Isotopologues of MC4r agonist and uses thereof

Abstract

Provided herein are isotopologues of MC4R agonist, processes for the preparation of the compounds, pharmaceutical compositions comprising the compounds, and methods of treating, managing, or preventing certain conditions, diseases, or disorders using the compounds or pharmaceutical compositions described herein.

Description

Attorney Docket No. 14859-002-228ISOTOPOLOGUES OF MC4R AGONIST AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims priority' to U. S. Provisional Application No. 63 / 723,315 filed on November 21, 2024 and U. S. Provisional Application No. 63 / 838,201 filed on July 3, 2025, the entirety' of each of which is incorporated herein by reference.BACKGROUND

[0002] The melanocortin 4 receptor (MC4R) is a heterotrimeric G protein-coupled receptor (GPCR), which is collectively the largest family of transmembrane (TM) receptors in humans, consisting of nearly 800 distinct genes and their corresponding gene products. GPCR possess both extracellular and intracellular elements, making them ideal transducers of stimuli across the cellular membrane. GPCRs can recognize a wide variety’ of extracellular stimuli, including small molecules, ions, and peptides, and communicate the stimuli across an impermeable membrane barrier to the intracellular domain to effect changes in cell function.

[0003] The role of MC4R in governing metabolic homeostasis and energy expenditure makes it a potential drug target for the treatment of various diseases. For example, WO 2005 / 077935 describes the preparation and use of small molecular MC4R agonists, such as PF- 00446687, for the treatment of sexual dysfunctions. PF-00446687 was tested in clinical trials for treating erectile dysfunction m men (NCT00862888) and for treating post-menopausal women with sexual dysfunction (NCT00479570). Some MC4R agonists were also found to have various side effects, such as increase in blood pressure and heart rate (Greenfield et al.. New England Journal of Medicine. 2009;360:44-52),

[0004] Favorable properties for MCR4 agonist compounds include high MCR4 potencies, selectivity' for MCR4 versus MCR1, MCR3, or MCR5, good biopharmaceutical properties, and appropriate stabilities. There remains unmet medical needs to develop MCR4 agonist with improved properties and to explore their uses in different indications, such as in weight managementSUMMARY

[0005] The present application provides certain MCR4 agonist, particularly deuterated compounds, their pharmaceutical compositions, and uses in treating or managing various diseases, disorders, or conditions, such as obesity', diabetes, weight management, erectileNAI-5006781290vl 1Attorney Docket No. 14859-002-228dysfunction, or hypoactive sexual desire disorder. These deuterated compounds may provide improved pharmacokinetics.

[0006] Provided herein is a compound of Formula (I):(I),or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11. Y12, Y13. Y14, Y13, ylo yl7 yl8 yl9 y20 y21 y22 y23 y24 y25 y26 y27 y28 y29 y30 y31 y32 y33 y34 y35 and Y36is a hydrogen that is isotopically enriched with deuterium, and the others of Y1, Y2, Y3, y4 5 y-6 y7 y8 y9 ylO yll y 12 yl3 y!4 y]5 yl6 yl7 y!8 y!9 y20 y21 y22 y23 y24 Y23, y26, y27, y28, y29 y30, y31_ y32, y33, y34, y35, y36afenOU-enrlched hydrogen atOIHS

[0007] Also provided herein are pharmaceutical compositions comprising a compound described herein, such as compounds of Formula (I) and any sub-formula

[0008] Also provided herein are methods of treating, managing, or preventing disease or disorders, such as obesity, diabetes, erectile dysfunction, or hypoactive sexual desire disorder, or methods of managing body weight, using a compound described herein, such as compound of Formula (I) and any sub-formula. Also provided herein are compounds for use in treating, managing, or preventing disease or disorders, such as obesity', diabetes, erectile dysfunction, or hypoactive sexual desire disorder, or for use in managing body weight. Also provided herein are uses of compounds in the manufacture of medicaments for treating, managing, or preventing disease or disorders, such as obesity, diabetes, erectile dysfunction, or hypoactive sexual desire disorder, or for uses in managing body weight.NAI-5006781290v1Attorney Docket No. 14859-002-228BRIEF DESCRIPTION OF THE DRAWING

[0009] Figure 1 shows the pharmacokinetic data of several compounds in rats.DETAILED DESCRIPTION DEFINITIONS

[0010] To facilitate understanding of the application set forth herein, a number of terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0011] The term “isotopic composition’’ refers to the amount of each isotope present for a given atom, and “natural isotopic composition’" refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural isotopic composition.

[0012] The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. As used herein, an “isotopologue” is an isotopically enriched compound.

[0013] The term “isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom's natural isotopic composition. For example, deuterium enrichment of 1% at a given position means that 1 % of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.NAI-5006781290v1Attorney Docket No. 14859-002-228

[0014] The term “isotopic enrichment factor"’ refers to the ratio between the isotopic composition and the natural isotopic composition of a specified isotope. The isotopic enrichment or isotopic enrichment factor of the compounds provided herein can be determined using analytical methods known to one of ordinary skill in the art, including mass spectrometry' and nuclear magnetic resonance spectroscopy.

[0015] With regard to the compounds provided herein, when a particular atomic position is designated as deuterium or “D,” it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.0156%. A position designated as deuterium typically has a minimum isotopic enrichment factor of, in certain embodiments, at least about 1000 (about 15% deuterium incorporation), at least about 2000 (about 30% deuterium incorporation), at least about 3000 (about 45% deuterium incorporation), at least about 3500 (about 52.5% deutenum incorporation), at least about 4000 (about 60% deuterium incorporation), at least about 4500 (about 67.5% deuterium incorporation), at least about 5000 (about 75% deuterium incorporation), at least about 5500 (about 82.5% deuterium incorporation), at least about 6000 (about 90% deuterium incorporation), at least about 6333.3 (about 95% deuterium incorporation), at least about 6466.7 (about 97% deuterium incorporation), at least about 6600 (about 99% deuterium incorporation), or at least about 6633.3 (about 99.5% deuterium incorporation) at each designated deuterium atom. In one embodiment, a position designated as deuterium has an isotopic enrichment factor of at least about 6000 (about 90% deuterium incorporation). In one embodiment, a position designated as deuterium has an isotopic enrichment factor of at least about 6333.3 (about 95% deuterium incorporation). In one embodiment, a position designated as deutenum has an isotopic enrichment factor of at least about 6600 (about 99% deuterium incorporation).

[0016] The terms “overall deuterium incorporation” or “% D” are used interchangeably and refer to the percent of deuterium at enriched positions) in a sample relative to the number of all hydrogen isotopes at the enriched position(s) in that sample (without taking into account of hydrogen and deuterium at non-ennched positions or m impurities). For example, a sample of NIl2-C(CD3)3 with 98% of overall deuterium incorporation (or 98% D) means that 98% of the hydrogen isotopes in the t-butyl group of are D, and 2% of the hydrogen isotopes in the t- butyl group are H. A sample of NHz-CXCDsJs may include small amount of molecules with 0 to 8 deuterium atoms, such as NH2-C(CD3)2(CD2H), NH2-C(CD3)2(CDIl2) and NH2-C(CD3)2(CH3), all of which are taken into account in determining overall deuteriumNAI-5006781290v1 4Attorney Docket No. 14859-002-228incorporation. A person of ordinary skill in the art will understand that the overall deuterium incorporation of a sample depends on the starting materials used to prepare such sample and can be measured by conventional analytical methods, including mass spectrometry, nuclear magnetic resonance spectroscopy, and combustion elemental analysis.

[0017] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March 's Advanced Organic Chemistry, 5th ed., John Wiley & Sons, Inc., New York. 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press. Cambridge, 1987

[0018] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), chiral supercritical fluid chromatograph (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See. for example. Jacques et al.. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al.. Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and. Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The application additionally encompasses compounds descnbed herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers including racemic mixtures. When a stereochemistry is specifically drawn, unless otherw ise contradictory from context, it should be understood that with respect to that particular chiral center or axial chirality, the compound can exist predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%. less than 5%. less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the otherNAI-5006781290v1 5Attorney Docket No. 14859-002-228stereoisomer(s). For example, in some embodiments, the compound can exist predominantly as the as-drawn stereoisomer having an enantiomeric excess (“ee") of greater than 80%. such as having an ee of 90% or above, 95% or above, 98% or above, 99% or above, or have a non- detectable amount of the other enantiomer. The presence and / or amounts of stereoisomers can be determined by those skilled in the art in view of the present application, including through the use of a chiral HPLC or chiral SFC. As understood by those skilled in the art, when a is shown in the chemical structures herein, unless otherwise contradictory from context, it is to designate that the corresponding chiral center is enantiomerically pure or enriched in either of the configurations or is enantiomerically pure or enriched in the as-dawn configuration, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer(s). Also, when no stereochemistry7is specifically drawn, and noc'*'’ is used in the chemical structures, unless otherwise contradictory7from context, it should be understood that such structures include the corresponding compound in any stereoisomeric forms, including individual isomers substantially free of other isomers and mixtures of various isomers including racemic mixtures.

[0019] In some embodiments, the compound is a racemic mixture of (5)- and (7?)- isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or ( / ?)- isomeric configuration. For example, in some embodiments, the compound mixture has an (S)-enantiomenc excess of greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%. greater than about 55%. greater than about 60%, greater than about 65%, greater than about 70%. greater than about 75%. greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, or greater than about 99%. In some embodiments, the compound mixture has an (6)-enantiomeric excess of about 55%, about 60%, about 65%. about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%. about 97%, about 98%, about 99%, or about 99.5%, or more In some embodiments, the compound mixture has an (< ST)-enantiomeric excess of about 55% to about 99.5%, about 60% to about 99,5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%.NAI-5006781290v1 6Attorney Docket No. 14859-002-228

[0020] In other embodiments, the compound mixture has an (J?)-enantiomeric excess of greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%. greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, or greater than about 99%. In some embodiments, the compound mixture has an (?)-enantiomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%, or more. In some embodiments, the compound mixture has an (?)-enantiomeric excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99,5%. about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97'6, to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%.

[0021] In other embodiments, the compound mixture contains identical chemical entities except for their stereochemical orientations, namely (5)- or (7?)-isomers. For example, if a compound provided herein has -CH(R)- unit, and R is not hydrogen, then the -CH(R)- is in an (» )- or ( / ?)- stereochemical orientation for each of the identical chemical entities (z.e., (S)-or (.^-stereoisomers). In some embodiments, the mixture of identical chemical entities (i.e., mixture of stereoisomers) is a racemic mixture of (5')- and (7?)- isomers. In another embodiment, the mixture of the identical chemical entities (i.e., mixture of stereoisomers) contains predominately (S)-isomer or predominately (?)-isomer. For example, in some embodiments, the (5)-isomer in the mixture of identical chemical entities (i.e,, mixture of stereoisomers) is present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% by weight, or more, relative to the total weight of the mixture of OS')- and (H)~ isomers. In some embodiments, the (S)-isomer in the mixture of identical chemical entities (i.e., mixture of stereoisomers) is present at an ( )-enantiomeric excess of about 10% to about 99,5%, about 20% to about 99.5%, about 30% to about 99,5%, about 40% to about 99.5%, about 50% to about 99.5%, about 55% to about 99.5%, about 60% to about 99.5%, about 6.5% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%. about 80% to about 99.5%. about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%,NAI-5006781290v1 7Attorney Docket No. 14859-002-228about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%. or more than about 99.5%.

[0022] In other embodiments, the (7?)-isomer in the mixture of identical chemical entities ( / .e., mixture of stereoisomers) is present at about 55%, about 60%. about 65%, about 70%. about 75%, about 80%, about 85%, about 90%. about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% by weight, or more, relative to the total weight of the mixture of (5)- and (7?)-isomers.. In some embodiments, the ( / ?)-isomers in the mixture of identical chemical entities (z.e., mixture of stereoisomers) is present at an (R)-enantiomeric excess of about 10% to about 99.5%, about 20% to about 99.5%, about 30% to about 99.5%, about 40% to about 99.5%, about 50% to about 99.5%. about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%.

[0023] Enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), the formation and crystallization of chiral salts, or prepared by asymmetric synthesis. See, for example, Enantiomers, Racemates anil Resolutions (Jacques, Ed., Wiley Interscience, New York, 1981); When et al, Tetrahedron 33:2725 (1977): Stereochemistry of Carbon Compounds (E. L. Eliel. Ed., McGraw-Hill, NY, 1962): and Tables of Resolving Agents and Optical Resolutions p 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).

[0024] When a range of values is listed, it is intended to encompass each value and sub¬ range within the range. For example, “Ci 6” is intended to encompass. Ci, C2, C3, C4, Cs, Co, Ci -6, C1-5, C1-4, C1-3. Ci -2, C20, C2-5, C2-4. C2-3, C3 6, C3-5, C3-4, C4-6, C4 5. and C5-6.

[0025] As used herein, the phrase “administration” of a compound, “administering” a compound, or other variants thereof means providing the compound or a prodrug of the compound to the individual in need of treatment.

[0026] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use m 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. Pharmaceutically acceptable salts of compounds described herein includeNAI-5006781290v1 8Attorney Docket No. 14859-002-228acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable. When the compound has a basic group, such as. for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalene sulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals, ammonia, or organic amines.

[0027] The term ‘■tautomers’' or “tautomeric’' refers to two or more interconvertible compounds resulting from tautomerization. The exact ratio of the tautomers depends on several factors, including for example temperature, solvent, and pH. Tautomerizations are known to those skilled in the art. Exemplars' tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0028] The term “MC4R agonist” refers to any class of molecules that lead to activation of downstream signaling of MC4R. Without bound by the theory, on the cell membrane, upon agonist binding, MC4Ris activated and undergoes conformational changes, thereby generating intracellular signaling, including G protein-dependent and / or -independent signaling. Once MC4R is activated, the a-subunit of Gs protein will disassociate from the [5y heterodimer and then activate adenylyl cyclase (AC) to increase the intracellular cAMP levels and subsequently activate protein kinase A (PKA). In some embodiments, provided herein are isotopologues of MC4R agonist.

[0029] The term “GLP-1 receptor agonist” refers to a compound, such as a small molecule or a peptide, capable of binding to and activating downstream signaling cascades from glucagon-like peptide- 1 receptor (GLP1R). Examples of GLP-1 receptor agonist include but not limited to liraglutide, exenatide, efpeglenatide, lixisenatide, albiglutide, beinaglutide, dulaglutide, danugrlipron. orfoglipron, semaglutide. pegapamodutide, tirzepatide, taspoglutide, CT-996, ECC5004. or GS-4571. In some embodiments, the compound provided herein is used in combination with one or more GLP-1 receptor agonist. In some embodiments, the compound provided herein is administered to a subject who has been treated with one or more GLP- 1 receptor agonist.NAI-5006781290v1 9Attorney Docket No. 14859-002-228

[0030] The term “Amylin receptor agonist” refers to a compound, such as a small molecule or a peptide, capable of binding to and activating downstream signaling cascades from any one of the three amylin receptors AMY1, AMY2, and AMY3. Examples of Amylin receptor agonist include but not limited to pramlintide, cagrilintide, eloralintide, colulintide, petrelintide, or GUB-014295. In some embodiments, the compound provided herein is used in combination with one or more Amylin receptor agonist. In some embodiments, the compound provided herein is administered to a subject who has been treated with one or more Amylin receptor agonist.

[0031] The term “subject” (alternatively referred to herein as “patient”) as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of management, treatment, observation, or experiment,

[0032] As used herein, the terms “prevent.” “preventing” and “prevention” are art-recognized, and when used in relation to a condition, such as obesity or diabetes, is well understood in the art, and includes administration of a compound provided herein, which reduces the frequency of. or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.

[0033] As used herein, the terms “manage,” "managing,” and “management” encompass maintaining a condition (e.g., body weight) or preventing, delaying, or reducing a recurrence of condition (e.g., obesity, diabetes, or metabolic syndrome). In some embodiments, a subject is administered one or more therapies to “manage” body weight, so as to prevent significant increase or decrease of body weight (e.g., after treatment of weight disorders). In some embodiments, compounds described herein are used as maintenance therapies (e.g., to reduce the likelihood of disease or disorder recurrence or progression),

[0034] As used herein, the terms “treat,” “treating,” and “treatment” refer to the reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in manner to improve or stabilize a subject's condition. The terms “treat” and “treatment” also refer to the eradication or amelioration of the disease or symptoms associated with the disease. In certain embodiments, such terms refer to minimizing the spread or worsening of the disease resulting from the administration of a compound provided herein or a pharmaceutically acceptable salt, solvate or hydrate thereof to a patient with such a disease,

[0035] The term “effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including,NAI-5006781290v1 10Attorney Docket No. 14859-002-228but not limited to, prophylaxis or treatment of diseases, or maintenance of a condition such as body weight. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated or managed (e.g., the weight, age, and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells and / or tissues. The specific dose will vary depending on the particular compound chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0036] As used herein, the singular form “a”. “an”, and “the”, includes plural references unless it is expressly stated or is unambiguously clear from the context that such is not intended.

[0037] The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A. B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0038] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments.

[0039] As used herein, and unless otherwise specified, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as provided herein is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.NAI-5006781290v1 11Attorney Docket No. 14859-002-228

[0040] As used herein, and unless otherwise indicated, the term ‘'about’’ or ‘"approximately’’ refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about’’ or “approximately’’ means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or "‘approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%. 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0041] It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.COMPOUNDS

[0042] Provided herein are isotopologues of certain MC4R agonist. In some embodiment, the compounds are capable of selectively binding to MC4R (e.g, over MC1R, MC1R, MC3R, or MC5R).

[0043] Without being limited by a particular theory, the compounds described herein may provide certain advantages, for example, (1) improved pharmacokinetics such as increased half-life (rt / z), area under the curve (AUC). or maximum concentration (C max); (2) improved target selectivity; (3) reduced or eliminated unwanted metabolites, and / or (4) decreased doses needed to achieve a desired effect

[0044] Replacement of an atom for one of its isotopes, such as deuterium, may result in a change in the reaction rate. This phenomenon is known as the Kinetic Isotope Effect (“KIE”) or Deuterium Kinetic Isotope Effect (“DKIE”). DKIE can be expressed as a ratio of the rate constants (KH / KD). However, the DKIE is often unpredictable. In specific cases. DKIE might be less than 1 (inverse DKIE) or greater than 5 (larger DKIE). The magnitude of DKIE in vivo depends on many factors, such as the route of metabolism, the enzyme or protein involved, and the specific substrate. Deuteration at one site may divert the compound to other biotransformation route and increase the metabolism at other sites. Additionally, selective and quantitative deuteration during synthesis is also particularly challenging. See Martino et al., Nat Rev Drug Discov 22, 562-584 (2023), which is incorporated herein by reference in its entirety.NAI-5006781290v1Attorney Docket No. 14859-002-228

[0045] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C H bond is broken, and the same reaction where deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen. Without being limited by a particular theory, high DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy.. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.

[0046] The animal body expresses a variety of enzy mes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. Examples of such enzymes include the cytochrome P450 enzymes (‘ CYPs ”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic or pharmacodynamic profile relative to the parent compounds. In some embodiments, the compounds provided herein have improved pharmacokinetic and / or toxicological profiles compared with compounds having a natural isotopic composition.

[0047] In some embodiments, provided herein are isotopologues of Compound I:or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen positions is / are isotopically enriched with deuterium.

[0048] In some embodiments, provided herein are isotopologues of a pharmaceutically acceptable salt of Compound 1:NAI-5006781290v1 13Attorney Docket No. 14859-002-228or a stereoisomer, a mixture of stereoisomers, or a tautomer thereof, wherein one or more hydrogen positions is / are isotopically enriched with deuterium.

[0049] In some embodiments, provided herein is a compound of Formula (I):(D.or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, Y15, Y16, Y17, Y18, Y19, Y20, Y21, Y22, Y23, Y24, Y25, Y26, Y27, Y28, Y29, Y30, Y31, Y32, Y33, Y34, Y35, and Y36is a hydrogen that is isotopically enriched with deuterium ( ‘D”), and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Yi3, Y14, Y15, Y36, Y17, Y18, Y19, Y20, Y21, Y22, Y23, Y24, Y25, Y26, Y27, Y28, Y29, Y-’0, Y33, Y32, Y33, Y34, Y3’, and Y36are non-enriched hydrogen atoms (-‘FT).

[0050] In some embodiments, Y36is H. In some embodiments, Y'6is D.

[0051] In some embodiments, Y33, Y34, and Y35are all H. In some embodiments, one of Y33, Y34, and Y35is D. and the others of Y33, Y34. and Y33are H. In some embodiments, two of Y33, Y34, and Y3’ are D, and the other of Y33, Y34, and Y3' is H. In some embodiments, Y33, Y34, and Y35are all D.NAI-5006781290v1 14Attorney Docket No. 14859-002-228

[0052] In some embodiments, Y29, Y30, Y31, and Y32are all H. In some embodiments, at least one of Y29, Y30. Y31, and Y32is D, and the others of Y29, Y30. Y31, and Y32are H. In some embodiments, at least two of Y29, Y30, Y31, and Y32are D, and the others of Y29, Y30, Y31, and Y32are H. In some embodiments, at least three of Y29, Y30, Y33, and Y32are D, and the other of Y29, Y30, Y?i, and Y’2is H. In some embodiments, one of Y29, Y30, Y3’, and Y32is D, and the others of Y2, Y~30, Yjl, and Y’32are H. In some embodiments, two of Y29, Y30. Y31, and Yj2are D, and the others of Y’29, Y’30, Y31, and Y’32are H, In some embodiments, three of Y’29, Y3°, Y31, and Y32are D, and the other of Y29, Y3U, Y31, and Y32is H. In some embodiments, Y29, Y30, Y31, and Y32are all D.

[0053] In some embodiments, the compound is a compound of formula (I-A):F(I-A),or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein at least one of Y1, Y2, Y3, Y4, Y'5, Y6, Y’7, Y8, Y9, Y10, Y33. Yi2, Yi3. Y14, Y'15, Y16, Y17, Y18, Y39, Y20, Y21. Y22, Y23, Y24, Y25, Y26, Y27, Y28, Y29, Y30, Y31, and Y32is a hydrogen that is isotopically enriched with deuterium, and the others of Y1, Y2, Y3, Y4, Y3, Y”, Y7, Y8, Y9Y10Y33Y12Y33 T34Y33Y39Y37Y38Y39Y29Y23Y"22Y~23Y24Y23Y23*T27Y28Y29, Y39, Y33, and Yj2are non-enriched hydrogen atoms.

[0054] In some embodiments, the compound is a compound of formula (I-A). wherein Y29, Y-’9, Yjl, and Yj2are all D

[0055] In some embodiments, the compound is a compound of formula (II);NAI-5006781290v1 15Attorney Docket No. 14859-002-228F(ID,or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9Y10, Y11, Yi2, Yi3, Y14, Y15, Y16, Y17. Y18, Y19, Y20, Y21, Y22, Y23, Y24, Y25, Y26, Y27. and Y28is a hydrogen that is isotopically enriched with deuterium, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, Y15, Y16, Y17, Y18, Y19, Y20, Y21, Y22, Y23, Y24, Y25, Y26, Y27, and Y28are non-enriched hydrogen atoms.

[0056] In some embodiments, the compound is a compound of Formula (II-A), (II-B), (11- C), (II-D), or (1I-E):NAI-5006781290v1 16Attorney Docket No. 14859-002-228_ (II-E) _ _or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are all H In some embodiments, at least one of Y1, Y2. Y3. Y4. Y5, Y6. Y7. Y8, and Y9is D, and the others of Y1, Y2. Y3, Y4, Y5, Y6, Y7, Y8, and Y9are H. In some embodiments, one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9is D, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are H. In some embodiments, two of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are D, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are H. In some embodiments, three of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are D, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are H. In some embodiments, four of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are D, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are H. In some embodiments, five of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are D, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are H. In some embodiments, six of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are D, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are H. In some embodiments, seven of Y1, Y2, Y3, Y4, Y5, Y6, Y'_ Y8, and Y9are D, and the others of Y1, Y2, Y3, Y4, Y3, Y”, Y7, Y8, and Y9are H. In some embodiments, eight of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are D, and the other of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9is H. In some embodiments, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are all D.

[0058] In some embodiments, Y10, Y11, Y12, Y13, Y14, and Y15are all H. In some embodiments, at least one of Y10, Y11, Y12, Y13, Y14, and Y15is D, and the others of Y10, Y11, Y12, Y13, Y14, and Y15are H. In some embodiments, one of Y10, Y11, Y12, Y13, Y14, and Y15is D, and the others of Y10, Y11, Y12, Y13, Y14, and Y15are H In some embodiments, two of Y10, Y11, Y12, Y13, Y14, and Y15are D, and the others of Y10, Y11, Y12, Y13, Y14, and Y15are H. In some embodiments, Y10and Y11are both D, and Y12, Y’13, Y’14, and Y15are all II. In some embodiments, three of Y10, Y11, Y12, Y13, Y14, and Y15are D, and the others of Y10, Y11, Y12,NAI-5006781290v1 17Attorney Docket No. 14859-002-228Y13, Y14, and Y15are H. In some embodiments, four of Y10, Y11, Y12, Y13, Y14, and Y15are D, and the others of Y10, Y11, Y12, Y13, Y14, and Y15are H. In some embodiments, Y10and Y11are both H, and Y12, Y13, Y14, and Y15are all D. In some embodiments, five of Y10, Y11, Y12, Y13, Y14, and Y15are D, and the other of Y10, Y11, Y12, Y13, Y14, and Y15is H. In some embodiments, Y10, Y11, Y12, Y13, Y14, and Y15are all D.

[0059] In some embodiments, Y16, Y17, Y18, Y19, Y20, and Y21are all H. In some embodiments, at least one of Y16, Y17, Y18, Y19, Y20, and Y21is D, and the others of Y16, Y17, Y18, Y19, Y20, and Y21are H. In some embodiments, one of Y16, Y’7. Y18, Y19, Y20, and Y21is D, and the others of Y16, Y17, Y18, Y19, Y20, and Y21are H. In some embodiments, two of Y16, Y17, Y18, Y19. Y20, and Y21are D, and the others of Y16, Y17, Y18, Y19, Y20, and Y21are H. In some embodiments, three of Y16, Y17, Y18, Y19, Y20, and Y21are D, and the others of Y16, Y17, Y18, Y19, Y20, and Y21are H In some embodiments, Y16, Y17, Y'sare all D, and Y1. Y21’, and Y21are all H. In some embodiments, Y16, Y17, Y18are all H, and Y19, Y20, and Y21are all D. In some embodiments, four of Y16, Y17, Y18, Y19, Y20, and Y21are D, and the others of Y16, Y17, Y18, Y19, Y20, and Y21are H. In some embodiments, five of Y16, Yi7, Y18, Y19, Y20, and Y21are D, and the other of Y16, Y17, Y18, Y19, Y20, and Y2’ is H. In some embodiments, Y16, Y17, Y18, Y19, Y20, and Y21are all D.

[0060] In some embodiments, Y10, Y11, Y12, Y13, Y14, Y15, Y16, Y17, Y18, Y19, Y20, and Y21are all H. In some embodiments, one, two, three, four, five, six, seven, eight, nine, ten, eleven, or all of Y10, Y11, Y12, Y13, Y14, Y15, Y16, Y17, Y18, Y19, Y20, and Y21are D

[0061] In some embodiments, Y22, Y23, Y24, Y25, and Y26are all H. In some embodiments, at least one of Y22, Y23, Y24, Y25, and Y2” is D, and the others of Y22, Y23, Y24, Y23, and Y26are H. In some embodiments, one of Y22, Y23, Y24, Y25, and Y26is D, and the others of Y22, Y23, Y24, Y25, and Y26are H. In some embodiments, two of Y22, Y23, Y24, Y25, and Y26are D, and the others of Y22, Y23, Y24, Y25, and Y26are H. In some embodiments, three of Y22, Y23, Y24, Y25, and Y26are D, and the others of Y22, Y23, Y24, Y25, and Y26are H. In some embodiments, four of Y22, Y23, Y24, Y25, and Y26are D, and the other of Y22, Y23, Y24, Y25, and Y26is H. In some embodiments, Y22, Y23, Y24, Y25, and Y26are all D.

[0062] In some embodiments, Y27and Y28are both H. In some embodiments, at least one of Y27and Y28is D. In some embodiments, Y27and Y28are both D In some embodiments, Y29and Y30are both D, and Y31and Y32are both H. In some embodiments, Y29and Y30are both H, and Y31and Y32are both D.NAI-5006781290v1 18Attorney Docket No. 14859-002-228

[0063] In some embodiments, Y27, Y28, Y29, Y30, Y31, Y32are all H. In some embodiments, one, two, three, four, five, or all of Y27, Y28, Y29, Y30, Y31, Y32are D.

[0064] In some embodiments, the compound is a compound of Formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I), (III-J), (III-K), (III-L), or (III-M):(III-E), (III-F),NAI-5006781290v1 19Attorney Docket No. 14859-002-228(III-L). oror a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments of Formula (III- A), (III-B). (III-C), (III-D), (III-E), (III-G), (III-H). (III-I), (III-J), (III-K), or (III-L), Y’, Y2, Y3, Y4, Y5, Y6, Y7, Ys, and Y9are all D. InNAI-5006781290v1 20Attorney Docket No. 14859-002-228some embodiments of Formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-G), (III-H). (III-I), (III- J), (III-K), or (III-L), Y1. Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are all H.

[0066] In some embodiments, the compound is a compound of Formula (III-E), (III-F), (III-G). (III-H), (III-I). (III-J). or (III-M), wherein Y29. Y30, Y31. and Y32are all D In some embodiments, the compound is a compound of Formula (III-E), (III-F), (III-G), (III-H), (III-I), (III-J), or (III-M), wherein Y29, Y30, Y31, and Y32are all H.

[0067] In some embodiments, the compound is a compound of formula (III-E), (III-F), (III- G). (III-H), (III-I), or (III-J). wherein Y29. Y30, Y31. and Y32are all D and Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are all D. In some embodiments, the compound is a compound of formula (III-K), wherein Y31and Y32are both D and Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are ail D. In some embodiments, the compound is a compound of formula (III-L), wherein Y29and Y30are both D and Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are all D.

