Orexin receptor agonists and uses thereof

Abstract

This document provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y, and Z are as defined herein. This document also provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof, and methods of using compounds of formula (I) or pharmaceutically acceptable salts thereof, for example, for treating diseases or conditions that can be treated by administration of orexin agonists.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 183,321, filed May 3, 2021, the contents of which are hereby incorporated, in their entirety, for all purposes. Background Technology

[0003] Orexin is a neuropeptide produced specifically in particular neurons sparsely located in and around the lateral hypothalamus. Orexin consists of two subtypes: orexin A and orexin B. Both orexin A (OX-A) and orexin B (OX-B) are endogenous ligands of the orexin receptor, which is primarily located in the brain. Two orexin receptors have been cloned and characterized in mammals. These two orexin receptors 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 both OX-A and OX-B with similar affinity. It is believed that the physiological functions speculated to involve orexin are expressed via one or both of the two orexin receptor subtypes, OX1 and OX2.

[0004] Orexin regulates sleep and wakefulness, making the orexin system a potential target for treatment of sleep disorders. Orexin has been found to stimulate food consumption in rats, suggesting a mediator role for these peptides in the central feedback mechanisms regulating feeding behavior. Orexin has also been indicated to play roles in arousal, mood, energy homeostasis, reward, learning, and memory.

[0005] Compounds that need to modulate orexin receptors, and compositions and methods for treating diseases or conditions that can be treated by administration of orexin agonists. Summary of the Invention

[0006] This disclosure relates to compounds as orexin-2 receptor agonists, pharmaceutical compositions thereof, and their use in treating diseases or conditions that can be treated by administration of orexin agonists.

[0007] In one aspect, this disclosure provides a compound of formula (I):

[0008]

[0009] Or its pharmaceutically acceptable salt.

[0010] in

[0011] n and m are independently 0 or 1;

[0012] A1 is -O-, -CR4R5-, -NR6-, -S-, or a bond;

[0013] A2 is -C(O)- or -S(O)2-;

[0014] A3 and A4 are independently -O-, -CR4R5-, -NR6, -S-, bonds; or A3 and A4 together are -C(R4) = C(R5)-;

[0015] A5 and A6 are independently -O-, -CR4R5-, -NR6, -S- or bonds; the condition is that the ring including A2, A3, A4, A5 and A6 does not contain -OO-, -NR6-NR6- or -O-NR6-.

[0016] L1 is -O-, -CR4R5-, or a bond;

[0017] L2 is -CR4R5;

[0018] R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclic, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclic, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclic, -S(O)2-aryl, -S(O)2-heteroaryl, -(C=O)NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle or heteroaryl;

[0019] R2 and R3 are independently hydrogen, halogen, alkyl, cycloalkyl, heterocyclic group, or R2 and R3 together with the atoms they are attached to form a carbocyclic or heterocyclic ring;

[0020] R4 and R5 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, –O-cycloalkyl, –O-heterocyclic, halogen, or R4 and R5 together with the atoms they are attached to form a carbocyclic or heterocyclic ring;

[0021] R6 is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclic, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclic, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclic, -S(O)2-aryl, -S(O)2-heteroaryl, or -(C=O)NR7R8.

[0022] R7 and R8 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, or R7 and R8 together with the atoms they are attached to form a heterocycle;

[0023] Y is a cycloalkyl, heterocyclic, heteroaryl, or aryl group; and

[0024] Z is absent, or it is either a heteroaryl or aryl group.

[0025] In some embodiments, this disclosure provides a compound of formula (II):

[0026]

[0027] Or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are as defined herein.

[0028] In some embodiments, this disclosure provides a compound of formula (III):

[0029]

[0030] Or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3 and Z are as defined herein.

[0031] In some embodiments, this disclosure provides a compound of formula (IV):

[0032]

[0033] Or a pharmaceutically acceptable salt thereof, wherein n, m, p, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, R A Z is as defined in this article.

[0034] In some embodiments, this disclosure provides a compound of formula (VA):

[0035]

[0036] Or its pharmaceutically acceptable salt, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A and R B As defined in this article.

[0037] In some embodiments, this disclosure provides a compound of formula (VB):

[0038]

[0039] Or its pharmaceutically acceptable salt, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A and R B As defined in this article.

[0040] In some embodiments, this disclosure provides a compound of formula (VC):

[0041]

[0042] Or its pharmaceutically acceptable salt, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A and R B As defined in this article.

[0043] In some embodiments, this disclosure provides a compound of formula (VI-A):

[0044]

[0045] Or its pharmaceutically acceptable salts, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3 and R B As defined in this article.

[0046] In some embodiments, this disclosure provides a compound of formula (VI-B):

[0047]

[0048] Or its pharmaceutically acceptable salts, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3 and R B As defined in this article.

[0049] In some embodiments, this disclosure provides a compound of formula (VI-C):

[0050]

[0051] Or its pharmaceutically acceptable salts, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3 and R B As defined in this article. Detailed Implementation

[0052] Throughout this disclosure, numerous patents, patent applications, and publications are cited. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety for all purposes to more fully describe the present art as known to those skilled in the art up to the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0053] For convenience, certain terms used in the specification, embodiments, and appended claims are collected herein. 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 pertains.

[0054] The term “about” immediately preceding a numerical value indicates a range (e.g., plus or minus 10% of the value). For example, unless the context of this disclosure otherwise indicates or is inconsistent with such an interpretation, “about 50” may mean 45 to 55, “about 25,000” may mean 22,500 to 27,500, and so on. For example, in a list of numerical values ​​such as “about 49, about 50, about 55…”, “about 50” means a range extending to less than half the interval between the preceding and following values, e.g., greater than 49.5 to less than 50.5. Furthermore, the phrase “less than about” or “greater than about” should be understood according to the definition of the term “about” provided herein. Similarly, when preceding a series of numerical values ​​or ranges of values ​​(e.g., “about 10, 20, 30” or “about 10-30”), the term “about” refers to all values ​​in the series, or the endpoints of the range, respectively.

[0055] As used herein, the term "administer / administering / administration" refers to the administration of a compound or a pharmaceutically acceptable salt thereof, or a composition or preparation containing the compound or a pharmaceutically acceptable salt thereof, to a patient.

[0056] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound that acts as a base with an inorganic or organic acid to form a salt, such as salts of 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, and carbonic acid. Base addition salts include, but are not limited to, ethylenediamine, N-methylglucosamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, benzylphenylethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, 1-diphenylhydroxymethylamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, and basic amino acids, such as lysine and arginine dicyclohexylamine. Examples of metal salts include lithium, sodium, potassium, magnesium, and calcium salts. Examples of ammonium salts and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, and tetramethylammonium salts. 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 any of a variety of known methods through the reaction of the compound with a suitable inorganic or organic acid.

[0057] As used in this article, the term "treatment" refers to the improvement of at least one symptom of a patient's condition. Treatment can be the improvement or at least partial improvement of the condition or related symptoms.

[0058] The terms “effective amount” and “therapeutic effective amount” are used interchangeably in this disclosure and refer to the amount of a compound or a salt thereof (or a pharmaceutical composition containing said compound or salt) that, when administered to a patient, achieves the desired results. The “effective amount” will vary depending on the active ingredient, the state to be treated, the condition or disease and its severity, and the age, weight, physical condition, and responsiveness of the mammal to be treated.

[0059] The term “therapeuticly effective” when applied to dosage or amount refers to the amount of a compound or pharmaceutical preparation that is sufficient to produce the desired clinical benefit when administered to a patient in need.

[0060] As may be used interchangeably herein, the terms "carrier" or "medium" include carriers, excipients, adjuvants, and diluents, or any combination thereof, and refer to materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that participate in the transport or delivery of a pharmaceutical agent from one organ or body part to another. In addition to adjuvants, excipients, and diluents known to those skilled in the art, carriers also include nanoparticles of both organic and inorganic properties.

[0061] When listing a series of values, the aim is to cover every value and subrange within the stated range. For example, "C1-C6 alkyl" is intended to cover 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.

[0062] "alkyl" or "alkyl group" refers to a fully saturated straight-chain or branched hydrocarbon chain having one to twelve carbon atoms, connected to the rest of the molecule by a single bond. This includes alkyl groups containing any number of carbon atoms from 1 to 12. Alkyl groups containing up to 12 carbon atoms are C1-C1. 12 Alkyl groups, which contain up to 10 carbon atoms, are C1-C6. 10 Alkyl groups, specifically C1-C6 alkyl groups containing up to six carbon atoms, and C1-C5 alkyl groups containing up to five carbon atoms, are further defined. C1-C5 alkyl groups include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups include all the C1-C5 alkyl groups described above, but also include C6 alkyl groups. C1-C 10 Alkyl groups include all the portions of C1-C5 and C1-C6 alkyl groups mentioned above, but also include C7, C8, C9 and C6 alkyl groups. 10 Alkyl group. Similarly, C1-C 12 Alkyl groups include all of the above-mentioned portions, but also include C. 11 and C 12 Alkyl group. C1-C 12Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated in the specification, alkyl groups may optionally be substituted.

[0063] "alkylene" or "alkylene chain" refers to a fully saturated straight-chain or branched divalent hydrocarbon chain group having one to twelve carbon atoms. C1-C 12 Non-limiting examples of alkylenes include methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the remainder of the molecule by a single bond and to a group (e.g., those described herein) by a single bond. The connection point between the alkylene chain and the remainder of the molecule and the group can be one carbon or any two carbons in the chain. Unless otherwise specifically stated in the specification, the alkylene chain may optionally be substituted.

[0064] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched hydrocarbon chain having two to twelve carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is connected to the rest of the molecule by a single bond. This includes alkenyl groups containing any number of carbon atoms from 2 to 12. Alkenyl groups containing up to 12 carbon atoms are C2-C. 12 Alkenyl groups, which contain up to 10 carbon atoms, are C2-C. 10 Alkenyl groups, specifically C2-C6 alkenyl groups containing up to six carbon atoms and C2-C5 alkenyl groups containing up to five carbon atoms, are categorized as follows: C2-C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl groups include all the aforementioned C2-C5 alkenyl groups, but also include C6 alkenyl groups. C2-C... 10 The alkenyl group includes all the C2-C5 and C2-C6 alkenyl groups mentioned above, but also includes C7, C8, C9, and C6 alkenyl groups. 10 Alkenyl. Similarly, C2-C 12 The alkenyl group includes all the aforementioned parts, but also includes C. 11 and C 12 Alkenyl. C2-C 12Non-limiting examples of alkenyl groups include ethenyl, 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, 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 otherwise specifically stated in the specification, the alkyl group may optionally be substituted.

[0065] "Alkenyl" or "alkenyl chain" refers to an unsaturated, straight-chain or branched divalent hydrocarbon chain group having one or more olefins and two to twelve carbon atoms. C2-C 12 Non-limiting examples of alkenyl groups include vinylene, propenene, n-butenene, etc. The alkenyl chain is attached to the remainder of the molecule by a single bond and to a group (e.g., those described herein) by a single bond. The connection point between the alkenyl chain and the remainder of the molecule and the group can be one carbon or any two carbons in the chain. Unless otherwise specifically stated in the specification, the alkenyl chain may optionally be substituted.

[0066] "Alynyl" or "alkynyl group" refers to a straight-chain or branched hydrocarbon chain having two to twelve carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is connected to the rest of the molecule by a single bond. This includes alkynyl groups containing any number of carbon atoms from 2 to 12. Alynyl groups containing up to 12 carbon atoms are C2-C. 12 The alkynyl group, which contains up to 10 carbon atoms, is C2-C. 10The ynyl group is categorized into C2-C6 ynyl groups, which contain up to six carbon atoms, and C2-C5 ynyl groups, which contain up to five carbon atoms. C2-C5 ynyl groups include C5, C4, C3, and C2 ynyl groups. C2-C6 ynyl groups include all the aforementioned C2-C5 ynyl groups, but also include C6 ynyl groups. C2-C 10 The alkynyl group includes all the C2-C5 and C2-C6 alkynyl groups mentioned above, but also includes C7, C8, C9, and C6 alkynyl groups. 10 Alkyne group. Similarly, C2-C 12 The alkynyl group includes all the aforementioned parts, but also includes C. 11 and C 12 Alkyne group. C2-C 12 Non-limiting examples of alkenyl groups include ethynyl, propynyl, butynyl, pentyynyl, etc. Unless otherwise specified in the specification, alkyl groups may optionally be substituted.

[0067] "Imyynyl" or "Imyynyl chain" refers to an unsaturated, straight-chain or branched divalent hydrocarbon chain group having one or more alkynes and two to twelve carbon atoms. C2-C 12 Non-limiting examples of ynylenes include ethynylene, propynylene, n-butynylene, etc. The ynylene chain is attached to the remainder of the molecule by a single bond and to a group (e.g., those described herein) by a single bond. The connection points of the ynylene chain to the remainder of the molecule and to the group can be via any two carbons within the chain having suitable valences. Unless otherwise specifically stated in the specification, the ynylene chain may optionally be substituted.

[0068] "Alkoxy" refers to the formula -OR a The group, wherein R a It is an alkyl, alkenyl, or alkynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in the specification, the alkoxy group may optionally be substituted.

[0069] "Aryl" refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, which is connected to the remainder of the molecule by a single bond. For the purposes of this disclosure, 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, derivatives of aceanthrylene, acenaphthene, acephenanthrylene, anthracene, azulene, benzene, chrysopraseene, fluorene, as-indacene, s-indacene, indene, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated in the specification, "aryl" may optionally be substituted.

[0070] "Arylalkyl" or "arylalkyl" refers to the formula -R b -R c The group, wherein R b It is an alkylene group as defined above and R c It is one or more aryl groups as defined above, such as benzyl, diphenylmethyl, etc. Unless otherwise specified in the specification, the aryl group may optionally be substituted.

[0071] "Carbocyclic group," "carbocyclic ring," or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon and is connected to the rest of the molecule by a single bond. A carbocyclic ring can contain 3 to 20 carbon atoms. Carbocyclic rings include aryl and cycloalkyl, cycloalkenyl, and cycloynyl groups as defined herein. Unless otherwise specifically stated in the specification, the carbocyclic group may optionally be substituted.

