, and R24is D.

[0249] As defined above and described herein, R19is H or D.

[0250] In some embodiments, R19is D. In some embodiments, R19is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R23, and R24is D.

[0251] As defined above and described herein, R20is H or D.

[0252] In some embodiments, R20is D. 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, R22, R23, and R24is D.

[0253] As defined above and described herein, R21is H or D.

[0254] In some embodiments, R21is D. 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, R22, R23, and R24is D.

[0255] As defined above and described herein, R22is H or D.

[0256] In some embodiments, R22is D. 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, R21, R23, and R24is D.

[0257] As defined above and described herein, R23is H or D.

[0258] In some embodiments, R23is D. In some embodiments, R23is 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 R24is D.

[0259] As defined above and described herein, R24is H or D. 38 61651714.1PAT27218PCT01

[0260] In some embodiments, R24is D. In some embodiments, R24is 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 R23is D.

[0261] In some embodiments, the present invention provides a compound of any one of Formulae IV-a, IV-b, and IV-c, or a pharmaceutically acceptable salt thereof, wherein each of R10, R11, and R12is as defined above and described herein, and wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R13, R14, R15, R16, R17, R18, R19, R23, and R24is as defined in an entry set forth in Table 4, below.

[0262] In some embodiments, present invention provides a compound of Formula I selected from these depicted in Table 4, below, or a pharmaceutically acceptable salt thereof. Table 4. Exemplary Deuterium-Enriched Compounds. Entry R1R2R3R4R5R6R7R8R9R13R14R15R16R17R18R19R23R241 H H H H H H H H H H H H H H H H H H H61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R8R9R13R14R15R16R17R18R19R23R2436 D D D D D D D H H H H H H H H H H H 37 H H H H H H H D D H H H H H H H H H61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R8R9R13R14R15R16R17R18R19R23R2488 D D D D D D D D D H H H H D D D H H 89 H H H H H H H H H D D D D D D D D D

[0263] In some embodiments, at least one of R10, R11, and R12has a % deuterium incorporation of 50% or greater. In some embodiments, at least two of R10, R11, and R12has a % deuterium incorporation of 50% or greater. In some embodiments, each of R10, R11, and R12has a % deuterium incorporation of 50% or greater.

[0264] In some embodiments, at least one of R10, R11, and R12has a % deuterium incorporation of 70% or greater. In some embodiments, at least two of R10, R11, and R12has a 41 61651714.1PAT27218PCT01 % deuterium incorporation of 70% or greater. In some embodiments, each of R10, R11, and R12has a % deuterium incorporation of 70% or greater.

[0265] In some embodiments, at least one of R10, R11, and R12has a % deuterium incorporation of 80% or greater. In some embodiments, at least two of R10, R11, and R12has a % deuterium incorporation of 80% or greater. In some embodiments, each of R10, R11, and R12has a % deuterium incorporation of 80% or greater.

[0266] In some embodiments, at least one of R10, R11, and R12has a % deuterium incorporation of 90% or greater. In some embodiments, at least two of R10, R11, and R12has a % deuterium incorporation of 90% or greater. In some embodiments, each of R10, R11, and R12has a % deuterium incorporation of 90% or greater.

[0267] In some embodiments, at least one of R10, R11, and R12has a % deuterium incorporation of 95% or greater. In some embodiments, at least two of R10, R11, and R12has a % deuterium incorporation of 95% or greater. In some embodiments, each of R10, R11, and R12a % deuterium incorporation of 95% or greater.

[0268] In some embodiments, the present invention provides a deuterium-enriched compound or pharmaceutically acceptable salt thereof of Formula IV-a, IV-b, and IV-c, wherein a variable indicated as D in Table 4, has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater; or about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 99.5% or greater.

[0269] In some embodiments, the present invention provides a compound selected from those recited in Table 4, or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, the present invention provides a compound of Formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V- t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc, and V-dd: 42 61651714.14361651714.14461651714.14561651714.14661651714.1PAT27218PCT01or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein, either singly or in combination.

[0271] The following embodiments are applicable to each of the preceding formulae. 47 61651714.1PAT27218PCT01

[0272] As defined above and described herein, R1is H or D.

[0273] 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, R23, and R24is D. In some embodiments, R1is D.

[0274] As defined above and described herein, R2is H or D.

[0275] 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, R23, and R24is D. In some embodiments, R2is D.

[0276] As defined above and described herein, R3is H or D.

[0277] 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, R23, and R24is D. In some embodiments, R3is D.

[0278] As defined above and described herein, R4is H or D.

[0279] 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, R23, and R24is D. In some embodiments, R4is D.

[0280] As defined above and described herein, R5is H or D.

[0281] 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, R23, and R24is D. In some embodiments, R5is D.

[0282] As defined above and described herein, R6is H or D.

[0283] 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, R23, and R24is D. In some embodiments, R6is D.

[0284] As defined above and described herein, R7is H or D.

[0285] 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, R23, and R24is D. In some embodiments, R7is D.

[0286] As defined above and described herein, R8is H or D.

[0287] In some embodiments, R8is D. 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, R23, and R24is D.

[0288] As defined above and described herein, R9is H or D.

[0289] In some embodiments, R9is D. 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, R23, and R24is D.

[0290] As defined above and described herein, R10is H or D.

[0291] In some embodiments, R10is D. 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, R23, and R24is D.

[0292] As defined above and described herein, R11is H or D.

[0293] In some embodiments, R11is D. 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, R23, and R24is D.

[0294] As defined above and described herein, R12is H or D. 48 61651714.1PAT27218PCT01

[0295] In some embodiments, R12is D. 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, R23, and R24is D.

[0296] As defined above and described herein, R13is H or D.

[0297] In some embodiments, R13is D. 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, R23, and R24is D.

[0298] As defined above and described herein, R14is H or D.

[0299] In some embodiments, R14is D. 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, R23, and R24is D.

[0300] As defined above and described herein, R15is H or D.

[0301] In some embodiments, R15is D. 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, R23, and R24is D.

[0302] As defined above and described herein, R16is H or D.

[0303] In some embodiments, R16is D. 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, R23, and R24is D.

[0304] As defined above and described herein, R17is H or D.

[0305] In some embodiments, R17is D. In some embodiments, R17is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18, R19, R23, and R24is D.

[0306] As defined above and described herein, R18is H or D.

[0307] In some embodiments, R18is D. 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, R23, and R24is D.

[0308] As defined above and described herein, R19is H or D.

[0309] In some embodiments, R19is D. In some embodiments, R19is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R23, and R24is D.

[0310] As defined above and described herein, R20is H or D.

[0311] In some embodiments, R20is D. 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, R22, R23, and R24is D.

[0312] As defined above and described herein, R21is H or D.

[0313] In some embodiments, R21is D. 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, R22, R23, and R24is D.

[0314] As defined above and described herein, R22is H or D. 49 61651714.1PAT27218PCT01

[0315] In some embodiments, R22is D. 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, R21, R23, and R24is D.

[0316] As defined above and described herein, R23is H or D.

[0317] In some embodiments, R23is D. In some embodiments, R23is 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 R24is D.

[0318] As defined above and described herein, R24is H or D.

[0319] In some embodiments, R24is D. In some embodiments, R24is 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 R23is D.

[0320] In some embodiments, the present invention provides a compound of any one of Formulae V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V- q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc, and V-dd, or a pharmaceutically acceptable salt thereof, wherein each of R13, R14, R15, R16, and R23is as defined above and described herein, and wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R17, R18, R19, and R24is as defined in an entry set forth in Table 5, below.

[0321] In some embodiments, present invention provides a compound of Formula I selected from these depicted in Table 5, below, or a pharmaceutically acceptable salt thereof. Table 5. Exemplary Deuterium-Enriched Compounds. Entry R1R2R3R4R5R6R7R8R9R10R11R12R17R18R19R241 H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H50 61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R8R9R10R11R12R17R18R19R2423 H H H H D D D D D H H H D D D H 24 D D D D D D D D D H H H D D D H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H D D D D D D D D D D61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R8R9R10R11R12R17R18R19R2475 H H H H D D D H H D D D H H H D 76 D D D D D D D H H D D D H H H D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R8R9R10R11R12R17R18R19R24127 H H H H D D D D D D D D D D D D 128 D D D D D D D D D D D D D D D D [0032deuterium incorporation of 50% or greater. In some embodiments, at least two of R13, R14, R15, R16, and R23has a % deuterium incorporation of 50% or greater. In some embodiments, at least three of R13, R14, R15, R16, and R23has a % deuterium incorporation of 50% or greater. In some embodiments, at least four of R13, R14, R15, R16, and R23has a % deuterium incorporation of 50% or greater. In some embodiments, each of R13, R14, R15, R16, and R23has a % deuterium incorporation of 50% or greater.

[0323] In some embodiments, at least one of R13, R14, R15, R16, and R23has a % deuterium incorporation of 70% or greater. In some embodiments, at least two of R13, R14, R15, R16, and R23has a % deuterium incorporation of 70% or greater. In some embodiments, at least three of R13, R14, R15, R16, and R23has a % deuterium incorporation of 70% or greater. In some embodiments, at least four of R13, R14, R15, R16, and R23has a % deuterium incorporation of 70% or greater. In some embodiments, each of R13, R14, R15, R16, and R23has a % deuterium incorporation of 70% or greater.

[0324] In some embodiments, at least one of R13, R14, R15, R16, and R23has a % deuterium incorporation of 80% or greater. In some embodiments, at least two of R13, R14, R15, R16, and R23has a % deuterium incorporation of 80% or greater. In some embodiments, at least three of R13, R14, R15, R16, and R23has a % deuterium incorporation of 80% or greater. In some embodiments, at least four of R13, R14, R15, R16, and R23has a % deuterium incorporation of 80% or greater. In some embodiments, each of R13, R14, R15, R16, and R23has a % deuterium incorporation of 80% or greater.

