Orexin receptor agonists and uses thereof

Abstract

Provided herein are compounds of formula (I), or pharma- ceutically acceptable salts thereof, where n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y, and Z are defined herein. Also provided herein are pharmaceutical compositions comprising compounds of formula (I), or pharma- ceutically acceptable salts thereof, and methods of using compounds of formula (I), or pharma- ceutically acceptable salts thereof, for example, in the treatment of diseases or disorders treatable by administration of an orexin agonist. [Formula 1] TIFF2024516033000342.tif58165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 183,321, filed May 3, 2021, the contents of which are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Orexin is a neuropeptide specifically produced by certain neurons scattered throughout the lateral hypothalamus and surrounding areas. Orexin consists of two subtypes: orexin A and orexin B. Both orexin A (OX-A) and orexin B (OX-B) are endogenous ligands for orexin receptors, which are primarily present in the brain. Two orexin receptors have been cloned and characterized in mammals. They belong to the G protein-coupled receptor superfamily. The orexin-1 receptor (OX or OX1R) is partially selective for OX-A, while the orexin-2 receptor (OX2 or OX2R) can bind to OX-A and OX-B with similar affinity. The physiological actions thought to be mediated by orexin are thought to be expressed as two subtypes of orexin receptors via either or both the OX1 and OX2 receptors.

[0003] Orexins regulate states of sleep and wakefulness, making the orexin system a target for potential therapeutic approaches to treat sleep disorders. Orexins have been shown to stimulate feeding in rats, suggesting a physiological role for these peptides as mediators in central feedback mechanisms regulating feeding behavior. Orexins have also been shown to play roles in wakefulness, emotion, energy homeostasis, reward, learning, and memory.

[0004] There is a need for compounds that modulate orexin receptors, as well as compositions and methods for treating diseases or disorders treatable by administration of orexin agonists. Summary of the Invention

[0005] The present disclosure is directed to compounds that are agonists of the orexin-2 receptor, and pharmaceutical compositions thereof, and their use in treating diseases or disorders treatable by administration of an orexin agonist.

[0006] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, n and m are independently 0 or 1; A1 is -O-, -CR4R5-, -NR6-, -S- or a bond; A2 is -C(O)- or -S(O)2-; A3 and A4 are independently -O-, -CR4R5-, -NR6, -S-, a bond, or A3 and A4 together are -C(R4)=C(R5)-; A5 and A6 are independently -O-, -CR4R5-, -NR6, -S- or a bond, provided that the ring containing A2, A3, A4, A5 and A6 does not contain -OO-, -NR6-NR6- or -O-NR6-; L1 is -O-, -CR4R5- or a bond; L2 is -CR4R5, R1 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclyl, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclyl, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, -S(O)2-heteroaryl, -(C=O)NR7R8, or R1 and R2 together with the atoms to which they are attached form a heterocycle or heteroaryl, R2 and R3 are independently hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, or R2 and R3 together with the atoms to which they are attached form a carbocycle or heterocycle; R4 and R5 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, alkoxy, -O-cycloalkyl, -O-heterocyclyl, halogen, or R4 and R5 together with the atoms to which they are attached form a carbocycle or heterocycle; R6 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclyl, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclyl, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, -S(O)2-heteroaryl or -(C=O)NR7R8; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R7 and R8 together with the atoms to which they are attached form a heterocycle; Y is cycloalkyl, heterocyclyl, heteroaryl, or aryl; Z is absent, heteroaryl or aryl.

[0007] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are defined herein.

[0008] In some embodiments, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, and Z are defined herein.

[0009] In some embodiments, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein n, m, p, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, R A , and Z are defined herein.

[0010] In some embodiments, the present disclosure provides a compound of formula (VA): [ka] or a pharmaceutically acceptable salt thereof, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A , and R B is defined herein.

[0011] In some embodiments, the present disclosure provides a compound of formula (VB): [ka] or a pharmaceutically acceptable salt thereof, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A , and R B is defined herein.

[0012] In some embodiments, the present disclosure provides a compound of formula (VC): [ka] or a pharmaceutically acceptable salt thereof, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A , and R B is defined herein.

[0013] In some embodiments, the present disclosure provides a compound of formula (VI-A): [ka] or a pharmaceutically acceptable salt thereof, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, and R B is defined herein.

[0014] In some embodiments, the present disclosure provides a compound of formula (VI-B): [ka] or a pharmaceutically acceptable salt thereof, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, and R B is defined herein.

[0015] In some embodiments, the present disclosure provides a compound of formula (VI-C): [ka] or a pharmaceutically acceptable salt thereof, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, and R B is defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0016] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure for all purposes in order to more fully describe the state of the art known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the aforementioned patents, patent applications, and publications and this disclosure, the present disclosure shall control.

[0017] For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0018] The term "about" immediately preceding a numerical value denotes a range (e.g., ±10% of that value). For example, unless otherwise indicated in the context of this disclosure or inconsistent with such an interpretation, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc. For example, in a list of numerical values, e.g., "about 49, about 50, about 55, ...," "about 50" means a range spanning less than half the interval(s) of the preceding and following values, e.g., a range greater than 49.5 and less than 50.5. Furthermore, expressions such as "about," "less than," or "about," "greater than" a value should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" before a series of numerical values ​​or ranges of values ​​(e.g., "about 10, 20, 30," or "about 10 to 30") refer to all values ​​in the series or to the endpoints of the range, respectively.

[0019] As used herein, the terms "administer," "administering," or "administration" refer to administering a compound or a pharmaceutically acceptable salt of the compound, or a composition or formulation comprising the compound or a pharmaceutically acceptable salt of the compound, to a patient.

[0020] The term "pharmaceutically acceptable salts" includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt, such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, and the like. Examples of base addition salts include, but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine dicyclohexylamine, and the like. Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, and the like. Examples of ammonium salts and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting the compound with the appropriate inorganic or organic acid by any of a number of known methods.

[0021] As used herein with respect to a patient, the term "treating" refers to improving at least one symptom of the patient's disorder. Treatment can be improving, or at least partially improving, the disorder or a symptom associated with the disorder.

[0022] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound, or a salt thereof (or a pharmaceutical composition containing said compound or salt), that is capable of achieving an intended result when administered to a patient. The "effective amount" will vary depending on the active ingredient, the condition, disease, or condition being treated and its severity, and the age, weight, health, and responsiveness of the mammal being treated.

[0023] The term "therapeutically effective" as applied to a dose or amount refers to that quantity of a compound or pharmaceutical formulation sufficient to result in a desired clinical benefit after administration to a patient in need thereof.

[0024] The terms "carrier" or "vehicle," as used interchangeably herein, encompass carriers, excipients, adjuvants, and diluents, or any combination of the foregoing, and refer to substances, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating agents, that are involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another organ or part of the body. In addition to adjuvants, excipients, and diluents known to those skilled in the art, such carriers include organic and inorganic nanoparticles.

[0025] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" means C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0026] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain having from 1 to 12 carbon atoms, attached to the rest of the molecule by a single bond. Alkyl groups containing any number of carbon atoms from 1 to 12 are included. Alkyl groups containing up to 12 carbon atoms include C1-C 12 Alkyl, and alkyl containing up to 10 carbon atoms is C1-C 10 An alkyl having up to 6 carbon atoms is a C1-C6 alkyl, and an alkyl having up to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties described above for C1-C5 alkyl, as well as C6 alkyl. C1-C 10 Alkyl includes all of the above C1-C5 alkyl and C1-C6 alkyl moieties, as well as C7, C8, C9 and C 10 Similarly, C1-C 12 Alkyl includes all of the above moieties, as well as C 11 and C 12 Contains alkyl. C1-C 12 Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise in the specification, an alkyl group may be optionally substituted.

[0027] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical having from 1 to 12 carbon atoms. 12Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., one described herein) through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically, an alkylene chain can be optionally substituted.

[0028] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are defined as C2-C 12 Alkenyl containing up to 10 carbon atoms is C2-C 10 An alkenyl group containing up to 6 carbon atoms is C2-C6 alkenyl, and an alkenyl containing up to 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all of the above-mentioned moieties for C2-C5 alkenyl as well as C6 alkenyl. C2-C 10 Alkenyl includes all of the above C2-C5 alkenyl and C2-C6 alkenyl moieties as well as C7, C8, C9 and C 10 Alkenyl is also included. 12 Alkenyl includes all of the moieties listed above, as well as C 11 and C 12 Contains alkenyl. C2-C 12Non-limiting examples of alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, and 3-nonenyl. , 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise in the specification, an alkyl group may be optionally substituted.

[0029] "Alkenylene" or "alkenylene chain" refers to an unsaturated, linear or branched divalent hydrocarbon chain radical having one or more olefins and 2 to 12 carbon atoms. C-C 12 Non-limiting examples of alkenylene include ethylene, propenylene, n-butenylene, etc. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., one described herein) through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically, an alkenylene chain can be optionally substituted.

[0030] "Alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain having from 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms include C2-C 12 Alkynyl containing up to 10 carbon atoms is C2-C 10 An alkynyl group containing up to 6 carbon atoms is C2-C6 alkynyl, and an alkynyl containing up to 5 carbon atoms is C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl, and C2 alkynyl. C2-C6 alkynyl includes all of the moieties above for C2-C5 alkynyl as well as C6 alkynyl. C2-C 10 Alkynyl includes all of the above C2-C5 alkynyl and C2-C6 alkynyl moieties as well as C7, C8, C9 and C 10 Alkynyl is also included. 12 Alkynyl includes all of the above moieties and C 11 and C 12 Alkynyl is included. C2-C 12 Non-limiting examples of alkenyl include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise in the specification, an alkyl group may be optionally substituted.

[0031] "Alkynylene" or "alkynylene chain" refers to an unsaturated, linear or branched divalent hydrocarbon chain radical having one or more alkynes and 2 to 12 carbon atoms. C2-C 12 Non-limiting examples of alkynylene include ethynylene, propynylene, n-butynylene, etc. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., one described herein) through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain with appropriate valences. Unless stated otherwise herein, the alkynylene chain can be optionally substituted.

[0032] "Alkoxy" means a group of the formula -OR a where R a is alkyl, alkenyl, or alkynyl as defined above containing 1 to 12 carbon atoms. Unless stated otherwise in the specification, an alkoxy group may be optionally substituted.

[0033] "Aryl" refers to a hydrocarbon ring system containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, and is attached to the rest of the molecule by a single bond. For purposes of this disclosure, the aryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl includes, but is not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, "aryl" may be optionally substituted.

[0034] An "aralkyl" or "arylalkyl" is a group of the formula -R b -R c where R b is an alkylene group as defined above, and R c is one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl, etc. Unless stated otherwise in the specification, an aralkyl group may be optionally substituted.

[0035] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a ring structure in which the atoms forming the ring are each carbon and are attached to the rest of the molecule by a single bond. Carbocyclic rings can contain from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryl and cycloalkyl, cycloalkenyl, and cycloalkynyl, as defined herein. Unless otherwise specified herein, carbocyclyl groups can be optionally substituted.

[0036] "Cycloalkyl" refers to a stable non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon, consisting solely of carbon and hydrogen atoms, which may include fused, bridged, or spirocyclic ring systems, having 3 to 20 carbon atoms (e.g., 3 to 10 carbon atoms), and attached to the remainder of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specified in the specification, cycloalkyl groups may be optionally substituted.

[0037] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon, consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, which may include fused or bridged ring systems, having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Examples of polycyclic cycloalkenyls include bicyclo[2.2.1]hept-2-enyl, and the like. Unless otherwise specified herein, cycloalkenyl groups may be optionally substituted.

[0038] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon, consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds, which may include fused or bridged ring systems, having from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, and attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkynyls include cycloheptynyl, cyclooctynyl, and the like. Unless otherwise specified in the specification, cycloalkynyl groups may be optionally substituted.

[0039] As used herein, the term "halo" refers to fluoro, chloro, bromo, or iodo.

[0040] "Haloalkyl" refers to an alkyl, as defined above, substituted by one or more halo radicals, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise in the specification, a haloalkyl group may be optionally substituted.

[0041] "Heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a stable, saturated, unsaturated, or aromatic 3- to 20-membered ring, consisting of 2 to 19 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, attached to the remainder of the molecule by a single bond. Heterocyclyl or heterocyclic rings include heteroaryl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl. Unless otherwise stated herein, a heterocyclyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused, bridged, and spirocyclic ring systems; the nitrogen, carbon, or sulfur atoms of a heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially saturated or fully saturated. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, heterocyclic groups may be optionally substituted.

[0042] "Heteroaryl" refers to a 5- to 20-membered ring system consisting of a hydrogen atom, 1 to 19 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring, attached to the remainder of the molecule by a single bond. For purposes of this disclosure, heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atom of a heteroaryl can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoindolyl, and isoindolyl. These include, but are not limited to, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted.

[0043] "Heterocyclylalkyl" refers to a group of the formula -R b -R e where R b is an alkylene, alkenylene, or alkynylene group as defined above, and R e is a heterocyclyl radical as defined above. Unless stated otherwise in the specification, a heterocyclylalkyl group may be optionally substituted.

[0044] As used herein, the term "substituted" means that in any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and / or heteroaryl), at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, for example, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means that in any of the above groups, one or more hydrogen atoms are replaced by a heteroatom, such as the oxygen of oxo, carbonyl, carboxy, and ester groups, and a higher bond (e.g., a double or triple bond) to the nitrogen of groups such as imine, oxime, hydrazone, and nitrile. For example, "substituted" includes the replacement of one or more hydrogen atoms in any of the above groups by a higher bond (e.g., a double or triple bond) to the nitrogen of groups such as -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NRg C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h "Substituted" also includes replacing one or more hydrogen atoms in any of the above groups with -C(=O)R. g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R g and R hare the same or different and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" also means that in any of the above groups, one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl group, and / or heteroarylalkyl group. In addition, each of the foregoing substituents may be optionally substituted with one or more of the above substituents.

[0045] As used herein, the symbols [ka] (hereinafter sometimes referred to as "bond point") indicates a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the bond point and the other of which is not depicted as being attached to the bond point. For example, [ka] indicates that a chemical entity "XY" is attached to another chemical entity through that point of attachment. Furthermore, specific points of attachment for chemical entities not depicted can be identified by inference. For example, R 3 is H or [ka] The compound CH3-R 3 is R 3 When "XY" is selected, the point of attachment is R 3 is inferred to be the same bond depicted as being attached to CH3.

[0046] compound The present disclosure provides compounds that are agonists of the orexin type 2 receptor, and pharmaceutical compositions thereof, and their uses in treating various diseases and disorders.

[0047] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, n and m are independently 0 or 1; A1 is -O-, -CR4R5-, -NR6-, -S- or a bond; A2 is -C(O)- or -S(O)2-; A3 and A4 are independently -O-, -CR4R5-, -NR6, -S-, a bond, or A3 and A4 together are -C(R4)=C(R5)-; A5 and A6 are independently -O-, -CR4R5-, -NR6, -S- or a bond; provided that the ring containing A2, A3, A4, A5 and A6 does not contain -OO-, -NR6-NR6- or -O-NR6-; L1 is -O-, -CR4R5- or a bond; L2 is -CR4R5, R1 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclyl, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclyl, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, -S(O)2-heteroaryl, -(C=O)NR7R8, or R1 and R2 together with the atoms to which they are attached form a heterocycle or heteroaryl, R2 and R3 are independently hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, or R2 and R3 together with the atoms to which they are attached form a carbocycle or heterocycle; R4 and R5 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, alkoxy, -O-cycloalkyl, -O-heterocyclyl, halogen, or R4 and R5 together with the atoms to which they are attached form a carbocycle or heterocycle; R6 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclyl, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclyl, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, -S(O)2-heteroaryl -(C=O)NR7R8, R7 and R8 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R7 and R8 together with the atoms to which they are attached form a heterocycle; Y is cycloalkyl, heterocyclyl, heteroaryl, or aryl; Z is absent, heteroaryl or aryl.

[0048] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are defined herein.

[0049] In some embodiments, the compound of formula (I) is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are defined herein.

[0050] In some embodiments, the compound of formula (I) is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are defined herein.

[0051] In some embodiments, the compound of formula (I) is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are defined herein.

[0052] In some embodiments, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, and Z are defined herein.

[0053] In some embodiments, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, and Z are defined herein.

[0054] In some embodiments, provided herein is a compound of formula (IV): [ka]

[0055] or a pharmaceutically acceptable salt thereof, wherein n, m, p, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, R A and Z are defined herein. In some embodiments, provided herein are compounds of formula (VA): [ka] or a pharmaceutically acceptable salt thereof, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A , and R B is defined herein.

[0056] In some embodiments, provided herein is a compound of formula (VB): [ka] or a pharmaceutically acceptable salt thereof, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A , and R B is defined herein.

[0057] In some embodiments, provided herein are compounds of formula (VC): [ka] or a pharmaceutically acceptable salt thereof, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A , and R B is defined herein.

[0058] In some embodiments, provided herein is a compound of formula (VI-A): [ka] or a pharmaceutically acceptable salt thereof, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, and R B is defined herein.

[0059] In some embodiments, provided herein is a compound of formula (VI-B): [ka] or a pharmaceutically acceptable salt thereof, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, and R B is defined herein.

[0060] In some embodiments, provided herein is a compound of formula (VI-C): [ka] or a pharmaceutically acceptable salt thereof, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, and R B is defined herein.

[0061] In some embodiments of the compound of Formula (I), (II), (III), or (IV), A1 is -O-, -CR4R5-, -NR6-, -S-, or a bond.

[0062] In some embodiments of the compounds of Formula (I), (II), (III), or (IV), A1 is -CR4R5-.

[0063] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A2 is -C(O)- or -S(O)2-.

[0064] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A2 is —C(O)—.

[0065] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A2 is -S(O)2-.

[0066] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A3 and A4 are independently -O-, -CR4R5-, -NR6, -S-, a bond, or A3 and A4 together are -C(R4)=C(R5)-.

[0067] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A3 and A4 are independently -O-, -CR4R5-, or -NR6.

[0068] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A3 and A4 are independently -O-, or -CR4R5-.

[0069] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A3 is -O-, -CR4R5-, or -NR6. In some embodiments, A3 is -O-. In some embodiments, A3 is -CR4R5-. In some embodiments, A3 is -NR6.

[0070] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A4 is -O-, or -CR4R5-. In some embodiments, A4 is -O-. In some embodiments, A4 is -CR4R5-. In some embodiments, A4 is -O-, -CR4R5-, or -NR6. In an embodiment, A4 is -NR6.

[0071] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A5 and A6 are independently -O-, -CR4R5-, -NR6, -S-, or a bond.

[0072] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A5 is -CR4R5- or a bond. In embodiments, A5 is -CR4R5-. In embodiments, A5 is a bond.

[0073] In some embodiments of the compounds of Formula (I), (II), (III), or (IV), A6 is a bond.

[0074] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A2 is —C(O)— and A3 is —O—.

[0075] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A2 is -S(O)2- and A3 is -NR6.

[0076] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A2 is -C(O)- and A3 and A4 are independently -O- or -CR4R5-.

[0077] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), the ring comprising A2, A3, A4, A5, and A6 does not comprise -OO-, -NR6-NR6-, or -O-NR6-.

[0078] In some embodiments of a compound of Formula (I), (II), (III), or (IV), A5 and A6 are independently -CR4R5- or a bond. In some embodiments, A5 is -CR4R5- and A6 is a bond. In some embodiments, A5 and A6 are both a bond.

[0079] In some embodiments of compounds of Formula (I), (II), (III), or (IV), A2, A3, A4, A5, and A6, together with the atoms to which they are attached, form a 5-membered heterocycle.

[0080] In some embodiments of compounds of Formula (I), (II), (III), or (IV), A2, A3, A4, A5, and A6, together with the atoms to which they are attached, form a 6-membered heterocycle.

[0081] In some embodiments of compounds of Formula (I), (II), (III), or (IV), A2, A3, A4, A5, and A6, together with the atoms to which they are attached, form a 7-membered heterocycle.

[0082] In some embodiments of compounds of Formula (I), (II), (III), or (IV), A2, A3, A4, A5, and A6, together with the atoms to which they are attached, form a 6- or 7-membered heterocycle.

[0083] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), A2 is -C(O)- or -S(O)2-; A3 is -O-, -CR4R5-, or -NR6-; A4 is -CR4R5-, A5 and A6 are bonds.

[0084] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), A2 is -C(O)- or -S(O)2-; A3 and A4 are independently -O-, -CR4R5-, or -NR6-; A5 is -CR4R5-, A6 is a bond.

[0085] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), A2 is -C(O)- or -S(O)2-; A3, A4, and A6 are -CR4R5-; A5 is -O-.

[0086] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), L is -O-, -CR4R5-, or a bond. In some embodiments, L is a bond. In some embodiments, L is -O-.

[0087] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), L2 is -CR4R5. In embodiments, L2 is CH2.

[0088] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclyl, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C ═O)-O-cycloalkyl, -(C═O)-O-heterocyclyl, -(C═O)-O-aryl, -(C═O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, -S(O)2-heteroaryl, -(C═O)NR7R8, or R1 and R2 together with the atoms to which they are attached form a heterocycle or heteroaryl.

[0089] In some embodiments of the compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R is aryl, heteroaryl, —(C═O)C 1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)C 4-6 saturated heterocyclyl, -(C=O)-OC 1-6 Alkyl, -(C=O)-OC 3-6 Cycloalkyl, -(C=O)-OC 4-6 Saturated heterocyclyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-C 4-6 heterocyclyl, -(C=O)NR7R8, or R1 and R2 together with the atoms to which they are attached form a 4- to 7-membered heterocycle or a 5- to 6-membered heteroaryl.

[0090] In some embodiments of the compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R is —(C═O)C1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)C 4-6 saturated heterocyclyl, -(C=O)-OC 1-6 Alkyl, -(C=O)-OC 3-6 Cycloalkyl, -(C=O)-OC 4-6 Saturated heterocyclyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-C 4-6 saturated heterocyclyl, or -(C=O)NR7R8.

[0091] In some embodiments of the compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R is C 1-6 Alkyl, 5- or 6-membered heteroaryl, -(C=O)NR7R8, -(C=O)-OC 1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)C 1-6 Alkyl, -(C=O)C 4-6 saturated heterocyclyl, or -S(O)2-C 1-6 alkyl, and each C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-6 The saturated heterocyclyl and heteroaryl independently optionally contain one or more hydroxy, -C 1-6 Alkyl, -OC 1-6 It is substituted with alkyl or fluoro.

[0092] In some embodiments of the compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R is —(C═O)NR, —(C═O)—OC 1-6 Alkyl, -(C=O)-OC 4-6 In some embodiments, R is -(C=O)NR7R8. In some embodiments, R is -(C=O)-OC 1-6In some embodiments, R is -(C=O)-OC 4-6 It is a saturated heterocyclyl.

[0093] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R is —(C═O)N(H)(C 1-6 alkyl), -(C=O)-OC 1-3 alkyl, or -(C=O)-O-cyclopropyl.

[0094] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R is -(C=O)N(H)(CHCH). In some embodiments, R is -(C=O)-O-CH. In some embodiments, R is -(C=O)-O-cyclopropyl.

[0095] In some embodiments of the compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R is —(C═O)NR, —(C═O)—OC 1-6 alkyl, -(C=O)cyclopropyl optionally substituted with one or more fluoro, -(C=O)-C 1-6 Alkyl-OH, -(C=O)-OC 1-6 Haloalkyl, -C 1-6 Haloalkyl, -(C=O)-C 1-6 Haloalkyl, -(C=O)-C 1-3 Alkyl-OC 1-3 alkyl, -(C=O)-cyclobutyl optionally substituted with one or more fluoro, -(C=O)-azetidin-1-yl optionally substituted with one or more fluoro, -(C=O)-bicyclo[1.1.1]pentan-1-yl optionally substituted with one or more fluoro, -(C=O)- 1-3 Pyridyl substituted with alkyl, optionally C 1-3Alkyl-substituted tetrazolyl, -(C=O)-oxetan-2-yl or -S(O)2-C 1-3 It is alkyl.

[0096] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R2 and R3 are independently hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, or R2 and R3 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring.

[0097] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R and R are independently hydrogen, C 1-5 Alkyl, C 3-6 Cycloalkyl, C 4-6 It is a saturated heterocyclyl, or R2 and R3 together with the atoms to which they are attached form a 3- to 6-membered carbocyclic ring or a 4- to 7-membered saturated heterocyclic ring.

[0098] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R and R are independently hydrogen, fluorine, C 1-5 Alkyl, C 3-6 Cycloalkyl, C 4-6 It is a saturated heterocyclyl, or R2 and R3 together with the atoms to which they are attached form a 3- to 6-membered carbocyclic ring or a 5- to 6-membered saturated heterocyclic ring.

[0099] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R is independently hydrogen, fluorine, C 1-5 Alkyl, C 3-6 Cycloalkyl, C 4-6It is a saturated heterocyclyl, or R2 and R3 together with the atoms to which they are attached form a 3- to 6-membered carbocyclic ring or a 5- to 6-membered saturated heterocyclic ring, and R3 is hydrogen.

[0100] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R and R are independently hydrogen or C 1-5 alkyl, C 1-5 The alkyl is optionally substituted with one or more fluorines.

[0101] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R and R are independently hydrogen, C 1-3 Alkyl, or C 1-3 It is haloalkyl.

[0102] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R2 is an optionally substituted C 1-5 In an embodiment, R2 is an optionally substituted (R)-C alkyl and R3 is hydrogen. 1-5 alkyl and R3 is hydrogen, or in embodiments, R2 is optionally substituted (S)-C 1-5 is alkyl and R3 is hydrogen.

[0103] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R2 and R3 are both hydrogen.

[0104] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R4 and R5 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, alkoxy, -O-cycloalkyl, -O-heterocyclyl, halogen, or R4 and R5 together with the atoms to which they are attached form a carbocycle or heterocycle.

[0105] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R and R are independently hydrogen, C 1-5 Alkyl, C 3-6 Cycloalkyl, C 4-6 Saturated heterocyclyl, C 1-6 Alkoxy, -O-(C=O)C 3-6 Cycloalkyl, -OC 4-6 saturated heterocyclyl, fluorine, or R4 and R5 together with the atoms to which they are attached form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring.

[0106] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R and R are independently hydrogen, halo, or C 1-5 It is alkyl.

[0107] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R4 and R5 are both hydrogen.

[0108] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R6 is hydrogen, C 1-6 Alkyl, C 3-6Cycloalkyl, C 4-6 Saturated heterocyclyl, aryl, heteroaryl, -(C=O)C 1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)C 4-6 Saturated heterocyclyl, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-OC 1-6 Alkyl, -(C=O)-OC 3-6 Cycloalkyl, -(C=O)-OC 4-6 Saturated heterocyclyl, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-C 4-6 It is saturated heterocyclyl, -S(O)2-aryl, -S(O)2-heteroaryl or -(C=O)NR7R8.

[0109] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R6 is hydrogen, C 1-5 Alkyl, C 3-6 Cycloalkyl, C 4-6 saturated heterocyclyl, -(C=O)C 1-6 Alkyl, -(C=O)C 3-6 Cycloalkyl, -(C=O)C 4-6 saturated heterocyclyl, -(C=O)-OC 1-6 Alkyl, -(C=O)-OC 3-6 Cycloalkyl, -(C=O)-OC 4-6 Saturated heterocyclyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-C 4-6 heterocyclyl, or -(C=O)NR7R8.

[0110] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R6 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0111] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R6 is -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclyl, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclyl, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, -S(O)2-heteroaryl, or -(C=O)NR7R8.

[0112] In some embodiments of the compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R6 is hydrogen or alkyl. In some embodiments, R6 is hydrogen.

[0113] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R6 is hydrogen or C 1-5 In some embodiments, R6 is C 1-5 In some embodiments, R6 is CH3.

[0114] In some embodiments, R7 and R8 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R7 and R8 together with the atoms to which they are attached form a heterocycle.

[0115] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R7 and R8 are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-6 heterocyclyl, 5- to 6-membered heteroaryl, or R7 and R8 together with the atoms to which they are attached form a heterocycle.

[0116] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R7 and R8 are independently selected from hydrogen and C 1-6 In some embodiments, R7 is hydrogen and R8 is C 1-6 It is alkyl.

[0117] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R7 and R8 are independently hydrogen or C 1-6 alkyl, or R7 and R8 together with the atoms to which they are attached form a saturated heterocycle, 1-6 The alkyl and saturated heterocycle may independently optionally be one or more fluoro or -OC 1-6 It is substituted with alkyl.

[0118] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R7 and R8 are independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 alkoxy, or R7 and R8 together with the atoms to which they are attached form a saturated 4-membered heterocycle optionally substituted with one or more fluoro.

[0119] In some embodiments of the compounds of Formula (I) or (II), Y is cycloalkyl, heterocyclyl, heteroaryl, or aryl.

[0120] In some embodiments of a compound of Formula (I) or (II), Y is a 3- to 7-membered monocycloalkyl, a 5- to 8-membered bicyclic cycloalkyl, a 4- to 7-membered saturated heterocyclyl, a 5- to 8-membered bicyclic heterocyclyl, a 5- to 6-membered heteroaryl, or phenyl.

[0121] In some embodiments of compounds of Formula (I) or (II), Y is a 3- to 7-membered monocycloalkyl, a 4- to 7-membered saturated heterocyclyl, or a phenyl, wherein the phenyl is optionally substituted with one or more fluoro.

[0122] In some embodiments of compounds of Formula (I) or (II), Y is cyclohexyl, phenyl, or saturated 6-membered heterocyclyl, wherein the phenyl is optionally substituted with one or more fluoro.

[0123] In some embodiments of a compound of Formula (I) or (II), Y is a 3-7 membered monocycloalkyl. In some embodiments, Y is a 5-8 membered bicyclic cycloalkyl. In some embodiments, Y is a 4-7 membered saturated heterocyclyl. In some embodiments, Y is a 5-8 membered bicyclic heterocyclyl. In some embodiments, Y is a 5-6 membered heteroaryl. In some embodiments, Y is phenyl.

[0124] In some embodiments, Y is optionally -(R A ) p is replaced by R A and p are defined herein.

[0125] In some embodiments of a compound of Formula (I), (II), (III), or (IV), Z is absent, heteroaryl, or aryl. In some embodiments of a compound of Formula (I), (II), (III), or (IV), Z is heteroaryl or aryl. In some embodiments, Z is absent, a 5- to 10-membered heteroaromatic, or phenyl. In some embodiments, Z is a 5- to 10-membered heteroaromatic or phenyl. In some embodiments, Z is aryl.

[0126] In some embodiments of compounds of Formula (I), (II), (III), or (IV), Z is a 6-membered heteroaromatic or phenyl, wherein the 6-membered heteroaromatic and phenyl are independently optionally substituted with one or more fluoro.

[0127] In some embodiments of compounds of Formula (I), (II), (III), or (IV), Z is

[0128] [ka] and R B and o are defined herein.

[0129] In some embodiments of compounds of Formula (I), (II), (III), or (IV), Y is cyclohexyl and Z is substituted at the para-position (or 4-position) of Y.

[0130] In some embodiments of compounds of Formula (I), (II), (III), or (IV), Y is phenyl and Z is substituted at the meta position (or 3 position) of Y.

[0131] In some embodiments, Z is optionally -(R B ) o is replaced by R B and o are defined herein.

[0132] In some embodiments of the compounds of Formula (I) or (II), Y is aryl and Z is aryl. In some embodiments, Y and Z are phenyl.

[0133] In some embodiments of the compounds of Formula (I) or (II), Y is cyclohexyl and Z is aryl. In some embodiments, Y is cyclohexyl and Z is phenyl.

[0134] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), n and m are independently 0 or 1. In some embodiments, m and n are 0. In some embodiments, m is 1 and n is 0. In some embodiments, m is 0 and n is 1. In some embodiments, m is 1 and n is 1.

[0135] In some embodiments of a compound of Formula (I), (II), (IV), (VA), (VB), or (VC), p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 0 or 1. In some embodiments, p is 1.

[0136] In some embodiments of a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), o is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 0, 1, or 2.

[0137] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), R A and R Bis independently, at each occurrence, hydroxy, halo, -NO2, -CN, -NR7R8, -CO2R9, -OC(O)R9, -COR9, -C(O)NR7R8, -NR7C(O)R8, -OC(O)NR7R8, -NR7C(O)OR9, -S(O) w R9 (w is 0, 1, or 2), -OSO2R9, -SO3R9, -S(O)2NR7R8, -NR7S(O)2R9, -NR7C(O)NR7R8, -C 1-6 Alkyl-NR7R8, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, and C 2-6 alkynyl.

[0138] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), R A is a halo.

[0139] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), R B is a halo.

[0140] In some embodiments of compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), R is independently at each occurrence hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 It is selected from the group consisting of alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl.

[0141] In some embodiments, the compounds disclosed herein are racemic mixtures. In some embodiments, the compounds disclosed herein are enriched in one enantiomer. In some embodiments, the enriched compounds disclosed herein are substantially free of the other enantiomer. In embodiments, provided herein are (+)-enantiomers of the compounds disclosed herein. In embodiments, provided herein are (-)-enantiomers of the compounds disclosed herein. In some embodiments, the compounds disclosed herein have an enantiomeric excess of about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5% or more, or more, including all subranges and values ​​therebetween. In embodiments, the compounds disclosed herein are enriched in the (+)-enantiomer. In embodiments, the compounds disclosed herein are enriched in the (-)-enantiomer.

[0142] In some embodiments, the compounds of the present disclosure are provided as mixtures of diastereomers. In some embodiments, the diastereomers of the compounds of the present disclosure are provided substantially free of other possible diastereomer(s). In some embodiments, the compounds of the present disclosure are designated as "cis-relative" or "trans-relative" as described herein.

[0143] The present disclosure includes tautomers of any of these compounds.

[0144] In some embodiments, provided herein are one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0145] In some embodiments, provided herein are one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or an enantiomer thereof.

[0146] In some embodiments, provided herein are one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a diastereomer thereof, or a mixture of diastereomers.

[0147] In some embodiments, provided herein is one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a diastereomer or a mixture of diastereomers thereof, or an enantiomer or a mixture of enantiomers thereof.