[0072] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon consisting only of carbon and hydrogen atoms. It may include fused, bridged, or spirocyclic systems, having three to twenty carbon atoms (e.g., three to ten carbon atoms) connected to the remainder of the molecule by single bonds. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, cycloalkyl groups may optionally be substituted.

[0073] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which may include fused or bridged ring systems, having three to twenty carbon atoms, preferably three to ten carbon atoms, and connected to the rest of the molecule by single bonds. Monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyls include, for example, bicyclic [2.2.1]hept-2-enyl, etc. Unless otherwise specifically stated in the specification, cycloalkenyl groups may optionally be substituted.

[0074] "Cycloynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting only of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which may include fused or bridged ring systems, having three to twenty carbon atoms, preferably three to ten carbon atoms, and connected to the rest of the molecule by single bonds. Monocyclic cycloynyl groups include, for example, cycloheptynyl, cyclooctyynyl, etc. Unless otherwise specifically stated in the specification, the cycloynyl group may optionally be substituted.

[0075] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0076] "Halogenated alkyl" refers to an alkyl group as defined above that has been substituted with one or more halogenated groups, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specifically stated in the specification, halogenated alkyl groups may optionally be substituted.

[0077] "Heterocyclic group," "heterocyclic ring," or "heterocycle" refers to a stable saturated, unsaturated, or aromatic 3- to 20-membered ring consisting of two to nineteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, connected to the rest of the molecule by a single bond. Heterocyclic groups or heterocycles include heteroaryl, heterocyclic alkyl, heterocyclic alkenyl, and heterocyclic alkynyl groups. Unless otherwise specified in the specification, a heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, bridged, or spirocyclic systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolanecycloyl, thiophene[1,3]dithiohexacyclohexyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperylyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylyl, pyrazolylyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiohexacyclohexyl, tetrahydropyranyl, thiomorpholinyl, thio-morpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the heterocyclic group may optionally be substituted.

[0078] "Heteroaryl" refers to a 5- to 20-membered ring system comprising a hydrogen atom, one to nineteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring, which is connected to the remainder of the molecule by a single bond. For the purposes of this disclosure, heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples include, but are not limited to, nitrogen-containing heteroaryl rings. Benzyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzo-m-dioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptatrienyl, 1,4-benzodioxylalkyl, benzonaphthuryl, benzooxazolyl, benzo-m-dioxacyclopentenyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl (ben zothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, zolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, isothiazolyl, imidazoyl, indazole, indolyl, indazole, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, indene, isoxazolyl, naphthidyl, oxadiazolyl, 2-oxoazines The following groups are included: alkyl, oxazolyl, ethylene oxide, 1-oxobridged pyridyl, 1-oxobridged pyrazinyl, 1-oxobridged pyridazinyl, 1-oxobridged pyridazinyl, 1-phenyl-1H-pyrroloyl, phenazinyl, phenothiazinyl, phenothiazinyl, terazinyl, pteridinyl, purine, pyrroloyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalolinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified in the specification, heteroaryl groups may optionally be substituted.

[0079] "Heterocyclic alkyl" refers to formula -R b -R e The group, wherein R b It is an alkylene, alkenylene, or ynylene group as defined above, and R e It is a heterocyclic group as defined above. Unless otherwise specified in the specification, the heterocyclic alkyl group may optionally be substituted.

[0080] As used herein, the term “substituted” means any of the groups described herein (e.g., alkyl, alkenyl, alkoxy, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclic and / or heteroaryl) in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to, the following: a halogen atom, such as F, Cl, Br and I; an oxygen atom in groups such as hydroxyl, alkoxy and ester; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl and sulfoxide; a nitrogen atom in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide and enamine; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl and triarylsilyl; and other heteroatoms in various other groups. "Substituted" also means any of the aforementioned groups in which one or more hydrogen atoms are replaced by heteroatoms, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, via higher-order bonds (e.g., double or triple bonds); and nitrogen in groups such as imine, oxime, hydrazone, and nitrile groups. For example, "substituted" includes groups in which one or more hydrogen atoms are replaced by -NR. g R h -NR g C(=O)R h -NR g C(=O)NR g R h -NR g 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 Replacement. "Replaced" also means that one or more hydrogen atoms are replaced by -C(=O)R g -C(=O)OR g -C(=O)NR g R h -CH2SO2R g -CH2SO2NR g R h Replace any of the aforementioned groups. In the foregoing, R g and R hThe same or different and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substituted" further means any of the above groups, wherein one or more hydrogen atoms are attached to amino, cyano, hydroxyl, imino, nitro, oxo, thionyl, halogen, alkyl, alkenyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. Additionally, each of the foregoing substituents may optionally be substituted by one or more of the foregoing substituents.

[0081] As used in this article, symbols (Hereinafter referred to as a "connection point bond") represents a bond that serves as a connection point between two chemical entities, one of which is depicted as connected to a connection point bond, while the other is not depicted as connected to a connection point bond. For example, This indicates that chemical entity "XY" is bonded to another chemical entity via a linker bond. Furthermore, specific linkers with undescribed chemical entities can be inferred. For example, the compound CH3-R 3 , where R 3 Is it H or This means that when R 3 When it is "XY", connect the dot key and R. 3 The bond described as being bonded to CH3 is the same bond.

[0082] compound

[0083] This disclosure provides compounds as orexin type 2 receptor agonists, pharmaceutical compositions thereof, and their use in the treatment of various diseases and conditions.

[0084] In one aspect, this disclosure provides a compound of formula (I):

[0085]

[0086] Or its pharmaceutically acceptable salt.

[0087] in

[0088] n and m are independently 0 or 1;

[0089] A1 is -O-, -CR4R5-, -NR6-, -S-, or a bond;

[0090] A2 is -C(O)- or -S(O)2-;

[0091] A3 and A4 are independently -O-, -CR4R5-, -NR6, -S-, bonds; or A3 and A4 together are -C(R4) = C(R5)-;

[0092] A5 and A6 are independently -O-, -CR4R5-, -NR6, -S-, or bonds;

[0093] The condition is that the rings including A2, A3, A4, A5, and A6 do not contain -OO-, -NR6-NR6-, or -O-NR6-;

[0094] L1 is -O-, -CR4R5-, or a bond;

[0095] L2 is -CR4R5;

[0096] R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclic, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclic, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclic, -S(O)2-aryl, -S(O)2-heteroaryl, -(C=O)NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle or heteroaryl;

[0097] R2 and R3 are independently hydrogen, halogen, alkyl, cycloalkyl, heterocyclic group, or R2 and R3 together with the atoms they are attached to form a carbocyclic or heterocyclic ring;

[0098] R4 and R5 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, –O-cycloalkyl, –O-heterocyclic, halogen, or R4 and R5 together with the atoms they are attached to form a carbocyclic or heterocyclic ring;

[0099] R6 is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclic, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclic, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclic, -S(O)2-aryl, -S(O)2-heteroaryl-(C=O)NR7R8,

[0100] R7 and R8 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, or R7 and R8 together with the atoms they are attached to form a heterocycle;

[0101] Y is a cycloalkyl, heterocyclic, heteroaryl, or aryl group; and

[0102] Z is absent, or it is either a heteroaryl or aryl group.

[0103] In some embodiments, this disclosure provides a compound of formula (II),

[0104]

[0105] Or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are as defined herein.

[0106] In some embodiments, the compound of formula (I) is a compound of the following formula:

[0107] Or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are as defined herein.

[0108] In some embodiments, the compound of formula (I) is a compound of the following formula:

[0109] Or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are as defined herein.

[0110] In some embodiments, the compound of formula (I) is a compound of the following formula:

[0111] Or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are as defined herein.

[0112] In some embodiments, this disclosure provides a compound of formula (III),

[0113]

[0114] Or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3 and Z are as defined herein.

[0115] In some embodiments, this disclosure provides a compound of formula (III),

[0116]

[0117] Or a pharmaceutically acceptable salt thereof, wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3 and Z are as defined herein.

[0118] In some embodiments, this document provides a compound of formula (IV):

[0119]

[0120] 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 as defined herein. In some embodiments, this document provides a compound of formula (VA):

[0121]

[0122] Or its pharmaceutically acceptable salt, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A and R B As defined in this article.

[0123] In some implementations, this document provides a compound of formula (VB):

[0124]

[0125] Or its pharmaceutically acceptable salt, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A and R B As defined in this article.

[0126] In some implementations, this document provides a compound of formula (VC):

[0127]

[0128] Or its pharmaceutically acceptable salt, wherein p, o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3, R A and R B As defined in this article.

[0129] In some embodiments, this document provides a compound of formula (VI-A):

[0130]

[0131] Or its pharmaceutically acceptable salts, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3 and RB As defined in this article.

[0132] In some embodiments, this document provides a compound of formula (VI-B):

[0133]

[0134] Or its pharmaceutically acceptable salts, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3 and R B As defined in this article.

[0135] In some embodiments, this document provides a compound of formula (VI-C):

[0136]

[0137] Or its pharmaceutically acceptable salts, wherein o, m, A2, A3, A4, A5, L1, L2, R1, R2, R3 and R B As defined in this article.

[0138] In some embodiments of compounds of formula (I), (II), (III) or (IV), A1 is -O-, -CR4R5-, -NR6-, -S- or a bond.

[0139] In some embodiments of compounds of formula (I), (II), (III) or (IV), A1 is -CR4R5-.

[0140] 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-.

[0141] 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)-.

[0142] 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-.

[0143] 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-, bonds; or A3 and A4 together are -C(R4)=C(R5)-.

[0144] 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-, or -NR6.

[0145] 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- or -CR4R5-.

[0146] In some embodiments of compounds 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.

[0147] In some embodiments of compounds 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 one embodiment, A4 is -NR6.

[0148] In some embodiments of compounds 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 bonds.

[0149] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), A5 is -CR4R5- or a bond. In some embodiments, A5 is -CR4R5-. In some embodiments, A5 is a bond.

[0150] In some embodiments of compounds of formula (I), (II), (III) or (IV), A6 is a bond.

[0151] 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)- and A3 is -O-.

[0152] 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.

[0153] 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)- and A3 and A4 are independently -O- or -CR4R5-.

[0154] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), the rings of A2, A3, A4, A5, and A6 do not contain -OO-, -NR6-NR6-, or -O-NR6-.

[0155] In some embodiments of compounds of formula (I), (II), (III), or (IV), A5 and A6 are independently -CR4R5- or bonds. In some embodiments, A5 is -CR4R5- and A6 is a bond. In some embodiments, both A5 and A6 are bonds.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] In some embodiments of compounds of formulas (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C),

[0161] A2 is -C(O)- or -S(O)2-;

[0162] A3 is -O-, -CR4R5-, or -NR6-;

[0163] A4 is -CR4R5-; and

[0164] A5 and A6 are keys.

[0165] In some embodiments of compounds of formulas (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C):

[0166] A2 is -C(O)- or -S(O)2-;

[0167] A3 and A4 are independently -O-, -CR4R5-, or -NR6-;

[0168] A5 is -CR4R5-; and

[0169] A6 is a key.

[0170] In some embodiments of compounds of formulas (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C):

[0171] A2 is -C(O)- or -S(O)2-;

[0172] A3, A4, and A6 are -CR4R5-; and

[0173] A5 is -O-.

[0174] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), L1 is -O-, -CR4R5-, or a bond. In some embodiments, L1 is a bond. In some embodiments, L1 is -O-.

[0175] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), L2 is -CR4R5. In some embodiments, L2 is CH2.

[0176] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclic, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)- O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclic, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclic, -S(O)2-aryl, -S(O)2-heteroaryl, -(C=O)NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle or heteroaryl.

[0177] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R1 is aryl, heteroaryl, or -(C=O)C. 1-6 Alkyl, -(C=O)C 3-6 cycloalkyl, -(C=O)C 4-6 Saturated heterocyclic groups, -(C=O)-OC 1-6 Alkyl, -(C=O)-OC 3-6 cycloalkyl, -(C=O)-OC 4-6 Saturated heterocyclic groups, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 cycloalkyl, -S(O)2-C 4-6 Heterocyclic groups, -(C=O)NR7R8, or R1 and R2 together with the atoms they are attached to form 4-7 membered heterocycles or 5-6 membered heteroaryl groups.

[0178] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R1 is -(C=O)C 1-6 Alkyl, -(C=O)C 3-6 cycloalkyl, -(C=O)C 4-6 Saturated heterocyclic groups, -(C=O)-OC 1-6 Alkyl, -(C=O)-OC 3-6 cycloalkyl, -(C=O)-OC 4-6 Saturated heterocyclic groups, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 cycloalkyl, -S(O)2-C 4-6 Saturated heterocyclic group or -(C=O)NR7R8.

[0179] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R1 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 heterocyclic groups or -S(O)2-C 1-6 Alkyl; wherein each C 1-6 Alkyl, C 3-6 cycloalkyl, C 4-6 Saturated heterocyclic groups and heteroaryl groups are independently and optionally separated by one or more hydroxyl groups, -C 1-6 Alkyl, -OC 1-6 Alkyl or fluorine substituted.

[0180] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R1 is -(C=O)NR7R8, -(C=O)-OC 1-6 Alkyl or -(C=O)-OC 4-6 Saturated heterocyclic group. In some embodiments, R1 is -(C=O)NR7R8. In some embodiments, R1 is -(C=O)-OC. 1-6 Alkyl group. In some embodiments, R1 is -(C=O)-OC. 4-6 Saturated heterocyclic group.

[0181] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R1 is -(C=O)N(H)(C 1-6 Alkyl), -(C=O)-OC 1-3 Alkyl or -(C=O)-O-cyclopropyl.

[0182] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R1 is -(C=O)N(H)(CH2CH3). In some embodiments, R1 is -(C=O)-O-CH3. In some embodiments, R1 is -(C=O)-O-cyclopropyl.

[0183] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R1 is -(C=O)NR7R8, -(C=O)-OC 1-6 Alkyl, -(C=O)-cyclopropyl, -(C=O)-C substituted with one or more fluorine groups 1-6 Alkyl-OH, -(C=O)-OC 1-6 Halogenated alkyl, -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 fluorines, -(C=O)-azacyclobutane-1-yl optionally substituted with one or more fluorines, -(C=O)-bicyclo[1.1.1]pent-1-yl optionally substituted with -OC 1-3 Alkyl-substituted pyridyl group, optionally C 1-3 Alkyl-substituted tetrazolium, -(C=O)-oxetane-2-yl or -S(O)2–C 1-3 alkyl.