[0325] In some embodiments, at least one of R13, R14, R15, R16, and R23has a % deuterium incorporation of 90% or greater. In some embodiments, at least two of R13, R14, R15, R16, and R23has a % deuterium incorporation of 90% or greater. In some embodiments, at least three of R13, R14, R15, R16, and R23has a % deuterium incorporation of 90% or greater. In some embodiments, at least four of R13, R14, R15, R16, and R23has a % deuterium incorporation of 90% or greater. In some embodiments, each of R13, R14, R15, R16, and R23has a % deuterium incorporation of 90% or greater.

[0326] In some embodiments, at least one of R13, R14, R15, R16, and R23has a % deuterium incorporation of 95% or greater. In some embodiments, at least two of R13, R14, R15, R16, and R23has a % deuterium incorporation of 95% or greater. In some embodiments, at least three 53 61651714.1PAT27218PCT01 of R13, R14, R15, R16, and R23has a % deuterium incorporation of 95% or greater. In some embodiments, at least four of R13, R14, R15, R16, and R23has a % deuterium incorporation of 95% or greater. In some embodiments, each of R13, R14, R15, R16, and R23has a % deuterium incorporation of 95% or greater.

[0327] In some embodiments, the present invention provides a deuterium-enriched compound or pharmaceutically acceptable salt thereof of Formula V-a, V-b, V-c, V-d, V-e, V- f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc, and V-dd, wherein a variable indicated as D in Table 5, has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater; or about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 99.5% or greater.

[0328] In some embodiments, the present invention provides a compound selected from those recited in Table 5, or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the present invention provides a compound of Formula VI- a, VI-b, or VI-c:, , ther singly or in combination.

[0330] In some embodiments, the compound is not 54 61651714.1PAT27218PCT01 or a phar

[0331] The following embodiments are applicable to each of the preceding formulae.

[0332] As defined above and described herein, R1is H or D.

[0333] 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, R23, and R24is D. In some embodiments, R1is D.

[0334] As defined above and described herein, R2is H or D.

[0335] 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, R23, and R24is D. In some embodiments, R2is D.

[0336] As defined above and described herein, R3is H or D.

[0337] 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, R23, and R24is D. In some embodiments, R3is D.

[0338] As defined above and described herein, R4is H or D.

[0339] 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, R23, and R24is D. In some embodiments, R4is D.

[0340] As defined above and described herein, R5is H or D.

[0341] 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, R23, and R24is D. In some embodiments, R5is D.

[0342] As defined above and described herein, R6is H or D.

[0343] 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, R23, and R24is D. In some embodiments, R6is D.

[0344] As defined above and described herein, R7is H or D.

[0345] 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, R23, and R24is D. In some embodiments, R7is D.

[0346] As defined above and described herein, R8is H or D.

[0347] In some embodiments, R8is D. 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, R23, and R24is D.

[0348] As defined above and described herein, R9is H or D. 55 61651714.1PAT27218PCT01

[0349] In some embodiments, R9is D. 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, R23, and R24is D.

[0350] As defined above and described herein, R10is H or D.

[0351] In some embodiments, R10is D. 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, R23, and R24is D.

[0352] As defined above and described herein, R11is H or D.

[0353] In some embodiments, R11is D. 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, R23, and R24is D.

[0354] As defined above and described herein, R12is H or D.

[0355] In some embodiments, R12is D. 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, R23, and R24is D.

[0356] As defined above and described herein, R13is H or D.

[0357] In some embodiments, R13is D. 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, R23, and R24is D.

[0358] As defined above and described herein, R14is H or D.

[0359] In some embodiments, R14is D. 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, R23, and R24is D.

[0360] As defined above and described herein, R15is H or D.

[0361] In some embodiments, R15is D. 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, R23, and R24is D.

[0362] As defined above and described herein, R16is H or D.

[0363] In some embodiments, R16is D. 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, R23, and R24is D.

[0364] As defined above and described herein, R17is H or D.

[0365] In some embodiments, R17is D. In some embodiments, R17is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18, R19, R23, and R24is D.

[0366] As defined above and described herein, R18is H or D.

[0367] In some embodiments, R18is D. 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, R23, and R24is D.

[0368] As defined above and described herein, R19is H or D.

[0369] In some embodiments, R19is D. In some embodiments, R19is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R23, and R24is D.

[0370] As defined above and described herein, R20is H or D. 56 61651714.1PAT27218PCT01

[0371] In some embodiments, R20is D. 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, R22, R23, and R24is D.

[0372] As defined above and described herein, R21is H or D.

[0373] In some embodiments, R21is D. 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, R22, R23, and R24is D.

[0374] As defined above and described herein, R22is H or D.

[0375] In some embodiments, R22is D. 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, R21, R23, and R24is D.

[0376] As defined above and described herein, R23is H or D.

[0377] In some embodiments, R23is D. In some embodiments, R23is 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 R24is D.

[0378] As defined above and described herein, R24is H or D.

[0379] In some embodiments, R24is D. In some embodiments, R24is 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 R23, is D.

[0380] In some embodiments, the present invention provides a compound of any one of Formulae VI-a, VI-b, and VI-c, or a pharmaceutically acceptable salt thereof, wherein each of R17, R18, and R19is as defined above and described herein, and wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R23, and R24is as defined in an entry set forth in Table 6, below.

[0381] In some embodiments, present invention provides a compound of Formula I selected from these depicted in Table 6, below, or a pharmaceutically acceptable salt thereof. Table 6. Exemplary Deuterium-Enriched Compounds. Entry R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R23R241 H H H H H H H H H H H H H H H H H H57 61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R23R2412 D D D D D D D H H D D D H H H H H H 13 H H H H H H H D D D D D H H H H H H61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R23R2464 D D D D D D D D D D D D D D D D D H 65 H H H H H H H H H H H H H H H H H H61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R23R24116 D D D D D D D H H H H H D D D D D D 117 H H H H H H H D D H H H D D D D D D [0038euterium incorporation of 50% or greater. In some embodiments, at least two of R17, R18, and R19has a % deuterium incorporation of 50% or greater. In some embodiments, each of R17, R18, and R19has a % deuterium incorporation of 50% or greater.

[0383] In some embodiments, at least one of R17, R18, and R19has a % deuterium incorporation of 70% or greater. In some embodiments, at least two of R17, R18, and R19has a % deuterium incorporation of 70% or greater. In some embodiments, each of R17, R18, and R19has a % deuterium incorporation of 70% or greater.

[0384] In some embodiments, at least one of R17, R18, and R19has a % deuterium incorporation of 80% or greater. In some embodiments, at least two of R17, R18, and R19has a % deuterium incorporation of 80% or greater. In some embodiments, each of R17, R18, and R19has a % deuterium incorporation of 80% or greater.

[0385] In some embodiments, at least one of R17, R18, and R19has a % deuterium incorporation of 90% or greater. In some embodiments, at least two of R17, R18, and R19has a % deuterium incorporation of 90% or greater. In some embodiments, each of R17, R18, and R19has a % deuterium incorporation of 90% or greater.

[0386] In some embodiments, at least one of R17, R18, and R19has a % deuterium incorporation of 95% or greater. In some embodiments, at least two of R17, R18, and R19has a % deuterium incorporation of 95% or greater. In some embodiments, each of R17, R18, and R19a % deuterium incorporation of 95% or greater.

[0387] In some embodiments, the present invention provides a deuterium-enriched compound or pharmaceutically acceptable salt thereof of Formula VI-a, VI-b, and VI-c, wherein a variable indicated as D in Table 6, has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% 60 61651714.1PAT27218PCT01 or greater; or about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 99.5% or greater.

[0388] In some embodiments, the present invention provides a compound selected from those recited in Table 6, or a pharmaceutically acceptable salt thereof.

[0389] In some embodiments, the present invention provides a compound of Formula VII- a, VII-b, VII-c, VII-d, VII-e, VII-f, VII-g, VII-h, VII-i, VII-j, VII-k, VII-l, VII-m, VII-n, VII-o, VII-p, VII-q, VII-r, VII-s, VII-t, VII-u, VII-v, VII-w, VII-x, VII-y, VII-z, VII-aa, VII-bb, VII-cc, VII-dd, VII-de, or VII-df:61 61651714.1PAT27218PCT0161651714.1PAT27218PCT0163 61651714.1PAT27218PCT0164 61651714.1PAT27218PCT0165 61651714.1PAT27218PCT01or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein, either singly or in combination.

[0390] In some embodiments, the compound is of Formula VIII: 66 61651714.1PAT27218PCT01or a pharmaceutically acceptable salt thereof.

[0391] In some embodiments, the compound of Formula VIII is further characterized in that each of R1, R2, R3, R4, R5, R6, R7, R8, and R9are H and R13, R14, R15, R16, R17, R23, and R24are independently H or D. In some embodiments, the compound of Formula VIII is further characterized in that each of R1, R2, R3, R4, R5, R6, R7, R8, and R9are H and one of R13, R14, R15, R16, R17, R23, and R24is D. In some embodiments, the compound of Formula VIII is further characterized in that each of R1, R2, R3, R4, R5, R6, R7, R8, and R9are H and two, three, four, five, six, or seven of R13, R14, R15, R16, R17, R23, and R24is D.

[0392] The following embodiments are applicable to each of the preceding formulae of VII-a, VII-b, VII-c, VII-d, VII-e, VII-f, VII-g, VII-h, VII-i, VII-j, VII-k, VII-l, VII-m, VII- n, VII-o, VII-p, VII-q, VII-r, VII-s, VII-t, VII-u, VII-v, VII-w, VII-x, VII-y, VII-z, VII- aa, VII-bb, VII-cc, VII-dd, VII-de, VII-df, and VIII.

[0393] As defined above and described herein, R1is H or D.

[0394] In some embodiments, R1is H and at least one of R2, R3, R4, R5, R6, R7, R8, R9, R13, R14, R15, R16, R23, and R24is D. In some embodiments, R1is D.

[0395] As defined above and described herein, R2is H or D.

[0396] In some embodiments, R2is H and at least one of R1, R3, R4, R5, R6, R7, R8, R9, R13, R14, R15, R16, R23, and R24is D. In some embodiments, R2is D.

[0397] As defined above and described herein, R3is H or D.