[0148] In some embodiments, provided herein are one or more compounds selected from Table 1. In some embodiments, provided herein are one or more compounds selected from Table 2. In embodiments, provided herein are compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90-i, 90, 91, 92, or 93. In embodiments, provided herein is compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32.

[0149] In some embodiments, provided herein are one or more pharmaceutically acceptable salts of a compound selected from Table 1. In some embodiments, provided herein are one or more pharmaceutically acceptable salts of a compound selected from Table 2. In embodiments, provided herein are compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90-i, 90, 91, 92, or 93. In embodiments, provided herein are pharmaceutically acceptable salts of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

[0150] composition The present disclosure provides pharmaceutical compositions for modulating an orexin receptor (e.g., orexin type 2 receptor) in a subject. In some embodiments, the pharmaceutical compositions comprise one or more compounds of the present disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments of the present disclosure, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the pharmaceutical composition comprises one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as described herein.

[0153] In embodiments, the pharmaceutical composition comprises Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 21, 22, 23, 24, 25, 26, 27, 28, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90-i, 90, 91, 92, or 93. In embodiments, the pharmaceutical composition comprises one or more compounds selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32, as described herein.

[0154] In some embodiments, the pharmaceutical composition comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof, as described herein.

[0155] In embodiments, the pharmaceutical composition comprises Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90-i, 90, 91, 92, or 93, or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises one or more compounds selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32, or a pharmaceutically acceptable salt thereof, as described herein.

[0156] Some embodiments of the present disclosure provide pharmaceutical compositions comprising one or more compounds of the present disclosure (e.g., compounds of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or adjuvant. The pharmaceutically acceptable excipients and adjuvants are added to the compositions or formulations for various purposes. In some embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprises a pharmaceutically acceptable carrier. In some embodiments, pharmaceutically acceptable carriers include pharmaceutically acceptable excipients, binders, and / or diluents. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, saline, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0157] For the purposes of this disclosure, the compounds of the present disclosure can be formulated into formulations containing pharmaceutically acceptable carriers, adjuvants, and vehicles for administration by various means, including oral, parenteral, inhalation spray, topical, or rectal. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, and intraarterial injections with various infusion techniques. As used herein, intraarterial and intravenous injections include administration via a catheter.

[0158] Generally, the compounds of the present disclosure are administered in a therapeutically effective amount. The amount of compound actually administered will usually be determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0159] Treatment method The compounds of the present disclosure are used in many ways. For example, in some embodiments, the compounds are useful in methods for modulating orexin receptors, such as the orexin type 2 receptor. Thus, in some embodiments, the present disclosure provides the use of any one of the compounds of the foregoing formulas (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1, or a pharmaceutically acceptable salt thereof, for modulating orexin receptor (e.g., orexin type 2 receptor) activity. For example, in some embodiments, the modulation of orexin receptor (e.g., orexin type 2 receptor) activity is in mammalian cells. The modulation of orexin receptor (e.g., orexin type 2 receptor) activity is for the treatment of any of the above-mentioned conditions or diseases in a subject in need thereof (e.g., a mammalian subject, e.g., a human).

[0160] In some embodiments, modulating the activity of an orexin receptor (e.g., an orexin type 2 receptor) is binding. In some embodiments, modulating the activity of an orexin receptor (e.g., an orexin type 2 receptor) is agonizing or stimulating the orexin receptor.

[0161] In some embodiments, the present disclosure provides methods for treating a disease or disorder treatable by administration of an orexin agonist, the methods comprising administering a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1).

[0162] In some embodiments, compounds of the disclosure are used to treat, prevent, ameliorate, control, or reduce the risk of various disorders associated with orexin receptors, including one or more of the following conditions or diseases: narcolepsy, narcoleptic syndrome with narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, endogenous hypersomnia, hypersomnia with excessive daytime sleepiness, sleep awakenings, sleep apnea, hypersomnia with sleep apnea, nocturnal myoclonus, disorders of consciousness, e.g., coma, REM sleep interruptions, jet lag, excessive daytime sleepiness, shift work sleep disorder, dyssomnia, sleep disorder ... hypersomnia associated with depression, affective / mood disorders, substance use, Alzheimer's disease or cognitive impairment, Parkinson's disease, Guillain-Barré syndrome, Kleine-Lewin syndrome, and sleep disorders associated with aging, muscular dystrophy, immune-mediated diseases, Alzheimer's nightfall symptoms, conditions associated with circadian rhythms and mental and physical disorders associated with time zone travel and shift work schedules, fibromyalgia, heart failure, diseases associated with bone loss, sepsis, syndromes characterized by non-restorative sleep and muscle pain or sleep apnea with disordered breathing during sleep, conditions resulting from poor quality sleep, and other diseases associated with general orexin system dysfunction. In some embodiments, the compounds of the present invention are useful for treating, preventing, ameliorating, controlling, or reducing the risk of side effects and complications caused by various conditions, including narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Lewin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness such as coma, anesthesia, or anesthetic antagonists.

[0163] In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof, is used to treat a disease or disorder or condition associated with excessive sleepiness in a subject in need thereof. In some embodiments, the excessive sleepiness is caused by any one of the following: insufficient quality or quantity of nighttime sleep; environmental misalignment of the body's circadian pacemaker (e.g., caused by the need to remain awake at night due to work, e.g., shift work, or personal reasons, e.g., illness, or caring for a minor or elderly family member), e.g., jet lag, shift work, and other circadian rhythm sleep disorders; another underlying sleep disorder, e.g., narcolepsy (e.g., narcolepsy type 1, narcolepsy type 2, probable narcolepsy), sleep apnea (e.g., obstructive sleep apnea, obstructive sleep apnea using continuous positive airway pressure), idiopathic hypersomnia, idiopathic excessive sleepiness, and restless legs syndrome, clinical or atypical depression, tumor, head trauma, anemia, renal failure, hypothyroidism, central nervous system injury, drug abuse, genetic vitamin deficiencies, e.g., biotin deficiency, and certain classes of prescription and over-the-counter medications.

[0164] In some embodiments, a compound of the disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof, is used to treat any one of the following: shift work disorder, shift work sleep disorder, and jet lag. In some embodiments, the methods and uses herein are used to treat any one of the following: narcolepsy type 1, narcolepsy type 2, probable narcolepsy, idiopathic hypersomnia, idiopathic excessive sleepiness, hypersomnolence, hypersomnolence, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea using continuous positive airway pressure), or narcolepsy syndrome with disturbances of consciousness such as coma and narcolepsy-like symptoms, hypersomnolence or hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson's disease ... Excessive daytime sleepiness in Parkinson's disease, Prader-Willi syndrome, depression (depression, atypical depression, major depressive disorder, treatment-resistant depression), ADHD, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea using continuous positive airway pressure), and other insomnia disorders, excessive residual daytime sleepiness in sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea using continuous positive airway pressure), etc. Narcolepsy (e.g., narcolepsy type 1, narcolepsy type 2, probable narcolepsy) can be diagnosed according to diagnostic criteria commonly used in the art, such as the International Classification of Sleep Disorders, Third Edition (ICSD-3) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). In some embodiments, the excessive sleepiness is excessive daytime sleepiness or excessive sleepiness during working hours, or excessive sleepiness or poor quality of sleep caused by the need to stay awake at night due to work (for example, shift work) or personal reasons (for example, caring for sick, minor or elderly family members).In some embodiments, the subject has a disease or disorder or symptom that is accompanied by excessive sleepiness.In some embodiments, the subject is a sleep-deprived subject, a subject with excessive sleepiness, a subject whose regular sleep cycle is disrupted, or a subject who needs to reduce sleepiness.In some embodiments, the present disclosure provides a method for reducing or treating excessive sleepiness. In some embodiments, the excessive sleepiness is caused by narcolepsy type 1, narcolepsy type 2, or idiopathic hypersomnia. In some embodiments, the excessive sleepiness is caused by obstructive sleep apnea despite the use of continuous positive airway pressure (CPAP). In some embodiments, a method for increasing wakefulness in a subject in need thereof is provided. In some embodiments, orexin levels in the subject are intact or partially intact.

[0165] Some embodiments of the present disclosure provide methods for treating a sleep disorder (e.g., those disclosed herein) in a subject in need thereof, the methods comprising administering a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof, is used to treat a subject with a sleep disorder, to treat a sleep disorder, or to treat a symptom of a sleep disorder.

[0166] Some embodiments of the present disclosure provide methods for treating narcolepsy in a subject in need thereof, the methods comprising administering a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof, is used to treat a subject with narcolepsy, to treat narcolepsy, or to treat the symptoms of narcolepsy.

[0167] Some embodiments of the present disclosure provide methods for treating idiopathic hypersomnia (IH) in a subject in need thereof, the methods comprising administering a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or Table 1), or a pharmaceutically acceptable salt thereof, is used to treat a subject with IH, to treat IH, or to treat the symptoms of IH. [Example]

[0168] Having now generally described the present disclosure, it will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the present disclosure and are not intended to limit the invention.

[0169] The compounds of the present disclosure can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art.

[0170] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th Ed., Wiley & Sons, 2006, and Jerry March, Advanced Organic Chemistry, 4 th edition, John Wiley & Sons, publisher, New York, 1992. Abbreviation AcOH acetic acid DCM dichloromethane DIPEA N,N-Diisopropylethylamine DMPU N,N'-Dimethylpropyleneurea DMSO dimethyl sulfoxide EtOAc ethyl acetate IPA Isopropyl Alcohol LDA Lithium diisopropylamide NMO N-methylmorpholine-N-oxide TEA Triethylamine TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran

[0171] general synthesis In embodiments, compounds of the present invention may be synthesized using the following methods: General reaction conditions are given, and reaction products may be purified by commonly known methods, including silica gel chromatography or preparative reverse-phase high pressure liquid chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol, etc.

[0172] In some embodiments, compounds of the present disclosure are designated as "cis-relative" or "trans-relative."

[0173] As used herein, the term "cis-relative" refers to the ring A * " refers to a compound of the present disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in which the amino and -L2-L1-YZ substituents at the carbon labeled with are on the same face of Ring A. It is understood that "cis-relative stereochemistry" at Ring A can be represented herein in the following equivalent manner: [ka] wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are defined herein.

[0174] As used herein, the term "trans-relative" refers to the ring A * and -L2-L1-YZ substituents at the carbon labeled with -L2-L1-YZ are on opposite faces of Ring A. It is understood that "trans-relative stereochemistry" at Ring A can be represented herein in the following equivalent manner: [ka] wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are defined herein.

[0175] Scheme 1: Representative Synthesis of Compounds of the Disclosure [ka]

[0176] As shown in Scheme 1, compounds of formula (I) (n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are defined herein) can be prepared from compounds of formula (IA).

[0177] Compounds of formula (IA) (R0 is -C(O)-OC 1-6 alkyl, for example, —C(O)—O—CH2CH3 or —C(O)—O—CH3, and PG 1 is a protecting group, for example, tert-butyloxycarbonyl (Boc) or carboxybenzyl (Cbz), and n, m, A1, R2, and R3 are defined herein) is reacted in a first step i) with a compound of formula (IB) (L1, L2, Y, and Z are defined herein, LG 1 can be alkylated with a leaving group, e.g., -Cl, -Br, -I, or a sulfonate (e.g., mesylate or tosylate), in the presence of a base, e.g., an alkali metal amide base such as LDA, and a solvent (e.g., DMPU and / or an ether, e.g., THF) cooled (e.g., below about -50°C, or about -78°C). Then, in a second step ii), the R ester can be saponified and decarboxylated by reacting this intermediate with an alkali metal halide salt, e.g., sodium chloride, in the presence of an organic solvent, e.g., DMSO, and water, and heating (e.g., at about or at least about 130°C) to give a compound of formula (IC).

[0178] Alternatively, compounds of formula (IA) (where R is H and PG 1 is a protecting group, for example, tert-butyloxycarbonyl (Boc) or carboxybenzyl (Cbz), and n, m, A1, R2, and R3 are defined herein) is reacted in a first step i) with a base, for example, pyrrolidine, in an aromatic solvent, for example, toluene, and heated (for example, to reflux), and then in a second step ii) to give a compound of formula (IB) (L1, L2, Y, and Z are defined herein, LG 1can be alkylated with a leaving group, such as -Cl, -Br, -I, or a sulfonate (e.g., mesylate or tosylate), and heated (e.g., to about or at least about 85°C) to provide a compound of formula (IC).

[0179] Compounds of formula (IC) can be converted to compounds of formula (ID) by condition A: [ka] In a first step (i), the compound of formula (IC) can be reacted with hydroxylamine hydrochloride in the presence of a tertiary amine base, such as triethylamine or diisopropylethylamine, and an alcohol (e.g., ethanol), and heated (e.g., to about or at least about 90°C). In a second step (ii), this intermediate can then be reacted with TFAA and HO-urea in the presence of a base, such as NaHCO, and a solvent, such as acetonitrile, and heated (e.g., to about or at least about 80°C). In a third step (iii), the resulting intermediate can be reacted with formaldehyde in the presence of a tertiary amine base, such as triethylamine, and a solvent, such as an ethereal solvent, such as THF, and heated (e.g., to about or at least about 70°C). In a fourth step (iv), the resulting intermediate can then be reacted with Zn in the presence of an acid, such as AcOH, and a solvent, such as an alcoholic solvent, such as ethanol, to reduce the nitro group and produce a compound of formula (ID).

[0180] Alternatively, compounds of formula (IC) can be converted to compounds of formula (ID) by condition B: [ka] In a first step i), the compound of formula (IC) can be reacted with an alkylsulfinamide, such as (R)-2-methylpropane-2-sulfinamide, in the presence of a Lewis acid, such as Ti(OEt) and a solvent, such as an ether, such as THF, and heated (e.g., at about or at least about 60°C). In a second step ii), this intermediate can then be reacted with EtOAc in the presence of an alkali metal amide base, such as LDA, and a solvent, such as an ether, such as THF, at low temperature (e.g., about -78°C). In a third step iii), the resulting intermediate ester can be reduced to an alcohol with a hydride reducing agent, such as LiBH, in an ether solvent, such as THF. The sulfinamide group can be cleaved in a fourth step iv) in the presence of an acid, such as HCl, and a solvent, such as an ether solvent, such as dioxane, to produce a compound of formula (ID).

[0181] The compound of formula (ID) can be cyclized to form a compound of formula (IE) under condition A by reacting the compound of formula (ID) with i) a base, for example, dipotassium carbonate and chloroacetyl chloride in the presence of a solvent, for example, an ethereal solvent such as THF, followed by ii) a base, for example, an alkoxide (for example, t-BuOK) in the presence of an alcohol solvent, for example, isopropyl alcohol.

[0182] Alternatively, compounds of formula (ID) can be cyclized to form compounds of formula (IE) by reacting them with triphosgene under condition B in the presence of a tertiary amine base, for example DIPEA, and a solvent, for example a chlorinated solvent such as dichloromethane.

[0183] The compound of formula (IE) can be deprotected to give the compound of formula (IF). PG 1 When PG is Cbz, hydrogenation with, for example, Pd / C and H2 in an alcoholic solvent, such as ethanol, provides a compound of formula (IF). 1When is Boc, the compound of formula (IE) is reacted with an acid in a solvent (for example, with trifluoroacetic acid in dichloromethane or with HCl in methanol) to provide the compound of formula (IF).

[0184] The compound of formula (IF) is reacted with R1-LG 2 (R1 is defined herein and LG 2 can be reacted with a leaving group, for example, -Cl, -Br, -I, or a sulfonate (e.g., mesylate or tosylate), in the presence of a base, for example, a tertiary amine such as triethylamine, in a solvent, for example, dichloromethane, to produce a compound of formula (I).

[0185] Alternatively, a compound of formula (IF) can be prepared by reacting a compound of formula [ka] with an isocyanate in the presence of a base, for example a tertiary amine such as triethylamine, to produce a compound of formula (I).

[0186] Materials and Methods Analysis conditions: [Table 2] [Table 3] [Table 4] [Table 5] Synthesis of (CIS)-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecan-2-one

[0001] (Intermediate 8). [ka] 1-tert-butyl 4-ethyl 3-oxo-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1,4-dicarboxylate (Intermediate 1): [ka]

[0187] To a solution of 4-phenylcyclohexanol (9.65 g, 54.8 mmol) in anhydrous DCM (97 mL) was added paraformaldehyde (1.64 g, 54.8 mmol), followed by chloro(trimethyl)silane (28 mL, 21.9 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was filtered through a pad of NaSO and concentrated in vacuo at 30 °C to give [4-(chloromethoxy)cyclohexyl]benzene as a pale yellow oil. In a separate flask, (diisopropylamino)lithium (2 M in THF) (60 mL, 12.0 mmol) was added over 30 minutes to a stirred solution of 1,3-dimethylhexahydropyrimidin-2-one (26 mL, 21.9 mmol) and 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (14.85 g, 54.8 mmol) in anhydrous THF (200 mL) at −78° C. The solution was maintained at this temperature for 20 minutes. An oil containing [4-(chloromethoxy)cyclohexyl]benzene was added over 15 minutes to the reaction mixture in anhydrous THF (20 mL). The reaction mixture was stirred at −78° C. for 1 hour. The reaction was quenched with saturated aqueous NH4Cl (80 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-20% TBME in heptane) to give the title compound (14.3 g) as a pale orange viscous material. [M+H] + m / z 460.5

[0188] tert-Butyl 3-oxo-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 2) [ka]

[0189] To a solution of Intermediate 1 (14.30 g, 31.1 mmol) in DMSO (90 mL) was added sodium chloride (3.64 g, 62.2 mmol) and water (10 mL). The reaction was heated to 130 °C for 5.5 h. Additional sodium chloride (3.64 g, 62.2 mmol) was added, and the reaction was stirred at 130 °C for 4 h. The reaction mixture was cooled to room temperature and partitioned between EtO (200 mL) and 5% aqueous LiCl (200 mL). The biphasic mixture was separated, and the organic layer was washed with 5% aqueous LiCl (3 × 200 mL). The organic extract was concentrated in vacuo to give an orange oil (11 g). The aqueous layer was re-extracted with ether (300 mL), which was also concentrated in vacuo. The crude material was purified by silica gel column chromatography (0–10% EtOAc in heptane) to give the title compound (8.2 g) as a pale yellow oil. [M+H] + m / z 388.4

[0190] tert-Butyl 3-(hydroxyimino)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 3) [ka]

[0191] A solution of triethylamine (4.3 mL, 31.0 mmol), hydroxylamine hydrochloride (1:1) (2.15 g, 31.0 mmol), and Intermediate 2 (4.00 g, 10.3 mmol) in ethanol (20 mL) was heated to 90° C. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×75 mL). The organic extract was passed through a phase separator and concentrated in vacuo to give the title compound (3.48 g) as a pale yellow foamy viscous material. [M+H]+ m / z 403.4

[0192] tert-Butyl 3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 4). [ka]

[0193] Trifluoroacetic anhydride (3.0 mL, 21.6 mmol) in anhydrous acetonitrile (14 mL) was added to a stirred solution of hydrogen peroxide-urea (1:1) (2.85 g, 30.3 mmol) in anhydrous acetonitrile (14 mL) at 0 °C. The reaction was stirred at 0 °C for 2 h. The resulting solution was added dropwise to a mixture of Intermediate 3 (3.48 g, 8.65 mmol) and NaHCO (3.63 g, 43.2 mmol) in anhydrous acetonitrile (20 mL) at 80 °C, followed by stirring at 80 °C for 1 h. The reaction was cooled to room temperature, quenched with saturated aqueous NaSO, diluted with water (50 mL), and extracted with EtOAc (3 × 75 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO, filtered, and concentrated in vacuo to give a pale yellow gum. The crude material was purified by silica gel column chromatography (0-20% EtOAc in heptane) to give the title compound (1.78 g) as a colorless gum that precipitated to a white solid. [M+H] + m / z 419.4

[0194] tert-Butyl (CIS) 3-(hydroxymethyl)-3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 5). [ka]

[0195] Formaldehyde (aq) (37%, 2.5 mL, 33.3 mmol) was added to a solution of Intermediate 4 (1.55 g, 3.70 mmol) and triethylamine (0.52 mL, 3.70 mmol) in THF (20 mL) at room temperature. The solution was heated to 70 °C for 18 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were concentrated in vacuo, and the crude material was purified by silica gel column chromatography (0-40% EtOAc in heptane) to give the title compound (1.55 g) as a colorless gum. [M+H] + m / z 449.4

[0196] tert-Butyl (CIS)-3-amino-3-(hydroxymethyl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 6). [ka]

[0197] Zinc (1.90 g, 29.0 mmol) was added in three portions to a stirred solution of Intermediate 5 (1.30 g, 2.90 mmol) in ethanol (36 mL) and acetic acid (7.8 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 5 h. The reaction was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated in vacuo, diluted with water, neutralized with saturated aqueous NaHCO3, and extracted with DCM (3 x 25 mL). The organic extract was concentrated in vacuo and purified by silica gel column chromatography (0-5% methanol in DCM) to give the title compound (1.09 g) as a colorless gum. [M+H] + m / z 419.4.

[0198] tert-Butyl (CIS)-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (Intermediate 7) [ka]

[0199] To a solution of intermediate 6 (800 mg, 1.91 mmol) in THF (9 mL) was added dipotassium carbonate (792 mg, 5.73 mmol) in water (8.6 mL) at 0° C. To this mixture was added chloroacetyl chloride (0.17 mL, 2.13 mmol) dropwise at 0° C. The reaction was stirred at 0° C. for 1 h. Additional 2-chloroacetyl chloride (46 μL, 0.578 mmol) was added and the reaction was stirred for 1 h. The mixture was quenched with water, extracted with DCM (2×20 mL), passed through a phase separator, and concentrated in vacuo. This intermediate was dissolved in DCM (17 mL) and potassium 2-methylpropan-2-olate (858 mg, 7.65 mmol) in IPA (17 mL) was added at 0° C. The reaction was allowed to warm to room temperature and stirred for 16 h. The solution was neutralized with 2 M HCl, adjusted to pH 8 with saturated aqueous NaHCO3, diluted with water, and extracted with DCM (3 x 50 mL). The organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-20% methanol in EtOAc) to give the title compound (550 mg) as a colorless gum. [MH] - m / z 457.5.

[0200] (CIS)-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecan-2-one (intermediate 8). [ka]

[0201] TFA (1.3 mL) was added to a solution of Intermediate 7 (550 mg, 1.20 mmol) in DCM (2.6 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (2 x 10 mL). The organic layers were combined, passed through a phase separator, and concentrated in vacuo to give the title compound (400 mg) as a white solid. [MH] - m / z 357.5

[0202] Example 1: (CIS)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (1). [ka] To a stirred solution of triethylamine (0.23 mL, 1.67 mmol) and Intermediate 8 (300 mg, 0.837 mmol) in DCM (12 mL) was added ethyl isocyanate (0.13 mL, 1.67 mmol) at room temperature. The reaction was stirred for 2 h and quenched with 2 M NaOH (10 mL). The mixture was extracted with DCM, and the organic extract was passed through a phase separator and concentrated in vacuo. The crude material was purified by reverse-phase column chromatography (10–70% MeCN in water (0.1% NH)) to give the title compound (228 mg) as a white solid.

[0203] 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 2H), 7.23 - 7.15 (m, 3H), 6.32 (brs, 1H), 4.43 - 4.37 (m, 1H), 4.27 (d, J = 16.8 Hz, 1H), 4.17 - 4.02 (m, 3H), 3.87 - 3.74 (m, 2H), 3.69 - 3.61 (m, 1H), 3.34 (d, J = 11.8 Hz, 1H), 3.25 (q, J = 7.2 Hz, 2H), 3.01 (td, J = 13.0, 3.1 Hz, 1H), 2.61-2.49 (m, 1H), 2.08-1.97 (m, 2H), 1.90 (td, J = 13.5, 4.9 Hz, 1H), 1.85 - 1.50 (m, 9H), 1.13 (t, J = 7.2 Hz, 3H). 1 NH not observed. LCMS (Method A): [M+H] + m / z 430.4, RT 3.19 min

[0204] Example 2: (6R,7S)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (2) and Example 3: (6S,7R)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (3) [ka] Example 1 (209 mg) was subjected to chiral preparative purification using a Waters 600 column, eluting with 80 / 20% v / v n-hexane / ethanol, Chiralpak AS-H (25 x 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compounds (Peak 1, 94.4 mg, 100% ee, and Peak 2, 87 mg, 100% ee). The absolute stereochemistry of each of the separated compounds 2 and 3 was not conclusively identified but has been assigned as shown below.

[0205] Peak 1 (assigned to piperidine 6R,7S); 11H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 8.2, 7.0 Hz, 2H), 7.23 - 7.14 (m, 3H), 6.26 (s, 1H), 4.78 (s, 1H), 4.41 (t, J = 5.4 Hz, 1H), 4.27 (d, J = 16.9 Hz, 1H), 4.16 - 4.03 (m, 3H), 3.86 - 3.72 (m, 2H), 3.65 (t, J = 3.0 Hz, 1H), 3.35 (d, J = 11.8 Hz, 1H), 3.25 (qd, J = 7.2, 5.2 Hz, 2H), 3.01 (td, J = 13.1, 3.5 Hz, 1H), 2.54 (tt, J = 10.5, 5.2 Hz, 1H), 2.06 - 1.98 (m, 2H), 1.91 (td, J = 13.6, 4.9 Hz, 1H), 1.85 - 1.76 (m, 1H), 1.76 - 1.64 (m, 4H), 1.64 - 1.49 (m, 4H), 1.12 (t, J = 7.2 Hz, 3H). LCMS (Method C): [M+H] + m / z 430.3, RT 0.95 min. Chiral analysis (Chiralpak AS-H, 25x0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 8.3 min

[0206] Peak 2 (assigned to 6S,7R of piperidine): 1H NMR (400 MHz, CDCl3) δ 7.29 (dd, J = 8.2, 6.9 Hz, 2H), 7.20 (dt, J = 8.2, 2.0 Hz, 3H), 6.48 (s, 1H), 4.81 (t, J = 5.4 Hz, 1H), 4.40 (dd, J = 7.1, 3.6 Hz, 1H), 4.27 (d, J = 16.8 Hz, 1H), 4.19 - 4.05 (m, 3H), 3.80 (qd, J = 9.8, 5.3 Hz, 2H), 3.64 (p, J = 2.9 Hz, 1H), 3.34 (d, J = 11.8Hz, 1H), 3.25 (qd, J = 7.2, 5.3 Hz, 2H), 2.99 (td, J = 13.1, 3.5 Hz, 1H), 2.54 (tt, J = 10.6, 5.0 Hz, 1H), 2.01 (dq, J = 14.9, 2.9 Hz, 2H), 1.90 (td, J = 13.5, 5.0 Hz, 1H), 1.83 - 1.75 (m, 1H), 1.75 - 1.49 (m, 8H), 1.12 (t, J = 7.2 Hz, 3H). LCMS (Method C): [M+H] + m / z 430.3, RT 0.95 min. Chiral analysis (Chiralpak AS-H, 25x0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 13.7 min.

[0207] Example 4: Methyl (CIS)-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (4) [ka] Methyl carbonochloridate (22 μL, 0.279 mmol) was added to a stirred solution of Intermediate 8 (50 mg, 0.139 mmol) and triethylamine (39 μL, 0.279 mmol) in DCM (2 mL) at room temperature and stirred for 1.5 h. The reaction was cooled to 0 °C, and additional triethylamine (78 μL, 0.558 mmol) and methyl carbonochloridate (86 μL, 1.12 mmol) were added, and the reaction was then stirred for 18 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM (3 × 5 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica gel column chromatography (50–100% EtOAc in heptane, followed by 0–10% methanol in EtOAc) to afford the title compound (21 mg) as a white solid.

[0208] 1 H NMR (500 MHz, CDCl3) δ 7.28 - 7.20 (m, 2H), 7.17 - 7.07 (m, 3H), 6.24 - 5.97 (m, 1H), 4.69 - 4.41 (m, 1H), 4.25 - 3.84 (m, 4H), 3.76 (s, 2H), 3.66 (s, 3H), 3.56 (s, 1H), 3.33 (s, 1H), 3.10 (s, 1H), 2.58 - 2.44 (m, 1H), 2.08 (s, 1H), 2.02 - 1.90 (m, 2H), 1.76 (s, 1H), 1.73 - 1.58 (m, 5H), 1.58 - 1.40 (m, 3H). Rotamers observed. LCMS (Method A): [M+H] + m / z 417.3, RT 3.50 min.

[0209] Example 5: Methyl (6R,7S)-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (5) and Example 6: Methyl (6S,7R)-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (6) [ka] Example 4 (16 mg) was subjected to chiral preparative purification using a Waters 600 column, eluting with 65 / 35% v / v n-hexane / ethanol, Chiralpak AS-H (25 x 2.0 cm), 5 μm, at a flow rate of 17 mL / min to give the title compounds (Peak 1, 4.9 mg, 100% ee, and Peak 2, 4.6 mg, 100% ee). The absolute stereochemistry of each of the isolated compounds 5 and 6 was not conclusively identified but has been assigned as shown below.

[0210] Peak 1 (assigned to 6R,7S of piperidine): 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.29 (m, 2H), 7.25 - 7.17 (m, 3H), 6.11 (brs, 1H), 4.58 (brs, 1H), 4.33 - 4.07 (m, 3H), 4.01 (brs, 1H), 3.84 (brs, 2H), 3.74 (s, 3H), 3.65 (brs, 1H), 3.42 (brs, 1H), 3.21 (brs, 1H), 2.62 - 2.53 (m, 1H), 2.16 (brs, 1H), 2.11 - 2.00 (m, 2H). 1.85 (d, J = 9.46 Hz, 1H), 1.80 - 1.68 (m, 5H), 1.67 - 1.58 (m, 2H). LCMS (Method C): [M+H] + m / z 417.3, RT 1.04 min. Chiral analysis (Chiralpak AS-H, 25x0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 7.5 min.

[0211] Peak 2 (assigned to 6S,7R of piperidine): 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.29 (m, 2H), 7.25 - 7.17 (m, 3H), 6.11 (brs, 1H), 4.58 (brs, 1H), 4.33 - 4.07 (m, 3H), 4.01 (brs, 1H), 3.84 (brs, 2H), 3.74 (s, 3H), 3.65 (brs, 1H), 3.42 (brs, 1H), 3.21 (brs, 1H), 2.62 - 2.53 (m, 1H), 2.16 (brs, 1H), 2.11 - 2.00 (m, 2H), 1.85 (d, J = 9.46 Hz, 1H), 1.80 - 1.68 (m, 5H), 1.67 - 1.58 (m, 2H). LCMS (Method C): [M+H] + m / z 417.3, RT 1.04 min. Chiral analysis (Chiralpak AS-H, 25x0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 11.2 min.

[0212] Example 7: (CIS)-8-cyclopropanecarbonyl-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecan-2-one (7) [ka] Cyclopropanecarbonyl chloride (25 μL, 0.279 mmol) was added to a stirred solution of Intermediate 8 (50 mg, 0.139 mmol) and triethylamine (39 μL, 0.279 mmol) in DCM (2 mL) at room temperature and stirred for 1.5 h. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and extracted with DCM (3 × 5 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica gel column chromatography (100% EtOAc) to afford the title compound (40 mg) as a white solid.

[0213] 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 2H), 7.24 - 7.14 (m, 3H), 6.45 - 6.09 (m, 1H), 5.11 - 4.75 (m, 1H), 4.61 (d, J = 11.1 Hz, 0.5H), 4.26 (t, J = 18.4 Hz, 1H), 4.20 - 4.04 (m, 2H), 3.95-3.77 (m, 2.5H), 3.70 - 3.51 (m, 1.5H), 3.39 (dd, J = 36.2, 12.0 Hz, 1H), 3.00 - 2.83 (m, 0.5H), 2.54 (s, 1H), 2.32 - 1.89 (m, 3H), 1.89 - 1.39 (m, 9H), 1.11 - 0.92 (m, 2H), 0.86 - 0.69 (m, 2H). 1H was exchanged with solvent. LCMS (Method A): [M+H] + m / z 427.3, RT 3.43 min

[0214] Example 8: (6R,7S)-8-Cyclopropanecarbonyl-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecan-2-one (8) and Example 9: (6S,7R)-8-Cyclopropanecarbonyl-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecan-2-one (9) [ka] Example 7 (28 mg) was subjected to chiral preparative purification using a Waters 600 column, eluting with 80 / 20% v / v n-hexane / ethanol, Chiralpak AS-H (25 x 2.0 cm), 5 μm, at a flow rate of 17 mL / min to give the title compounds (Peak 1, 10.5 mg, 100% ee, and Peak 2, 10.3 mg, 100% ee). The absolute stereochemistry of each of the separated compounds 8 and 9 was not conclusively identified but has been assigned as shown below.

[0215] Peak 1 (assigned 6R,7S of piperidine): 1 H NMR (400 MHz, CDCl3) δ 7.44 - 7.30 (m, 2H), 7.26 - 7.15 (m, 3H), 6.17 (d, J = 118.2 Hz, 1H), 4.95 (d, J = 117.3 Hz, 1H), 4.69 - 2.87 (m, 9H), 2.58 (s, 1H), 2.37 - 1.66 (m, 13H), 1.16 - 0.95 (m, 2H), 0.91 - 0.68 (m, 2H). LCMS (Method C): [M+H] + m / z 427.3, RT 1.02 min. Chiral analysis (Chiralpak AS-H, 25x0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 11.0 min.

[0216] Peak 2 (assigned 6S,7R of piperidine): 1 HNMR (500 MHz, CDCl3) δ 7.36 - 7.30 (m, 2H), 7.26 - 7.17 (m, 3H), 6.17 (d, J = 119.9 Hz, 1H), 4.95 (d, J = 117.5 Hz, 1H), 4.68 - 2.86 (m, 9H), 2.58 (s, 1H), 2.37 - 1.61 (m, 13H), 1.10 - 0.95 (m, 2H), 0.92 - 0.71 (m, 2H). LCMS (Method C): [M+H] + m / z 427.3, RT 1.02 min. Chiral analysis (Chiralpak AS-H, 25x0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 18.9 min.