[0068] In some embodiments, the compound is a compound of formula (III-E), (III-F), (III- G), (III-H), (III-I), or (III-J), wherein Y29, Y30, Y31, and Y32are all D and Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are all H

[0069] In some embodiments, the compound is a compound of formula (III-E), wherein Y29, Y30, Y31. and Y32are all D and Y1, Y2, Y3, Y4. Y5. Y6. Y7. Y8. and Y9are all D. In some embodiments, the compound is a compound of formula (III-F), wherein Y29, Y30, Y31, and Y32are all D.

[0070] In some embodiments, the compound is a compound of Formula (VI):FYor a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein at least one of Y1, Y2, Y3, Y4, Y5, Y6. Y7, Y8, and Y9is a hydrogen that is isotopically enriched with deuterium, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8are non-enriched hydrogen atoms.

[0071] In some embodiments, the compound is a compound of Formula (V):NAI-5006781290v1 21Attorney Docket No. 14859-002-228F(V),or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein at least one ofY10, Y!!, Y12, Y1’, Y14, and Y15is a hydrogen that is isotopically enriched with deuterium, and the others of Y10, Y11, Y12, Y13, Y14, and Y15are non-enriched hydrogen atoms.

[0072] In some embodiments, the compound is a compound of Formula (VI):(VI),or a stereoisomer, a mixture of stereoisomers, tautomer, or a pharmaceutically acceptable salt thereof, wherein at least one of Y16, Y17, Y18, Y19, Y20, and Y21is a hydrogen that is isotopically enriched with deuterium, and the others of Y16, Y17, Y18, Y19, Y20, and Y21are non-enriched hydrogen atoms.

[0073] In some embodiments, the compound is a compound of Formula ( VII):or a stereoisomer, a mixture of stereoisomers, tautomer, or a pharmaceutically acceptable saltNAI-5006781290v1 22Attorney Docket No. 14859-002-228thereof, wherein at least one of Y22, Y23, Y24, Y25, and Y26is a hydrogen that is isotopically enriched with deuterium, and the others of Y22, Y23. Y24, Y25, and Y26are non-enriched hydrogen atoms.

[0074] Deuterium enrichment of the compound of Formula (I) (or a sub-formula thereof) can be at the t-butyl moiety (option 1), the phenyl moiety connected to the piperidine moiety (option 2), the piperidine moiety (option 3), or the pyrrolidine moiety (option 4), or any combinations thereof.

[0075] In some embodiments, the t-butyl moiety of the compound (i.e..CD3CD2H pDH2CDH2CD2H CD3H-CD3 ty-CD3>.CD> ^-CDH2> I ( CD2H > (-CD3CD3CD33I option 1) is CD3CD3CD3CH3CD3CDH2CD2H CH3> > I — ^~CH3| CDH2| CD2H | — ^-CH3CH3, CDH2, CD2H,orCH3jn someembodiments, each methylgroup in the t-butyl moiety is independently CD₃, CD₂H, CDH₂, or CH₃. In some> |— (" CD3embodiments, the t-butyl moiety is CD3 jnsome embodiments, the t-butyl moiety is CH3I~4-CH3CH3

[0076] In some embodiments, the phenyl moiety connected to the piperidine moiety (i.e..some embodiments, each aromatic hydrogen in the phenyl moiety connected to the piperidine ring (option 2) is independently H or D. In some embodiments, the phenyl moiety connectedNAI-5006781290v1 23Attorney Docket No. 14859-002-228In some embodiments, the phenyl moiety connected tothe piperidine ring is

[0077] In some embodiments, the piperidine moiety of the compound ( / . e.,NAI-5006781290v1 24Attorney Docket No. 14859-002-228D3CHOCDsome embodiments, the piperidine moiety is3in some embodiments, the JD DDHO X V rDpiperidine moietyis D jn someembodiments, the piperidine moiety is D3C D3CDX / DH0KZ^ NA H0KZ^ NA X / T'D I D < D ^^3, In some embodiments, the piperidine moietyis, In D3C ^ P, DHOMJ^ NAX yloI D D CDsome embodiments, the piperidine moiety' is3. In some embodiments, theHo.y ^ NApiperidine moietyis •

[0078] In some embodiments, the pyrrolidine moiety' of the compound ( / . e..NAI-5006781290v1 25Attorney Docket No. 14859-002-228embodiments, the pyrrolidine moietyis In some embodiments, theIn some embodiments, the pyrrolidine moiety isthe left is to the carbonyl group of the compound.

[0079] Ali combinations of the options 1, 2, 3, and / or 4 are specifically provided herein. In some embodiments, options 1 and 2 of the compound of Formula (I) have deuterium enrichment. In some embodiments, options 1 and 3 have deuterium enrichment. In some embodiments, options 1 and 4 have deuterium enrichment. In some embodiments, options 2 and 3 have deuterium enrichment. In some embodiments, options 2 and 4 have deuterium enrichment. In some embodiments, options 3 and 4 have deuterium enrichment. In some embodiments, options 1. 2, and 3 have deuterium enrichment In some embodiments, options 1, 2, and 4 have deuterium enrichment. In some embodiments, options 1, 3, and 4 have deuterium enrichment. In some embodiments, options 2, 3, and 4 have deuterium enrichment. In some embodiments, options 1, 2, 3, and 4 have deuterium enrichment.NAI-5006781290v1 26Attorney Docket No. 14859-002-228

[0080] In some embodiments, each methyl group of the compound of formula (I) (or a sub¬ formula thereof) is independently optionally deuterated. In some embodiments, each methyl group is independently -CHs, -CH2D, -CIID2, or -CDs.

[0081] In some embodiments, the compound is a compound of formula (I- A), or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Y1to Y32are as defined in Table 1 A.Table 1A. Compounds of Formula (I-A) (or its sub-formulas):Compd Y1to Y9Y29to Y31to Y27to Y12to Y10to Y16to Y22to ID are all Y30are Y32are Y28are Y13are Y11are Y21are Y26are all all all all all all all 1 D H H H H H H H 2 H D D H H H H H 3 H H H D H H H H 4 H H H H D H H H 5 H H H H H D H H 6 H H H H H H D H 7 H H H H H H H D 8 D D D H II H II II 9 D H II D H II II H 10 D H H H D H H H 11 D H H H H D H H 12 D H H H H H D H 13 D H H H H H H D 14 H D D D H H H H 15 H D D H D H H H 16 II D D II H D II H 17 II D D H II H D II 18 H D D H H H H D 19 H H H D D H H H 20 H H H D H D H H 21 H H H D H H D H 22 H H H D H H H D 23 H H H H D D H H 24 H H H H D H D H 25 II H II II D II II D 26 H II H H II D D II 27 H H H H H D H D 28 H H H H H H D D 29 D D D D H H H H 30 D D D H D H H H 31 D D D H H D H H 32 D D D H H H D H 33 D D D H H H II D 34 D H II D D II II H 35 D II H D II D H II 36 D H H D H H D H 37 D H H D H H H D38 D H H H D D H HNAI-5006781290v1 27Attorney Docket No. 14859-002-22839 D II H H D II D H 40 D H H H D H H D 41 D II H H II D D I-I 42 D H II II H D I-I D 43 D II H H II I-I D D 44 H D D D D H H H 45 H D D D H D H H 46 H D D D H H D H 47 H D D D H H H D 48 H D D H D D H H 49 H D D H D H D H 50 H D D H D H II D 51 II D D II H D D H 52 H D D H H D H D 53 H D D H H H D D 54 H H H D D D H H 55 H H H D D H D H 56 H H H D D H H D / H H H D H D D H 58 II H II D II D I-I D 59 H II II D II I-I D D 60 H H H H D D D H 61 H H H H D D H D 62 H H H H D H D D 63 H H H H H D D D 64 H H H H D D D D 65 H H H D H D D D 66 H H H D D H D D 67 I-I H II D D D I-I D 68 H II II D D D D I-I 69 H D D H H D D D 70 H D D H D H D D 71 H D D H D D H D 72 H D D H D D D H 73 H D D D H H D D 74 H D D D H D H D 75 H D D D H D D H 76 II D D D D I-I II D 77 H D D D D I-I D I-I 78 H D D D D D H H 79 D H H H H D D D 80 D H H H D H D D 81 D H H H D D H D 82 D H H H D D D H 83 D H H D H H D D 84 D II H D II D I-I D 85 D H II D H D D H 86 D H H D D H H D 87 D H H D D H D H 88 D H H D D D H H 89 D D D H H H D D 90 D D D H H D H D91 D D D H H D D HNAI-5006781290v1 28Attorney Docket No. 14859-002-22892 D D D H D H H D 93 D D D H D H D H 94 D D D H D D II II 95 D D D D H II II D 96 D D D D II H D II 97 D D D D H D H H 98 D D D D D H H H 99 H H H D D D D D 100 H D D H D D D D 101 H D D D H D D D 102 H D D D D H D D 103 H D D D D D H D 104 II D D D D D D H 105 D H H H D D D D 106 D H H D H D D D 107 D H H D D H D D 108 D H H D D D H D 109 D H H D D D D H 110 D D D H H D D D 111 D D D II D II D D 112 D D D H D D II D 113 D D D H D D D H 114 D D D D H H D D 115 D D D D H D H D 116 D D D D H D D H 117 D D D D D H H D 118 D D D D D H D H 119 D D D D D D H H 120 D D D D D D D H 121 D D D D D D II D 122 D D D D D H D D 123 D D D D H D D D 124 D D D H D D D D 125 D H H D D D D D 126 H D D D D D D D 127 D D D D D D D D 128 H H D H H H H H 129 II D II II H II II H 130 H II D H II H II D 131 H D H H H H H D 132 H H D H H H D H 133 H D H H H H D H 134 H H D H H H D D 135 H D H H H H D D 136 H H D H H D H H 137 H D II II II D II II 138 II H D II H D II D 139 H D H H H D H D 140 H H D H H D D H 141 H D H H H D D H 142 H H D H H D D D 143 H D H H H D D D144 H H D H D H H HNAI-5006781290v1 29Attorney Docket No. 14859-002-228145 H D H H D II H H 146 H H D H D H H D 147 H D II H D I-I I-I D 148 II II D II D II D H 149 H D II H D I-I D I-I 150 H H D H D H D D 151 H D H H D H D D 152 H H D H D D H H 153 H D H H D D H H 154 H H D H D D H D 155 H D H H D D H D 156 H II D H D D D H 157 II D II II D D D H 158 H H D H D D D D 159 H D H H D D D D 160 H H D D H H H H 161 H D H D H H H H 162 H H D D H H H D 163 H D H D H H H D 164 II II D D II I-I D H 165 H D II D II II D I-I 166 H H D D H H D D 167 H D H D H H D D 168 H H D D H D H H 169 H D H D H D H H 170 H H D D H D H D 171 H D H D H D H D 172 H H D D H D D H 173 I-I D II D H D D H 174 H II D D II D D D 175 H D H D H D D D 176 H H D D D H H H 177 H D H D D H H H 178 H H D D D H H D 179 H D H D D H H D 180 H H D D D H D H 181 H D H D D H D H 182 II II D D D II D D 183 H D II D D I-I D D 184 H H D D D D H H 185 H D H D D D H H 186 H H D D D D H D 187 H D H D D D H D 188 H H D D D D D H 189 H D H D D D D H 190 H II D D D D D D 191 II D II D D D D D 192 D H D H H H H H 193 D D H H H H H H 194 D H D H H H H D 195 D D H H H H H D 196 D H D H H H D H197 D D H H H H D HNAI-5006781290v1 30Attorney Docket No. 14859-002-228198 D II D H H II D D 199 D D H H H H D D 200 D II D H II D II II 201 D D II II H D II H 202 D II D H H D II D 203 D D H H H D H D 204 D H D H H D D H 205 D D H H H D D H 206 D H D H H D D D 207 D D H H H D D D 208 D H D H D H H H 209 D D H H D H H II 210 D II D II D II II D 211 D D H H D H H D 212 D H D H D H D H 213 D D H H D H D H 214 D H D H D H D D 215 D D H H D H D D 216 D H D H D D H H 217 D D II II D D II H 218 D II D H D D II D 219 D D H H D D H D 220 D H D H D D D H 221 D D H H D D D H 222 D H D H D D D D 223 D D H H D D D D 224 D H D D H H H H 225 D D H D H H H H 226 D H D D H II H D 227 D D II D II II II D 228 D H D D H H D H 229 D D H D H H D H 230 D H D D H H D D 231 D D H D H H D D 232 D H D D H D H H 233 D D H D H D H H 234 D H D D H D H D 235 D D II D H D II D 236 D II D D II D D II 237 D D H D H D D H 238 D H D D H D D D 239 D D H D H D D D 240 D H D D D H H H 241 D D H D D H H H 242 D H D D D H H D 243 D D II D D II II D 244 D II D D D II D H 245 D D H D D H D H 246 D H D D D H D D 247 D D H D D H D D 248 D H D D D D H H 249 D D H D D D H H250 D H D D D D H DNAI-5006781290v1 31Attorney Docket No. 14859-002-228251 D D H D D D H D 252 D H D D D D D H 253 D D H D D D D II 254 D H D D D D D D255 D D H D D D D D

[0082] In some embodiments, the compound is a compound of Formula (I) selected from any one of the compounds in Table 1, or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.Table 1: Deuterium enriched compounds of Formula (I) (or its sub -formulas):NAI-5006781290v1 32Attorney Docket No. 14859-002-228NAI-5006781290v1 33Attorney Docket No. 14859-002-228NAI-5006781290v1 34Attorney Docket No. 14859-002-228

[0084] In some embodiments, for the compounds provided herein, including any compound specifically provided m Tables 1 and 1A, each position designated as deuterium independently has a minimum isotopic enrichment factor of at least 1000 (about 15% deuterium incorporation), at least 2000 (about 30% deuterium incorporation), at least 3000 (about 45% deuterium incorporation), at least 3500 (about 52.5% deuterium incorporation), at least 4000 (about 60% deuterium incorporation), at least 4500 (about 67.5% deuterium incorporation), at least 5000 (about 75% deuterium incorporation), at least 5500 (about 82.5% deuterium incorporation), at least 6000 (about 90% deuterium incorporation), at least 6333.3 (about 95% deuterium incorporation), at least 6466.7 (about 97% deuterium incorporation), at least 6600 (about 99% deuterium incorporation), or at least 6633.3 (about 99.5% deuterium incorporation) at each designated deuterium atom. In some embodiments, each position designated as deuterium independently has an isotopic enrichment factor of at least about 6000 (about 90% deuterium incorporation), at least about 6333.3 (about 95% deuterium incorporation), or at least about 6600 (about 99% deuterium incorporation).

[0085] In some embodiments, for the compounds provided herein, including any compound specifically provided in Tables 1 and 1 A, the overall deuterium incorporation (or % D) of the compound is at least about 60%, at least about 67.5%, at least about 75%, at least about 82.5%, at least about 90%, at least about 95%. or at least about 99%. In some embodiments, the overall deuterium incorporation is at least about 90%, at least about 95%, or at least about 99%.

[0086] In some embodiments, for the compounds provided herein, including any compound specifically provided in Tables 1 and I A, the molecules that are deuterated at all of the position(s) designated as deuterium consists of at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 80%, at least about 90%, or at least about 95 % of the compound. In some embodiments, theNAI-5006781290v1 35Attorney Docket No. 14859-002-228molecules that are deuterated at all of the position(s) designated as deuterium consists of at least about 65%. at least about 70%, at least about 80%, at least about 90%. or at least about 95% of the compound. As an illustrative example, a sample of Compound la may contain 80% of Compound la molecules (i.e., with a -C(CD3)s group) and 20% of other molecules with less deuterium atoms, such as molecules with a -C(CD3)?.(CD2H) or -CtCDs^tCDH?) group. A person of ordinary' skill in the art will understand that the percent of the compound itself in a sample can depend on the starting materials used to prepare such sample and can be measured by conventional analytical methods, including mass spectrometry' and nuclear magnetic resonance spectroscopy.

[0087] In some embodiments, the compounds provided herein, including any compound specifically provided in the tables above, have a diastereomeric excess (de) of at least about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 75%, about 90%, about 95%, or about 99%. In some embodiments, the diastereomeric excess is at least 50%. In some embodiments, the diastereomeric excess is at least 75% In some embodiments, the di stereomeric excess is at least 90%. In some embodiments, the diastereomeric excess is at least 95%. In some embodiments, the diastereomeric excess is at least 99%.

[0088] In some embodiments, the compounds provided herein, including any compound specifically provided in the tables above, have an enantiomeric excess (ee) of at least about 1%, about 5%. about 10%, about 20%, about 30%, about 40%. about 50%, about 75%, about 90%, about 95%, or about 99%, at one or more chiral centers. In some embodiments, the enantiomeric excess is at least 50%. In some embodiments, the enantiomeric excess is at least 75%. In some embodiments, the enantiomeric excess is at least 90%, In some embodiments, the enantiomeric excess is at least 95%. In some embodiments, the enantiomeric excess is at least 99%.

[0089] In some embodiments, the compounds provided herein have a MC4 ECso level of less than 200 nM, less than 100 nM, less than 50 nM. less than 25 nM, less than 20 nM, less than 15 nM, or less than 10 nM. In some embodiments, the compounds provided herein have a MC4 EC-io level of less than 15 nM. In some embodiments, the compounds provided herein have a MC4 ECso level of less than 10 nM.

[0090] In some embodiments, the compounds described herein provide increased half-life (riz?) in vivo. In some embodiments, the compounds described herein have an in vivo half-life (ti / .?) of at least 10%, at least 15%, at least 20%, at least 25%. at least 30%, at least 35%, at leastNAI-5006781290v1 36Attorney Docket No. 14859-002-22840%, or at least 50% higher than the reference compound without deuterium. In some embodiments, the compounds described herein has an in vivo half-life (ti / 2) of at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 24 hours, at least 26 hours, at least 28 hours, at least 30 hours, at least 32 hours, at least 34 hours, at least 36 hours, at least 38 hours, at least 40 hours, or at least 45 hours as measured in vivo. In some embodiments, the half-life is measured in human.

[0091] The synthesis of the compounds provided herein may be readily achieved by synthetic chemists of ordinary skill by reference to the exemplary synthesis and examples provided herein. Analogous procedures used for the preparation of certain non-deuterium enriched MC4R are provided in U. S. Patent Application Publication No. 2005 / 0176772, the entirely of which is incorporated herein by reference,PHARMACEUTICAL COMPOSITIONS

[0092] Certain embodiments are directed to a pharmaceutical composition comprising one or more compounds described herein.

[0093] The pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound described herein (e.g, any of the specific compounds described in Table 1 herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which describes various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof

[0094] The pharmaceutical composition can include any one or more of the compounds described herein. For example, in some embodiments, the pharmaceutical composition comprises any of the specific compounds described in Table 1 herein, or a pharmaceutically acceptable salt thereof, e.g., in a therapeutically effective amount. In any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effectiveNAI-5006781290v1 37Attorney Docket No. 14859-002-228amount (e.g., for treating obesity or diabetes or managing body weight) of a compound selected from any the specific compounds described in Table 1 herein, or a pharmaceutically acceptable salt thereof.

[0095] The pharmaceutical composition herein can be formulated for delivery via any of the known routes of delivery', which include but not limited to administering orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally.

[0096] In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound, and one or more excipients. In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection).

[0097] Compounds of the present application can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, e.g, in combination with one or more additional therapeutic agent, such as therapeutic agents to treat or manage obesity or diabetes, or any other drugs used to manage or maintain body weight.

[0098] When used in combination 'ith one or more additional therapeutic agents, compounds of the present application or pharmaceutical compositions herein can be administered to the subject either concurrently or sequentially in any order with such additional therapeutic agents. In some embodiments, the pharmaceutical composition can comprise one or more compounds of the present application and the one or more additional therapeutic agents in a single composition or separate compositions In some embodiments, the pharmaceutical composition comprising one or more compounds of the present application can be included m a kit which also comprises a separate pharmaceutical composition comprising the one or more additional therapeutic agents

[0099] The pharmaceutical composition can include various amounts of the compounds of the present application, depending on various factors such as the intended use and potency and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present application. In some embodiments, the pharmaceutical composition comprises a therapeutically effectiveNAI-5006781290v1 38Attorney Docket No. 14859-002-228amount of the compound of the present application and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present application is an amount effective to treat, prevent, or manage a disease, disorder, or condition as described herein, such as obesity, diabetes, body weight management, erectile dysfunction, or hypoactive sexual desire disorder, which can depend on the recipient of the treatment, the disorder, condition, or disease being treated or managed and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.METHOD OF TREATMENT

[0100] Compounds of the present application have various utilities. For example, compounds of the present application can be used as therapeutic active substances for treating obesity or diabetes or managing body weight, or for treating erectile dysfunction or hypoactive sexual desire disorder. Accordingly, some aspects of the present application are also directed to methods of using one or more compounds of the present application or pharmaceutical compositions herein for treating, managing, or preventing obesity or diabetes or managing body weight in a subject in need thereof Other aspects of the present application are directed to methods of using one or more compounds or pharmaceutical compositions described herein for treating, managing, or preventing sexual dysfunctions, such as erectile dysfunction or hypoactive sexual desire disorder.

[0101] In some embodiments, the compounds described here are used in the treatment of diseases or disorders related to the leptin-melanocortin pathway. In some embodiment, the compound described here are used in treating, managing, or preventing diseases, disorders, or conditions including, but not limited to, obesity (e g., by reducing appetite, increasing metabolic rate, reducing fat intake, or reducing carbohydrate craving), diabetes mellitus (e.g., by enhancing glucose tolerance or decreasing insulin resistance), body weight management, erectile dysfunction, or hypoactive sexual desire disorder

[0102] In some embodiments, provided herein is a method of treating, preventing, or managing metabolic disease or medical condition accompanied by weight gain, such as obesity or feeding disorders, by administering an effective amount of the compound described herein. Without bound by theory-, it is believed that an agonist anti-obesity effect is elicited from the leptin-melanocortin receptor. In some embodiments, the disease or condition treated orNAI-5006781290v1 39Attorney Docket No. 14859-002-228managed is obesity. In some embodiments, the disease or condition treated or managed is a feeding disorder.

[0103] In some embodiments, provided herein is a method of decreasing food intake, decreasing body weight, managing body weight, or a combination thereof, by administering an effective amount of the compound described herein. In some embodiments, provided herein is a method of decreasing food intake, decreasing body weight, managing body weight, or a combination thereof, by eliciting an agonist or antagonist effect from a leptin-melanocortin receptor by administering an effective amount of a compound described herein. In some embodiments, provided herein is a method of managing weight.

[0104] In some embodiments, provided herein is a method of decreasing appetite without compromising body weight by administering an effective amount of a compound described herein. In some embodiments, provided herein is a method of decreasing food consumption while decreasing body weight by administering an effective amount of a compound described herein. In some embodiments, provided herein is a method for increasing or normalizing energy' expenditure, e.g., facilitating and / or effecting weight loss due to a reduction in fat mass in the subject.1001051 In some embodiments, the method described herein comprises ameliorating or improving a clinical symptom or indicators associated with a disorder described herein, such as obesity, type-I diabetes, type-II diabetes, pre-diabetic condition, blood level of hemoglobin A1C (HblAc) above 6%, hyperinsulinemia, hyperlipidemia, insulin insensitivity, or glucose intolerance. In some embodiments, the method described herein delays, inhibits, or prevents the progression of obesity or obesity related indications.

[0106] In some embodiments, provided herein is a method of treating a subject having obesity by administering an effective amount of the compound described herein. In embodiments, the subject has early onset severe obesity'. In embodiments, the subject is hyperphagic. In embodiments, the subject experiences severe hunger. In embodiments, the subject has a body mass index (BMI) greater than 25 kg / m2(e.g., 25, 30. 31, 32, 33, 34, 35, 36.37, 38, 39, 40, 41, 42. 43, 44, 45, 46, 47, 48, 49, or 50 kg / m2or greater). In some embodiments, the subject having obesity has failed one or more previous therapies, e.g., exercise, diet, or behavioral therapies, prior to administration of the compound described herein. In some embodiments, the subject has a lower body weight or BMI after administration of the compound described herein.NAI-5006781290v1 40Attorney Docket No. 14859-002-228

[0107] In some embodiments, administration of the compounds described herein results in no detectable / significant decrease in resting energy expenditure (REE) in the subject, e.g., over a period of 24 hours, a week, or 30 days or longer. In some embodiments, administration of the compounds described herein results in a reduction in food intake. In embodiments, administration of the compounds described herein results in a reduction in waist circumference of the subject. In some embodiments, administration of the compounds described herein results in increases in resting energy expenditure (REE) in the subject.

[0108] In some embodiments, administration of the compounds described herein results in no detectable increase in blood pressure (e.g., diastolic and / or systolic blood pressure). In some embodiments, administration of the compounds described herein results in a reduction in blood pressure. In some embodiments, administration of the compounds described herein results in an increase in blood pressure.

[0109] In embodiments, administration of the compounds described herein results in a reduction of hunger in a subject. The reduction of hunger may result in a reduction of food intake, decrease in resting energy expenditure (REE), reduction of weight, reduction in waist circumference, or reduction in blood pressure in the subject. In embodiments, administration of the compounds described herein results in an increase in hunger in a subject.

[0110] In some embodiments, provided herein is a method of treating a reproductive or sexual medical condition, such as endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction, and decreased sexual response, by administering a pharmaceutically effective amount of a compound of described herein. In some embodiments, provided herein is a method of treating male and female sexual dysfunction, particularly male erectile dysfunction. In some embodiments, provided herein is a method of treating female sexual dysfunction (FSD), such as female sexual arousal disorder (FSAD), desire disorders such as hypoactive sexual desire disorder, or orgasmic disorders such as anorgasmia. In some embodiments, provided herein is a method of treating male sexual dysfunction, including male erectile dysfunction (MED) and ejaculatory disorders such as anorgasmia, or desire disorders such as hypoactive sexual desire disorder.

[0111] In some embodiments, the compounds described herein are used to treat patients with Female Sexual Dysfunction (FSD) that arises from:NAI-5006781290v1 41Attorney Docket No. 14859-002-228(i) Vasculogenic etiologies, e.g., cardiovascular or atherosclerotic diseases, hypercholesterolemia, cigarette smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury to the iliohypogastric pudendal vascular system;(ii) Neurogenic etiologies such as spinal cord injuries or diseases of the central nervous system including multiple sclerosis, diabetes, Parkinsonism, cerebrovascular accidents, peripheral neuropathies, trauma or radical pelvic surgery;(iii) Hormonal / endocrine etiologies such as dysfunction of the hypothalamic / pituitary / gonadal axis, or dysfunction of the ovaries, dysfunction of the pancreas, surgical or medical castration, androgen deficiency, high circulating levels of prolactin e.g. hyperprolactinemia, natural menopause, premature ovarian failure, hyperand hypothyroidism;(iv) Psychogenic etiologies such as depression, obsessive compulsive disorder, anxiety disorder, postnatal depression Baby Blues”, emotional and relational issues, performance anxiety, marital discord, dysfunctional attitudes, sexual phobias, religious inhibition, or a traumatic past experience; and / or(v) Drug-induced sexual dysfunction resulting from therapy with selective serotonin reuptake inhibitors (SSRIs) and other antidepressant therapies (tricyclics and major tranquillizers), anti-hypertensive therapies, sympatholytic drugs, chronic oral contraceptive pill therapy,

[0112] The administering in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. In some embodiments, the administering is a parenteral injection, such as an intravenous injection. In some embodiments, the administering is orally.

[0113] Compounds of the present application can be used as a monotherapy or in a combination therapy. In some embodiments according to the methods described herein, one or more compounds of the present application can be administered as the only' active ingredient (s). In some embodiments according to the methods described herein, one or more compounds of the present application can also be co-administered with an additional therapeutic agent, either concurrently or sequentially in any order, to the subject in need thereof.

[0114] In one aspect, the compound described herein is administered in combination with one or more additional therapeutic agent, such as therapeutic agents to treat, manage, or prevent obesity or diabetes or therapeutic agents to manage body weight.NAI-5006781290v1 42Attorney Docket No. 14859-002-228

[0115] In some embodiments, provided herein is a method of managing weight in a subject by administering an effective amount of the compound described herein. In some embodiments, the subject is a healthy subject. In some embodiments, the subject has ongoing obesity or diabetes (e.g, type 2 diabetes). In some embodiments, the subject has a history of obesity or diabetes (e.g., type 2 diabetes). In some embodiments, the subject has been treated with one or more GLP-1 receptor agonist before administration of the compound described herein, including but not limited to, injectable peptidic GLP-1 receptor agonist, oral peptidic GLP-1 receptor agonist, or oral small molecule GLP-1 receptor agonist. In some embodiments, the subject has been treated with one or more injectable or oral peptidic GLP-1 receptor agonists, including but not limited to, semaglutide, liraglutide, dulaglutide, exenatide, albiglutide. or lixisenatide. before administration of the compound described herein. In some embodiments, the subject has been treated with one or more of the oral small molecule GLP-1 receptor agonists, including but not limited to, orfoglipron, danugrlipron, CT-996, ECC5004, or GS-4571, before administration of the compounds described herein. In some embodiments, the compounds provided herein help maintain the body mass index (BMI) of the subject below about 50 kg / m2, below about 45 kg / m2, below about 40 kg / m2, or below about 30 kg / m2.

[0116] In some embodiments, the compound described herein is administered in combination with one or more GLP-1 receptor agonist, including but not limited to, injectable peptidic, oral peptidic, or oral small molecule GLP-1 receptor agonist. In some embodiments, the subject is or has been treated with a combination of an injectable or oral peptidic GLP-1 receptor agonist, including but not limited to, semaglutide, liraglutide, dulaglutide, exenatide, albiglutide. or lixisenatide, and a compound described herein. In some embodiments, the subject is or has been treated with a combination of an oral small molecule GLP-1 receptor agonist, including but not limited to, orfoglipron, danuglipron, CT-996, ECC5004, or GS-4571, and a compound described herein. The compound provided herein may be administered to a subject simultaneously with, prior to, or after administration of one or more GLP-1 receptor agonist In some embodiment, the combination is used for treating, managing, or preventing obesity. In some embodiments, the combination is used for managing body weight. In some embodiments, the combination is used for treating, managing, or preventing diabetes. In some embodiments, the combination helps maintain or enhance the effects on treating, managing, or preventing obesity.