[0398] In some embodiments, R3is H and at least one of R1, R2, R4, R5, R6, R7, R8, R9, R13, R14, R15, R16, R23, and R24is D. In some embodiments, R3is D.

[0399] As defined above and described herein, R4is H or D.

[0400] In some embodiments, R4is H and at least one of R1, R2, R3, R5, R6, R7, R8, R9, R13, R14, R15, R16, R23, and R24is D. In some embodiments, R4is D. 67 61651714.1PAT27218PCT01

[0401] As defined above and described herein, R5is H or D.

[0402] In some embodiments, R5is H and at least one of R1, R2, R3, R4, R6, R7, R8, R9, R13, R14, R15, R16, R23, and R24is D. In some embodiments, R5is D.

[0403] As defined above and described herein, R6is H or D.

[0404] In some embodiments, R6is H and at least one of R1, R2, R3, R4, R5, R7, R8, R9, R13, R14, R15, R16, R23, and R24is D. In some embodiments, R6is D.

[0405] As defined above and described herein, R7is H or D.

[0406] In some embodiments, R7is H and at least one of R1, R2, R3, R4, R5, R6, R8, R9, R13, R14, R15, R16, R23, and R24is D. In some embodiments, R7is D.

[0407] As defined above and described herein, R8is H or D.

[0408] In some embodiments, R8is D. In some embodiments, R8is H and at least one of R1, R2, R3, R4, R5, R6, R7, R9, R13, R14, R15, R16, R23, and R24is D.

[0409] As defined above and described herein, R9is H or D.

[0410] In some embodiments, R9is D. In some embodiments, R9is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R13, R14, R15, R16, R23, and R24is D.

[0411] As defined above and described herein, R13is H or D.

[0412] In some embodiments, R13is D. In some embodiments, R13is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R14, R15, R16, R23, and R24is D.

[0413] As defined above and described herein, R14is H or D.

[0414] In some embodiments, R14is D. In some embodiments, R14is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R13, R15, R16, R23, and R24is D.

[0415] As defined above and described herein, R15is H or D.

[0416] In some embodiments, R15is D. In some embodiments, R15is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R13, R14, R16, R23, and R24is D.

[0417] As defined above and described herein, R16is H or D.

[0418] In some embodiments, R16is D. In some embodiments, R16is H and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R13, R14, R15, R23, and R24is D.

[0419] As defined above and described herein, R23is H or D.

[0420] In some embodiments, R23is D. In some embodiments, R23is 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 R24is D.

[0421] As defined above and described herein, R24is H or D.

[0422] In some embodiments, R24is D. In some embodiments, R24is 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 R23is D. 68 61651714.1PAT27218PCT01

[0423] In some embodiments, present invention provides a compound of Formula I’ selected from these depicted in Table 7, below, or a pharmaceutically acceptable salt thereof. Table 7. Exemplary Deuterium-Enriched Compounds. Entry R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R23R241 H H H H H H H H H H H H H H H H H H H H H 2 D D D D H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R23R2447 H H H H D D D D D D D D H H H H D D D H H 48 D D D D D D D D D D D D H H H H D D D H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H D D D D D D D D D D D D D D D D H H61651714.1PAT27218PCT01 Entry R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R23R2499 H H H H D D D H H H H H H H H H D D D H H 100 D D D D D D D H H H H H H H H H D D D H H H H H H H H H H H H H H D D D D D D D D D D D D D D D D

[0424] In some embodiments, the present invention provides a deuterium-enriched compound or pharmaceutically acceptable salt thereof of Formula I’, wherein a variable indicated as D in Table 7 has a deuterium % incorporation (% abundance) of about 30% or greater. In some embodiments, the % deuterium incorporation is about 50% or greater; or about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 99.5% or greater.

[0425] In some embodiments, the present invention provides a compound selected from those recited in Table 7, or a pharmaceutically acceptable salt thereof.

[0426] In some embodiments, the present invention provides any compound described herein comprising one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or more deuterium atoms (i.e., one or more variables in a Formula depicted herein having deuterium enrichment). 71 61651714.1PAT27218PCT01

[0427] In some embodiments, each position comprising deuterium has a % deuterium incorporation in an amount of at least 5%. In some embodiments, each position comprising deuterium has a % deuterium incorporation in an amount of at least 30%. In some embodiments, each position comprising deuterium has a % deuterium incorporation in an amount of at least 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%, or at least about 99.5%.

[0428] 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%, 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%, 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% or about 99.5%. In some embodiments, every position of deuterium enrichment 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%, or about 100%. As used herein in the context of deuterium enrichment, the term “about” means ± 2%.

[0429] In some embodiments, each position comprising deuterium has a % deuterium incorporation in an amount of about 5% to 99%, 10% to 95%, 15% to 90%, 20% to 85%, 25% to 80%, 30% to 80%, 35% to 75%, 40% to 70%, 30% to 99%, 30% to 95%, 30% to 90%, 50% to 75%, 50% to 99%, 50% to 95%, 50% to 90%, 60% to 99%, 60% to 95%, 60% to 90%, 70% to 99%, 70% to 95%, 70% to 90%, 80% to 99%, 80% to 95%, 80% to 90%, 90% to 99%, 90% to 95%, or 95% to 99%.

[0430] In some embodiments, the compound of Formula I is a compound shown in Table 8, or a pharmaceutically acceptable salt thereof. Table 8. Exemplary Compounds Compound No. Structure72 61651714.161651714.161651714.161651714.161651714.161651714.161651714.161651714.161651714.161651714.161651714.161651714.161651714.161651714.1PAT27218PCT0186 61651714.161651714.18861651714.18961651714.19061651714.161651714.161651714.1PAT27218PCT0193 61651714.1PAT27218PCT0194 61651714.1PAT27218PCT0195 61651714.1PAT27218PCT0161651714.1PAT27218PCT0197 61651714.1PAT27218PCT0198 61651714.1PAT27218PCT0199 61651714.1PAT27218PCT01100 61651714.1PAT27218PCT01101 61651714.1PAT27218PCT01102 61651714.1PAT27218PCT014. Uses of Compounds and Pharmaceutically Acceptable Compositions Thereof

[0431] Certain compounds described herein are found to be useful in treating, preventing, or ameliorating various diseases, disorders, and conditions, such as those described herein.

[0432] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered 103 61651714.1PAT27218PCT01 in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). In some cases, treatment is continued after symptoms have resolved, for example to prevent, delay or lessen the severity of their recurrence.

[0433] The invention relates to compounds described herein for the treatment, prevention, and / or reduction of a risk of autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer’s disease, and hormone-related diseases. Compounds herein (e.g., compounds of Formula I) may be formulated into a pharmaceutical formulation described infra for therapeutic use as described herein.

[0434] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g. IFN-α, IFN-β, IFN-κ, IFN- δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitin), and interleukins (e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Velasquez et al., “A protein kinase in the interferon α / β signaling pathway,” Cell (1992) 70:313; Stahl et al., “Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components,” Science (1994) 263:92; Finbloom et al., “IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes,” J. Immunol. (1995) 155:1079; Bacon et al., “Interleukin 12 (IL-12) induces tyrosine phosphorylation of Jak2 and Tyk2: differential use of Janus family kinases by IL-2 and IL-12,” J. Exp. Med. (1995) 181:399; Welham et al., “Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin,” J. Biol. Chem. (1995) 270:12286; Parham et al., “A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R,” J. Immunol. (2002) 168:5699. The activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0435] TYK2 activation by IL-23, has been linked to inflammatory bowel disease (IBD), Crohn’s disease, and ulcerative colitis. Duerr et al., “A Genome-Wide Association Study 104 61651714.1PAT27218PCT01 Identifies IL23R as an Inflammatory Bowel Disease Gene,” Science (2006) 314:1461-1463. As the downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Behçet’s disease. Cho et al., “Genomics and the multifactorial nature of human auto-immune disease,” N. Engl. J. Med (2011) 365:1612-1623; Cortes et al., “Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune- related loci,” Nat. Genet. (2013) 45(7):730-738; Remmers et al., “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease,” Nat. Genet. (2010) 42:698-702. A genome-wide association study of 2,622 individuals with psoriasis identified associations between disease susceptibility and TYK2. Strange et al., “A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1,” Nat. Genet. (2010) 42:985-992. Knockout or tyrphostin inhibition of TYK2 significantly reduces both IL-23 and IL-22-induced dermatitis. Ishizaki et al., “Tyk2 is a therapeutic target for psoriasis-like skin inflammation,” Intl. Immunol. (2013), doi: 10.1093 / intimm / dxt062.

[0436] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucous hypersecretion is mediated by IL-13-induced activation of TYK2, which in turn activates STAT6. Zhang et al., “Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2 / STAT6 pathway,” FASEB J. (2012) 26:1-11.

[0437] Decreased TYK2 activity leads to protection of joints from collagen antibody- induced arthritis, a model of human rheumatoid arthritis. Mechanistically, decreased Tyk2 activity reduced the production of Th1 / Th17-related cytokines and matrix metalloproteases, and other key markers of inflammation. Ishizaki et al., “Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice,” Intl. Immunol. (2011) 23(9):575-582.

[0438] TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)), with no infiltration of CD4 T cells in the spinal cord, as compared to controls, suggesting that TYK2 is essential to pathogenic CD4-mediated disease development in MS. Oyamada et al., “Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis,” J. Immunol. (2009) 183:7539-7546. This corroborates earlier studies linking increased TYK2 expression with MS susceptibility. Ban et al., “Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor,” Eur J. Hum. Genet. (2009) 17:1309-1313. Loss of function mutation in TYK2, leads to decreased 105 61651714.1PAT27218PCT01 demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.

[0439] TYK2 is the sole signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice.

[0440] Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder), showed a strong, and significant correlation between loss of function mutations to TYK2 and decreased prevalence of SLE in families with affected members. Sigurdsson et al., “Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus,” Am. J. Hum. Genet. (2005) 76:528-537. Genome-wide association studies of individuals with SLE versus an unaffected cohort showed highly significant correlation between the TYK2 locus and SLE. Graham et al., “Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus,” PLoS Genetics (2011) 7(10):e1002341.