[0217] Example 10: (CIS)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (10) [ka] tert-Butyl (CIS)-2-oxo-6-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.5]decane-7-carboxylate (Intermediate 9) [ka]

[0218] N-Ethyl-N-(propan-2-yl)propan-2-amine (68 μL, 0.392 mmol) was added to a stirred solution of Intermediate 6 (164 mg, 0.392 mmol) and bis(trichloromethyl)carbonate (116 mg, 0.392 mmol) in anhydrous DCM (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then quenched with saturated aqueous NaHCO (1 mL) and purged with N (g) for 30 min using a 20% NaOH scrubber to quench excess phosgene gas. The solution was extracted with DCM (2×5 mL), passed through a phase separator, and concentrated in vacuo to give the title compound (219 mg) as a white gum. [M+NH] + m / z 462.4

[0219] (CIS)-6-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.5]decan-2-one (Intermediate 10) [ka]

[0220] Trifluoroacetic acid (1.0 mL, 13.1 mmol) was added to a stirred solution of Intermediate 9 (174 mg, 0.391 mmol) in DCM (1 mL) at room temperature and stirred for 1 h. The reaction was neutralized with saturated aqueous NaHCO3 and extracted with DCM (3 x 5 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give the title compound (207 mg) as a white solid. [M+H] + m / z 345.3.

[0221] (CIS)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (10) [ka]

[0222] Ethyl isocyanate (0.24 mL, 3.00 mmol) was added to a stirred solution of triethylamine (0.25 mL, 1.80 mmol) and Intermediate 10 (207 mg, 0.601 mmol) in DCM (8 mL) at room temperature and stirred for 30 min. The reaction was quenched with 2 M aqueous NaOH, stirred for 20 min, and then extracted with DCM (3 x 5 mL). The organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by reverse-phase column chromatography (10-100% MeCN in water (0.1% NH)) to give the title compound (55 mg) as a white solid.

[0223] 1 H NMR (500 MHz, CDCl3) δ 7.33 - 7.27 (m, 2H), 7.23 - 7.16 (m, 3H), 6.10 (s, 1H), 4.93 (brs, 1H), 4.32 (d, J = 8.9 Hz, 1H), 4.20 (t, J = 5.8 Hz, 1H), 4.11 (d, J = 8.9 Hz, 1H), 3.98 (dd, J = 13.5, 3.9 Hz, 1H), 3.77 - 3.69 (m, 2H), 3.66 (p, J = 3.0 Hz, 1H), 3.24 (qd, J = 7.2, 3.0 Hz, 2H), 2.87 (td, J = 13.1, 2.8 Hz, 1H), 2.58 - 2.50 (m, 1H), 2.08 - 1.90 (m, 3H), 1.85 - 1.63 (m, 7H), 1.62 - 1.44 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H). LCMS (Method A): [M+H] + m / z 416.3, RT 3.31 min.

[0224] Example 11: (CIS)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (Example 11) and Example 12: (Trans)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (Example 12) [ka] tert-Butyl-3-{[(R)-2-methylpropane-2-sulfinyl]imino}-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 11) [ka]

[0225] Titanium(4+) tetraethanolate (4.1 mL, 19.7 mmol) was added to a stirred solution of Intermediate 2 (3.82 g, 9.86 mmol) and (R)-2-methylpropane-2-sulfinamide (1.19 g, 9.86 mmol) in THF (62 mL) at room temperature, and the solution was then heated at 60 °C for 2 h. The reaction was cooled to room temperature, poured into saturated aqueous NaHCO (100 mL), and filtered through a pad of Celite, which was washed with DCM (2 x 50 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were concentrated in vacuo and purified by silica gel column chromatography (0-60% EtOAc in heptane) to give the title compound (2.47 g) as an orange gum. [M+H] + m / z 491.5

[0226] tert-Butyl 3-(2-ethoxy-2-oxoethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 12) [ka]

[0227] Lithium diisopropylamide solution (2 M in THF) (24 mL, 48.3 mmol) was added to a stirred solution of EtOAc (4.7 mL, 48.3 mmol) in anhydrous THF (24 mL) at −78°C, and the mixture was stirred for 30 min. A solution of Intermediate 11 (2.37 g, 4.83 mmol) in anhydrous THF (2 × 10 mL) was added dropwise to the above mixture at −78°C and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NH₄Cl (20 mL), extracted with EtOAc (3 × 25 mL), and the organic layer was passed through a phase separator. The organic extract was concentrated in vacuo and purified by silica gel column chromatography (0–100% EtOAc in heptane) to give the title compound (1.43 g) as a solid gum. [M+H] + m / z 579.6.

[0228] tert-Butyl 3-(2-hydroxyethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 13) [ka]

[0229] Lithium tetrahydroborate solution (2 M in THF) (6 mL, 12.6 mmol) was added dropwise to a stirred solution of Intermediate 12 (1.46 g, 2.51 mmol) in THF (23 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was heated at 50° C. for 2 hours and then cooled to room temperature. Additional lithium tetrahydroborate (2 M in THF) (2.5 mL, 5.03 mmol) was added and the solution was heated at 50° C. for 2 hours, then at 60° C. for 1 hour. The reaction was cooled to room temperature and carefully quenched with water (25 mL), followed by saturated aqueous NH4Cl (25 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography (40-100% EtOAc in heptane, then 0-10% methanol in EtOAc) to give the title compound (755 mg) as a yellow gum. [M+H] + m / z 537.5

[0230] tert-Butyl 3-amino-3-(2-hydroxyethyl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 14) [ka]

[0231] Hydrogen chloride (4 M in dioxane) (1.0 mL, 4.05 mmol) was added dropwise to a stirred solution of Intermediate 13 (725 mg, 1.35 mmol) in methanol (34 mL) at 0 °C and stirred at 0 °C for 4 h. The reaction was placed in a refrigerator overnight and quenched with saturated aqueous NaHCO at 0 °C, after which the methanol was removed in vacuo. The aqueous solution was then extracted with DCM:methanol (9:1, 3 x 25 ml). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give the crude material. This crude material was purified by silica gel column chromatography (0-2% methanol in DCM) to give the title compound as a 4:1 mixture of cis and trans diastereomers (529 mg) as a pale yellow gum. [M+H] + m / z 433.7

[0232] tert-Butyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (Intermediate 15) [ka]

[0233] N-Ethyl-N-(propan-2-yl)propan-2-amine (0.21 mL, 1.22 mmol) was added to a stirred solution of Intermediate 14 (529 mg, 1.22 mmol) and bis(trichloromethyl)carbonate (363 mg, 1.22 mmol) in anhydrous DCM (16 mL) at 0 °C. The reaction was stirred at 0 °C for 1.5 h, then quenched with saturated aqueous NaHCO (1 mL) and purged with N (g) for 30 min using a 20% NaOH scrubber to quench excess phosgene gas. The solution was extracted with DCM (3 × 10 mL), passed through a phase separator, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (50–100% EtOAc in heptane) to give the title compound as a diastereomeric mixture (326 mg) as a colorless gum. [M+H] + m / z 459.4

[0234] 7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecan-2-one (Intermediate 16) [ka]

[0235] A solution of trifluoroacetic acid (1.5 mL, 19.6 mmol) and Intermediate 15 (163 mg, 0.355 mmol) in DCM (3 mL) was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM (3 x 5 mL). The organic extracts were passed through a phase separator and concentrated in vacuo to give the title compound (diastereomeric mixture) in quantitative yield as a colorless gum. [M+H] + m / z 359.3

[0236] (CIS)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (11) and

[0237] (Trans)-N-Ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (12) [ka]

[0238] Intermediate 16 was dissolved in DCM (3 mL), and triethylamine (99 μL, 0.711 mmol) and then ethyl isocyanate (56 μL, 0.711 mmol) were added sequentially at room temperature. The reaction was stirred for 2 hours, quenched with 2 M NaOH, and extracted with DCM. The organic extract was passed through a phase separator and concentrated in vacuo. The crude material was purified by reverse-phase column chromatography (10-60% MeCN in water (0.1% NH)) to afford 128 mg of the title compound (Example 11) as a white solid and 18 mg of (Example 12) as a pale yellow solid.

[0239] 1 H NMR (400 MHz, CDCl3) δ 7.33 - 7.27 (m, 2H), 7.23 - 7.14 (m, 3H), 6.02 (s, 1H), 4.42 - 4.19 (m, 3H), 3.91 (d, J = 11.9 Hz, 1H), 3.87 - 3.73 (m, 2H), 3.69 - 3.61 (m, 1H), 3.31 - 3.13 (m, 2H), 3.08 - 2.94 (m, 1H), 2.60 - 2.46 (m, 1H), 2.30 - 2.20 (m, 1H), 2.07 - 1.91 (m, 3H), 1.77 - 1.61 (m, 8H), 1.61 - 1.47 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). 1H was exchanged with solvent. LCMS (Method A): [M+H] + m / z 430.4, RT 3.15 min (Example 11)

[0240] 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 2H), 7.22 - 7.15 (m, 3H), 5.88 - 5.80 (m, 1H), 4.40 - 4.27 (m, 2H), 4.14 (dd, J = 13.1, 4.2 Hz, 1H), 3.96 - 3.89 (m, 1H), 3.75 - 3.54 (m, 3H), 3.23 (q, J = 7.2 Hz, 2H), 2.90 (td, J = 13.2, 3.3 Hz, 1H), 2.61 - 2.46 (m, 1H), 2.14 - 2.01 (m, 1H), 2.01 - 1.73 (m, 6H), 1.72 - 1.64 (m, 5H), 1.63 - 1.44 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H). 1H was exchanged with solvent. LCMS (Method A): [M+H] + m / z 430.4, RT 3.40 min (Example 12)

[0241] Example 13: (6S,7S)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (13) Example 14: (6R,7R)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (14) [ka] Example 11 (109 mg) was subjected to chiral preparative purification using a Waters 600 column, eluting with 70 / 30% v / v n-hexane / ethanol, Chiralpak AS-H (25 x 2.0 cm), 5 μm, at a flow rate of 17 mL / min to give the title compounds (Peak 1, 70.2 mg, 100% ee, and Peak 2, 26.4 mg, 100% ee). The absolute stereochemistry of each of the separated compounds 13 and 14 was not conclusively identified but has been assigned as shown below.

[0242] Peak 1 (assigned to piperidine 6S,7S); 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 7.0 Hz, 2H), 7.21 (d, J = 7.5 Hz, 3H), 5.54 - 5.35 (m, 1H), 4.74 (brs., 1H), 4.34 (dd, J = 4.9, 3.6 Hz, 3H), 3.78 (d, J = 3.5 Hz, 1H), 3.91 - 3.77 (m, 3H), 3.66 (brs., 1H), 3.31 - 3.18 (m, 2H), 3.17 - 3.06 (m, 1H), 2.56 (t, J = 7.6 Hz, 1H), 2.24 (d, J = 13.9 Hz, 1H), 1.97 - 2.09 (m, 3H), 1.71 (brs., 8H), 1.59 (d, J = 2.4 Hz, 1H), 1.13 (t, J = 7.1 Hz, 3H). LCMS (Method C): [M+H] + m / z 430.3, RT 0.96 min. Chiral analysis (Chiralpak AS-H, 25x0.46 cm, 5 μm, 70:30 n-hexane:ethanol): RT 6.4 min.

[0243] Peak 2 (assigned to 6R,7R of piperidine): 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 7.0 Hz, 2H), 7.21 (d, J = 7.5 Hz, 3H), 5.35 (s, 1H), 4.78 - 4.68 (m, 1H), 4.46 - 4.26 (m, 3H), 3.82 - 3.77 (m, 1H), 3.91 - 3.76 (m, 3H), 3.66 (t, J = 2.6 Hz, 1H), 3.32 - 3.18 (m, 2H), 3.18 - 3.06 (m, 1H), 2.56 (dt, J = 15.7, 7.7 Hz, 1H), 2.24 (d, J = 13.9 Hz, 1 H), 2.08 - 1.97 (m, 3H), 1.78 - 1.68 (m, 8H), 1.65 - 1.59 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H). LCMS (Method C): [M+H] + m / z 430.3, RT 0.96 min. Chiral analysis (Chiralpak AS-H, 25x0.46 cm, 5 μm, 70:30 n-hexane:ethanol): RT 11.7 min.

[0244] Example 15: (CIS)-N-ethyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (15) [ka] 1-Benzyl 3-ethyl 4-oxo-5-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1,3-dicarboxylate (Intermediate 17) [ka]

[0245] To a solution of 4-phenylcyclohexanol (5.00 g, 28.4 mmol) in anhydrous DCM (67 mL) was added paraformaldehyde (0.85 g, 28.4 mmol), followed by chloro(trimethyl)silane (14 mL, 0.113 mol), and the mixture was stirred at room temperature for 2 h. The reaction was filtered through sodium sulfate and concentrated in vacuo at 30 °C to give a colorless oil of 4-(chloromethoxy)cyclohexylbenzene. In a separate flask, 2 M (diisopropylamino)lithium (2 M in THF) (31 mL, 62.4 mmol) was added to a stirred solution of 1-benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (8.26 g, 28.4 mmol) in anhydrous THF (50 mL) and DMPU (14 mL, 0.113 mol) at −78 °C. The reaction mixture was stirred at this temperature for 20 min. An oil of [4-(chloromethoxy)cyclohexyl]benzene in anhydrous THF (15 mL) was added to the reaction mixture at -78 °C, and the mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) followed by water (50 mL) and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (5.2 gm) as a pale yellow oil. [M+H] + m / z 480.2

[0246] Benzyl 3-oxo-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate (Intermediate 18) [ka]

[0247] To a solution of Intermediate 17 (30%, 5.00 g, 3.13 mmol) in DMSO (15 mL) was added sodium chloride (362 mg, 6.20 mmol) and water (1.5 mL), and the reaction mixture was heated to 130 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with TBME (2 x 50 mL). The combined organic layers were washed with water (3 x 25 mL), brine (50 mL), dried over NaSO, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (1.96 g) as a pale yellow oil. [M+H] + m / z 408.2

[0248] Benzyl 3-(hydroxyimino)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate (Intermediate 19) [ka]

[0249] A solution of triethylamine (2.0 mL, 14.4 mmol), hydroxylamine hydrochloride (1:1) (1.00 g, 14.4 mmol), and Intermediate 18 (1.96 g, 4.81 mmol) in ethanol (9.3193 mL) was heated to 90 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO, filtered, and concentrated in vacuo to give the title compound (2 g) as a pale yellow sticky oil. [M+H] + m / z 423.2

[0250] Benzyl 3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate (Intermediate 20) [ka]

[0251] Trifluoroacetic anhydride (1.6 mL, 11.8 mmol) in anhydrous acetonitrile (8 mL) was added to a stirred solution of hydrogen peroxide-urea (1:1) (1.56 g, 16.6 mmol) in anhydrous acetonitrile (8 mL) at 0 °C. The reaction was stirred at 0 °C for 2 h. The resulting solution was added dropwise to a mixture of Intermediate 19 (2.00 g, 4.73 mmol) and NaHCO (1.99 g, 23.7 mmol) in anhydrous acetonitrile (11 mL) at room temperature. The mixture was then heated to 80 °C and then stirred at 80 °C for 1 h. The reaction was cooled to room temperature, quenched with saturated aqueous NaSO, diluted with water (50 mL), and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO, filtered, and concentrated in vacuo to give a pale yellow gum. The crude material was purified by silica gel column chromatography (0-60% EtOAc in heptane) to give the title compound (1.27 g) as a colorless oil. [M+H] + m / z 439.3

[0252] Benzyl (CIS)-3-(hydroxymethyl)-3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate (Intermediate 21) [ka]

[0253] Formaldehyde (aq) (37%, 1.9 mL, 26.1 mmol) was added to a solution of Intermediate 20 (1.27 g, 2.90 mmol) and triethylamine (0.48 mL, 3.48 mmol) in THF (16 mL) at room temperature. The solution was heated to 70 °C for 3.5 h. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (7-70% EtOAc in heptane) to give the title compound (510 mg) as a viscous colorless oil. [M+H] +m / z 469.1

[0254] Benzyl (CIS) 3-amino-3-(hydroxymethyl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate (Intermediate 22) [ka]

[0255] A solution of Intermediate 21 (500 mg, 1.07 mmol) and zinc (698 mg, 10.7 mmol) in acetic acid (5 mL) and ethanol (35 mL) was stirred at room temperature for 18 hours. The reaction was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated in vacuo, neutralized with saturated aqueous NaHCO3, and extracted with DCM (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated to give the title compound as a sticky brown foam in quantitative yield. [M+H] + m / z 439.1.

[0256] Benzyl (CIS)-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (Intermediate 23) [ka]

[0257] To a solution of intermediate 22 (300 mg, 0.684 mmol) in THF (3 mL) was added dipotassium carbonate (284 mg, 2.05 mmol) followed by water (3 mL) at 0° C. To this mixture was added chloroacetyl chloride (76 μL, 0.958 mmol) dropwise at 0° C. The reaction was stirred at 0° C. for 1 hour. The mixture was quenched with water and extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give an oily residue. This intermediate was dissolved in DCM (6 mL) and IPA (6 mL), cooled to 0° C., potassium 2-methylpropan-2-olate (307 mg, 2.74 mmol) was added, and the reaction was stirred at 0° C. for 1 hour. The mixture was quenched with water (10 mL) and allowed to stand at room temperature for 40 hours. The mixture was poured into saturated aqueous NaHCO3 (20 mL). After extraction with DCM (3 x 20 mL), the combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give a pale yellow oil. The residue was purified by silica gel column chromatography (10-100% EtOAc in heptane) to give the title compound (170 mg) as a colorless oil. [M+H] + m / z 479.1

[0258] (CIS)-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one (Intermediate 24) [ka]

[0259] Intermediate 23 (150 mg, 0.313 mmol) was dissolved in ethanol (15 mL) and the atmosphere was evacuated and filled with nitrogen three times. Palladium on carbon (10%, 15 mg, 0.313 mmol) was added and the atmosphere was evacuated and filled with hydrogen three times. The reaction was stirred for 2 hours, then filtered through Celite, washed with EtOAc, and concentrated in vacuo to give the title compound (75 mg) as a light brown gum. [M+H] + m / z 345.33

[0260] (CIS)-N-ethyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (Example 15) [ka]

[0261] Ethyl isocyanate (18 μL, 0.232 mmol) was added to a solution of triethylamine (32 μL, 0.232 mmol) and Intermediate 24 (40 mg, 0.116 mmol) in anhydrous DCM (0.8 mL) at room temperature. The reaction was stirred for 1 h, then quenched with 2 M aqueous NaOH and extracted with DCM (3 × 10 mL). The organic layers were combined, washed with brine (25 mL), passed through a phase separator, and concentrated in vacuo. The crude material was purified by reverse-phase column chromatography (10–60% MeCN in water (0.1% NH)) to give the title compound (29 mg) as a white solid.

[0262] 1H NMR (400 MHz, CDCl3) δ 7.35 - 7.28 (m, 2H), 7.24 - 7.17 (m, 3H), 6.41 (s, 1H), 4.45 (s, 1H), 4.25 (d, J = 16.7 Hz, 1H), 4.18 (d, J = 16.7 Hz, 1H), 4.09 (t, J = 2.3 Hz, 1H), 3.99 (dd, J = 10.3, 2.1 Hz, 1H), 3.73 (d, J = 11.7 Hz, 1H), 3.69 - 3.64 (m, 1H), 3.61 (dd, J = 10.3, 3.0 Hz, 1H), 3.55 (d, J = 11.7 Hz, 1H), 3.51 - 3.42 (m, 1H), 3.38 - 3.18 (m, 3H), 2.56 (tt, J = 10.9, 5.3 Hz, 1H), 2.44 - 2.30 (m, 1H), 2.28 - 2.15 (m, 1H), 2.12 - 1.95 (m, 2H), 1.80 - 1.44 (m, 6H), 1.13 (t, J = 7.2 Hz, 3H). LCMS (Method A): [M+H] + m / z 416.4, RT 3.07 min.

[0263] Example 16: (1R,5S)-N-ethyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (16) Example 17: (1S,5R)-N-ethyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (17) [ka] Example 15 (22 mg) was subjected to chiral preparative purification using a Waters 600 column, eluting with 80 / 20% v / v n-hexane / ethanol, Chiralpak AD-H (25 x 2.0 cm), 5 μm, at a flow rate of 17 mL / min to give the title compounds (Peak 1, 9.4 mg, 100% ee, and Peak 2, 9.1 mg, 100% ee). The absolute stereochemistry of each of the isolated compounds 16 and 17 was not conclusively identified but has been assigned as shown below.

[0264] Peak 1 (assigned to 1R,5S of pyrrolidine); 1 H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 8.1, 6.9 Hz, 2H), 7.24 - 7.16 (m, 3H), 6.37 (s, 1H), 4.42 (s, 1H), 4.30 - 4.13 (m, 2H), 4.07 (t, J = 2.6 Hz, 1H), 3.98 (dd, J = 10.4, 2.3 Hz, 1H), 3.72 (d, J = 11.7 Hz, 1H), 3.65 (q, J = 2.9 Hz, 1H), 3.60 (dd, J = 10.3, 3.0 Hz, 1H), 3.54 (d, J = 11.7 Hz, 1H), 3.45 (td, J = 9.5, 1.9 Hz, 1H), 3.36 - 3.17 (m, 3H), 2.61 - 2.49 (m, 1H), 2.42 - 2.29 (m, 1H), 2.24 - 2.15 (m, 1H), 2.07 - 1.98 (m, 2H), 1.77 - 1.45 (m, 6H), 1.12 (t, J = 7.2 Hz, 3H). LCMS (Method C): [M+H] + m / z 416.3, RT 0.94 min. Chiral analysis (Chiralpak AD-H, 25x0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 9.5 min.

[0265] Peak 2 (assigned to 1S,5R of pyrrolidine): 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 2H), 7.24 - 7.16 (m, 3H), 6.37 (s, 1H), 4.42 (s, 1H), 4.28 - 4.12 (m, 2H), 4.07 (t, J = 2.5 Hz, 1H), 3.98 (dd, J = 10.4, 2.3 Hz, 1H), 3.72 (d, J = 11.7 Hz, 1H), 3.65 (t, J = 2.9 Hz, 1H), 3.60 (dd, J = 10.3, 3.0 Hz, 1H), 3.54 (d, J = 11.7 Hz, 1H), 3.45 (td, J = 9.6, 2.0 Hz, 1H), 3.37 - 3.17 (m, 3H), 2.63 - 2.50 (m, 1H), 2.43 - 2.31 (m, 1H), 2.24 - 2.15 (m, 1H), 2.07 - 1.98 (m, 2H), 1.78 - 1.44 (m, 6H), 1.12 (t, J = 7.2 Hz, 3H). LCMS (Method C): [M+H] + m / z 416.3, RT 0.94 min. Chiral analysis (Chiralpak AD-H, 25x0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 14.7 min.

[0266] Example 18: (CIS)-N-ethyl-2-oxo-6-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.4]nonane-7-carboxamide (18) [ka] Benzyl (CIS)-2-oxo-6-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.4]nonane-7-carboxylate (Intermediate 25) [ka]

[0267] N-Ethyl-N-(propan-2-yl)propan-2-amine (50 μL, 0.286 mmol) was added to a stirred solution of Intermediate 22 (110 mg, 0.251 mmol) and bis(trichloromethyl)carbonate (74 mg, 0.251 mmol) in anhydrous DCM (3 mL) at 0° C. The reaction was stirred at 0° C. for 1 h, then quenched with saturated aqueous NaHCO (1 mL) and purged with N (g) for 30 min using a 20% NaOH scrubber to quench excess phosgene gas. The solution was extracted with DCM (3×3 mL), passed through a phase separator, and concentrated in vacuo to give a gum. The crude material was purified by silica gel column chromatography (0–50% EtOAc in heptane) to give the title compound (57 mg) as a white gum. [M+H] + m / z 465.4

[0268] (CIS)-6-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.4]nonan-2-one (Intermediate 26) [ka]

[0269] A stirred solution of Intermediate 25 (57 mg, 0.123 mmol) and palladium on carbon (10%, 13 mg, 0.123 mmol) in ethanol (6 mL) was stirred at room temperature under a hydrogen atmosphere. The reaction was stirred for 2 hours, then filtered through a pad of Celite, washed with methanol, and concentrated in vacuo to give the title compound (39 mg) as a white residue. [M+H] + m / z 331.3

[0270] (CIS)-N-ethyl-2-oxo-6-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.4]nonane-7-carboxamide (18) [ka]

[0271] To a stirred solution of triethylamine (28 μL, 0.201 mmol) and Intermediate 26 (33 mg, 0.100 mmol) in DCM (1.5 mL) was added ethyl isocyanate (16 μL, 0.202 mmol) at room temperature. The reaction was stirred for 1 h and quenched with 2 M aqueous NaOH (3 mL). The mixture was extracted with DCM (3 × 3 mL), and the organic extract was passed through a phase separator and concentrated in vacuo. The crude material was purified by reverse-phase column chromatography (10–60% MeCN in water (0.1% NH)) to give the title compound (17 mg) as a white solid.

[0272] 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 2H), 7.22 - 7.15 (m, 3H), 5.51 (s, 1H), 4.59 (s, 1H), 4.32 (d, J = 8.6 Hz, 1H), 4.23 (d, J = 8.6 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.66 - 3.63 (m, 1H), 3.61 (dd, J = 11.0, 4.2 Hz, 1H), 3.43 (td, J = 9.3, 2.2 Hz, 1H), 3.36 - 3.18 (m, 3H), 2.61 - 2.45 (m, 2H), 2.14 (ddd, J = 12.3, 7.2, 2.1 Hz, 1H), 2.06 - 1.93 (m, 2H), 1.77 - 1.44 (m, 6H), 1.12 (t, J = 7.2 Hz, 3H). LCMS (Method A): [M+H] + m / z 402.5, RT 3.02 min

[0273] Example 19: Methyl 7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate [ka] tert-Butyl 2-({[1,1'-biphenyl]-3-yl}methyl)-3-oxopiperidine-1-carboxylate (Intermediate 27) [ka]

[0274] A solution of pyrrolidine (6.3 mL, 75.3 mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (10 g, 50.2 mmol) in toluene (150 mL) was heated to reflux for 1.5 h using a Dean-Stark trap. The reaction mixture was cooled to room temperature and evaporated to dryness to give the crude material. This was dissolved in acetonitrile (100 mL) and reacted with 3-(bromomethyl)biphenyl (14.88 g, 60.2 mmol) in acetonitrile (50 mL) at room temperature, and the mixture was heated at 85 °C for 16 h. The reaction mixture was cooled to room temperature and evaporated to give the crude material. This was dissolved in water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and evaporated to dryness to give the crude material. The crude material was purified by silica gel column chromatography (0-20% EtOAc in heptane) to give the title compound (14 g) as an orange oil. [M+Na] + m / z 388.2

[0275] tert-Butyl-2-({[1,1'-biphenyl]-3-yl}methyl)-3-{[(R)-2-methylpropane-2-sulfinyl]imino}piperidine-1-carboxylate (Intermediate 28) [ka]

[0276] Intermediate 27 (2.50 g, 6.84 mmol), 2-methylpropane-2-sulfinamide (0.83 g, 6.84 mmol), and titanium(4+) tetraethanolate (2.9 mL, 13.7 mmol) were dissolved in THF (50 mL). The solution was heated at 60 °C under a N2(g) atmosphere for 3 h. The reaction was cooled to room temperature, poured into saturated aqueous NaHCO3 (25 mL), and filtered through a pad of Celite, which was washed with DCM (2 x 25 mL). The organic layer was separated, the aqueous phase extracted with DCM (2 x 25 mL), and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-60% EtOAc in heptane) to give the title compound (2.35 g) as a yellow oil. [M+H] + m / z 469.5.

[0277] tert-Butyl 2-({[1,1'-biphenyl]-3-yl}methyl)-3-(2-ethoxy-2-oxoethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylate (Intermediate 29) [ka]

[0278] A 2M solution of lithium dipropan-2-ylazanide (21 mL, 42.7 mmol) was added to a stirred solution of EtOAc (4.2 mL, 42.7 mmol) in THF (20 mL) at −78° C., and the mixture was stirred for 30 min. A solution of Intermediate 28 (2.00 g, 4.27 mmol) in anhydrous THF (10 mL) was added dropwise to the above mixture at −78° C. and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) followed by water (20 mL) at −78° C., warmed to room temperature, and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and evaporated to dryness to give the crude material. The crude material was purified by silica gel column chromatography (0–100% EtOAc in heptane) to give the title compound (1.4 g) as a pale orange oil. [M+H] +m / z 557.6

[0279] tert-Butyl 2-({[1,1'-biphenyl]-3-yl}methyl)-3-(2-hydroxyethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylate (Intermediate 30) [ka]

[0280] A solution of lithium tetrahydroborate (4 M in THF) (900 μL, 3.60 mmol) was added dropwise to a stirred solution of Intermediate 29 (1.26 g, 2.26 mmol) in anhydrous THF (18 mL) at 0° C. and stirred for 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Additional lithium tetrahydroborate (4 M in THF) (2.0 mL, 8.00 mmol) was added and stirred at room temperature for 18 hours. Additional 4 M lithium tetrahydroborate in THF (2.0 mL, 8.00 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was treated with additional lithium tetrahydroborate (4 M in THF) (4.0 mL, 16.00 mmol) and stirred at room temperature for 18 hours. The reaction mixture was carefully quenched with water (25 mL), followed by saturated aqueous NH4Cl (25 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and evaporated to dryness to give the crude material, which was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (1 g) as an off-white solid. [M+H] + m / z 515.6

[0281] tert-Butyl 3-amino-2-({[1,1'-biphenyl]-3-yl}methyl)-3-(2-hydroxyethyl)piperidine-1-carboxylate (Intermediate 31) [ka]

[0282] Intermediate 30 (900 mg, 1.75 mmol) was dissolved in methanol (15 mL) and cooled to 0 °C. Hydrogen chloride (4 M in dioxane) (450 μL, 1.80 mmol) was added dropwise, and the reaction was stirred at 0 °C for 3 h. Additional hydrogen chloride (4 M in dioxane) (50 μL, 0.200 mmol) was added, and the mixture was stirred for 2 h. The reaction was quenched at 0 °C by the dropwise addition of saturated aqueous NaHCO3 (10 mL) and extracted with 10% methanol in DCM (3 × 5 mL). The combined organic layers were filtered through a phase separator and evaporated to dryness to give the crude product. The crude material was purified by silica gel column chromatography (0–100% EtOAc in heptane, followed by 0–10% methanol in DCM) to give the title compound (700 mg) as an off-white solid. [M+H] + m / z 411.4

[0283] tert-Butyl 7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (Intermediate 32) [ka]

[0284] N-Ethyl-N-(propan-2-yl)propan-2-amine (360 μL, 2.07 mmol) was added dropwise to a stirred solution of Intermediate 32 (700 mg, 1.71 mmol) and bis(trichloromethyl)carbonate (600 mg, 2.02 mmol) in DCM (10 mL) at 0–10°C and stirred for 2 h. The reaction mixture was carefully quenched with saturated aqueous NaHCO (5 mL) and purged with N (g) for 30 min using a 20% NaOH scrubber to quench phosgene gas, then extracted with DCM (2 × 25 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0–100% EtOAc in heptane) to give the title compound (587 mg) as an off-white solid. [M+H] + m / z 437.5.

[0285] 7-({[1,1'-biphenyl]-3-yl}methyl)-3-oxa-1,8-diazaspiro[5.5]undecan-2-one (Intermediate 33) [ka]

[0286] Intermediate 32 (200 mg, 0.458 mmol) was dissolved in DCM (2 mL), then TFA (1 mL) was added dropwise and the mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous Na2CO3 (10 mL) and extracted with DCM (2 x 10 mL). The organic layers were combined, passed through a phase separator and evaporated to dryness to give the title compound (150 mg) as an off-white solid. [M+H+ MeCN] + m / z 378.6

[0287] Methyl 7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (19) [ka]

[0288] Methyl carbonochloridate (200 μL, 2.59 mmol) was added dropwise to a stirred solution of Intermediate 33 (151 mg, 0.448 mmol) and triethylamine (370 μL, 2.65 mmol) in DCM (3 mL) at room temperature and stirred for 30 min. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and evaporated to dryness to give the crude material. The crude material was purified by silica gel column chromatography (0–100% EtOAc in heptane) to give the title compound (154 mg) as an off-white solid.

[0289] 1H NMR (500 MHz, CDCl3) δ 7.64 - 7.52 (m, 2H), 7.48 - 7.39 (m, 3H), 7.39 - 7.30 (m, 3H), 7.23 - 7.07 (m, 1H), 6.18 (brs, 1H), 4.82 - 3.84 LCMS (Method A): [M+H] + m / z 395.2, RT 2.95 and 3.08 min

[0290] Example 20: Methyl (6R,7S)-7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate Example 21: Methyl (6S,7R)-7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate Example 22: Methyl (6R,7R)-7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate Example 23: Methyl (6S,7S)-7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate [ka] Example 19 (150 mg) was subjected to chiral SFC using a Waters Prep SFC80 with a gradient of 20% ethanol, 80% CO, Chiralpak AD-H, 10x250 mm, 5 μm, and a flow rate of 15 mL / min to give the title compounds (Peak 1, 42 mg, 100% ee, and Peak 2, 34 mg, 100% ee, Peak 3, 5 mg, 100% ee, Peak 4, 12 mg, 100% ee) as off-white solids. The absolute stereochemistry of compounds 10, 21, 22, and 23 was not conclusively identified but has been assigned as shown below.

[0291] Peak 1 (stereochemistry assigned to piperidine 6R,7S); 1 H NMR (500 MHz, CDCl3) δ 7.62 - 7.51 (m, 2H), 7.45 - 7.37 (m, 3H), 7.37 - 7.28 (m, 3H), 7.22 - 7.06 (m, 1H), 6.60 (s, 1H), 4.78 (d, J = 8.4 Hz, 0.5H), 4.57 - 4.46 (m, 0.5H), 4.35 - 4.27 (m, 2H), 4.12 (d, J = 11.8 Hz, 0.5H), 3.89 (d, J = 12.1 Hz, 0.5H), 3.44 (s, 1H), 3.14 (s, 2H), 3.09 - 2.87 (m, 3H), 2.24 - 2.13 (m, 1H), 2.13 - 1.94 (m, 1H), 1.81 - 1.51 (m, 4H). LCMS (Method B): [M+H] + m / z 395.3, RT 2.93 min. Chiral analysis (Chiralpak AD-H, 4.6x250mm, 5µm, 80:20 CO2:ethanol): RT 5.68 min.