[0184] In some embodiments of compounds 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, heterocyclic, or R2 and R3 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring.

[0185] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R2 and R3 are independently hydrogen, C 1-5 Alkyl, C 3-6 cycloalkyl, C 4-6 Saturated heterocyclic groups, or R2 and R3 together with the atoms they are attached to form 3-6 membered carbon rings or 4-7 membered saturated heterocycles.

[0186] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R2 and R3 are independently hydrogen, fluorine, C 1-5 Alkyl, C 3-6 cycloalkyl, C 4-6 Saturated heterocyclic groups, or R2 and R3 together with the atoms they are attached to form 3-6 membered carbon rings or 5-6 membered saturated heterocycles.

[0187] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R2 is independently hydrogen, fluorine, C 1-5 Alkyl, C 3-6 cycloalkyl, C 4-6 A saturated heterocyclic group, or R2 and R3 together with the atoms they are attached to form a 3-6 membered carbon ring or a 5-6 membered saturated heterocycle, and R3 is hydrogen.

[0188] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R2 and R3 are independently hydrogen or C. 1-5 Alkyl; wherein C 1-5 The alkyl group may optionally be substituted with one or more fluorine molecules.

[0189] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R2 and R3 are independently hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0190] 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. 1-5Alkyl group and R3 is hydrogen. In embodiments, R2 is optionally substituted (R)-C. 1-5 Alkyl and R3 is hydrogen, or in an embodiment R2 is optionally substituted (S)-C. 1-5 Alkyl group and R3 is hydrogen.

[0191] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R2 and R3 are both hydrogen.

[0192] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R4 and R5 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, –O-cycloalkyl, –O-heterocyclic, halogen, or R4 and R5 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring.

[0193] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R4 and R5 are independently hydrogen, C 1-5 Alkyl, C 3-6 cycloalkyl, C 4-6 Saturated heterocyclic group, C 1-6 Alkoxy group, –O-(C=O)C 3-6 cycloalkyl, -OC 4-6 Saturated heterocyclic groups, fluorine, or R4 and R5 together with the atoms they are attached to form 3-6 membered carbon rings or 4-6 membered saturated heterocycles.

[0194] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R4 and R5 are independently hydrogen, halogroup, or C. 1-5 alkyl.

[0195] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R4 and R5 are both hydrogen.

[0196] 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, C3-6 cycloalkyl, C 4-6 Saturated heterocyclic groups, aryl groups, heteroaryl groups, -(C=O)C 1-6 Alkyl, -(C=O)C 3-6 cycloalkyl, -(C=O)C 4-6 Saturated heterocyclic group, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-OC 1-6 Alkyl, -(C=O)-OC 3-6 cycloalkyl, -(C=O)-OC 4-6 Saturated heterocyclic groups, -(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 Saturated heterocyclic group, -S(O)2-aryl, -S(O)2-heteroaryl or -(C=O)NR7R8.

[0197] 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 heterocyclic groups, -(C=O)C 1-6 Alkyl, -(C=O)C 3-6 cycloalkyl, -(C=O)C 4-6 Saturated heterocyclic groups, -(C=O)-OC 1-6 Alkyl, -(C=O)-OC 3-6 cycloalkyl, -(C=O)-OC 4-6 Saturated heterocyclic groups, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 cycloalkyl, -S(O)2-C 4-6 Heterocyclic group or -(C=O)NR7R8.

[0198] 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, heterocyclic, aryl, or heteroaryl.

[0199] In some embodiments of compounds 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)heterocyclic, -(C=O)aryl, -(C=O)heteroaryl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclic, -(C=O)-O-aryl, -(C=O)-O-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclic, -S(O)2-aryl, -S(O)2-heteroaryl, or -(C=O)NR7R8.

[0200] 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 an alkyl group. In some embodiments, R6 is hydrogen.

[0201] 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 Alkyl group. In some embodiments, R6 is C6. 1-5 Alkyl group. In the embodiments, R6 is CH3.

[0202] In some embodiments, R7 and R8 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, or R7 and R8 together with the atoms to which they are attached form a heterocycle.

[0203] In some embodiments of compounds 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 Heterocyclic groups, 5-6 membered heteroaryl groups, or R7 and R8 together with the atoms they are attached to form heterocycles.

[0204] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R7 and R8 are independently hydrogen and C. 1-6 Alkyl group. In some embodiments, R7 is hydrogen and R8 is C. 1-6 alkyl.

[0205] In some embodiments of compounds 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 groups or R7 and R8, together with the atoms they are attached to, form saturated heterocycles, wherein C 1-6 Alkyl groups and saturated heterocycles are independently and optionally separated by one or more fluorine or -OC groups. 1-6 Alkyl substitution.

[0206] In some embodiments of compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), or (VI-C), R7 and R8 are independently hydrogen and -C. 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-6 Alkoxy groups, or R7 and R8, together with the atoms they are attached to, form saturated 4-membered heterocycles that are optionally substituted with one or more fluorine atoms.

[0207] In some embodiments of compounds of formula (I) or (II), Y is a cycloalkyl, heterocyclic, heteroaryl, or aryl group.

[0208] In some embodiments of compounds of formula (I) or (II), Y is a 3-7 member monocycloalkyl, a 5-8 member bicycloalkyl, a 4-7 member saturated heterocyclic group, a 5-8 member bicycloalkyl, a 5-6 member heteroaryl, or a phenyl.

[0209] In some embodiments of compounds of formula (I) or (II), Y is a 3-7 membered monocycloalkyl, a 4-7 membered saturated heterocyclic group, or a phenyl group; wherein the phenyl group is optionally substituted with one or more fluorine molecules.

[0210] In some embodiments of compounds of formula (I) or (II), Y is cyclohexyl, phenyl, or a saturated 6-membered heterocyclic group; wherein the phenyl group is optionally substituted with one or more fluorine groups.

[0211] In some embodiments of compounds of formula (I) or (II), Y is a 3-7 membered monocyclic alkyl group. In some embodiments, Y is a 5-8 membered bicyclic alkyl group. In some embodiments, Y is a 4-7 membered saturated heterocyclic group. In some embodiments, Y is a 5-8 membered bicyclic heterocyclic group. In some embodiments, Y is a 5-6 membered heteroaryl group. In some embodiments, Y is a phenyl group.

[0212] In some implementations, Y is optionally -(R A ) p Replace, where R A p is as defined in this paper.

[0213] In some embodiments of compounds of formula (I), (II), (III), or (IV), Z is absent, or is a heteroaryl or aryl group. In some embodiments of compounds of formula (I), (II), (III), or (IV), Z is a heteroaryl or aryl group. In some embodiments, Z is absent, or is a 5-10-membered heteroaryl or phenyl group. In some embodiments, Z is a 5-10-membered heteroaryl or phenyl group. In some embodiments, Z is an aryl group.

[0214] In some embodiments of compounds of formula (I), (II), (III) or (IV), Z is a 6-membered heteroaryl or phenyl; wherein the 6-membered heteroaryl and phenyl are optionally substituted independently with one or more fluorine molecules.

[0215] In some embodiments of compounds of formula (I), (II), (III) or (IV), Z is:

[0216] Where R B And o as defined in this article.

[0217] In some embodiments of compounds of formula (I), (II), (III) or (IV), Y is cyclohexyl, and Z is substituted at the para (or 4) position of Y.

[0218] In some embodiments of compounds of formula (I), (II), (III) or (IV), Y is phenyl, and Z is substituted at the meta (or 3) position of Y.

[0219] In some implementations, Z is optionally -(R B ) O Replace, where R B And o as defined in this article.

[0220] In some embodiments of compounds of formula (I) or (II), Y is aryl and Z is aryl. In some embodiments, Y and Z are phenyl.

[0221] In some embodiments of compounds of formula (I) or (II), Y is cyclohexyl and Z is aryl. In some embodiments, Y is cyclohexyl and Z is phenyl.

[0222] In some embodiments of compounds of formulas (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.

[0223] In some embodiments of compounds 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.

[0224] In some embodiments of compounds 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.

[0225] In some embodiments of compounds of formulas (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), R A and R B Each occurrence is independently selected from the following groups: hydroxyl, halogen, -NO2, -CN, -NR7R8, -CO2R9, -OC(O)R9, -COR9, -C(O)NR7R8, -NR7C(O)R8, -OC(O)NR7R8, -NR7C(O)OR9, -S(O) w R9 (where 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 Alkyne group.

[0226] In some embodiments of compounds of formulas (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), R A It is a halogen group.

[0227] In some embodiments of compounds of formulas (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), R B It is a halogen group.

[0228] In some embodiments of compounds of formulas (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), and / or (VI-C), R9 is independently selected from the group consisting of hydrogen, C, and C each time it appears. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, aryl, cycloalkyl, heterocyclic and heteroaryl.

[0229] 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 compounds disclosed herein are enriched and substantially free of the opposite enantiomer. In embodiments, (+)-enantiomers of the compounds disclosed herein are provided herein. In embodiments, (-)-enantiomers of the compounds disclosed herein are provided herein. In some embodiments, the compounds disclosed herein have an enantiomer excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, about 99.5%, or more, including all subranges and values ​​therebetween. In some embodiments, the compounds disclosed herein are rich in (+)-enantiomers. In some embodiments, the compounds disclosed herein are rich in (-)-enantiomers.

[0230] In some embodiments, the compounds of this disclosure are provided as a mixture of diastereomers. In some embodiments, diastereomers of the compounds of this disclosure are provided that are substantially free of other possible diastereomers. In some embodiments, the compounds of this disclosure are designated as “cis-relative” or “trans-relative” as described herein.

[0231] This disclosure includes any tautomers of the compounds described.

[0232] In some embodiments, this document provides one or more compounds selected from Table 1, or pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0233] In some embodiments, this document provides one or more compounds selected from Table 1, or pharmaceutically acceptable salts thereof, or enantiomers thereof.

[0234] In some embodiments, this document provides one or more compounds selected from Table 1, or pharmaceutically acceptable salts of the compounds thereof, or diastereomers, or mixtures of diastereomers.

[0235] In some embodiments, this document provides one or more compounds selected from Table 1 or pharmaceutically acceptable salts thereof, or diastereomers thereof, or mixtures of diastereomers thereof, or enantiomers thereof or mixtures of enantiomers thereof.

[0236] In some embodiments, this document provides one or more compounds selected from Table 1. In some embodiments, this document provides one or more compounds selected from Table 2. In embodiments, this document provides 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, 4 7, 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, 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 are provided herein.

[0237] In some embodiments, this document provides one or more pharmaceutically acceptable salts selected from the compounds in Table 1. In some embodiments, this document provides one or more pharmaceutically acceptable salts selected from the compounds in Table 2. In embodiments, this document provides 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, and 48. Pharmaceutically acceptable salts of 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 the embodiments, 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 are provided herein.

[0238] Table 1. Compounds

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261] Composition

[0262] This disclosure provides pharmaceutical compositions for modulating orexin receptors (e.g., orexin type 2 receptors) in subjects. In some embodiments, the pharmaceutical composition comprises one or more compounds of this disclosure (e.g., compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or the compounds in Table 1) or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments of this disclosure, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of this disclosure (e.g., compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C) or the compounds in Table 1) or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, the pharmaceutical composition described herein comprises one or more compounds selected from Table 1, or pharmaceutically acceptable salts thereof or stereoisomers thereof.

[0265] In the embodiments, the pharmaceutical composition as described herein 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, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 4 Compounds of the following order: 5, 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, the pharmaceutical composition as described herein 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.

[0266] In some embodiments, the pharmaceutical composition described herein comprises one or more compounds selected from Table 1 or their pharmaceutically acceptable salts.

[0267] In the embodiments, the pharmaceutical composition as described herein 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, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46. Compounds of 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, or pharmaceutically acceptable salts thereof. In embodiments, the pharmaceutical composition as described herein 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, or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments of this disclosure, pharmaceutical compositions are provided comprising one or more compounds of this disclosure (e.g., formulas (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or compounds in Table 1) or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients or adjuvants. Pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes. In some embodiments, pharmaceutical compositions comprising one or more compounds disclosed herein or pharmaceutically acceptable salts thereof further comprise 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, salt solutions, alcohols, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicate, viscous paraffin, etc.

[0269] For the purposes of this disclosure, the compounds of this disclosure can be formulated into formulations containing pharmaceutically acceptable carriers, adjuvants, and excipients for administration via a variety of routes, including oral, parenteral, inhalation spray, local, or rectal administration. The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular, and intra-arterial injection, as well as various infusion techniques. Intra-arterial and intravenous injection, as used herein, include administration via catheter.

[0270] Generally, the compounds disclosed herein are administered in therapeutically effective amounts. The actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the disease to be treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0271] Treatment

[0272] The compounds disclosed herein can be used in a variety of methods. For example, in some embodiments, the compounds can be used in methods for modulating orexin receptors, such as orexin type 2 receptors. Therefore, in some embodiments, this disclosure provides the use of any of the compounds of formulas (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C) or Table 1, or pharmaceutically acceptable salts 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 performed in mammalian cells. Modulation of orexin receptor (e.g., orexin type 2 receptor) activity can be performed in a subject in need (e.g., a mammalian subject, such as a human) and for the treatment of any of the described disorders or diseases.

[0273] In some embodiments, modulating orexin receptor (e.g., orexin type 2 receptor) activity is by binding. In some embodiments, modulating orexin receptor (e.g., orexin type 2 receptor) activity is by activating or stimulating the orexin receptor.

[0274] In some embodiments, this disclosure provides a method for treating a disease or condition that can be treated by administration of an orexin agonist, the method comprising administering a therapeutically effective amount of one or more compounds of this disclosure (e.g., compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C) or the compounds of Table 1).