[0441] TYK2 has been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response, and accelerated tumor development. However, these effects were linked to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 has been suggested as a superior target because of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects. Simma et al. “Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumour Surveillance,” Cancer Res. (2009) 69:203-211.

[0442] However, paradoxically to the decreased tumour surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukaemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via TYK2 via STAT1-mediated signal transduction to maintain cancer cell survival through upregulation of anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations to TYK2 that promote cancer cell survival include those to the FERM domain (G36D, S47N, and R425H), the JH2 domain (V731I), and the kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for increased cancer cell survival, as TYK2 enzymes featuring kinase-dead mutations (M978Y or M978F) in addition to an 106 61651714.1PAT27218PCT01 activating mutation (E957D) resulted in failure to transform. Sanda et al. “TYK2-STAT1- BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia,” Cancer Disc. (2013) 3(5):564-577.

[0443] Thus, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and / or BCL2-addicted tumors, such as 70% of adult T-cell leukaemia cases. Fontan et al. “Discovering What Makes STAT Signaling TYK in T-ALL,” Cancer Disc. (2013) 3:494-496.

[0444] TYK2 mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Aβ) peptide. Decreased TYK2 phosphorylation of STAT3 following Aβ administration led to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in post-mortem brains of Alzheimer’s patients. Wan et al. “Tyk / STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer’s Disease,” J. Neurosci. (2010) 30(20):6873-6881.

[0445] Inhibition of JAK-STAT signaling pathways is also implicated in hair growth, and the reversal of the hair loss associated with alopecia areata. Xing et al., “Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition,” Nat. Med. (2014) 20: 1043-1049; Harel et al., “Pharmacologic inhibition of JAK-STAT signaling promotes hair growth,” Sci. Adv. (2015) 1(9):e1500973.

[0446] Accordingly, compounds that inhibit the activity of TYK2 are beneficial, especially those with selectivity over JAK2. Such compounds should deliver a pharmacological response that favorably treats one or more of the conditions described herein without the side-effects associated with the inhibition of JAK2.

[0447] Even though TYK2 inhibitors are known in the art, there is a continuing need to provide novel inhibitors having more effective or advantageous pharmaceutically relevant properties. For example, compounds with increased activity, selectivity over other JAK kinases (especially JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Thus, in some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising a compound of the disclosure that is an inhibitor of TYK2 which shows selectivity over JAK2.

[0448] The activity of compounds of the disclosure utilized in this invention as an inhibitor of TYK2, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity and / or the subsequent functional consequences, or ATPase activity of activated TYK2, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to TYK2. 107 61651714.1PAT27218PCT01 Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with TYK2 bound to known radioligands. Representative in vitro and in vivo assays useful in assaying a TYK2 inhibitor include those described and disclosed in, e.g., each of which is herein incorporated by reference in its entirety.

[0449] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0450] Compound 1 is an inhibitor of TYK2 and it and deuterated analogues therefore are useful for treating one or more disorders associated with activity of TYK2 or mutants thereof. Thus, in certain embodiments, the present invention provides a method for treating a TYK2- mediated disorder comprising the step of administering to a patient in need thereof a pharmaceutical composition, formulation, or unit dosage form described herein, comprising a compound of the disclosure, or pharmaceutically acceptable salt, or hydrate thereof.

[0451] As used herein, the term “TYK2-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which TYK2 or a mutant thereof is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which TYK2, or a mutant thereof, is known to play a role. Such TYK2-mediated disorders include but are not limited to autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders and disorders associated with transplantation.

[0452] In some embodiments, the present invention provides a method for treating one or more disorders, wherein the disorders are selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders associated with transplantation, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising an effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising compounds of the disclosure as described herein. 108 61651714.1PAT27218PCT01

[0453] In some embodiments, the disorder is an autoimmune disorder. In some embodiments the disorder is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behçet’s disease, POEMS syndrome, Crohn’s disease, ulcerative colitis, and inflammatory bowel disease.

[0454] In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn’s disease, ulcerative colitis, inflammatory bowel disease.

[0455] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocytosis.

[0456] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon’s syndrome, or type 1 diabetes.

[0457] In some embodiments, the disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer’s disease.

[0458] In some embodiments the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0459] In some embodiments, the disorder is associated with transplantation. In some embodiments the disorder associated with transplantation is transplant rejection, or graft versus host disease.

[0460] In some embodiments the disorder is associated with type I interferon, IL-10, IL- 12, or IL-23 signaling. In some embodiments the disorder is associated with type I interferon signaling. In some embodiments the disorder is associated with IL-10 signaling. In some embodiments the disorder is associated with IL-12 signaling. In some embodiments the disorder is associated with IL-23 signaling.

[0461] Formulations comprising compounds according to the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, 109 61651714.1PAT27218PCT01 scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0462] Formulations comprising compounds according to the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn’s disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Grave’s disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in 110 61651714.1PAT27218PCT01 conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0463] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic juvenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.

[0464] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is a Th1 or Th17 mediated disease. In some embodiments the Th17 mediated disease is selected from cutaneous lupus erythematosus, Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis).

[0465] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren’s syndrome, psoriasis, psoriatic arthritis, irritable bowel disease, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0466] According to one embodiment, the invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a formulation comprising a compound according to this invention.

[0467] According to another embodiment, the invention relates to a method of inhibiting TYK2, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. In certain embodiments, the invention relates to a method of irreversibly inhibiting 111 61651714.1PAT27218PCT01 TYK2, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a formulation comprising a compound according to this invention.

[0468] In another embodiment, the invention provides a method of selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In some embodiments, a formulation comprising a compound according to this invention is more than 2-fold selective over JAK1 / 2 / 3. In some embodiments, a compound of the present invention is more than 5-fold selective over JAK1 / 2 / 3. In some embodiments, the compound of the present invention is more than 10-fold selective over JAK1 / 2 / 3. In some embodiments, the compound of the present invention is more than 50-fold selective over JAK1 / 2 / 3. In some embodiments, the compound of the present invention is more than 100-fold selective over JAK1 / 2 / 3.

[0469] The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0470] Inhibition of TYK2 (or a mutant thereof) activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0471] Another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a formulation comprising a compound according to this invention.

[0472] According to another embodiment, the invention relates to a method of inhibiting activity of TYK2, or a mutant thereof, in a patient comprising the step of administering to said patient a formulation comprising a compound according to this invention. According to certain embodiments, the invention relates to a method of reversibly or irreversibly inhibiting one or more of TYK2, or a mutant thereof, activity in a patient comprising the step of administering to said patient a formulation comprising a compound according to this invention. In other embodiments, the present invention provides a method for treating a disorder mediated by TYK2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a formulation comprising a compound according to this invention. Such disorders are described in detail herein. Pharmaceutical Compositions, Formulations, and Unit Dosage Forms

[0473] Furthermore, the invention provides the use of a formulation comprising compounds according to the definitions herein, for the preparation of a medicament for the 112 61651714.1PAT27218PCT01 treatment of an autoimmune disorder, an inflammatory disorder, or a proliferative disorder, or a disorder commonly occurring in connection with transplantation.

[0474] Compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. A compound of the disclosure is preferably formulated in 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 agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compound and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0475] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compound of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 0.01 mg / kg to about 5 mg / kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of up to about 200 mg (e.g., from about 20 mg to about 100 mg) to the patient. In other embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg, about 5 mg, about 10 mg, about 15 mg, or about 30 mg to the patient. 113 61651714.1PAT27218PCT01

[0476] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0477] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic 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 water, Ringer's solution, U.S.P. 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 can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0478] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0479] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and 114 61651714.1PAT27218PCT01 i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0480] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0481] The active compound can also be in micro-encapsulated form with one or more excipients as noted above. In some embodiments, hydroxypropyl methyl cellulose (HMPC) capsules encapsulate the composition or formation of the invention. In some embodiments, the capsules are size 2 hard Swedish orange HPMC capsules. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0482] Dosage forms for topical or transdermal administration of a formulation comprising a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated 115 61651714.1PAT27218PCT01 as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0483] A unit dosage form of the invention can be formulated for oral administration. Pharmaceutical compositions / formulations that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In some embodiments, such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy known to those skilled in the art. See generally, Remington’s Pharmaceutical Sciences, 18thed., Mack Publishing, Easton Pa. (1990). As used herein, oral administration also includes buccal, lingual, and sublingual administration.

[0484] In some embodiments, the formulation further comprises one or more pharmaceutically acceptable excipients or carriers.

[0485] A person of ordinary skill would recognize that pharmaceutical formulation ingredients may serve multiple purposes within a formulation. Accordingly, a person of ordinary skill would recognize that certain formulation components may be classified according to multiple functions (e.g., a component may be both a filler and a binder).

[0486] In some embodiments, a unit dosage form provided herein are prepared by combining the active ingredients in an intimate admixture with one or more pharmaceutically acceptable excipients or carriers, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide, according to conventional pharmaceutical compounding techniques. Excipients or carriers can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients or carriers suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients or carriers suitable for use in solid oral dosage 116 61651714.1PAT27218PCT01 forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[0487] In some embodiments, the active ingredient, such as a compound of the disclosure or a pharmaceutically acceptable salt thereof, is incorporated into the pharmaceutical composition as spray-dried powder or granules. The use of spray-drying to produce powders from fluid feed stocks is well known, with applications ranging from powdered milk to bulk chemicals and pharmaceuticals. See U.S. Pat. No. 4,187,617 and Mujumbar et al., 91 Drying, pages 56-73 (1991). The use of spray-drying to form solid amorphous dispersions of drugs and concentration-enhancing polymers is also known. See commonly owned European Patent Applications Nos. 0901786, 1027886, 1027887, 1027888, and commonly owned PCT Applications Nos. WO 00 / 168092 and WO 00 / 168055, each of which is hereby incorporated by reference. A typical spray-drying apparatus comprises a drying chamber, atomizing means for atomizing a solvent-containing liquid feed into the drying chamber, a source of heated drying gas directed into the drying chamber and dried product collection means for separating the dried product from the cooled drying gas and vaporized solvent stream following its exit from the drying chamber. Examples of such apparatus include Niro Models PSD-1, PSD-2 and PSD-4 (Niro A / S, Soeborg, Denmark).