[0292] Peak 2 (stereochemistry assigned to piperidine 6S,7R): 11H NMR (500 MHz, CDCl3) δ 7.63 - 7.51 (m, 2H), 7.46 - 7.38 (m, 3H), 7.38 - 7.29 (m, 3H), 7.22 - 7.06 (m, 1H), 6.15 (s, 1H), 4.78 (d, J = 8.3 Hz, 0.5H), 4.60 - 4.37 (m, 0.5H), 4.36 - 4.29 (m, 2H), 4.13 (d, J = 11.4 Hz, 0.5H), 3.90 (d, J = 11.5 Hz, 0.5H), 3.45 (s, 1H), 3.14 (s, 2H), 3.06 - 2.92 (m, 3H), 2.22 - 2.15 (m, 1H), 2.08 - 1.90 (m, 1H), 1.72 - 1.66 (m, 4H). LCMS (Method B): [M+H] + m / z 395.3, RT 2.93 min. Chiral analysis (Chiralcel AD-H, 4.6x250mm, 5μm, 80:20 CO2:ethanol): RT 8.24 min

[0293] Peak 3 (the stereochemistry was assigned as 6R,7R of piperidine); 1 1H NMR (500 MHz, CDCl3) δ 7.62 - 7.51 (m, 2H), 7.48 - 7.39 (m, 3H), 7.38 - 7.31 (m, 3H), 7.09 (d, J = 7.4 Hz, 1H), 5.84 (s, 1H), 4.42 - 4.28 (m, 2H), 4.23 (t, J = 11.2 Hz, 2H), 3.47 (s, 1H), 3.12 (s, 2H), 3.09 - 3.05 (m, 1H), 2.96 (d, J = 11.7 Hz, 1H), 2.82 (dd, J = 13.7, 3.3 Hz, 1H), 2.08 - 1.97 (m, 1H), 1.97 - 1.84 (m, 2H), 1.84 - 1.73 (m, 3H). LCMS (Method B): [M+H] +m / z 395.3, RT 3.07 min. Chiral analysis (Chiralcel AD-H, 4.6x250mm, 5µm, 80:20 CO2:ethanol): RT 9.93 min.

[0294] Peak 4 (stereochemistry assigned to piperidine 6S,7S); 1 H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 7.5 Hz, 2H), 7.44 (q, J = 11.1, 9.4 Hz, 3H), 7.35 (dd, J = 15.4, 7.8 Hz, 3H), 7.09 (d, J = 7.4 Hz, 1H), 5.62 (s, 1H), 4.36 (s, 2H), 4.22 (t, J = 13.7 Hz, 2H), 3.47 (s, 1H), 3.14 (s, 2H), 3.09 - 3.04 (m, 1H), 3.01 - 2.93 (m, 1H), 2.82 (dd, J = 13.6, 2.9 Hz, 1H), 2.09 - 1.99 (m, 1H), 1.93 (d, J = 11.8 Hz, 1H), 1.86 (d, J = 13.8 Hz, 1H), 1.85 - 1.70 (m, 3H). Notes: Rotamer mixture.LCMS (Method B): [M+H] + m / z 395.3, RT 3.07 min. Chiral analysis (Chiralcel AD-H, 4.6x250mm, 5µm, 80:20 CO2:ethanol): RT 10.77 min.

[0295] Example 24: (CIS)-7-({[1,1'-biphenyl]-3-yl}methyl)-N-ethyl-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (24) Example 25: (Trans)-7-({[1,1'-biphenyl]-3-yl}methyl)-N-ethyl-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (25) [ka] Ethyl isocyanate (71 μL, 0.892 mmol) was added to a stirred solution of triethylamine (0.19 mL, 1.34 mmol) and Intermediate 33 (150 mg, 0.446 mmol) in DCM (2 mL) at room temperature and stirred for 1 h. The reaction mixture was quenched with 2 M NaOH (5 mL) and extracted with DCM (3 × 5 mL). The organic layer was dried over NaSO, filtered, and evaporated to dryness to give the crude product. This crude material was purified by preparative HPLC standard column: XBridge™ Prep. C18 10 um OBD™, 30 x 100 mm, mobile phase: 30-95% acetonitrile (0.2% ammonium hydroxide) water (0.2% ammonium hydroxide) over 10 min, flow rate: 40 mL / min, UV: 215 and 254 nm to give the title compounds Example 24 (80 mg) and Example 25 (15 mg) as off-white solids.

[0296] Example 24: 1 H NMR (400 MHz, CDCl3) δ 7.61 - 7.50 (m, 2H), 7.47 - 7.37 (m, 4H), 7.37 - 7.24 (m, 3H), 7.16 (d, J = 7.4 Hz, 1H), 4.61 - 4.37 (m, 2H), 4.37 - 4.24 (m, 1H), 3.73 (brs, 1H), 3.20 - 3.05 (m, 2H), 3.05 - 2.93 (m, 1H), 2.93 - 2.78 (m, 2H), 2.23 (d, J = 14.1 Hz, 1H), 2.17 - 2.01 (m, 1H), 1.80 - 1.58 (m, 4H), 0.70 (td, J = 7.1, 2.6 Hz, 3H). Note: 1H exchanged with solvent. LCMS (Method A): [M+H] + m / z 408.5, RT 2.86 min.

[0297] Example 25: 1H NMR (400 MHz, CDCl3) δ 7.59 - 7.53 (m, 2H), 7.49 - 7.40 (m, 3H), 7.40 - 7.32 (m, 3H), 7.21 - 7.11 (m, 1H), 5.90 (s, 1H), 4.40 - 4.26 (m, 2H), 4.12 (dd, J = 13.4, 4.5 Hz, 1H), 4.06 - 3.94 (m, 1H), 3.12 - 2.97 (m, 2H), 2.90 - 2.76 (m, 3H), 2.09 - 1.97 (m, 1H), 1.97 - 1.89 (m, 1H), 1.89 - 1.79 (m, 2H), 1.79 - 1.68 (m, 2H), 0.69 (t, J = 7.2 Hz, 3H). Comment: Loss of 1H can be exchanged with solvent. LCMS (Method B): [M+H] + m / z 408.5, RT 3.07 min.

[0298] Example 26: (6S,7R)-7-({[1,1'-biphenyl]-3-yl}methyl)-N-ethyl-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (26) Example 27: (6R,7S)-7-({[1,1'-biphenyl]-3-yl}methyl)-N-ethyl-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (27) [ka] Example 24 (81 mg) was subjected to chiral preparative purification using a Waters 600 column, eluting with 40 / 60% v / v n-hexane / ethanol, Chiralpak IC (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min to give the title compounds (peak 1, 38 mg, 100% ee, and peak 2, 28 mg, 100% ee). The absolute stereochemistry of each of the isolated compounds 26 and 27 was not conclusively identified but has been assigned as shown below.

[0299] Peak 1 (assigned to piperidine 6R,7S); 1 H NMR (400 MHz, CDCl3) δ 7.57 - 7.51 (m, 2H), 7.45 - 7.40 (m, 3H), 7.39 (d, J = 1.8 Hz, 1H), 7.33 (t, J = 7.4 Hz, 2H), 7.16 (dt, J = 7.5, 1.5 Hz, 1H), 6.21 (s, 1H), 4.45 (td, J = 12.1, 2.5 Hz, 2H), 4.33 (ddd, J = 11.9, 4.7, 2.6 Hz, 1H), 3.78 (d, J = 12.5 Hz, 1H), 3.47 (d, J = 9.7 Hz, 1H), 3.15 - 2.94 (m, 3H), 2.92 - 2.77 (m, 2H), 2.29 - 2.20 (m, 1H), 2.07 - 1.94 (m, 1H), 1.77 - 1.64 (m, 4H), 0.70 (t, J = 7.2 Hz, 3H). LCMS (Method C): [M+H] + m / z 408.3, RT 0.9 min. Chiral analysis (Chiralcelpak IC, 25x0.46 cm, 5 μm, 40:60 n-hexane:ethanol): RT 6.7 min.

[0300] Peak 2 (assigned 6R,7S of piperidine): 1H NMR (400 MHz, CDCl3) δ 7.57 - 7.51 (m, 2H), 7.45 - 7.40 (m, 3H), 7.39 (d, J = 1.8 Hz, 1H), 7.35 (s, 2H), 7.16 (dt, J = 7.6, 1.4 Hz, 1H), 6.29 - 6.24 (m, 1H), 4.45 (td, J = 12.1, 2.5 Hz, 2H), 4.32 (ddd, J = 11.9, 4.8, 2.6 Hz, 1H), 3.78 (d, J = 12.8 Hz, 1H), 3.48 (d, J = 14.1Hz, 1H), 3.17 - 2.94 LCMS (Method C): [M+H] + m / z 408.3, RT 0.9 min. Chiral analysis (Chiralcelpak IC, 25x0.46 cm, 5 μm, 40:60 n-hexane:ethanol): RT 13.6 min.

[0301] Example 28: Methyl 6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-1,7-diazaspiro[4.5]decane-7-carboxylate [ka] tert-Butyl 2-({[1,1'-biphenyl]-3-yl}methyl)-3-(3-ethoxy-3-oxoprop-1-yn-1-yl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylate (Intermediate 34) [ka]

[0302] n-Butyllithium solution (2.5 M in cyclohexane) (1.2 mL, 2.99 mmol) was added dropwise to a solution of ethyl prop-2-ynoate (0.32 mL, 3.20 mmol) in THF (20 mL) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 10 minutes, after which a solution of Intermediate 28 (1.00 g, 2.13 mmol) in THF (10 mL) was added dropwise at −78° C. The reaction was stirred for an additional 10 minutes at −78° C., and then the reaction was quenched with a 4:1 heptane:acetic acid solution (1 mL) at −78° C. The reaction was allowed to warm to room temperature for 1 hour, and then the reaction was partitioned between water (10 mL), saturated aqueous NH4Cl (10 mL), and EtOAc (20 mL). The aqueous layer was further extracted with EtOAc (20 mL), and the organic layers were combined, washed with brine (20 mL), dried over MgSO4, and concentrated to give the crude material, which was purified by silica gel column chromatography (0-60% EtOAc in heptane) to give the title compound (600 mg) as an orange solid. [M+NH4] + m / z 584.6

[0303] tert-Butyl 3-amino-2-({[1,1'-biphenyl]-3-yl}methyl)-3-(3-methoxy-3-oxoprop-1-yn-1-yl)piperidine-1-carboxylate (Intermediate 35) [ka]

[0304] Intermediate 34 (450 mg, 0.794 mmol) was dissolved in methanol (7.2 mL) and cooled to 0 °C. Hydrogen chloride (4 M in dioxane) (0.30 mL, 1.19 mmol) was added dropwise, and the reaction was stirred at 0 °C for 3 h. The reaction was quenched at 0 °C by the dropwise addition of 2 M aqueous NaOH (2 mL) and diluted with EtOAc (10 mL) and water (10 mL). The solution was separated, and the aqueous layer was further extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried over MgSO and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0–80% EtOAc in heptane) to give the title compound (80 mg) as a yellow oil. [M+H] + m / z 449.4

[0305] tert-Butyl 6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-1,7-diazaspiro[4.5]decane-7-carboxylate (Intermediate 36) [ka]

[0306] Intermediate 35 (100 mg, 0.216 mmol) and 1,4-dioxane (2 mL) with acetic acid (25 μL, 0.432 mmol) were placed under vacuum, the atmosphere replaced with N2(g), re-evacuated twice, and palladium on carbon (10%, 46 mg, 0.0432 mmol) was added. The flask was evacuated, refilled with H2(g), pressurized to 4 bar, and the solution stirred at room temperature for 3 h. The reaction was filtered through Celite and concentrated in vacuo. The crude material was purified by silica gel column chromatography (20-100% EtOAc in heptane) to give the title compound (55 mg) as a white solid. [M+H] + m / z 421.4

[0307] 6-({[1,1'-biphenyl]-3-yl}methyl)-1,7-diazaspiro[4.5]decan-2-one (Intermediate 37) [ka]

[0308] Intermediate 36 (45 mg, 0.107 mmol) was dissolved in DCM (0.5 mL) and TFA (0.5 mL) and stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaCO (10 mL) and extracted with DCM (2 x 10 mL). The organic layers were combined, passed through a phase separator, and concentrated in vacuo to give the title compound (30 mg) as a yellow solid, which was used without further purification. [M+H] + m / z 321.4.

[0309] Methyl 6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-1,7-diazaspiro[4.5]decane-7-carboxylate (Example 28) [ka]

[0310] Intermediate 37 (30 mg, 0.0936 mmol) was dissolved in DCM (1 mL) and triethylamine (78 μL, 0.562 mmol) and methyl carbonochloridate (10 μL, 0.131 mmol) were added. The solution was stirred for 1 h, after which additional methyl carbonochloridate (10 μL, 0.131 mmol) was added. The reaction was stirred for 30 min, methyl carbonochloridate (10 μL, 0.131 mmol) was added, the reaction was stirred for 30 min, then diluted with DCM (10 mL) and water (10 mL), separated, and the aqueous layer extracted with DCM (2×10 mL). The organic layers were combined, dried, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography (0–8% methanol in DCM) to give the title compound (15 mg) as a white solid.

[0311] 1H NMR (500 MHz, CDCl3) δ 7.62 - 7.52 (m, 2H), 7.46 - 7.39 (m, 3H), 7.39 - 7.32 (m, 3H), 7.22 - 7.08 (m, 1H), 6.98 (s, 1H), 4.25 (m, 1H), 4.20 - 4.07 (m, 1H), 3.17 (s, 3H), 3.09 - 2.94 (m, 2H), 2.69 - 2.48 (m, 1H), 2.36 (d, J = 16.6 Hz, 1H), 2.29 - 2.00 (m, 3H), 1.98 - 1.87 (m, 1H), 1.84 - 1.57 (m, 3H). LCMS (Method B): [M+H] + m / z 379.4, RT 3.12 and 3.26 min.

[0312] Example 29: Methyl (5S,6S)-6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,7-diazaspiro[4.5]decane-7-carboxylate [ka] tert-Butyl (2S,3R)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-ethenyl-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylate (Intermediate 38) [ka]

[0313] Intermediate 28 (1.40 g, 2.99 mmol) in anhydrous THF (14 mL) was added to a stirred bromo(ethenyl)magnesium solution (1 M in THF) (9.0 mL, 8.96 mmol) at −78° C. The reaction was stirred at −78° C. for 1 h. The reaction mixture was warmed to 0° C. and stirred for 30 min, then quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (20–100% EtOAc in heptane) to afford the title compound (148 mg) as a white residue / gummy material. [M+H] + m / z = 497.5

[0314] tert-Butyl (2S,3S)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-(1,2-dihydroxyethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylate (Intermediate 39) [ka]

[0315] To a stirred solution of potassium dioxide(dioxo)osmium hydrate (2:1:2) (5.2 mg, 0.0141 mmol) and Intermediate 38 (140 mg, 0.282 mmol) in water (0.28 mL) and THF (0.7 mL) was added 4-methyl-4-oxide-morpholin-4-ium (58 mg, 0.493 mmol) at room temperature, and the reaction was then heated to 50 °C for 2 h. The reaction was quenched with saturated aqueous NaSO and extracted with EtOAc (3 × 5 mL). The organic extract was passed through a phase separator and concentrated in vacuo. The crude material was purified by silica gel column chromatography (30–100% EtOAc in heptane) to give the title compound (103 mg) as a colorless solid. [M+H] + m / z = 531.5

[0316] tert-Butyl (2S,3S)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-formyl-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylate (Intermediate 40) [ka]

[0317] To a stirred solution of Intermediate 39 (91 mg, 0.171 mmol) in acetone (2.4 mL) at 0° C. was added a solution of sodium periodate (58 mg, 0.273 mmol) in water (0.7 mL). The reaction was stirred at 0° C. for 1 h and then warmed to room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (3×5 mL). The organic extracts were passed through a phase separator and concentrated in vacuo to give the title compound (66 mg) as a colorless residue. [M+H] + m / z = 499.5

[0318] tert-Butyl (2S,3S)-2-({[1,1'-biphenyl]-3-yl}methyl))-3-(hydroxymethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylate (Intermediate 41) [ka]

[0319] Sodium tetrahydroborate (11 mg, 0.291 mmol) was added to a stirred solution of Intermediate 40 (66 mg, 0.132 mmol) in methanol (2 mL) at room temperature. The reaction was stirred for 30 minutes, then quenched with water and extracted with DCM (3 x 5 mL). The organic extracts were passed through a phase separator and concentrated in vacuo to give the title compound (59 mg) as a colorless residue. [M+H] + m / z = 501.5

[0320] tert-Butyl (2S,3S)-3-amino-2-({[1,1'-biphenyl]-3-yl}methyl)-3-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 42) [ka]

[0321] Hydrogen chloride (4M in dioxane) (26 μL, 0.104 mmol) was added dropwise to a stirred solution of Intermediate 41 (50 mg, 0.0990 mmol) in methanol (2 mL) at 0° C. and stirred for 1 h. Additional hydrogen chloride (4M in dioxane) (49 μL, 0.198 mmol) was added and the reaction stirred for an additional 2 h. The reaction was quenched with saturated aqueous NaHCO3 at 0° C., after which the methanol was removed in vacuo. The aqueous solution was then extracted with DCM:methanol (9:1, 3×5 ml). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0–2% methanol in DCM) to give the title compound (39 mg) as a colorless gum. [M+H] + m / z = 397.4

[0322] tert-Butyl (5S,6S)-6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,7-diazaspiro[4.5]decane-7-carboxylate (Intermediate 43) [ka]

[0323] N-Ethyl-N-isopropyl-propan-2-amine (20 μL, 0.114 mmol) was added to a stirred solution of Intermediate 42 (38 mg, 0.0954 mmol) and bis(trichloromethyl)carbonate (34 mg, 0.114 mmol) in anhydrous DCM (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The reaction was quenched with 20% NaOH and extracted with DCM (3×3 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-5% methanol in DCM) to give the title compound (35 mg) as a white solid. [M+NH4] + m / z = 440.6

[0324] (5S,6S)-6-({[1,1'-biphenyl]-3-yl}methyl)-3-oxa-1,7-diazaspiro[4.5]decan-2-one (Intermediate 44) [ka]

[0325] A solution of intermediate 43 (30 mg, 0.0710 mmol) in TFA (0.18 mL) and DCM (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM (3 x 3 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give the title compound (28 mg) as a pale yellow gum. [M+H+MeCN] + m / z = 364.5

[0326] Methyl (5S,6S)-6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,7-diazaspiro[4.5]decane-7-carboxylate (29) [ka]

[0327] Methyl carbonochloridate (67 μL, 0.868 mmol) was added to a stirred solution of Intermediate 44 (28 mg, 0.0868 mmol) and triethylamine (73 μL, 0.521 mmol) in DCM (2 mL) at 0° C. The reaction was then warmed to room temperature for 30 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM (3 × 3 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by reverse-phase column chromatography (10–100% MeCN in water (0.1% NH3)) to afford the title compound (19 mg) as a white solid.

[0328] 1 H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 7.4 Hz, 2H), 7.48 - 7.40 (m, 3H), 7.39 - 7.31 (m, 3H), 7.21 - 7.08 (m, 1H), 5.96 - 5.72 (m, 1H), 4.48 (d, J = 8.9 Hz, 1H), 4.38 - 4.23 (m, 1H), 4.19 (d, J = 8.9 Hz, 1H), 4.16 - 4.06 (m, 1H), 3.17 (s, 3H), 3.06 - 2.93 (m, 2H), 2.89 (s, 1H), 2.09 - 2.01 (m, 1H), 1.89 - 1.75 (m, 2H), 1.54 - 1.43 (m, 1H). LCMS (Method A): [M+NH4] + m / z 398.5, RT 2.98 min.

[0329] Example 30: (CIS)-6-({[1,1'-biphenyl]-3-yl}methyl)-N-ethyl-2,2-dioxo-2λ 6 -Thia-1,3,7-triazaspiro[4.5]decane-7-carboxamide [ka] tert-Butyl (CIS)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-3-(nitromethyl)piperidine-1-carboxylate (Intermediate 45) [ka]

[0330] A heterogeneous solution of N,N,N-tributylbutan-1-aminium fluoride (1 M in THF) (1.5 mL, 1.54 mmol) and Intermediate 28 (1.50 g, 3.07 mmol) in nitromethane (15 mL) was heated at 23 °C for 2 h. The reaction was diluted with EtOAc (25 mL) and water (25 mL) and separated. The aqueous layer was extracted with EtOAc (2 x 10 mL), and the organic layers were combined, dried over MgSO4, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-70% EtOAc in heptane) to give the title compound (1.1 g) as a pale yellow solid. [M+H] + m / z = 530.5

[0331] tert-Butyl-(CIS)-3-(aminomethyl)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylate (Intermediate 46) [ka]

[0332] A solution of Intermediate 45 (1.00 g, 1.89 mmol), iron (527 mg, 9.44 mmol), and ammonium chloride (505 mg, 9.44 mmol) was dissolved in ethanol (10 mL) and water (10 mL) and then heated at 80° C. for 2 h. The mixture was poured into water (20 mL) and extracted with EtOAc (3×25 mL). The organic phases were combined, passed through a phase separator, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-10% methanol in DCM) to give the title compound (814 mg) as a white solid. [M+H] + m / z = 500.5

[0333] tert-Butyl (CIS)-3-amino-3-(aminomethyl)-2-({[1,1'-biphenyl]-3-yl}methyl)piperidine-1-carboxylate (Intermediate 47) [ka]

[0334] Intermediate 46 (800 mg, 1.60 mmol) was dissolved in methanol (20 mL) and cooled to 0 °C. Hydrogen chloride (4 M in dioxane) (1.2 mL, 4.80 mmol) was added dropwise and the solution was stirred at 0 °C for 5 h. The reaction was quenched by the addition of saturated aqueous NaHCO (10 mL) and EtOAc (10 mL). The solution was separated and the aqueous layer was extracted with EtOAc (2 × 10 mL). The organic layers were combined, washed with brine (20 mL), passed through a phase separator, and concentrated in vacuo to give the title compound (650 mg) as a colorless oil. [M+H] + m / z = 396.4

[0335] tert-Butyl (CIS)-6-({[1,1'-biphenyl]-3-yl}methyl)-2,2-dioxo-2λ 6 -Thia-1,3,7-triazaspiro[4.5]decane-7-carboxylate (Intermediate 48) [ka]

[0336] Intermediate 47 (450 mg, 1.14 mmol) and sulfamide (131 mg, 1.37 mmol) were dissolved in pyridine (15 mL), and the reaction was stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with water (25 mL) and EtOAc (25 mL). The mixture was separated, and the aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were combined, washed with 2 M HCl (50 mL) and brine (50 mL), dried over MgSO4, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (20-100% EtOAc in heptane) to give the title compound (122 mg) as a cream-colored solid. [M+NH4] + m / z = 475.4

[0337] (CIS)-6-({[1,1'-biphenyl]-3-yl}methyl)-2λ 6 -Thia-1,3,7-triazaspiro[4.5]decane-2,2-dione (Intermediate 49) [ka]

[0338] Intermediate 48 (100 mg, 0.219 mmol) was dissolved in DCM (0.5 mL) and TFA (0.5 mL) and stirred at room temperature for 1 h. The reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and extracted with DCM (3 x 10 mL). The organic layers were combined, passed through a phase separator, and concentrated in vacuo to give the title compound (60 mg) as a cream-colored solid. [M+H] + m / z = 358.3

[0339] (CIS)-6-({[1,1'-biphenyl]-3-yl}methyl)-N-ethyl-2,2-dioxo-2λ 6 -Thia-1,3,7-triazaspiro[4.5]decane-7-carboxamide (30) [ka]

[0340] To a solution of intermediate 49 (50 mg, 0.140 mmol) and triethylamine (58 μL, 0.420 mmol) in DCM (1 mL) at room temperature, ethyl isocyanate (22 μL, 0.280 mmol) was added, and the solution was stirred at room temperature for 30 min. The solution was quenched by the addition of 2 M aqueous NaOH (5 mL) and extracted with DCM (3 × 10 mL). The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel column chromatography (0–100% EtOAc in heptane) to give the title compound (47 mg) as a white solid.

[0341] 1 H NMR (400 MHz, CDCl3) δ 7.59 - 7.53 (m, 2H), 7.49 - 7.40 (m, 4H), 7.41 - 7.29 (m, 2H), 7.21 (d, J = 7.5 Hz, 1H), 4.41 (d, J = 10.0 Hz, 1H), 4.27 - 4.14 (m, 1H), 4.02 (d, J = 10.9 Hz, 1H), 3.69 (d, J = 11.9 Hz, 1H), 3.58 (s, 1H), 3.31 (dd, J = 13.7, 2.7 Hz, 1H), 3.24 (d, J = 11.9 Hz, 1H), 3.05 (td, J = 13.3, 2.6 Hz, 1H), 2.95 (dd, J = 13.6, 11.8 Hz, 1H), 2.83 (ddt, J = 19.8, 13.0, 6.9 Hz, 2H), 2.16 - 2.05 (m, 1H), 1.85 - 1.73 (m, 2H), 1.66 - 1.55 (m, 1H), 0.68 (t, J = 7.2 Hz, 3H). The loss of NH can be exchanged with solvent. LCMS (Method A): [M+NH] + m / z 446.4, RT 3.09 min.

[0342] Example 31: (5R,6S)-6-({[1,1'-biphenyl]-3-yl}methyl)-N-ethyl-2,2-dioxo-2λ6 -thia-1,3,7-triazaspiro[4.5]decane-7-carboxamide and Example 32: (5S,6R)-6-({[1,1'-biphenyl]-3-yl}methyl)-N-ethyl-2,2-dioxo-2λ 6 -Thia-1,3,7-triazaspiro[4.5]decane-7-carboxamide [ka] Example 30 (35 mg) was subjected to chiral HPLC using a gradient of 85 heptane, 15% ethanol, Chiralcel OD-H, 4.6 x 250 mm, 5 μm, at a flow rate of 18 mL / min to give the title compounds (Peak 1, 12 mg, 100% ee, and Peak 2, 6 mg, 100% ee). The absolute stereochemistry of each of the separated compounds 31 and 32 was not conclusively identified but has been assigned as shown below.

[0343] Peak 1 (assigned to piperidine 5R,6S); 11H NMR (400 MHz, CDCl3) δ 7.59 - 7.53 (m, 2H), 7.48 - 7.40 (m, 4H), 7.40 - 7.31 (m, 2H), 7.20 (dt, J = 7.5, 1.2 Hz, 1H), 5.08 (s, 1H), 4.38 (d, J = 9.9 Hz, 1H), 4.30 (s, 1H), 4.02 (d, J = 11.2 Hz, 1H), 3.67 (d, J = 11.8 Hz, 2H), 3.29 (dd, J = 13.7, 2.7 Hz, 1H), 3.23 (d, J = 11.9 Hz, 1H), 3.03 (td, J = 13.3, 2.8 Hz, 1H), 2.94 (dd, J = 13.6, 11.8 Hz, 1H), 2.82 (ddt, J = 20.6, 13.2, 6.9 Hz, 2H), 2.09 (td, J = 13.5, 4.6 Hz, 1H), 1.83 - 1.70 (m, 2H), 1.59 (ddt, J = 17.9, 9.1, 4.6 Hz, 1H), 0.66 (t, J = 7.2 Hz, 3H). LCMS (Method A): [M+NH4] + m / z 446.4, RT 2.96 min. Chiral analysis (Chiralcel OD-H, 4.6x250mm, 5μm, 85:15 heptane:ethanol): RT 8.97 min

[0344] Peak 2 (assigned to 5S,6R of piperidine): 1H NMR (400 MHz, CDCl3) δ 7.60 - 7.52 (m, 2H), 7.48 - 7.40 (m, 4H), 7.39 - 7.31 (m, 2H), 7.20 (d, J = 7.5 Hz, 1H), 5.08 (s, 1H), 4.39 (d, J = 10.0 Hz, 1H), 4.29 (s, 1H), 4.01 (d, J = 9.8 Hz, 1H), 3.67 (d, J = 11.8 Hz, 2H), 3.29 (dd, J = 13.7, 2.4 Hz, 1H), 3.23 (d, J = 11.9 Hz, 1H), 3.03 (t, J = 12.0 Hz, 1H), 2.99 - 2.90 (m, 1H), 2.82 (ddt, J = 20.3, 13.1, 6.7 Hz, 2H), 2.15 - 2.04 (m, 1H), 1.87 - 1.70 (m, 2H), 1.65 - 1.51 (m, 1H), 0.67 (t, J = 7.2 Hz, 3H). LCMS (Method A): [M+NH4] + m / z 446.4, RT 2.97 min. Chiral analysis (Chiralcel OD-H, 4.6x250mm, 5µm, 85:15 heptane:ethanol): RT 29.24 min.

[0345] Example 33: rel-(6S,7R)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxamide [ka] tert-Butyl-rel-(2R,3R)-3-nitro-3-(prop-2-en-1-yl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 50): [ka]

[0346] Potassium hydroxide (235 mg, 4.18 mmol) was dissolved in IPA (17 mL) and methanol (17 mL), and the solution was stirred for 30 minutes. Intermediate 4 (92%, 1.73 g, 3.80 mmol) in methanol (20 mL) was added, and the solution was then degassed. Palladium diacetate (43 mg, 0.190 mmol) was added, followed by triphenylphosphine (150 mg, 0.570 mmol). The solution was heated to 45°C and stirred for 5 minutes, after which prop-2-en-1-yl acetate (0.45 mL, 4.18 mmol) was added. The reaction mixture was heated to 55°C for 3 hours and then cooled to room temperature. Additional palladium diacetate (43 mg, 0.190 mmol), triphenylphosphine (150 mg, 0.570 mmol), and prop-2-en-1-yl acetate (0.45 mL, 4.18 mmol) were added in that order. The reaction was heated to 55° C. for 1 hour and then concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-20% TBME in heptane) to give the title compound (1.44 g) as an oil. [M+H] + m / z 459.4.

[0347] tert-Butyl-rel-(2R,3R)-3-amino-3-(prop-2-en-1-yl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 51): [ka]

[0348] Zinc (1.9 g, 28.6 mmol) was added to a stirred solution of Intermediate 50 (1.31 g, 2.86 mmol) in ethanol (36 mL) and acetic acid (8 mL) at room temperature, and the mixture was stirred for 7 h. The reaction mixture was filtered through a pad of Celite and washed with methanol. The volume of the solution was reduced to approximately half, then neutralized with saturated aqueous NaHCO3 (100 mL) and extracted with DCM (2 x 100 mL). The organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by basic silica gel column chromatography (0-100% EtOAc in DCM) to give the title compound (924 mg) as an oil. [M+H] + m / z 429.8

[0349] tert-Butyl-rel-(2R,3R)-3-(prop-2-en-1-yl)-3-(prop-2-enamido)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 52): [ka]

[0350] A solution of prop-2-enoyl chloride (0.16 mL, 1.94 mmol) was added to a stirred solution of Intermediate 51 (416 mg, 0.971 mmol) and triethylamine (0.27 mL, 1.94 mmol) in DCM (2 mL) at room temperature, and the mixture was stirred for 1 h. The reaction mixture was quenched with 2 M aqueous NaOH (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the title compound (500 mg) as an orange gum. [M+H] + m / z 483.5

[0351] tert-Butyl-rel-(6R,7R)-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undec-3-ene-8-carboxylate (Intermediate 53): [ka]

[0352] A solution of Intermediate 52 (400 mg, 0.829 mmol) in anhydrous toluene (800 mL) was degassed with N2 (g) for 15 minutes and heated to 65°C. [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro{[5-(dimethylsulfamoyl)-2-(propan-2-yloxy)phenyl]methylidene}ruthenium (30 mg, 0.0414 mmol) was then added and the reaction mixture was heated at 65°C for 2 hours with nitrogen bubbling through the solution for 2 hours. Additional [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro{[5-(dimethylsulfamoyl)-2-(propan-2-yloxy)phenyl]methylidene}ruthenium (30 mg, 0.0414 mmol) was added and the mixture was heated at 65°C for 2 hours. Additional [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro{[5-(dimethylsulfamoyl)-2-(propan-2-yloxy)phenyl]methylidene}ruthenium (30 mg, 0.0414 mmol) was added, and the mixture was heated at 65° C. for 4 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (134 mg). [M+H] + m / z 455.4

[0353] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxylate (Intermediate 54): [ka]

[0354] A suspension of Intermediate 53 (50 mg, 0.110 mmol) and 10% Pd / C (50% wet) (12 mg, 0.0055 mmol) in ethanol (5 mL) was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered through a pad of Celite and washed with methanol. The combined organic layers were concentrated in vacuo to give the title compound (21 mg). [M+H] + m / z =457.4.

[0355] rel-(6S,7R)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxamide (33): [ka]

[0356] A solution of trifluoroacetic acid (1.0 mL, 13.1 mmol) and Intermediate 54 (21 mg, 0.046 mmol) in DCM (1 mL) was stirred at room temperature for 4 hours. The reaction was quenched with saturated NaHCO3 (2 mL) and extracted with DCM (3 x 2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. This crude material was dissolved in DCM (1 mL) and cooled to 0 °C. Triethylamine (26 μL, 0.184 mmol) followed by isocyanatoethane (7.3 μL, 0.092 mmol) were added sequentially at 0 °C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with 2 M aqueous NaOH (2 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse phase column chromatography (10-60% MeCN in water (0.1% NH3)) to give the title compound (10.4 mg) as a solid.