[0275] In some embodiments, the compounds of this disclosure are used to treat, prevent, improve, control, or reduce the risk of a variety of conditions associated with orexin receptors, including one or more of the following disorders or diseases: narcolepsy, narcolepsy syndrome with narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, narcolepsy, idiopathic narcolepsy, repetitive narcolepsy, intrinsic narcolepsy, narcolepsy with daytime narcolepsy, sleep disturbances, sleep apnea, narcolepsy associated with sleep apnea, nocturnal myoclonus, disturbances of consciousness (such as coma), REM sleep disturbances, jet lag, excessive daytime sleepiness, sleep disturbances in shift workers, insomnia, sleep disorders, sleep disturbances, narcolepsy associated with depression, affective / mood disorders, drug use, Alzheimer's disease or cognitive impairment, Parkinson's disease, Guillain-Barré syndrome, Klein-Levin syndrome. Levin syndrome and age-related sleep disorders, muscular dystrophy, immune-mediated diseases; Alzheimer's sunset syndrome; disorders related to circadian rhythms and mental and physical disorders related to cross-time zone travel and shift work schedules; fibromyalgia; heart failure; diseases related to bone loss; sepsis; syndromes characterized by non-recovery sleep and muscle pain or sleep apnea associated with breathing disturbances during sleep; disorders resulting from poor sleep quality; and other diseases related to general orexin system dysfunction. In some embodiments, the compounds of the present invention can be used to treat, prevent, improve, control, or reduce the risk of various narcolepsy, idiopathic narcolepsy, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime narcolepsy (e.g., Parkinson's disease, Guillain-Barré syndrome, and Klein-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, altered consciousness (such as coma), and side effects and complications caused by anesthesia or anesthetic antagonists.

[0276] In some embodiments, the compounds of this disclosure (e.g., those of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C) or the compounds in Table 1) or pharmaceutically acceptable salts thereof are used to treat a subject in need of a disease or condition or symptom associated with excessive somnolence. In some implementations, excessive sleepiness is caused by any of the following: inadequate quality or quantity of sleep at night; a misalignment between the body's circadian rhythm and the environment (e.g., due to the need to stay awake at night to perform tasks such as shift work or personal obligations such as caring for sick, young, or elderly family members)); jet lag, shift work, and other circadian rhythm sleep disorders; another underlying sleep disorder, such as narcolepsy (e.g., narcolepsy type 1, narcolepsy type 2, possible 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; medical conditions such as clinical or atypical depression; tumors; head trauma; anemia; renal failure; hypothyroidism; central nervous system injury; substance abuse; hereditary vitamin deficiencies such as biotin deficiency; and certain classes of prescription and over-the-counter medications.

[0277] In some embodiments, the compounds of this disclosure (e.g., those of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C) or the compounds in Table 1) or pharmaceutically acceptable salts thereof are used to treat any of the following: shift work disorder; shift work sleep disorder; and jet lag syndrome. In some implementations, the methods and uses described herein are intended to treat any of the following: type 1 narcolepsy, type 2 narcolepsy, possible narcolepsy, idiopathic hypersomnia, idiopathic excessive hypersomnia, hypersomnia, narcolepsy, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea using continuous positive airway pressure); or disturbances of consciousness (such as coma); and narcolepsy syndrome with narcolepsy-like symptoms; narcolepsy or narcolepsy syndrome with daytime hypersomnia (e.g., Parkinson's disease, Guillain-Barré syndrome, and Klein-Levin syndrome); Parkinson's disease, Prader-Willi syndrome. Excessive daytime sleepiness in the following conditions: sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), depression (depression, atypical depression, major depressive disorder, treatment-resistant depression), ADHD, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), and other alertness disorders; residual excessive daytime sleepiness in sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure); etc. Narcolepsy (e.g., type 1 narcolepsy, type 2 narcolepsy, probable narcolepsy) can be diagnosed using 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, excessive sleepiness is excessive daytime sleepiness or excessive sleepiness during working hours, or excessive sleepiness or decreased sleep quality caused by work (e.g., shift work) or personal obligations (e.g., caring for a sick, young, or elderly family member). In some embodiments, the subject suffers from a disease or condition or symptom associated with excessive sleepiness. In some embodiments, the subjects are sleep-deprived subjects, subjects with excessive sleepiness, subjects with disrupted regular sleep cycles, or subjects who need to reduce sleepiness. In some embodiments, this disclosure provides methods for reducing or treating excessive sleepiness. In some embodiments, the excessive sleepiness is caused by narcolepsy type 1, narcolepsy type 2, or idiopathic narcolepsy. In some embodiments, the excessive sleepiness is caused by obstructive sleep apnea despite the use of continuous positive airway pressure (CPAP). In some embodiments, methods are provided for increasing the wakefulness of subjects in need. In some embodiments, the subjects' orexin levels are unimpaired or partially impaired.

[0278] In some embodiments of this disclosure, a method for treating a sleep disorder (e.g., a sleep disorder as disclosed herein) in a subject in need is provided, comprising administering to the subject in need a compound of this disclosure (e.g., a compound of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or a compound of Table 1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of this disclosure (e.g., a compound of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or a compound of Table 1) or a pharmaceutically acceptable salt thereof is used to treat a subject suffering from a sleep disorder, to treat the sleep disorder, or to treat symptoms of the sleep disorder.

[0279] In some embodiments of this disclosure, a method for treating narcolepsy in a subject in need is provided, comprising administering to the subject in need a compound of the present disclosure (e.g., compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or a compound of Table 1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the present disclosure (e.g., compounds of formula (I), (II), (III), (IV), (VA), (VB), (VC), (VI-A), (VI-B), (VI-C), or a compound of Table 1) or a pharmaceutically acceptable salt thereof are used to treat a subject suffering from narcolepsy, to treat narcolepsy, or to treat symptoms of narcolepsy.

[0280] In some embodiments of this disclosure, a method for treating idiopathic narcolepsy (IH) in a subject of need is provided, comprising administering to the subject of need 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 a compound of Table 1) or a pharmaceutically acceptable salt thereof. In some embodiments, the 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 a compound of Table 1) or a pharmaceutically acceptable salt thereof is used to treat a subject suffering from IH, to treat IH, or to treat symptoms of IH.

[0281] Example

[0282] The present disclosure will now be described in general terms and will be more readily understood by referring to the following embodiments, which are merely illustrative of certain aspects and implementations of the disclosure and are not intended to limit the invention.

[0283] The compounds disclosed herein can be synthesized using the methods described below, as well as synthetic methods or variations thereof known in the field of synthetic organic chemistry as understood by those skilled in the art.

[0284] The preparation of compounds may involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection, as well as the selection of appropriate protecting groups. For example, the chemical properties of protecting groups can be found in Greene and Wuts, *Protective Groups in Organic Synthesis*, 44th edition, Wiley & Sons, 2006, and Jerry March, *Advanced Organic Chemistry*, 4th edition, John Wiley & Sons, publisher, New York, 1992, which are incorporated herein by reference in their entirety.

[0285] abbreviation

[0286] AcOH (acetic acid)

[0287] DCM dichloromethane

[0288] DIPEA N,N-Diisopropylethylamine

[0289] DMPU N,N'-Dimethylacrylurea

[0290] DMSO (dimethyl sulfoxide)

[0291] EtOAc (ethyl acetate)

[0292] IPA isopropanol

[0293] LDA (Lithium diisopropylamino)

[0294] NMO N-methylmorpholine-N-oxide

[0295] TEA Triethylamine

[0296] TFA (trifluoroacetic acid)

[0297] TFAA (trifluoroacetic anhydride)

[0298] THF Tetrahydrofuran

[0299] General Synthesis

[0300] In the embodiments, the compounds of the present invention can be synthesized using the following methods. General reaction conditions are given, and the reaction products can be purified by commonly known methods, including silica gel chromatography or preparative reversed-phase high-performance liquid chromatography using various organic solvents (such as hexane, dichloromethane, ethyl acetate, methanol, etc.).

[0301] In some embodiments, the compounds of this disclosure are designated as "cis-relative" or "trans-relative".

[0302] As described below, the term "cis-relative" as used herein refers to compounds of this disclosure (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) wherein the amino group on the carbon marked with * and the -L2-L1-YZ substituent are located on the same face of ring A. It should be understood that the "cis-relative stereochemistry" at ring A can be described herein in the following equivalent manner:

[0303]

[0304] Where n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y, and Z are as defined in this paper.

[0305] As described below, the term "trans-relative" as used herein refers to compounds of this disclosure (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof), wherein the amino group on the carbon marked with * and the -L2-L1-YZ substituent are located on opposite faces of ring A. It should be understood that the "trans-relative stereochemistry" at ring A can be described herein in the following equivalent manner:

[0306]

[0307]

[0308] Where n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y, and Z are as defined in this paper.

[0309] Scheme 1: Representative synthesis of the compounds disclosed herein

[0310]

[0311] As shown in Scheme 1, compounds of formula (I) can be prepared from compounds of formula (IA), wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y and Z are as defined herein.

[0312] Compound of formula (IA) may be alkylated in step i) with compound of formula (IB) in the presence of a base (such as an alkali metal amide base (e.g., LDA) and a solvent (e.g., DMPU and / or ether, such as THF) that has been cooled (e.g., cooled to about -50°C or lower, or about -78°C), wherein in compound of formula (IA), R0 is -C(O)-OC. 1-6 Alkyl groups, such as -C(O)-O-CH2CH3 or -C(O)-O-CH3, PG 1 These are protecting groups, such as tert-butyloxycarbonyl (Boc) or carboxybenzyl (Cbz), and n, m, Al, R2, and R3 are as defined herein, L1, L2, Y, and Z are as defined herein, and LG 1 It is a leaving group (such as -Cl, -Br, -I or a sulfonate (e.g., methanesulfonate or toluenesulfonate)). In the second step ii), the intermediate can then be saponified and decarboxylated by treating it with an alkali metal halide salt (such as sodium chloride) in the presence of an organic solvent (such as DMSO) and water, and by heating (e.g., at about or at least about 130°C) to obtain the compound of formula (IC).

[0313] Alternatively, the compound of formula (IA) can be treated with a base (such as pyrrolidine) in an aromatic solvent (such as toluene) and heated (e.g., to reflux) in a first step i), and then alkylated with the compound of formula (IB) and heated (e.g., to about or at least about 85°C) in a second step ii) to obtain the compound of formula (IC), in which R0 is H and PG 1 These are protecting groups, such as tert-butyloxycarbonyl (Boc) or carboxybenzyl (Cbz), and n, m, Al, R2, and R3 are as defined herein, L1, L2, Y, and Z are as defined herein, and LG 1 It is a leaving group, such as -Cl, -Br, -I or a sulfonate (such as methanesulfonate or toluenesulfonate).

[0314] Compound of formula (IC) can be converted into compound of formula (ID) under condition A:

[0315]

[0316] 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 (such as ethanol) and heated (e.g., at about or at least about 90°C) in a first step i). In a second step ii), the intermediate can then be treated with TFAA and H2O2-urea in the presence of a base (such as NaHCO3) and a solvent (such as acetonitrile) and heated (e.g., to about or at least about 80°C). 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 ether solvent, such as THF) in a third step iii) and heated (e.g., to about or at least about 70°C). The resulting intermediate can then be treated with Zn in the presence of an acid (such as AcOH) and a solvent (such as an alcohol solvent, such as ethanol) in a fourth step iv) followed by nitro reduction to form the compound of formula (ID).

[0317] Alternatively, the compound of formula (IC) can be converted into the compound of formula (ID) under condition B:

[0318]

[0319] The compound of formula (IC) can be reacted in a first step i) with an alkyl sulfinamide (such as (R)-2-methylpropane-2-sulfinamide) in the presence of a Lewis acid (such as Ti(OEt)4) and a solvent (such as an ether, e.g., THF) and heated (e.g., at about or at least about 60 °C). In a second step ii), the intermediate can then be treated with EtOAc at a low temperature (e.g., about -78 °C) in the presence of an alkali metal amide base (such as LDA) and a solvent (such as an ether, e.g., THF). The resulting intermediate ester can be reduced to an alcohol in a third step iii) with a hydride reducing agent (such as LiBH4) 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, e.g., dioxane) to form the compound of formula (ID).

[0320] Compound of formula (ID) can be cyclized under conditions A by reacting it sequentially with i) a base (such as dipotassium carbonate and chloroacetyl chloride) in the presence of a solvent (such as an ether solvent, such as THF) and ii) a base (such as an alkoxide (e.g., t-BuOK)) in the presence of an alcohol solvent (such as isopropanol) to form compound of formula (IE).

[0321] Alternatively, the compound of formula (ID) can be cyclized under condition B by reacting the compound of formula (ID) with triphosgene in the presence of a tertiary amine base (such as DIPEA) and a solvent (such as a chlorinated solvent, such as dichloromethane) to form the compound of formula (IE).

[0322] Compounds of formula (IE) can be deprotected to form compounds of formula (IF). When PG... 1 When it is Cbz, for example, hydrogenation with Pd / C and H2 in an alcohol solvent (such as ethanol) yields a compound of formula (IF). When PG 1 When it is Boc, the compound of formula (IE) is treated with an acid in a solvent (such as trifluoroacetic acid / dichloromethane, or HCl / methanol) to obtain the compound of formula (IF).

[0323] Compounds of formula (IF) can react with R1-LG 2 The reaction in a solvent (such as dichloromethane) in the presence of a base (such as a tertiary amine, like triethylamine) forms a compound of formula (I), wherein R1 is as defined herein and LG 2 It is a leaving group, such as -Cl, -Br, -I or a sulfonate (such as methanesulfonate or toluenesulfonate).

[0324] Alternatively, compounds of formula (IF) can be combined with formula... Isocyanates react in the presence of a base (such as a tertiary amine, like triethylamine) to form a compound of formula (I).