[0488] The spray-dried powder or granules generally include the active compound in combination with a polymer such as a concentration-enhancing polymer. One class of polymers suitable for use with the present invention comprises non-ionizable (neutral) non- cellulosic polymers. Exemplary polymers include vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclicamido; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone; and polyethylene polyvinyl alcohol copolymers; and polyoxyethylene- polyoxypropylene copolymers.

[0489] Exemplary neutral non-cellulosic polymers are comprised of vinyl copolymers of at least one hydrophilic, hydroxyl-containing repeat unit and at least one hydrophobic, alkyl- or aryl-containing repeat unit. Such neutral vinyl copolymers are termed “amphiphilic hydroxyl-functional vinyl copolymers.” Amphiphilic hydroxyl-functional vinyl copolymers are believed to provide high concentration enhancements due to the amphiphilicity of these copolymers which provide both sufficient hydrophobic groups to interact with the hydrophobic, low-solubility drugs and also sufficient hydrophilic groups to have sufficient 117 61651714.1PAT27218PCT01 aqueous solubility for good dissolution. The copolymeric structure of the amphiphilic hydroxyl-functional vinyl copolymers also allows their hydrophilicity and hydrophobicity to be adjusted to maximize performance with a specific low-solubility drug.

[0490] Another class of polymers suitable for use with the present invention comprises ionizable non-cellulosic polymers. Exemplary polymers include carboxylic acid-functionalized vinyl polymers, such as the carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as the EUDRAGITTMseries manufactured by Rohm Tech Inc., of Malden, Mass.; amine-functionalized polyacrylates and polymethacrylates; proteins such as gelatin and albumin; and carboxylic acid functionalized starches such as starch glycolate.

[0491] Non-cellulosic polymers that are amphiphilic are copolymers of a relatively hydrophilic and a relatively hydrophobic monomer. Examples include acrylate and methacrylate copolymers. Exemplary commercial grades of such copolymers include the EUDRAGITTMseries, which are copolymers of methacrylates and acrylates.

[0492] An additional class of polymers comprises ionizable and neutral (or non-ionizable) cellulosic polymers with at least one ester- and / or ether-linked substituent in which the polymer has a degree of substitution of at least 0.05 for each substituent. It should be noted that in the polymer nomenclature used herein, ether-linked substituents are recited prior to “cellulose” as the moiety attached to the ether group; for example, “ethylbenzoic acid cellulose” has ethoxybenzoic acid substituents. Analogously, ester-linked substituents are recited after “cellulose” as the carboxylate; for example, “cellulose phthalate” has one carboxylic acid of each phthalate moiety ester-linked to the polymer and the other carboxylic acid unreacted.

[0493] In some embodiments, the pharmaceutically acceptable excipients and carriers are selected from fillers, binders, diluents, disintegrants, glidants, and lubricants.

[0494] In some embodiments, the present invention provides a capsule or tablet which comprises a provided pharmaceutical composition in the form of a solid dosage form. In some embodiments, the present invention provides a capsule. In some embodiments, the present invention provides a tablet.

[0495] In certain embodiments, the dosage form is a tablet, wherein the tablet is manufactured using standard, art-recognized tablet processing procedures and equipment. In certain embodiments, the method for forming the tablets is direct compression of a powdered, crystalline and / or granular composition comprising a solid form provided herein, alone or in combination with one or more excipients or carriers, such as, for example, carriers, additives, polymers, or the like. In certain embodiments, as an alternative to direct compression, the 118 61651714.1PAT27218PCT01 tablets may be prepared using wet granulation or dry granulation processes. In certain embodiments, the tablets are molded rather than compressed, starting with a moist or otherwise tractable material. In certain embodiments, compression and granulation techniques are used.

[0496] In certain embodiments, the dosage form is a capsule, wherein the capsules may be manufactured using standard, art-recognized capsule processing procedures and equipment. In certain embodiments, soft gelatin capsules may be prepared in which the capsules contain a mixture comprising a solid form provided herein and vegetable oil or non-aqueous, water miscible materials, such as, for example, polyethylene glycol and the like. In certain embodiments, hard gelatin capsules may be prepared containing granules of solid forms provided herein in combination with a solid pulverulent carrier, such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. In certain embodiments, a hard gelatin capsule shell may be prepared from a capsule composition comprising gelatin and a small amount of plasticizer such as glycerol. In certain embodiments, as an alternative to gelatin, the capsule shell may be made of a carbohydrate material. In certain embodiments, the capsule composition may additionally include polymers, colorings, flavorings and opacifiers as required. In certain embodiments, the capsule comprises HPMC.

[0497] A therapeutically effective dose, of a compound described herein in an oral formulation, may vary from 0.15 mg / kg to 20 mg / kg patient body weight per day, more particularly 0.015 to 1.0 mg / kg, which can be administered in single or multiple doses per day. For oral administration, the drug can be delivered in the form of tablets or capsules containing 1 mg to 100 mg of the active ingredient specifically, 1 mg, 5 mg, 10 mg, 20 mg, 50 mg, or 100 mg, or in the forms of tables or capsules containing at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50% (w / w) of the active ingredient. For example, the capsules may contain 50 mg of the active ingredient, or 5-10% (w / w) of the active ingredient. For example, the tablets may contain 100 mg of the active ingredient, or 20-50% (w / w) of the active ingredient. For example, the tablet may contain, in addition to the active ingredient, a disintegrant or emollient (e.g., croscarmellose or its sodium salt and methyl cellulose), a diluent (e.g., microcrystalline cellulose), and a lubricant (e.g., sodium stearate and magnesium stearate). The drug can be administered on a daily basis either once, twice or more per day.

[0498] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered once, twice, thrice, or four times per day. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered twice per day. In some 119 61651714.1PAT27218PCT01 embodiments, the dose of the compound or pharmaceutically acceptable salt thereof is between about 1 mg BID (i.e., twice per day) to about 20 mg BID.

[0499] In some embodiments, the pharmaceutical composition is administered daily in one or more divided doses. In some embodiments, the composition is administered once per day (qua diem; QD). In some embodiments, the composition is administered twice per day (bis in die; BID). In some embodiments, the composition is administered thrice per day (ter in die; TID). In some embodiments, the composition is administered four times per day (quater in die; QID). In some embodiments, the composition is administered every four (4) hours (quaque four hours; q4h). Synthesis of Compounds

[0500] Compounds of the disclosure G may be synthesized according to the general procedure shown in Scheme 1 and the specific procedures disclosed in the Examples. Pyrazolo[1,5-a]pyrimidine A may be amidated using aminocyclobutyl compound B (prepared as shown in the examples) to produce C. C is Buchwald-Hartwig cross-coupled with compound D (prepared as shown in the examples) to produce F which when deprotected gives compounds G of the disclosure. Scheme 1120 61651714.1PAT27218PCT01

[0501] Deuterium may be incorporated into certain starting materials and reagents used in the Examples, to provide various deuterated compounds of the disclosure I-1, I-2, I-4, I-5, I- 153 and I-154, as shown in Scheme 2. Techniques for incorporation of deuterium into starting materials or reagents will be known to those of skill in the art and it is within routine experimentation to incorporate deuterium at a starting material, reagent or intermediate needed to arrive at a compound of the disclosure. See Kopf et al., Chem. Rev.2022, 122, 6, 6634–6718; Cargnin et al., “A primer of deuterium in drug design,” Future Medicinal Chemistry Vol. 11 No.16; and Yang et al., Asian Journal of Organic Chemistry Vol.10, Issue 10, October 2021, 2473-2485. Scheme 2p pp y p mutandis. 121 61651714.1PAT27218PCT01

[0503] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. EXEMPLIFICATION

[0504] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Example 1. Methods of Preparation of Compound 1

[0505] As depicted in this and other Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of particular compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to the full scope of deuterated compounds described herein.

[0506] Scheme 2 shown below exemplifies the detailed synthetic procedure to produce Compounds 6, 2, and 1. Deuterium-enriched compounds of the present invention may be prepared using methods described in US 2020 / 0131201, WO 2020 / 081508, US 11,046,698 and WO 2019 / 023468, which are hereby incorporated by reference. Scheme 2: Detailed synthetic procedure for synthesis of Compound 1 122 61651714.1PAT27218PCT01 S

[0507] Compound 7 may be prepared as shown in the scheme below. 123 61651714.1PAT27218PCT01Overa ye : 9%. s process was use to prepare Compoun 7 on a 60.0 kg scale, starting from 140.0 kg of ethyl 3-amino-1H-pyrazole-4-carboxylate. The campaign produced 29.31 kg of 7 with a chemical purity of 99.0% and 41.16 kg of 7 with a chemical purity of 98.8%.

[0508] Compound 7 (1.9 kg, 5.82 mol, 1.00 eq), the hydrochloride salt of Compound 5 (800.9 g, 5.82 mol, 1.00 eq), DIPEA (4.5 kg, 34.92 mol, 6.00 eq), T3P (50% in EtOAc) (7.4 kg, 11.64 mol, 2.00 eq) were dissolved in DCM (50.3 kg, 48.0 L, 20 vol) at 0 ± 5oC.

[0509] After agitating at 0 ± 5oC for 1 h, the HPLC (30 min method, UV 242 nm) of the reaction sample showed 81% of desired product Compound 6.

[0510] After agitating the reaction at 0 ± 5oC for additional 1 h, the HPLC of a second reaction sample showed 82% of desired product Compound 6. The sum of starting material Compound 7 and two activated ester intermediates was 18%. At this stage, Applicant proceeded to water quench. Reaction quench and work up

[0511] The reaction mixture was quenched with water (3.8 kg, 3.8 L, 2 vol). The DCM was distilled and the residue was dissolved in EtOAc (68.6 kg, 76.1 L, 40 vol). The organic layer was washed with 20% aqueous K2CO3 solution (33.4 kg, 15 vol), 10% K2CO3 (2 × 19.0 kg, 2 × 10 vol). 124 61651714.1PAT27218PCT01

[0512] HPLC analysis of the organic layer showed 99.05% of desired product Compound 6. The sum of starting material Compound 7 and two by-product activated ester intermediates was 1%.