[0117] In some embodiments, provided herein is a method of managing weight in a subject by administering an effective amount of the compound described herein. In someNAI-5006781290v1 43Attorney Docket No. 14859-002-228embodiments, the subject is a healthy subject. In some embodiments, the subject has ongoing obesity or diabetes (e.g. ty pe 2 diabetes). In some embodiments, the subject has a history’ of obesity or diabetes (e.g., type 2 diabetes). In some embodiments, the subject has been treated yvith one or more Amylin receptor agonist before administration of the compound described herein, including but not limited to, injectable peptidic Amylin receptor agonist, oral peptidic Amylin receptor agonist, or oral small molecule Amylin receptor agonist. In some embodiments, the subject has been treated with one or more injectable or oral peptidic Amylin receptor agonists, including but not limited to, pramlintide, cagrilintide, eloralintide, colulintide, petrelintide, or GUB-014295, before administration of the compound described herein. In some embodiments, the subject has been treated with one or more oral small molecule Amylin receptor agonists before administration of the compounds described herein. In some embodiments, the compounds provided herein help maintain the body mass index (BMI) of the subject below about 50 kg / m2, below about 45 kg / m2, below about 40 kg / m2, or below about 30 kg / m2.

[0118] In some embodiments, the compound described herein is administered in combination with one or more Amylin receptor agonist, including but not limited to, injectable peptidic, oral peptidic, or oral small molecule Amylin receptor agonist. In some embodiments, the subject is or has been treated with a combination of an injectable or oral peptidic Amylin receptor agonist, including but not limited to. pramlintide, cagrilintide. eloralintide, colulintide, petrelintide, or GUB-014295, and a compound described herein. In some embodiments, the subject is or has been treated with a combination of an oral small molecule Amylin receptor agonist and a compound described herein. The compound provided herein may be administered to a subject simultaneously with, prior to, or after administration of one or more Amylin receptor agonist. In some embodiment, the combination is used for treating, managing, or preventing obesity. In some embodiments, the combination is used for managing body weight. In some embodiments, the combination is used for treating, managing, or preventing diabetes. In some embodiments, the combination helps maintain or enhance the effects on treating, managing, or preventing obesity.

[0119] Dosing regimen including doses for the methods described herein can vary’ and be adjusted, which can depend on the recipient of the treatment, the disorder, condition or disease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administeredNAI-5006781290v1 44Attorney Docket No. 14859-002-228EXAMPLES

[0120] The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and / or techniques well known in the art. Unless otherwise specified, all overall deuterium incorporation (% D) and percent of D molecules as shown in the structures herein are calculated from measured mass spectrometry data of the compound samples, assuming that only the D molecules and D-l molecules are present. D molecules refer to the molecules that are deuterated at all of the position(s) designed as deuterium, and D-l molecules refer to the molecules that has one deuterium replaced by hydrogen as compared to the D molecules. The mass of D-l molecules is 1 amu less than the D molecules.AbbreviationsDCM: dichloromethane THF: tetrahydrofuranMeOH: methanol EtOH: ethanolNH4Cl: ammonium chloride i-PrOH: isopropyl alcoholMTBE: methyl tert-butyl ether DMSO: dimethyl sulfoxide MeCN / ACN: acetonitrile EtOAc: ethyl acetateTEA: triethylamine K2CO3: potassium carbonateMel: iodomethane EtI: iodoethaneEt20: diethyl ether PdCl2: palladium(TI) chlorideNaHCO3: sodium bicarbonate NH4HCO3: ammonium bicarbonate ClPO(O-iPr)2: diisopropyl n-BuLi: n-butyllithium phosphorochloridateNaOH: sodium hydroxide EDC1: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide DMAP: 4-dimethylaminopyridine Na2SO4: sodium sulfateDIEA: N,N-diisopropylethylamine TBAC: tetrabutylammonium chloride TBAI: tetrabutylammonium iodide TrP: 1,3,5,2,4,6-Trioxatriphosphorinane,2,4,6-tributyl-, 2,4,6-trioxideDMF: N, 7V-di methylformamide NMO: N-methylmorpholine N-oxide m-CPBA: meta-chloroperoxy benzoic acid LiHMDS: lithium bis(trimethylsilyl)arnide tBu-ONa: sodium tert-butoxide CDCl3: chloroform-dCD3OD / MeOD: methanol-d D2O: deuterium oxide1HNMR: proton nuclear magnetic resonance19FNMR: fluorine- 19 nuclear magneticNAI-5006781290v1 45Attorney Docket No. 14859-002-228resonanceSynthetic Procedures(3S,4R)-4-(2,4- ifluorophenyl)-l-(2-(methyI- 3)propan-2-yl-l,l,1 -d6)pyrrolidine-3- carboxylic acid. Common Intermediate ASynthesis of (S)-2-chloro-l-(2,4-difluorophenyl)elhan-l-ol

[0121] To a mixture of (3aS)-l-methyI-3,3-diphenyl-3a,4,5,6-tetrahydropyrroIo[l,2- c][l,3,2]oxazaborole (290 mg. 1.05 mmol, 0.01 eq) and BH3·THF (1 M in THF. 104 mL, 1.0 eq) in MTBE (200 mL) was added 2-chloro-1-(2,4-difluorophenyl)ethanone (20 g, 104 mmol, 1.0 eq) at 40 °C under N2 atmosphere. The mixture was stirred at 40 °C for 1 h under N2 atmosphere. Then the mixture was cooled to 20 °C and stirred at 20 °C for 16 h under N2 atmosphere. Hie reaction mixture was quenched by adding MeOH (8.5 mL) and HC1 (3 M, 105 mL). The mixture was extracted with MTBE (100 mL x 3). The combined organic phase was washed with brine (300 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage: 220 g SepaFlash Silica Flash Column, eluent of 0-10% ethyl acetate / petroleum ether gradient at 150 mL / min) to give (S)-2-chloro-l-(2,4- difluorophenyl)ethan-l-ol as a light-yellow oil. Yield: 18 g, 89%; MS (ESI) m / z 175.1 [M-18]+; ’HNMR (400 MHz, DMSO-ds) 8 7.65-7.50 (m, 1H), 7.25-7.15 (m, 1H). 7.14-7.05 (m, 1H), 6.00 (d, J - 5.2 Hz, 1H), 5.06-4.97 (m, 1H), 3.80-3.65 (m, 2H).Synthesis of (S)-2-(2,4-difluorophenyl)oxirane

[0122] To a solution of (S)-2-chloro-l-(2,4-difluorophenyl)ethan-l-ol (5 g, 25.9 mmol, 1.0 eq) in THF (60 mL) was added NaOH (2 M, 30 mL, 2.31 eq) at 20 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched by adding H? O (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (300 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (S)-2-(2,4-difluorophenyl)oxirane as a light-yellow oil. Yield: 3.5 g, crude; ’HNMR (400 MHz,NAI-5006781290v1 46Attorney Docket No. 14859-002-228DMSO-de) 8 7.20-7.11 (m, 1H), 6.91-6.77 (m, 2H), 4.11-4.08 (m, 1H), 3.20-3.14 (m, 1H), 2.80-2.75 (m, 1H).Synthesis of (S)-l-(2, 4-difluorophenyl)-2-((2-(melhyl-ds)propan-2-yl-l, 1,1, 3, 3, 3-d6)am inolethan- l-ol

[0123] To a solution of (S)-2-(2,4-difiuorophenyl)oxirane (1.8 g, 1 1.5 mmol, 1.0 eq) in EtOH (10 mL) was added 2-(methyl-d3)propan-1,1,1,3,3,3-d6-2-amine (1.14 g, 13.8 mmol, 1.2 eq, > 98% of overall deuterium incorporation) at 20 °C. The mixture was heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was triturated with n-heptane (20 mL) at 20 °C for 3 h to give (S)-l-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl-l, 1,1, 3,3,3- d6)amino)ethan-l -ol as white solid. Yield: 1.8 g, 65%; MS (ESI) m / z 239.2 [M+1]f;1HNMR (400 MHz, DMSO-d6) 6 7.60-7.44 (m, 1H), 6.95-6.85 (m, 1H), 6.82-6.73 (m, 1H), 4.95-4.80 (m, 1H), 3.01-2.93 (m. 1H), 2.55-2.47 (m, 1H).Synthesis of (S)-3-((2-(2.4-d{fluorophenyl)-2-hydroxyethyl)(2-(methyl-d3)propan-2-yl- 1.1.1.3.3.3-d6)amino)propanenitrile

[0124] To a mixture of (S)-l-(2,4-difluorophenyl)-2-((2-(methyl-d.3)propan-2-yl- 1.1.1.3.3.3-d6)amino)ethan-l-ol (1.45 g, 6.08 mmol, 1.0 eq) and acrylonitrile (6.46 g, 121 mmol, 20.0 eq) was added EtOH (280 mg, 6.08 mmol. 1.0 eq) and formamide (274mg. 6.08 mmol, 1.0 eq) at 20 °C, The mixture was heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-20% ethyl acetate / hexanes gradient at 60 mL / min) to give (S)-3-((2-(2.4-difluorophenyl)-2 -hy droxyethyl)(2-(methyl-d.3)propan-2-yl-l.1,1, 3,3,3- d6)amino)propanenitrile as a white solid. Yield: 1.5 g. 84%; MS (ESI) m / z 292.1 [M+1]+; 1HNMR (400 MHz, DMSO-d6) δ 7.65-7.50 (m, 1H), 6.95-6.85 (m, 1H), 6.82-6.73 (m, 1H), 4.90-4.80 (m, 1H), 3.67 (s, 1H), 3.01-2.81 (m, 3H), 2.63-2.49 (m, 2H), 2.47-2.39 (m, 1H). Synthesis of (4R)-4-(2, 4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1, 1, 3, 3, 3-d6)pyrrolidine-3-carbonitrile

[0125] To a solution of (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl)(2-(methyl- d?0propan-2-yl-l, I,l,3,3.3-d6)amino)propanenitrile (650 mg, 2.23 mmol, 1.0 eq) in THF (15 mL) was added diisopropyl phosphorochloridate (492 mg, 2.45 mmol, 1.1 eq) and LiHMDS (1 M, 4.68 mL, 2.1 eq) at -15 °C under N2 atmosphere. The mixture w as stirred at -15 °C for 2 h under N2 atmosphere. The reaction mixture was quenched by adding sat. aq. NH4CI (20 ml.)NAI-5006781290v1 47Attorney Docket No. 14859-002-228and extracted with n-hexane (20 mL x 3). The combined organic phase was washed with HC1 (3 M, 20 mL). The aqueous phase was adjusted pH to 11—12 with NaOH (50%) and extracted with n-hexane (20 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (4R)~ 4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carbonitrile as a light-yellow oil. Yield: 0.6 g, crude, MS (ESI) m / z 274.1 [M+1]+; 1HNMR (400 MHz, DMSO-d6) 6 7.39-7.31 (m, 1H), 6.90-6.81 (m. 2H). 3.78-3.70 (m, 1H), 3.27-3.23 (m. 1H).3.18-3.14 (m, 1H), 3.06-3.01 (m, 2H), 2.83-2.21 (m, 1H).Synthesis of (3S.4R)-4-(2.4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1.1, 3.3.3-d6)pyrrolidine-3-carboxylic acid

[0126] To a solution of (4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3.3.3-d6)pyrrolidine-3-carbonitrile (600 mg. 2.19 mmol, 1.0 eq) in EtOH (12 mL) was added NaOH (266 mg, 3.0 mmol, 1.37 eq) at 20 °C. The mixture was heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and adjusted pH to 6-7 with H2SO4 (2 M). The mixture was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with 1-PrOH / MTBE (1:5) at 20 °C for 16 h to give (3S,4R)-4-(2,4-difluorophenyl)-1-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidine-3-carboxylic acid. Yield: 530 mg, 82%; MS (ESI) m / z 293.1 [M+1]+;1HNMR (400 MHz, CD3OD) 57.53-7.47 (m, 1H), 7.01-6.97 (m, 2H), 3.91- 3.76 (m, 3H), 3.65-3.55 (m, 1H), 3.31-3.27 (m, 2H);19FNMR (376 MHz, CD3OD) 8 -113.08 - -113.10 (m, 2F); [a]25D - -50.0 (c === 0.13, MeOH, 96% ee).(3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyI-d3)propan-2-yl-l,l,l^J r3-d6)pyrrolidine-3-carboxylic-2,2,5,5-d4 acid, Common Intermediate BNAI-5006781290v1 48Attorney Docket No. 14859-002-228Synthesis of 2-chloro-l -(2, 4-dfluorophenyl)ethan-l-one-2, 2-ds

[0127] To a solution of 2-chloro-l -(2, 4-difluorophenyl)ethan-l -one (1.0 g, 5.25 mmol, 1.0 eq) in D2O (7.5 mL, >99.0% of overall deuterium incorporation) was added acetic-d4 acid-d (315 mg, 5.25 mmol, 1.0 eq, >99.0% of overall deuterium incorporation) at 20 °C. The mixture was then heated to 180 °C and stirred for 0.5 h in a microwave reactor. This reaction was repeated three times. The combined reaction mixture was cooled to room temperature, quenched by adding H2O (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried w th anhydrous Na2SOi, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 40 g SepaFlash Silica Flash Column, eluent of 0-15% ethyl acetate / hexanes gradient at 60 mL / min) to give 2-chloro-l -(2, 4-difluoropheny l)ethan-l-one-2,2-d2 as a white solid. Yield: 2.6 g, 64%; 1HNMR (400 MHz, CDCl3) δ 8.08-7.98 (m, 1H), 7.07-6.99 (m, 1H), 6.96-6.89 (m, 1H).Synthesis of (S)-2-chloro-l-(2.4-difluorophenyl)ethan-2.2-d2-l-ol

[0128] To a mixture of (3aS)-l-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[l,2-c][l,3,2]oxazaborole (S-2-Me-CBS, 50.3 mg, 181 ptnol, 0.01 eq) and BH3 THF (1 M in THF, 18.17 mL, 1.0 eq) in MTBE (40 mL) was added 2-chloro-l -(2, 4-difluoropheny l)ethan-l-one-2,2-d2 (3.50 g, 18.1 mmol, 1.0 eq) at 40 °C under N2 atmosphere. The mixture was stirred at 40 °C for 1 h wider N2 atmosphere. Then the mixture was cooled to 20 °C and stirred at 20 °C for 16 h under N2 atmosphere. The reaction mixture was quenched by adding MeOH (1.2 mL) and HC1 (3 M, 14 mL). The mixture was diluted with H2O (20 mL) and extracted with MTBE (20 mL x 3). The combined organic phase was washed with brine (60 mLx2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. TheNAI-5006781290v1 49Attorney Docket No. 14859-002-228residue was purified by flash silica gel chromatography (Biotage: 40 g SepaFlash Silica Flash Column, eluent of 0-10% ethyl acetate / petroleum ether gradient at 60 mL / min) to give (S)-2-chloro-l-(2,4-difluorophenvl)ethan-2,2-d2-l-ol as a light-yellow oil Yield: 3 g, 84%; ¹HNMR (400 MHz, CDCh) 5 7.58-7.52 (m, 1H), 7.00-6.90 (m, 1H), 6 88-6.79 (m, 1H), 5.19 (s, 1H), 2.72 (s, 1H).Synthesis of (S)-2-(2,4-difluorophenyl)oxirane-3,3-d2

[0129] To a solution of (S)-2-chloro-l-(2,4-difluorophenyl)ethan-2,2-d2-l-ol (3.0 g, 15.4 mmol, 1 eq) in THF (36 mL) was added NaOH (2 M, 18.50 mL, 2.4 eq) at 20 °C. Ihe mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched by adding H? O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (60 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (S)-2-(2,4-difluorophenyl)oxirane-3,3-d2 as white solid. Yield: 2 g, 82%: ’HNMR (400 MHz, CDCh) 57.21-7.12 (m, 1H), 6.91-6.78 (m, 2H), 4.09 (s, 1H).Synthesis of (S)-l-(2,4-difluorophenyl)-2-((2-(melhyl-d3)propan-2-yl-l, 1, 1,3, 3, 3-d6)amino)ethan-2.2-d2-l -ol

[0130] To a solution of (S)-2-(2,4-difluorophenyl)oxirane-3,3-d2 (1.5 g, 9.49 mmol, 1 0 eq) in EtOH (20 mL) was added 2-(methyl-d3)propan-l,l,l,3,3,3-d6-2-amine (1.17 g, 14.2 mmol, 1.5 eq, >98% of overall deuterium incorporation) at 20 °C. The mixture was heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was triturated with n-heptane (20 mL) at 20 °C for 3 h to give (S)-l-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)amino)ethan-2,2-d2-l-ol as a white solid. Yield: 1.3 g, 57%; MS (ESI) m / z.241.2 [M+1]+; *HNMR (400 MHz, CDCh) 5 7.59-7.48 (m, 1H), 6.95-6.85 (m, 1H), 6.81-6.73 (m, 1H), 4.83 (s, 1H).Synthesis of benzyl (S)-3-( (2-( 2, 4-dtfluorophenyl)-2-hydroxyethyl- 1. l-d2)(2-(methyl-d})propan-2-yl-l, 1, 1,3,3.3-d.6)amino)propanoate-3,3-d2

[0131] A mixture of (S)-I-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)amino)ethan-2,2-d2-1-ol (1.30 g, 5.41 mmol, 1.0 eq) and benzyl acrylate-3,3-d2 (4.44 g, 27.0 mmol, 5.0 eq) was heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 40 g SepaFlash Silica Flash Column, eluent of 0-30% ethyl acetate / hexanes gradient at 60 mL / min) to give benzyl (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d2)(2-(methyl-d3)propan-2-yl-l.1.1, 3.3.3-NAI-5006781290v1 50Attorney Docket No. 14859-002-228d6)amino)propanoate-3,3-d2 as a colorless oil. Yield: 1.5 g, 68%; MS (ESI) m / z 405.2 [M+1]+;1HNMR (400 MHz. CDCh) 6 7.61-7.52 (m, 1H), 7.43-7.31 (m, 5H), 6.9-6.85 (m. IH), 6.81-6.73 (m, 1H),5.21 -5.10 (m, 2H), 4.82 (s, IH), 4.24 (s, IH), 2.66-2.51 (m, 2H).

[0132] Synthesis of (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d2)(2-(methyl-di)propan-2-yl-l. 1, 1,3.3,3-d6)amino)propanoic-3,3-d2 acid

[0133] To a solution of benzyl (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d?.)(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)amino)propanoate-3,3-d2 (1.2 g, 2.97 mmol, 1.0 eq) in MeOH (15 ml..) was added PdCh (105 mg, 593 pmol, 0.2 eq) at 20 °C under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 20 °C for 16 h under H₂ atmosphere (15 Psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl-1,1-d2)(2-(methyl-d₃)propan-2-yl-1,1,1,3,3,3-d6)amino)propanoic-3,3-d2 acid as a white solid. Yield: 0.9 g, crude; MS (ESI) m / z 315.1 [M+l ]; ¹HNMR (400 MHz. DMSO-de) 87.63-7.54 (m. IH), 7.25-7.17 (m, IH), 7.15-7.08 (m, IH). 4.97 (s, IH). 2.69-2.55 (m, 2H).Synthesis of ethyl (S)-3-((2-(2.4-difluoroph£nyl)-2-hydroxyethyl-l, l-d2)(2-(methyl-d3)propan-2-yl-l, 1,1, 3.3.3-d6)amino)propanoate-3, 3 -ch

[0134] To a solution of (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d2)(2-(methyl- ds)propan-2-y1-l,l J,3,3,3-d6)amino)propanoic-3,3-d2 acid (900 mg, 2.86 mmol, 1,0 eq) in DMF (10 mL) was added K2CO3 (791 nig, 5.73 mmol, 2.0 eq) and iodoethane (535 mg. 3.44 mmol, 1.2 eq) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by adding H2O (30 mL) and extracted with ethy l acetate (20 mL x 3). The combined organic phase was washed with brine (60 ml..x2), dried with anhydrous NacSOi, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-25% ethyl acetate / hexanes gradient at 36 mL / min) to give ethyl (S)-3-((2-(2,4-difluorophenyl)-2-hy droxy ethyl-1, l-d2)(2-(methyl-d3 )propan-2-yl-l, 1,1, 3, 3, 3-d6)amino)propanoate-3,3-d2 as a light-yellow oil. Yield: 780 mg, 79%; MS (ESI) m / z 343.1 [M+1]+; ’HNMR (400 MHz, CDCI3) 5 7.63-7.52 (m, IH). 6.95-6.85 (m, IH), 6.81-6.72 (m, IH), 4.83 (s. IH), 4.26 (s. IH), 4.23- 4.11 (m, 2H), 2.60-2.45 (m, 2H), 1.29 (t. J = 7.2 Hz, 3H).Synthesis of ethyl (4R)-4-(2, 4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1, 1, 3, 3.3-d6)pyrrolidine-3-carboxylate-2.2, 5, 5-d4NAI-5006781290v1 51Attorney Docket No. 14859-002-228

[0135] To a solution of ethyl (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d2)(2- (methyl-d3)propaii-2-yl-l, Ll,3,3,3-d6)amino)propanoate-3,3-d2 (580 mg, 1.69 mmol, 1.0 eq) in THF (5 mL) was added LiHMDS (1 M, 5.93 mL, 3.5 eq) and dimethyl phosph orochloridate (318 mg, 2.20 mmol, 1.3 eq) at -20 °C under Ar atmosphere. The mixture was stirred at -20 °C for 2 h wider Ar atmosphere. The reaction mixture was quenched by adding HC1 (0.5 M, 10 mL) and extracted with n-hexane (10 mL x 3). The combined organic phase 'as concentrated under reduced pressure to give ethyl (4R)-4-(2.4-difluorophenyl)- 1 -(2-(methyl-d3)propan-2-yl- 1.1.1.3.3.3-d6)pyrrolidine-3-carboxylate-2,2,5,5-d4 as a light-yellow oil. Yield: 600 mg, crude; MS (ESI) m / z 325.2 [M+1]4;1HNMR (400 MHz, CDCh) 5 7.43-7.32 (m, IH), 6.88-6.41 (m, 2H), 4.19-4.04 (m. 2H), 3.98-3.77 (m, IH), 3.45-3.05 (m, IH), 1.22-0.85 (m, 3H),,9FNMR (376 MHz, CDCh) 5 -112.37 - -113.36 (m, 2F).Synthesis of (3S, 4R)-4-(2, 4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l.1, 1, 3, 3, 3-d6)pyrrolidine-3-carboxylic-2, 2, 5, 5-d4 acid

[0136] To a solution of ethyl (4R)-4-(2.4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl- 1.1.1.3.3.3-d6)pyrrolidine-3-carboxylate-2,2,5,5-d4 (600 mg, 1,85 mmol, 1.0 eq) in EtOH (10 mL) and H2O (1 mL) was added NaOH (2.23 g, 55.8 mmol, 30.2 eq) at 20 °C. The mixture was heated to 100 °C and stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and adjusted pH to 6~7 with H2SO4 (2 M). The mixture was dried with anhydrous Na2SOr, filtered and concentrated under reduced pressure to give (3S,4R)-4-(2,4-difluorophenyl)- l-(2-(methyl-d₃)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidine-3-carboxylic-2,2,5,5-d₄ acid as a brown solid. Yield: 520 mg, crude; MS (ESI) m / z 297.1 [M+1]⁺; ’HNMR (400 MHz. DMSO-de) 5 7.82-7.65 (m, IH), 7.28-7.18 (m, IH). 7.16-7.06 (m, 1H). 3.93-3.81 (m. IH), 3.48-3.37 (m, 1H);19FNMR (376 MHz, DMSO-d₆) δ -111.17- -111.33 (m, 1F), -113.22- -113.53 (m, 1F); [α]25D = -59.33 (c = 0.10, MeOH, 89% ee).Synthesis of benzyl acrylate-3,3-d2

[0137] To a solution of benzyl 2-(triphenyl-15-phosphaneylidene)acetate (15 g, 36.5 mmol, 1.0 eq) in toluene (150 mL) was added paraformaldehyde-D2 (3.29 g, 36.5 mmol, 1.0 eq, >98% of overall deuterium incorporation) at 20°C. The mixture was heated to 50 °C and stirred at 50 °C for 1 h The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 220 g SepaFlash Silica Flash Column, eluent of 0~10 % ethyl acetate / hexanes gradient at 200 mL / min) to give benzyl acrylate-3,3-d2. Yield: 6 g, 99%; ‘HNMR (400 MHz, CDCh) 8 7.44-7.31 (m, 5H), 6.20-6. 15 (m, IH), 5.22 (s, 2H).NAI-5006781290v1 52Attorney Docket No. 14859-002-228Example la: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l',3^-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyI-4-phenylpiperidin-l-yl)methanoneSynthesis of dimethyl 2, 4-dimethyl-3-oxopentanedioate

[0138] To a solution of dimethyl 3-oxopentanedioate (20 g, 115 mmol, 1.0 eq) in THF (200 mL) was added K₂CO₃ (39.7 g, 287 mmol, 2.5 eq) at 20 °C. The mixture was heated to 45 °C and Mel (40.8 g, 287 mmol, 2.5 eq) was added dropwise to the reaction at 45-60 °C. The reaction was stirred at 50 °C for 1 h under N2. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 220 g SepaFlash Silica Flash Column, eluent of 0-25% ethyl acetate / n-hexane gradient at 150 mL / min) to give dimethyl 2,4-dimethyl-3-oxopentanedioate as a colorless oil. Yield: 20 g, 86%; MS (ESI) m / z 203.1 [M+l ]+; ’HNMR (400 MHz, DMSO-dc,) 54.04-3.95 (m, 2H), 3.65-3.63 (m, 6H), 1.23- 1.21 (m, 6H).Synthesis of dimethyl l-benzyl-3,5-dimethyl-4-oxopiperidine-3.5-dicarboxylate

[0139] To a solution of dimethyl 2,4-dimethyl-3-oxopentanedioate (8 g, 39,6 mmol, 1.0 eq) and phenylmethanamine (4.66 g, 43.5 mmol. 1.1 eq) in MeOH (160 mL) was added aq. HC1 (1 M, 8 mL) and aq. HCHO (119 mmol. 8.84 mL, 37%, 3.0 eq) at 20 °C. The reaction was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 220 g SepaFlash Silica Flash Column, eluent of 0-20% ethyl acetate / n-hexane gradient at 150 mL / min) to give dimethyl l-benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate as a colorless oil Yield: 7.8 g, 59%; MS (ESI) m / z 334.0 [M+1]+; ’HNMR (400 MHz, CDCI3) 8NAI-5006781290v1 53Attorney Docket No. 14859-002-2287.36-7.29 (m, 5H), 3.68 (s, 6H), 3.65 (s, 2H), 3.53 (d, J = 11.6 Hz, 2H), 2.22 (d, J = 11.2 Hz, 2H), 1.31 (s, 6H).Synthesis of (3S,5R)-1-benzyl-3,5-dimethylpiperidin-4-one

[0140] A solution of dimethyl l-benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate (3 g, 9.0 mmol. 1.0 eq) in aq HC1 (1 M, 30.0 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was cooled to room temperature and the pH of the solution was adjusted to 8 with NaOH (2 M). The aqueous phase was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 80 g SepaFlash Silica Flash Column, eluent of 0-20% ethyl acetate / n-hexane gradient at 80 mL / min) to give (3S,5R)-l-benzyl-3,5-dimethylpiperidin-4- one as a colorless oil. Yield: 1.4 g, 72%; MS (ESI) m / z 218.2 [M+1]+;JHNMR (400 MHz, CDCh) 67.37-7.30 (m, 5H). 3.61 (s. 2H), 3.18-3.14 (m. 2H), 2.76-2.70 (m. 2H), 2.09-2.03 (m, 2H), 0.97 (d, J = 6.8 Hz, 6H).Synthesis of (3S,4s,5R)-1-benzyl-3,5-dimethyl-4-phenylpiperidin-4-ol

[0141] To a solution of (3S,5R)-1-benzyl-3,5-dimethylpiperidin-4-one (300 mg, 1.38 mmol, 1.0 eq) in THF (5 mL) was added PhMgBr (3 M in EtzO, 1.38 mL, 3.0 eq) at -65 °C under N2. Then the reaction was warm to 20 °C and stirred at 20 °C for 12 h under Nz. The reaction mixture was quenched by adding H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 70 mL / min) to give (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-phenylpiperidin-4-ol as a colorless oil. Yield: 340 mg, 83%; MS (ESI) m / z 296.2 | M+l |+; ¹HNMR (400 MHz, CDCh) 87.37-7.23 (m, 10H), 3.58 (s, 2H), 2.74-2.71 (m, 2H), 2.25-2.24 (m, 2H), 2.18-2.12 (m, 2H), 1.59 (s, 1H), 0.56 (d, J = 6.8 Hz, 6H).Synthesis of (3S.4s, 5R)-3, 5-dimethyl-4-phenylpiperidin-4-ol

[0142] To a solution of (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-phenylpiperidin-4-ol (0.2 g, 677 pmol, 1.0 eq) in MeOH (5 mL) was added PdCh (24.0 mg. 135 pmol, 0.2 eq) at 20 °C under N2 Then the reaction was heated to 50 °C and stirred at 50 °C for 12 h under H₂ (15 Psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-4-ol as a yellow- solid. Yield: 130 mg, crude; MS (ESI) m / z 206.1 [M+1]+;1HNMR (400 MHz, DMSO-db) 89.08-8.99 (m. 1H),NAI-5006781290v1 54Attorney Docket No. 14859-002-2288.85-8.84 (m, 1H), 7.58-7.55 (m, 1H), 7.39-7.36 (m, 2H), 7.26-7.17 (m, 2H), 5.05-4.96 (m, 1H), 3.09 (d, J = 12.0 Hz, 2H). 2.93-2.84 (m, 2H). 2.37-2.31 (m, 2H). 0.50 (d, J = 6.4 Hz. 6H). Synthesis of ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(melhyl-d3)propan-2-yl-l, 1, I,3,3,3-d6)pyrrolidln-3-yl)((3S.4R.5R)-4-hydroxy-3,5-dimethyl-4-phe>iylpiperidin-l-yl)methanone