[0325] Materials and methods

[0326] Analysis conditions:

[0327] Method A:

[0328] Column: Waters BEH TM C18, part number 186002352, 2.1×100mm, 1.7μm

[0329] Column temperature: 40℃

[0330] Mobile phase A: 2 mM ammonium bicarbonate, buffered to pH 10

[0331] Mobile phase B: Acetonitrile; Injection volume: 1 μL

[0332] Gradient program: Flow rate 0.6 mL / min

[0333]

[0334] UV light 215 nm, PDA spectrum 200-400 nm, step size: 1 nm

[0335] MSD scan (positive): 100-1000; Scan (positive / negative): 150-850; Scan (negative): 100-1000

[0336] Method B:

[0337] Column: Phenomenex, Kinetex-XB C18, Part No. 00D-4498-AN, 2.1mm × 100mm, 1.7μm

[0338] Column temperature: 40℃

[0339] Mobile phase A: 0.1% formic acid / water

[0340] Mobile phase B: 0.1% formic acid / acetonitrile

[0341] Injection volume: 1 μL

[0342] Gradient program: Flow rate 0.6 mL / min

[0343]

[0344] UV light 215 nm, PDA spectrum 200-400 nm, step size: 1 nm

[0345] MSD scan (positive): 100-1000; Scan (positive / negative): 150-850

[0346] Method C:

[0347] Column: Acquity UPLC CSH C18 (5.0mm × 2.1mm, 1.7μm) column

[0348] Column temperature: 40℃

[0349] Mobile phase A: 0.1% formic acid / water

[0350] Mobile phase B: 0.1% formic acid / acetonitrile

[0351] Gradient program: Flow rate 1 mL / min

[0352]

[0353] Method D:

[0354] Column: Kintex EVO C18 (1.7μm, 2.1×50mm) column

[0355] Column temperature: 40℃

[0356] Mobile phase A: 10 mM ammonium bicarbonate aqueous solution, adjusted to pH 10 with NH3.

[0357] Mobile phase B: Acetonitrile

[0358] Gradient procedure:

[0359] Synthesize (cis)-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-2-one (intermediate 8).

[0360]

[0361] 3-O-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (intermediate 1):

[0362]

[0363] Paraformaldehyde (1.64 g, 54.8 mmol) was added to a solution of 4-phenylcyclohexanol (9.65 g, 54.8 mmol) in anhydrous DCM (97 mL), followed by the addition of chloro(trimethyl)silane (28 mL, 21.9 mmol). The reaction was stirred at room temperature for 2 h. The reaction was filtered through a Na2SO4 pad and concentrated under vacuum at 30 °C to give [4-(chloromethoxy)cyclohexyl]benzene as a pale yellow oil. In a separate flask, lithium (diisopropylamino) (2 M in THF) (60 mL, 12.0 mmol) was added at -78 °C for 30 min to a stirred solution of 1,3-dimethylhexahydropyrimidin-2-one (26 mL, 21.9 mmol) and 1-tert-butyl 4-ethyl 3-oxopiperidinium-1,4-dicarboxylate (14.85 g, 54.8 mmol) in anhydrous THF (200 mL). The solution was kept at this temperature for 20 minutes. After 15 minutes, an oily substance containing [4-(chloromethoxy)cyclohexyl]benzene was added to anhydrous THF (20 mL) of the reaction mixture. The reaction mixture was stirred at -78 °C for 1 hour. The reaction was quenched with saturated NH4Cl aqueous solution (80 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (0–20% TBME / heptane) to give the title compound (14.3 g) as a pale orange gel. [M+H] + m / z 460.5

[0364] 3-O-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 2)

[0365]

[0366] Sodium chloride (3.64 g, 62.2 mmol) and water (10 mL) were added to a solution of intermediate 1 (14.30 g, 31.1 mmol) in DMSO (90 mL). The reaction mixture was heated to 130 °C and maintained for 5.5 h. Sodium chloride (3.64 g, 62.2 mmol) was added again and the reaction mixture was stirred at 130 °C for 4 h. The reaction mixture was cooled to room temperature and partitioned between Et₂O (200 mL) and 5% LiCl aqueous solution (200 mL). The two-phase mixture was separated and the organic layer was washed with 5% LiCl aqueous solution (3 × 200 mL). The organic extract was concentrated under vacuum to give an orange oil (11 g). The aqueous layer was re-extracted with diethyl ether (300 mL) and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (0-10% EtOAc / heptane) to give the title compound (8.2 g) as a pale yellow oil. [M+H] + m / z 388.4

[0367] 3-(hydroxyimino)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 3)

[0368]

[0369] 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 hour. 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 under vacuum to give the title compound (3.48 g) as a pale yellow, foamy gel. [M+H] + m / z 403.4

[0370] 3-Nitro-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 4).

[0371]

[0372] At 0 °C, 14 mL of anhydrous acetonitrile containing 3.0 mL (21.6 mmol) trifluoroacetic anhydride was added to a stirred solution of hydrogen peroxide-urea (1:1) (2.85 g, 30.3 mmol) in 14 mL of anhydrous acetonitrile. The reaction was stirred at 0 °C for 2 hours. The resulting solution was added dropwise at 80 °C to a mixture of intermediate 3 (3.48 g, 8.65 mmol) and NaHCO3 (3.63 g, 43.2 mmol) in 20 mL of anhydrous acetonitrile, and then stirred at 80 °C for 1 hour. The reaction was cooled to room temperature and quenched with a saturated aqueous solution of Na2SO3, diluted with water (50 mL), and extracted with EtOAc (3 × 75 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under vacuum to give a pale yellow gel. The crude substance was purified by silica gel column chromatography (0-20% EtOAc / heptane) to give the title compound (1.78 g) as a colorless gel, which precipitated as a white solid. [M+H] + m / z 419.4

[0373] (cis)-3-(hydroxymethyl)-3-nitro-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 5)

[0374]

[0375] Formaldehyde (in water) (37%, 2.5 mL, 33.3 mmol) was added to 20 mL of THF containing intermediate 4 (1.55 g, 3.70 mmol) and triethylamine (0.52 mL, 3.70 mmol). The solution was heated to 70 °C and held for 18 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were concentrated under vacuum, and the crude substance was purified by silica gel column chromatography (0–40% EtOAc / heptane) to give the title compound (1.55 g) as a colorless gel. [M+H] + m / z 449.4

[0376] (cis)-3-amino-3-(hydroxymethyl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 6).

[0377]

[0378] At 0 °C, zinc (1.90 g, 29.0 mmol) was added in three portions to a stirred intermediate 5 (1.30 g, 2.90 mmol) in ethanol (36 mL) and acetic acid (7.8 mL). The reaction was heated to room temperature and stirred for 5 hours. The reaction mixture was filtered through a diatomaceous earth mat and washed with methanol. The filtrate was concentrated under vacuum, diluted with water, neutralized with a saturated aqueous solution of NaHCO3, and extracted with DCM (3 × 25 mL). The organic extract was concentrated under vacuum and purified by silica gel column chromatography (0–5% methanol / DCM) to give the title compound (1.09 g) as a colorless gel. [M+H] + m / z 419.4.

[0379] (cis)-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylic acid tert-butyl ester (intermediate 7)

[0380]

[0381] At 0°C, 8.6 mL of water containing dipotassium carbonate (792 mg, 5.73 mmol) was added to a solution of intermediate 6 (800 mg, 1.91 mmol) in THF (9 mL). Chloroacetyl chloride (0.17 mL, 2.13 mmol) was added dropwise to this mixture at 0°C. The reaction was stirred at 0°C for 1 h. Then, 46 μL of 2-chloroacetyl chloride (0.578 mmol) was added and the reaction was stirred for 1 h. The mixture was quenched with water and extracted with DCM (2 × 20 mL), passed through a phase separator, and concentrated under vacuum. The intermediate was dissolved in DCM (17 mL), and IPA (17 mL) containing potassium 2-methylprop-2-ol (858 mg, 7.65 mmol) was added at 0°C. The reaction was heated to room temperature and stirred for 16 h. The solution was neutralized with 2 M HCl and adjusted to pH 8 with a saturated NaHCO3 aqueous solution, diluted with water, and extracted with DCM (3 × 50 mL). The organic extract was passed through a phase separator and concentrated under vacuum. The crude material was purified by silica gel column chromatography (0-20% methanol / EtOAc) to give the title compound (550 mg) as a colorless gel. [MH] - m / z457.5.

[0382] (cis)-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-2-one (intermediate 8).

[0383]

[0384] TFA (1.3 mL) was added to intermediate 7 (550 mg, 1.20 mmol) in a solution of DCM (2.6 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with a saturated aqueous solution of NaHCO3 (10 mL) and extracted with DCM (2 × 10 mL). The organic layers were combined, separated by a phase separator, and concentrated under vacuum to give the title compound (400 mg) as a white solid. [MH] - m / z 357.5

[0385] Example 1: (cis)-N-ethyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (1).

[0386]

[0387] Ethyl isocyanate (0.13 mL, 1.67 mmol) was added to a solution of triethylamine (0.23 mL, 1.67 mmol) and intermediate 8 (300 mg, 0.837 mmol) in DCM (12 mL) 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 under vacuum. The crude substance was purified by reversed-phase column chromatography (10-70% MeCN / water (0.1% NH3)) to give the title compound (228 mg) as a white solid.

[0388] 1 H NMR (400MHz, CDCl3) δ7.34-7.27(m,2H),7.23-7.15(m,3H),6.32(brs,1H),4.43-4.37(m, 1H),4.27(d,J=16.8Hz,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). 1NH was not observed. LCMS (Method A): [M+H] + m / z 430.4, RT 3.19 minutes.

[0389] 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

[0390] 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)

[0391]

[0392] Example 1 (209 mg) was purified by chiral preparation using a Waters 600, eluted with 80 / 20% v / v hexane / ethanol, Chiralpak AS-H (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (peak 1, 94.4 mg, 100% ee; and peak 2, 87 mg, 100% ee). The absolute stereochemistry of the isolated compounds 2 and 3 was not definitively determined, but is assigned as follows.

[0393] Peak 1 (assigned as 6R, 7S at piperidine); 1 H NMR(400MHz, CDCl3)δ7.30(dd,J=8.2,7.0Hz,2H),7.23-7.14(m,3H),6.26(s,1H),4.78(s,1H),4.41(t,J=5.4H z,1H),4.27(d,J=16.9Hz,1H),4.16-4.03(m,3H),3.86-3.72(m,2H),3.65(t,J=3.0Hz,1H),3.35(d,J=11.8Hz, 1H),3.25(qd,J=7.2,5.2Hz,2H),3.01(td,J=13.1,3.5Hz,1H),2.54(tt,J=10.5,5.2Hz,1H),2.06-1.98(m,2H) ,1.91(td,J=13.6,4.9Hz,1H),1.85-1.76(m,1H),1.76-1.64(m,4H),1.64-1.49(m,4H),1.12(t,J=7.2Hz,3H). LCMS (Method C):[M+H] + m / z 430.3, RT 0.95 min. Chiral analysis (Chiralpak AS-H, 25 × 0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 8.3 min.

[0394] Peak 2 (assigned as 6S, 7R at piperidine): 1H NMR (400MHz, CDCl3) δ7.29 (dd, J=8.2, 6.9Hz, 2H), 7.20 (dt, J=8.2, 2.0Hz, 3H), 6.48 (s, 1H), 4.81 (t, J=5.4Hz, 1H), 4. 40(dd,J=7.1,3.6Hz,1H),4.27(d,J=16.8Hz,1H),4.19-4.05(m,3H),3.80(qd,J=9.8,5.3Hz,2H),3.64(p,J=2.9Hz,1H ),3.34(d,J=11.8Hz,1H),3.25(qd,J=7.2,5.3Hz,2H),2.99(td,J=13.1,3.5Hz,1H),2.54(tt,J=10.6,5.0Hz,1H),2. 01(dq,J=14.9,2.9Hz,2H),1.90(td,J=13.5,5.0Hz,1H),1.83-1.75(m,1H),1.75-1.49(m,8H),1.12(t,J=7.2Hz,3H). LCMS (Method C):[M+H] + m / z 430.3, RT 0.95 min. Chiral analysis (Chiralpak AS-H, 25 × 0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 13.7 min.

[0395] Example 4: Methyl (cis)-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (4)

[0396]

[0397] Methyl chloroformate (22 μL, 0.279 mmol) was added to a 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 triethylamine (78 μL, 0.558 mmol) and methyl chloroformate (86 μL, 1.12 mmol) were added, and the reaction was stirred for 18 h. The reaction was quenched with saturated NaHCO3 aqueous solution and extracted with DCM (3 × 5 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (50–100% EtOAc / heptane, followed by 0–10% methanol / EtOAc) to give the title compound (21 mg) as a white solid.

[0398] 1¹H NMR (500MHz, 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). Rotational isomers were observed. LCMS (Method A): [M+H] + m / z 417.3, RT 3.50 minutes.

[0399] 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

[0400] Example 6: Methyl (6S,7R)-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (6)

[0401]

[0402] Example 4 (16 mg) was purified chirally using a Waters 600, eluted with 65 / 35% v / v hexane / ethanol, Chiralpak AS-H (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (peak 1, 4.9 mg, 100% ee; and peak 2, 4.6 mg, 100% ee). The absolute stereochemistry of the isolated compounds 5 and 6 was not definitively determined, but is assigned as follows.

[0403] Peak 1 (assigned as 6R,7S at piperidine): 1H NMR(400MHz, CDCl3)δ7.36-7.29(m,2H),7.25-7.17(m,3H),6.11(brs,1H),4.5 8(brs,1H),4.33-4.07(m,3H),4.01(brs,1H),3.84(brs,2H),3.74(s,3H),3.6 5(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=9.46Hz,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, 25 × 0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 7.5 min.

[0404] Peak 2 (assigned as 6S,7R at piperidine): 1H NMR(400MHz, CDCl3)δ7.36-7.29(m,2H),7.25-7.17(m,3H),6.11(brs,1H),4.5 8(brs,1H),4.33-4.07(m,3H),4.01(brs,1H),3.84(brs,2H),3.74(s,3H),3.6 5(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=9.46Hz,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, 25 × 0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 11.2 min.

[0405] Example 7: (cis)-8-cyclopropanecarbonyl-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-2-one (7)

[0406]

[0407] At room temperature, cyclopropane carbonyl chloride (25 μL, 0.279 mmol) was added to a solution of intermediate 8 (50 mg, 0.139 mmol) and triethylamine (39 μL, 0.279 mmol) in DCM (2 mL) and stirred for 1.5 h. The reaction was quenched with saturated NaHCO3 aqueous solution (2 mL) and extracted with DCM (3 × 5 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (100% EtOAc) to give the title compound (40 mg) as a white solid.