[0513] After passing purity test, the organic layer was sequentially washed with water (9.5 kg, 5 vol), and brine (2 × 9.5 kg, 2 × 5 vol). The resultant organic layer was filtered over a silica plug (5.7 kg, 2% w / w) with 5.0 kg sand on the top. The silica plug was washed with EtOAc (34.4 kg, 38.0 L, 20 vol). Trituration in n-heptane

[0514] The combined filtrates were concentrated to about 6 L (3.2 vol). n-Heptane (7.8 kg, 11.4 L, 6 vol) was slowly charged over a period of 30 min. The mixture was stirred at 20 ± 5oC for at least 2 h (actual agitation time: overnight, 15.4 h). The solid was collected through filtration and washed with n-heptane [2 × 5.2 kg (2 × 7.6 L, 2 × 4 vol)]. Drying and packaging

[0515] After drying in a vacuum tray dryer at 43oC for 23 h, a sample was pulled for LOD (limit of detection) test, that showed a 0.35% LOD result. The material was packaged, 1.73 kg product Compound 6 was obtained as white solid in 72.4% yield.1H NMR (DMSO-d6) ppm: 1.29 (s, 9H), 1.51 (m, 2H), 2.04 (m, 2H), 3.22 (s, 3H), 3.32 (s, 3H), 3.84 (m, 1H), 4.28 (m, 1H), 7.53 (s, 1H), 8.03 (d, 1H), 8.63 (s, 1H). Step 2: Synthesis of Compound 2

[0516] Compound 4 may be prepared as shown in the scheme below. 125 61651714.1PAT27218PCT01 Overall yield: 74.5%. The above route was used to deliver 3x20 kg of 4. The production batches were initiated using ~18.0 kg (corrected by assay) of 3-aminopyridin-2-ol and ~22.2 kg 2-fluoropyridine. The campaign produced 23.91 kg of 4 with 99.8% chromatographic purity and 22.84 kg of 4 with 99.8% chromatographic purity and 22.90 kg of 4 with 99.8% chromatographic purity respectively.

[0517] Compound 6 (1.7 kg, 4.15 mol, 1.00 eq), Compound 4 (799.3 g, 4.27 mol, 1.03 eq), Pd(OAc)2(18.0 g, 0.08 mol, 0.020 eq), Xantphos (46.3 g, 0.08 mol, 0.020 eq), K2CO3(1.26 kg, 9.13 mol, 2.20 eq) in DME (26.5 kg, 30.6 L, 18 vol) at 80 ± 5oC were combined in a 50 Gallon tank. The reaction was complete after 4 h at 80oC. HPLC (UV 266 nm) analysis of the reaction mixture showed 0.06% remaining Compound 6. Two crops of crude solid

[0518] After reaction completion was confirmed, the reaction mixture was cooled to 20 ± 5oC and stirred at 20 ± 5oC for at least 30 min. The solid was filtered and washed with MTBE twice (4.2 kg and 3.6 kg) to provide “first crop of crude solid.” The filtrate was transferred back to the 50 gallon reactor. The mixture was concentrated until no distillates were observed. DME (3.3 kg) and MTBE (5.6 kg) were charged. The mixture was stirred at 20 ± 5oC for at least 30 min. The solid was collected through filtration and washed with MTBE (6.1 kg) to provide the “second crop of crude solid.” Extractions with DCM

[0519] The two crops of crude solids obtained were combined and transferred to the 50 gallon reactor. DCM (37.9 kg) and water (28.5 kg) were added. The mixture was stirred at 20 ± 5oC for at least 15 min and then allowed to settle for phase separation. The mixture was held to settle overnight (17.5 h) to eliminate emulsion.

[0520] After transferring the DCM layer, the aqueous layer was back extracted with DCM twice (12.6 kg each time). The first back extraction was allowed to settle for 6 h and the second back extraction was allowed to settle overnight (15 h).

[0521] Optionally, the DCM / water mixture could be filtered over celite to remove the insoluble solids before phase separations. The lab runs indicated that after filtration and 126 61651714.1PAT27218PCT01 removal of the insoluble solids, the phase separation became very fast. Additionally, the product loss can be avoided due to an unclear phase separation. Washes with aq. N-Ac-L-Cys, water, and brine

[0522] The combined product in DCM solution was washed with 10% aq. N-Ac-L- Cysteine (NAC) three times (38.0 kg each time). After settling for 30 min, a clean phase separation was obtained. The DCM layer was then washed successively with water (19.0 kg) and saturated aq. NaCl solution (19.0 kg). Activated charcoal treatment

[0523] After NAC treatment, water and brine washes, the product solution in DCM was distilled and solvent swapped to THF (twice with 5.1 kg THF). Activated charcoal (340.0 g, 20wt% with respect to 1.7 kg Compound 6 as starting material) and THF (30.4 kg, 34.2 L, 20 vol with respect to 1.7 kg Compound 6 as starting material) were charged. The mixture was heated to 60 ± 5oC and agitated at 60 ± 5oC for at least 6 h (agitated overnight, ~18 h). Then, the mixture was cooled to 20 ± 5oC and the charcoal was filtered off over celite (3.2 kg). The celite pad was washed with THF (5.0 kg). A sample of the THF solution was pulled. The sample solution was concentrated and tested for palladium (Pd) content analysis. Pd content was found to be < 7.88 ppm. SPM32 treatments

[0524] Three SPM32 treatments (570 g SPM32 for each treatment) were carried out in THF at 60 ± 5oC for at least 6 hours. After cooling to 20 ± 5oC, scavenger SPM32 was filtered off over celite and the celite was washed with THF. The three treatments were as follows:

[0525] 1stSPM32 treatment (570 g SPM32): 60 ± 5oC for 18 h, Celite: 2.4 kg, THF for celite wash: 7.3 kg.

[0526] 2ndSPM32 treatment (570 g SPM32): 60 ± 5oC for 20.4 h, Celite: 1.5 kg, THF for celite wash: 7.2 kg.

[0527] 3rdSPM32 treatment (570 g SPM32): 60 ± 5oC for 21 h, Celite: 1.5 kg, THF for celite wash: 8.1 kg.

[0528] A sample of the THF solution was pulled. The sample solution was concentrated tested for Pd content analysis. Pd content was found to be < 7.94 ppm.

[0529] Distillation

[0530] After SPM32 treatments, the THF solution was concentrated to about 20 L in the 50 gallon tank. The THF solution was transferred to a clean drum. The tank was rinsed with THF (10.4 kg) and the rinse was transferred to the drum. Product isolation was carried out in a 100 L reactor as follows. 127 61651714.1PAT27218PCT01

[0531] Distillation in 100 L reactor: The THF solution in the drum was transferred to a 100 L reactor and concentrated to about 10 L under vacuum. MTBE (14.8 kg, 20.0 L) was charged and the mixture was concentrated to about 10 L. MTBE swap distillation was repeated two more times (14.8 kg MTBE each time and concentrated to about 10 L). Trituration in MTBE

[0532] After solvent distillation (about 10 L remained), MTBE (11.1 kg, 15 L) was charged. The mixture was heated to 50 ± 5oC and stirred at 50 ± 5oC for 1 h. After cooling to 20 ± 5oC, the mixture was stirred at 20 ± 5oC overnight (19.5 h). The batch was filtered and the wet cake was washed with MTBE twice (2.8 kg and 4.8 kg, respectively). A sample of wet cake was pulled and analyzed via HPLC that showed a purity of 99.29%. Drying and packaging

[0533] The material was dried in a vacuum tray dryer at ≤ 45oC for at least 16 h. After drying at 43oC for 21.7 h, a sample was pulled for LOD test that showed a LOD of 0.88%. The material was packaged. 1.5 kg Compound 2 was obtained as an off-white solid with yield of 65.2%.1H NMR (DMSO-d6)ppm: 1.33 (s, 9H), 1.50 (m, 2H), 2.10 (m, 2H), 3.21 (s, 3H), 3.25 (s, 3H), 3.77 (m, 1H), 4.34 (m, 1H), 6.49 (m, 1H), 7.18 (s, 1H), 7.55 (dd, 1H), 7.71 (dd, 1H), 7.88 (d, 1H), 8.0 (d, 1H), 8.05 (dd, 1H), 8.29 (s, 1H), 8.5 (dd, 1H), 8.65 (dd, 1H), 9.75 (s, 1H). Synthesis of Reagent Compounds 5 and 8

[0534] Compound 5 used in the above protocol may be prepared from cyclobutanone according to the scheme and sequences shown below. 128 61651714.1PAT27218PCT01s. Charged DCM (1330 kg, 10 vol.) into a 2000L-stainless-steel reactor under N2protection, and followed by cyclobutanone (100 kg, 1.0 eq.) and TEA (216.6 kg, 1.5 eq.) successively. Cooled to -15 to -25℃. Charged TMSOTf (381.1 kg, 1.2 eq.) in dropwise manner to the reactor at -15 to -25℃ for about 7h. Stirred at -15 to -25℃ for 2 h. Charged N-bromosuccinimide (NBS) (253.3 kg, 1.0 eq.) in portions at -15 to -25℃ for about 16 h. Stirred for 2h at -15 to -25℃. Warmed to 0-10℃, then charged soft water (200 kg, 2 vol.) and stirred for 20 min at 10-20℃. Transferred the mixture to a 3000L-glass-line reactor, charged water (300 kg, 3.0 vol.), stirred for 20 min at 20-30℃. Separated and collected the lower organic layer. Washed organic layer with soft water (500 kg, 5 vol.). Charged 0.5 N HCl (533 kg, 5 vol.) into organic layer and then stirred at 10-20℃ for 1 h. Separated and collected the lower organic layer. Washed organic layer with soft water (500 kg, 5 vol.). Washed organic layer with 10% brine (535 kg, 5 vol.). Concentrated organic layer to 2-3 vol. under vacuum no more than 35℃. Charged DCM (665 kg, 5 vol.), then concentrated to 1-2 vol under vacuum no more than 35℃. Repeat this operation 2 times to remove water. Sample for KF (The criterion: KF ≤0.5%; Result <0.01%). Collected the residual to give light brown oil 2-bromocyclobutan-1-one (331. 8 kg of DCM solution, Assay: 32%, 106.3 kg, KF: <0.01%, Assay yield: 50%). 129 61651714.1PAT27218PCT01