[0143] To a solution of (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-4-ol (35.1 mg, 171 μmol, 1.0 eq) and (3S,4R)-4-(2.4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyirolidine-3 -carboxy lie acid (50 mg, 171 prnol, 1.0 eq) in DCM (1.5 mL) was added TEA (43.3 mg, 428 pmol. 2.5 eq) and 2,4,6-tributyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T4P, 148 mg. 205 pmol, 50% purity, 1.2 eq) at 0 °C. The reaction was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by adding sat.aq NaHCOs (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150x40x10 pm; mobile phase:[ACN in H₂O (10mM NH₄HCO₃)]; gradient: 55%-95% over 8.0 min) to give ((3S,4R)-4-(2,4- difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l-yl)methanone. Yield: 10.5 mg, 13%; MS (ESI) in / z 480.1 Mi l]4; ¹HNMR (400 MHz, DMSO-de) 5 7.63-7.61 (m, 1H), 7.32-7.28 (m. 3H), 7.21- 7.05 (m, 4H), 4.61-4.58 (m, 1H), 4.22-4.19 (m, 1H), 3.83-3.75 (m, 1H). 3.55-3.51 (m, 2H).3.09-3.00 (m, 3H), 2.82-2.80 (m, 1H), 2.69-2.56 (m, 2H), 1.86-1.61 (m, 1H), 1.21-1.18 (m, 1H), 0.47-0.42 (m, 4H), 0.27 (d, J = 6.4 Hz, 2H);19FNMR (376 MHz, DMSO) δ -112.94 - -113.86 (m, 2F); overall deuterium incorporation: 98.4%; percent of Compound la molecules: 85.2%.Example 6a: ((3S,4R)-4-(2,4-difluorophenyl)-1-(2-(methyl-d₃)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl-3,5-d2)methanoneSynthesis of (3S,5R)-l-benzyl-3,5-dimethylpiperidin-4-one-3.5-d2NAI-5006781290vl 55Attorney Docket No. 14859-002-228

[0144] To a solution of (3S,5R)-l-benzyl-3,5-dimethylpiperidin-4-one (1 g, 4.60 mmol, 1.0 eq) in CH3OD (3 mL) and D2O (9 mL. >99.0% of overall deuterium incorporation) was added t-BuONa (2.65 g, 27.6 mmol, 6.0 eq) at 20 °C, then the reaction was heated to 85°C and stirred at 85 °C for 12 h. The reaction mixture was cooled to room temperature, quenched by adding aq. HC1 (1 M) (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-20% ethyl acetate / n-hexane gradient at 70 mL / min) to give (3S,5R)-1-benzyl-3,5-dimethylpiperidin-4-one-3,5-d2 as a colorless oil. Yield: 740 mg, 73%, MS (ESI) m / z 220.2 [M+l ]+: ’HNMR(400 MHz, CDCI3) 6 7.37-7.30 (m, 5H), 3.60 (s, 2H). 3.15 (d, J = 11.2 Hz, 2H), 2.06 (t, J = 5.2 Hz, 2H), 0.96 (s, 6H).Synthesis of (3S, 4s.5R)-l-benzyl-3, 5-dimethyl-4-phenylpiperidm-3, 5-d2-4-ol

[0145] To a solution of (3S,5R)-l-benzyl-3,5-dimethylpiperidin-4-one-3,5-d2 (0.2 g, 912 pmol, 1.0 eq) in THF (4 mL) was added bromo(phenyl)magnesium (3 M, 912 pL, 3.0 eq) at -65 °C under N2. Then the reaction was warmed to 20 °C and stirred at 20 °C for 5 h. The reaction mixture was quenched by adding sat.aq. NH4CI (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried overNa2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 70 mL / min) to give (3S,4s,5R)-l-benzyl-3,5-dimethyI-4-phenylpipendin-3.5-d2-4-ol as a white solid. Yield: 260 mg. 96%: MS (ESI) m / z 298.2 [M+1]+; ¹HNMR (400 MHz, CDCl₃) δ7.39-7.23 (m, 10H), 3.57 (s, 2H), 2.72 (d, J = 11.6 Hz, 2H), 2.14 (d, J = 11.6 Hz, 2H), 0.55 (s, 6H).Synthesis of (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidm-3.5-d2-4-ol

[0146] To a solution of (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-phenylpiperidin-3,5-d2-4-ol (260 mg. 874 pmol, 1.0 eq) in MeOH (5 mL) was added PdCh (31.0 mg. 175 pmol, 0.2 eq) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The reaction mixture was heated to 50 °C and stirred at 50 °C for 12 h under H2 atmosphere (15 psi). I'he reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-3,5-d2-4-ol as a white solid. Yield: 170 rag, crude: MS (ESI) m / z 208.2 [M+1]!; fllNMR (400 MHz, DMSO-ds) 5NAI-5006781290v1 56Attorney Docket No. 14859-002-2289.37 (s, 1H), 9.02 (s, IH), 7.55 (s, 1H), 7.39-7.35 (m, 2H), 7.25-7.17 (m, 2H), 4.99(s, IH), 3.06 (d, J = 12.0 Hz, 2H), 2.88 (d, J = 11.2 Hz, 2H), 0.49 (s, 6H).Synthesis of ((3S,4R)-4-(2,4-difluorophenyl)-1-(2-(methyl-d₃)propan-2-yl-1,1,1,3,3,3-d₆)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl-3,5-d₂)methanone

[0147] To a solution of (3S,4s,5R)-3,5-dimetliyl-4-phenylpiperidin-3,5-d2-4-ol (45.9 mg, 188 pmol, 1.1 eq, HC1) and (3S,4R)-4-(2.4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidine-3-carboxylic acid (50 mg, 171 pmol, 1.0 eq) in DCM (2 mL) was added TEA (43.3 mg. 428 pmol, 2.5 eq) and TiP (148 mg, 205 pmol, 50% purity, 1.2 eq) at 0 °C. The reaction was stirred at 0 °C for 30 min under N2. The reaction mixture was quenched by adding sat. aq. NaHCO₃ (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL). dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC 18 150x30x7 pm; mobile phase: [ACN in H2O (lOmM NIL1HCO3)]; gradient: 45%-75% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l-yl-3,5-d2)methanone Yield: 11.2 mg, 13%; MS (ESI) m / z 482.1 [M+l ]+¹HNMR (400 MHz, DMSO-d₆) δ7.63-7.62 (m, 1H), 7.33-7.29 (m, 3H), 7.21-7.06 (m, 4H), 4.62-4.58 (m, IH), 4.21 (d, J = 12.8 Hz, IH), 3.78-3.76 (m, IH), 3.56-3.51 (m, 2H), 3.10-2.99 (m, 3H), 2.83-2.81 (m, IH), 2.79-2.60 (m, 2H), 0.49-0.43 (m, 4H), 0.27 (s, 2H);19FNMR (376 MHz, DMSO) δ -112.92 - -113.89 (m, 2F); overall deuterium incorporation: 98.4%; percent of Compound 6a molecules: 82, 1%,Example 7a: ((3S,4R)-4-(2,4-difluorophenyl)-1-(2-(methyl-d₃)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl-2,2,6,6-d₄)methanoneNAI-5006781290v1 57Attorney Docket No. 14859-002-228Synthesis of dimethyl 1-benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate-2,2,6,6-d₄

[0148] To a solution of dimethyl 2,4-dimethyl-3-oxopentanedioate (4.5 g, 22.3 mmol, 1.0 eq) and phenylmethanamine (2.62 g, 24.5 mmol, 1.1 eq) in MeOH (90 mL) was added HC1 (1 M, 4.50 mL) and formaldehyde-d2 (7.49 g, 467 mmol, 20%. 2.1 eq) at 20 °C. The reaction was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 120 g SepaFlash Silica Flash Column, eluent of 0-15% ethyl ace tate / n -hexane gradient at 100 mL / min) to give dimethyl 1-benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate-2,2,6,6-d₄ as a colorless oil. Yield: 4 g, 53%; MS (ESI) m / z 338.1 [M+1]⁺; ’HNMR (400 MHz, CDCh) 87.36-7.29 (in, 5H), 3.68 (s, 6H), 3.65 (s, 211), 1.31 (s, 6H).Synthesis of (3S,5R)-1-benzyl-3,5-dimethylpiperidin-4-one-2,2,6,6-d₄

[0149] A solution of dimethyl 1-benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate-2,2,6,6-d₄ (4 g, 11.9 mmol, 1.0 eq) in HC1 (1 M, 58.8 mL) was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature and the pH was adjusted to 8 with NaOH (2 M). The aqueous phase was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 80 g SepaFlash Silica Flash Column, eluent of 0-20% ethyl acetate / n -hexane gradient at 80 mL / min) to give (3S,5R)-l-benzyl-3,5-dimethylpiperidin-4-one-2,2,6,6-d4 as a colorless oil. Yield: 1.6 g, 61%; MS (ESI) m / z 222.1 [M+1]+;5HNMR (400 MHz, CDCh) 8 7.37-7.31 (m, 5H), 3.61 (s. 2H), 2.71 (s, 2H), 0.97 (d, J = 6.4 Hz, 6H).Synthesis of (3S,4s,5R)-l-benzyl-3.5-dimethyl-4-phenylpiperidin-2,2,6,6-d4-4-ol

[0150] To a solution of (3S,5R)-l-benzyl-3,5-dimethylpiperidin-4-one-2.2.6.6-d4(l 10 mg, 497 pmol, 1.0 eq) in THF (3 mL) was added bromo(phenyl)magnesium (3 M in Et₂O, 497 μL, 3.0 eq) at -65 °C under N2. Then the reaction was warmed to 20 °C and stirred at 20 °C for 4 h under N2. The reaction mixture was quenched by adding sat.aq NH4CI (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 70 mL / min) to give (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-phenylpiperidin-2,2,6,6-d4-4-ol as a white solid. Yield: 100 mg, 67%; MS (ESI) m / z 300.2 [M+1]+; ¹HNMR (400 MHz, CDCl₃) δ7.37-7.23 (m, 10H). 3.57 (s, 2H), 2.24- 2.22 (m, 2H), 1.53 (s, 1H), 0.55 (d, J = 6.8 Hz, 6H).NAI-5006781290v1 58Attorney Docket No. 14859-002-228Synthesis of (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-2,2,6,6-d₄-4-ol| 00151| To a solution of (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-phenylpiperidin-2,2,6.6-d4-4-ol (100 mg, 334 pmol, 1.0 eq) m MeOH (4 mL) was added PdCh (11.8 mg, 66.8 pmoL 0.2 eq) under N2 atmosphere. The suspension was degassed and purged with H2 three times. I’he reaction mixture was heated to 50 °C and stirred at 50 °C for 12 h under H₂ atmosphere (15 psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-2,2,6,6-d4-4-ol as a white solid. Yield: 80 mg, crude; MS (ESI) m / z 210.2 [M+1]+; ¹HNMR (400 MHz, DMSO-d₆) δ 9.16-9.13 (m, 1H), 8.90-8.88 (m, 1H), 7.57-7.55 (m, 1H), 7.39-7.35 (m, 2H). 7.26-7.17 (m, 2H), 5.05-4.95 (m, 1H), 2.38-2.32 (m, 2H), 0.49 (d, J = 6.8 Hz, 6H).Synthesis of ((3S,4R)-4-(2,4-difluorophenyl)-1-(2-(methyl-d₃)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl-2,2,6,6-d₄)methanone

[0152] To a solution of (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-2,2,6,6-d4-4-ol (42.0 mg, 171.02 pmol, 1.0 eq HCI) and (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic acid (50 mg, 171 umol, 1.0 eq) in DCM (2 mL) was added TEA (51.9 mg, 513 μmol, 3.0 eq) and T₄P (148 mg, 205 μmol, 50% purity, 1.2 eq) at 0 °C. The reaction was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by adding sat. aq. NaHCO₃ (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL). dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. Die residue was purified by prep-HPLC (column: WePure Biotech XP tC 18 150x30x7 pm; mobile phase: [ACN in H₂O (10mM NH₄HCO₃)]; gradient:45%-75% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-1-(2-(methyl-d₃)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl-2,2,6,6-d4)methanone. Yield: 15.81 mg, 19%; MS (ESI) m / z 484.1 [M+1]*; ’HNMR (400 MHz, DMSO-de) 5 7.65-7.63 (m. 1H), 7.33-7.28 (m, 3H). 7.21-7.07 (m, 4H), 4.62-4.58 (m.1H), 3.85-3.75 (m, 1H), 3.54-3.52 (m, 1H), 3.16-3.03 (m, 2H), 2.82-2.66 (m, 2H). 1.85-1.58 (m, 1H), 1.18-1.15 (m, 1H), 0.46-0.44 (in, 4H), 0.27 (d, J = 6.8 Hz, 2H);19FNMR (376 MHz, DMSO) δ -112.92 - -113.89 (m, 2F); overall deuterium incorporation: 98.5%; percent of Compound 7a molecules: 80.4%.Example 8a: ((3S,4R)-4-(2,4-difluorophenyl)-1-(2-(methyl-d₃)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d₃)-4-phenylpiperidin-1-yl)methanoneNAI-5006781290v1 59Attorney Docket No. 14859-002-228Synthesis of dimethyl 2, 4-bis(methyl-d3)-3-oxopentanedioate

[0153] To a solution of dimethyl 3-oxopentanedioate (20 g, 114 mmol, 1.0 eq) in THF (200 mL) was added K2CO3 (39.6 g, 287 mmol. 2.5 eq) and Iodomethane-d₃ (41.6 g, 287 mmol, 2.5 eq, > 99.0% of overall deuteration incorporation) at 20 °C under N₂ atmosphere. The mixture was heated to 50 °C and stirred at 50 °C for 2 h under N2 atmosphere. The reaction mixture was cooled to room temperature, quenched by adding H2O (500 mL) and extracted with ethyl acetate (300 mLx3). 'The combined organic phase was washed with brine (1000 mLx2), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 330 g SepaFlash Silica Flash Column, eluent of 0~10% ethyl acetate / hexanes gradient at 200 mL / min ) to give dimethyl 2,4-bis(methyl-d₃)-3-oxopentanedioate as a light-yellow oil. Yield: 22 g. 91%; ¹HNMR (400 MHz, DMSO-d₆) δ3.96 (d, J = 7.6 Hz, 2H), 3.63 (d, J = 5.2 Hz, 6H).Synthesis of dimethyl l-benzyl-3,5-bis(methyl-d3)-4-oxopiperidine-3,5-dicarboxylate

[0154] To a mixture of dimethyl 2,4-bis(methyl-d3)-3-oxopentanedioate (2.1 g, 10.08 mmol, 1.0 eq) and phenylmethanamine (1.30 g, 12.1 mmol, 1.2 eq) in MeOH (30 mL) was added HC1 (1 M. 2.05 mL, 0.2 eq) and HCHO (2.46 g, 30.2 mmol. 3.0 eq) at 20 °C under N2 atmosphere. The mixture was stirred at 20 °C for 20 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 40 g SepaFlash Silica Flash Column, eluent of 0-20% ethyl acetate / n-hexane gradient at 60 mL / min) to give dimethyl l-benzyl-3,5- bis(methyl-d3)-4-oxopiperidine-3,5-dicarboxylate as a colorless oil. Yield: 2.5 g. 73%; MS (ESI) m / z 340.2 [M+1]+; ‘HNMR (400 MHz, CDCh) 8 7.36-7.29 (m, 5H), 3.67 (s, 6H), 3.65 (s, 2H), 3.55-3.49 (m, 2H), 2.26-2.17 (m, 2H).Synthesis of (3S,5R)-l-benzyl-3,5-bis(methyl-d3)piperidin-4-one

[0155] Dimethyl l-benzyl-3,5-bis(methyl-d3)-4-oxopiperidine-3,5-dicarboxylate (2.5 g, 7.37 mmol, 1.0 eq) was dissolved in HC1 (1.5 M, 25.0 mL, 5.1 eq) at 20 °C. The mixture wasNAI-5006781290v1 60Attorney Docket No. 14859-002-228heated to 100 °C and stirred at 100 °C for 48 h. The reaction mixture was cooled to room temperature and the pH was adjusted to 8 with aq. NaOH (2 M). The aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NasSC, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 40 g SepaFlash Silica Flash Column, eluent of 0-30% ethyl acelate / n-hexane gradient at 60 mL / min) to give (3S, 5R)-l-benzyi-3, 5-bis(methyl-d )piperidin-4-one as a colorless oil. Yield: 850 mg, 51%; MS (ESI) m / z 224.3 [M+1]+:5HNMR (400 MHz, CDCh) 8737-7.30 (m, 5H), 3.61 (s, 2H), 3.20- 3.10 (m, 2H), 2.76-2.65 (m, 2H). 2.11-2.01 (m, 2H).Synthesis of (3S, 4s.5R)-l-bemyi-3,5-his(methyl-d3)-4-phenylpiperidin-4-ol

[0156] To a solution of (3S, 5R)-l-benzyl-3, 5-bis(methyl-d3)piperidin-4-one (300 mg, 1.34 mmol, 1.0 eq) in THF (5 mL) was added bromo(phenyl)magnesium (3 M in EtiO. 1.34 mL, 3.0 eq) at -60 °C under N2 atmosphere. The mixture was warmed to 20 °C and stirred at 20 °C for 20 h under N2 atmosphere. The reaction mixture was quenched by adding H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over NazSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-20% ethyl acetate / n-hexane gradient at 60 mL / min) to give (3S, 4s. 5R)-l-benzyl-3,5-bis(methyl-d3)-4-phenylpiperidin-4-ol as a colorless oil. Yield: 350 mg, 86%; MS (ESI) m / z 302.3 [M+1]+; 'HNMR (400 MHz, CDCh) 57.65-7.20 (m, 10H), 3.58 (s, 2H). 2.74-2.71 (m, 2H), 2.30-2.10 (m, 4H), 1.53 (s, 1H).Synthesis of (3S,4s,5R)-3,5-bis(methyl-d)-4-pltenylpiperidin-4-ol

[0157] To a solution of (3S, 4s, 5R)-l-benzyl-3.5-bis(methyl-d3)-4-phenylpiperidin-4-ol (300 mg, 995 pmol, 1.0 eq) in MeOH (3 mL) was added PdClz (35.2 mg, 199 pmol, 0.2 eq) at 20 °C under H atmosphere. The mixture was heated to 50 °C and stirred at 50 °C for 16 h under H2 atmosphere (15 Psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s,5R)-3,5-bis(methyl-d3)-4-phenylpipendin-4-ol as a light-yellow oil. Yield: 200 mg, crude; MS (ESI) m / z 212.2 [M+l j+; 'HNMR (400 MHz, DMSO-ds) 57.70-7.15 (m, 5H), 4.55 (s, 1H), 2.84-2.69 (ra, 4H), 2.13-2.04 (m, 2H).Synthesis of ("(3S.4R)-4-(2, 4-difl.uorophenyl)-l-(2~(methyl-d3)propan-2~yl-l, 1, 1, 3, 3, 3- d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d3)-4-phenylpiperidin-l- yl)methanoneNAI-5006781290v1 61Attorney Docket No. 14859-002-228

[0158] To a solution of (3S,4s,5R)-3,5-bis(methyl-d3)-4-phenylpiperidin-4-ol (28.9 mg, 136 pmol, 1.0 eq) in DCM (2 mL) was added (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic acid (40 mg, 136 pmol, 1.0 eq), TEA (41.5 mg. 410.4 pmol, 3.0 eq) and T4P (118 mg, 164 pmol, 50% purity', 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by' adding sat.aq NaHCOs (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 pm;mobile phase: [ACN in HzOdOmM NH4HCO3)]; gradient: 50%-80% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d3)-4-phenylpiperidin-l-yl)methanone. Yield: 10.5 mg, 15%; MS (ESI) m / z 486.2 [M+1]’; ’HNMR(400 MHz. DMSO-d6) 5 7.66-7.53 (m, 1H), 7.45-7.28 (tn, 3H), 7.27-6.95 (m, 4H), 4.61-4.58 (m, HI), 4.24-4.19 (m, 1H), 3.90-3.71 (m, 1H), 3.63-3.49 (m, 2H), 3.15-2.91 (m, 3H), 2.85-2.78 (m, 1H), 2.72-2.61 (m, 2H), 1.86-1.14 (m, 2H);19FNMR (376 MHz, DMSO) 6 -112.93 - -113.88 (m, 2F); overall deuterium incorporation: 99.0%: percent of Compound 8a molecules: 84.3%.Example 9a: ((3S,4R)-4-(2,4-difluorophenyI)-l-(2-(methyI-d3)propan-2-yl-l, 1,1, 3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy~3,5-dimethyl-4-(phenyI-d5)piperidin-l-yl)methanoneSynthesis of (3S,4s.5R)-l-benzyl-3,5-dimethyl-4-(phenyl-d5)piperidin-4-ol

[0159] To a solution of l-bromobenzene-2,3,4,5,6-d5 (745 mg, 4.60 mmol, 5.0 eq, > 99.0% of overall deuteration incorporation) in THF (8 mL) was added n-BuLi (2.5 M, 1.66 mL, 4.5 eq) at -65 °C under N?„ The reaction was stirred at -65 °C for 0.5 h under Nz, Then to the mixture was added a solution of (3S,5R)-l-benzyl-3,5-dimethylpiperidin-4-one (200 mg, 920NAI-5006781290v1 62Attorney Docket No. 14859-002-228pmol, 1.0 eq) in THF (2 mL) at -65 °C under N2. The reaction was then warmed to 20 °C and stirred at 20 °C for 2 h under N?.. The reaction mixture was quenched by adding sat.aq NH4CI (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4. filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 70 mL / min) to give (3S.4s,5R)-l-benzyl-3,5-dimethyl-4-(phenyl-d5 piperidm-4-oi as a white solid. Yield: 240 mg. 86%; MS (ESI) m / z 301.2 [M+ 1]+; ‘HNMR (400 MHz, CDCh) 87.40-7.28 (m, 5H), 3.58 (s, 2H), 2.75-2.72 (m, 2H), 2.25-2.13 (m, 4H), 1.59 (s, 1H), 0.56 (d, J = 6.8 Hz. 6H).Synthesis of ( 3S.4s, 5R)-3, 5-dimethyl-4-(phenyl-ds)piperidin-4-ol

[0160] To a solution of (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-(phenyl-d5)piperidin-4-ol (240 mg, 799 umol, 1.0 eq) m MeOH (5 mL) was added PdCh (28.3 mg, 160 pmol, 0.2 eq) under N2 atmosphere. The suspension was degassed and purged with H2 three times The reaction mixture was heated to 50 °C and stirred at 50 °C for 12 h under H2 atmosphere (15 psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S.4s,5R)-3.5-dimethyl-4-(phenyl-d5)piperidin-4-ol as a white solid. Yield: 170 mg. crude; MS (ESI) m / z 211.2 [M+l ]’; ’HNMR (400 MHz, DMSO-ck) 8 9.38-9.36 (m, 1H), 9.04-9.02 (m, 1H), 5.01-4.88 (m, 1H), 3.08-2.93 (m, 2H), 2.90-2.87 (m, 2H), 2.43-2.38 (m, 2H), 0.49 (d, J = 6.8 Hz, 6H).Synthesis of ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l, 1.3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3.5-dimelhyl-4-(phenyl-d5)piperidin-l-yl)methanone100161 ] To a solution of (3S,4s,5R)-3.5-dimethyl-4-(phenyl-d5)piperidin-4-ol (46.4 mg, 188 umol, 1.1 eq, HC1) and (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl- l,l,i,3,3,3-d6)pyrrolidine-3-carboxylic acid (50 mg, 171 yrnol, 1.0 eq) in DCM (2 mL) was added TEA (43.3 mg, 428 pmol. 2.5 eq) and T4P (148 mg, 205 pmol, 50% purity, 1.2 eq) at 0 °C. The reaction was stirred at 0 °C for 0.5 h under N2. The reaction mixture was quenched by adding sat.aq NaHCOs (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over N 2SO, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150x30x7ym; mobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient:50%-80% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(rnefhyl-NAI-5006781290v1 63Attorney Docket No. 14859-002-228d3)propan-2-yl-l,l,l,3,3.3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4- (phenyl-d5)piperidin-l-yl)methanone. Yield: 30.1 mg, 36%; MS (ESI) m / z 485.2 [M-H; 4INMR (400 MHz, DMSO-ds) 5 7.63-7.59 (m, 1H), 7.24-7.14 (m, 1H), 7.07-7.05 (m, 1H), 4.61-4.58 (m, 1H). 4.23-4.19 (m, 1H), 3.78-3.76 (m, 1H), 3.55-3.32 (m, 2H), 3.09-3.00 (m, 3H), 2.82-2.80 (m, 1H), 2.69-2.56 (m, 2H), 1.86-1.61 (m, 1H), 1.21-1.17 (m, 1H), 0.46-0.42 (m, 4H), 0.27 (d, J === 6.8 Hz, 2H):19FNMR (376 MHz, DMSO) 5 -112.94 - -113.88 (m, 2F); overall deuterium incorporation: 98.8%: percent of Compound 9a molecules: 83.6%.Example 10a: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l -d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l-yl-2,2,3,5,6,6-d6)methanoneSynthesis of (3S.5R)-l-benzyl-3, 5-dimethylpiperidin-4-one-2, 2, 3, 5.6.6-dt,

[0162] To a solution of (3S,5R)-1 -benzjd-3,5-dimethylpiperidin-4-one-2,2,6,6-d4 (500 mg, 2.26 mmol, 1.0 eq) in CH OD (2,5 mt) and D2O (7.5 L, >99.0% of overall deuterium incorporation) was added t-BuONa (1.30 g, 13.6 mmol, 6.0 eq) at 20 °C. The reaction was heated to 85°C and stirred at 85 °C for 12 h. The reaction mixture was cooled to room temperature, quenched by adding aq. HC1 (1 M) (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried overNa2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-20% ethyl acetate / n -hexane gradient at 70 mL / min) to give (3S.5R)-l-benzyl-3,5-dimethylpiperidin-4-one-2,2,3,5,6.6-d6 as a colorless oil. Yield: 400 mg, 79%; MS (ESI) m / z 224.1 [M+1] f 'HNMR (400 MHz, CDCh) 57.31-7.28 (m, 5H), 3.61 (s, 2H), 0.96 (s, 6H). Synthesis of (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-phenylpiperidin-2,2,3,5,6,6-d6-4-ol

[0163] To a solution of (3S,5R)-1 -benzyl-3.5-dimethylpiperidin-4-one-2,2.3,5.6,6-d6 (150 mg. 672 ymol, 1.0 eq) in THF (3 mL) was added bromo(phenyl)magnesium (3 M in EfeO, 672 pL, 3.0 eq) at -65 °C under N?.. Then the reaction was warmed to 20 °C and stirred at 20 °C forNAI-5006781290v1 64Attorney Docket No. 14859-002-2283 h under N2. The reaction mixture was quenched by adding sat.aq NH4CI (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S€L, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 70 mL / min) to give (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-phenylpiperidin-2,2,3,5,6,6-d6-4-ol as a white solid. Yield: 150 mg. 74%: MS (ESI) m / z 302.2 [M+1] '; ’HNMR (400 MHz, CDCI3) 57.37-7.22 (m.10H). 3.57 (s. 2H), 1 52 (s. 1H), 055 (s, 6H).Synthesis of (3S.4s, 5R / -3.5-dimethyl-4-phenyipiperidm-2, 2, 3, 5, 6, 6-d.6-4-ol

[0164] To a solution of (3S,4s,5R)-l-benzy4-3,5-dimethyl-4-phenylpiperidin-2,2,3,5,6,6-de-4-ol (150 mg, 498 pmol, 1.0 eq) in MeOH (5 mL) was added PdCb (17.65 mg, 99.52 pmol, 0.2 eq) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The reaction mixture was heated to 50 °C and stirred at 50 °C for 12 h under H? atmosphere (15 psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s,5R)-3,5-dimethyl-4-phenyIpiperidin-2,2,3,5,6,6-d6-4-ol as a white solid. Yield: 120 mg, crude; MS (ESI) m / z 212.2 [M+l ]+; 'HNMR (400 MHz, DMSO-de) 57.57-7.55 (m. 1H), 7.38-7.23 (m. 3H), 7.21-7.18 (m. 2H), 4.93 (s, 1H), 0.48 (s, 6H). Synthesis of ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)p!'opan-2-yl-l, 1, 1,3, 3,3-d6)pyrrolidin-3-yl) ((3S.4R.5R)-4-hydroxy-3, 5-dimethyl-4-phenylpiperidin-l-yl-2.2, 3.5, 6, 6-djmethanone

[0165] To a solution of (3S,4s,5R)-3,5-dimethyl-4-phenylpipendin-2,2.3,5,6,6-d6-4-ol (42,4 mg, 171 pmol, 1.0 eq HC1) and (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l, L3,3,3-d6)pyrrolidine-3-carboxyIic acid (50.0 mg, 171 pmol, 1.0 eq) in DCM (2 mL) was added TEA (51.9 mg, 513 pmol. 3.0 eq) and T4P (148 mg, 205 pmol, 50% purity', 1.2 eq) at 0 °C. The reaction was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by adding sat.aq NaHCCb (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL). dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP1C18 150x40x7 pm; mobile phase: [ACN in H2O (lOmMNH-iHCCL)]; gradient: 40%-70% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl- l,l, L3,3,3-d6)pyrrolidin-3-yl)((3S,4R5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l-yl-2, 2, 3.5.6.6-de (methanone. Yield: 13.88 mg, 17%: MS (ESI) m / z 486.2 [M+l|!; T-INMR (400 MHz, DMSO-de) 5 7.63-7.61 (m, 1H), 7.32-7.28 (m, 3H), 7 21-7.05 (m, 4H), 4.61-4.57 (m.NAI-5006781290v1 65Attorney Docket No. 14859-002-2281H), 3.85-3.75 (m, 1H), 3.54-3.32 (m, 1H), 3.15-3.03 (m, 2H), 2.82-2.66 (m, 2H), 0.45-0.42 (m. 4H), 0.26 (s, 2H);19FNMR (376 MHz, DMSO) 5 -112.92 - -113.89 (m. 2F); overall deuterium incorporation: 99.1%; percent of Compound 10a molecules: 86.5%.Example Ila: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3 -d6)pyrroIidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyI-d3)-4-phenyIpiperidin-1-y!-3,5-d2)methanoneSynthesis of (3S,5R)-l-benzyl-3,5-bis(methyl-d3)piperidm-4-one-3,5-d2