[0408] 1 H NMR (400MHz, CDCl3) δ7.34-7.27(m,2H),7.24-7.14(m,3H),6.45-6.09(m,1H),5.11-4. 75(m,1H),4.61(d,J=11.1Hz,0.5H),4.26(t,J=18.4Hz,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 is exchanged with the solvent. LCMS (Method A): [M+H] + m / z 427.3, RT 3.43 minutes

[0409] Example 8: (6R,7S)-8-cyclopropanecarbonyl-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-2-one (8) and

[0410] Example 9: (6S,7R)-8-cyclopropanecarbonyl-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-2-one (9)

[0411]

[0412] Example 7 (28 mg) was purified chirally using a Waters 600, eluted with 80 / 20% v / v hexane / ethanol, Chiralpak AS-H (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (peak 1, 10.5 mg, 100% ee; and peak 2, 10.3 mg, 100% ee). The absolute stereochemistry of the isolated compounds 8 and 9 was not definitively determined, but is assigned as follows.

[0413] Peak 1 (assigned as 6R, 7S at piperidine): 1 ¹H NMR (400MHz, 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, 25 × 0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 11.0 min.

[0414] Peak 2 (assigned as 6S, 7R at piperidine): 1 H NMR (500MHz, CDCl3) δ7.36-7.30(m,2H),7.26-7.17(m,3H),6.17(d,J=119.9Hz,1H),4.95(d,J=117. 5Hz,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, 25 × 0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 18.9 min.

[0415] Example 10: (cis)-N-ethyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (10)

[0416]

[0417] (cis)-2-oxo-6-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.5]decane-7-carboxylic acid tert-butyl ester (intermediate 9)

[0418]

[0419] At 0 °C, N-ethyl-N-(propyl-2-yl)propyl-2-amine (68 μL, 0.392 mmol) was added to a solution of intermediate 6 (164 mg, 0.392 mmol) and bis(trichloromethyl) carbonate (116 mg, 0.392 mmol) in anhydrous DCM (5 mL). The reaction mixture was stirred at 0 °C for 1 h, then quenched with a saturated aqueous solution of NaHCO3 (1 mL) and purged with N2 (gas) for 30 min using a 20% NaOH scrubber to quench excess phosgene gas. The solution was extracted with DCM (2 × 5 mL), and concentrated under vacuum through a phase separator to give the title compound (219 mg) as a white gel. [M+NH4] + m / z 462.4

[0420] (cis)-6-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.5]dec-2-one (intermediate 10)

[0421]

[0422] 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 hour. The reaction was neutralized with saturated NaHCO3 aqueous solution and extracted with DCM (3 × 5 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum to give the title compound (207 mg) as a white solid. [M+H] + m / z 345.3.

[0423] (cis)-N-ethyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (10)

[0424]

[0425] 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 NaOH aqueous solution, stirred for 20 min, and then extracted with DCM (3 × 5 mL). The organic extract was passed through a phase separator and concentrated under vacuum. The crude substance was purified by reversed-phase column chromatography (10-100% MeCN / water (0.1% NH3)) to give the title compound (55 mg) as a white solid.

[0426] 1 H NMR (500MHz, CDCl3) δ7.33-7.27(m,2H),7.23-7.16(m,3H),6.10(s,1H),4.93(brs,1H),4.32(d ,J=8.9Hz,1H),4.20(t,J=5.8Hz,1H),4.11(d,J=8.9Hz,1H),3.98(dd,J=13.5,3.9Hz,1H),3.77- 3.69(m,2H),3.66(p,J=3.0Hz,1H),3.24(qd,J=7.2,3.0Hz,2H),2.87(td,J=13.1,2.8Hz,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=7.2Hz,3H). LCMS (Method A):[M+H] + m / z 416.3, RT 3.31 minutes.

[0427] 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

[0428] 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)

[0429]

[0430] tert-Butyl-3-{[(R)-2-methylpropane-2-sulfinyl]imino}-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 11)

[0431]

[0432] Tetraethanolamine (4+) (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), and the solution was then heated at 60 °C for 2 h. The reaction was cooled to room temperature and poured into a saturated aqueous solution of NaHCO3 (100 mL), filtered through a diatomaceous earth mat, and washed with DCM (2 × 50 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were concentrated under vacuum and purified by silica gel column chromatography (0–60% EtOAc / heptane) to give the title compound (2.47 g) as an orange gel. [M+H] + m / z 491.5

[0433] 3-(2-ethoxy-2-oxoethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 12)

[0434]

[0435] Diisopropylaminolithium (2M 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. 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 the mixture was stirred for 1 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (20 mL), extracted with EtOAc (3 × 25 mL), and the organic layer was passed through a phase separator. The organic extract was concentrated under vacuum and purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (1.43 g) as a solid gel. [M+H] + m / z 579.6.

[0436] 3-(2-hydroxyethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 13)

[0437]

[0438] Lithium tetrahydroborate (2M in THF) (6 mL, 12.6 mmol) was added dropwise to a stirred solution of intermediate 12 (1.46 g, 2.51 mmol) in 23 mL of THF. The reaction mixture was heated to room temperature and stirred for 16 h. The reaction was heated at 50 °C for 2 h and then cooled to room temperature. Lithium tetrahydroborate (2M in THF) (2.5 mL, 5.03 mmol) was added again, and the solution was heated at 50 °C for 2 h and then at 60 °C for 1 h. The reaction was cooled to room temperature and carefully quenched with water (25 mL), followed by the addition of 25 mL of saturated NH4Cl aqueous solution and extraction with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under vacuum to give the crude product. The crude substance was purified by column chromatography (40-100% EtOAc / heptane, then 0-10% methanol / EtOAc) to give the title compound (755 mg) as a yellow gel. [M+H] + m / z 537.5

[0439] 3-Amino-3-(2-hydroxyethyl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 14)

[0440]

[0441] Hydrogen chloride (4M 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 the mixture was stirred at 0 °C for 4 h. The reaction was placed in a refrigerator overnight and quenched at 0 °C with a saturated aqueous solution of NaHCO3, followed by removal of methanol under vacuum. The aqueous solution was then extracted with DCM:methanol (9:1; 3 × 25 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum to give a crude compound. The crude compound was purified by silica gel column chromatography (0–2% methanol / DCM) to give the title compound (529 mg) as a pale yellow gel, a mixture of 4:1 cis and trans diastereomers. [M+H] + m / z 433.7

[0442] tert-Butyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate (intermediate 15)

[0443]

[0444] At 0 °C, N-ethyl-N-(propyl-2-yl)propyl-2-amine (0.21 mL, 1.22 mmol) was added to a solution of intermediate 14 (529 mg, 1.22 mmol) and bis(trichloromethyl) carbonate (363 mg, 1.22 mmol) in anhydrous DCM (16 mL). The reaction was stirred at 0 °C for 1.5 h, then quenched with a saturated aqueous solution of NaHCO3 (1 mL) and purged with N2 (gas) for 30 min using a 20% NaOH scrubber to quench excess phosgene gas. The solution was extracted with DCM (3 × 10 mL) and concentrated under vacuum through a phase separator to obtain a crude compound. The crude compound was purified by silica gel column chromatography (50–100% EtOAc / heptane) to give the title compound (326 mg) as a colorless, colloidal mixture of diastereomers. [M+H] + m / z459.4

[0445] 7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-2-one (intermediate 16)

[0446]

[0447] 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 hour. The reaction was quenched with a saturated aqueous NaHCO3 solution and extracted with DCM (3 × 5 mL). The organic extract was passed through a phase separator and concentrated under vacuum to give the title compound (a mixture of diastereomers) as a colorless gel in quantitative yield, [M+H]. + m / z 359.3

[0448] (cis)-N-ethyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (11) and

[0449] (trans)-N-ethyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxamide (12)

[0450]

[0451] Intermediate 16 was dissolved in DCM (3 mL), and triethylamine (99 μL, 0.711 mmol) and ethyl isocyanate (56 μL, 0.711 mmol) were added sequentially at room temperature. The reaction was stirred for 2 h, quenched with 2 M NaOH, and extracted with DCM. The organic extract was passed through a phase separator and concentrated under vacuum. The crude material was purified by reversed-phase column chromatography (10-60% MeCN / water (0.1% NH3)) to give 128 mg of the title compound (Example 11) as a white solid and 18 mg of the title compound (Example 12) as a pale yellow solid.

[0452] 1 ¹H NMR (400MHz, 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 is exchanged with the solvent. LCMS (Method A): [M+H] + m / z 430.4, RT 3.15 minutes (Example 11)

[0453] 1 H NMR (400MHz, CDCl3) δ7.34-7.27(m,2H),7.22-7.15(m,3H),5.88-5.80(m,1H),4.40 -4.27(m,2H),4.14(dd,J=13.1,4.2Hz,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 is exchanged with the solvent. LCMS (Method A): [M + H] + m / z 430.4, RT 3.40 minutes (Example 12)

[0454] 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)

[0455] 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)

[0456]

[0457] Example 11 (109 mg) was purified by chiral preparation using a Waters 600, eluted with 70 / 30% v / v n-hexane / ethanol, Chiralpak AS-H (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (peak 1, 70.2 mg, 100% ee; and peak 2, 26.4 mg, 100% ee). The absolute stereochemistry of the isolated compounds 13 and 14 was not definitively determined, but is assigned as follows.

[0458] Peak 1 (assigned as 6S, 7S in piperidine); 1 H NMR(400MHz, CDCl3) δ7.30(d,J=7.0Hz,2H),7.21(d,J=7.5Hz,3H),5.54-5.35(m,1H),4. 74(brs.,1H),4.34(dd,J=4.9,3.6Hz,3H),3.78(d,J=3.5Hz,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=7.6Hz,1H),2.24(d,J=13.9 Hz, 1H), 1.97-2.09 (m, 3H), 1.71 (brs., 8H), 1.59 (d, J = 2.4Hz, 1H), 1.13 (t, J = 7.1Hz, 3H). LCMS (Method C):[M+H] + m / z 430.3, RT 0.96 min. Chiral analysis (Chiralpak AS-H, 25 × 0.46 cm, 5 μm, 70:30 n-hexane:ethanol): RT 6.4 min.

[0459] Peak 2 (assigned as 6R, 7R at piperidine): 1H NMR(400MHz, CDCl3)δ7.30(d,J=7.0Hz,2H),7.21(d,J=7.5Hz,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=2.6Hz,1 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, 1H), 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, 25 × 0.46 cm, 5 μm, 70:30 n-hexane:ethanol): RT 11.7 min.

[0460] Example 15: (cis)-N-ethyl-7-oxo-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (15)

[0461]

[0462] 4-O-5-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester (Intermediate 17)

[0463]

[0464] Paraformaldehyde (0.85 g, 28.4 mmol) was added to a solution of 4-phenylcyclohexanol (5.00 g, 28.4 mmol) in anhydrous DCM (67 mL), followed by the addition of chloro(trimethyl)silane (14 mL, 0.113 mol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through sodium sulfate and concentrated under vacuum at 30 °C to give a colorless oily substance of 4-(chloromethoxy)cyclohexylbenzene. In a separate flask, 2M (diisopropylamino)lithium (2M in THF) (31 mL, 62.4 mmol) was added to a stirred solution of 1-benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylic acid (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 oily substance containing [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 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (50 mL), followed by quenching with water (50 mL), and then extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum to give a crude substance. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (5.2 g) as a pale yellow oil. [M+H] + m / z 480.2

[0465] 3-O-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylic acid benzyl ester (Intermediate 18)

[0466]

[0467] Sodium chloride (362 mg, 6.20 mmol) and water (1.5 mL) were added to a solution of intermediate 17 (30%, 5.00 g, 3.13 mmol) in DMSO (15 mL), and the reaction mixture was heated to 130 °C and maintained for 2 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with TBME (2 × 50 mL). The combined organic layers were washed with water (3 × 25 mL) and brine (50 mL), dried over Na₂SO₄, and concentrated under vacuum to give the crude substance. The crude substance was purified by silica gel column chromatography (0–100% EtOAc / heptane) to give the title compound (1.96 g) as a pale yellow oil. [M+H] + m / z 408.2

[0468] Benzyl-3-(hydroxyimino)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate (Intermediate 19)

[0469]

[0470] 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 and maintained for 1 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (2 g) as a pale yellow, viscous oil. [M+H] + m / z423.2

[0471] 3-Nitro-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylic acid benzyl ester (Intermediate 20)

[0472]

[0473] At 0 °C, 8 mL of anhydrous acetonitrile containing 1.6 mL (11.8 mmol) trifluoroacetic anhydride was added to a stirred solution of hydrogen peroxide-urea (1:1) (1.56 g, 16.6 mmol) in 8 mL of anhydrous acetonitrile. The reaction was stirred at 0 °C for 2 h. At room temperature, the resulting solution was added dropwise to a mixture of intermediate 19 (2.00 g, 4.73 mmol) and NaHCO3 (1.99 g, 23.7 mmol) in 11 mL of anhydrous acetonitrile. The mixture was then heated to 80 °C and stirred at 80 °C for 1 h. The reaction was cooled to room temperature and quenched with a saturated aqueous solution of Na2SO3, diluted with water (50 mL), and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered, and concentrated under vacuum to give a pale yellow gel. The crude substance was purified by silica gel column chromatography (0-60% EtOAc / heptane) to give the title compound (1.27 g) as a colorless oil. [M+H] + m / z 439.3

[0474] (cis)-3-(hydroxymethyl)-3-nitro-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylic acid benzyl ester (intermediate 21)

[0475]

[0476] Formaldehyde (in water) (37%, 1.9 mL, 26.1 mmol) was added to 16 mL of THF containing intermediate 20 (1.27 g, 2.90 mmol) and triethylamine (0.48 mL, 3.48 mmol). The solution was heated to 70 °C and held for 3.5 h. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (7-70% EtOAc / heptane) to give the title compound (510 mg) as a viscous, colorless oil. [M+H] + m / z 469.1

[0477] (cis)3-amino-3-(hydroxymethyl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylic acid benzyl ester (intermediate 22)

[0478]

[0479] 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 h. The reaction mixture was filtered through a diatomaceous earth mat and washed with methanol. The filtrate was concentrated under vacuum, neutralized with a saturated aqueous solution of NaHCO3, and extracted with DCM (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated to give the title compound, a viscous brown foam, in quantitative yield. [M+H] + m / z439.1.