[0357] 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 2H), 7.23 - 7.15 (m, 3H), 6.16 (s, 1H), 4.34 - 4.22 (m, 1H), 3.90 (d, J = 12.5 Hz, 1H), 3.81 (dd, J = 9.7, 7.1 Hz, 1H), 3.74 (dd, J = 9.7, 3.3 Hz, 1H), 3.65 (p, J = 3.0 Hz, 1H), 3.30 - 3.16 (m, 2H), 3.11 - 3.02 (m, 1H), 2.59 - 2.49 (m, 1H), 2.45 (dt, J = 17.8, 4.3 Hz, 1H), 2.37 - 2.26 (m, 1H), 2.21 (dt, J = 13.7, 4.0 Hz, 1H), 2.08 - 1.97 (m, 2H), 1.97 - 1.49 (m, 12H), 1.45 - 1.35 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H). 1 NH exchange.

[0358] LCMS (Method A): [M+H] + m / z 428.4, RT 3.21 min.

[0359] Example 34: (6R,7S)—N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxamide Example 35: (6S,7R)-N-ethyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxamide [ka] Example 33 (5.3 mg) was subjected to chiral preparative purification using a Waters 600 column, eluting with 70 / 30% v / v n-hexane / ethanol, Chiralpak AS-H (25 x 2.0 cm), 5 μm, at a flow rate of 17 mL / min to give the title compounds (peak 1, 2.5 mg, 100% ee, and peak 2, 2.6 mg, 100% ee). The absolute stereochemistry of each of the isolated compounds 34 and 35 was not conclusively identified but has been assigned as shown below.

[0360] Example 34: Peak 1 (assigned 6R, 7S of piperidine); 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.28 (m, 2H), 7.25 - 7.14 (m, 3H), 5.96 (s, 1H), 4.76 (br s, 1H), 4.28 (br d, J = 4.4 Hz, 1H), 3.93 (br d, J = 12.8 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.76 - 3.68 (m, 1H), 3.67 - 3.59 (m, 1H), 3.35 - 3.17 (m, 2H), 3.05 (br t, J = 12.6 Hz, 1H), 2.63 - 2.50 (m, 1H), 2.49 - 2.39 (m, 1H), 2.37 - 2.26 (m, 1H), 2.25 - 2.16 (m, 1H), 2.02 (br d, J = 14.0 Hz, 2H), 1.98 - 1.49 (m, 12H), 1.40 (ddd, J = 13.8, 10.5, 5.3 Hz, 1H), 1.12 (t, J = 7.2 Hz, 3H).

[0361] LCMS (Method C): [M+H] + m / z 428.5, RT 0.96 min.

[0362] Chiral analysis (Chiralpak AS-H, 25x0.46cm, 5µm, 70 / 30 n-hexane:ethanol): RT 5.0min.

[0363] Example 35: Peak 2 (assigned 6R, 7S of piperidine): 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.28 (m, 2H), 7.25 - 7.14 (m, 3H), 5.96 (s, 1H), 4.76 (br s, 1H), 4.28 (br d, J = 4.4 Hz, 1H), 3.93 (br d, J = 12.8 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.76 - 3.68 (m, 1H), 3.67 - 3.59 (m, 1H), 3.35 - 3.17 (m, 2H), 3.05 (br t, J = 12.6 Hz, 1H), 2.63 - 2.50 (m, 1H), 2.49 - 2.39 (m, 1H), 2.37 - 2.26 (m, 1H), 2.25 - 2.16 (m, 1H), 2.02 (br d, J = 14.0 Hz, 2H), 1.98 - 1.49 (m, 12H), 1.40 (ddd, J = 13.8, 10.5, 5.3 Hz, 1H), 1.12 (t, J = 7.2 Hz, 3H).

[0364] CMS (Method C): [M+H] + m / z 428.5, RT 0.96 min.

[0365] Chiral analysis (Chiralpak AS-H, 25x0.46cm, 5µm, 70 / 30 n-hexane:ethanol): RT 9.4min.

[0366] Example 36: rel-(6S,7R)-N-ethyl-2,2-dioxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxamide [ka] tert-Butyl-rel-(2R,3S)-3-(chloromethanesulfonamido)-3-(hydroxymethyl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 55): [ka]

[0367] Chloromethanesulfonyl chloride (65 μL, 0.717 mmol) was added to a solution of Intermediate 6 (150 mg, 0.358 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (0.19 mL, 1.08 mmol) in anhydrous DCM (5 mL) at 0° C. The reaction was stirred for 30 minutes and then diluted with DCM (5 mL) and water (5 mL). The reaction was separated and the aqueous phase was extracted with DCM (2×5 mL). The organic phases were combined, passed through a phase separator, and concentrated in vacuo to give the title compound (190 mg) as a yellow gum. [M+Na] + m / z 553.2

[0368] tert-Butyl-rel-(6S,7R)-2,2-dioxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxylate (Intermediate 56): [ka]

[0369] Intermediate 55 (190 mg, 0.358 mmol) was dissolved in THF (5 mL) and potassium 2-methylpropan-2-olate (100 mg, 0.894 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL) and EtOAc (10 mL). The pH was adjusted to 7 with saturated aqueous NH4Cl (ca. 5 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (15 mL), passed through a phase separator, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (45 mg) as a solid. [M+Na] + m / z 517.3.

[0370] rel-(6S,7R)-N-ethyl-2,2-dioxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxamide (36) [ka]

[0371] Intermediate 56 (45 mg, 0.0910 mmol) was dissolved in anhydrous DCM (0.5 mL) and TFA (0.5 mL) and stirred at room temperature for 30 minutes. The reaction was evaporated, dissolved in anhydrous DCM (0.5 mL), and cooled to 0 °C. Triethylamine (51 μL, 0.364 mmol) was added, followed by isocyanatoethane (14 μL, 0.182 mmol), and the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with water (5 mL) and DCM (5 mL) and separated. The aqueous layer was further extracted with DCM (2 × 5 mL), and the organic layers were combined, washed with brine, passed through a phase separator, and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% MeCN in water (0.1% NH)) to give the title compound (15 mg) as a solid.

[0372] 1H NMR (400 MHz, CDCl3) δ 7.33 - 7.28 (m, 2H), 7.23 - 7.15 (m, 3H), 5.11 (s, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.73 (dd, J = 8.2, 4.1 Hz, 1H), 4.56 (s, 1H), 4.53 (d, J = 11.4 Hz, 1H), 4.29 (d, J = 12.2 Hz, 1H), 4.22 (d, J = 11.7 Hz, 1H), 4.06 (dd, J = 9.4, 4.2 Hz, 1H), 3.79 (t, J = 8.8 Hz, 1H), 3.74 - 3.67 (m, 1H), 3.40 (d, J = 12.1 Hz, 1H), 3.27 (q, J = 5.6 Hz, 2H), 2.91 (t, J = 11.4 Hz, 1H), 2.53 (ddd, J = 15.2, 7.9, 3.8 Hz, 1H), 2.10 - 1.97 (m, 2H), 1.88 - 1.48 (m, 10H), 1.13 (t, J = 7.1 Hz, 3H).

[0373] LCMS (Method A): [M+H] + 466.4 , RT =3.43 minutes

[0374] Example 37: rel-(6R,7R)-N-ethyl-2,2-dioxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxamide [ka] tert-Butyl-rel-(2R,3R)-3-ethenesulfonamido-3-(prop-2-en-1-yl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 57) [ka]

[0375] To a stirred solution of Intermediate 51 (200 mg, 0.467 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (0.24 mL, 1.40 mmol) in anhydrous DCM (5 mL) was added 2-chloroethanesulfonyl chloride (93 μL, 0.933 mmol) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl (10 mL), water (10 mL), and extracted with DCM (3×15 mL). The combined organic layers were washed with brine (30 mL), passed through a phase separator, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0–100% EtOAc in heptane) to give the title compound (130 mg) as a colorless gum. [M+Na] + m / z 541.3.

[0376] tert-Butyl-rel-(6R,7R)-2,2-dioxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-2λ 6 -Thia-1,8-diazaspiro[5.5]undec-3-ene-8-carboxylate (Intermediate 58): [ka]

[0377] A solution of Intermediate 57 (120 mg, 0.231 mmol) in anhydrous toluene (200 mL) was heated to 65 °C and degassed with N2 (g) for 15 minutes. [1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro{[5-(dimethylsulfamoyl)-2-(propan-2-yloxy)phenyl]methylidene}ruthenium (8.5 mg, 0.0116 mmol) was added, and the reaction mixture was maintained at 65 °C for 4 hours with nitrogen bubbling through the solution. Additional [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro{[5-(dimethylsulfamoyl)-2-(propan-2-yloxy)phenyl]methylidene}ruthenium (8.5 mg, 0.0116 mmol) was added, and the mixture was heated for 4 hours. The reaction mixture was cooled to room temperature and stirred for 16 hours, after which additional [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro{[5-(dimethylsulfamoyl)-2-(propan-2-yloxy)phenyl]methylidene}ruthenium (8.5 mg, 0.0116 mmol) was added and the reaction mixture was heated for 4 hours. Additional [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro{[5-(dimethylsulfamoyl)-2-(propan-2-yloxy)phenyl]methylidene}ruthenium (8.5 mg, 0.0116 mmol) was added and the mixture was heated for 4 hours. The reaction mixture was concentrated in vacuo and the crude material was purified by reverse phase column chromatography (10-100% MeCN in water (0.1% NH3)) to give the title compound (56 mg) as an oil. [M+Na] + m / z 513.1

[0378] tert-Butyl-rel-(6R,7R)-2,2-dioxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxylate (Intermediate 59): [ka]

[0379] Intermediate 58 (55 mg, 0.112 mmol) was dissolved in ethanol (10 mL) and evacuated and filled with nitrogen three times. Palladium on carbon (10% w / w) (10%, 5.9 mg, 5.60 μmol) was added and the reaction was evacuated and filled with hydrogen three times. The reaction was stirred for 16 h, evacuated and filled with nitrogen three times, filtered through Celite, and eluted with ethanol (10 mL) and EtOAc (20 mL). The solution was concentrated in vacuo to give the title compound (55 mg) as a colorless gum, which was used without further purification. [M+Na] + m / z 515.1.

[0380] rel-(6R,7R)-N-ethyl-2,2-dioxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxamide (37): [ka]

[0381] Intermediate 59 (55 mg, 0.112 mmol) was dissolved in anhydrous DCM (0.5 mL) and TFA (0.5 mL) and stirred at room temperature for 30 min. The mixture was evaporated, dissolved in anhydrous DCM (0.5 mL), and cooled to 0 °C. Triethylamine (62 μL, 0.447 mmol) was added, followed by isocyanatoethane (18 μL, 0.223 mmol), and the mixture was stirred for 30 min. The reaction mixture was diluted with water (5 mL) and DCM (5 mL) and separated. The aqueous layer was further extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, passed through a phase separator, and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% MeCN in water (0.1% NH)) to give the title compound (43 mg) as a white solid.

[0382] 1H NMR (500 MHz, CDCl3) δ 7.34 - 7.25 (m, 2H), 7.25 - 7.13 (m, 3H), 5.13 (s, 1H), 4.58 (dd, J = 8.6, 3.5 Hz, 1H), 4.31 (s, 1H), 4.20 (d, J = 11.9 Hz, 1H), 4.08 (dd, J = 9.4, 3.9 Hz, 1H), 3.78 (t, J = 9.1 Hz, 1H), 3.74 - 3.67 (m, 1H), 3.29 - 3.14 (m, 3H), 2.98 - 2.82 (m, 2H), 2.52 (tt, J = 11.6, 3.8 Hz, 1H), 2.39 (tdd, J = 15.0, 7.6, 3.3 Hz, 1H), 2.31 (dt, J = 14.1, 3.9 Hz, 1H), 2.23 (dp, J = 14.2, 4.5 Hz, 1H), 2.10 - 1.97 (m, 2H), 1.78 (pd, J = 14.2, 13.7, 3.6 Hz, 3H), 1.72 - 1.59 (m, 5H), 1.59 - 1.48 (m, 2H), 1.37 - 1.28 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H).

[0383] LCMS (Method A): [M+H] + m / z 464.4, RT 3.57 min.

[0384] Example 38: rel-(1R,6S)-N-ethyl-8,8-dioxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-8λ 6 -Thia-2,7-diazaspiro[5.6]dodecane-2-carboxamide [ka] tert-Butyl-rel-(1R,6S)-8,8-dioxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-8 lambda 6-thia-2,7-diazaspiro[5.6]dodecane-2-carboxylate (Intermediate 60) [ka]

[0385] To a stirred solution of Intermediate 6 (150 mg, 0.358 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (0.19 mL, 1.08 mmol) in anhydrous DCM (3.75 mL) was added 2-chloroethanesulfonyl chloride (71 μL, 0.717 mmol) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was warmed to room temperature, quenched with saturated aqueous NH4Cl (10 mL), water (10 mL), and extracted with DCM (3×15 mL). The combined organic layers were washed with brine (30 mL), passed through a phase separator, and concentrated in vacuo to give the title compound (110 mg) as a colorless oil, which was carried on to the next step without further purification. [M+H] + m / z 509.3.

[0386] rel-(1R,6S)-N-ethyl-8,8-dioxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-8λ 6 -Thia-2,7-diazaspiro[5.6]dodecane-2-carboxamide (38) [ka]

[0387] Intermediate 60 (100 mg, 0.197 mmol) was dissolved in anhydrous DCM (1.1 mL) and TFA (1.1 mL) and stirred for 30 min. The reaction was evaporated, dissolved in anhydrous DCM (1.1 mL), and cooled to 0 °C. Triethylamine (110 μL, 0.786 mmol) was added, followed by isocyanatoethane (31 μL, 0.393 mmol), and the reaction was stirred for 30 min. The reaction was diluted with water (5 mL) and DCM (5 mL) and separated. The aqueous layer was further extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, passed through a phase separator, and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% MeCN in water (0.1% NH)) to give the title compound (26 mg) as a solid.

[0388] 1 H NMR (400 MHz, CDCl3) δ 7.35 - 7.29 (m, 2H), 7.24 - 7.14 (m, 3H), 4.91 (s, 1H), 4.57 (d, J = 13.2 Hz, 1H), 4.46 - 4.35 (m, 1H), 4.15 (d, J = 15.9 Hz, 2H), 3.83 (s, 1H), 3.79 - 3.70 (m, 1H), 3.67 (s, 1H), 3.56 - 3.15 (m, 6H), 2.86 (t, J = 11.5 Hz, 1H), 2.55 (tt, J = 10.9, 5.1 Hz, 1H), 2.01 (dd, J = 10.0, 4.1 Hz, 2H), 1.89 (s, 1H), 1.79 - 1.44 (m, 9H), 1.13 (t, J = 7.2 Hz, 3H). NH protons are unclear.

[0389] LCMS (Method A): [M+H] + m / z 480.4, RT 3.60 min.

[0390] Example 39: (6R,7S)—N-ethyl-3-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide and Example 40: (6S,7R)-N-ethyl-3-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide [ka] tert-Butyl-rel-(6S,7R)-3-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (Intermediate 61) [ka]

[0391] A solution of K2CO3 (99 mg, 0.717 mmol) in water (2 mL) was added to a stirred solution of Intermediate 6 (100 mg, 0.239 mmol) in THF (2 mL) at 0 °C. 2-Bromopropanoyl chloride (48 μL, 0.476 mmol) was added, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with water (2 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were concentrated in vacuo to give the crude material. The residue was dissolved in anhydrous DMF (2 mL), then sodium hydride (8.6 mg, 0.358 mmol) was added at room temperature, and the mixture was stirred for 1 h. The reaction mixture was quenched with water (5 mL), the pH was adjusted to pH 7 with 1 M aqueous HCl and saturated aqueous NaHCO3, and then extracted with ethyl acetate (2 × 50 mL) and DCM (3 × 50 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. This crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane, then 0-20% methanol in EtOAc) to give the title compound (41 mg) as a colorless residue. This material was not further purified. [MH] - m / z 471.5.

[0392] (6R,7S)-N-ethyl-3-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (39) and

[0393] (6S,7R)-N-Ethyl-3-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (40) [ka]

[0394] A solution of trifluoroacetic acid (1.0 mL, 13.1 mmol) and Intermediate 61 (41 mg, 0.0868 mmol) in DCM (2 mL) was stirred at room temperature for 1 h. The reaction was quenched with saturated NaHCO3 (2 mL) and extracted with DCM (3 x 2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The residue was dissolved in DCM (2 mL), and triethylamine (24 μL, 0.174 mmol) followed by isocyanatoethane (14 μL, 0.174 mmol) were added sequentially at room temperature, and the mixture was stirred for 0.5 h. The reaction mixture was quenched with 2 M aqueous NaOH (2 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. Purification of this crude material was accomplished by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give a white solid. This was then purified by chiral preparative purification using a Waters 600 column eluting with 75 / 25% v / v n-hexane / ethanol + 0.1% isopropylamine, Chiralpak AS-H (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min to give the title compounds (peak 1, 2.8 mg, 100% ee, and peak 2, 4.9 mg, 100% ee). The absolute stereochemistry of each of the isolated compounds 39 and 40 was not conclusively identified but has been assigned as shown below.

[0395] Example 39: Peak 1 (assigned 6R,7S of piperidine); 1H NMR (500 MHz, CDCl3) δ 7.34 - 7.28 (m, 2H), 7.25 - 7.16 (m, 3H), 6.42 - 5.74 (m, 1H), 4.88 - 4.60 (m, 1H), 4.48 - 4.35 (m, 1H), 4.34 - 4.12 (m, 1H), 4.11 - 3.88 (m, 1H), 3.88 - 3.73 (m, 4H), 3.70 - 3.62 (m, 1H), 3.33 - 3.21 (m, 2H), 3.13 - 2.96 (m, 1H), 2.55 (tt, J = 11.3, 4.2 Hz, 1H), 2.09 - 1.85 (m, 4H), 1.82 - 1.53 (m, 8H), 1.53 - 1.45 (m, 3H), 1.14 (t, J = 7.2 Hz, 3H).

[0396] LCMS (Method C): [M+H] + m / z 444.3, RT 1.00 min.

[0397] Chiral analysis (Chiralcelpak AS-H, 25x0.46cm, 5µm, 75 / 25 n-hexane / ethanol + 0.1% isopropylamine): RT 5.0min.

[0398] Example 40: Peak 2 (assigned 6S,7R of piperidine): 1H NMR (500 MHz, CDCl3) δ 7.34 - 7.28 (m, 2H), 7.25 - 7.16 (m, 3H), 6.42 - 5.74 (m, 1H), 4.88 - 4.60 (m, 1H), 4.48 - 4.35 (m, 1H), 4.34 - 4.12 (m, 1H), 4.11 - 3.88 (m, 1H), 3.88 - 3.73 (m, 4H), 3.70 - 3.62 (m, 1H), 3.33 - 3.21 (m, 2H), 3.13 - 2.96 (m, 1H), 2.55 (tt, J = 11.3, 4.2 Hz, 1H), 2.09 - 1.85 (m, 4H), 1.82 - 1.53 (m, 8H), 1.53 - 1.45 (m, 3H), 1.14 (t, J = 7.2 Hz, 3H).

[0399] LCMS (Method C): [M+H] + m / z 444.3, RT 1.00 min.

[0400] Chiral analysis (Chiralcelpak AS-H, 25x0.46cm, 5µm, 75 / 25 n-hexane / ethanol + 0.1% isopropylamine): RT 8.0min.

[0401] Example 41: rel-(6S,7R)-N-ethyl-3-fluoro-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide [ka] rel-(6S,7R)-tert-butyl-3-fluoro-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (Intermediate 62) [ka]

[0402] A solution of 2-chloro-2-fluoroacetyl chloride (282 mg, 2.15 mmol) in DCM (11 mL) was added to a stirred solution of Intermediate 6 (450 mg, 1.08 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (0.56 mL, 3.23 mmol) in DCM (11 mL) at 0° C., and the mixture was stirred for 0.5 h. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The residue was dissolved in anhydrous THF (11 mL) and sodium hydride (60%, 82 mg, 2.04 mmol) was added at room temperature, and the mixture was stirred at 50° C. for 0.5 h. Additional sodium hydride (60%, 82 mg, 2.04 mmol) was added at room temperature, and the reaction was stirred at 50° C. for 0.5 h. Additional sodium hydride (60%, 82 mg, 2.04 mmol) was added at room temperature and the reaction was stirred at 50° C. for 0.5 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (450 mg). [MH] - m / z 457.4.

[0403] rel-(6S,7R)-N-ethyl-3-fluoro-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (41) [ka]

[0404] A solution of trifluoroacetic acid (24 mL, 0.311 mmol) and Intermediate 62 (521 mg, 1.09 mmol) in DCM (23 mL) was stirred at room temperature for 1 h. The reaction was quenched with saturated NaHCO3 (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude mixture was dissolved in DCM (22 mL), and triethylamine (609 μL, 4.37 mmol) followed by isocyanatoethane (173 μL, 2.19 mmol) were added sequentially at room temperature, and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched with 2 M aqueous NaOH (15 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse phase column chromatography (10-60% MeCN in water (0.1% NH3)) to give the title compound (43 mg) as a white solid.

[0405] 1 H NMR (400 MHz, CDCl3) δ 7.33 - 7.27 (m, 2H), 7.23 - 7.16 (m, 3H), 6.49 (s, 1H), 5.57 (d, J = 51.8 Hz, 1H), 4.78 (t, J = 5.3 Hz, 1H), 4.51 - 4.46 (m, 1H), 4.17 (d, J = 11.9 Hz, 1H), 4.07 - 3.99 (m, 1H), 3.87 - 3.70 (m, 3H), 3.64 (p, J = 2.9 Hz, 1H), 3.31 - 3.21 (m, 2H), 3.05 (td, J = 13.2, 3.0 Hz, 1H), 2.63 - 2.48 (m, 1H), 2.09 - 1.92 (m, 3H), 1.80 - 1.47 (m, 9H), 1.13 (t, J = 7.2 Hz, 3H).

[0406] LCMS (Method A): [M+H] + m / z 448.4, RT 3.39 min.

[0407] Example 42: (6R,7S)-N-ethyl-3-fluoro-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (42) and Example 43: (6S,7R)-N-ethyl-3-fluoro-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (43) [ka] Example 41 (39 mg) was subjected to chiral preparative purification using a Waters 600 column, eluting with 80 / 20% v / v n-hexane / ethanol, Chiralpak AS-H (25 x 2.0 cm), 5 μm, at a flow rate of 17 mL / min to give the title compounds (peak 1, 15.5 mg, 100% ee, and peak 2, 15.2 mg, 99.6% ee). The absolute stereochemistry of each of the isolated compounds 42 and 43 was not conclusively identified but has been assigned as shown below.

[0408] Example 42: Peak 1 (assigned 6R,7S of piperidine); 11H NMR (500 MHz, CDCl3) δ 7.34 - 7.29 (m, 2H), 7.23 - 7.17 (m, 3H), 5.94 (br s, 1H), 5.59 (d, J = 51.9 Hz, 1H), 4.72 (br t, J = 4.9 Hz, 1H), 4.53 (br d, J = 3.4 Hz, 1H), 4.17 (br d, J = 11.8 Hz, 1H), 4.00 (br d, J = 10.6 Hz, 1H), 3.87 - 3.78 (m, 2H), 3.75 (dd, J = 9.9, 2.7 Hz, 1H), 3.67 - 3.61 (m, 1H), 3.32 - 3.22 (m, 2H), 3.18 - 3.04 (m, 1H), 2.64 - 2.48 (m, 1H), 2.09 - 1.96 (m, 3H), 1.80 (br d, J = 12.6 Hz, 1H), 1.77 - 1.66 (m, 5H), 1.64 - 1.56 (m, 3H), 1.14 (t, J = 7.3 Hz, 3H).

[0409] LCMS (Method C): [M+H] + m / z 448.3, RT 1.01 min.

[0410] Chiral analysis (Chiralcelpak AS-H, 25x0.46 cm, 5 μm, 80 / 20 n-hexane:ethanol): RT 6.3 min

[0411] Example 43: Peak 2 (assigned 6S,7R of piperidine); 1H NMR (500 MHz, CDCl3) δ 7.34 - 7.28 (m, 2H), 7.24 - 7.16 (m, 3H), 6.07 (br s, 1H), 5.59 (d, J = 51.9 Hz, 1H), 4.74 (br t, J = 5.1 Hz, 1H), 4.52 (br d, J = 4.0 Hz, 1H), 4.17 (br d, J = 11.9 Hz, 1H), 4.01 (br d, J = 11.8 Hz, 1H), 3.90 - 3.79 (m, 2H), 3.75 (dd, J = 9.9, 2.7 Hz, 1H), 3.69 - 3.59 (m, 1H), 3.35 - 3.20 (m, 2H), 3.19 - 3.05 (m, 1H), 2.63 - 2.49 (m, 1H), 2.12 - 1.95 (m, 3H), 1.80 (br d, J = 13.0 Hz, 1H), 1.76 - 1.66 (m, 5H), 1.66 - 1.58 (m, 3H), 1.14 (t, J = 7.2 Hz, 3H).

[0412] LCMS (Method C): [M+H] + m / z 448.3, RT 1.01 min.

[0413] Chiral analysis (Chiralcelpak AS-H, 25x0.46cm, 5µm, 80 / 20 n-hexane:ethanol): RT 9.4 min

[0414] Example 44: N-ethyl-8-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5.6]dodecane-2-carboxamide (44) [ka] tert-Butyl 4,4-difluoro-3-oxo-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 63) [ka]

[0415] Intermediate 2 (1.63 g, 4.21 mmol) in anhydrous THF (10 mL) was added dropwise to a 2 M solution of sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (2.5 mL, 5.05 mmol) in anhydrous THF (10 mL) at -78 °C and stirred for 30 minutes. After stirring, N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (1592 mg, 5.05 mmol) in anhydrous THF (10 mL) was added and the mixture was stirred at this temperature for 3 hours. The mixture was quenched with saturated aqueous NaHCO (20 mL), diluted with water (20 mL), and extracted with DCM (3 x 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the title compound (2.43 g) as a crude product. [M+Na] + m / z 446.1

[0416] tert-Butyl (3E / Z)-4,4-difluoro-3-{[(R)-2-methylpropane-2-sulfinyl]imino}-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 64) [ka]

[0417] Intermediate 63 (2.43 g, 5.74 mmol), (R)-2-methylpropane-2-sulfinamide (509 mg, 4.20 mmol), and titanium(4+) tetraethanolate (1.8 mL, 8.41 mmol) were dissolved in anhydrous THF (35 mL) and stirred at 60 °C overnight. The mixture was concentrated in vacuo, and the crude material was purified on a silica gel column (0-60% TBME in heptane) to give the title compound (729 mg, 50% purity) as a yellow gum. [M+Na] + m / z 549.2

[0418] tert-Butyl 3-(2-ethoxy-2-oxoethyl)-4,4-difluoro-3-{[(S)-2-methylpropane-2-sulfinyl]amino}-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 65) [ka]

[0419] A solution of anhydrous ethyl acetate (0.68 mL, 6.92 mmol) was added dropwise to a stirred solution of 2 M lithium dipropan-2-ylazanide (3.5 mL, 6.92 mmol) in THF (3 mL) at −78° C. The mixture was stirred for 30 minutes, after which a solution of Intermediate 64 (365 mg, 0.692 mmol) in dry THF (5 mL) was added dropwise, and the mixture was stirred at −78° C. for 1 hour. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl (10 mL), water (10 mL), and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography (0–100% EtOAc in heptane) to give the title compound (200 mg) as a beige solid. [M+H] + m / z 615.3

[0420] tert-Butyl 4,4-difluoro-3-(2-hydroxyethyl)-3-{[(S)-2-methylpropane-2-sulfinyl]amino}-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 66) [ka]

[0421] A 4 M solution of lithium tetrahydroborate (0.13 mL, 0.517 mmol) was added dropwise to a stirred solution of Intermediate 65 (200 mg, 0.325 mmol) in THF (2.6 mL) at 0° C. and stirred for 1 h. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with water (5 mL), extracted with EtOAc (3×5 mL), washed with brine (5 mL), dried over MgSO4, and concentrated in vacuo to give the title compound (155 mg) as a yellow gum. [M+H] + m / z 573.5

[0422] tert-Butyl 3-amino-4,4-difluoro-3-(2-hydroxyethyl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 67) [ka]

[0423] Intermediate 66 (155 mg, 0.271 mmol) was dissolved in methanol (2.3 mL) and cooled to 0 °C. 4 M HCl in dioxane (0.070 mL, 0.279 mmol) was added dropwise, and the reaction was stirred at 0 °C for 3 h. Additional 4 M HCl in dioxane (7.7 μL, 0.0310 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched at 0 °C by the dropwise addition of saturated aqueous NaHCO (5 mL) and extracted with 10% methanol in DCM (3 × 5 mL). The combined organic layers were filtered through a phase separator and concentrated in vacuo to give the title compound (150 mg) as a pale yellow oil, which was carried on to the next step without purification. [M+H] + m / z 469.5

[0424] tert-Butyl 11,11-difluoro-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (Intermediate 68) [ka]

[0425] N-Ethyl-N-(propan-2-yl)propan-2-amine (0.036 mL, 0.208 mmol) was added to a stirred solution of Intermediate 67 (65%, 150 mg, 0.208 mmol) and bis(trichloromethyl)carbonate (62 mg, 0.208 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 h, then quenched with saturated aqueous NaHCO (1 mL) and purged with N (g) for 30 min using a 20% NaOH scrubber to quench excess phosgene gas. The solution was extracted with DCM (3 × 1 mL), passed through a phase separator, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0–100% EtOAc) to give the title compound (60 mg) as a colorless gum. [M+H] + m / z 469.5

[0426] N-Ethyl-8-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5.6]dodecane-2-carboxamide (44) [ka]

[0427] A solution of trifluoroacetic acid (2.6 mL, 34.5 mmol) and Intermediate 68 (60 mg, 0.121 mmol) in DCM (2.6 mL) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was dissolved in DCM (1 mL) and cooled to 0 °C. Triethylamine (68 μL, 0.485 mmol) followed by isocyanatoethane (19 μL, 0.243 mmol) were added sequentially at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 2 M aqueous NaOH (2 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–60% MeCN in water (0.1% NH)) to give the title compound (8.0 mg) as a white solid.

[0428] 1 H NMR (400 MHz, CDCl3) δ 7.27 - 7.19 (m, 2H), 7.14 - 7.06 (m, 3H), 5.27 (s, 2H), 4.38 (d, J = 12.6 Hz, 1H), 4.34 - 4.18 (m, 2H), 4.12 (d, J = 9.3 Hz, 1H), 3.75 - 3.58 (m, 3H), 3.17 - 3.05 (m, 2H), 2.94 (td, J = 14.0, 3.8 Hz, 1H), 2.53 - 2.41 (m, 1H), 1.97 (td, J = 31.5, 28.3, 12.3 Hz, 6H), 1.68 - 1.54 (m, 6H), 1.01 (t, J = 7.2 Hz, 3H).

[0429] LCMS (Method A): [M+H] + m / z 466.4, RT 3.44 min

[0430] Example 45: (6R,7R)-N-ethyl-11,11-difluoro-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide Example 46: (6S,7S)-N-ethyl-11,11-difluoro-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide [ka] Example 44 (4.3 mg) was subjected to chiral preparative purification using a Waters 600 column, eluting with 80 / 20% v / v n-hexane / ethanol, Chiralpak AD-H (25 x 2.0 cm), 5 μm, at a flow rate of 17 mL / min to give the title compounds (peak 1, 2.1 mg, 100% ee, and peak 2, 1.7 mg, 100% ee). The absolute stereochemistry of each of the separated compounds 45 and 46 was not conclusively identified but has been assigned as shown below.

[0431] Example 45: Peak 1 (assigned 6R,7R of piperidine); 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 2H), 7.23 - 7.17 (m, 3H), 5.38 (s, 1H), 5.33 (br t, J = 5.1 Hz, 1H), 4.52 - 4.43 (m, 1H), 4.43 - 4.28 (m, 2H), 4.26 - 4.17 (m, 1H), 3.82 - 3.71 (m, 2H), 3.72 - 3.67 (m, 1H), 3.29 - 3.13 (m, 2H), 3.09 - 2.98 (m, 1H), 2.61 - 2.51 (m, 1H), 2.17 - 1.95 (m, 6H), 1.75 - 1.59 (m, 6H), 1.10 (t, J = 7.3 Hz, 3H).

[0432] LCMS (Method C): [M+H] + m / z 466.2, RT 1.03 min.

[0433] Chiral analysis (Chiralcelpak AD-H, 25x0.46cm, 5µm, 80:20 n-hexane:ethanol): RT 4.6 min

[0434] Example 46: Peak 2 (assigned 6S,7S of piperidine): 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 2H), 7.23 - 7.17 (m, 3H), 5.38 (s, 1H), 5.33 (br t, J = 5.1 Hz, 1H), 4.52 - 4.43 (m, 1H), 4.43 - 4.28 (m, 2H), 4.26 - 4.17 (m, 1H), 3.82 - 3.71 (m, 2H), 3.72 - 3.67 (m, 1H), 3.29 - 3.13 (m, 2H), 3.09 - 2.98 (m, 1H), 2.61 - 2.51 (m, 1H), 2.17 - 1.95 (m, 6H), 1.75 - 1.59 (m, 6H), 1.10 (t, J = 7.3 Hz, 3H).

[0435] LCMS (Method C): [M+H] + m / z 466.1, RT 1.03 min.