[0166] To a solution of (3S,5R)-l-benzyl-3,5-bis(methyl-d3)piperidin-4-one (1.0 g, 4.40 mmol, 1 eq) in D2O (9 mL, >99.0% of overall deuterium incorporation) and methanol-d (3 mL, >99,0% of overall deuterium incorporation) was added t-BuONa (2.58 g, 26.8 mmol, 6.0 eq) at 20 °C. The mixture was heated to 85 °C and stirred at 85 °C for 16 h. The reaction mixture was cooled to room temperature, quenched by adding aq. HC1 (1 M, 20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na SOg filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-20% ethyl acetate / n-hexane gradient at 70 mL / min) to give ((3S,5R)-l-benzyl-3,5-bis(methyl-dj)piperidin-4-one-3,5-d2 as a light-yellow oil Yield: 720 mg, 71%; MS (ESI) m / z 226.2 [M+1]+; ‘HNMR (400 MHz, CDCh 5 7.40-7.28 (m, 5H), 3.60 (s, 2H). 3.19-3.11 (m, 2H), 2.10-2.00 (m, 2H).Synthesis of (3S,4s,5R)-l-benzyl-3.5-bis(methyl-d3)-4-phenylpiperidin-3,5-d2-4-ol

[0167] To a solution of ((3S,5R)-l-benz.yI-3,5-bis(methyl-d3)piperidin-4-one-3,5-d2 (250 mg. 1.11 mmol, 1.0 eq) in THF (5 mL) was added bromo(phenyl)magnesium (3 M m Et? O.1.11 mL, 3 0 eq) at -60 °C under N?. atmosphere. The mixture was warmed to 20 °C and stirred at 20 °C for 4 h under N2 atmosphere. The reaction mixture was quenched by adding sat.aq. NH4CI (20 ml.) and extracted with EtOAc (10 mL x 3). The combined organic layers wereNAI-5006781290v1 66Attorney Docket No. 14859-002-228washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 70 mL / min) to give (3S,4s,5R)-l-benzyl-3,5-bis(methyl-d )-4-phenylpiperidin-3,5-d2-4-ol as a white solid. Yield: 240 mg, 71%; MS (ESI) m / z 304.1 [M+1]+;1HNMR(400 MHz, CDCh 57.65-7.20 (m, 10H), 3.58 (s, 2H), 2.72 (d, J - 11.6 Hz, 2H), 2.14 (d, J - 11.6 Hz, 2H). Synthesis of (3S,4s,5R)-3,5-bis(methyl-ds)-4-phenylpiperidin-3,5-d2-4-ol

[0168] To a solution of ((3S,4s,5R)-l-benzyl-3,5-bis(methyl-d3)-4-phenylpiperidin-3,5-d2-4-ol (230 mg, 757 pmol, 1.0 eq) m MeOH (5 mL) was added PdCh (26.8 mg, 151 pmol, 0.2 eq) under lb atmosphere. The mixture was degassed and purged with lh three times. The mixture was heated to 50 °C and stirred at 50°C for 16 h under H2 atmosphere (15 psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give a residue to give (3S.4s,5R)-3,5-bis(methyl-d3)-4-phenylpiperidin-3.5-d2-4-ol as a white solid. Yield: 160 mg, crude; MS (ESI) m / z 214.3 [M+1]'; T-INMR (400 MHz, DMSO-ds) 87.70-7.50 (m, 1H), 7.40-7.10 (m, 5H), 4.77(s, 1H), 292 (d, J = 12.4 Hz, 2H). 2.81 (d, J = 12.4 Hz, 2H).Synthesis of ((3S.4R)-4-(2, 4-difluorophenyl)-l-(2-(methyl-d3)propan~2-yl-l,l, 1, 3, 3, 3- d6)pyrrolidm-3-yl)((3S.4R.5R)-4-hydroxy-3,5-bis(methyl-d3)-4-phenylpiperidin-l-yl-3,5-d2)methanone

[0169] To a solution of (3S,4s,5R)-3,5-bis(methyI-d )-4-phenylpiperidin-3,5-d2-4-ol (36.4 mg, 171 pmol, 1.0 eq) in DCM (2 mL) was added (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, Ll,3,3,3-d6)pyrrolidine-3-carboxylic acid (50 mg, 171 pmol, 1.0 eq), TEA (51.9 mg, 513 pmol, 3.0 eq) and lhP (147 mg. 205 pmol, 50% purity, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding sat.aq NallCOs (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried overNa2SO-i, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25mm*10pm;mobile phase: | ACN m H2O (lOmM NH4HCO3)]; gradient:40%-70% over 80 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yLl,l,l,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d3)-4-phenylpiperidin-l-yl-3,5- d?.)methanone. Yield: 30.6 mg, 36%; MS (ESI) m / z 488.2 [M+l ]+;lHNMR (400 MHz, DMSO- de) 67.68-7.53 (m. 1H), 7.45-7.27 (m. 3H), 7.25-7.00 (m. 4H), 4.62-4.54 (m. 1H), 4.20 (d. J === 12.8 Hz, IH), 3.90-3.70 (m, 1H). 3.65-3.40 (m, 2H), 3.20-294 (m, 3H), 2.85-2.75 (m, IH),NAI-5006781290v1 67Attorney Docket No. 14859-002-2282.72-2.55 (m, 2H);19FNMR (376 MHz, DMSO) 5 -112.94 - -113.89 (m, 2F): overall deuterium incorporation: 98.9%; percent of Compound Ila molecules: 81.2%.Example 12a: ((3S,4R)-4-(2,4-difluoropheny!)-l-(2-(methyl-d3)propan-2-yI-l,l,l'>3,3 - d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyI-d5)piperidin-l-yl-3,5-d2)methanoneSynthesis of (3S,4s,5R)-l-henzyl-3,5-dimethyl-4-(phenyl-d5)piperidin-3,5- 2-4-ol

[0170] To a solution of l-bromobenzene-2, 3,4,5, 6-ds (739 mg, 4.56 mmol, 5.0 eq. > 99.0% of overall deuteration incorporation) in THF (8 mL) was added n-BuLi (2.5 M, 1.64 m, 4.5 eq) at -65 °C under N2. After the reaction was stirred at -65 °C for 0.5 h under N2, a solution of (3S,5R)-l-benzyl-3,5-dimethylpiperidin-4-one-3,5-d2 (200 mg, 912 pmol, 1.0 eq) in THF (1 mL) was added wider N?. Then the mixture was warmed to 20 °C and stirred at 20 °C for 4 h wider N2. The reaction mixture was quenched by adding sat.aq NH-iCl (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated wider reduced pressure to give a residue. The residue ■was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 70 mL / min) give (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-(phenyl-d5)piperidin-3,5-d2-4-ol as a white solid. Yield: 230 mg. 83%; MS (ESI) m / z 303.2 ]M+1JHNMR (400 MHz, CDCls 5 7.40-7.28 (m. 5H), 3.58 (s, 2H), 2.73 (d, J = 12.0 Hz, 2H), 2, 15 ( d. J = 11.6 Hz, 2H), 0.56 (s, 6H).Synthesis of (3S,4s.5R)-3.5-dimethyl-4-(phe l-d5)piperidin-3,5-d2-4-ol

[0171] To a solution of (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-(phenyl-d5)piperidm-3,5-d2-4-ol (230 mg, 760 pmol, 1.0 eq) in MeOH (5 mL) was added PdCb (27.0 mg, 152 pmol, 0.2 eq) under N2 atmosphere. The suspension was degassed and purged with H2 three times. TheNAI-5006781290v1 68Attorney Docket No. 14859-002-228reaction mixture was heated to 50 °C and stirred at 50 °C for 12 h under H2 atmosphere (15 psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S, 4s, 5R)-3,5-dimethyl-4-(phenyl-d5)piperi din-3, 5-d2-4-ol as a white solid. Yield: 180 mg, crude; MS (ESI) m / z 213.2 [M+1]+;JHNMR (400 MHz, DMSO-de) 3 9.21 (s, 1H), 8.93 (s, IH), 4.99(s, IH), 3.07 (d, J = 12.0 Hz, 2H), 2.91-2.86 (m, 2H), 0.49 (s, 6H).Synthesis of ((3S,4R)-4-(2,4-difluoropjhenyl)-l-(2-(methyl-d3)propan-2-yl-l,1, 1,3,3,3-d6)pyrrolidm-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyl-d5)piperidin-l-yl-3,5-d?)methcmone|00172| To a solution of (3S,4s,5R)-3,5-dimethyl-4-(phenyl-d5)piperidin-3,5-d2-4-ol (46.8 mg, 188 praol, 1.1 eq, HC1) and (3S,4R)-4-(2,4-difluoropheny])-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3.3-d6)pyrrolidine-3-carboxylic acid (50 mg, 171 pmol, 1.0 eq) in DCM (4 mL) was added TEA (43.3 mg, 428 pmol. 2.5 eq) and T4P (148 mg, 205 pmol, 50% purity, 1.2 eq) at 0 °C. The reaction was stirred at 0 °C for 0.5 h under N2. The reaction mixture was quenched by adding sat.aq NaHCOs (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL). dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC 18 150x30x7 pm: mobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient: 45%-75% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyl-d5)piperidin-l-yl-3,5-d2)melhanone. Yield: 15.16 mg, 18%; MS (ESI) m / z. 487.2 [M+ 1]+; 'HNMR (400 MHz. DMSO-de) 8 7 63-7.55 (m. IH), 7.24-7.18 (m. IH), 7.07-7.05 (m. 1H).4.61-4.57 (m, IH), 4.20 (d, J = 12.4 Hz, IH), 3.85-3.76 (m, IH), 3.55-3.53 (m, 2H), 3.45-2.97 (m, 3H), 2.83-2.81 (in, IH), 2.69-2.56 (m, 2H), 0.47-0.42 (m, 4H), 0.26 (s, 2H);19FNMR (376 MHz, DMSO) 5 -112.94 - -113.89 (m, 2F); overall deuterium incorporation: 98,8%; percent of Compound 12a molecules: 80.3%.Example 13a: ((3S,4R)-4-(2,4-difkiorophenyl)-l-(2-(niethyl-d3)propan-2-yl-l, 1,1,3?3,3-d6)pyrroIidiii-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d3)-4-phenylpiperidin-l-yI- 2,2,6,6-d4)methanoneNAI-5006781290vl 69Attorney Docket No. 14859-002-228Synthesis of dimethyl l-benzyl-3,5-bis(methyl-d3)-4-oxopiperidine-3,5-dicarboxylate-2, 2,6.6- d4

[0173] To a mixture of dimethyl 2,4-bis(methyl-d3)-3-oxopentanedioate (300 mg, 1.44 mmol, 1.0 eq) and phenylmethanamine (185 mg. 1.73 mmol, 1.2 eq) in MeOH (5 mL) was added HC1 (1 M, 300 pL, 0.76 eq) and formaldehyde^ (484 mg. 3.03 mmol, 2.1 eq) at 20 °C under N2 atmosphere. The mixture was stirred at 20 °C for 20 h under N2 atmosphere The reaction mixture was concentrated under reduced pressure to give a residue. Hie residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFIash Silica Flash Column, eluent of 0-15% ethyl acetate / n-hexane gradient at 36 mL / min) to give dimethyl l-benzyl-3,5- bis(methyl-d3)-4-oxopiperidme-3,5-dicarboxylate-2,2.6,6-d4 as a light-yellow oil. Yield: 280 mg, 53%; MS (ESI) m / z 344.1 [M+1]+; ‘HNMR (400 MHz, CDCh) 67.39-7.29 (m, 5H), 3.68 (s, 6H), 3.65 (s, 2H).Synthesis of (3S,5R)-l-benzyl-3,5-bis(methyl-d3)piperidin-4-one-2,2,6,6-d4

[0174] Dimethyl l-benzyl-3, 5-bis(metliyl-d3)-4-oxopiperidine-3,5-dicarboxylate-2, 2,6,6-dr (280 mg, 815 pmol, 1.0 eq) was dissolved in HC1 (1.5 M, 2.80 mL, 5 15 eq) at 20 °C. The mixture was heated to 100CC and stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and the pH was adjusted to 8 with aq. NaOH (2 M) The aqueous layer was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFIash Silica Flash Column, eluent of 0-20% ethyl acetate / n-hexane gradient at 60 mL / min) to give (3S,5R)-l-benzyl-3,5-bis(methyl-d3)piperidin-4-one-2.2,6.6-d4as a colorless oil. Yield: 110 mg, 59%; MS (ESI) m / z 228.3 [M+1]+; ‘HNMR (400 MHz, CDCh) 5 7.41-7.31 (m. 5H), 3 61 (s. 2H), 2.69 (s, 2H).Synthesis of (3S,4s.5R)-l-benzyl-3.5-bis(methyl-d3)-4-phenylpiperidin-2,2, 6, 6-d4-4-olNAI-5006781290v1 70Attorney Docket No. 14859-002-228

[0175] To a solution of (3S,5R)-l-benz 'l-3,5-bis(methyl-d3)piperidin-4-one-2,2,6,6-d4 (170 mg, 747 pmol, 1.0 eq) in THF (5 mL) was added bromo(phenyl)magnesium (3 M in Et?. O, 747 pL, 3.0 eq) at -60 °C under N2 atmosphere. The mixture was warmed to 20 °C and stirred at 20 °C for 4 h under N2 atmosphere. The reaction mixture was quenched by adding sat.aq NHrCI (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate, fi-hexane gradient at 60 mL / min) to give (3S,4s,5R)-l-benzyl-3,5-bis(methyl-d3)-4-phenylpiperidin-2,2,6.6-dr-4-oI as a white solid. Yield: 180 mg, 78%; MS (ESI) m / z 306.3 [M+1]+; ’HNMR (400 MHz, CDCh) 5 7.45-7.20 (m, 10H), 3.58 (s, 2H), 2.22 (s, 2H).Synthesis of (3S,4s.5R)-3,5-bis(methyl-d3)-4-phenylpiperidin-2,2,6,6-d4-4-ol

[0176] To a solution of (3S.4s,5R)-l-benzyl-3,5-bis(methyl-d3)-4-phenylpiperidin-2,2,6,6-dr-4-ol (160 mg, 523 pmoL 1.0 eq) in MeOH (5 mL) was added PdCb (18.5 mg, 107 prnol, 0.2 eq) under H2 atmosphere. The mixture was degassed and purged with H2 three times. The mixture was heated to 50 °C and stirred at 50°C for 16 h under H2 atmosphere (15 psi). Hie reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s,5R)-3,5-bis(methyl-d3)-4-phenylpiperidin-2,2.6,6-d4-4-ol as a white solid. Yield: 100 mg, crude; MS (ESI) m / z 216.3 [M+1]+; H MR (400 MHz, DMSO-d6) 3 7.66-7.47 (m, 1H), 7.40-7.10 (m, 5H), 4.89 (s, 1H), 2.31 (s, 2H).Synthesis of ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l, 1.3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3.5-bis(methyl-d3)-4-phenylpiperidin-I-yl-2,2,6,6-dfmethanone

[0177] To a solution of (3S,4s,5R)-3,5-bis(methyl-d )-4-phenylpipendin-2,2.6,6-d4-4-ol (36.8 mg, 171 pmol, 1.0 eq) in DCM (1 mL) was added (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yI-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic acid (50 mg, 171 pmol, 1 0 eq). TEA (51.9 mg, 513 nmol, 3.0 eq) and T4P (147 mg, 205 pmol, 50% purity', 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding sat.aq NaHCOa (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2S€>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25mm*10 um;mobile phase: [ACN in IbCXlOmM NH4HCO3)]; gradient:40%-70% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-NAI-5006781290v1 71Attorney Docket No. 14859-002-228d6)pyn-olidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d3)-4-phenylpiperidin-l-yl-2,2,6,6- d4)methanone. Yield: 13.7 mg. 16%; MS (ESI) m / z 490.2 [M+l ]!;1HNMR (400 MHz, DMSO-d6) 6 7.68-7.53 (m, 1H), 7.45-7.27 (m, 3H). 7.25-7.00 (m. 4H), 4.62-4.54 (m, 1H), 3.90-3.70 (m, 1H), 3 60-3.40 (m, 1H), 3 18-3.01 (m, 2H), 2.85-2.75 (m, 1H), 2.72-2.67 (m,lH), 1.85- 1.14 (m, 2H);l9FNMR (376 MHz, DMSO) 5 -112.95 - -113.89 (m, 2F); overall deuterium incorporation: 99.1%; percent of Compound 13a molecules: 83.7%.Example 14a: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3>3-d6)pyrrolidm-3-yl)((3S,4R.5R)-4-hydroxy-3,5-diniethyl-4-(phenyl-d5)piperidin-l-yl-2,2,6,6-d4)methanoneSynthesis of(3S, 4s.5R)-l-benzyl-3.5-dimethyl-4-(phenyl-d5)piperidin-2.2.6.6-d4-4-ol [00178j To a solution of l-bromobenzene-2, 3,4,5, 6-ds (549 mg, 3.39 mmol, 5.0 eq, > 99.0% of overall deuteration incorporation) in THF (5 mL) was added n-BuLi (2.5 M, 1.22 mL, 4.5 eq) at -65 °C under Nz. The reaction was stirred at -65 °C for 1 h under N?. Then to the mixture was added a solution of (3S.5R)-l-benzyl-3,5-dimethvlpiperidin-4-one-2,2,6.6-d4 (150 mg, 678 pmol, 1.0 eq) in THF (1 L) at -65 °C under N2. The reaction was warmed to 20CC and stirred at 20 °C for 3 h under N2. The reaction mixture was quenched by adding sat.aq NH4CI (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic lay ers were washed with brine (10 mL), dried over NazSCh, filtered and concentrated under reduced pressure to give a residue. Ihe residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 70 mL / min) to give (3S,4s,5R)-l-benzy{-3,5-dimethyl-4-(phenyl-d5)piperidin-2,2,6,6-d -4-ol as a white solid. Yield: 200 mg, 97%; MS (ESI) m / z 305.3 [M+1]+;iHNMR (400 MHz, CDCb) 5 7.37-7.29 (m, 5H). 3.58 (s. 2H), 2.24-2.22 (m. 2H). 1.53 (s. 1H), 0.56 (d. J = 6.8 Hz. 6H).NAI-5006781290v1 72Attorney Docket No. 14859-002-228Synthesis of (3S,4s,5R)-3,5-dimethyl-4-(phenyl-d5)piperidin-2,2,6,6-d4-4-ol

[0179] To a solution of (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-(phenyl-d5)piperidin-2, 2,6,6-d -4-ol (200 mg, 657 pmol, 1.0 eq) in MeOH (5 mL) was added PdCl2 (23 3 mg, 131 pmol, 0.2 eq) under Nz atmosphere. The suspension was degassed and purged with H2 three times. The reaction mixture was heated to 50 °C and stirred at 50 °C for 12 h under H2 atmosphere (15 psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S.4s,5R)-3,5-dimethyl-4-(phenyl-d5)piperidin-2,2,6,6-d4-4-ol as a white solid. Yield: 140 mg, crude; MS (ESI) m / z 215.2 [M+1]+; ’HNMR (400 MHz. DMSO-de) 89.11 (s, 1H), 4.98 (s, 1H), 2.40-2.35 (m, 2H), 0.49 (d, J = 6.8 Hz, 6H).Synthesis of ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1,1,3,3,3-d6)pyYrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dim.ethyl-4-(phenyl-d:)piperidin-l-yl-2.2,6,6-dfmethanone

[0180] To a solution of (3S,4s,5R)-3.5-dimethyl-4-(phenyl-d5)piperidin-2,2,6.6-d4-4-ol (42.9 mg, 171 pmol, 1.0 eq HC1) and (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic acid (50 mg, 171 pmol, 1.0 eq) in DCM (1 mL) was added TEA (51.9 mg, 513 pmol, 3.0 eq) and T4P (148 mg, 205 pmol, 50% purity, 1.2 eq) at 0 °C. The reaction was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by adding sat.aq NaHCO? (10 mL) and extracted with DCM (5 ml. x 3). The combined organic layers were washed with brine (5 mL). dried over Na2SOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC 18 150x40x7 pm; mobile phase: [ACN inlLO (lOrnMNILHCOs)]; gradient: 40%-70% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl- 1.1,1, 3,3, 3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyl-d5)piperidin-l-yl-2,2,6,6-d4)methanone. Yield: 13.6 mg, 16%; MS (ESI) m'z 489.2 [M+1]+; ’HNMR (400 MHz, DMSO-ds) 5 7.63-7.55 (m, IH), 7.23-7.18 (m, 1H), 7.07-7.05 (m, 1H), 4.61-4.57 (m, IH), 3.85-3.76 (m. IH). 3.54-3.32 (m, 1H). 3.15-3.03 (m, 2H), 2.84-2.66 (m, 2H), 1.85-1.60 (m, IH), 1.18-1.14 (m, IH), 046-0.42 (m, 4H), 0.27 (d, J = 6.8 Hz, 2H);19FNMR (376 MHz, DMSO) 8 -112.94 - -113.89 (m, 2F); overall deuterium incorporation: 99.1%; percent of Compound 14a molecules: 83.2%.Example 15a: ((3S,4R)-4-(2,4-difluorophenyI)-l-(2-(methyI-d3)propan-2-yl-l,l9l'>3 -d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d3)-4-(pheiiyl-d5)piperidiii-l-yl)methanoneNAI-5006781290vl 73Attorney Docket No. 14859-002-228Synthesis of (3S,4s,5R)-l-benzyl-3.5-bis(Tnethyl-d3)-4-(phenyl-d5)piperidin-4-ol

[0181] To a solution of l-bromobenzene-2,3,4,,5,6-d5 (725 mg, 4,48 mmol, 5,0 eq, > 99.0% of overall deuteration incorporation) in THF (5 L) was added n-BuLi (2.5 M, 1.61 mL, 4.5 eq) at -65 °C under N2 atmosphere. The mixture was stirred at -65 °C for 1 h under N2 atmosphere. Then a solution of (3S,5R)-l-benzyl-3,5-bis(rnethyl-d3)piperidin-4-one (200 mg, 895 pmol, 1.0 eq) in THF (2 mL) was added into the mixture at -65 °C under N2 atmosphere. The mixture was warmed to 20 °C and stirred at 20 °C for 4 h under N2 atmosphere. The reaction mixture was quenched by adding sat.aq NILC1 (20 mL) and extracted with EtOAc (10 ml, x 3). The combined organic layers were washed with brine (10 ml,), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 60 mL / min) to give (3S,4s,5R)-l-benzyl-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidm-4-ol as a white solid. Yield: 180 mg, 65%: MS (ESI) m / z 307.3 [M+1]+;3HNMR (400 MHz, CDCls) 5 7.40-7.28 (m, 5H), 3.58 (s, 2H), 2.75-2.72 (m, 2FI), 2.30-2.15 (m, 4H), 1.53 (s, 1H).Synthesis of ( 3S.4s, 5R)-3, 5-bis(methyl-d3)-4-(phenyl-ds)piperidin-4-ol

[0182] To a solution of (3S.4s,5R)-l-benzyl-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-4- ol (180 mg, 587 umol, 1.0 eq) m MeOH (3 mL) was added PdCh (20.8 mg, 117 pmol, 0.2 eq) at 20 °C under Th atmosphere. The mixture was heated to 50 °C and stirred at 50 °C for 16 h under H2 atmosphere (15 Psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s,5R)-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidm-4-oI as a white solid. Yield: 120 mg, crude: MS (ESI) m / z 217.3 [M+1]4; 'HNMR (400 MHz, DMSO-de) 84.67 (s, 1H), 2.91 -2,83 (m, 2H), 2.81 -2.73 (m, 2H), 2.19-2.11 (in, 2H) Synthesis of ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l.1,1, 3, 3, 3-NAI-5006781290v1 74Attorney Docket No. 14859-002-228d6)p Trolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d3)-4-(phenyl-ds)piperidin-l-yl)methanone00183 To a solution of (3S,4s,5R)-3,5-bis(methyI-d3)-4-(phenyl-d5)piperidin-4-ol (43.2 mg. 171 pmol. 1.0 eq HC1) m DCM (2 mL) was added (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic acid (50.0 mg, 171 umol, 1.0 eq), TEA (51.9 mg, 513 pmol, 3.0 eq) and T P (147 mg. 205 ymol, 50% purity. 1.2 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was quenched by adding sat.aq NaHCOs (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: WePure Biotech XP tC18 150*40*7 umtmobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient:40%-75% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yI-l,l,l,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyi- d3)-4-(phenyl-ds)piperidin-l -yl)methanone. Yield: 31.44 mg, 37%; MS (ESI) m / z 491.2 [M+1]+; ‘HNMR (400 MHz, DMSO-de) 57.63-7.57 (m. 1H), 7.23-7.15 (m, 1H), 7.07-7.05 (m, 1H), 4.61-4.57 (m. 1H). 4.23-4.20 (m. 1H), 3.90-3.70 (m, 1H). 3.65-3.41 (m. 2H), 3.20-2.95 (m, 3H), 2.72-2.66 (m, 1H), 2.62-2.55 (m, 2H), 1.85-1.16 (m, 2H);19FNMR (376 MHz, DMSO) S -112,95 - -113.88 (m, 2F); overall deuterium incorporation: 99.1 %; percent of Compound 15a molecules: 82.8%.Example 16a: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(metliyl-d3)propan-2-yl-l,l, 1, 3,3,3- d6)pyrrolidin-3-yl)((3S,4R^R)-4-hydroxy-345-bis(methyI-d3)-4-phenylpiperidm-l-yI- 2,2,3,5,6,6-d6)methanoneSynthesis of (3S,5R)-l-benzyl-3,5-bis(methyl-d3)piperidin-4-one-2,2,3,5, 6, 6-dt>

[0184] To a solution of (3S,5R)-l-benzyl-3,5-bis(methyl-d3)piperidin-4-one-2,2,6,6-d4 (1.0 g, 440 mmol. 1.0 eq) in D2O (9 mL, >99.0% of overall deuterium incorporation) and methanol-d (3 mL, >99.0% of overall deuterium incorporation) was added t-BuONa (2.54 g, 26.3 mmol, 6.0 eq) at 20 °C. The mixture was heated to 85 °C and stirred at 85 °C for 16 h.NAI-5006781290v1 75Attorney Docket No. 14859-002-228The reaction mixture was cooled to room temperature, quenched by adding aq. HC1 (1 M. 20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-20% ethyl acetate / n-hexane gradient at 60 mL / min) to give (3S,5R)-l-benzyl-3,5-bis(metliyl-d3)piperidin-4-one-2,2,3,5,6,6-d6 as a colorless oil. Yield: 730 mg, 72%; MS (ESI) m / z 230.2 [M+ 1 ] '; 'HNMR (400 MHz, CDCh) 57 39-7.28 (m. 5H).3.61 (s, 2H)Synthesis of (3S, 4s, 5R)-1 -benzyl- 3.5-bis(methyl-d3)-4-phenylpiperidin-2.2.3.5.6.6-de>-4-ol 100185| To a solution of (3S,5R)-l-benzyl-3,5-bis(methyl-d3)piperidin-4-one-2,2,3,5,6,6-d6 (200 mg, 871 pmol, 1.0 eq) in THF (5 mL) was added bromo(phenyl)magnesium (3 M in Et O, 871 pL, 3.0 eq) at -60 °C under N2 atmosphere. The mixture was warmed to 20 °C and stirred at 20 °C for 4 h under N2 atmosphere. The reaction mixture was quenched by adding sat.aq NILiCl (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 ml,), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 60 mL / min) to give (3S,4s,5R)-l-benzyl-3,5-bis(methyl-d3)-4-phenylpiperidin- 2.2.3.5.6.6-d6-4-ol (54) as a white solid. Yield: 200 mg, 74%; MS (ESI) m / z 308.3 [M+1]+; 'HNMR (400 MHz, CDCh) 57.65-7.24 (m, 10H), 3.58 (s, 2H), 1.52 (s, 1H).Synthesis of (3S,4s,5R)-3, 5-bis(methyl-d3)-4-phenylpiperidin-2, 2,3,5, 6,6-d&-4-ol

[0186] To a solution of (3S,4s,5R)-l-benzyl-3,5-bis(methyl-cb)-4-phenyIpiperidin- 2.2.3.5.6.6-de-4-ol (54) (200 mg, 650 pmol. 1.0 eq) in MeOH (5 mL) was added PdCb (23.0 mg, 130 pmol, 0.2 eq) at 20 °C under M2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was heated to 50 °C and stirred at 50 °C for 16 h under H2 atmosphere (15 Psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s,5R)-3,5-bis(methyl-d3)-4-phenylpiperidin- 2.2.3.5.6.6-dfi-4-ol as a white solid. Yield: 140 mg, crude; MS (ESI) m / z 218.3 [M+lf; 'HNMR (400 MHz, DMSO-de) 57.70-7.45 (m, 1H), 7.40-7.15 (m, 5H), 4.64 (s, 1H).Synthesis of ((3S.4R)-4-(2.4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1, 1, 3, 3, 3-d6)pyrrolidin-3-yl)((3S.4R5R)-4-hydroxy-3,5-bis(methyl-d3)-4-phenylpiperidin-l-yl- 2.2.3.5.6.6-d6)methanoneNAI-5006781290v1 76Attorney Docket No. 14859-002-228

[0187] To a solution of (3S, 4s, 5R)-3,5-bis(methyl-d.3)-4-phenylpipendin-2, 2,3,5, 6.6-cU-4- ol (34.7 mg, 136 pmol, 1.0 eq HC1) in DCM (2 mL) was added (3S,4R)-4-(2,4-difluorophenyl)-]-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic acid (40 mg, 136 pmol, 1.0 eq). TEA (41.5 mg, 410 pmol, 3.0 eq) and T4P (118 mg, 164 pmol, 50% purity, 1.2 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was quenched by adding sat.aq NaHCOs (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2S€>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 pm; mobile phase: [ACN in H2O (lOmM NII1HCO3)]; gradient:45%-75% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)- 1 -(2-(methyl-d3)propan-2-yl- 1, 1, l,3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d3)-4-phenylpipendin-l-yl-2,2,3,5,6,6-d6)methanone. Yield: 15.3 mg, 23%; MS (ESI) m / z 492.3 [M+1]+: ’HNMR (400 MHz, DMSO-ds) 87.66-7.54 (m, 1H), 7.51- 728 (m, 3H), 7.21-7.05 (m, 4H), 4.63-4.55 (m, 1H), 3.89-3 72 (m, 1H), 3.56-3.41 (m, 1H), 3.19-3.00 (m, 2H). 2.84-2.66 (m, 2H);19FNMR (376 MHz, DMSO) 6 -112.92 - -113.88 (m, 2F); overall deuterium incorporation: 99.1%; percent of Compound 16a molecules: 81.0%.Example 17a: ((3S4R)-4-(24-difluorophenyI)-l-(2-(methyI-d3)propan-2-yl-l, 1,1,3’3 -d6)pyiTolidin-3-yl)((3S,4R,5R)-4-hydroxy~3,5-dimethyl-4-(phenyI-d5)piperidin-l-yl- 2,2,5,6,6-d6)methanoneH2, PdCI-Synthesis of (3S,4s,5R)-l-henzyl-3,5-dimethyl-4-(phe >l-d5)piperidin-2,2,3,5,6,6-d6-4-ol