[0480] (cis)-7-oxo-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid benzyl ester (intermediate 23)

[0481]

[0482] Potassium dicarbonate (284 mg, 2.05 mmol) and water (3 mL) were added sequentially to a solution of intermediate 22 (300 mg, 0.684 mmol) in THF (3 mL) at 0 °C. Chloroacetyl chloride (76 μL, 0.958 mmol) was added dropwise to this mixture at 0 °C. The reaction was stirred at 0 °C for 1 h. 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. The intermediate was dissolved in DCM (6 mL) and IPA (6 mL), cooled to 0 °C, potassium 2-methylprop-2-ol (307 mg, 2.74 mmol) was added, and the reaction was stirred at 0 °C for 1 h. The mixture was quenched with water (10 mL) and allowed to stand at room temperature for 40 h. The mixture was poured onto a saturated aqueous solution of NaHCO3 (20 mL). After extraction with DCM (3 × 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 / heptane) to give the title compound (170 mg) as a colorless oil. [M+H] + m / z 479.1

[0483] (cis)-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]dec-7-one (intermediate 24)

[0484]

[0485] Intermediate 23 (150 mg, 0.313 mmol) was dissolved in ethanol (15 mL), and the mixture was evacuated to atmospheric pressure and backfilled with nitrogen three times. Palladium / carbon (10%, 15 mg, 0.313 mmol) was added, and the mixture was evacuated to atmospheric pressure and backfilled with hydrogen three times. The reaction was stirred for 2 h, and then filtered through diatomaceous earth, washed with EtOAc, and concentrated under vacuum to give the title compound (75 mg) as a light brown gel. [M+H] + m / z 345.33

[0486] (cis)-N-ethyl-7-oxo-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (Example 15)

[0487]

[0488] 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 NaOH aqueous solution and extracted with DCM (3 × 10 mL). The organic layers were combined, washed with brine (25 mL), passed through a phase separator, and concentrated under vacuum. The crude substance was purified by reversed-phase column chromatography (10–60% MeCN / water (0.1% NH3)) to give the title compound (29 mg) as a white solid.

[0489] 1 H NMR (400MHz, CDCl3) δ7.35-7.28(m,2H),7.24-7.17(m,3H),6.41(s,1H),4.45(s,1H),4.25(d,J=16.7Hz,1H),4. 18(d,J=16.7Hz,1H),4.09(t,J=2.3Hz,1H),3.99(dd,J=10.3,2.1Hz,1H),3.73(d,J=11.7Hz,1H),3.69-3.64(m, 1H),3.61(dd,J=10.3,3.0Hz,1H),3.55(d,J=11.7Hz,1H),3.51-3.42(m,1H),3.38-3.18(m,3H),2.56(tt,J=10. 9,5.3Hz,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=7.2Hz,3H). LCMS (Method A):[M+H] + m / z 416.4, RT 3.07 minutes.

[0490] 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)

[0491] 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)

[0492]

[0493] Example 15 (22 mg) was purified chirally using a Waters 600, eluted with 80 / 20% v / v n-hexane / ethanol, Chiralpak AD-H (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (peak 1, 9.4 mg, 100% ee; and peak 2, 9.1 mg, 100% ee). The absolute stereochemistry of the isolated compounds 16 and 17 was not definitively determined, but is assigned as follows.

[0494] Peak 1 (assigned as 1R,5S at pyrrolidine); 1 H NMR(400MHz, CDCl3)δ7.30(dd,J=8.1,6.9Hz,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=2.6Hz,1H),3.98(dd,J=10.4,2.3Hz,1H),3.72(d,J=11.7Hz,1H),3.65(q,J=2.9Hz,1H),3. 60(dd,J=10.3,3.0Hz,1H),3.54(d,J=11.7Hz,1H),3.45(td,J=9.5,1.9Hz,1H),3.36-3.17(m,3H),2.61-2.4 9(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=7.2Hz,3H). LCMS (Method C):[M+H] + m / z 416.3, RT 0.94 min. Chiral analysis (Chiralpak AD-H, 25 × 0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 9.5 min.

[0495] Peak 2 (assigned as 1S,5R at pyrrolidine): 1H NMR (400MHz, CDCl3) δ7.34-7.27(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=2.5Hz,1H),3.98(dd,J=10.4,2.3Hz,1H),3.72(d,J=11.7Hz,1H),3.65(t,J=2.9Hz,1H),3.60(d d,J=10.3,3.0Hz,1H),3.54(d,J=11.7Hz,1H),3.45(td,J=9.6,2.0Hz,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=7.2Hz,3H). LCMS (Method C):[M+H] + m / z 416.3, RT 0.94 min. Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 80:20 n-hexane:ethanol): RT 14.7 min.

[0496] Example 18: (cis)-N-ethyl-2-oxo-6-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.4]nonane-7-carboxamide (18)

[0497]

[0498] (cis)-2-oxo-6-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.4]nonane-7-carboxylic acid benzyl ester (intermediate 25)

[0499]

[0500] At 0 °C, N-ethyl-N-(prop-2-yl)prop-2-amine (50 μL, 0.286 mmol) was added to a solution of intermediate 22 (110 mg, 0.251 mmol) and bis(trichloromethyl) carbonate (74 mg, 0.251 mmol) in anhydrous DCM (3 mL). The reaction was stirred at 0 °C for 1 h, then quenched with a saturated aqueous solution of NaHCO3 (1 mL), and purged with N2 (gas) 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 under vacuum to give a gel. The crude substance was purified by silica gel column chromatography (0-50% EtOAc / heptane) to give the title compound (57 mg) as a white gel. [M+H] + m / z 465.4

[0501] (cis)-6-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.4]non-2-one (intermediate 26)

[0502]

[0503] A solution of intermediate 25 (57 mg, 0.123 mmol) and palladium / 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 h, then filtered through a diatomaceous earth pad, washed with methanol, and concentrated under vacuum to give the title compound (39 mg) as a white residue. [M+H] + m / z 331.3

[0504] (cis)-N-ethyl-2-oxo-6-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,7-diazaspiro[4.4]nonane-7-carboxamide (18)

[0505]

[0506] Ethyl isocyanate (16 μL, 0.202 mmol) was added to a solution of triethylamine (28 μL, 0.201 mmol) and intermediate 26 (33 mg, 0.100 mmol) in DCM (1.5 mL) at room temperature. The reaction was stirred for 1 h and quenched with 2 M NaOH aqueous solution (3 mL). The mixture was extracted with DCM (3 × 3 mL), and the organic extract was passed through a phase separator and concentrated under vacuum. The crude substance was purified by reversed-phase column chromatography (10-60% MeCN / water (0.1% NH3)) to give the title compound (17 mg) as a white solid.

[0507] 1 H NMR (400MHz, CDCl3) δ7.34-7.27(m,2H),7.22-7.15(m,3H),5.51(s,1H),4.59(s,1H),4.32 (d,J=8.6Hz,1H),4.23(d,J=8.6Hz,1H),3.97-3.90(m,2H),3.66-3.63(m,1H),3.61(dd,J= 11.0, 4.2Hz, 1H), 3.43(td, J = 9.3, 2.2Hz, 1H), 3.36-3.18(m, 3H), 2.61-2.45(m, 2H), 2.14(ddd, J = 12.3, 7.2, 2.1Hz, 1H), 2.06-1.93(m, 2H), 1.77-1.44(m, 6H), 1.12(t, J = 7.2Hz, 3H). LCMS (Method A): [M+H] + m / z 402.5, RT 3.02 minutes

[0508] Example 19: Methyl 7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0509]

[0510] 2-({[1,1'-biphenyl]-3-yl}methyl)-3-oxoperidin-1-carboxylic acid tert-butyl ester (intermediate 27)

[0511]

[0512] A solution of pyrrolidine (6.3 mL, 75.3 mmol) and tert-butyl 3-oxopiperidinium-1-carboxylate (10 g, 50.2 mmol) in toluene (150 mL) was heated to reflux and held for 1.5 h using a Dean-Stark water separator. The reaction mixture was cooled to room temperature and evaporated to dryness to give crude material. This crude material was dissolved in acetonitrile (100 mL) and treated with acetonitrile (50 mL) containing 3-(bromomethyl)biphenyl (14.88 g, 60.2 mmol) 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 crude material. This crude material was dissolved in water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and evaporated to dryness to give crude material. The crude substance was purified by silica gel column chromatography (0-20% EtOAc / heptane) to give the title compound (14 g) as an orange oil. [M+Na] + m / z 388.2

[0513] tert-Butyl-2-({[1,1'-biphenyl]-3-yl}methyl)-3-{[(R)-2-methylpropane-2-sulfinyl]imino}piperidine-1-carboxylate (Intermediate 28)

[0514]

[0515] Intermediate 27 (2.50 g, 6.84 mmol), 2-methylpropane-2-sulfinamide (0.83 g, 6.84 mmol), and tetraethanolamine (4+) (2.9 mL, 13.7 mmol) were dissolved in THF (50 mL). The solution was heated at 60 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of NaHCO3 (25 mL). The solution was filtered through a diatomaceous earth filter and washed with DCM (2 × 25 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The crude material was purified by silica gel column chromatography (0–60% EtOAc / heptane) to give the title compound (2.35 g) as a yellow oil. [M+H] + m / z 469.5.

[0516] 2-({[1,1'-biphenyl]-3-yl}methyl)-3-(2-ethoxy-2-oxoethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylic acid tert-butyl ester (intermediate 29)

[0517]

[0518] A 2M solution of dipropyl-2-yl-N-hydroxide (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. An intermediate 28 solution (2.00 g, 4.27 mmol) in anhydrous THF (10 mL) was added dropwise to the mixture at -78 °C, and the mixture was stirred for 1 h. The reaction mixture was quenched sequentially at -78 °C with saturated NH4Cl aqueous solution (20 mL) and water (20 mL), heated 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 compound. The crude compound was purified by silica gel column chromatography (0–100% EtOAc / heptane) to give the title compound (1.4 g) as a pale orange oil. [M+H] + m / z 557.6

[0519] 2-({[1,1'-biphenyl]-3-yl}methyl)-3-(2-hydroxyethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylic acid tert-butyl ester (intermediate 30)

[0520]

[0521] At 0 °C, 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), and the mixture was stirred for 15 min. The reaction mixture was heated to room temperature and stirred for 3 h. Lithium tetrahydroborate (4 M in THF) (2.0 mL, 8.00 mmol) was then added and the mixture was stirred for 18 h at room temperature. THF containing 4 M lithium tetrahydroborate (2.0 mL, 8.00 mmol) was then added and the mixture was stirred for 2 h at room temperature. The reaction mixture was further treated with lithium tetrahydroborate (4 M in THF) (4.0 mL, 16.00 mmol) and stirred for 18 h at room temperature. The reaction mixture was carefully quenched sequentially with water (25 mL) and saturated NH4Cl aqueous solution (25 mL), 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 obtain the crude substance. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (1 g) as a grayish-white solid. [M+H] + m / z515.6

[0522] 3-Amino-2-({[1,1'-biphenyl]-3-yl}methyl)-3-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 31)

[0523]

[0524] 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. Hydrogen chloride (4 M in dioxane) (50 μL, 0.200 mmol) was then added, and the mixture was stirred for 2 h. The reaction was quenched at 0 °C by dropwise addition of saturated NaHCO3 aqueous solution (10 mL), and extracted with 10% methanol / DCM (3 × 5 mL). The combined organic layers were filtered through a phase separator and evaporated to dryness to obtain the crude substance. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane, then 0-10% methanol / DCM) to give the title compound (700 mg) as a grayish-white solid. [M+H]+ m / z 411.4

[0525] 7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylic acid tert-butyl ester (intermediate 32)

[0526]

[0527] N-ethyl-N-(propyl-2-yl)propyl-2-amine (360 μL, 2.07 mmol) was added dropwise to a 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 the mixture was stirred for 2 h. The reaction mixture was carefully quenched with saturated aqueous NaHCO3 solution (5 mL) and purged with N2 (gas) for 30 min using a 20% NaOH scrubber to quench phosgene gas, followed by extraction with DCM (2 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude material. The crude material was purified by silica gel column chromatography (0–100% EtOAc / heptane) to give the title compound (587 mg) as a grayish-white solid. [M+H] + m / z 437.5.

[0528] 7-({[1,1'-biphenyl]-3-yl}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-2-one (intermediate 33)

[0529]

[0530] Intermediate 32 (200 mg, 0.458 mmol) was dissolved in DCM (2 mL), followed by dropwise addition of TFA (1 mL) solution, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated Na₂CO₃ aqueous solution (10 mL) and extracted with DCM (2 × 10 mL). The organic layers were combined, passed through a phase separator, and evaporated to dryness to give the title compound (150 mg) as a grayish-white solid. [M+H+MeCN] + m / z 378.6

[0531] 7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylic acid methyl ester (19)

[0532]

[0533] At room temperature, methyl chloroformate (200 μL, 2.59 mmol) was added dropwise to a solution of intermediate 33 (151 mg, 0.448 mmol) and triethylamine (370 μL, 2.65 mmol) in DCM (3 mL), and the mixture was stirred for 30 min. The reaction mixture was quenched with water (10 mL) and then extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated to dryness to give crude material. The crude material was purified by silica gel column chromatography (0–100% EtOAc / heptane) to give the title compound (154 mg) as a grayish-white solid.

[0534] 1 H NMR (500MHz, CDCl3) δ7.64-7.52(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(m,5H),3.14(d,J=5.1Hz,2H),3.07-2.89(m,2H),2.22-2.13(m,1H),2.09-1.89(m,2H),1.87-1.62(m,4H). LCMS (Method A):[M+H] + m / z 395.2, RT 2.95 and 3.08 minutes

[0535] Example 20: Methyl (6R,7S)-7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0536] Example 21: Methyl (6S,7R)-7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0537] Example 22: Methyl (6R,7R)-7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0538] Example 23: Methyl (6S,7S)-7-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0539]

[0540] Example 19 (150 mg) was subjected to chiral SFC using Waters Prep SFC80 with a gradient of 20% ethanol and 80% CO2, Chiralpak AD-H, 10 × 250 mm, 5 μm, and a flow rate of 15 mL / min, yielding the title compound as a grayish-white solid (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). The absolute stereochemistry of compounds 10, 21, 22, and 23 was not definitively determined but is assigned as follows.