[0436] Chiral analysis (Chiralcelpak AD-H, 25x0.46cm, 5µm, 80:20 n-hexane:ethanol): RT 8.5 min

[0437] Example 47: (1R,3R,5S)-N-ethyl-3-methyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide [ka] Intermediate 69 [ka]

[0438] Methyl (3R)-3-{[(benzyloxy)carbonyl]({[methoxy(methyl)carbamoyl]methyl})amino}butanoate

[0439] To a solution of methyl (3R)-3-aminobutanoate hydrochloride (36.0 g, 0.234 mol) in acetonitrile (500 mL) was added dipotassium carbonate (71.3 g, 0.516 mol) followed by 2-chloro-N-methoxy-N-methylacetamide (32.2 g, 0.234 mol) in portions. The reaction mixture was heated to 40° C. and stirred for 7 days. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo, and the crude material was dissolved in DCM (500 mL) and cooled to 0° C. After which triethylamine (33 mL, 0.234 mol) and benzyl carbonochloridate (43 mL, 0.305 mol) were added dropwise, and the mixture was stirred at room temperature for 24 hours. The solution was diluted with DCM (500 mL), washed with NaHCO (300 mL), passed through a phase separator, and concentrated in vacuo to give the crude material. The crude material was purified (0-100% EtOAc in heptane) to give the title compound methyl (39.5 g) as a pale yellow oil. [M+H] + m / z 353.3

[0440] Intermediate 70 [ka]

[0441] 1-benzyl 3-methyl(2R)-2-methyl-4-oxopyrrolidine-1,3-dicarboxylate

[0442] To a stirred solution of Intermediate 69 (7.60 g, 21.6 mmol) in anhydrous THF (150 mL) was added 2 M sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (11 mL, 21.6 mmol) dropwise at −78° C. After stirring the solution at the same temperature for 10 min, the reaction was quenched with 1 M aqueous HCl (22 mL) and water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0–80% methanol in DCM) to give the title compound (4.40 g) as a yellow oil. [M+H]+ m / z 292.2

[0443] Intermediate 71 [ka]

[0444] 1-benzyl-3-methyl(2R)-2-methyl-4-oxo-5-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1,3-dicarboxylate

[0445] To a solution of 4-phenylcyclohexanol (5.99 g, 34.0 mmol) in anhydrous DCM (50 mL) was added paraformaldehyde (1.02 g, 34.0 mmol), followed by chloro(trimethyl)silane (17 mL, 0.136 mol). The reaction was stirred at room temperature for 2 hours, and the solution was concentrated in vacuo at 30 °C to give a pale yellow oil of [4-(chloromethoxy)cyclohexyl]benzene. In a separate flask, 2.4 M butyllithium (34 mL, 81.6 mmol) was added to a stirred solution of N-(propan-2-yl)propan-2-amine (11 mL, 81.6 mmol) in anhydrous THF (37.438 mL) at 0 °C. The reaction was held at this temperature for 0.5 hours. In a third flask, freshly prepared LDA was added to a stirred solution of 1,3-dimethylhexahydropyrimidin-2-one (16 mL, 0.136 mol) and Intermediate 70 (9.90 g, 34.0 mmol) in anhydrous THF (100 mL) at −78° C., and the solution was maintained at this temperature for 20 min. [4-(chloromethoxy)cyclohexyl]benzene was added to the reaction mixture in anhydrous THF (24 mL). The reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was quenched with NH4Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (1 × 50 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0–40% methanol in DCM) to give the title compound (9.90 g) as a colorless oil. [M+H] + m / z 480.3

[0446] Intermediates 72a and 72b [ka]

[0447] Intermediate 72a: benzyl (2S,5R)-5-methyl-3-oxo-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine di-1-carboxylate and

[0448] Intermediate 72b: Benzyl (2R,5R)-5-methyl-3-oxo-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine di-1-carboxylate

[0449] A suspension of intermediate 71 (7.80 g, 16.3 mmol) and sodium chloride (1.78 g, 30.5 mmol) in DMSO (78 mL) and water (7.8 mL) was heated to 130 °C for 2.5 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (3 × 30 mL), brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0–70% EtOAc in heptane) to give the title compounds 72a (2.4 g) and 72b (3.60 g) as pale yellow oils. [M+H] + m / z 422.3

[0450] Intermediate 73 [ka]

[0451] Benzyl-(2R,5R)-3-(hydroxyimino)-5-methyl-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate.

[0452] A solution of triethylamine (3.4 mL, 24.2 mmol), hydroxylamine hydrochloride (1:1) (1.68 g, 24.2 mmol), and Intermediate 72a (3.40 g, 8.07 mmol) in ethanol (15 mL) was heated to 90 °C for 1 h. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO, filtered, and concentrated in vacuo to give the title compound (3.30 g) as a colorless oil. [M+H] + m / z = 437.3

[0453] Intermediate 74 [ka]

[0454] Benzyl (2R,5R)-5-methyl-3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0455] Trifluoroacetic anhydride (1.4 mL, 10.4 mmol) in anhydrous acetonitrile (6.7 mL) was added to a stirred solution of hydrogen peroxide-urea (1:1) (1.37 g, 14.6 mmol) in anhydrous acetonitrile (6.7 mL) at 0 °C. The reaction was stirred at 0 °C for 2 h. The resulting solution was added dropwise to a mixture of Intermediate 73 (2.49 g, 4.16 mmol) and sodium bicarbonate (1.75 g, 20.8 mmol) in anhydrous acetonitrile (9.6184 mL) at 80 °C, and the mixture was stirred at 80 °C for 1 h. The reaction was cooled to room temperature, quenched with saturated aqueous NaSO, diluted with water (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (1.20 g) as a white solid. [M+H] + m / z = 453.3

[0456] Intermediate 75 [ka]

[0457] Benzyl (2R,3S,5R)-3-(hydroxymethyl)-5-methyl-3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0458] Formaldehyde (37% aqueous solution, 1.9 mL, 26.1 mmol) was added to Intermediate 74 (1.27 g, 2.90 mmol) and triethylamine (0.48 mL, 3.48 mmol) in THF (13 mL) at room temperature, and the solution was heated to 70 °C for 18 h. After cooling, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO, filtered, and concentrated in vacuo to give the title compound (1.42 g) as a colorless oil. [M+H] + m / z 483.3

[0459] Intermediate 76 [ka]

[0460] Benzyl (2R,3S,5R)-3-amino-3-(hydroxymethyl)-5-methyl-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0461] A suspension of Intermediate 75 (1.16 g, 2.40 mmol) and zinc (1.6 g, 24.0 mmol) in acetic acid (11.2 mL) and ethanol (83 mL) was stirred at room temperature for 2 hours. Additional zinc (1.55 g, 24.0 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was neutralized with saturated aqueous NaHCO3 and extracted with DCM (3 x 50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give the title compound (1.22 gm) as a white solid. [M+H] + m / z 453.4

[0462] Intermediate 77 [ka]

[0463] Benzyl (1R,3R,5S)-3-methyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0464] To a solution of intermediate 76 (200 mg, 0.442 mmol) in THF (2 mL) was added dipotassium carbonate (183 mg, 1.33 mmol) followed by water (2 mL) at 0° C. To this mixture was added chloroacetyl chloride (49 μL, 0.619 mmol) dropwise at 0° C. The reaction was stirred at 0° C. for 2 hours. The mixture was quenched with water and extracted with DCM (3×5 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. This intermediate was dissolved in DCM (4 mL) and IPA (4 mL), cooled to 0° C., potassium 2-methylpropan-2-olate (198 mg, 1.77 mmol) was added, and the reaction was stirred at 0° C. for 1 hour, then allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with water (5 mL). The mixture was poured into saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (80 mg) as a colorless oil. [M+H] + m / z 493.2

[0465] Intermediate 78 [ka]

[0466] (1R,3R,5S)-3-Methyl-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one

[0467] Intermediate 77 (80 mg, 0.162 mmol) was dissolved in ethanol (8 mL) and the atmosphere was evacuated and filled with nitrogen three times. Palladium on carbon (10%) (20 mg, 0.162 mmol) was added and the atmosphere was evacuated and filled with hydrogen three times. The reaction was stirred for 2 hours and then filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated in vacuo to give the title compound (58 mg) as a white gum. [M+H] + m / z 359.3

[0468] (1R,3R,5S)-N-Ethyl-3-methyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (47) [ka]

[0469] Isocyanatoethane (26 □L, 0.324 mmol) was added to a solution of triethylamine (45 □L, 0.324 mmol) and Intermediate 78 in anhydrous DCM (1.2 mL) at room temperature. The reaction was stirred for 1 h. The reaction mixture was quenched with 2 M aqueous NaOH and extracted with DCM (3 × 10 mL). The organic layers were combined, washed with brine (25 mL), passed through a phase separator, and concentrated in vacuo. The crude material was purified by reverse-phase flash column chromatography (10–100% MeCN in HO (0.1% NH)) to give the title compound (24 mg) as a white powder.

[0470] 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 2H), 7.24 - 7.15 (m, 3H), 6.36 (s, 1H), 5.14 (s, 1H), 4.24 (d, J = 16.8 Hz, 1H), 4.17 - 4.07 (m, 2H), 3.94 - 3.83 (m, 1H), 3.78 - 3.68 (m, 3H), 3.49 (dd, J = 9.4, 6.9 Hz, 1H), 3.43 (d, J = 11.7 Hz, 1H), 3.33 - 3.18 (m, 2H), 2.57 (tt, J = 10.6, 4.9 Hz, 1H), 2.27 (dd, J = 13.0, 7.4 Hz, 1H), 2.12 - 2.00 (m, 2H), 1.81 (dd, J = 13.0, 9.6 Hz, 1H), 1.73 (td, J = 9.0, 8.1, 3.5 Hz, 4H), 1.65 - 1.55 (m, 2H), 1.37 (d, J = 5.9 Hz, 3H), 1.13 (t, J = 7.3 Hz, 3H).

[0471] LCMS (Method A): [M+H] + m / z 430.4, RT 3.35 min

[0472] Example 48: (1S,3R,5R)-N-ethyl-3-methyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide [ka] Example 48 was synthesized using Intermediate 72b following the same procedure used to synthesize Example 47. The material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to afford Example 48 (44 mg) as a white powder. [M+H] + m / z 430.3

[0473] 1H NMR (500 MHz, CDCl3) δ 7.31 (t, J = 7.6 Hz, 2H), 7.20 (dd, J = 13.4, 7.1 Hz, 3H), 6.27 (s, 1H), 4.24 (d, J = 16.7 Hz, 2H), 4.12 - 4.05 (m, 3H), 4.03 - 3.90 (m, 2H), 3.65 - 3.59 (m, 1H), 3.56 (d, J = 11.6 Hz, 1H), 3.52 (dd, J = 10.5, 1.7 Hz, 1H), 3.34 - 3.21 (m, 2H), 2.65 - 2.48 (m, 2H), 2.04 - 1.95 (m, 2H), 1.81 (d, J = 13.1 Hz, 1H), 1.72 (td, J = 10.9, 10.0, 3.0 Hz, 2H), 1.69 - 1.42 (m, 5H), 1.29 (d, J = 6.4 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H).

[0474] LCMS (Method A): [M+H] + m / z 430.3, RT 3.28 min.

[0475] Example 49: (1R,3R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-methyl-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one [ka] A solution of intermediate 78 in anhydrous DMF (0.2 mL) was added to a stirred solution of 2-hydroxy-2-methylpropanoic acid (19 mg, 0.181 mmol), HATU (80 mg, 0.209 mmol), and DIPEA (49 μL, 0.279 mmol) in anhydrous DMF (1 mL) at room temperature, and the mixture was stirred for 18 h. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give the title compound (8.3 mg) as a beige solid.

[0476] 1 H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.4 Hz, 2H), 7.27 - 7.18 (m, 3H), 6.34 (s, 1H), 4.95 - 4.84 (m, 1H), 4.29 (d, J = 16.8 Hz, 1H), 4.23 - 4.14 (m, 2H), 3.86 (dd, J = 10.0, 3.1 Hz, 1H), 3.77 - 3.73 (m, 1H), 3.71 - 3.62 (m, 2H), 3.43 (d, J = 11.8 Hz, 1H), 2.60 (tt, J = 10.8, 5.0 Hz, 1H), 2.21 (dd, J = 13.1, 8.5 Hz, 1H), 2.11 (d, J = 12.0 Hz, 2H), 1.87 (dd, J = 12.9, 9.0 Hz, 1H), 1.77 (dd, J = 7.6, 4.5 Hz, 4H), 1.70 - 1.55 (m, 4H), 1.55 (s, 3H), 1.49 (s, 3H), 1.44 (d, J = 6.2 Hz, 3H).

[0477] LCMS (Method A): [M+H] + m / z 445.4, RT 3.46 min.

[0478] Example 50: (1R,3R,5S)—N-(2,2-difluoroethyl)-3-methyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide [ka] A solution of 2,2-difluoroethanamine (22 μL, 0.307 mmol) and N-ethyl-N-isopropyl-propan-2-amine (78 μL, 0.446 mmol) in anhydrous DCM (1.7 mL) was added dropwise to a stirred solution of carbonyl dichloride (20%, 0.15 mL, 0.279 mmol) and stirred at room temperature for 2 hours. This mixture was added to a solution of Intermediate 78 (50 mg, 0.139 mmol) in anhydrous DCM (1.7 mL), and the reaction was stirred at room temperature for 3 hours. Additional carbonyl dichloride (20%, 0.15 mL, 0.279 mmol) was added, and the reaction was stirred at room temperature for 15 minutes. Additional 2,2-difluoroethanamine (22 μL, 0.307 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 (5 mL) and purged with N2(g) (20% aqueous NaOH was used as a scrubber) for 30 minutes. The reaction mixture was extracted with DCM (3 x 3 mL), and the combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10-100% acetonitrile in water (0.1% NH3)) to give the title compound (23 mg) as a white powder.

[0479] 1H NMR (400 MHz, CDCl3) δ 7.33 - 7.27 (m, 2H), 7.23 - 7.14 (m, 3H), 6.41 (s, 1H), 6.06 - 5.63 (m, 2H), 4.25 (d, J = 16.9 Hz, 1H), 4.18 - 4.10 (m, 2H), 3.92 (dt, J = 9.6, 7.0 Hz, 1H), 3.82 - 3.59 (m, 4H), 3.55 - 3.36 (m, 3H), 2.57 (p, J = 8.7, 8.2 Hz, 1H), 2.27 (dd, J = 13.1, 7.4 Hz, 1H), 2.11 - 1.99 (m, 2H), 1.79 (dd, J = 13.1, 9.8 Hz, 1H), 1.76 - 1.66 (m, 4H), 1.64 (s, 2H), 1.37 (d, J = 6.0 Hz, 3H)

[0480] LCMS (Method A): [M+H] + m / z 466.4, RT 3.34 min.

[0481] Example 51: (1R,3R,5S)—N-(2-methoxyethyl)-3-methyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide [ka] A solution of 1-isocyanato-2-methoxyethane (12 μL, 0.112 mmol) was added dropwise to a stirred solution of Intermediate 78 (20 mg, 0.0558 mmol) and triethylamine (16 μL, 0.112 mmol) in anhydrous DCM (0.5 mL) at room temperature, and the mixture was stirred for 1 h. The reaction mixture was quenched with 2 M aqueous NaOH (1 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give the title compound (17 mg) as a white solid.

[0482] 1 H NMR (500 MHz, CDCl3) δ 7.35 - 7.29 (m, 2H), 7.26 - 7.18 (m, 3H), 6.29 (s, 1H), 5.24 (s, 1H), 4.26 (d, J = 16.8 Hz, 1H), 4.19 - 4.13 (m, 2H), 3.90 - 3.81 (m, 1H), 3.79 (dd, J = 9.7, 2.3 Hz, 1H), 3.75 - 3.65 (m, 1H), 3.57 (dd, J = 9.7, 5.2 Hz, 1H), 3.51 - 3.37 (m, 5H), 3.35 (s, 3H), 2.59 (tt, J = 11.5, 4.0 Hz, 1H), 2.32 (dd, J = 13.0, 7.5 Hz, 1H), 2.16 - 2.03 (m, 2H), 1.91 (dd, J = 13.0, 9.5 Hz, 1H), 1.86 - 1.68 (m, 4H), 1.68 - 1.63 (m, 2H), 1.41 (d, J = 6.0 Hz, 3H).

[0483] LCMS (Method B): [M+H] + m / z 460.4, RT 2.96 min.

[0484] Example 52: (1R,3R,5S)-2-(3,3-difluoroazetidine-1-carbonyl)-3-methyl-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one [ka] A solution of Intermediate 78 (40 mg, 0.112 mmol) in anhydrous DCM (0.7 mL) was added dropwise to a stirred solution of carbonyl dichloride (20%, 0.12 mL, 0.223 mmol) and N-ethyl-N-isopropyl-propan-2-amine (31 μL, 0.179 mmol) in anhydrous DCM (1.4 mL) at room temperature, and the mixture was stirred for 3 h. A solution of 3,3-difluoroazetidin-1-ium chloride (22 μL, 0.245 mmol) in anhydrous DCM (1.4 mL) and N-ethyl-N-isopropyl-propan-2-amine (31 μL, 0.179 mmol) was added dropwise to the reaction mixture at room temperature, and the reaction was stirred for 18 h. The reaction mixture was quenched with saturated aqueous NaHCO (5 mL) and purged with N (20% aqueous NaOH as a scrubber) for 30 min. The reaction mixture was extracted with DCM (3x3 mL) and the combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material, which was purified by reverse-phase column chromatography (10-100% acetonitrile in water (0.1% NH)) to give the title compound (16 mg) as a white powder.

[0485] 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.28 (m, 2H), 7.25 - 7.15 (m, 3H), 6.32 (s, 1H), 4.46 - 4.35 (m, 2H), 4.24 (d, J = 16.7 Hz, 1H), 4.21 - 4.11 (m, 3H), 4.00 (s, 1H), 3.93 (dd, J = 10.5, 2.2 Hz, 1H), 3.82 - 3.72 (m, 1H), 3.72 - 3.64 (m, 3H), 3.47 (d, J = 11.7 Hz, 1H), 2.64 - 2.52 (m, 1H), 2.27 (dd, J = 12.8, 7.8 Hz, 1H), 2.13 - 2.00 (m, 3H), 1.83 - 1.70 (m, 4H), 1.68 - 1.57 (m, 2H), 1.41 (d, J = 6.1 Hz, 3H).

[0486] LCMS (Method B): [M+H] + m / z 478.4, RT 3.50 min.

[0487] Example 53: (1S,3R,5S)-N-ethyl-3-methyl-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide [ka] Intermediate 79 [ka]

[0488] Benzyl (2R)-2-methyl-4-oxopyrrolidine-1-carboxylate

[0489] To a solution of Intermediate 70 (3.10 g, 10.6 mmol) in DMSO (55 mL) was added sodium chloride (1.18 g, 20.3 mmol) and water (5.5 mL), and the reaction mixture was heated to 130° C. for 2.5 h. The reaction mixture was cooled to room temperature, quenched with water (25 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (3×10 mL), brine (10 mL), dried over sodium sulfate, filtered, and evaporated to dryness to give the title compound (2.31 g) as a brown oil. [M+H] + m / z 234.2

[0490] Intermediate 80 [ka]

[0491] Benzyl (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-5-methyl-3-oxopyrrolidine-1-carboxylate

[0492] A solution of pyrrolidine (1.1 mL, 13.3 mmol) and Intermediate 79 (90%, 2.30 g, 8.87 mmol) in toluene (26 mL) was heated to reflux for 1.5 h using a Dean-Stark trap. The reaction mixture was cooled to room temperature and evaporated to dryness to give the crude material. This was dissolved in acetonitrile (18 mL) and treated with 1-bromo-3-(bromomethyl)-2-fluorobenzene (2.85 g, 10.6 mmol) in acetonitrile (9 mL) at room temperature, and the mixture was heated at 85 °C for 16 h. The reaction mixture was cooled to room temperature and evaporated to give the crude material. This was dissolved in water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated to dryness to give the crude material. The crude material was purified by silica gel column chromatography (0-85% EtOAc in heptane) to give the title compound (2.8 g) as an orange oil. [M+H] + m / z 420.2 / 422.1

[0493] Intermediate 81 [ka] Benzyl (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxyimino)-5-methylpyrrolidine-1-carboxylate

[0494] A solution of triethylamine (0.60 mL, 4.32 mmol), hydroxylamine hydrochloride (1:1) (0.30 g, 4.32 mmol) and Intermediate 80 (55%, 1.10 g, 1.44 mmol) in ethanol (4 mL) was heated to 90° C. for 1 h. After cooling, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.1 g) as a yellow oil. [M+H] + m / z 435.1 / 437.1

[0495] Intermediate 82 [ka]

[0496] Benzyl (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-5-methyl-3-nitropyrrolidine-1-carboxylate

[0497] Trifluoroacetic anhydride (1.6 mL, 11.3 mmol) in anhydrous acetonitrile (7.2916 mL) was added to a stirred solution of hydrogen peroxide-urea (1:1) (1.48 g, 15.8 mmol) in anhydrous acetonitrile (7.3 mL) at 0 °C. The reaction was stirred at 0 °C for 2 h. The resulting solution was added dropwise to a mixture of Intermediate 81 (1.96 g, 4.50 mmol) and sodium bicarbonate (1.89 g, 22.5 mmol) in anhydrous acetonitrile (10 mL) at room temperature. The mixture was then heated to 80 °C and stirred for 1 h. The reaction was cooled to room temperature, quenched with saturated aqueous NaSO, diluted with water (50 mL), and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-97% EtOAc in heptane) to give the title compound (0.19 g) as a colorless viscous material. [M+H] + m / z 451.1 / 453.1

[0498] Intermediate 83 [ka]

[0499] Benzyl (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-5-methyl-3-nitropyrrolidine-1-carboxylate

[0500] Formaldehyde (37% aqueous solution, 1.9 mL, 26.1 mmol) was added to a solution of Intermediate 82 (1.27 g, 2.90 mmol) and triethylamine (0.48 mL, 3.48 mmol) in THF (1.249 mL) at room temperature. The solution was heated to 70 °C for 6 h. After cooling, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (100 mg) as a colorless oil. [M+H] + m / z 481.9 / 482.9

[0501] Intermediate 84 [ka]

[0502] Benzyl (5R)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate

[0503] A suspension of Intermediate 83 (0.24 g, 0.499 mmol) and zinc (326 mg, 4.99 mmol) in acetic acid (2.3 mL) and ethanol (17 mL) was stirred at room temperature for 2 hours. Additional zinc (326 mg, 4.99 mmol) was added to the reaction, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was neutralized with saturated aqueous NaHCO3 and extracted with DCM (3 x 20 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give the title compound (220 mg) as a colorless oil. [M+H] + m / z 453.1

[0504] Intermediate 85 [ka]

[0505] Benzyl (3R)-1-[(3-bromo-2-fluorophenyl)methyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0506] To a solution of intermediate 84 (220 mg, 0.487 mmol) in THF (2.2 mL) was added dipotassium carbonate (202 mg, 1.46 mmol) followed by water (2.2 mL) at 0° C. To this mixture, chloroacetyl chloride (54 μL, 0.682 mmol) was added dropwise at 0° C. and stirred for 1 hour. The mixture was quenched with water and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to give the intermediate as an oily residue. This intermediate was dissolved in DCM (5 mL) and IPA (5 mL), cooled to 0° C., potassium 2-methylpropan-2-olate (219 mg, 1.95 mmol) was added, and the reaction was stirred at 0° C. for 1 hour. The mixture was quenched with water (10 mL). The mixture was poured into saturated aqueous NaHCO3 (5 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (140 mg) as a colorless oil. [M+NH4] + m / z = 510.2

[0507] Intermediate 86 [ka]

[0508] Benzyl (3R)-3-methyl-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0509] A mixture of Intermediate 85 (120 mg, 0.244 mmol), 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (78 mg, 0.488 mmol), 1 M aqueous potassium phosphate tribasic solution (0.73 mL, 0.733 mmol), and THF (2.4 mL) was added to N 2(g) The mixture was degassed at rt for 15 min. XPhos Pd G3 (21 mg, 0.0244 mmol) was added and the reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 1 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3 (3 mL), and extracted with ethyl acetate (3 x 3 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (90 mg) as a black oil. [M+H] + m / z 525.2

[0510] Intermediate 87 [ka]

[0511] (3R)-3-Methyl-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one

[0512] Intermediate 86 (90 mg, 0.172 mmol) was dissolved in ethanol (8.2 mL) and the atmosphere was evacuated and filled with nitrogen three times. Palladium on carbon (10%) (20 mg, 0.172 mmol) was added and the atmosphere was evacuated and filled with hydrogen three times. The reaction was stirred for 2 hours, filtered through a pad of Celite, washed with EtOAc, and concentrated in vacuo to give the title compound (65 mg) as a pale yellow oil. [M+H] + m / z 391.2

[0513] (1S,3R,5S)-N-Ethyl-3-methyl-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (53) [ka]

[0514] Isocyanatoethane (26 μL, 0.333 mmol) was added to a solution of triethylamine (46 μL, 0.333 mmol) and Intermediate 87 (65 mg, 0.166 mmol) in anhydrous DCM (1.3 mL) at room temperature. The reaction was stirred for 1 h, then quenched with 2 M aqueous NaOH and extracted with DCM (3 × 10 mL). The organic layers were combined, washed with brine (25 mL), passed through a phase separator, and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase flash column chromatography (10–60% MeCN in water) to give the title compound (12 mg) as a white solid.

[0515] 1 H NMR (400 MHz, CDCl3) δ 7.39 - 7.30 (m, 2H), 7.25 - 7.17 (m, 1H), 7.09 - 7.02 (m, 2H), 6.84 (tt, J = 8.9, 2.3 Hz, 1H), 6.35 (s, 1H), 4.24 - 4.05 (m, 3H), 4.04 - 3.93 (m, 1H), 3.66 (d, J = 11.8 Hz, 1H), 3.51 (s, 1H), 3.41 (d, J = 11.8 Hz, 1H), 3.13 (dd, J = 13.4, 4.8 Hz, 1H), 3.04 - 2.85 (m, 2H), 2.76 (dd, J = 13.0, 10.1 Hz, 1H), 2.28 (dd, J = 13.4, 7.6 Hz, 1H), 1.75 (dd, J = 13.4, 9.8 Hz, 1H), 1.40 (d, J = 6.1 Hz, 3H), 0.78 (t, J = 7.2Hz, 3H).

[0516] LCMS (Method A) [M+H] + m / z 462.3, RT 3.31 min

[0517] Example 54: (1S,3R,5S)-2-(2-hydroxy-2-methylpropanoyl)-3-methyl-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one [ka] Intermediate 87 (40 mg, 0.102 mmol) was added to a stirred solution of 2-hydroxy-2-methylpropanoic acid (14 mg, 0.133 mmol), HATU (58 mg, 0.154 mmol), and DIPEA (36 μL, 0.205 mmol) in anhydrous DMF (0.7 mL) at room temperature, and the mixture was stirred for 24 h. The reaction mixture was filtered and directly purified by prep-HPLC using the Acidic Early Elute Method on a Waters Sunfire C18 column (30 mm x 100 mm, 5 μm, room temperature). The flow rate was 40 mL / min and the injection volume was 1500 μL. The gradient was 10% B (A = 0.1% formic acid in water, B = 0.1% formic acid in acetonitrile) for 1.90 min, followed by a gradient of 10–95% B over 14.1 min with a 1.9 min hold. A second gradient of 95-10% B was applied over 0.3 min and held for an additional 0.9 min. The UV spectrum was recorded at 215 nm using a Gilson detector to give the title compound (7.8 mg) as a beige solid.

[0518] 1H NMR (400 MHz, CDCl3) δ 7.61 - 7.48 (m, 1H), 7.23 - 7.07 (m, 4H), 6.82 (ddd, J = 11.2, 5.6, 2.3 Hz, 1H), 6.00 (s, 1H), 5.08 (d, J = 8.7 Hz, 1H), 4.17 (s, 1H), 3.96 (d, J = 17.0 Hz, 1H), 3.86 (d, J = 17.6 Hz, 1H), 3.61 (d, J = 11.7 Hz, 1H), 3.33 (d, J = 11.8 Hz, 1H), 3.19 (dd, J = 14.6, 10.4 Hz, 1H), 3.09 (d, J = 14.3 Hz, 1H), 2.26 - 2.18 (m, 1H), 1.80 - 1.63 (m, 2H), 1.57 (s, 3H), 1.53 (s, 3H), 1.41 (d, J = 6.0 Hz, 3H).

[0519] LCMS (Method A): [M+H] + m / z 477.3, RT 3.29 min.

[0520] Example 55: rel-(1R,6S)-N-ethyl-8-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5.6]dodecane-2-carboxamide [ka] Intermediate 88 [ka]

[0521] tert-Butyl-rel-(2R,3S)-3-({[(1E / Z)-3-methoxy-3-oxoprop-1-en-1-yl]oxy}methyl)-3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0522] Methyl prop-2-ynoate (77 μL, 0.869 mmol) was added to a stirred solution of Intermediate 5 (300 mg, 0.669 mmol) and 1,4-diazabicyclo[2.2.2]octane (7.5 mg, 0.0669 mmol) in DCM (2.7 mL) at room temperature and stirred for 3 days. The reaction was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to afford the title compound (257 mg) as a colorless gum. [M+NH4] + m / z 550.4

[0523] Intermediate 89 [ka]

[0524] tert-Butyl-rel-(2R,3S)-3-[(3-methoxy-3-oxopropoxy)methyl]-3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0525] A suspension of Intermediate 88 (257 mg, 0.483 mmol) and palladium (10% on carbon, 50% wet) (5.0%, 103 mg, 0.0483 mmol) in ethyl acetate (6 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated in vacuo to give the title compound as a colorless gum (206 mg). [M+H] + m / z 535.5

[0526] Intermediate 90 [ka]

[0527] tert-Butyl-rel-(2R,3S)-3-amino-3-[(3-methoxy-3-oxopropoxy)methyl]-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0528] Zinc (462 mg, 7.07 mmol) was added to a stirred solution of Intermediate 89 (189 mg, 0.354 mmol) in ethanol (5 mL) and acetic acid (1.5 mL) at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was heated to reflux for 1 h. The reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated in vacuo, neutralized with saturated aqueous NaHCO3 (25 mL), and extracted with DCM (3×25 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the title compound (179 mg) as a colorless gum. [M+H] + m / z 505.7

[0529] Intermediate 91 [ka]

[0530] 3-{[rel-(2R,3S)-3-amino-1-[(tert-butoxy)carbonyl]-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidin-3-yl]methoxy}propanoic acid

[0531] A 2M aqueous solution of lithium hydroxide (1.0 mL, 2.00 mmol) was added to a stirred solution of Intermediate 90 (149 mg, 0.295 mmol) in THF (2 mL) at room temperature and stirred for 1 h. The reaction mixture was diluted with water (10 mL), brine (10 mL), and extracted with diethyl ether (2 x 20 mL). The aqueous layer was acidified to pH 1 with 2M aqueous HCl and re-extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (138 mg) as a colorless glass. [MH] - m / z 489.5.

[0532] Intermediate 92 [ka]

[0533] tert-Butyl-rel-(1R,6S)-8-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5.6]dodecane-2-carboxylate

[0534] A solution of T3P (50% in EtOAc) (0.38 mL, 0.637 mmol) was added to a stirred solution of Intermediate 91 (125 mg, 0.255 mmol) and triethylamine (0.12 mL, 0.892 mmol) in 1,4-dioxane (25 mL) at room temperature, and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (25 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (132 mg) as a colorless gum. [M+Na] + m / z 495.4

[0535] Intermediate 93 [ka]

[0536] rel-(1R,6S)-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5.6]dodecan-8-one

[0537] A solution of Intermediate 92 (132 mg, 0.279 mmol) in TFA (0.5 mL) and DCM (1 mL) was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the title compound (65 mg) as a colorless gum. [M+H] + m / z 373.4

[0538] rel-(1R,6S)-N-ethyl-8-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5.6]dodecane-2-carboxamide (55) [ka]

[0539] Isocyanatoethane (14 μL, 0.172 mmol) was added to a stirred solution of Intermediate 93 (32 mg, 0.086 mmol) and triethylamine (24 μL, 0.172 mmol) in DCM (1 mL) at room temperature, and the mixture was stirred for 0.5 h. The reaction mixture was quenched with 2 M aqueous NaOH (2 mL), and the reaction mixture was passed through a phase separator and washed with DCM (3 × 5 mL). The combined organic layers were concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give the title compound (20.2 mg) as a white solid.

[0540] 1 H NMR (500 MHz, CDCl3) δ 7.32 - 7.27 (m, 2H), 7.25 - 7.22 (m, 2H), 7.20 - 7.15 (m, 1H), 6.20 (s, 1H), 4.56 (t, J = 5.2 Hz, 1H), 4.14 (d, J = 12.8 Hz, 1H), 4.08 - 3.97 (m, 2H), 3.83 (dd, J = 9.7, 5.7 Hz, 1H), 3.75 (ddd, J = 12.2, 10.3, 1.5 Hz, 1H), 3.68 (dd, J = 9.7, 5.0 Hz, 1H), 3.64 (p, J = 3.2 Hz, 1H), 3.51 (d, J = 12.8 Hz, 1H), 3.27 (qd, J = 7.2, 1.1 Hz, 2H), 2.97 - 2.82 (m, 2H), 2.68 (dd, J = 16.3, 5.8 Hz, 1H), 2.52 (tt, J = 11.9, 3.5 Hz, 1H), 2.07 - 1.98 (m, 2H), 1.94 - 1.87 (m, 1H), 1.82 - 1.48 (m, 10H), 1.14 (t, J = 7.2 Hz, 3H). NH protons are unclear

[0541] LCMS (Method B): [M+H] + m / z 444.4, RT 2.95 min.