[0536] 2-bromocyclobutan-1-one was converted to 2-(dibenzylamino)cyclobutan-1-one according to the following steps: Charged DCM (707 kg, 5 vol.) into a 3000L-glass-line reactor under N2protection, followed by Bn2NH (140 kg, 1.0 eq.) and DIPEA (115 kg, 1.25 eq.) successively. Charged 2-bromocyclobutan-1-one (106 kg, 1.0 eq.) into the reactor at 15-25℃. Stirred at 15-25℃ for 16 h. Concentrated to 4-5 volumes under vacuum no more than 40 ℃. Charged EtOAc (572 kg, 6 vol.), then concentrated to 4-5 volumes under vacuum no more than 40℃. Charged EtOAc (572 kg, 6 vol.). Washed with water (636 kg, 6 vol.) for once (emulsification layer was separated to aqueous layer). Washed with 2% brine (649 kg, 6 vol.) for once. Extracted EtOAc with 1N HCl (2×636 L, 1×318 L; 2×6 vol., 1×3 vol.), combined aqueous layer. Adjusted pH of the aqueous phase to 9-10 with 20% NaOH. Charged NaCl (212 kg, 2 w / w), stirred until the solid dissolved. Extracted the aqueous layer with THF (755 kg, 8 vol.) once. Extracted the aqueous layer with THF (472 kg, 5 vol.) once again. Combined organic layer and washed with 10% brine (340 kg, 3 vol.) once. Collected the organic layer to give a light yellow solution of 2-(dibenzylamino)cyclobutan-1-one (1155 kg of THF solution, Assay: 14.98%, 173 kg of 5028-2 (Assay corrected), Purity: 93.0% ( Bn2NH: 3.0 %), KF: 7.9%, Assay Yield: 92%), which was used in the next reaction sequence.

[0537] 2-(dibenzylamino)cyclobutan-1-one was converted to racemic trans-2- (dibenzylamino)cyclobutan-1-ol according the the following sequence: Charged the solution of 2-(dibenzylamino)cyclobutan-1-one from the previous sequence (775 kg, contained 116 kg of 2-(dibenzylamino)cyclobutan-1-one) into a 2000 L-stainless steel reactor under N2protection. Charged soft water (47 kg, 0.41 vol. due to THF solution contains 0.59 volume of water) and THF (266 kg, 2.68 vol.) into the reactor. Cooled to -50℃ to -60℃. Charged NaBH4(16.5 kg, 1.0 eq.) to the reactor in several portions at -50℃ to -60℃. Stirred for 1 h at -50℃ to -60℃. Warmed to -10℃ and charged drop wise acetone (90.5 kg, 1 vol.) to quench the reaction. Charged soft water (406 kg, 3.5 vol.) to the reaction ≤ 30℃.Charged MTBE (429 kg, 5 vol.) to dilute the reaction mixture. Separated the mixture and extracted water layer with MTBE (172 kg, 2 vol.), combined the organic layers. Washed the organic layer with 5% brine (300 kg, 2.5 vol.). Washed the organic phase with 20% brine (348 kg, 2.5 vol.). Concentrated the organic layer under vacuum at no more than 45℃ to 220 L (1.9 vol., target: 1-2 vol.) Charged n-heptane (6.0 vol.). Charged n-heptane (3.0 vol.). Concentrated under vacuum at no more than 45℃ to 4-5 vol. Charged n-heptane (3.0 vol.). Stirred at 15-25℃ until a large amount of solid precipitated (no less than 3 h). Heated up to 40℃-45℃, stirred until the material (stuck on the wall of reactor) to the system, then charged n-heptane (2.0 vol.). Cooled to 10-20℃, stirred for no less than 3 h. Filtered and washed the filter cake with n-heptane (2.0 vol.). Dried 130 61651714.1PAT27218PCT01 under vacuum below 35℃, until KF≤0.5%, then Sampled for LOD and report the result. Collected the product to give an off-white solid racemic trans-2-(dibenzylamino)cyclobutan- 1-ol (66.0 kg, P: 98.7% (Bn2NH: 0.51%, Cis: 0.56% ), Isolated Yield: 56.4%).

[0538] Racemic trans-2-(dibenzylamino)cyclobutan-1-ol was enzymatically chirally resolved according to the following sequence: Charged Acetone (1422 kg, 20 vol.) to a 3000 L reactor under N2 protection. Stirred for 20 min and sample for KF (The criterion:KF≤0.5%, the result: KF=0.30%). Charged Racemic racemic trans-2-(dibenzylamino)cyclobutan-1-ol (95.8 kg, 1.0 eq.) to the reactor under N2 protection. Charged Novozymes 435 lipase enzyme (18.84 kg, 0.2 w / w) to the reactor under N2protection. Stirred for 0.5 h at 20-25℃. Charged succinic anhydride (23.3 kg, 0.65 eq.) to the reactor at 20-25℃ under N2 protection. Stirred for 26 h at 20-25℃. Filtered and washed the filter cake with MTBE (1 vol.) for 3 times. Charged water (1.0 eq.) into the filtrate. Collected all filtrate and concentrated under vacuum below 40℃ to 1-3 volumes. Charge MTBE (5.0 vol.) to the residual and concentrate under vacuum below 40℃ to 1-3 vol. Repeat the procedure twice. Diluted the residual with MTBE (10 vol.) and 2.5% aq. K2CO3 (6 vol.), then stirred for 0.5h at 10-15℃. Separated and extracted the MTBE phase with 2.5% aq. K2CO3 (2*6 vol.) at 10-15℃ to ensure no ester into MTBE. Combined all aqueous phase and washed with MTBE (2*2 vol.) (Note: the solid at the interface was separated into aqueous phase). Charged solid NaOH (4.0 eq.) in portions into the aqueous phase below 10℃. Stirred for over 4 h at 15-20℃. Extracted the reaction mixture with MTBE (5.0 vol.) once. Extracted the reaction mixture with MTBE (3.0 vol.) once again (the solid at the interface was separated into aqueous phase). Combined all MTBE phases and washed with water (2*2 vol.). Concentrated the MTBE phase under vacuum below 40℃ to 2-2.5 vol. Charged heptane (5 vol.) into residual and concentrated system under vacuum below 40℃ to 3-3.5 vol. Charged heptane (5 vol.) into residual and concentrated system under vacuum below 40℃ to 3.5-4 vol. Charged heptane to (5 vol.) into residual and stirred for 6 h at 15-25℃. Filtered and washed the filter cake with n-heptane (0.5 vol.) once. Collected filter cake and dried the cake under vacuum, until KF≤0.5%, then Sampled for LOD and report the result. Collected the product to give an off-white chirally resolved solid (1R,2R)-2-(dibenzylamino)cyclobutan-1-ol. (61.93 kg, KF: 0.1%, LOD: 0.75%, HPLC purity: 99.9%, Chiral purity: 99.7%, Isolated yield: 33.5%).

[0539] (1R,2R)-2-(dibenzylamino)cyclobutan-1-ol was converted to (1R,2R)-N,N- dibenzyl-2-methoxycyclobutan-1-amine according the the following sequence: Charged the 2- MeTHF (588 kg, 12.0 vol.) to a 2000 L-glass-line reactor under N2protection. Stirred for 15 min. Charged the (1R,2R)-2-(dibenzylamino)cyclobutan-1-ol (57.0 kg, 1.0 eq.) to the reactor. Stirred for 20 min to give a clear solution. Cooled reaction system to -5 to 0℃. Charged t- 131 61651714.1PAT27218PCT01 BuOK (33.52 kg, 1.4 eq.) in several portions into the reactor at 0±5℃. Stirred for 2 h at 0-5℃. Charged CH3I (42.35 kg, 1.4 eq.) drop wise into the reactor at 0±5℃. Stirred for 4 h at 5±5℃. Charged soft water (5.0 vol.) at 0-30℃, and stirred for 30 min. Separated and collected the organic layer. Extracted aqueous layer with MTBE (3 vol.). Combined the organic phase and washed with soft water (2*2.5 vol.). Washed with brine (2.5 vol.) (The emulsion layer was collected separately as washing with brine). Extracted the emulsion layer with MTBE (2 vol.). Combined the organic layers. Filtered through the activated carbon filter. Concentrated the organic phase to 4-6 vol. under vacuum no more than 50℃. Charged methanol (10.0 vol.) to the reactor, concentrated to 4-6 vol. under vacuum no more than 55℃ (Jacket temperature). Charged methanol (10.0 vol.) to the reactor, concentrated to 4-6 vol. under vacuum no more than 55℃ (Jacket temperature). Collected the concentrated residue to give a solution of (1R,2R)-N,N-dibenzyl-2-methoxycyclobutan-1-amine in MeOH, with HPLC purity: 99.9%.