[0188] To a solution of l-bromobenzene-2,3,4,5,6-ds (726 mg, 4.48 mmol, 5.0 eq, > 99.0% of overall deuteration incorporation) in THF (7 mL) was added n-BuLi (2.5 M, 1.61 mL, 4.5 eq) at -65 °C under N2. The reaction was stirred at -65 °C for 1 h under N2. Then to the mixture was added a solution of (3S,5R)-l-benzyl-3,5-dirnethylpiperidin-4-one-2,2,3,5,6,6-d6 (200 mg.NAI-5006781290v1 77Attorney Docket No. 14859-002-228895 pmol, 1.0 eq) in THF (1 mL) at -65 °C under N2. The reaction was warmed to 20 °C and stirred at 20 °C for 3 h under N2. The reaction mixture was quenched by adding sat.aq NH4CI (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4. filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 70 mL / min) to give (3S,4s.5R)-l-benzyl-3,5-dimethyl-4-(phenyl-d5)piperidin-2,2,3,5,6,6-d6-4-ol as a white solid. Yield: 190 mg, 69%; MS (ESI) m / z 307.2 [M+1]+;!HNMR (400 MHz, CDCJ.fl 87.39-7.28 (m, 5H), 3.58 (s, 2H), 1.52 (s, 1H), 0.55 (s, 6H).Synthesis of (3S, 4s, 5R)-3, 5-dimethyl-4-(phenyl-ds)piperidin-2, 2, 3, 5.6, 6-de-4-ol|00189| To a solution of (3S,4s,5R)-l-benzyl-3,5-dimethyl-4-(phenyl-d5)piperidin- 2.2.3.5.6.6-d6-4-ol (190 mg, 620 pmol, 1.0 eq) in MeOH (5 mL) was added PdCh (22.0 mg, 124 pmol, 0.2 eq) under N?. atmosphere. The suspension was degassed and purged with H2 three times. The reaction mixture was heated to 50 °C and stirred at 50 °C for 12 h under II2 atmosphere (15 psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s.5R)-3,5-dimethyl-4-(phenyl-d5)piperidin- 2.2.3.5.6.6-dfi-4-ol as a white solid. Yield: 150 mg, crude; MS (ESI) m / 'z 217.3 [M+1]4; fl-INMR (400 MHz, DMSO-de) 88.97-8.80 (rn, 1H), 4.94 (s, 1H), 0.48 (s, 6H).Synthesis of ((3S, 4R)-4-(2, 4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1, 1, 3,3, 3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyl-ds)piperidin-l-yl- 2.2.3.5.6.6-dfi)methanone

[0190] To a solution of (3S,4s,5R)-3,5-dimethyl-4-(phenyl-d5)piperidin-2,2,3,5,6,6-d6-4- ol (34.6 mg, 137 pmol, 1,0 eq HO) and (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl- d3)propan-2-yl-l,l,l,3,3.3-d6)pyrrolidine-3-carboxylic acid (40 mg. 137 pmol, 1.0 eq) in DCM (2 mL) was added TEA (41.5 mg, 410 pmol, 3.0 eq) and T; P (118 mg, 164 pmol, 50% purity, 1.2 eq) at 0 °C The reaction was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by adding sat.aq NaHCCh (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Hie residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150x40x7 pm; mobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient:45%-75% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl- d3)propan-2-yl-l,l,l,3,3.3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyl-d5)piperidin-l-yl-2,2,3,5,6,6-d6)methanone. Yield: 13.57 mg. 20%; MS (ESI) m / zNAI-5006781290v1 78Attorney Docket No. 14859-002-228491.2 [Mrl]+;lHNMR (400 MHz, DMSO-do) 5 7.63-7.57 (m, 1H), 7.24-7.19 (m, 1H), 7.07- 7.05 (m, 1H), 4.61-4.57 (m. 1H), 3.85-3.75 (m, 1H). 3.54-3.52 (m, 1H), 3.15-3.03 (m. 2H), 2.84-2.67 (m, 2H), 0.44-0.42 (m, 4H), 0.26 (s, 2H);19FNMR (376 MHz, DMSO) 8 -112.92 - - 113.90 (m, 2F); overall deuterium incorporation: 99.0%; percent of Compound 17amolecules: 80.5%.Example 18a: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyI-d3)propan-2-yl-l,l,l'>3^3 -de)py rroIidin-3-yl)((3S,4R^R)-4-hy droxy-3,5-bis(methy I-d3)-4-(phenyl-ds)piperidin- 1 - yl-3,5-d2)methanoneSynthesis of (3S,4s,5R)-l-henzyl-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-3,5-d2-4-ol

[0191] To a solution of l-bromobenzene-2,3,4,5,6-d5 (898 mg, 5.55 mmol, 5.0 eq, > 99.0% of overall deuteration incorporation) in THF (5 mL) was added n-BuLi (2.5 M, 2.00 m, 4.5 eq) at -65 °C under Nz atmosphere. The mixture was stirred at -65 °C for 1 h under N2 atmosphere. Then a solution of (3S,5R)-l-benzyl-3,5-bis(methyl-d3)piperidin-4-one-3,5-d2 (250 mg, 1 11 mmol, 1.0 eq) m THF (2 mL) was added into the mixture at -65 °C under N2 atmosphere. The mixture was warmed to 20 °C and stirred at 20 °C for 4 h under N2 atmosphere. The reaction mixture was quenched by adding sat.aqNH4Cl (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was pwified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 60 mL / min) give (3S,4s,5R)-l-benzyl-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-3,5-d2-4-ol as a while solid. Yield: 180 mg, 52%; MS (ESI) m / z 309.3 [M+lf;!HNMR (400 MHz, CDCh) 8 7.45-7.28 (m, 5H). 3.58 (s, 2H), 2.72 (d, J === 11.6 Hz, 2H), 2.15 (d, J - 11.6 Hz, 2H).NAl-5006781290vl 79Attorney Docket No. 14859-002-228Synthesis of (3S,4s,5R)-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-3,5-d2-4-ol|00192| To a solution of (3S,4s,5R)-l-benzyl-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-3,5-d2-4-ol (180 mg, 583 pmol, 1 0 eq) in MeOII (5 mL) was added PdCb (206 mg, 116.6 pmol. 0.2 eq) at 20 °C under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was heated to 50 °C and stirred at 50 °C for 16 h under H2 atmosphere ( 15 Psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S.4s,5R)-3.5-bis(methyl-d3)-4-(pheny]-d5)piperidm-3.5-d2-4-ol as a white solid. Yield: 120 mg, crude; MS (ESI) m / z 219.3 [M+1]+; 'HNMR (400 MHz. DMSO-dr,) S 4.67(s, 1H), 2.88 (d, J = 12.4 Hz, 2H), 2.77 (d, J = 12.4 Hz, 2H).Synthesis of ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1, 1,3,3, 3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d)-4-(phenyl-d5)piperidin-l-yl-3,5-d2)methanone

[0193] To a solution of (3S,4s,5R)-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-3.5-d2-4-ol (43.5 mg, 171 p ol, 1.0 eq HC1) in DCM (2 mL) was added (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3.3-d6)pyrrolidine-3-carboxylic acid (50.0 mg. 171 pmol, 1.0 eq), TEA (51.9 mg, 513 pmol, 3 eq) and T4P (147 mg, 205 pmol. 50% purity, 1.2 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was quenched by adding sal aq NaHCOs (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL). dried over Na2§04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP 1C18 150x30x7 pm; mobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient: 45%-75% over 8.0 min) to give ((3S.4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l, L3,3,3-d6)pyrrolidin-3-yl)((3S,4R,5R)-4- hydroxy-3,5-bis methyl-d3)-4- phenyl-d5)piperidin-l-yl-3,5-d2)methanone. Yield: 16.5 mg, 19%; MS (ESI) m / z 493.3 [M+1]+; 'HNMR (400 MHz, DMSO-de) 57.66-7.53 (m, 1H), 7.25-7.01 (m, 2H), 4.61-4.54 (m, 1H), 4.20 (d. J = 13.2 Hz, 1H), 3.90-3.71 (m, 1H), 3.62-3.41 (m, 2H), 3 20-2.95 (m, 3H), 2.84-2.76 (m, 1H), 2.72-2.55 (m, 2H);19FNMR (376 MHz, DMSO) 5 -112.95 - -113.89 (in, 2F); overall deuterium incorporation: 99.0%; percent of Compound 18a molecules: 79.0%,Example 19a: ((3S,4R)-4-(2,4-difluorophenyI)-l-(2-(methyI-d3)propan-2-yI-l,l9l'>3 -d6)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3,5-bis(methyl-d3)-4-(pheiiyl-d5)piperidiii-l-yl-2,2,6,6-d4)methanoneNAI-5006781290vl 80Attorney Docket No. 14859-002-228T4P, TEA, DCM, 0 °C, 1 h Synthesis of ( 3S.4s, 5R)-l-benzyl-3, 5-bls(methyl-d3)-4-(phenyl-d5)piperidin-2,2, 6, 6-d4-4-ol

[0194] To a solution of l-bromobenzene-2,3,4,5,6-d5 ( 12 mg, 4.40 mmol, 5.0 eq, > 99.0% of overall deuteration incorporation) in THF (5 mL) was added n-BuLi (2.5 M in hexane, 1.58 mL, 4.5 eq) at -65 °C under Nz atmosphere. The mixture was stirred at -65 °C for 1 h under Nz atmosphere. Then a solution of (3S,5R)-l-benzyl-3,5-bis(methyl-d3)piperidin-4-one-2,2,6,6-d4 (200 mg. 879 umol, 1.0 eq) in THF (2 mL) was added into the mixture at -65 °C under Nz atmosphere. The mixture was warmed to 20 °C and stirred at 20 °C for 4 h under Nz atmosphere. The reaction mixture was quenched by adding sat.aqNH-iCl (20 mL) and extracted with EtOAc (10 mL x 3) The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 60 mL / min) to give (3S,4s,5R)- 1 -benzyl -3,5-dimethyl-4-(phenyl-d5)piperidm-2,2,6,6-d4-4-ol as a white solid. Yield: 230 mg, 84%; MS (ESI) m / z 311.4 [M+1]4; TLNMR (400 MHz, CDCh) 8 7.44-7.28 (m, 5H), 3.58 (s, 2H), 2.22 (s, 2H). 1.52 (s, 1H).Synthesis of (3S,4s,5R)-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-2.2, 6.6-d4-4-ol

[0195] To a solution of (3S.4s,5R)-l-benzyl-3,5-dimethyl-4-(phenyl-d5)piperidin-2,2,6,6- d4-4-ol (220 mg, 708 pmol, 1.0 eq) in MeOH (5 mL) was added PdCh (25.1 mg, 141.7 pmol, 02 eq) at 20 °C under Nz atmosphere. The suspension was degassed and purged with Hz three times. The mixture was heated to 50 °C and stirred at 50 °C for 16 h under Hz atmosphere (15 Psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s,5R)-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-2,2,6,6-d4-4-ol as a white solid. Yield: 130 mg, crude; MS (ESI) m / z 220.3 [M+1]1HNMR (400 MHz, DMSO-de) 84.25 (s, 1H), 1.85 (s, 2H).NAI-5006781290v1 81Attorney Docket No. 14859-002-228Synthesis of ((3S.4R)-4-(2, 4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1, 1, 3, 3, 3-d6)pyTrolidin-3-yl)((3S.4R,5R)-4-hydroxy-3,5-bis(methyl-d3)-4-(phenyl-ds)piperidin-l-yl- 2, 2.6.6-d4) methanone

[0196] To a solution of (3S,4s,5R)-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-2,2.6,6-d4-4- ol (43.9 mg, 171 pmol, 1.0 eq HC1) in DCM (2 mL) was added (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3.3-d6)pyrrolidine-3-carboxylic acid (50 mg, 171 pmol, 1 0 eq), TEA (51.9 mg, 513 pmol, 3.0 eq) and TrP (147 mg, 205 pmol, 50% purity, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding sat.aq NaHCOs (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over NajSOr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150x40x7 pm; mobile phase: [ ACN m H2O (lOmM NH4HCO3)]; gradient: 45%-75% over 8.0 mm) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl- 1,1,1,3.3, 3-d6)pyrrolidin-3-yl)((3S,4R.5R)-4-hydroxy-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-l-yl-2,2,6,6-d4)methanone. Yield: 17.1 mg, 20%; MS (ESI) m / z 495.2 [M+1]+; ’HNMR (400 MHz. DMSO-ds) 5 7.65-7.53 (m, 1H), 7.25-7.12 (m, 1H), 7.10-7.02 (m, 1H).4.63-4.55 (m, 1H), 3.90-3.70(m, 1H), 3.57-3.40 (m, 1H), 3.18-3.02 (m. 2H), 2 85-2.64 (m, 2H), 1.85-1.13 (m, 2H);19FNMR (376 MHz, DMSO) 8 -112.95 - -113.89 (m, 2F); overall deuterium incorporation: 99.3%; percent of Compound 19a molecules: 82.4%.Example 20a: ((3S, 4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l, 1, 3,3,3-d6)pyrrolidin-3-yl)((3S,4R^R)-4-hydroxy-345-bis(methyI-d3)-4-(phenyl-d5)piperidin-l-yl-2,2,3,5,6,6-d6)methanoneSynthesis of (3S, 4s, 5R)-l-benzyl-3, 5-bls(methyl-d3)-4-(phenyl-d5)piperidin-2, 2, 3, 5, 6, 6-d6-4-olNAI-5006781290vl 82Attorney Docket No. 14859-002-228

[0197] To a solution of l-bromobenzene-2,3,4,5,6-ds (706 mg, 4.36 mmol, 5.0 eq, > 99.0% of overall deuteration incorporation) in THF (5 mL) was added n-BuLi (2.5 M in hexane, 1.57 mL, 4.5 eq) at -65 °C under N2 atmosphere. The mixture was stirred at -65 °C for 1 h under N2 atmosphere. Then a solution of (3S,5R)-l-benzyl-3,5-bis(methyl-cb)piperidin-4-one- 2.2.3.5.6.6-ds (200 mg, 871 umol, 1.0 eq) in THF (2 mL) was added into the mixture at -65 °C under N2 atmosphere. The mixture was warmed to 20 °C and stirred at 20 °C for 4 h under N2 atmosphere. The reaction mixture was quenched by adding sat.aqNHiCl (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash Silica Flash Column, eluent of 0-50% ethyl acetate / n-hexane gradient at 60 mL / min) to give ((3S.4s,5R)-l-benzyl-3,5-bis(methyl-d3)-4-(phenyl-d5)pipendin-2,2.3,5,6,6-d6-4-ol as a white solid. Yield: 230 mg, 84%; MS (ESI) m / z 313.2 [M+lf; ‘HNMR (400 MHz, CDCh) S 7.41-7.28 (m, 5H), 3.58 (s, 2H), 1.52 (s, 1H).Synthesis of (3S,4s,5R)-3,5-bis(methyl-ds)-4-(phenyl-d5)piperidin-2,2,3,5,6,6-d6-4-ol

[0198] To a solution of ((3S,4s,5R)-l-benzyl-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin- 2.2.3.5.6.6-de-4-ol (210 mg, 671 pmol, 1.0 eq) in MeOH (5 L) was added PdCb (23.8 mg, 134 pmol, 0.2 eq) at 20 °C under H2 atmosphere. The mixture was heated to 50 °C and stirred at 50 °C for 16 h under H2 atmosphere (15 Psi). The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give (3S,4s,5R)-3,5-bis(methyl-d3)-4-(phenyl-ds)piperidin-2,2.3.5.6.6-d6-4-ol as a white solid. Yield: 160 mg, crude: MS (ESI) m / z 223.3 [M+l J+:!HNMR (400 MHz, DMSO-de) 84.73 (s, 1H) Synthesis of ((3S, 4R)-4-(2, 4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1, 1, 3, 3, 3-d6)pyrrohdm-3-yl)((3S.4R,5R)-4-hydroxx>-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-l-yl- 2.2.3.5.6.6-de)methanone

[0199] To a solution of (3S,4s,5R)-3,5-bis(methyl-d3)-4-(phenyl-d5)piperidin-2,2,3,5,6,6-d6-4-ol (35.4 mg, 136 pmol, 1.0 eq HC1) in DCM (2 mL) was added (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d.3)propan-2-yl-l.l,l,3,3,3-d6)pyrrolidine-3-carboxyhc acid (40 mg, 136 ymol, 1.0 eq), TEA (41.5 mg, 410 pmol, 3.0 eq) and T4P (118 mg, 164 pmol, 50% purity', 1.2 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was quenched by adding sat.aq NaHCOs (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over NaiSCh, filtered and concentrated under reduced pressure to give a residue. TheNAI-5006781290v1 83Attorney Docket No. 14859-002-228residue was purified by prep-HPLC (column: WePure Biotech XP tC 18 150x40x7 pm; mobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient:45%-75% over 8.0 min) to give ((3S,4R)-4-(2,4-ditluorophenyl)-l-(2-(methyl-d3)propan-2-yLl,l,l,3,3,3-ds)pyrrolidin-3-yl)((3S,4R,5R)-4-hydroxy-3.5-bis(methyl-d3)-4-(phenyl-d5)piperidin-l-yl-2,2,3,5,6,6-d6)methanone. Yield: 15.95 mg, 23%; MS (ESI) m / z 497.3 [M+1]+; ‘HNMR (400 MHz, DMSO-ds) 5 7.65-7.53 (m, IH), 7.25-7.12 (m. IH), 7.10-7.02 (m, IH), 4.63-4.55 (m, IH), 3 90-3.70(m. IH). 3 57-3.40 (m, IH). 3.18-3 02 (m. 2H), 2.85-2.64 (m, 2H);19FNMR (376 MHz. DMSO) 5 -112 92 - -113.88 (m, 2F); overall deuterium incorporation: 99.2%; percent of Compound 20a molecules: 79.4%.Example 22a: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3 -d6)py roIidin-3-yl-2,2,5,5-d4)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-pheny5piperidin-l-yl)methanone

[0200] To a solution of (3S,4s,5R)-3,5-dimetbyl-4-phenylpiperidin-4-ol (18.2 mg, 89.0 pmol, 1.1 eq. HC1) in DCM (1 mL) was added (3S.4R)-4-(2.4-difluorophenyl)-l-(2-(methyl- d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic-2,2,5,5-d4 acid (40 mg, 80.9 pmol, 1.0 eq), TEA (24.5 mg, 242 pmol, 3.0 eq) and TjP (70.0 mg. 97.1 pmol. 50% purity, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding sat, aq NaHCOs (3 mL) and extracted with dichloromethane (3 mLx3). The combined organic phase was dried with anhydrous NazSCh, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 pm;mobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient:50%-7 % over 8.0 min) to give ((3S.4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidin-3-yl-2,2,5,5-d4)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l-yl)methanone. Y’ield: 3.63 mg, 9%; MS (ESI) m / z 484.1 [M+1]+; ‘HNMR (400 MHz, DMSO-de) 57.66-7.53 (m. IH), 7.45-7.28 (m, 3H). 7.28-7.06 (m, 4H), 4.63-4.55 (m, IH), 4.26-4.15 (m, IH), 3.87- 3.72 (m, IH), 3.63-3.39 (m. 2H). 3.04-2.91 (m, IH). 2.62-2.56 (m, IH), 1.90-1.10 (m. 2H),NAI-5006781290vl 84Attorney Docket No. 14859-002-2280.49-0.25 (m, 6H);l9FNMR (376 MHz, DMSO-dc,) 8 -112.96- -113.85 (m, 2F); overall deuterium incorporation: 98.3%: percent of Compound 22a molecules: 77.5%.Example 23a: ((3S,4R)-4-(2,4-difluoropheny!)-l-(2-(inethyl-d3)propan-2-yl-l, 1,193,3,3- d6)pyrrolidm-3-yl-2^^,5-d4)((3S,4R,5R)-4-hydroxy-3^-dimethyl-4-(phenyl-ds)piperidin- 1 -yl)methanone

[0201] To a solution of (3S,4s,5R)-3,5-dimethyl-4-(phenyl-d5)pipendin-4-ol (27.4 mg, 111 pmol, 1.1 eq, HC1) in DCM (1 mL) was added (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyi- d3)propan-2-yl-l,l,l,3,3.3-d6)pyrrolidine-3-carboxylic-2,2,5,5-d4 acid (30 mg. 101 pmol, 1.0 eq), TEA (30.7 mg, 303 pmol, 3.0 eq) and T4P (87.51 mg, 121 pmol. 50% purity, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. Hie reaction mixture was quenched by adding sat. aq. NaHCOs (3 mL) and extracted with dichloromethane (3 mLx3). The combined organic phase was dried with anhydrous NasSC, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 pmimobile phase: [ACN in IbO (lOmM NHrHCOi)]; gradient:45%-75% over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrroiidin- 3-yl-2,2,5,5-d4)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyl-d:>)piperidin-l-yl)methanone. Yield: 6.17 mg, 12%; MS (ESI) m / z 489.2 [M+ 1 ]+; ’HNMR (400 MHz, DMSO-ds) 57.66-7.53 (m, 1H), 7.26-7.02 (m, 2H). 4.63-4.55 (m. 1H), 4.26-4.15 (m, 1H), 3.87-3.72 (m, 1H), 3.63-3.39 (m, 2H), 3.04-2.91 (m, 1H), 2.62-2.56 (m. 1H), 1.90-1.10 (m, 2H), 0.49-0.25 (m, 6H);i9FNMR (376 MHz, DMSO-de) 8 -112.94 - -113.89 (m, 2F); overall deuterium incorporation: 98.5%; percent of Compound 23a molecules: 73.2%.NAI-5006781290v1 85Attorney Docket No. 14859-002-228Example 24a: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l',3^-d6)pyrrolidin-3-yl-2,2,5,5-d4)((3S,4R,5R)-4-hydroxy-3,5-dimetliyI-4-(pheiiyl- d5)piperidin-l-yl-2,2,6,6-d4)methanone

[0202] To a solution of (3S,4s,5R)-3,5-dimethyl-4-(phenyl-d5)piperidin-2,2,6,6-d4-4-ol (25.4 mg, 101 pmol, 1.0 eq HC1) and (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic-2,2,5,5-d4 acid (30 mg, 101 pmol, 1.0 eq) in DCM (3 mL) was added TEA (30 7 mg, 304 pmol. 3 0 eq) and TiP (94.8 mg, 132 pmol. 50% purity, 1.3 eq) at 0 °C under N2. The reaction was stirred at 0 °C for 0.5 h under N2. The reaction mixture was quenched by adding H2O (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tCl 8 150x40x7 pm; mobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient:40%-75% over 8.0 min) to give (( S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidin-3-yl-2.2,5,5-d4)((3S,4R,5R)-4-hydroxy-3,5-dimethyI-4-(phenyl-d5)piperidin-l-yI-2,2,6,6-d )methanone. Yield: 633 mg, 11%; MS (ESI) m / z 493.2 [M+1]+; 'HNMR (400 MHz, DMSO-de) 8 7 64-7.57 (m, 1H), 7.23-7.05 (ra. 2H), 4.60-4.56 (m, 1H), 3.85-3.74 (m, 1H), 3.52-3.40 (m, 1H), 1.87-1.14 (m, 2H). 0.46-0.26 (m, 6H);19FNMR (376 MHz. DMSO) 3 -112.95 - -113.88 (m. 2F); overall deuterium incorporation: 98.8%; percent of Compound 24a molecules: 73 5%.NAI-5006781290v1 86Attorney Docket No. 14859-002-228Example 25a: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l',3^-d6)pyrrolidin-3-yl-2,2,5,5-d4)((3S,4R,5R)-4-hydroxy-3,5-bis(inethyl-d3)-4-(phenyl-d5)piperidin-l-yl)methanone

[0203] To a solution of (3S,4s,.5R)-3,5-bis(niethyl-d3)-4-(phenyl-d5)piperidm-4-ol (28.1 mg, 111 pmol, 1.1 eq, HC1) in DCM (1 ml) was added (3S,4R)-4-(2,4-difluorophenyl)-l-(2- (raethyl-d3)propan-2-yI-l,],l,3,3,3-d6)pyrrolidine-3-carboxylic-2,2,5,5-d4 acid (30.0 mg, 101 umol, 1.0 eq), TEA (30.7 mg, 303 pmol, 3.0 eq) and T4P (87.5 mg, 121 pmol, 50% purity, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding sat aq. NallCCh (3 mL) and extracted with di chloromethane (3 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 pm iobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient:40%-75% over 8.0 min)) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d?)propan-2-yl-Ll,l,3,3,3-d6)pyrrolidin-3-yl-2,2,5,5-d4)((3S,4R,5R)-4-hydroxy-3,5-bis(raethyl-d3)-4-(phenyl-d5)piperidin-l-yl)methanone. Yield: 6.53 mg, 13%; MS (ESI) m / z 495.2 [M+ 1 ]’; 'HNMR (400 MHz, DMSO-de) 5 7.66-7.53 (m, 1H), 7.26-7.02 (m, 2H), 4.63-4.55 (m, 1H), 4.26-4.15 (m, 1H), 3.87-3.72 (m. 1H). 3 63-3.39 (m, 2H). 3.04-2.91 (m, 1H), 2.62-256 (m, 1H), 1.85-1.15 (m, 2H);19FNMR (376 MHz, DMSO-dr,) 5 -112.95 - -113.89 (m, 2F); overall deuterium incorporation: 98.9%; percent of Compound 25a molecules: 72.7%.NAI-5006781290v1 87Attorney Docket No. 14859-002-228Example 26a: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l',3^-d6)pyrrolidin-3-yl-2,2,5,5-d4)((3S,4R,5R)-4-hydroxy-3,5-bis(inethyl-d3)-4-(phenyl-d5)piperidin-l-yl-2,2,6,6-d4)methanone

[0204] To a solution of (3S,4s,5R)-3,5-bis(methyl-d.3)-4-(phenyl-d5)piperidin-2,2,6,6-d4-4-ol (28.60 mg, 111.34 pmol, 1.1 eq, HC1) in DCM (1 mL) was added (3S,4R)-4-(2,4-difluorophenyl)- 1 -(2-(methyl-d3)propan-2-yl- 1,1.1, 3,3, 3-d6)pyrrolidme-3-carboxylic-2, 2,5,5-•;h acid (30 mg. 101 nmol, 1 0 eq), TEA (30.7 mg, 303 pmol, 3.0 eq) and TiP (87.5 mg, 121 pmol, 50% purity, 1.2 eq) at 0 °C. Hie mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding sat. aq, NaHCOs (3 ml,) and extracted with di chloromethane (3 mLx3). The combined organic phase was dried with anhydrous NazSO, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 pm;mobile phase: [ACN in IhO (lOmM NH4HCO3)]; gradient:40%-70% over 8.0 min ) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(rnethyl-d.3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidin-3-yl-2,2,5,5-d4)((3S,4R,5R)-4-hydroxy-3,5- bis(methyl-d3)-4-(phenyl-ds)piperidin-l-yl-2,2,6,6-d4)methanone. Yield: 6.05 mg, 12%; MS (ESI) m / z 4992 [M+1]f;!HNMR (400 MHz, DMSO-ds) 5 7.66-7.53 (m, 1H), 7.25-7.03 (m, 2H), 4.63-4.55 (m, 1H), 3.87-3.72 (m, 1H). 3.53-3.41 (m, 1H), 1.85-1.15 (m, 2H);19FNMR (376 MHz, DMSO-de) 6 -112.95 - -113.88 (m, 2F); overall deuterium incorporation: 99.1%; percent of Compound 26a molecules: 73.5%.NAI-5006781290v1 88Attorney Docket No. 14859-002-228Example 27 a: ((3S,4R)-l-(tert-biityl)-4-(2,4-difluoroplienyl)pyrrolidin-3-yl-2,2^^-d4)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l-yl)methanoneSynthesis of (S) -2-( tert-butylamino)-l-( 2, 4-difluorophenyl)ethan-2, 2-cb-l-ol

[0205] To a solution of (S)-2-(2,4-difluorophenyl)oxirane-3,3-d2 (1.00 g, 6.32 mmol, 1.0 eq) in EtOH (10 mL) was added 2-methylpropan-2-amine (9.25 g. 126 mmol. 20.0 eq) at 20 °C. The mixture was heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was triturated with n-heptane (20 ml,) at 20 °C for 3 h to give (S)-2-(tert-butylamino)- l-(2,4-difluorophenyl)ethan-2.2-d’-l-ol as a white solid. Yield: 1.0 g, 68%; MS (ESI) m / z 232.3 [M+ If; 'HNMR (400 MHz, CDCh) 57.59-7.48 (m, 1H), 6.95-6.85 (m, 1H), 6.81-6.73 (m, 1H), 4.83 (s, 1H), 1.13 (s, 9H);19FNMR (376 MHz. CDCh) 8 -112.39 - -112.43 (m, IF), - 116.18 - -116.23 (m, IF).Synthesis of benzyl (S)-3-(tert-butyl(2-(2.4-difluorophenyl)-2-hydroxyethyl-l, 1 - d2)amino)propanoate-3,3-d?.