[0542] Example 56: 2,2-Difluoroethyl-rel-(6R,7R)-4-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,4,8-triazaspiro[5.5]undecane-8-carboxylate [ka] Intermediate 94 [ka]

[0543] tert-Butyl-rel-(2R,3R)-3-[(2-methylpropane-2-sulfinyl)amino]-3-(nitromethyl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0544] A 1M solution of N,N,N-tributylbutan-1-aminium fluoride in THF (1.9 mL, 1.94 mmol) was added dropwise to a stirred solution of Intermediate 11 (1.90 g, 3.87 mmol) in nitromethane (20 mL) at room temperature, and the mixture was stirred for 4 hours. The reaction mixture was concentrated in vacuo, then diluted with water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (1.25 g) as a white solid. [M+H] + m / z 552.5

[0545] Intermediate 95 [ka]

[0546] tert-Butyl-rel-(2R,3R)-3-[(2-methylpropane-2-sulfinyl)amino]-3-(nitromethyl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0547] Zinc (1.48 g, 22.7 mmol) was added to a stirred solution of Intermediate 94 (1.25 g, 2.27 mmol) in acetic acid (7 mL) and ethanol (25 mL) at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was quenched, neutralized with saturated aqueous NaHCO3 (30 mL), filtered through Celite (washed with EtOAc), and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (1.03 g). [M+H] + m / z 522.4

[0548] Intermediate 96 [ka]

[0549] tert-Butyl-rel-(2R,3R)-3-(aminomethyl)-3-[(2-methylpropane-2-sulfinyl)amino]-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0550] A solution of ethyl bromoacetate (255 μL, 2.30 mmol) was added dropwise to a stirred solution of triethylamine (534 μL, 3.83 mmol) and Intermediate 95 (1.00 g, 1.92 mmol) in anhydrous THF (25 mL) at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0–100% EtOAc in heptane, then 0–20% methanol in DCM) to give the title compound (1 g) as a colorless oil. [M+H] + m / z 608.4

[0551] Intermediate 97 [ka]

[0552] tert-Butyl-rel-(2R,3R)-3-{[(2-ethoxy-2-oxoethyl)amino]methyl}-3-[(2-methylpropane-2-sulfinyl)amino]-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0553] A 4M solution of hydrogen chloride (4M in dioxane) (1.1 mL, 4.44 mmol) was added dropwise to a stirred solution of Intermediate 96 (900 mg, 1.48 mmol) in methanol (5 mL) at 0° C., and the mixture was stirred for 16 h. The reaction mixture was warmed to room temperature, quenched with saturated aqueous NaHCO (25 mL), and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material (600 mg) as a yellow oil, which was used without further purification. [M+H] + m / z 504.5

[0554] Intermediate 98 [ka]

[0555] tert-Butyl-rel-(6R,7R)-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,4,8-triazaspiro[5.5]undecane-8-carboxylate

[0556] Lithium hydroxide solution (2 M aqueous solution) (1.5 mL, 3.0 mmol) was added to a stirred solution of Intermediate 97 (600 mg, 1.49 mmol) in THF (10 mL) at room temperature, and the mixture was stirred for 1 h. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The crude material was purified by reverse-phase column chromatography (10-100% acetonitrile in water (0.1% NH)) to give the title compound (48 mg) as a white solid. [M+H] + m / z 458.4

[0557] Intermediate 99 [ka]

[0558] tert-Butyl-rel-(6R,7R)-4-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,4,8-triazaspiro[5.5]undecane-8-carboxylate

[0559] Formaldehyde solution (37% aqueous) (37%, 32 μL, 0.393 mmol) was added dropwise to a stirred solution of tert-butyl intermediate 98 (15 mg, 0.0328 mmol) in DCM (0.6 mL) at room temperature, and the mixture was stirred for 1 h. Sodium triacetoxyborohydride (28 mg, 0.131 mmol) was added, and the reaction was stirred for an additional 1 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (15 mg) as a colorless oil. [M+H]+ m / z 472.5

[0560] 2,2-Difluoroethyl-rel-(6R,7R)-4-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,4,8-triazaspiro[5.5]undecane-8-carboxylate (56) [ka]

[0561] Intermediate 99 (20 mg, 0.0424 mmol) was stirred in a mixture of anhydrous DCM (0.25 mL) and TFA (0.25 mL) at room temperature for 30 minutes. The reaction mixture was quenched with NaHCO solution (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give the crude material. A solution of 2,2-difluoroethyl chloroformate (5.3 μL, 0.0509 mmol) was added dropwise to a stirred solution of the crude material and triethylamine (14 μL, 0.102 mmol) in anhydrous DCM (0.5 mL) at 0 °C, and the mixture was stirred for 30 minutes. Additional 2,2-difluoroethyl chloroformate (5.3 μL, 0.0509 mmol) was added, and the reaction was stirred for an additional 30 minutes. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10-100% acetonitrile in water (0.1% ammonia)) to give the title compound (8.6 mg) as a white solid.

[0562] 1H NMR (400 MHz, DMSO) δ 7.75 (s, 1H), 7.27 (dd, J = 8.0, 7.0 Hz, 2H), 7.22 - 7.12 (m, 3H), 6.17 (tdd, J = 54.8, 7.4, 3.8 Hz, 1H), 4.81 - 4.73 (m, 1H), 4.48 - 4.05 (m, 3H), 3.95 - 3.84 (m, 1H), 3.72 (t, J = 10.3 Hz, 1H), 3.59 (s, 1H), 3.48 (dd, J = 10.3, 4.3 Hz, 1H), 3.18 (d, J = 16.3 Hz, 1H), 2.97 (d, J = 11.7 Hz, 1H), 2.86 (d, J = 11.4 Hz, 1H), 2.58 (dd, J = 16.3, 3.5 Hz, 1H), 2.50 - 2.44 (m, 1H), 2.22 (s, 3H), 2.02 - 1.77 (m, 4H), 1.71 - 1.41 (m, 8H). The two rotamers and the peak at 2.44-2.50 were obscured by the DMSO peak.

[0563] LCMS (Method B): [M+H] + m / z 480.1, RT 3.11 min.

[0564] Example 57: 2,2-Difluoroethyl-rel-(6R,7R)-3-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,3,8-triazaspiro[5.5]undecane-8-carboxylate [ka] Intermediate 100 [ka]

[0565] tert-Butyl-rel-(2R,3R)-3-nitro-3-(2-oxoethyl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0566] To a solution of Intermediate 50 (1.00 g, 2.18 mmol) in THF (25 mL) and water (6.25 mL) was added potassium dioxide(dioxo)osmium hydrate (2:1:2) (40 mg, 0.109 mmol) and stirred at room temperature for 10 minutes. Sodium periodate (1.40 g, 6.54 mmol) was added and the reaction was stirred for 20 hours. Additional sodium periodate (1.40 g, 6.54 mmol) was added and the reaction was stirred for 4 hours. The reaction was quenched by the addition of sodium sulfite solution (20 mL) and water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, dried (MgSO), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-60% EtOAc in heptane) to give the title compound (660 mg) as a colorless oil. [M+H-Boc] + m / z 361.3

[0567] Intermediate 101 [ka]

[0568] tert-Butyl-rel-(2R,3R)-3-(2-hydroxyethyl)-3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0569] Sodium tetrahydroborate (80 mg, 2.12 mmol) was added to a stirred solution of Intermediate 100 (650 mg, 1.41 mmol) in anhydrous methanol (15 mL) at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo, then diluted with water (10 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (615 mg) as a white solid. [M+H-Boc] + m / z 363.3

[0570] Intermediate 102 [ka]

[0571] tert-Butyl-rel-(2R,3R)-3-[2-(methanesulfonyloxy)ethyl]-3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0572] A solution of methanesulfonyl chloride (125 μL, 1.62 mmol) was added dropwise to a stirred solution of Intermediate 101 (600 mg, 1.30 mmol) and triethylamine (226 μL, 1.62 mmol) in anhydrous DCM (10 mL) at 0° C., and the mixture was stirred for 3 h. The reaction mixture was warmed to room temperature, quenched with water (25 mL), and extracted with DCM (3×25 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0–50% EtOAc in heptane) to give the title compound (560 mg) as a colorless gum. [M+Na] + m / z 563.3

[0573] Intermediate 103 [ka]

[0574] tert-Butyl-rel-(2R,3R)-3-[2-(methylamino)ethyl]-3-nitro-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0575] A solution of methanamine (33% in ethanol) (33%, 5.0 mL, 40.2 mmol) was added dropwise to a stirred solution of tert-butyl Intermediate 102 (550 mg, 1.02 mmol) in THF (15 mL) at room temperature, and the mixture was heated at 65° C. for 16 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, then diluted with saturated aqueous NaHCO (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give the crude material. This crude material was used without further purification to give the title compound (430 mg) as a yellow oil. [M+H] + m / z 476.8

[0576] Intermediate 104 [ka]

[0577] tert-Butyl-rel-(2R,3R)-3-amino-3-[2-(methylamino)ethyl]-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0578] Zinc (591 mg, 9.04 mmol) was added to a stirred solution of Intermediate 103 (430 mg, 0.904 mmol) in acetic acid (3 mL) and ethanol (11 mL) at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL), filtered through Celite (washed with EtOAc), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material (135 mg) was used without further purification. [M+H]+ m / z 446.3

[0579] Intermediate 105 [ka]

[0580] tert-Butyl-rel-(6R,7R)-3-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,3,8-triazaspiro[5.5]undecane-8-carboxylate

[0581] CDI (18 mg, 0.112 mmol) was added to a stirred solution of Intermediate 104 (100 mg, 0.224 mmol) in anhydrous DMF (2.5 mL) at room temperature, and the mixture was stirred for 30 minutes. Further di-1H-imidazol-1-ylmethanone (18 mg, 0.112 mmol) was added, and the reaction was stirred for 30 minutes. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% formic acid)) to give the title compound (41 mg) as a white solid. [M+H] + m / z 472.4

[0582] 2,2-Difluoroethyl-rel-(6R,7R)-3-methyl-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-1,3,8-triazaspiro[5.5]undecane-8-carboxylate (57) [ka]

[0583] Intermediate 105 (40 mg, 0.0848 mmol) was stirred in a mixture of anhydrous DCM (0.5 mL) and TFA (0.5 mL) at room temperature for 30 minutes. The reaction mixture was quenched with NaHCO solution (1 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give the crude material. A solution of 2,2-difluoroethyl chloroformate (8.8 μL, 0.0848 mmol) was added dropwise to a stirred solution of the crude material and triethylamine (28 μL, 0.204 mmol) in anhydrous DCM (1 mL) at 0 °C, and the mixture was stirred for 30 minutes. The reaction mixture was quenched with methanol (0.5 mL), followed by water (5 mL), and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material, which was purified by reverse-phase column chromatography (10-100% acetonitrile in water (0.1% formic acid)) to give the title compound (23 mg) as a white solid.

[0584] 1 H NMR (400 MHz, DMSO) δ 7.29 - 7.23 (m, 2H), 7.22 - 7.18 (m, 2H), 7.18 - 7.12 (m, 1H), 6.17 (tt, J = 54.7, 3.4 Hz, 1H), 5.88 (s, 1H), 4.32 (s, 3H), 3.90 (d, J = 12.9 Hz, 1H), 3.76 (dd, J = 10.5, 8.8 Hz, 1H), 3.66 (dd, J = 10.6, 4.7 Hz, 1H), 3.60 (s, 1H), 3.33 (td, J = 11.9, 4.4 Hz, 1H), 3.14 (ddd, J = 12.5, 5.7, 3.3 Hz, 1H), 2.95 (d, J = 15.1 Hz, 1H), 2.80 (s, 3H), 2.59 - 2.52 (m, 1H), 2.05 (d, J = 14.4 Hz, 1H), 2.01 - 1.83 (m, 3H), 1.81 - 1.40 (m, 10H).

[0585] LCMS (Method B): [M+H] + m / z 480.4, RT 3.64 min.

[0586] Example 58: (1R,3R,5S)-2-Cyclobutanecarbonyl-3-methyl-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one [ka] A solution of intermediate 78 (69%, 15 mg, 0.0289 mmol) in anhydrous DMF (0.1 mL) was added to a stirred solution of cyclobutanecarboxylic acid (4.8 μL, 0.0499 mmol), HATU (24 mg, 0.0631 mmol), and DIPEA (15 μL, 0.0859 mmol) in anhydrous DMF (0.3 mL) at room temperature, and the mixture was stirred for 18 h. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% formic acid)) to give the title compound (1.8 mg) as a colorless gum.

[0587] 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.6 Hz, 2H), 7.25 - 7.15 (m, 3H), 6.51 - 6.11 (m, 1H), 4.40 - 4.10 (m, 3H), 4.06 - 3.94 (m, 1H), 3.92 - 3.76 (m, 1H), 3.72 - 3.66 (m, 1H), 3.65 - 3.55 (m, 1H), 3.49 - 3.35 (m, 1H), 3.33 - 3.11 (m, 1H), 2.65 - 2.25 (m, 3H), 2.26 - 2.14 (m, 2H), 2.11 - 2.03 (m, 2H), 2.01 - 1.86 (m, 2H), 1.80 - 1.66 (m, 6H), 1.65 - 1.53 (m, 2H), 1.43 (d, J = 6.1 Hz, 3H)

[0588] LCMS (Method B): [M+H] + m / z 441.4, RT 3.58 min.

[0589] Example 59: (1R,3R,5S)-3-methyl-2-[(1s,3s)-3-fluorocyclobutanecarbonyl]-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one [ka] A solution of intermediate 78 (20 mg, 0.0558 mmol) in anhydrous DMF (0.1 mL) was added to a stirred solution of 3-fluorocyclobutanecarboxylic acid (9.0 mg, 0.0762 mmol), HATU (32 mg, 0.0842 mmol), and DIPEA (20 μL, 0.115 mmol) in anhydrous DMF (0.4 mL) at room temperature, and the mixture was stirred for 18 h. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give the title compound (5.1 mg) as a beige solid.

[0590] 1 H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.6 Hz, 2H), 7.25 - 7.16 (m, 3H), 6.40 (s, 0.5H), 6.12 (s, 0.5H), 4.93 (ddd, J = 55.5, 15.3, 8.3 Hz, 1H), 4.36 (s, 0.5H), 4.28 - 4.08 (m, 2H), 4.02 (d, J = 3.1 Hz, 1H), 3.92 -3.79 (m, 1H), 3.67 (dd, J = 8.4, 4.1 Hz, 2.5H), 3.59 (d, J = 11.7 Hz, 1H), 3.43 (dd, J = 22.9, 11.8 Hz, 1H), 2.80 - 2.34 (m, 6H), 2.19 (dd, J = 12.9, 8.1 Hz, 1H), 2.10 - 2.01 (m, 2H), 1.94 (dd, J = 13.0, 9.5 Hz, 1H), 1.83- 1.60 (m, 6H), 1.43 (dd, J = 6.1, 1.8 Hz, 3H).

[0591] LCMS (Method A): [M+H] + m / z 459.5, RT 3.65 min.

[0592] Example 60: (1R,3R,5S)-2-{bicyclo[1.1.1]pentane-1-carbonyl}-3-methyl-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one Example 60 [ka] A solution of intermediate 78 (20 mg, 0.0558 mmol) in anhydrous DMF (0.1 mL) was added to a stirred solution of bicyclo[1.1.1]pentane-1-carboxylic acid (8.1 mg, 0.0725 mmol), HATU (32 mg, 0.0837 mmol), and DIPEA (19 μL, 0.112 mmol) in anhydrous DMF (0.4 mL) at room temperature, and the mixture was stirred for 18 h. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give the title compound (10 mg) as a white powder.

[0593] 1 H NMR (400 MHz, CDCl3) δ 7.35 - 7.28 (m, 2H), 7.24 - 7.16 (m, 3H), 6.25 (s, 1H), 4.37 (s, 1H), 4.26 (d, J = 16.7 Hz, 1H), 4.21 - 4.10 (m, 1H), 4.05 - 3.87 (m, 1H), 3.75 (dd, J = 10.1, 2.6 Hz, 1H), 3.72 - 3.64 (m,2H), 3.60 (d, J = 11.6 Hz, 1H), 3.43 (d, J = 11.6 Hz, 1H), 2.63 - 2.52 (m, 1H), 2.50 (s, 1H), 2.26 - 2.03 (m, 9H), 1.92 (dd, J = 12.9, 9.3 Hz, 1H), 1.84 - 1.69 (m, 4H), 1.61 (s, 2H), 1.52 - 1.36 (m, 3H).

[0594] LCMS (Method A): [M+H] + m / z 453.4, RT 3.62 min.

[0595] Example 61: 2,2-Difluoroethyl (1R,3R,5S)-3-methyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate [ka] A solution of 2,2-difluoroethyl chloroformate (8.6 μL, 0.0837 mmol) was added dropwise to a stirred solution of Intermediate 78 (20 mg, 0.0558 mmol) and triethylamine (19 μL, 0.134 mmol) in anhydrous DCM (0.5 mL) at 0° C., and the mixture was stirred for 1 h. The reaction mixture was quenched with methanol (1 mL) and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give the title compound (11 mg) as a white solid.

[0596] 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.4 Hz, 2H), 7.25 - 7.16 (m, 3H), 6.29 (d, J = 26.4 Hz, 1H), 5.96 (t, J = 54.7 Hz, 1H), 4.47 - 4.31 (m, 1H), 4.31 - 4.02 (m, 4H), 3.87 - 3.74 (m, 2H), 3.74 - 3.67 (m, 2H), 3.63(d, J = 10.4 Hz, 1H), 3.49 (dd, J = 11.6, 4.0 Hz, 1H), 2.67 - 2.49 (m, 1H), 2.40 - 2.15 (m, 1H), 2.11 - 1.95 (m, 3H), 1.84 - 1.68 (m, 4H), 1.68 - 1.59 (m, 2H), 1.43 (dd, J = 11.4, 5.9 Hz, 3H).

[0597] LCMS (Method B): [M+H] + m / z 467.3, RT 3.69 min.

[0598] Example 62: (1R,3R,5S)-3-methyl-7-oxo-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-N-(2,2,2-trifluoroethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide [ka] A solution of Intermediate 78 (40 mg, 0.112 mmol) in anhydrous DCM (1.4 mL) was added dropwise to a stirred solution of carbonyl dichloride (20%, 0.12 mL, 0.223 mmol) and N-ethyl-N-isopropyl-propan-2-amine (62 μL, 0.357 mmol) at room temperature, and the mixture was stirred for 3 h. A solution of 2,2,2-trifluoroethanamine (24 mg, 0.245 mmol) was added dropwise to the reaction mixture at room temperature, and the reaction was stirred for 18 h. The reaction mixture was quenched with saturated aqueous NaHCO (5 mL) and purged with N (g) (20% aqueous NaOH was used as a scrubber) for 30 min. The reaction mixture was extracted with DCM (3x3 mL) and the combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material, which was purified by reverse-phase column chromatography (10-100% acetonitrile in water (0.1% NH)) to give the title compound (10 mg) as a white powder.

[0599] 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.26 (m, 2H), 7.19 (dd, J = 7.3, 4.2 Hz, 3H), 6.23 (s, 1H), 5.91 (s, 1H), 4.27 (d, J = 16.9 Hz, 1H), 4.19 - 4.10 (m, 2H), 4.10 - 4.02 (m, 1H), 3.96 (dt, J = 9.8, 7.0 Hz, 1H), 3.79 -3.69 (m, 3H), 3.63 (ddd, J = 14.9, 9.0, 5.8 Hz, 1H), 3.49 - 3.41 (m, 2H), 2.61 - 2.51 (m, 1H), 2.28 (dd, J = 13.1, 7.4 Hz, 1H), 2.09 - 2.00 (m, 2H), 1.82 - 1.58 (m, 7H), 1.37 (d, J = 6.0 Hz, 3H).

[0600] LCMS (Method B): [M+H] + m / z 484.4, RT 3.36 min.

[0601] Example 63: (1R,3R,5S)-2-(3-methoxypyridin-2-yl)-3-methyl-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one [ka] A solution of Intermediate 78 (20 mg, 0.0558 mmol), 2-fluoro-3-methoxypyridine (8 μL, 0.0725 mmol), and cesium carbonate (36 mg, 0.112 mmol) in DMF (0.6 mL) was heated at 140° C. for 3 days. The reaction mixture was cooled to room temperature, quenched with water (1 mL), and extracted with ethyl acetate (3×1 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)), followed by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% formic acid)) to give the impure title compound (5 mg, 50%). This material was purified by preparative HPLC standard column: XBridge™ Prep. C18 10um OBD™, 30x100mm, mobile phase: 5-95% acetonitrile (0.2% ammonium hydroxide) water (0.2% ammonium hydroxide) over 10 min, flow rate: 40mL / min, UV: 215 and 254nm to give the title compound (0.5mg) as a colorless oil.

[0602] 1H NMR (500 MHz, CDCl3) δ 8.04 - 7.88 (m, 1H), 7.26 - 7.21 (m, 3H), 7.17 - 7.08 (m, 3H), 7.04 - 6.97 (m, 1H), 6.41 - 6.27 (m, 1H), 4.72 (s, 1H), 4.24 - 4.13 (m, 1H), 4.08 (dd, J = 16.7, 4.6 Hz, 1H), 3.98 - 3.90 (m, 1H), 3.87 - 3.81 (m, 4H), 3.65 (d, J = 2.7 Hz, 1H), 3.59 - 3.49 (m, 1H), 3.42 - 3.34 (m, 1H), 2.52 (dt, J = 15.4, 8.7 Hz, 1H), 2.34 - 2.25 (m, 1H), 2.22 - 2.13 (m, 1H), 2.07 - 1.96 (m, 2H), 1.76 - 1.70 (m, 3H), 1.69 - 1.62 (m, 3H), 1.27 (d, J = 3.6 Hz, 3H).

[0603] LCMS (Method A): [M+H] + m / z 466.4, RT 4.30 min.

[0604] Example 64: (1R,3R,5S)-3-methyl-2-(1-methyl-1H-1,2,3,4-tetrazol-5-yl)-1-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one [ka] 5-Chloro-1-methyl-tetrazole (21 mg, 0.181 mmol) was added to a stirred solution of Intermediate 78 (50 mg, 0.139 mmol) and triethylamine (58 μL, 0.418 mmol) in DMF (1.4 mL) at room temperature, and the stirred mixture was heated at 140° C. for 48 h. The reaction mixture was cooled to room temperature, quenched with water (1 mL), and extracted with ethyl acetate (3×2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give a mixture of compounds, which was further purified by acidic preparative HPLC (Waters CSH C18 column (19 mm × 100 mm, 5 μm, temperature: room temperature) with a flow rate of 20 mL / min and an injection volume of 1500 μL. 5% B (A = 0.2% formic acid in water, B = acetonitrile) was run for 2.0 min, followed by a gradient of 5–95% B over 18.0 min and a 2.0 min hold. A second gradient of 95–10% B over 0.2 min and a 0.9 min hold was applied. The UV spectrum was recorded at 215 nm using a Gilson detector to give the title compound (4 mg) as a white powder.

[0605] 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.27 (m, 2H), 7.23 - 7.15 (m, 3H), 6.65 (s, 1H), 4.31 - 4.12 (m, 2H), 4.15 - 4.08 (m, 1H), 4.04 - 3.97 (m, 4H), 3.90 (dd, J = 10.4, 2.8 Hz, 1H), 3.80 - 3.67 (m, 3H), 3.56 (d, J =11.9 Hz, 1H), 2.57 (p, J = 7.7 Hz, 1H), 2.37 (dd, J = 12.9, 7.4 Hz, 1H), 2.13 - 1.98 (m, 3H), 1.78 - 1.55 (m, 6H), 1.37 (d, J = 6.0 Hz, 3H).

[0606] LCMS (Method B): [M+H] + m / z 441.3, RT 3.05 min.

[0607] Example 65: 2,2-Difluoroethyl-rel-(6R,7R)-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate [ka] Intermediate 106 [ka]

[0608] tert-Butyl-rel-(2R,3R)-3-amino-3-(2-hydroxyethyl)-2-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0609] Zinc (1.84 g, 28.1 mmol) was added to a stirred solution of Intermediate 101 (650 mg, 1.41 mmol) in ethanol (19.5 mL) and acetic acid (5 mL) at 0° C., and the mixture was stirred for 2 hours while warming to room temperature. The reaction was filtered through a pad of Celite, washed with methanol (2×10 mL), and concentrated in vacuo. The reaction was neutralized with NaHCO3 solution and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (605 mg) as a colorless gum. [M+H] + m / z 433.5

[0610] Intermediate 107 [ka]

[0611] tert-Butyl-rel-(6R,7R)-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0612] A solution of N-ethyl-N-(propan-2-yl)propan-2-amine (0.36 mL, 2.08 mmol) was added dropwise to a stirred solution of bis(trichloromethyl)carbonate (535 mg, 1.80 mmol) and Intermediate 106 (600 mg, 1.39 mmol) in anhydrous DCM (20 mL) at 0 °C, and the mixture was stirred for 30 min. The reaction mixture was warmed to room temperature and purged with a stream of N2 through 5 N NaOH solution for 30 min (to quench excess phosgene). The reaction was then quenched with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by reverse phase column chromatography (10-100% acetonitrile in water (0.1% NH3)) to give the title compound (524 mg) as a white solid. [M+H] + m / z 459.5

[0613] Intermediate 108 [ka]

[0614] rel-(6R,7R)-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecan-2-one

[0615] Intermediate 107 (100 mg, 0.218 mmol) was dissolved in DCM (0.5 mL), then TFA solution (0.5 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated to dryness to give the title compound (80 mg) as a colorless sticky solid. [M+H] + m / z 359.3

[0616] Example 65 [ka]

[0617] 2,2-Difluoroethyl-rel-(6R,7R)-2-oxo-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0618] A solution of 2,2-difluoroethyl chloroformate (8.6 μL, 0.0837 mmol) was added dropwise to a stirred solution of Intermediate 108 (20 mg, 0.0558 mmol) and triethylamine (19 μL, 0.134 mmol) in anhydrous DCM (0.5 mL) at 0° C., and the mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with methanol (1 mL) and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10-100% acetonitrile in water (0.1% NH)) to give the title compound (10 mg) as a white solid.

[0619] 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 2H), 7.23 - 7.15 (m, 3H), 5.93 (tt, J = 55.1, 3.8 Hz, 1H), 5.55 - 5.42 (s, 1H), 4.49 - 3.96 (m, 6H), 3.91 - 3.74 (m, 2H), 3.68 - 3.61 (m, 1H), 3.30 - 3.04 (m, 1H), 2.63 - 2.46 (m, 1H), 2.26 - 1.93 (m, 4H), 1.77 - 1.65 (m, 7H), 1.60 - 1.47 (m, 3H).

[0620] LCMS (Method A): [M+H] + m / z 467.4, RT 3.60 min.

[0621] Example 66: (6R,7R)-8-[(CIS)-3-fluorocyclobutanecarbonyl]-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecan-2-one and Example 67: (6S,7S)-8-[(CIS)-3-fluorocyclobutanecarbonyl]-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecan-2-one [ka] A solution of intermediate 108 (45 mg, 0.126 mmol) in anhydrous DMF (0.23 mL) was added to a stirred solution of 3-fluorocyclobutanecarboxylic acid (20 mg, 0.169 mmol), HATU (72 mg, 0.189 mmol), and DIPEA (65 μL, 0.372 mmol) in anhydrous DMF (0.9 mL) at room temperature, and the mixture was stirred for 18 h. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give compound (47 mg) as a white solid. This was purified by basic preparative HPLC on a Waters XSelect CSH column (30 mm x 100 mm, 3 μm, room temperature) with a flow rate of 40 mL / min and an injection volume of 1000 μL. [A1: Waters + 0.1% NHOH], [B1: MeCN + 0.1% NHOH]. Gradient: 3% B1 to 99.9% B1 in 1.5 min (flow rate: 1.00 mL / min). Then, chiral preparative purification using a Waters 600 column was performed with 65 / 35% v / v n-hexane / ethanol, Chiralpak AS-H (25 x 2.0 cm), 5 μm column, at a flow rate of 17 mL / min, to give the title compounds (peak 1, 14.1 mg, 100% ee, and peak 2, 14.3 mg, 100% ee). The absolute stereochemistry of each of the isolated compounds 66 and 67 was not conclusively identified but has been assigned as shown below.

[0622] Example 66: Peak 1 (assigned 6R,7R of piperidine); 11H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 2H), 7.24 - 7.15 (m, 3H), 5.31 (br s, 1H), 5.15 - 4.73 (m, 2H), 4.46 - 4.23 (m, 2H), 3.96 - 3.70 (m, 2H), 3.69 - 3.38 (m, 3H), 2.86 - 2.67 (m, 1H), 2.65 - 2.40 (m, 5H), 2.38 - 2.22 (m, 1H), 2.12 - 1.92 (m, 3H), 1.88 - 1.46 (m, 10H).

[0623] LCMS (Method C): [M+H] + m / z 459.4, RT 1.07 minutes.

[0624] Chiral analysis (Chiralcelpak AS-H, 25x0.46 cm, 5 μm, 40:60 n-hexane:ethanol): RT 8.5 minutes

[0625] Example 67: Peak 2 (assigned 6S,7S of piperidine): 1 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 2H), 7.24 - 7.15 (m, 3H), 5.31 (br s, 1H), 5.15 - 4.73 (m, 2H), 4.46 - 4.23 (m, 2H), 3.96 - 3.70 (m, 2H), 3.69 - 3.38 (m, 3H), 2.86 - 2.67 (m, 1H), 2.65 - 2.40 (m, 5H), 2.38 - 2.22 (m, 1H), 2.12 - 1.92 (m, 3H), 1.88 - 1.46 (m, 10H).

[0626] LCMS (Method C): [M+H] + m / z 459.4, RT 1.07 minutes.

[0627] Chiral analysis (Chiralcelpak AS-H, 25x0.46cm, 5µm, 40:60 n-hexane:ethanol): RT 13.9 min

[0628] Example 68: rel-(6R,7R)-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-8-(2,2,2-trifluoroethyl)-3-oxa-1,8-diazaspiro[5.5]undecan-2-one [ka] rel-(6R,7R)-7-({[(CIS)-4-phenylcyclohexyl]oxy}methyl)-8-(2,2,2-trifluoroethyl)-3-oxa-1,8-diazaspiro[5.5]undecan-2-one

[0629] A solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (24 μL, 0.167 mmol) was added to a stirred solution of Intermediate 108 (41 mg, 0.110 mmol) and DIPEA (45 μL, 0.258 mmol) in anhydrous THF (1 mL) at room temperature, and the mixture was stirred for 60 h. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give the title compound (13 mg) as a white powder.

[0630] LCMS (Method A): [M+H] + m / z 441.5, RT 4.30 min.

[0631] 1H NMR (400 MHz, CDCl3) δ 7.35 - 7.27 (m, 2H), 7.23 - 7.16 (m, 3H), 5.61 (s, 1H), 4.38 - 4.27 (m, 2H), 3.82 (dd, J = 10.3, 6.9 Hz, 1H), 3.72 (dd, J = 10.3, 3.4 Hz, 1H), 3.62 (s, 1H), 3.43 (dq, J = 19.2, 9.4 Hz, 1H), 3.30 (dq, J = 18.1, 9.1 Hz, 1H), 3.05 - 2.92 (m, 2H), 2.76 - 2.66 (m, 1H), 2.60 - 2.47 (m, 2H), 2.03 (d, J = 14.3 Hz, 2H), 1.87 - 1.64 (m, 8H), 1.62 - 1.52 (m, 3H).