[0540] Compound 5 was prepared from (1R,2R)-N,N-dibenzyl-2-methoxycyclobutan-1- amine according to the following sequence: Charged the solution of (1R,2R)-N,N-dibenzyl-2- methoxycyclobutan-1-amine (30.0 kg, counted with 100% conversion rate) in MeOH (about 150 L, 5 vol., from previous sequence) into a 1000 L-autoclave under N2 atmosphere, then charged MeOH (14 vol. ). Charged the wet 20% Pd(OH)2 / C (50% water content, 3.0 kg, 0.1 w / w, based on wet weight) to the autoclave under N2atmosphere, then rinsed feeding port with MeOH (1.0 vol.). Stirred and charged the H2 (1.0 MPa) into the autoclave. Stirred about 24 h at 20-30℃. Filtered and washed the filter cake with MeOH (3*1.0 vol.) under N2atmosphere. Collected the filtrate. Charged 4.0 N HCl(g) in MeOH (2.0 eq.) to the filtrate at 20-30℃ in drop-wise. Stirred for 2 h at 20-30℃. Combined another batch. Concentrated the reaction mixture to 3.5-4.5 vol. Charged toluene (5.0 vol.), then concentrated the reaction mixture to 3.5-4.5 vol. Repeat the process once more to remove water in the mixture. Sample for KF (the criterion: 0.10%, result, 0.07%). Charged MTBE (5.0 vol.), then concentrated the reaction mixture to 5.5-6.5 vol, then charged MTBE (1 vol.). Stirred for 3 h at 15-25℃. Filtered and washed the cake with MTBE (2 vol.). Collected the filter cake and dried for 16 h under vacuum at 40-50℃. Collected the cake to give light pink solid Compound 5 (26.92 kg, Purity: 98.1 (GC), Chiral purity: 99.9% (by deriving), KF: 0.1%, The isolated yield: 91.8%).

[0541] Compound 8 and its enantiomer may be prepared using similar methods to those used for compound 5 by substituting d3 iodomethane for iodomethane in the penultimate step. Step 3: Synthesis of Compound 1 132 61651714.1PAT27218PCT01 [kg, 30.6 L, 15 vol) at 40 ± 5oC was charged into a 100 L reactor. The reaction was complete after 21 h at 40oC. HPLC (UV 266 nm) analysis of the reaction mixture showed 99.55% product Compound 1. No peak of starting material Compound 2 was detected in the HPLC. The major impurity peak (0.32%) of the reaction mixture was at 6.932 min (RRT: 0.454). The impurity peak also showed up in the HPLC of the use test reaction (0.29%, RRT 0.47) and the impurity was completely purged after Compound 1 HCl salt filtration. Filtration of HCl salt

[0543] Once the reaction completion was confirmed, the mixture was cooled to 20 ± 5oC and stirred at 20 ± 5oC for at least 30 min. The Compound 1 HCl salt was collected through filtration. The filtration was very slow and it took 5.6 h to filter. The wet cake was washed with EtOH (first wash: 1.8 kg, second wash: 0.8 kg). Neutralization with aqueous K2CO3

[0544] The Compound 1 HCl salt was suspended in aqueous 0.5 N K2CO3 solution (30.0 kg). The mixture was agitated at 20 ± 5oC for at least 1 h and a pH of 1.85 was observed. Additional amount of aqueous 0.5 N K2CO3 solution (42.1 kg) was charged until a pH of ≥ 10 was observed (actual pH: 10.05). The mixture was agitated at 20 ± 5oC for at least 12 h (actual agitation time: 17 h). The solid was collected through filtration. The filtration was very slow and it took 5.9 h to filter. The wet cake was washed twice with water (first wash: 3.0 kg, second wash: 4.5 kg). The wet cake was put back to the 100 L reactor and re-slurried in water (17.0 kg) for 1 h. The solid was collected through filtration. The wet cake was washed twice with water (first wash: 4.5 kg, second wash: 1.1 kg) and EtOH (1.2 kg). The wet cake was dried in a tray dryer at ≤ 60oC for at least 16 h.

[0545] Dryness test (1): After drying at 58oC for 16.4 h, a sample was pulled for KF test for information only (KF result: 12.55%).

[0546] Dryness test (2): After drying at 58oC for an additional 23.2 h (total: 39.6 h), a second sample was pulled for KF test for information only (KF result: 1.12%). This operation 133 61651714.1PAT27218PCT01 was done with a deviation (Deviation Report # 19-111). The material was packaged and 1.14 kg Compound 1 was obtained in 92.7 % yield.

[0547] 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 the 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. 134 61651714.1

Claims

1. PAT27218PCT01 CLAIMS We claim:

1. A compound of Formula I’: or a pharmaceutically acc each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R23, and R24is independently H or D; and R20, R21, and R22are H; 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, R23, and R24is D.

2. The compound of claim 1 of Formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, I-n, or I-o: 135 61651714.1I-d I-e I-f13661651714.161651714.1PAT27218PCT01 I-oor a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein each of R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R23, and R24is as defined in an entry set forth in Table 1.

4. The compound of claim 3, wherein a variable indicated as D in Table 1 has a deuterium % incorporation (% abundance) of about 95% or greater.

5. The compound of any one of claims 2-4, wherein at least one of R1, R2, R3, and R4has a % deuterium incorporation of 95% or greater.

6. The compound of claim 1 of Formula II-a, II-b, II-c, II-d, II-e, II-f, or II-g: 138 61651714.1PAT27218PCT0161651714.1PAT27218PCT01 II-f II-g or a pharmaceutically acceptable salt thereof.

7. The compound of claim 2, wherein each of R1, R2, R3, R4, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R23, and R24is as defined in an entry set forth in Table 2.

8. The compound of claim 7, wherein a variable indicated as D in Table 2 has a deuterium % incorporation (% abundance) of about 95% or greater.

9. The compound of any one of claims 6-8, wherein at least one of R5, R6, and R7has a % deuterium incorporation of 95% or greater.

10. The compound of claim 1 of Formula III-a, III-b, or III-c:

11. The compound of claim 2, wherein each of R1, R2, R3, R4, R5, R6, R7, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R23, and R24is as defined in an entry set forth in Table 3.

12. The compound of claim 11, wherein a variable indicated as D in Table 3 has a deuterium % incorporation (% abundance) of about 95% or greater. 140 61651714.1PAT27218PCT01 13. The compound of any one of claims 10-12, wherein at least one of R8and R9has a % deuterium incorporation of 95% or greater.

14. The compound of claim 1 of Formula IV-a, IV-b, and IV-c:or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R13, R14, R15, R16, R17, R18, R19, R23, and R24is as defined in an entry set forth in Table 4.

16. The compound of claim 15, wherein a variable indicated as D in Table 4 has a deuterium % incorporation (% abundance) of about 95% or greater.

17. The compound of any one of claims 14-16, wherein at least one of R10, R11, and R12has a % deuterium incorporation of 95% or greater.

18. The compound of claim 1 of Formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V- bb, V-cc, or V-dd: 141 61651714.114261651714.114361651714.114461651714.114561651714.1PAT27218PCT01. 146 61651714.1PAT27218PCT01 19. The compound of claim 18, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R17, R18, R19, and R24is as defined in an entry set forth in Table 5.

20. The compound of claim 19, wherein a variable indicated as D in Table 5, has a deuterium % incorporation (% abundance) of about 95% or greater.

21. The compound of any one of claims 18-20, wherein at least one of R13, R14, R15, R16, and R23has a % deuterium incorporation of 95% or greater.

22. The compound of claim 1 of Formula VI-a, VI-b, or VI-c:or a pharmaceutically acceptable salt thereof.

23. The compound of claim 22, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R23, and R24is as defined in an entry set forth in Table 6.

24. The compound of claim 23, wherein a variable indicated as D in Table 6 has a deuterium % incorporation (% abundance) of about 95% or greater.

25. The compound of any one of claims 22-24, wherein at least one of R17, R18, and R19has a % deuterium incorporation of 95% or greater. 147 61651714.1PAT27218PCT01 26. The compound of claim 1 of Formula VII-a, VII-b, VII-c, VII-d, VII-e, VII-f, VII-g, VII-h, VII-i, VII-j, VII-k, VII-l, VII-m, VII-n, VII-o, VII-p, VII-q, VII-r, VII-s, VII-t, VII-u, VII-v, VII-w, VII-x, VII-y, VII-z, VII-aa, VII-bb, VII-cc, VII-dd, VII-de, or VII- df: DDD NH R13D R15148 61651714.1PAT27218PCT01149 61651714.1PAT27218PCT01 DDD NH R8N R13D D150 61651714.1PAT27218PCT01151 61651714.1PAT27218PCT01 R13D D152 61651714.1PAT27218PCT01 or a pharmaceuticall27. The compound of claim 26, wherein the compound is of Formula VII-de or VII-df, or a pharmaceutically acceptable salt thereof.

28. The compound of claim 26 or 27, wherein each variable indicated as D has a deuterium % incorporation (% abundance) of about 50% or greater, about 75% or greater, or about 95% or greater.

29. A compound selected from one of those in Table 8, or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a compound according to any one of claims 1-29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

31. A method of inhibiting TYK2 in a biological sample comprising contacting the sample with the compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30.

32. A method of treating a TYK2-mediated disorder, disease, or condition in a patient comprising administering to said patient the compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30.

33. The method of claim 32, wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. 153 61651714.1PAT27218PCT01 34. The method of claim 33, wherein the disorder is an autoimmune disorder.

35. The method of claim 34, wherein the autoimmune disorder is selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, and inflammatory bowel disease.

36. The method of claim 33, wherein the disorder is an inflammatory disorder.

37. The method of claim 33, wherein the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, and inflammatory bowel disease.

38. The method of claim 33, wherein the disorder is a proliferative disorder.

39. The method of claim 38, wherein the proliferative disorder is a hematological cancer.

40. The method of claim 38, wherein the proliferative disorder is a leukemia.

41. The method of claim 40, wherein the leukemia is a T-cell leukemia.

42. The method of claim 41, wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

43. The method of claim 33, wherein the proliferative disorder is associated with one or more activating mutations in TYK2.

44. The method of claim 33, wherein the disorder is associated with transplantation.

45. The method of claim 44, wherein the disorder is transplant rejection or graft versus host disease.

46. The method of claim 33, wherein the disorder is an endocrine disorder.

47. The method of claim 46, wherein the endocrine disorder is polycystic ovary syndrome, Crouzon’s syndrome, or type 1 diabetes.

48. The method of claim 33, wherein the disorder is a neurological disorder.

49. The method of claim 48, wherein the neurological disorder is Alzheimer’s disease. 154 61651714.1PAT27218PCT01 50. The method of claim 32, wherein the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. 155 61651714.1

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