[0206] A mixture of (S)-2-(tert-butylamino)-l-(2,4-difluorophenyl)ethan-2,2-d2-l-ol (1.00 g, 4.32 mmol, 1.0 eq) and benzyl acrylate-3,3-d2 (2.84 g, 17.3 mmol. 40 eq) was heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 40 g SepaFlash Silica Flash Column, eluent of 0-30% ethyl acetate / liexanes gradient at 60 mL / min) to give benzyl (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d?.)amino)propanoate-3,3-d2 as a colorless oil. Yield: 1.4 g, 81%; MS (ESI) m / z 396.3 ] 1 ].iHNMR (400 MHz. CDCh) 87.61-7.52 (m, 1H), 7.43- 731 (m, 5H), 6.90-6.85 (m, 1H), 6.81-6.73 (m, 1H), 5.21-5.10 (m, 2H), 4.83 (s, 1H), 4.24 (s,NAl-5006781290vl 89Attorney Docket No. 14859-002-2281H), 2.66-2.51 (ni, 2H), 1.11 (s, 9H);19FNMR (376 MHz, CDCh) 5 -112.50 - -112.54 (m, IF), -116.05 - -116.09 (m, IF).Synthesis of (S)-3-(lert-butyl(2-(2,4-difluorophenyl)-2-hydroxyelhyl-l, l-dsjaminofpmpanoic-3, 3-ds acid

[0207] To a solution of (S)-3-(tert-buM(2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d2)amino)propanoate-3,3-d2 (1.40 g, 3.54 mmol, 1.0 eq) in MeOH (20 mL) was added PdCh (125 mg, 708 pmol, 0.2 eq) at 20 °C under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 20 °C for 16 h under H2 atmosphere (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give (S)-3-(tert-butyI(2-(2,4-dilluorophenyl)-2-hydroxyethyl-l,l-d2)amino)propanoic-3,3-d2 acid as a light-yellow oil. Yield: 1.1 g. crude; MS (ESI) m / z 306.3 [M+1J; 'HNMR (400 MHz, DMSO-db) 57.63-7.54 (m, 1H), 7.25-7.17 (m, 1H), 7.15-7.08 (m, 1H), 4.99 (s, IH), 2.69-2.55 (m, 2H), 1.20 (s, 9H);19FNMR (376 MHz. DMSO-de) 6 -111.60 - -112.05 (m, IF), -114.30 - -114.60 (m, IF).Synthesis of ethyl (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hydroxyethyl-l.1-dfamino)propanoate-3,3-d2

[0208] To a solution of (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d2)amino)propanoic-3,3-d2 acid (1.1 g, 3.60 mmol, 1.0 eq) in DMF (10 mL) was added K2CO3 (995 mg. 7.20 mmol. 2.0 eq) and iodoethane (674 mg, 4.32 mmol, 1.2 eq) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by adding H2O (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (40 mL x 2), dried with anhydrous Na2S€>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-25% ethyl acetate / hexanes gradient at 60 mL / min) to give ethyl (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hydroxyethyI-l,l- d2)amino)propanoate-3,3-d2 (10) as a light-yellow oil. Yield: 880 mg, 73%; MS (ESI) m / z 334.3 [M+ 1]+; ’HNMR (400 MHz, DMSO-de) 5 7.63-7.52 (m, 1H), 6.95-6.85 (m. 1H), 6.81-6.72 (m. 1H), 4.83 (s. 1H). 4.26 (s, 1H), 4.23-4.11 (m, 2H). 2.60-2.45 (m, 2H). 1.29 (t. J = 7.2 Hz, 3H), 1.13 (s, 9H);19FNMR (376 MHz. DMSO-ds) 5 -11254 - -112.58 (m, IF), -116.08 - -116.14 (m, IF).Synthesis of ethyl (4R)-l~(tert~butyl)-4-(2,4~difluorophenyl)pyrrolidine-3-carboxylate-2, 2,5,5- d4NAI-5006781290vl 90Attorney Docket No. 14859-002-228

[0209] To a solution of ethyl (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d?.)amino)propanoate-3,3-d2 (200 mg, 599 pmol, 1.0 eq) in THF (5 mL) was added LiHMDS (1 M in THF, 2.10 mL, 3.5 eq) and dimethyl phosphorochloridate (112 mg, 779 pmol, 1.3 eq) at -20 °C under Ar atmosphere. The mixture was stirred at -20 °C for 2 h under Ar atmosphere. The reaction mixture was quenched by adding HC1 (0.5 M. 10 mL) and extracted with n-hexane (20 mL x 3). The combined organic phases were concentrated under reduced pressure to give ethyl (4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate-2,2,5,5-d4 as alight-yellow oil. Yield: 200 mg, crude; MS (ESI) m / z 316.1 [M+ 1]+.Synthesis of (3S,4R)-l-(tert-butyl)-4-(2.4-difluorophenyl)pyrrolid 'ie-3-carboxylic-2.2.5.5-d4 acid

[0210] To a solution of ethyl (4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3- carboxylate-2,2,5,5-d4 (200 mg, 634 pmol, 1.0 eq) in EtOH (3 mL) and H2O (0.3 mL) was added NaOH (765 mg, 19.1 mmol, 30.2 eq) at 20 °C. The mixture was heated to 100 °C and stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and its pH was adjusted to 6-7 with H2SO4. The mixture was dried with anhydrous NaaSCh, filtered and concentrated under reduced pressure to give (3S, 4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic-2,2,5,5-d4 acid (12) as a brown oil. Yield: 160 mg, crude; MS (ESI) m / z 288.1 [M+1]+.Synthesis of ( ( 3S.4R)-1 -( tert-butyl)-4-(2, 4-difluorophenyl)pyrrolidin-3-yl-2, 2.5, 5-df ( < S, 4R, 5R)-4~hydroxy-3, 5-dimethyl~4~phenylpiperidin-l-yl)methanone

[0211] To a solution of (3S, 4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic-2.2.5,5-d4 acid (160 mg, 556 pmol, 1,0 eq) in DCM (5 mL) was added (3S,4s,5R)-3,5-dimetliyl-4-phenylpiperidin-4-ol (125 mg, 612 pmol. 1.1 eq), TEA (169 mg, 1.67 mmol, 3.0 eq) and T4P (481 mg, 668 pmol, 50% purity. 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding sat. aq. NaHCCh (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was dried with anhydrous Na> SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 pm;mobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient: 50%-80% over 8.0 min) to give ((3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidin-3-yl-2,2,5,5-d4)((3S,4R,5R)-4-hydroxy-3,5-dimetliyl-4-phenylpiperidin-l-yl)methanone. Yield: 18.10 mg, 6° / y MS (ESI) m / z 475.2 [M+1] '; ¹HNMR (400 MHz. DMSO-de) 57.66-7.53 (m. 1H), 7.45-7.28 (m. 3H), 7.28-7.08 (m.3H), 7 08-6.99 (m,1H), 4.62-4.58 (m, 1H), 4.23-4.19 (m, 1H), 3.87-3.72 (m, 1H), 3.63-3.39NAI-5006781290v1 91Attorney Docket No. 14859-002-228(m, 2H), 3.04-2.91 (m, 1H), 2.62-2.56 (m, 1H), 1.90-1.10 (m, 2H), 1.11-0.99 (m, 9H), 0.49-0.39 (m, 4H), 0.31-0.22 (m,2H);19FNMR (376 MHz, DMSO-de) 6 -112.90- -113.87 (m, 2F); overall deuterium incorporation: 98.3%; percent of Compound 27a molecules: 93.1 %.Example 28a: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3 -d6)pyrrolidin-3-yl-2,2-d2)((3S,4R45R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l-yl)methanoneSynthesis of benzyl (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl)(2-(melhyl-ds)propan-2-yl-1. i, 1.3, 3, 3-d6)amino)propanoate-3, 3-d

[0212] A mixture of (S)-l-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl- l,l,l,3.3,3-d6)amino)ethan-l-ol (520 mg, 2.18 mmol, 1.0 eq) and benzyl acrylate-3,3-d2 (1.79 g, 10.9 mmol, 5.0 eq) was heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0- 20% ethyl acetate / hexanes gradient at 36 inL / min) to give benzyl (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl)(2-(methyl-d3)propan-2-yl-l, 1,1, 3,3,3-d6)amino)propanoate-3,3-d2 as a colorless oil. Yield: 750 mg, 85%; MS (ESI) m / z 403.3 [M+l |+;1HNMR (400 MHz, DMSO-dfi) 57.61-7.52 (m, 1H), 7.43-7.31 (m, 5H), 6.91-6.85 (m, 1H), 6.81-6.73 (m, 1H), 5.21-5.10 (m, 2H), 4.87-4.80 (m, HI), 4.23 (s. 1H), 2.90-2.83 (in, 1H), 2.66-2.51 (m, 2H), 2.42-2.33 (m, 1H);,9FNMR (376 MHz, DMSO-de) 5 -112.40- -112.65 (m, IF), -114.15- -114.30 (m, IF).Synthesis of (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl)(2-(methyl-d3)propan-2-yl-1.1, 1.3, 3, 3-d6)amino)propanoic-3, 3-dz acid

[0213] To a solution of benzyl (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl)(2- (methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)amino)propanoate-3,3-d2 (750 mg, 1.86 mmol, 1.0 eq) in MeOH (10 mL) was added PdCh (66.0 mg, 372 nmol, 0.2 eq) at 20 °C under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 20 °CNA 500678129()vl 92Attorney Docket No. 14859-002-228for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give (S)-3-((2-(2,4-difluorophenyl)-2-hydroxy ethy l)(2-(methy l-d.3)propan-2-yl- 1, 1,1, 3,3,3-de)amino)propanoic-3,3-d2 acid as a light-yellow oil. Yield: 600 mg, crude; MS (ESI) m / z 313.4 [M+l ]+; ’HNMR (400 MHz, DMSO-de) 5 7.63-7.54 (m, 1H), 7.25-7.17 (m, 1H), 7.15- 7.08 (m, 1H), 5.15-5.00 (m, 1H), 3.15-3.00 (m, 2H), 2.82-2.67 (m, 2H);!9FNMR (376 MHz, DMSO-ds) 8 -111.60- -112.05 (m, IF), -114.30- -114.60 (m, IF).Synthesis of ethyl (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl)(2-(methyl-d3)propan-2-yl-1,1,1.3, 3, 3-d6)ammo)propanoate-3, 3-d

[0214] To a solution of (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl)(2-(methyl-d3)propan-2-yi-l,l,l,3,3.3-d6)amino)propanoic-3,3-d2 acid (600 mg, 1.92 mmol, 1.0 eq) in DMF (10 mL) was added K2CO3 (530 mg, 3.84 mmol, 2.0 eq) and iodoethane (359 mg. 2.30 mmol, 1.2 eq) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by adding H2O (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (60 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-25% ethyl acetate / hexanes gradient at 60 mL / min) to give ethyl (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl)(2-(methyl-d3)propan-2-yl-l,l,i,3,3,3-d6)amino)propanoate-3,3-d2 as a lightyellow oil. Yield: 500 mg, 76%; MS (ESI) m / z 341.1 [M+1]+; ’HNMR (400 MHz, DMSO-ds) 5 7.63-7.52 (m, 1H). 6.95-6.85 (m, 1H), 6.81-6.72 (m, 1H), 4.89-4.79 (m. 1H), 4.29 (s. 1H), 4.23-4.11 (m, 2H), 2.91-2.83 (m, 1H), 2.60-245 (m, 2H), 2.41-2.32 (m, 1H), 1.29 (t, J == 7.2 Hz, 3H);i9FNMR(376 MHz, DMSO-ds) 5 -112.46- -112.55 (m, IF), -116.08- -116.14 (m, IF). Synthesis of ethyl (4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1, 1, 3,3, 3-d6)pyrrolidine-3-carboxylate-2,2-d2

[0215] To a solution of e ethyl (S)-3-((2-(2,4-difIuorophenyl)-2-hydroxyethyl)(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)amino)propanoate-3,3-d2 (500 mg, 1.47 mmol, 1.0 eq) in THF (5 mL) was added LiHMDS (1 M, 5.14 mL, 3.5 eq) and [chloro(methoxy)phosphoryT|oxy methane (275 mg, 1.91 mmol, 1.3 eq) at -20 °C under Ar atmosphere. The mixture was stirred at -20 °C for 2 h under Ar atmosphere. The reaction mixture was quenched by adding HC1 (IM, 5 mL) and extracted with n-hexane (5 mLx 3). The combined organic phase was concentrated under reduced pressure to give ethyl (4R)-4-(2,4- di fluorophenyl)- 1 -(2-(methyl-d3)propan-2-yl-l, 1, l,3,3,3-d6)pyrrolidine-3-carboxylale-2,2-d2 as alight-yellow oil. Yield: 450 mg, crude; MS (ESI) m / z 323.4 [M+1]+.Synthesis of (3S.4R)~4~(2, 4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l, 1, 3, 3.3-NAI-5006781290vl 93Attorney Docket No. 14859-002-228d6)pyrrolidme-3~carboxylic-2, 2~d acid|00216| To a solution of ethyl (4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylate-2,2-d2 (450 mg, 1.40 mmol, 1.0 eq) in EtOH (5 mL) was added NaOH (19.1 M, 1.0 mL, 13.6 eq) at 20 °C. The mixture was heated to 100 °C and stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature and adjusted pH to 6~7 with cone. H2SO4. The mixture was dried with anhydrous Na2SO-i, filtered and concentrated under reduced pressure to give ((3S.4R)-4-(2,4-difluorophenyl)-l-(2- (methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic-2,2-d2 acid as a light-yellow oil. Yield: 400 mg, crude; MS (ESI) m / z 295.3 [M+1]1.Synthesis of ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyiTolidin-3-yl-2,2-d2)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l-yl)methanone

[0217] To a solution of ((3S.4R)-4-(2.4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-1,1,1,3,3, 3-d6)pyrrolidine-3-carboxy lie-2, 2-d2 acid (150 mg, 509 pmol, 1,0 eq) inDCM (5 mL) was added (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-4-ol (123 mg. 509 pmol, 1.0 eq HC1), TEA(154 mg, 1.53 mmol. 3.0 eq) andTrP (440 mg, 611 pmol, 50% purity, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding sat aq. NaHCOs (10 mL) and extracted with dichloromethane (10 mL x 3), The combined organic phases were dried with anhydrous NacSCU, filtered and concentrated wider reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 pmimobile phase: [ACN in ILOQO mM NH4HCO3)]; gradient: 50%-80% B over 8.0 min) to give ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1,1,3, 3,3- d6)pyrrolidin-3-yl-2,2-d2)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l- yl)methanone. Yield: 27.44 mg, 11%; MS (ESI) m / z 482.5 [MM]1; ¹HNMR (400 MHz, DMSO-d6) 6 7.66-7.53 (m, 1H), 7.45-7.28 (m, 3H), 7.28-7.08 (m, 3H), 7.08-6.99 (m,1H).4.62-4.58 (m, 1H). 4.23-4.19 (m, 1H), 3.89-3.71 (m, 1H), 3.63-3.43 (m, 2H), 3.08-2.91 (m, 2H), 2.71-2.55 (m, 2H), 1.90-1.16 (m, 2H), 0.47-0.42 (m, 4H), 0.31-0.26 (m,2H);19FNMR (376 MHz, DMSO-ds) 6 -112.93 - -113.89 (m, 2F); overall deuterium incorporation: 98.6%; percent of Compound 28a molecules: 84.5%.Example 29a: ((3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1,1, 3,3 -d6)pyrrolidin-3-yl-5,5-d2)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenyIpiperidin-l- yl)methanoneNAI-5006781290vl 94Attorney Docket No. 14859-002-228Synthesis of (S)-3-((2-(2,4-dijluorophenyl)-2-hydroxyethyl-l.l-d2)(2-(methyl-d3)propan-2-yl- 1.1.1.3.3.3-d6)amino)propanenitrile

[0218] A solution of (S)-l-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl- 1.1.1.3.3.3-d6)amino)ethan-2,2-d?.-l-ol (0.6 g. 2.50 mmol, 1.0 eq), acrylonitrile (3.31 g. 62.4 mmol, 25 eq), formamide (112 mg. 2.50 mmol. 1.0 eq), and EtOH (115 mg. 2,50 mmol, 1,0 eq) was stirred at 80 °C for 12 °C under N2 The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash Silica Flash Column, eluent of 0-30% Ethyl acetate / n-hexane gradient at 80 mL / min) to give (S)-3-((2-(2,4- difluorophenyl)-2-hy droxy ethy 1-1, 1 -d2)(2-(methyl-d3)propan-2-yl- 1, 1,1, 3,3.3-d6)amino)propanenitrile as a colorless oil. Yield: 650 mg, 88%, MS (ESI) m / z 294.4 [M+1]+;1HNMR (400 MHz, DMSO-rfe) 8 7.57-7.53 (in, 1H), 7.17-7.07 (m, 2H), 5.28 (d, J - -- -- 4.0 Hz, 1H), 4.74 (d, J = 4.0 Hz, 1H), 2.91-2.87 (m. 1H), 2.75-2.71 (m, 1H). 2.53-2.45 (m, 2H);19FNMR (376 MHz. CDCh) 5 -112.67 - -112.81 (m, IF). 114.80 - -115.42 (m, IF).Synthesis of (4R)-4-(2.4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, 1,1,3, 3, 3-dc)pyn‘olidine-3-carbonilrile-5,5-d2

[0219] To a solution of (S)-3-((2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d2)(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)amino)propanenitrile (650 mg, 2.22 mmol. 1.0 eq) in THF (15 mL) was added ClPO(O-iPr)2 (489 mg, 244 mmol, 1.1 eq) and LiHMDS (1 M, 4.65 mL, 2.1 eq) at -20C’C under N2. The reaction was stirred at -20CC for 2 h under N2. The reaction mixture was quenched by adding H2O (50 mL) and extracted with n-hexane (20 mL x 3). The organic layer was carefully extracted with HC1 (10 mL. 3 M). The HC1 aqueous layer was adjusted pH to 11-12 with aq. NaOH (50%) and extracted with n-hexane (20 L x 3). The combined organic layers were washed with brine (20 ml,), dried over Na SCh, filtered andNAI-5006781290v1 95Attorney Docket No. 14859-002-228concentrated under reduced pressure to give (4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3.3-ds)pyrrolidine-3-carbonitrile-5,5-d2 as a colorless oil. Yield: 600 mg. crude, MS (ESI) m / z 276.3 [M+l f.Synthesis of (3S, 4R)~4~(2, 4-difluorophenyl)-l~(2-(methyl-d3)propan-2-yl-lf, 1, 3, 3, 3- d6)pyrrolidine-3-carboxylic-5, 5-d?. acid

[0220] A solution of (4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl- 1, l,l,3.3,3-d6)pyrro!idme-3-carbomtriIe-5,5-d2 (600 mg, 2.18 mmol, 1.0 eq) in EtOH (6 mL) and NaOH (0 6 mL, 50% aq.) was stirred at 80 °C for 12 h. The reaction mixture was diluted with EtOH (3 mL) and MeOH (6 mL), adjusted pH=5-6 with H2SO4, filtered and concentrated under reduced pressure to give (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl- 1.1.1.3.3.3-d6)pyrrolidine-3-carboxylic-5,5-d2 acid as a yellow oil. Yield: 550 mg. crude, MS (ESI) m / z 295.3 [M+I]+.Synthesis of ((3S,4R)~4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,1, 1, 3,3,3-d6)pyrmlidin-3-yl-5, 5-ds) ( 3S, 4R, 5R)-4-hydroxy-3, 5-dimethyl-4-phenylpiperidin-l -yl)methanone

[0221] To a solution of (3S,4R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl- 1.1.1.3.3.3-d6)pyrrolidine-3-carboxylic-5,5-d2acid (150 mg, 510 pmol, 1.0 eq) and (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-4-ol (98,6 mg, 408 pmol, 0.8 eq HC1) in DCM (5 mL) was added TEA (1.27 mmol, 177 pL, 2.5 eq) and TrP (441 mg. 611 pmol, 50% purity, 1.2 eq) at 0 °C. The reaction was stirred at 0 °C for 0.5 h under N?_. The reaction mixture was quenched by adding sat.aq NaHCCh (20 mL) and extracted w ith DCM (10 mL x 3). The combined organic layers w-ere washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP 1C18 150x40x7 pm; mobile phase: [ACN in H2O (lOmM NH4HCO3)]; gradient:45%-75% B over 8.0 min) and further purification by SFC (column: Daicel ChiralPak IM (250x25 mm i.d. 10 um); mobile phase: [CO>-MeOH(0.1% NH. H2O)]; B%:40%, isocratic elution mode) to give ((3Y42?)-4-(2,4-difluorophenyl)-l-(2-(niethyl-d3)propan-2-yl- 1.1.1.3.3.3-iZ6)pyrrolidin-3-yl-5,5-t / 2)((35,47?,5A)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin- l-yl)methanone as a white solid. Yield: 15.63 mg, 35%; MS (ESI) m / z 482.5 [M+1]+; ’HNMR (400 MHz, DMSO-ds) 5 7.66-7.53 (m, 1H), 7.49-7.28 (m, 3H), 7.25-706 (m, 3H), 7 06-6.85 (m,1H), 4.65-4.55 (m, 1H), 4.26-4.15 (m, 1H), 3.89-3.71 (m, 1H), 3.65-3.39 (m, 2H), 3.17-2.91 (m, 2H), 2.86-2.74 (m, 1H), 2.63-2.55 (m, 1H). 1.86-1.17 (m, 2H), 0.47-0.44 (m, 4H), 0.28-0.26 (m,2H);19FNMR (376 MHz. DMSO-ds) 5 -112.95 - -113.86 (m, 2F); overall deuterium incorporation: 97.2%; percent of Compound 29a molecules: 69.1%.NAI-5006781290v1 96Attorney Docket No. 14859-002-228Example 30a: ((3S,4R)-l-(tert-butyl)-4-(2,4-difluoroplienyl)pyrrolidin-3-yl-2, 2,5,5- d4)((3S,4R,5R)-4-hydi-oxy-3,5-dimethyl-4-(phenyl-d5)piperidin-l-yl)inethanone

[0222] To a solution of (3S.4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3- carboxylic-2,2.5,5-d4 acid (140 mg, 487 pmol. 1.0 eq) in DCM (3 mL) was added (3S,4s.5R)-3,5-dimethyl-4-(phenyl-d5)piperidin-4-ol (120 mg, 487 pmol, 1.0 eq HC1), TEA (147 mg. 1.46 mmol, 3.0 eq) and T4P (421 nig, 584 pmol, 50% purity, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding sat. aq. NallCCh (10 mL) and extracted with di chloromethane (10 mL x 3). The combined organic phases were dried with anhydrous NaiSOi, filtered and concentrated under reduced pressure to give a residue The residue was purified by prep-HPLC (column: WePure Biotech XP tCl 8 150*40*7 pm; mobile phase: [H2O (lOmM NH4HCO3)-ACN]; gradient:50%-80% B over 8.0 min) to give ((3S,4R)- l-(tert-butyl)-4-(2.4-difluorophenyl)pynolidin-3-yl-2.2.5.5- 4)((3S,4R.5R)-4-hydroxy-3,5- dimethyl-4-(phenyl-< A)piperidm-l-yl)methanone as a white solid. Yield: 30.1 mg, 12%; MS (ESI) m / z 480.5 [M+l|+; ’HNMR (400 MHz, DMSO-de) 8 7.65-7.50 (m, 1H), 7.25-7.11 (m, 1H), 7.10-7.01 (m, 1H), 4.65-4.55 (m, 1H), 4.26-4.15 (m, 1H), 3.87-3.72 (m, 1H), 3.63-3.39 (m. 2H), 3.04-2.91 (m, 1H). 2.62-2.56 (m, 1H), 1.90-1.16 (m, 2H), 1.11-0.99 (m. 9H), 0.49- 0.39 (in, 4H). 0.29-0.24 (m,2H);19FNMR (376 MHz, DMSO-ds) 8 -112.94 - -113.87 (m, 2F); overall deuterium incorporation: 98.9%; percent of Compound 30a molecules: 90.3%.Example 31a: ((3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyi’rolidin-3-yl-2,2- d2)((3S,4R,5R)-4-hydroxy-3,5-diniethyl-4-phenylpiperidin-l-yI)inethanoneSynthesis of(S)-2-(tert-butylamino)-l-(2.4-difluorophenyl)ethan-l-olNA 500678129()vl 97Attorney Docket No. 14859-002-228

[0223] To a solution of (S)-2-(2,4-difluorophenyl)oxirane (1.0 eq) m EtOH is added 2- methylpropan-2-amine (1.2 eq) at 20 °C. The mixture is heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to give a residue. The residue is triturated with n-heptane at 20 °C for 3 h to give (S)-2-(tert-butylamino)- 1 -(2.4-difluorophenyl)ethan- 1 -ol.Synthesis of benzyl (S)-3-(tert-butyl(2-(2.4-difluorophenyl)-2-hydroxyethyl)amino)propanoate-3.3-d2

[0224] A mixture of (S)-2-(tert-butylamino)-l-(2,4-difluorophenyl)ethan-l-ol (1.0 eq) and benzyl acrylate-3,3-d2 (5.0 eq) is heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography to give benzyl (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hydroxyethyl)amino)propanoate-3,3-d2.Synthesis of (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hydroxyethyl)amino)propanoic-3.3-d2 acid

[0225] To a solution of benzyl (S)-3-(tert-butyl(2-(2.4-difluorophenyl)-2-hydroxyethyl)amino)propanoate-3,3-d2 (1.0 eq) in MeOH is added PdCb. (0.2 eq) at 20 °C under N2 atmosphere. The suspension is degassed and purged with H2 three times. The mixture is stirred at 20 °C for 16 h. The reaction mixture is filtered and concentrated under reduced pressure to give (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hydroxyethyl)amino)propanoic- 3.3-d?. acid.Synthesis of ethyl (S)-3-(tert-butyl(2-(2.4-difluorophenyl)-2-hydroxyethyl)amino)propanoate- 3.3-d 2

[0226] To a solution of (S)-3-(tert-butyl(2-(2.4-difluorophenyl)-2-hydroxyethyl)amino)propanoic-3,3-d2 acid (1.0 eq) in DMF is added K2CO3 (2.0 eq) and iodoethane (1.2 eq) at 20 °C. The mixture is stirred at 20 °C for 2 h The reaction mixture is quenched by adding H2O and extracted with ethyl acetate. The combined organic phase is washed with brine, dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography to give ethyl (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hydroxyethyl)amino)propanoate-3.3-d2. Synthesis of ethyl (4R)-l-(tertd)utyl)-4-(2>4-difluorophenyl)pyrrolidine-3-carboxylate-2,2-d2

[0227] To a solution of ethyl (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hvdroxyethyl)amino)propanoate-3,3-d2 (1.0 eq) in THF is added LiHMDS (3.5 eq) and [chloro(methoxy )phosphory 1] oxy methane ( 1.3 eq) at -20 °C under Ar atmosphere. The mixture is stirred at -20 °C for 2 h under Ar atmosphere. The reaction mixture is quenched by addingNAI-5006781290v1 98Attorney Docket No. 14859-002-228HC1 and extracted with n-hexane. The combined organic phase is concentrated under reduced pressure to give ethyl (4R)-l-(tert-butyl)-4-(2.4-difhiorophenyl)pyrrolidine-3-carboxylate-2,2-d2.Synthesis of (3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic-2,2-d2 acid

[0228] To a solution of ethyl (4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate-2,2-d2 (1.0 eq) in EtOH is added NaOH (13.6 eq) at 20 °C. The mixture is heated to 100CC and stirred at 100 °C for 16 h. The reaction mixture is cooled to room temperature and adjusted pH to 6~7 with cone. H2SO4. The mixture is dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic-2,2-d2 acid.Synthesis of ((3S, 4R)-l-( tert-butyl)-4-(2, 4-difluorophenyl)pyrroUdin-3-yl-2, 2-ds) ( ( 3S, 4R, 5R)~ 4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l-yl)methanone

[0229] To a solution of (3S?4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3- carboxylic-2,2-d2 acid (1.0 eq) in DCM is added (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-4-ol (1.0 eq). TEA (3.0 eq) and T4P (1.2 eq) at 0 °C. The mixture is stirred at 0 °C for 1 h. The reaction mixture is quenched by adding sat. aq. NaHCCh and extracted with di chloromethane. The combined organic phases are dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC to give ((3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidin-3-yl-2,2-d2)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidm-l-yl)methanone.Example 32a: ((3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidin-3-yl-5^-d2)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-l-yI)methanoneSynthesis of(S)-2-(tert-buiylamino)-l-(2,4-difluomphenyl)ethan-2,2-ch.-l-ol

[0230] To a solution of (S)-2-(2,4-difluorophenyl)oxirane-3.3-d2 (1.0 eq) in EtOH is added 2-methylpropan-2-amine (1 5 eq) at 20 °C The mixture is heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture is cooled to room temperature and concentrated underNAI-5006781290vl 99Attorney Docket No. 14859-002-228reduced pressure to give a residue. The residue is triturated with n-heptane at 20 °C for 3 h to give (S)-2-(tert-but 'lamino)-l-(2,4-difluorophenyl)etlian-2.2-d2.-l-ol.Synthesis of (S)-3-(tert-butyl(2-(2,4-dijluorophenyl)-2-kydroxyelhyl-i ',1-c aminopropanenitrile

[0231] A mixture of (S)-2-(tert-butylamino)-l-(2,4-difluorophenyl)ethan-2,2-d2-l-ol (1.0 eq), acrylonitrile (25 eq), formamide (1.0 eq) and EtOH (1.0 eq) is stirred at 80 °C for 12 °C under N2. Tire reaction mixture is cooled to room temperature and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography to give (S)-3-(tert-butv’l(2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d2.)amino)propanenitrile. Synthesis of (4R)-l-( tert-butyl) -4-( 2, 4-difluorophenyl)pyrrolidine-3-carbomtrile-5, 5-di

[0232] To a solution of (S)-3-(tert-butyl(2-(2,4-difluorophenyl)-2-hydroxyethyl-l,l-d2)ammo)propanenitrile (1.0 eq) inTHF is added ClPO(O-iPr)2 (1.1 eq) and LiHMDS (2.1 eq) at -20 °C under N2. The reaction is stirred at -20 °C for 2 h under N2. The reaction mixture is quenched by adding H2O and extracted with n-hexane. The organic layer is carefully extracted with HC1. The HC1 aqueous layer is adjusted pH to 11-12 with aq. NaOH (50%) and extracted with n-hexane. The combined organic layers are washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give (4R)-l-(tert-butyl)-4-(2,4- difluorophenyl)pyrrolidine-3-carbonitrile-5,5-d2.Synthesis of (3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic-5,5-d2 acid