[0632] Example 69: rel-(1S,5S)-(4R)-N-ethyl-4-methyl-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide and Example 70: rel-(1S,5S)-(4S)-N-ethyl-4-methyl-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide [ka] Intermediate 109 [ka]

[0633] 1-tert-butyl 3-methyl 5-[(3-bromo-2-fluorophenyl)methyl]-3-methyl-4-oxopyrrolidine-1,3-dicarboxylate

[0634] A 0.6 M solution of sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (14 mL, 8.11 mmol) was added to a stirred solution of 1-tert-butyl 3-ethyl 3-methyl-4-oxopyrrolidine-1,3-dicarboxylate (2.00 g, 7.37 mmol) in anhydrous THF (28 mL) at −78° C., and the mixture was stirred for 15 minutes. 1-Bromo-3-(bromomethyl)-2-fluoro-benzene (2.17 g, 8.11 mmol) in anhydrous THF (9 mL) was added, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with DCM (3×50 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-10% EtOAc in heptane) to give the title compound (2:1 ratio of diastereomers) (1.8 g) as a pale yellow oil. [M-Boc+H] + m / z 358.0 and 360.0

[0635] Intermediate 110 [ka]

[0636] tert-Butyl 2-[(3-bromo-2-fluorophenyl)methyl]-4-methyl-3-oxopyrrolidine-1-carboxylate

[0637] A suspension of Intermediate 109 (99%, 2.89 g, 6.24 mmol) in 3 M hydrogen chloride (42 mL, 0.125 mol) was heated to 105 °C for 6 h. The reaction was quenched with saturated aqueous NaCO (20 mL) and extracted with DCM (3 x 50 ml). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give the crude material as a brown liquid. The crude material was dissolved in DCM (25 mL) and methanol (25 mL), and triethylamine (2.6 mL, 18.7 mmol) and di-tert-butyl dicarbonate (2.04 g, 9.34 mmol) were added. The mixture was stirred at room temperature for 16 h and then concentrated. 0.5 M NaOH (50 ml) was added, and the mixture was extracted with DCM (3 x 50 ml). The combined organic extracts were dried (MgSO), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-40% EtOAc in heptane) to give the title compound (1.13 g) as a yellow oil. (M-tBu+H) + m / z 330.3 and 332.3

[0638] Intermediate 111 [ka]

[0639] tert-Butyl-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxyimino)-4-methylpyrrolidine-1-carboxylate

[0640] A solution of triethylamine (2.1 mL, 15.2 mmol), hydroxylamine hydrochloride (1:1) (1.06 g, 15.3 mmol), and Intermediate 110 (99%, 1.98 g, 5.07 mmol) in ethanol (10.3 mL) was heated to 90 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 75 mL). These organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (2 g) as a colorless gum. [MtButyl + H]+ m / z 345.0 and 347.0

[0641] Intermediate 112 [ka]

[0642] tert-Butyl 2-[(3-bromo-2-fluorophenyl)methyl]-4-methyl-3-nitropyrrolidine-1-carboxylate

[0643] A solution of trifluoroacetic anhydride (1.8 mL, 13.0 mmol) in acetonitrile (9.45 mL) was added to a stirred solution of hydrogen peroxide-urea (1:1) (1.70 g, 18.1 mmol) in acetonitrile (9.45 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The resulting solution was added dropwise to a mixture of Intermediate 111 (2.10 g, 5.18 mmol) and sodium bicarbonate (2.18 g, 25.9 mmol) in acetonitrile (9.45 mL) at 80 °C over 1 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaSO (10 mL), stirred for 10 min, and then extracted with EtOAc (2 × 25 mL). The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (1.24 g) as a pale yellow oil. + m / z 361.2 and 363.1

[0644] Intermediate 113 [ka]

[0645] tert-Butyl-rel-(2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-4-methyl-3-nitropyrrolidine-1-carboxylate

[0646] Formaldehyde (aq) (37%, 1.8 mL, 24.2 mmol) was added to a solution of Intermediate 112 (90%, 1.24 g, 2.67 mmol) and triethylamine (0.45 mL, 3.22 mmol) in THF (13.551 mL) at room temperature. The solution was heated to 70 °C for 18 h. After cooling, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO, filtered, concentrated in vacuo, and purified by silica gel column chromatography (0-90% EtOAc in heptane) to give the title compound (1.03 g) as a yellow oil. [M-tBu+H] + m / z 393.1 and 391.1

[0647] Intermediate 114 [ka]

[0648] tert-Butyl-rel-(2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate

[0649] A suspension of intermediate 113 (100%, 1.03 g, 2.30 mmol) and zinc (1.50 g, 22.9 mmol) in acetic acid (11 mL) and ethanol (79 mL) was stirred at room temperature for 2 hours. The reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was neutralized with NaHCO and extracted with DCM (3 x 25 mL). The organic layer was dried over MgSO and concentrated in vacuo to give the title compound (850 mg) as a colorless oil. [M+H] + m / z = 417.2 and 419.2

[0650] Intermediate 115 [ka]

[0651] tert-Butyl-rel-(1S,5S)-1-[(3-bromo-2-fluorophenyl)methyl]-4-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0652] To a solution of Intermediate 114 (77%, 425 mg, 0.784 mmol) in THF (3.3 mL) was added dipotassium carbonate (325 mg, 2.35 mmol) followed by water (3.3 mL) at 0° C. To this mixture was added chloroacetyl chloride (0.087 mL, 1.10 mmol) dropwise at 0° C. The reaction was stirred at 0° C. for 1 h. The mixture was quenched with water and extracted with DCM (3×15 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to give an oily residue. The crude material was dissolved in DCM (7 mL) and IPA (11 mL) and cooled to 0° C. Potassium 2-methylpropan-2-olate (351 mg, 3.13 mmol) was added and the reaction was stirred at 0° C. for 1 h. The reaction was quenched by the addition of water (2 mL). The mixture was poured into saturated aqueous NaHCO3 (10 mL). After extraction with DCM (3 x 15 mL), the combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give a pale yellow oil. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (274 mg) as a white solid. [MH] - m / z 455.3 and 457.3

[0653] Intermediate 116 [ka]

[0654] tert-Butyl-rel-(1S,5S)-4-methyl-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0655] A mixture of intermediate 115 (95%, 260 mg, 0.541 mmol), 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (259 mg, 1.08 mmol), 1 M potassium phosphate triphosphatase (1 M in HO) (1.6 mL, 1.62 mmol), and THF (5.3 mL) was degassed (N purged) for 15 min. XPhos Pd G3 (46 mg, 0.0548 mmol) was added, and the reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 1 h. The reaction mixture was poured into saturated aqueous NaHCO3 (10 mL), and the mixture was extracted with ethyl acetate (3 × 25 mL). The organic layer was passed through a phase separator and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0–100% EtOAc in heptane) to give the title compound (172 mg) as a yellow oil. [MH] - m / z 489.4

[0656] Intermediate 117 [ka]

[0657] rel-(1S,5S)-4-methyl-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one

[0658] A mixture of tert-butyl intermediate 116 (97%, 177 mg, 0.350 mmol) in TFA (0.4 mL) and anhydrous DCM (0.4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was quenched with NaHCO solution (5 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give the title compound (129 mg) as a white solid. [M+H] + m / z 391.3

[0659] rel-(1S,5S)-(4R)-N-ethyl-4-methyl-7-oxo-1-({2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (69), and

[0660] rel-(1S,5S)-(4S)-N-ethyl-4-methyl-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (70) [ka]

[0661] Isocyanatoethane (23 μL, 0.287 mmol) was added to a solution of triethylamine (40 μL, 0.288 mmol) and Intermediate 117 (56 mg, 0.144 mmol) in anhydrous DCM (1.1 mL) at room temperature. The reaction was stirred for 1 h, then quenched with 2 M NaOH and extracted with DCM (3×10 mL). The organic layers were combined, washed with brine (25 mL), passed through a phase separator, and concentrated in vacuo. The crude material was purified by using basic preparative HPLC (Waters Sunfire C18 column (30 mm×100 mm, 5 μm, temperature: room temperature) to give the title compounds Example 69 (14 mg) and Example 70 (17 mg).

[0662] Example 69: 1H NMR (400 MHz, CDCl3) δ 7.41 (t, J = 6.3 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 7.5 Hz, 2H), 6.84 (tt, J = 8.9, 2.3 Hz, 1H), 6.63 (s, 1H), 4.27 (dd, J = 8.7, 5.3 Hz, 1H), 4.14 (t, J = 5.3 Hz, 1H), 4.07 (d, J = 16.7 Hz, 1H), 3.86 - 3.71 (m, 2H), 3.52 (d, J = 11.9 Hz, 1H), 3.41 - 3.32 (m, 2H), 3.23 (ddd, J = 12.9, 7.3, 5.7 Hz, 2H), 3.08 (dd, J = 10.4, 8.7 Hz, 1H), 3.00 (dd, J = 14.0, 8.8 Hz, 1H), 2.23 (q, J = 7.9 Hz, 1H), 1.19 (d, J = 7.0 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H). LCMS (Method A) (ESI+) (M+H) + : 462.3 , rt = 3.09

[0663] LCMS (Method A): [MH] - m / z 462.3, RT 3.09 min.

[0664] Example 70: 1H NMR (400 MHz, CDCl3) δ 7.43 (t, J = 6.3 Hz, 1H), 7.28 - 7.25 (m, 1H), 7.24 - 7.19 (m, 1H), 7.12 (d, J = 7.5 Hz, 2H), 6.84 (tt, J = 8.9, 2.3 Hz, 1H), 6.30 (s, 1H), 4.45 (t, J = 6.9 Hz, 1H), 4.06 - 3.88 (m, 3H), 3.66 - 3.51 (m, 3H), 3.23 - 3.11 (m, 2H), 3.05 (t, J = 10.2 Hz, 1H), 3.00 (d, J = 6.7 Hz, 2H), 2.49 - 2.37 (m, 1H), 1.12 (d, J = 7.0 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H). LCMS (Method A) (ESI+) (M+H) + : 462.3 , rt = 3.00.

[0665] LCMS (Method A): [MH] - m / z 462.3, RT 3.0 min.

[0666] Example 71: rel-(1S,5S)-2-[(1s,3s)-3-fluorocyclobutanecarbonyl]-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one [ka] Intermediate 118 [ka]

[0667] Benzyl 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylate

[0668] Pyrrolidine (4.8 mL, 57.6 mmol) was added to a stirred solution of benzyl 3-oxopyrrolidine-1-carboxylate (8.42 g, 38.4 mmol) in toluene (118 mL) at room temperature, and the mixture was heated at 140 °C (external temperature) for 1.5 h using a Dean-Stark trap. The reaction mixture was cooled to room temperature and evaporated to dryness to give the crude material. This was dissolved in anhydrous acetonitrile (67 mL) and reacted with 1-bromo-3-(bromomethyl)-2-fluorobenzene (12.34 g, 46.1 mmol) in acetonitrile (34 mL) at room temperature, and the mixture was heated at 80 °C for 16 h. The reaction mixture, cooled to room temperature, was concentrated in vacuo to give the crude material. This was dissolved in water (50 mL), acidified to pH 1 with 1 M HCl, and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and evaporated to dryness to give the crude material, which was purified by silica gel column chromatography (0-40% EtOAc in heptane) to give the title compound (6.74 g) as a pale yellow viscous oil. [M+H] + m / z 406.1 and 408.1

[0669] Intermediate 119 [ka]

[0670] Benzyl-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxyimino)pyrrolidine-1-carboxylate

[0671] A solution of triethylamine (5.1 mL, 36.3 mmol), hydroxylamine hydrochloride (1:1) (2.52 g, 36.3 mmol), and Intermediate 118 (73%, 6.74 g, 12.1 mmol) in ethanol (24.5 mL) was heated to 90 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 75 mL). These organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by column chromatography (0-100% EtOAc in heptane) to give the title compound (6.60 g) as a colorless gum. [M+H] + m / z = 421.1 / 423.1

[0672] Intermediate 120 [ka]

[0673] Benzyl 2-[(3-bromo-2-fluorophenyl)methyl]-3-nitropyrrolidine-1-carboxylate

[0674] A solution of trifluoroacetic anhydride (3.9 mL, 27.8 mmol) in acetonitrile (20 mL) was added to a stirred solution of hydrogen peroxide-urea (1:1) (3.66 g, 38.9 mmol) in acetonitrile (20 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The resulting solution was added dropwise to a mixture of Intermediate 119 (71%, 6.60 g, 11.1 mmol) and sodium bicarbonate (4.67 g, 55.6 mmol) in acetonitrile (20 mL) at 80 °C over 1 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaSO (10 mL), stirred for 10 min, and then extracted with EtOAc (2 × 25 mL). The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (5.20 g) as a pale yellow oil. [M+H] + m / z 437.2 / 440.2

[0675] Intermediate 121 [ka]

[0676] Benzyl-rel-(2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-3-nitropyrrolidine-1-carboxylate

[0677] Formaldehyde (aq) (37%, 6.2 mL, 83.8 mmol) was added to a solution of Intermediate 120 (78%, 5.20 g, 9.28 mmol) and triethylamine (1.6 mL, 11.2 mmol) in THF (47 mL) at room temperature. The solution was heated to 70° C. for 18 hours. After cooling, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (EtOAc in heptane) to give the title compound (4.67 g) as a yellow oil. [M+H] + m / z 467.1 and 469.1

[0678] Intermediate 122 [ka]

[0679] Benzyl rel-(2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)pyrrolidine-1-carboxylate

[0680] A suspension of benzyl intermediate 121 (78%, 4.67 g, 7.80 mmol) and zinc (5.10 g, 78.0 mmol) in acetic acid (36 mL) and ethanol (269 mL) was stirred at room temperature for 2 h. The reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was neutralized with NaHCO and extracted with DCM (3 x 75 mL). The organic layer was dried (MgSO) and concentrated in vacuo to give the title compound (4.30 g) as a colorless oil. [M+H] + m / z 437.2 and 439.2

[0681] Intermediate 123 [ka]

[0682] Benzyl rel-(1S,5S)-1-[(3-bromo-2-fluorophenyl)methyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0683] To a solution of intermediate 122 (0.87 g, 1.99 mmol) in THF (8.5 mL) at 0° C. was added dipotassium carbonate (825 mg, 5.97 mmol) followed by water (8.5 mL). To this mixture was added chloroacetyl chloride (0.22 mL, 2.78 mmol) dropwise at 0° C. The reaction was stirred at 0° C. for 1 hour. The mixture was quenched with water and extracted with DCM (3×25 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give an oily residue. This intermediate was dissolved in DCM (18 mL) and IPA (28 mL) and cooled to 0° C. Potassium 2-methylpropan-2-olate (893 mg, 7.96 mmol) was added and the reaction was stirred at 0° C. for 1 hour. The reaction was quenched by the addition of water (20 mL). The mixture was poured into saturated aqueous NaHCO3 (30 mL). After extraction with DCM (3 x 25 mL), the combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give a pale yellow oil. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (430 mg) as a white solid. [M+H] + m / z 475.2 and 477.2

[0684] Intermediate 124 [ka]

[0685] Benzyl-rel-(1S,5S)-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0686] A mixture of intermediate 123 (250 mg, 0.524 mmol), 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (251 mg, 1.05 mmol), 1 M aqueous potassium phosphate (1.6 mL, 1.57 mmol), and THF (5.1 mL) was degassed (N purged) for 15 min. XPhos Pd G3 (45 mg, 0.0531 mmol) was added, and the reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 1 h. The reaction mixture was poured into saturated aqueous NaHCO3 (10 mL), and the mixture was extracted with ethyl acetate (3 × 25 mL). The organic layer was passed through a phase separator and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0–100% EtOAc in heptane) to give the title compound (180 g) as a yellow oil. [M+H] + m / z 511.3

[0687] Intermediate 125 [ka]

[0688] rel-(1S,5S)-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one

[0689] Intermediate 124 (240 mg, 0.465 mmol) was dissolved in ethanol (22 mL) and the atmosphere was evacuated and filled with nitrogen three times. Palladium on carbon (10%) (5.0%, 99 mg, 0.0465 mmol) was added and the atmosphere was evacuated and filled with hydrogen three times. The reaction was stirred for 2 hours, then filtered through Celite, washed with EtOAc, and concentrated in vacuo to give the title compound (163 mg) as an orange solid. [M+H] + m / z 377.2

[0690] rel-(1S,5S)-2-[(1s,3s)-3-fluorocyclobutanecarbonyl]-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one (71): [ka]

[0691] A solution of intermediate 125 (48 mg, 0.128 mmol) in anhydrous DMF (0.23 mL) was added to a stirred solution of 3-fluorocyclobutanecarboxylic acid (20 mg, 0.172 mmol), HATU (73 mg, 0.193 mmol), and DIPEA (66 μL, 0.379 mmol) in anhydrous DMF (0.9162 mL) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was filtered. The crude material was purified by preparative HPLC using an XBridge™ Prep. C18 10 μm OBD™ column (30 × 100 mm), mobile phase: 30–95% acetonitrile (0.2% ammonium hydroxide) in water (0.2% ammonium hydroxide) for 10 min, flow rate: 40 mL / min, UV: 215 and 254 nm, to give the title compound (9.5 mg) as a white solid.

[0692] 1 H NMR (400 MHz, CDCl3) δ 7.49 - 7.29 (m, 1H), 7.25 - 7.15 (m, 2H), 7.13 - 6.99 (m, 2H), 6.89 - 6.77 (m, 1H), 6.57 (s, 1H), 5.07 - 4.25 (m, 2H), 4.24 - 4.07 (m, 1H), 4.06 - 3.87 (m, 1H), 3.80 - 3.28 (m, 4H), 3.15 - 2.66 (m, 2H), 2.63 - 2.15 (m, 4H), 2.14 - 1.98 (m, 2H), 1.97 - 1.70 (m, 1H).

[0693] LCMS (Method B): [M+H] + m / z 477.2, RT 3.07 min.

[0694] Example 72: (1S,5S)-2-[(CIS)-3-fluorocyclobutanecarbonyl]-1-({2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one (Example 72) and Example 73: (1R,5R)-2-[(CIS)-3-fluorocyclobutanecarbonyl]-1-({2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one (Example 73) Examples 72 and 73 [ka] Example 71 (6 mg) was subjected to chiral preparative purification using a Waters 600 column, eluting with 75 / 25% v / v n-hexane / (ethanol + 0.1% isopropylamine) on a Chiralpak IC (25 x 2.0 cm), 5 μm, at a flow rate of 17 mL / min to give the title compounds (peak 1, 2.2 mg, 100% ee, and peak 2, 2.7 mg, 99.1% ee). The absolute stereochemistry of compounds 72 and 73 was not conclusively identified but was assigned as shown below.

[0695] Example 72: Peak 1 (assigned 1S,5S of pyrrolidine); 1 H NMR (500 MHz, CDCl3) δ 7.45 - 7.16 (m, 3H), 7.23 - 7.10 (m, 2H), 7.04 - 6.91 (m, 1H), 4.96 - 4.49 (m, 1H), 4.81 - 4.32 (m, 1H), 4.24 - 3.86 (m, 2H), 3.77 - 3.40 (m, 4H), 3.09 - 2.82 (m, 2H), 2.75 - 1.82 (m, 1H), 2.56 - 1.50 (m, 6H).

[0696] LCMS (Method C): [M+H] +m / z 477.3, RT 0.98 min.

[0697] Chiral analysis (Chiralpak IC, 25x0.46cm, 5µm, 75:25 n-hexane / (ethanol + 0.1% isopropylamine)): RT 10.0min.

[0698] Example 73: Peak 2 (assigned 1R,5R of pyrrolidine): 1 H NMR (500 MHz, CDCl3) δ 7.45 - 7.16 (m, 3H), 7.23 - 7.10 (m, 2H), 7.04 - 6.91 (m, 1H), 4.96 - 4.49 (m, 1H), 4.81 - 4.32 (m, 1H), 4.24 - 3.86 (m, 2H), 3.77 - 3.40 (m, 4H), 3.09 - 2.82 (m, 2H), 2.75 - 1.82 (m, 1H), 2.56 - 1.50 (m, 6H).

[0699] LCMS (Method C): [M+H] + m / z 477.3, RT 0.98 min.

[0700] Chiral analysis (Chiralpak IC, 25x0.46cm, 5µm, 75:25 n-hexane / (ethanol + 0.1% isopropylamine)): RT 12.1min.

[0701] Example 74: 2,2-Difluoroethyl (1S,5S)-8-fluoro-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate and Example 75: 2,2-Difluoroethyl (1R,5R)-8-fluoro-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate [ka] Intermediate 126 [ka]

[0702] Benzyl-rel-(1S,5S)-1-[(3-bromo-2-fluorophenyl)methyl]-8-fluoro-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0703] A solution of 2-chloro-2-fluoroacetyl chloride (125 mg, 0.956 mmol) in DCM (5 mL) was added to a stirred solution of Intermediate 122 (200 mg, 0.478 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (250 μL, 1.44 mmol) in DCM (5 mL) at 0° C., and the mixture was stirred for 0.5 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (20 mL×3). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The residue was dissolved in anhydrous THF (21 mL) and slowly added to sodium hydride (60%, 0.16 g, 4.00 mmol) in anhydrous THF (11.5 mL) at 0° C. The mixture was stirred at this temperature for 30 min, then heated at 50° C. for 5 h and then stirred at room temperature for 16 h. The crude was purified by silica gel chromatography (0-100% EtOAc in heptane) to give the title compound (150 mg) as a colorless oil. [M+H] + m / z 495.2 and 497.2

[0704] Intermediate 127 [ka]

[0705] Benzyl-rel-(1S,5S)-8-fluoro-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0706] A mixture of intermediate 126 (46%, 150 mg, 0.139 mmol), 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (66 mg, 0.275 mmol), 1M potassium phosphate tribasic (1M in HO) (0.42 mL, 0.420 mmol), and THF (1.35 mL) was degassed (N purged) for 15 min. XPhos Pd G3 (5.9 mg, 6.96 μmol) was added, and the reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 1 h. The reaction mixture was poured into saturated aqueous NaHCO3 (5 mL), and the mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was passed through a phase separator and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0–100% EtOAc in heptane) to give the title compound (148 mg) as a yellow oil. [M+H] + m / z 529.4

[0707] Intermediate 128 [ka]

[0708] rel-(1S,5S)-8-fluoro-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-7-one

[0709] Intermediate 127 (49 mg, 148 mg, 0.137 mmol) was dissolved in ethanol (6.5 mL) and the atmosphere was evacuated and filled with nitrogen three times. Palladium on carbon (10%) (5.0%, 29 mg, 0.0137 mmol) was added and the atmosphere was evacuated and filled with hydrogen three times. The reaction was stirred for 3 hours, then filtered through Celite, washed with EtOAc, and concentrated in vacuo to give the title compound (80 mg) as a yellow oil. [M+H] + m / z 395.2

[0710] 2,2-Difluoroethyl (1S,5S)-8-fluoro-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (74) and

[0711] 2,2-Difluoroethyl (1R,5R)-8-fluoro-7-oxo-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (75) [ka]

[0712] A solution of 2,2-difluoroethyl chloroformate (16 μL, 0.155 mmol) in anhydrous DCM (0.45 mL) was added dropwise to a stirred solution of Intermediate 128 (50%, 80 mg, 0.101 mmol) and triethylamine (34 μL, 0.244 mmol) in anhydrous DCM (0.45 mL) at 0° C., and the mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with methanol (1 mL) and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase column chromatography (10–100% acetonitrile in water (0.1% NH)) to give the product mixture (16 mg) as a white solid. [MH] - The latter was subjected to chiral preparative purification using a Waters 600 column, eluting with 75 / 25% v / v n-hexane / ethanol, Chiralcel OD-H (25 x 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compounds (peaks 1 + 2, 3.7 mg, 28.2% ee + 71.8% ee, and peaks 3 + 4, 3.5 mg, 28.7% ee + 70.6% ee, respectively). The absolute stereochemistry of each peak in compounds 74 and 75 was not conclusively identified but has been assigned as shown below.

[0713] Example 74: Peaks 1+2 (assigned 1S,5S of pyrrolidine, racemic of morpholinone); 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.28 (m, 1H), 7.20 (q, J = 7.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 9.7 Hz, 1H), 6.23 (d, J = 34.9 Hz, 1H), 5.95 - 5.06 (m, 2H), 4.55 (d, J = 28.3 Hz, 1H), 4.37 - 4.03 (m, 2H), 3.97 (s, 1H), 3.70 (t, J = 13.7 Hz, 1H), 3.49 (d, J = 45.0Hz, 2H), 3.13 - 2.77 (m, 2H), 2.49 - 1.94 (m, 2H).

[0714] LCMS (Method C): [M+H] + m / z 503.2, RT 1.09-1.10 min.

[0715] Chiral analysis (Chiralcel OD-H, 25x0.46cm, 5µm, 75:25 n-hexane:ethanol): RT Peak 1 6.9 min, Peak 2 7.7 min.

[0716] Example 75: Peaks 3+4 (assigned 1R,5R pyrrolidine, racemic morpholinone): 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.28 (m, 1H), 7.19 (q, J = 7.5 Hz, 2H), 7.14 - 7.03 (m, 2H), 6.83 (d, J = 9.5 Hz, 1H), 6.34 (t, J = 36.0 Hz, 1H), 6.06 - 5.08 (m, 2H), 4.55 (d, J = 29.1 Hz, 1H), 4.35 - 4.03 (m, 2H), 3.98 (d, J = 12.6 Hz, 1H), 3.69 (t, J = 13.8 Hz, 1H), 3.62 - 3.33 (m, 2H), 3.14 - 2.78 (m, 2H), 2.48 - 1.96 (m, 2H).

[0717] LCMS (Method C): [M+H] + m / z 503.2, RT 1.09-1.10 min.

[0718] Chiral analysis (Chiralcel OD-H, 25x0.46cm, 5µm, 75:25 n-hexane:ethanol): RT Peak 3 10.7 min, Peak 4 12.1 min.

[0719] Example 76: rel-(6S,7R)-N-ethyl-7-({[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]oxy}methyl)-2-oxo-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide [ka] Intermediate 129 [ka]

[0720] 1-tert-butyl-4-ethyl-2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-oxopiperidine-1,4-carboxylate

[0721] A 500 mL RBF equipped with a stir bar, rubber septum, and attached to a vacuum / nitrogen lamp via a needle line was charged with a solution of diisopropylamine (23.74 mL, 169.4 mmol) in anhydrous THF (70 mL) under nitrogen. The mixture was cooled to -5 °C, and a 2.5 M solution of nBuLi in hexanes (67.76 mL, 169.4 mmol) was added dropwise while maintaining the internal temperature below 0 °C. The mixture was stirred at this temperature for 20 min. A separate 1 L three-neck RBF equipped with a stir bar, rubber septum, vacuum / nitrogen stopcock, and thermometer was charged with a solution of ethyl 1-N-boc-3-oxo-piperidine-4-carboxylate (20.89 g, 77 mmol) and 1,3-dimethyl-1,3-diazinan-2-one (37.1 mL, 308 mmol) in anhydrous THF (160 mL). The mixture was cooled to below −65°C in an acetone / dry ice bath, and the previously prepared solution of LDA was added dropwise to the substrate mixture over 20 min, maintaining the internal temperature below −65°C. After the addition, the mixture was stirred at the same temperature for 30 min. A separate 25 mL RBB equipped with a stir bar, rubber septum, and attached to a vacuum / nitrogen lamp via a needle line was charged with a solution of benzyl 4-(chloromethoxy)piperidine-1-carboxylate (24.03 g, 84.7 mmol) in anhydrous THF (70 mL). This solution was precooled to 0°C and then added dropwise to the lithiated piperidone substrate mixture, maintaining the internal temperature below −65°C. The mixture was stirred at this temperature for 1 h. The mixture was slowly warmed to 0°C, and then the reaction was quenched with saturated aqueous NH4Cl (250 mL) and water (150 mL). The mixture was extracted with EtOAc (200 mL), then the organic phase was separated, washed with brine (200 mL), dried over NaSO, filtered, and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel column chromatography (0-26% EtOAc in cHex) to give the title compound (32 g) as a colorless oil. [M+H] + m / z 419.4

[0722] Intermediate 130 [ka]

[0723] tert-Butyl 2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-oxopiperidine-1-carboxylate

[0724] A suspension of Intermediate 129 (3.85 g, 7.42 mmol) and sodium chloride (1.25 g, 21.3 mmol) in DMSO (30 mL) and water (3.5 mL) was heated to 120 °C (external temperature) for 6 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with water (400 mL), brine (100 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography (0-80% EtOAc in heptane) to give the title compound (1.75 g) as a yellow oil. [M+H] + m / z 447.4

[0725] Intermediate 131 [ka]

[0726] tert-Butyl 2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-(hydroxyimino)piperidine-1-carboxylate

[0727] A solution of triethylamine (2.1 mL, 14.8 mmol) was added dropwise to a stirred solution of hydroxylamine hydrochloride (1:1) (1.03 g, 14.8 mmol) and Intermediate 130 (2.20 g, 4.93 mmol) in ethanol (15 mL) at room temperature, and the mixture was heated at 80 °C for 1 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with water (25 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (1.88 g) as a yellow oil. [M+H] + m / z 462.5

[0728] Intermediate 132 [ka]

[0729] tert-Butyl 2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-nitropiperidine-1-carboxylate

[0730] A solution of trifluoroacetic anhydride (1.4 mL, 9.75 mmol) was added to a stirred solution of hydrogen peroxide-urea (1:1) (1.28 g, 13.6 mmol) in acetonitrile (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The resulting solution was added dropwise to a mixture of Intermediate 131 (1.80 g, 3.90 mmol) and sodium bicarbonate (1.64 g, 19.5 mmol) in acetonitrile (10 mL) at 80 °C, and the mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaSO (10 mL), stirred for 10 min, and then extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptane) to give the title compound (1.4 g) as a colorless oil. [M+H] + m / z 478.3

[0731] Intermediate 133 [ka]

[0732] tert-Butyl rel-(2R,3S)-2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-(hydroxymethyl)-3-nitropiperidine-1-carboxylate

[0733] Formaldehyde solution (aqueous) (37%, 1.1 mL, 14.7 mmol) was added to a stirred solution of Intermediate 132 (1.40 g, 2.93 mmol) and triethylamine (0.41 mL, 2.93 mmol) in THF (15 mL) at room temperature, and the mixture was heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with water (40 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-60% EtOAc in heptane) to give the title compound (1.03 g) as a colorless oil. [M+Na] + m / z 530.3

[0734] Intermediate 134 [ka]

[0735] tert-Butyl-rel-(2R,3S)-3-amino-2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-(hydroxymethyl)piperidine-1-carboxylate

[0736] Zinc (1.29 g, 19.7 mmol) was added to a stirred solution of Intermediate 133 (1.00 g, 1.97 mmol) in acetic acid (2.5 mL) and ethanol (10 mL) at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL), filtered through Celite (washed with EtOAc), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material (700 mg) was used without further purification as a colorless gum. [M+H] + m / z 478.4

[0737] Intermediate 135 [ka]

[0738] tert-Butyl-rel-(6S,7R)-7-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-2-oxo-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0739] A solution of chloroacetyl chloride (163 μL, 2.05 mmol) was added dropwise to a stirred solution of intermediate 134 (700 mg, 1.47 mmol) and dipotassium carbonate (608 mg, 4.40 mmol) in THF (6 mL) and water (6 mL) at 0° C., and the mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give the crude intermediate. This crude intermediate was dissolved in DCM (12 mL) and IPA (20 mL), cooled to 0° C., potassium 2-methylpropan-2-olate (658 mg, 5.86 mmol) was added, and the reaction was stirred at 0° C. for 16 h. The reaction was quenched by the addition of water (20 mL). The mixture was pour...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony, n and m are independently 0 or 1; A １ is -O-, -CR ４ R ５ --, --NR ６ -, -S- or a bond; A ２ is -C(O)- or -S(O) ２ - and A ３ and A ４ are independently -O-, -CR ４ R ５ --, --NR ６ , -S-, a bond, or A ３ and A ４ Together -C(R ４ ) = C(R ５ ) - and A ５ and A ６ are independently -O-, -CR ４ R ５ --, --NR ６ , -S- or a bond, but A ２ , A ３ , A ４ , A ５ and A ６ The ring containing is -O-O-, -NR ６ -NR ６ -or-O-NR ６ - provided that it does not contain L １ is -O-, -CR ４ R ５ - or a bond, L ２ is -CR ４ R ５ and R １ is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclyl, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclyl, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O) ２ -alkyl, -S(O) ２ -cycloalkyl, -S(O) ２ -heterocyclyl, -S(O) ２ -aryl, -S(O) ２ -heteroaryl, -(C=O)NR ７ R ８ or R １ and R ２ together with the atoms to which they are attached form a heterocycle or heteroaryl; R ２ and R ３ are independently hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, or R ２ and R ３ form a carbocyclic or heterocyclic ring together with the atoms to which they are attached, R ４ and R ５ are independently hydrogen, halo, alkyl, cycloalkyl, heterocyclyl, alkoxy, -O-cycloalkyl, -O-heterocyclyl, halogen, or R ４ and R ５ form a carbocyclic or heterocyclic ring together with the atoms to which they are attached, R ６ is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclyl, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclyl, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O) ２ -alkyl, -S(O) ２ -cycloalkyl, -S(O) ２ -heterocyclyl, -S(O) ２ -aryl, -S(O) ２ -heteroaryl -(C=O)NR ７ R ８ and R ７ and R ８ are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R ７ and R ８ form a heterocycle together with the atoms to which they are attached, Y is cycloalkyl, heterocyclyl, heteroaryl or aryl; Z is absent, heteroaryl or aryl, or a pharma- ceutically acceptable salt thereof.

2. R １ But, C １－６ Alkyl, 5- or 6-membered heteroaryl, -(C=O)NR ７ R ８ , -(C=O)-OC １－６ Alkyl, -(C=O)C ３－６ Cycloalkyl, -(C=O)C １－６ Alkyl, -(C=O)C ４－６ Saturated heterocyclyl, or -S(O) ２ -C １－６ is alkyl, Each of the above C １－６ Alkyl, C ３－６ Cycloalkyl, C ４－６ Saturated heterocyclyl and heteroaryl independently optionally include one or more hydroxyl, —C １－６ Alkyl, —O—C １－６ The compound of claim 1 which is substituted with alkyl or fluoro.

3. R ２ and R ３ are independently hydrogen or C １－５ alkyl, １－５ 3. The compound of claim 1 or 2, wherein the alkyl is optionally substituted with one or more fluoro.

4. R ４ and R ５ are independently hydrogen, halo, or C １－５ The compound according to any one of claims 1 to 3, which is alkyl.

5. R ７ and R ８ are independently hydrogen or C １－６ alkyl or R ７ and R ８ form a saturated heterocycle together with the atoms to which they are attached, １－６ The alkyl and saturated heterocycles are independently optionally joined with one or more fluoro or -O-C １－６ The compound according to any one of claims 1 to 4, which is substituted with alkyl.

6. 6. The compound of any one of claims 1 to 5, wherein Y is a 3- to 7-membered monocycloalkyl, a 4- to 7-membered saturated heterocyclyl, or a phenyl, said phenyl optionally substituted with one or more fluoro.

7. The compound according to any one of claims 1 to 6, wherein m and n are 0.

8. The compound according to any one of claims 1 to 6, wherein m is 1 and n is 0.

9. A １ But -CR ４ R ５ The compound according to any one of claims 1 to 8,

10. A ２ The compound according to any one of claims 1 to 9, wherein is -C(O)-.

11. A ２ , A ３ , A ４ , A ５ , and A ６ The compound according to any one of claims 1 to 10, wherein, together with the atoms to which they are attached, form a six-membered heterocycle.

12. L １ The compound according to any one of claims 1 to 11, wherein is a bond or -O-.

13. The compound according to claim 1, which is a compound of formula (II) 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof. (i) Y is cyclohexyl and Z is aryl, or (ii) The compound of claim 13, wherein Y is aryl and Z is aryl.

15. The compound according to claim 1, which is a compound of formula (III): 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

16. The compound according to claim 1, which is a compound of formula (IV): 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof, In the formula, R Ａ is independently selected from each occurrence of hydroxy, halo, -NO ２ , -CN, -NR ７ R ８ , -CO ２ R ９ , -OC(O)R ９ , -COR ９ , -C(O)NR ７ R ８ , -NR ７ C(O)R ８ , -OC(O)NR ７ R ８ , -NR ７ C(O)OR ９ , -S(O) ｗ R ９ (w is 0, 1, or 2), -OSO ２ R ９ , -SO ３ R ９ , -S(O) ２ N.R. ７ R ８ , -NR ７ S (O) ２ R ９ , -NR ７ C(O)NR ７ R ８ , -C １－６ Alkyl-NR ７ R ８ , -C １－６ Alkyl-O-C １－６ Alkyl, -C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenyl, and C ２－６ alkynyl, R ７ and R ８ are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R ７ and R ８ form a heterocycle together with the atoms to which they are attached, R ９ is independently, at each occurrence, hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ selected from the group consisting of alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl; p is 0, 1, 2, 3, or 4.

17. The compound of formula (I) 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 2. The compound of claim 1, selected from the group consisting of:

18.

27. 【Chemistry 28】 【Chemical 29】 18. The compound of claim 17, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and a pharma- ceutically acceptable excipient.

20. A compound according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19 for use in a method for the treatment of a disease or disorder treatable by administration of an orexin agonist, comprising The compounds and pharmaceutical compositions, wherein the methods comprise administering a therapeutically effective amount of the compounds or the pharmaceutical compositions.

21. A compound according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19 for use in a method for the treatment of a sleep disorder in a subject in need thereof, comprising The compounds and pharmaceutical compositions, wherein the methods comprise administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition.

22. (i) Narcolepsy (ii) hypersomnia, or (iii) excessive sleepiness A compound according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19 for use in a method for the treatment of a subject in need thereof, comprising The compounds and pharmaceutical compositions, wherein the methods comprise administering to the subject an effective amount of the compound or the pharmaceutical composition.

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