[0233] A solution of (4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carbonitrile-5,5-d2 (1.0 eq) in EtOH and NaOH is stirred at 80 °C for 12 h. The reaction mixture is diluted with EtOH and MeOH, adjusted pH=5-6 with H2SO4, filtered and concentrated under reduced pressure to give (3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic-5.5-d2 acid.Synthesis of ((3S.4R)-l-( tert-butyl)-4-(2, 4-difluorophenyl)pyrrolidin-3-yl-5.5-ds) ( ( 3S.4R.5R)~ 4-hydroxy~3,5-dimethyl-4-phenylpiperidin-l-yl)methanone

[0234] To a solution of (3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic-5,5-d2 acid (1.0 eq) and (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-4-ol (0.8 eq) in DCM is added TEA (2.5 eq) and T4P (1.2 eq) at 0 °C. The reaction is stirred at 0 °C for 0.5 h under N2. The reaction mixture is quenched by adding sat.aq NaHCOs and extracted with DCM. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC to give ((3S.4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidin-3-yl-5,5-d2)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpipendin-l-yl)methanone.NAI-5006781290vl 100Attorney Docket No. 14859-002-228Example 33a: ((3S,4R)-l-(tei-t-butyl)-4-(2,4-difluorophenyl)pyrrolidin-3-yl-5^-d2)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyl-d5)piperidin-l-yl)methanone

[0235] To a solution of (3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic-5.5-d2 acid (1.0 eq) and (3S,4s,5R)-3.5-dimethyl-4-(phenyl-d5)piperidin-4-ol (0.8 eq) m DCM is added TEA (2.5 eq) and T4P (1.2 eq) at 0 °C. The reaction is stirred at 0 °C for 0.5 h under N2. The reaction mixture is quenched by adding sat.aq NaHCO3 and extracted with DCM. The combined organic layers are washed with brine, dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC to give ((3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidin-3-yl-5,5-d2)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyl-d5)piperidin-l-yl)methanone.Example 34a: ((3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidin-3-yl-2,2-d2)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyl-d5)piperidin-l-yl)methanone

[0236] To a solution of (3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidine-3- carboxylic-2.2-d2 acid (1.0 eq) and (3S,4s,5R)-3.5-dimethyl-4-(phenyl-d5)piperidin-4-ol (0.8 eq) m DCM is added TEA (2.5 eq) and T4P (1.2 eq) at 0 °C. The reaction is stirred at 0 °C for 0.5 h under N2. The reaction mixture is quenched by' adding sat.aq NaHCO3 and extracted with DCM. The combined organic layers are washed with brine, dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC to give ((3S,4R)-l-(tert-butyl)-4-(2,4-difluorophenyl)pyrrolidin-3-yl-2,2-d2)((3S.4R,5R)-4-hydroxy-3,5-dimethyl-4-(phenyl-d5)pipendin-l-yl)methanoneExample 35a: ((3S,4R^R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l, U53,3>3-d6)pyi’rolidin-3-yl-5-d)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4- phenylpiperidin- l-yl)methanoneNAI-5006781290vl 101Attorney Docket No. 14859-002-228Synthesis of i-(ethynyl-d)-2,4-difluorobenzene

[0237] To a solution of 1-ethynyl-2,4-difluorobenzene (1.0 eq) in MeCN is added K2CO3 (2.0 eq) at 20 °C. The mixture is stirred at 20 °C for 4 h. D2O (>99.0% of overall deuterium incorporation) is added and the reaction is stirred for another 8 h. The reaction is separated and the organic phase is dried with Na2SO4, filtered and concentrated under reduced pressure to give l-(ethynyl-d)-2.4-difluoro benzene.Synthesis of(Z)-2,4-dijh.ioro-l-(vinyl-2-d)benzene

[0238] To a solution of l-(ethynyl-d)-2,4-difluorobenzene (1.0 eq) in DCM is added Schwartz’s reagent (1.1 eq) at 0 °C in the dark. The mixture is warmed to 20 °C and stirred at 20 °C for 2 h in the dark. H2O is added and the reaction is stirred for another 2 h. The reaction is dried withNa2SO4, filtered and concentrated under reduced pressure to give (Z)-2,4-difluoro- 1 -(vinyl-2-d)benzene.Synthesis of (2S, 3R)-2-(2, 4-difluorophenyl)oxirane-3-d

[0239] A solution of (Z)-2,4-difluoro-l-(vinyl-2-d)benzene (1.0 eq). NMO (5.0 eq) and (salen)Mn complex in DCM is cooled to -78 °C. m-CPBA (2.0 eq) is added in portions. The reaction mixture is stirred for 1 h at -78 °C. NaOH solution is added. The organic phase is separated and washed with brine. The aqueous phase is combined and washed with DCM. The combined organic phases are dried with Na2SO4, filtered and concentrated under reduced pressure to give (2S,3R)-2-(2,4-difluorophenyl)oxirane-3-d.Synthesis of (1S,2R)-1-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)amino)ethan-2-d-1-ol

[0240] To a solution of (2S,3R)-2-(2,4-difluorophenyl)oxirane-3-d (1.0 eq) in EtOH is added 2-(methyl-d3)propan-1,1,1,3,3,3-d6-2-amine (1.5 eq, >98% of overall deuterium incorporation) at 20 °C. The mixture is heated to 80 °C and stirred at 80 °C for 16 h. TheNAI-5006781290v1 102Attorney Docket No. 14859-002-228reaction mixture is cooled to room temperature and concentrated under reduced pressure to give a residue. The residue is triturated with n-heptane (20 mL) at 20 °C for 3 h to give (1S.2R)- 1-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)amino)ethan-2-d-1-ol. Synthesis of 3-(((lR2S)-2-(2,4-difluorophenyl)~2~hydroxyethyl~l~d)(2-(methyl- 3)propan-2- yl-1, 1, 1,3, 3, 3-d6)ammo)propanenitrile

[0241] To a solution of (lS,2R)-l-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl- l,l,l,3.33-d6)amino)ethan-2-d-l-oI (1.0 eq), acrylonitrile (25 eq), formamide (1,0 eq) and EtOH (1.0 eq) is stirred at 80 °C for 12 h under N2. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography to give 3-(((lR,2S)-2-(2,4-difluorophenyl)-2-hydroxyethyl- 1 -d)(2-(methyl-d3)propan-2-yl- 1, 1, 1,3.3,3-d6)amino)propanenitrile.Synthesis of (4R,5R)-4-(2,4-difluorophenyl)-1-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrazolidine-3-carbonitrile-5-d

[0242] To a solution of 3-(((1R,2S)-2-(2,4-difluorophenyl)-2-hydroxyethyl-1-d)(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)amino)propanenitrile (1.0 eq) in THE is added ClPO(O-iPr)2, (1.1 eq) and LiHMDS (2.1 eq) at -20 °C under N2. The reaction is stirred at -20 °C for 2 h under N2. The reaction mixture is quenched by adding H2O and extracted with n-hexane. The organic layer is carefully extracted with HC1. The HC1 aqueous layer is adjusted pH to 11—12 with aq. NaOH (50%) and extracted with n-hexane. The combined organic layers are washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give (4R, 5R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrazolidine-3-carbonitrile-5-d.Synthesis of (3S,4R,5R)-4-(2,4-difluorophenyl)-1-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidine-3-carboxylic-5-d acid

[0243] A solution of (4R,5R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl- l,l,l,3,3,3-d6)pyrazolidine-3-carbonitrile-5-d (1.0 eq) in EtOH and NaOH is stirred at 80 °C for 12 h. The reaction mixture is diluted with EtOH and MeOH, adjusted pH=5-6 with H2SO4, filtered and concentrated under reduced pressure to give (3S,4R,5R)-4-(2.4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidine-3-carboxylic-5-d acid.Synthesis of ((3S,4R,5R)-4-(2,4-difluorophenyl)-1-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidin-3-yl-5-d)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl)methanone

[0244] To a solution of (3S,4R,5R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic-5-d acid (1.0 eq) and (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-4-ol (0.8 eq) in DCM is added TEA (2.5 eq) and T4P (1.2 eq) at 0 °C. TheNAI-5006781290v1 103Attorney Docket No. 14859-002-228reaction is stirred at 0 °C for 0.5 h under N2. The reaction mixture is quenched by adding sat.aq NaHCOs and extracted with DCM. The combined organic layers are washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC to give ((3S,4R,5R)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidin-3-yl-5-d)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperi din-1 -yl)methanone.Example 36a: ((3S,4R,5S)-4-(2,4-difluorophenyl)-1-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidin-3-yl-5-d)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl)methanoneSynthesis of (E)-2, 4-difluoro-l-(vinyl-2-d)benzene

[0245] To a solution of 1-ethynyl-2,4-difluorobenzene (1.0 eq) in DCM is added Schwartz's reagent (1.1 eq) at 0 °C in the dark. The mixture is warmed to 20 °C and stirred at 20 °C for 2 h in the dark. D2O (>99.0% of overall deuterium incorporation) is added and the reaction is stirred for another 2 h. The reaction is dried with Na2SO4, filtered and concentrated under reduced pressure to give (E)-2,4-difluoro-l -(vinyl-2-d)benzene.Synthesis of (2S, 3S)-2-(2, 4-difluorophenyl)oxirane-3-d

[0246] A solution of (E)-2,4-difluoro-l-(vinyl-2-d)benzene (1.0 eq), NMO (5.0 eq) and (salen)Mn complex in DCM is cooled to -78 °C. m-CPBA (2.0 eq) is added in portions. The reaction mixture is then stirred for 1 h at -78 °C, NaOH solution is then added. The organic phase is separated and washed with brine. The aqueous phase is combined and washed with DCM. The combined organic phases are dried with Na2SO4, filtered and concentrated underNAI-5006781290v1 104Attorney Docket No. 14859-002-228reduced pressure to give (2S,3S)-2-(2,4-difluorophenyl)oxirane-3-d.Synthesis of (1S,2S)-1-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)amino)ethan-2-d-1-ol

[0247] To a solution of (2S,3S)-2-(2.4-difluorophenyl)oxirane-3-d (1.0 eq) in EtOH is added 2-(methyl-d3)propan-1,1,1,3,3,3-d6-2-amine (1.5 eq, >98% of overall deuterium incorporation) at 20 °C. The mixture is heated to 80 °C and stirred at 80 °C for 16 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to give a residue. The residue is triturated with n-heptane (20 mL) at 20 °C for 3 h to give (1S,2S)-1-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)amino)ethan-2-d-1-ol. Synthesis of 3-(((lS,2S)-2-(2,4-difluorophenyl)-2-hydroxyethyl-l-d)(2-(methyl-d3)propan-2-yl- 1.1.1.3.3.3-d6)amino)propanenitrile.

[0248] To a solution of (lS,2S)-l-(2,4-difluorophenyl)-2-((2-(methyl-d3)propan-2-yl- 1.1.1.3.3.3-d6)amino)ethan-2-d-l-ol (1.0 eq), acrylonitrile (25 eq), formamide (1.0 eq) and EtOH (1.0 eq) is stirred at 80 °C for 12 °C under N2. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography to give 3-(((lS,2S)-2-(2,4-difluorophenyl)-2-hydroxyethyl-l-d)(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)amino)propanenitrile.Synthesis of (4R,5S)-4-(2,4-difluorophenyl)-1-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrazolidine-3-carbonitrile-5-d

[0249] To a solution of 3-(((lS,2S)-2-(2,4-difluorophenyl)-2-hydroxyethyl-l-d)(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)amino)propanenitrile (1.0 eq) in THF is added ClPO(O-iPr)2 (1.1 eq) and LiHMDS (2.1 eq) at -20 °C under N2. The reaction is stirred at -20 °C for 2 h under N2. The reaction mixture is quenched by adding H2O and extracted with n-hexane. The organic layer is carefully extracted with HC1. The HC1 aqueous layer is adjusted pH to 11-12 with aq NaOH (50%) and extracted with n-hexane. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give (4R,5S)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrazolidine-3- carbonitrile-5-d.Synthesis of (3S,4R,5S)-4-(2,4-difluorophenyl)-1-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidine-3-carboxylic-5-d acid

[0250] A solution of (4R,5S)-4-(2.4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl- 1,1,1,3,3,3-d6)pyrazolidine-3-carbonitrile-5-d (1.0 eq) in EtOH and NaOH is stirred at 80 °C for 12 h. The reaction mixture is diluted with EtOH and MeOH, adjusted pH=5-6 with H2SO4, filtered and concentrated under reduced pressure to give (3S,4R,5S)-4-(2,4-difluorophenyl)-l-NAI-5006781290vl 105Attorney Docket No. 14859-002-228(2-(methyl-d3)propan-2-yl-l,l.l,3.3,3-d6)pyrrolidine-3-carboxylic-5-d acid.Synthesis of ((3S,4R,5S)-4-(2,4-difluorophenyl)-1-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidin-3-yl-5-d)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl)methanone

[0251] To a solution of (3S,4R,5S)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)pyrrolidine-3-carboxylic-5-d acid (1.0 eq) and (3S,4s,5R)-3,5-dimethyl-4-phenylpiperidin-4-ol (0.8 eq) in DCM is added TEA (2.5 eq) and T4P (1.2 eq) at 0 °C. The reaction is stirred at 0 °C for 0.5 h under N2. The reaction mixture is quenched by adding sat.aq NaHCO3 and extracted with DCM. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC to give ((3S,4R,5S)-4-(2,4-difluorophenyl)-l-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)pyrrolidin-3-yl-5-d)((3S,4R,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl)methanone.

[0252] Examples 37a and 39a are prepared analogously to Example 35a. Examples 38a and 40a are prepared analogously to Example 36a.Biological StudiesExample IB. Evaluation of Metabolic Stability of Compounds in Human, Rat, and Mouse Liver Microsomes

[0253] Liver microsomal incubations were carried out with pooled human, SD rat, or CD-1 mouse liver microsomes (purchased from Discovery Life Sciences (human) or RILD (rat & mouse)). The final incubation volume of 500 pL per time point contained potassium phosphate buffer (0.1 M). MgCl2 (1mM), microsomal protein (0,5 mg / mL), and the test compound at a final concentration of 1 μM. Following 10 min incubation at 37°C, the reactions were initiated by the addition of NADPH (1 mM final concentration) and terminated by transferring an aliquot into solvent after different time points. Aliquots of microsomal incubation (100 pL) were removed over a 60 min period (at 5, 15, 30, 45, and 60 min) and immersed in ice-cold acetonitrile containing 250 nM tolbutamide and 250 nM labelalol as internal standards to terminate the reaction. The resulting samples were centrifuged at 3220 g for 20 min at 4°C and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The stability of the compounds in human and rate liver microsomes as measured by half-life in minutes are shown in Tables IB and 1C. respectively. Mouse liver microsome stability was assessed for Compound 1 and a certain compound in the instant application. The latter was found to be metabolically more stable than Compound 1 in mouse liver microsomes.NAI-5006781290vl 106Attorney Docket No. 14859-002-228Table IB: Human Liver Microsome Stability DataCompound Half-life Compound Half-life Compound Half-life ID (min) ID (min) ID (min) Compound 1 19.24 Example 14a 16.2 Example 25a 24.20 Example la 17.90 Example 15a 17.00 Example 26a 24.50 Example 6a 17.5 Example 16a 16.60 Example 27a 27.45 Example 7a 16.3 Example 17a 16.3 Example 28a 20.70 Example 8a 16.9 Example 18a 17.1 Example 29a 27.50 Example 9a 19.6 Example 19a 16.9 Example 30a 25.00 Example 10a 16.9 Example 20a 17.00Example Ila 15.8 Example 22a 26.44Example 12a 16.8 Example 23a 25.75Example 13a 18.1 Example 24a 24.40Table 1C. Rat Liver Microsome Stability DataCompound ID Tl / 2 CLint(mic)(min) (pL / min / mg) R2Compound 1 28.6 48.5 0.995Example 22a 38.7 35.8 0.988Example 23a 36.2 38.3 0.994Example 24a 38 36.5 0.995Example 25a 40.6 34.2 0.997Example 26a 36.2 38 3 0.989Example 2B. Evaluation of Oral Pharmacokinetics of Compounds in Rat

[0254] The compounds were dissolved in DMSO, then diluted with 20% SBE-beta cyclodextrin in 1 % NaCl solution, final pH ~5.0 for administration via oral gavage (PO). Male Sprague-Dawley rats (approximately 7-9 weeks of age and weighing about 250 g) had free access to food (rat diet pellets) and water throughout the duration of the study. Two or three rats each received each compound at a dose of 10 mg / kg via oral gavage. Blood samples (200 uL) were collected from the jugular vein into microcentrifuge tubes containing K2-EDTA and centrifuged (3200g for 10 min at 2-8°C) to obtain plasma before compound dosing and at 0.083.0.25, 0.5, 1, 2, 4, 8, and 24 hours or 0.5, 1, 3, 5, and 24 hours post-dose. Plasma samples were analyzed for concentrations of the dosed compound at each time point using LC-MS / MS. Similarly, 6 standard solutions of known concentration (1.0-100ng / ml) of the test compounds were measured to generate a calibration curve. The concentration (ng / mL) of the compound inNAI-5006781290vl 107Attorney Docket No. 14859-002-228the plasma was calculated using the calibration curve. The limit of quantitation of each compound was 1 ng / mL. The pharmacokinetic data is shown in Table 2B and Figure 1.Table 2B. Pharmacokinetic Analysis of Compounds in RatCompound Cmax (ng / mL) AUCo-iast (ng.h / mL) Compound 1 124 732 Cassette Study #1 Example 22a 172 1012Example 27a 145 854 Compound 1 144 551 Cassette Study #2Example 25a 265 1104 Example 3B. Metabolic Profiling of the Compounds

[0255] Method: Metabolic profiling was performed to identify and compare the major metabolites of Compound 1 and a certain compound in the instant application in human liver microsomes by LC-UV-MS. Ihe test compounds at 10 uM were incubated individually with human liver microsomes (1 mg / ml microsomal proteins) m the presence of ImM NADPH at 37°C for 45 min. The positive control. 7-ethoxy coumarin (7-EC) at 10 pM, was run concurrently to assess Phase I metabolic activities in liver microsomes. After incubation, the samples were analyzed by LC-UV-MS.

[0256] Result: In addition to the unchanged parental molecules, a total of 17 metabolites were detected and identified by LC-UV-MS from human liver microsomes across the two experiments. The relative abundance of the parental molecules and each of the putative metabolites were calculated using peak area under the UV spectrum at 240-280 nm and MS peak area of individual metabolites relative to the total area of all detected drug-related peaks. The results were consistent with that certain compound in the instant application having a slower metabolism in human liver microsomes than Compound 1. Moreover, no significant metabolic switching was observed for that certain compound m the instant application as compared with Compound 1.Example 4B. Melanocortin receptor in vitro functional EC50 Assessment:

[0257] In vitro functional potency estimates of the compounds against melanocortin receptors were obtained through determination of their effect on cellular cyclic adenosine monophosphate (cAMP). The compounds were assessed for agonist activity using the LANCE Ultra cAMP kit from Revvity following the manufacturer’s instructions. Flp-In 239 cells overexpressing hMC4R were seeded at 2000 cells / well m a 384 well plate then treated with 10 doses of the various test articles following 3-5-fold serial dilution depending on the article tested. The assay plate was read using an EnVison microplate reader (λex=337 nm, λem=615NAI-5006781290vl 108Attorney Docket No. 14859-002-228nm and 665 nm), and the ratio of Emission 665 nm to Emission 615 nm was plotted against the concentrations of compounds to calculate the EC50s. All assays included a standard agonist, Mel anotan I or MT-II, to ensure data quality. The results are shown in Table 4B, which shows that the deuterated compounds did not have a discernable impact on cAMP agonist activity as compared to Compound 1.Table 4B. cAMP agonist activityCompound ID EC50 (nM) Compound ID EC50 (nM) Melanotan I 0.5 Compound 22a 24.9 MT-II 0.1 Compound 23a 23.4Compound I 28.6 Compound 25a 27.1 Example 5B. Food intake and body weight in db / db mice:

[0258] db / db mice have homozygous loss-of-function mutations in the leptin receptor, which acts upstream of the MC4R. These mice exhibit abnormally low or absent signaling through MC4R resulting in hyperphagia and severe obesity. Male db / db mice maintained on a regular chow diet are dosed orally with the compound of the instant application 1 hour before the start of their dark cycle for several days. Food intake and body weight are measured. Blood samples are also collected for pharmacokinetic analysis.

[0259] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing descriptions. Such modifications are intended to fall within the scope of the appended claims. Various publications, patents and patent applications are cited herein, the applications of which are incorporated by reference in their entireties.NAI-5006781290v1 109

Claims

Attorney Docket No. 14859-002-228What is claimed is:

1. A compound of Formula (I):(I),or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein at least one of Y1. Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11. Y12, Y13. Y14, Y13, yl6 yl7 yl8 yl9 y20 y21 y22 y23 y24 y25 y26 y27 y28 y29 y30 y31 y32 y33 y34 y35 and Y’ is a hydrogen that is isotopically enriched with deuterium f‘D”), and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, Y15, Y16, Y17, Y18, Y19, Y20, Y21, Y22Y23, y24, y25, y26, y27, y28, y29, y30, y31. y32, y33, y34, y3^ y36arenon.enrlched hydrogen atoms CH”).

2. The compound of claim 1, wherein Yj6is H.

3. The compound of claim 1 or 2, wherein Yj3_ Yj4, and Y'13are all H.

4. The compound of any one of claims 1 to 3, which is a compound of Formula (I-A):(I-A).or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable saltNAI-5006781290v1 110Attorney Docket No. 14859-002-228thereof, wherein at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y'. Y8, Y9, Y10, Y11, Y32, Y13, Y14, Y35, Y16, Y17, Y18. Y19, Y20, Y21, Y22, Y23, Y24, Y25, Y26. Y27, Y28, Y29. Y30, Y33, and Y32is a hydrogen that is isotopically enriched with deuterium, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Ys, y9 ylO yl l yl2 yl3 y!4 y]5 yl6 yl7 y!8 y!9 y20 y21 y22 y23 y24 y25 y26 y27 y28 Y29, Y30, Y31, and Y32are non-enriched hydrogen atoms.

5. The compound of any one of claims 1 to 4, wherein at least one of Y29, Y30, Y3’, and Y32is D, and the others of Y29, Y30, Y31, and Y32are H.

6. The compound of any one of claims 1 to 5, wherein at least two of Y29, Y30, Y31, and Yj2are D, and the others of Y29. Y30, Y31, and Y32are H.7 The compound of any one of claims 1 to 6, wherein at least three of Y29, Y30, Y31, and Yd2are D, and the other of Y29, Y’°, Y31, and Y32is H.

8. The compound of any one of claims 1 to 7, wherein Y29. Y’°, Y31, and Y32are all D.

9. The compound of any one of claims 1 to 7, wherein Y29and Y' ° are both D. and Y31, and Y32are both H; or wherein Y29and Y30are both H, and Y31, and Y32are both D.

10. The compound of any one of claims 1 to 4, wherein Y29, Y30, Y33, and Y32are all II.

11. The compound of any one of claims I to 4, which is a compound of Formula (II):F(II),or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein at least one of Y3, Y2, Y3, Y4, Y5, Y6, Y7. Y8, Y9, Y10, Y11, Yi2, Y13, Y34, Y35, Y16, Yi 7. Y18, Y19, Y20, Y23, Y22, Y23, Y24. Y2’, Y26, Y27, and Y28is a hydrogen that is isotopically enriched with deuterium, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Yx. Y9, Y10,NAI-5006781290v1 111Attorney Docket No. 14859-002-228Y”, Y12, Y’3, Y14, Y15, Y16, Y17, Y’8, Y19. Y20, Y2’, Y22, Y23, Y24, Y25, Y26, Y27, and Y28are non-enriched hydrogen atoms.

12. The compound of any one of claims 1 to 4, which is a compound of (II-A), (Il-B), (II- C), (II-D), or (II-E):FY;7y16 / ==YY'S“K / Y24-Y14ffY« v y< HFY25— / xTS / 12 D“7\ / H 1 Y2''-l Y11Y24UX^Y22 AY19 I Y1Y23 Y6^~4^Y ~ CO <Y'Y6‘T'Y4J| 5- l QIYY5F Fy17 yl 6 L.. / L > / y17 Y15(YieX^4> \r «l“!Q >* Qz— 1?>oYY-18_Y Y y10X f 'Jy^4 O ’y 4 \ / / y26hT? I2-Y26 \ / N „ ■ p ¥v v =2" 1 '*• X / YX -131 ^ \25JL - \ / >— n Y —,, / \ XY12 k / uY!4" Y l! yX 1Y24-A^ TxA. >4 o227^Y19 YY2Y2M A.YY,,Y8N1 Y'! \Y / ZU1\91 I / y1AYo V^X- ( Y2J '~-r-V\1Y2y3' Y»)-+-vy4n i - w Y5(II-B) (II-C), orFY(7. Y16 / YY22J5YySL'""vlY2JYVY,912< ] / / ’Y23Y8‘Y |Y3Y7Y6zr,Y4YYs(II-D)or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claims 1 to 12, wherein Y1. Y2, Y’, Y4, Y5, Y6, Y7, Y8, and Y9are all II.NAI-5006781290v1 112Attorney Docket No. 14859-002-22814. The compound of any one of claims 1 to 12, wherein at least one of Y3, Y2, Y3, Y4, Y5, Y6, Y7. Y8, and Y9is D, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Ys, and Y9are H.

15. The compound of claim 14, wherein three of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are D, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are H.

16. The compound of claim 14, wherein six of Y3, Y2. Y3, Y4, Y5, Y6, Y7, Ys. and Y9are D, and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are H.

17. The compound of claim 14, wherein Y1, Y2, Y3, Y4, Y5. Y6. Y7. Y8. and Y9are all D.

18. The compound of any one of claims 1 to 17, wherein Y30, Y13, Y12, Y’3, Y34, and Y35are all H.

19. The compound of any one of claims 1 to 17, wherein at least one of Y10. Y33, Y12. Y13, Y14, and Y15is D, and the others of Y30, Y33, Y32, Y33Y14. and YL' are H.

20. The compound of claim 19, wherein two of of Y30, Y13, Y32. Y13, Y14, and Y15are D, and the others of Y3U. Y33, Y32, Ylj, Y14, and Y15are H.

21. The compound of claim 20, wherein Y30and Y33are both D, and Y32, Y, Y34, and Y3' are all H.

22. The compound of claim 19, wherein four of of Y10, Y11, Y12, Y13, Y14, and Yi3are D, and the others of Y30, Y31, Y12, Y13Y34, and Y35are H.

23. The compound of claim 22, wherein Y10and Y11are both H, and Y12, Y13, Y14, and Y35are all D.

24. The compound of claim 19, wherein Y30, Y33, Y12, Y33, Y34, and Y35are all D.

25. The compound of any one of claims 1 to 24. wherein Y36, Y37, Y18, Y19, Y2u, and Y21are all H.

26. The compound of any one of claims 1 to 24, wherein at least one of Y3C, Y37, Y18, Y19, Y20, and Y23is D, and the others of Yl,;. Y37, Y38, Y39Y20, and Y21are H.

27. The compound of claim 26, wherein three of Y16, Y17, Y18. Y19, Y20, and Y21are D, and the others of Y10. Y3Y18, Y39Y20. and Y23are H.NAI-5006781290v1 113Attorney Docket No. 14859-002-22828. The compound of claim 27, wherein Y’6, Y’1', Y18are all D, and Y19, Y20, and Y2’ are all H; or wherein Y16, Y17, Y18are all H, and Y19, Y20, and Y21are all D.

29. The compound of claim 26, wherein Y16, Y17, Y18. Y19, Y20, and Y21are all D.

30. The compound of any one of claims 1 to 29. wherein at least one of Y22, Y23. Y24, Y25, and Y26is D, and the others of Y22, Y23, Y24, Y23, and Y26are H.

31. The compound of claim 30, wherein Y22, Y23, Y24, Y25, and Y26are all D,32. The compound of any one of claims I to 31, wherein at least one of Y27and Y28is D 33. The compound of claim 32, wherein Y27and Y2Sare both D.

34. The compound of any one of claims 1 to 31, wherein Y27and Y2Sare both H35. The compound of claim 1, which is a compound of Formula (1II-A), (III-B), (III-C), or (III-D). (III-E). (1II-F). (1II-G), (I1I-H), (III-I). (III-J), (III-K). (III-L). or (I1I-M):(iii-A), (III-B),(III-C). (III-D),NAI-5006781290v1 114Attorney Docket No. 14859-002-228F(III-F),(III-K), NAI-5006781290v 1 115Attorney Docket No. 14859-002-228or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.

36. The compound of claim 35, wherein Y1. Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are all D, or wherein Y1, Y2, Y3, Y4, Y3, Y6, Y7, Y8, and Y9are all H.

37. The compound of claim 35 or 36, which is a compound of Formula (Ill-E), (III-F). (111-G), (1II-H), (1II-I), (III-J), or (1II-M), wherein Y29, Y30, Y3’, and Y32re all D.

38. The compound of claim 37, wherein Y29, Y30. Y31, and Y32are all D. and wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9are all D39. The compound of claim 1, which is a compound of Formula (IV), (V), (VI), or (VII):NAI-5006781290v1 116Attorney Docket No. 14859-002-228thereof.

40. A compound in Table 1 or Table 1A, or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.

41. The compound of any one of claims 1 to 40, wherein each position designated as deuterium independently has an isotopic enrichment factor of at least about 6000 (about 90% deuterium incorporation), at least about 6333.3 (about 95% deuterium incorporation), or at least about 6600 (about 99% deuterium incorporation).42 The compound of any one of claims 1 to 40, wherein the overall deuterium incorporation of the compound is at least 90%, at least 95%, or at least 99%.

43. The compound of any one of claims 1 to 40, wherein the molecules that are deuterated at all of the position(s) designated as deuterium consists of at least about 65?% at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the compound.

44. A pharmaceutical composition comprising the compound of any one of claims 1 to 43, and a pharmaceutically acceptable excipient.

45. A method of treating, managing, or preventing a disease or disorder in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 43 or the pharmaceutical composition of claim 44.

46. The method of claim 45. wherein the disease or disorder is obesity or diabetes.

47. The method of claim 45, wherein the disease or disorder is erectile dysfunction or hypoactive sexual desire disorder.

48. A method of managing body weight in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 43 or the pharmaceutical composition of claim 44.

49. The method of claim 48, wherein the subject has been treated with one or more GLP-1 receptor agonist, or one or more Amylin receptor agonist.

50. The method of any one of claims 45 to 49, comprising administering one or more additional therapeutic agents to the subj ect.NAI-5006781290v1 117

Images