[0541] Peak 1 (stereochemically assigned as 6R,7S at piperidine); 1 H NMR (500MHz, CDCl3) δ7.62-7.51(m,2H),7.45-7.37(m,3H),7.37-7.28(m,3H),7.2 2-7.06(m,1H),6.60(s,1H),4.78(d,J=8.4Hz,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, 4.6×250mm, 5μm, 80:20 CO2:ethanol): RT 5.68 min.

[0542] Peak 2 (stereochemically assigned as 6S, 7R at piperidine): 1H NMR (500MHz, CDCl3) δ7.63-7.51(m,2H),7.46-7.38(m,3H),7.38-7.29(m,3H),7.2 2-7.06(m,1H),6.15(s,1H),4.78(d,J=8.3Hz,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, 4.6×250mm, 5μm, 80:20 CO2:ethanol): RT 8.24 min.

[0543] Peak 3 (stereochemically assigned as 6R, 7R at piperidine); 1 H NMR (500MHz, CDCl3) δ7.62-7.51(m,2H),7.48-7.39(m,3H),7.38-7.31(m,3H) ,7.09(d,J=7.4Hz,1H),5.84(s,1H),4.42-4.28(m,2H),4.23(t,J=11.2Hz,2H) ,3.47(s,1H),3.12(s,2H),3.09-3.05(m,1H),2.96(d,J=11.7Hz,1H),2.82(dd ,J=13.7,3.3Hz,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, 4.6×250mm, 5μm, 80:20 CO2:ethanol): RT 9.93 min.

[0544] Peak 4 (stereochemically assigned as 6S, 7S at piperidine); 1H NMR (500MHz, CDCl3) δ7.56 (d, J=7.5Hz, 2H), 7.44 (q, J=11.1, 9.4Hz, 3H), 7.35 (dd, J=15. 4,7.8Hz,3H),7.09(d,J=7.4Hz,1H),5.62(s,1H),4.36(s,2H),4.22(t,J=13.7Hz,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). Note: Mixture of rotational isomers. LCMS (Method B): [M+H] + m / z 395.3, RT 3.07 min. Chiral analysis (Chiralcel AD-H, 4.6×250mm, 5μm, 80:20 CO2:ethanol): RT 10.77 min.

[0545] 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)

[0546] 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)

[0547]

[0548] 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 Na2SO4, filtered, and evaporated to dryness to give crude material. The crude material was purified by a preparative HPLC standard column: XBridge™ Prep.C18 10 μm OBD™, 30 × 100 mm, mobile phase: 30-95% acetonitrile (0.2% ammonium hydroxide) / water (0.2% ammonium hydroxide) for 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 grayish-white solids.

[0549] Example 24: 1 ¹H NMR (400MHz, 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 is exchanged with solvent. LCMS (Method A): [M+H] + m / z 408.5, RT 2.86 minutes.

[0550] Example 25: 1H NMR (400MHz, CDCl3) δ7.59-7.53(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=13.4,4.5Hz,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=7.2Hz,3H). Note: 1H deletion may be due to solvent exchange. LCMS (Method B): [M+H] + m / z 408.5, RT 3.07 minutes.

[0551] 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)

[0552] 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)

[0553]

[0554] Example 24 (81 mg) was purified chirally using a Waters 600, eluted with 40 / 60% v / v hexane / ethanol, Chiralpak IC (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (peak 1, 38 mg, 100% ee; and peak 2, 28 mg, 100% ee). The absolute stereochemistry of the isolated compounds 26 and 27 was not definitively determined, but is assigned as follows.

[0555] Peak 1 (assigned as 6R, 7S at piperidine); 1H NMR (400MHz, CDCl3) δ7.57-7.51(m,2H),7.45-7.40(m,3H),7.39(d,J=1.8Hz,1H),7.33(t,J=7 .4Hz,2H),7.16(dt,J=7.5,1.5Hz,1H),6.21(s,1H),4.45(td,J=12.1,2.5Hz,2H),4.33(ddd,J =11.9,4.7,2.6Hz,1H),3.78(d,J=12.5Hz,1H),3.47(d,J=9.7Hz,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=7.2Hz,3H). LCMS (Method C):[M+H] + m / z 408.3, RT 0.9 min. Chiral analysis (Chiralcelpak IC, 25 × 0.46 cm, 5 μm, 40:60 n-hexane:ethanol): RT 6.7 min.

[0556] Peak 2 (assigned as 6R, 7S at piperidine): 1 H NMR (400MHz, CDCl3) δ7.57-7.51(m,2H),7.45-7.40(m,3H),7.39(d,J=1.8Hz,1H),7.35(s,2H) ),7.16(dt,J=7.6,1.4Hz,1H),6.29-6.24(m,1H),4.45(td,J=12.1,2.5Hz,2H),4.32(ddd,J=1 1.9, 4.8, 2.6 Hz, 1H), 3.78 (d, J = 12.8 Hz, 1H), 3.48 (d, J = 14.1 Hz, 1H), 3.17-2.94 (m, 3H), 2.92-2.77 (m, 2H), 2.29-2.20 (m, 1H), 2.08-1.95 (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, 25 × 0.46 cm, 5 μm, 40:60 n-hexane:ethanol): RT 13.6 min.

[0557] Example 28: Methyl 6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-1,7-diazaspiro[4.5]decane-7-carboxylate

[0558]

[0559] 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-carboxylic acid tert-butyl ester (intermediate 34)

[0560]

[0561] A solution of n-butyllithium (2.5 M in cyclohexane) (1.2 mL, 2.99 mmol) was added dropwise to a solution of ethyl propargyl 2-acetate (0.32 mL, 3.20 mmol) in THF (20 mL) at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 10 min, and then intermediate 28 (1.00 g, 2.13 mmol) in THF (10 mL) was added dropwise at -78 °C. The reaction was stirred at -78 °C for another 10 min, and then quenched at -78 °C with a 4:1 solution of heptane:acetic acid (1 mL). The reaction was heated to room temperature and held for 1 h, and then the reaction was partitioned between water (10 mL), a saturated aqueous solution of 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 obtain the crude substance. The crude substance was purified by silica gel column chromatography (0-60% EtOAc / heptane) to give the title compound (600 mg) as an orange solid. [M+NH4] + m / z 584.6

[0562] 3-Amino-2-({[1,1'-biphenyl]-3-yl}methyl)-3-(3-methoxy-3-oxoprop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 35)

[0563]

[0564] 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 dropwise addition of 2 M NaOH aqueous solution (2 mL), and diluted in 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 MgSO4, and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (0–80% EtOAc / hexane) to give the title compound (80 mg) as a yellow oil. [M+H] + m / z 449.4

[0565] 6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-1,7-diazaspiro[4.5]decane-7-carboxylic acid tert-butyl ester (intermediate 36)

[0566]

[0567] Intermediate 35 (100 mg, 0.216 mmol), 1,4-dioxane (2 mL), and acetic acid (25 μL, 0.432 mmol) were placed under vacuum, and the atmosphere was changed to N2 (gas). Vacuum was then applied again and repeated twice, with palladium / carbon (10%, 46 mg, 0.0432 mmol) added. The flask was evacuated, refilled with H2 (gas), and pressurized to 4 bar. The solution was stirred at room temperature for 3 h. The reaction mixture was filtered through diatomaceous earth and concentrated under vacuum. The crude material was purified by silica gel column chromatography (20–100% EtOAc / heptane) to give the title compound (55 mg) as a white solid. [M+H] + m / z 421.4

[0568] 6-({[1,1'-biphenyl]-3-yl}methyl)-1,7-diazaspiro[4.5]dec-2-one (intermediate 37)

[0569]

[0570] 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 Na₂CO₃ aqueous solution (10 mL) and extracted with DCM (2 × 10 mL). The organic layers were combined, passed through a phase separator, and concentrated under vacuum to give the title compound (30 mg) as a yellow solid, which was used without further purification. [M+H] + m / z 321.4.

[0571] Methyl 6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-1,7-diazaspiro[4.5]decane-7-carboxylate (Example 28)

[0572]

[0573] Intermediate 37 (30 mg, 0.0936 mmol) was dissolved in DCM (1 mL) and triethylamine (78 μL, 0.562 mmol) and methyl chloroformate (10 μL, 0.131 mmol) were added. The solution was stirred for 1 h, and then methyl chloroformate (10 μL, 0.131 mmol) was added. The reaction was stirred for 30 min, and methyl chloroformate (10 μL, 0.131 mmol) was added, and the reaction was stirred for another 30 min. The mixture was then diluted with DCM (10 mL) and water (10 mL), separated, and the aqueous layer was extracted with DCM (2 × 10 mL). The organic layers were combined, dried, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (0–8% methanol / DCM) to give the title compound (15 mg) as a white solid.

[0574] 1 H NMR (500MHz, CDCl3) δ7.62-7.52(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=16.6Hz,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 minutes.

[0575] Example 29: Methyl (5S,6S)-6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,7-diazaspiro[4.5]decane-7-carboxylate

[0576]

[0577] (2S,3R)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-vinyl-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylic acid tert-butyl ester (intermediate 38)

[0578]

[0579] At -78 °C, 14 mL of anhydrous THF containing intermediate 28 (1.40 g, 2.99 mmol) was added to a stirred solution of magnesium bromo(vinyl)bromo(II) (1 M in THF) (9.0 mL, 8.96 mmol). The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was heated to 0 °C and stirred for 30 min, then quenched with a saturated aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (20–100% EtOAc / heptane) to give the title compound (148 mg) as a white residue / gel. [M+H] + m / z = 497.5

[0580] (2S,3S)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-(1,2-dihydroxyethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylic acid tert-butyl ester (intermediate 39)

[0581]

[0582] 4-Methyl-4-oxo-bridged-morpholino-4-onthium (58 mg, 0.493 mmol) was added to a stirred solution of potassium dioxo-bridged (2:1:2) hydrate (5.2 mg, 0.0141 mmol) and intermediate 38 (140 mg, 0.282 mmol) in water (0.28 mL) and THF (0.7 mL) at room temperature. The reaction was then heated to 50 °C and held for 2 h. The reaction was quenched with a saturated aqueous solution of Na₂SO₃ and extracted with EtOAc (3 × 5 mL). The organic extract was passed through a phase separator and concentrated under vacuum. The crude material was purified by silica gel column chromatography (30–100% EtOAc / heptane) to give the title compound (103 mg) as a colorless solid. [M+H] + m / z = 531.5

[0583] (2S,3S)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-formyl-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylic acid tert-butyl ester (intermediate 40)

[0584]

[0585] Water (0.7 mL) containing sodium periodate (58 mg, 0.273 mmol) was added to a solution of intermediate 39 (91 mg, 0.171 mmol) in acetone (2.4 mL) under stirring at 0 °C. The reaction was stirred at 0 °C for 1 h, then heated to room temperature and held for 16 h. The reaction was quenched with water and extracted with EtOAc (3 × 5 mL). The organic extract was passed through a phase separator and concentrated under vacuum to give the title compound (66 mg) as a colorless residue. [M+H] + m / z = 499.5

[0586] (2S,3S)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-(hydroxymethyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylic acid tert-butyl ester (intermediate 41)

[0587]

[0588] 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). The reaction was stirred for 30 min, then quenched with water and extracted with DCM (3 × 5 mL). The organic extract was passed through a phase separator and concentrated under vacuum to give the title compound (59 mg) as a colorless residue. [M+H] + m / z = 501.5

[0589] (2S,3S)-3-amino-2-({[1,1'-biphenyl]-3-yl}methyl)-3-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 42)

[0590]

[0591] 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. Then, hydrogen chloride (4M in dioxane) (49 μL, 0.198 mmol) was added and the reaction was stirred for another 2 h. The reaction was quenched at 0 °C with a saturated aqueous solution of NaHCO3, and then methanol was removed under vacuum. 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 under vacuum. The crude material was purified by silica gel column chromatography (0–2% methanol / DCM) to give the title compound (39 mg) as a colorless gel. [M+H] + m / z = 397.4

[0592] (5S,6S)-6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,7-diazaspiro[4.5]decane-7-carboxylic acid tert-butyl ester (intermediate 43)

[0593]

[0594] At 0 °C, N-ethyl-N-isopropyl-propyl-2-amine (20 μL, 0.114 mmol) was added to a solution of intermediate 42 (38 mg, 0.0954 mmol) and bis(trichloromethyl) carbonate (34 mg, 0.114 mmol) in anhydrous DCM (2 mL). 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 under vacuum. The crude substance was purified by silica gel column chromatography (0–5% methanol / DCM) to give the title compound (35 mg) as a white solid. [M+NH4] + m / z = 440.6

[0595] (5S,6S)-6-({[1,1'-biphenyl]-3-yl}methyl)-3-oxa-1,7-diazaspiro[4.5]dec-2-one (intermediate 44)

[0596]

[0597] Intermediate 43 (30 mg, 0.0710 mmol) was stirred in TFA (0.18 mL) and DCM (2 mL) at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 aqueous solution and extracted with DCM (3 × 3 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum to give the title compound (28 mg) as a pale yellow gel. [M+H+MeCN] + m / z = 364.5

[0598] (5S,6S)-6-({[1,1'-biphenyl]-3-yl}methyl)-2-oxo-3-oxa-1,7-diazaspiro[4.5]decane-7-carboxylic acid methyl ester (29)

[0599]

[0600] At 0 °C, methyl chloroformate (67 μL, 0.868 mmol) was added to a solution of intermediate 44 (28 mg, 0.0868 mmol) and triethylamine (73 μL, 0.521 mmol) in DCM (2 mL) under stirring. The reaction was then heated to room temperature and held for 30 min. The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM (3 × 3 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum. The crude substance was purified by reversed-phase column chromatography (10–100% MeCN / water (0.1% NH3)) to give the title compound (19 mg) as a white solid.

[0601] 1 H NMR (500MHz, CDCl3) δ7.57 (d, J = 7.4Hz, 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=8.9Hz,1H),4.38-4.2 3(m,1H),4.19(d,J=8.9Hz,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 minutes.

[0602] 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

[0603]

[0604] (cis)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-3-(nitromethyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 45)

[0605]

[0606] A heterogeneous solution of N,N,N-tributylbut-1-aminoonium fluoride (1M 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 mixture was diluted with EtOAc (25 mL) and water (25 mL) and separated. The aqueous layer was extracted with EtOAc (2 × 10 mL), and the organic layers were combined, dried over MgSO4, and concentrated under vacuum to give the crude compound. The crude compound was purified by silica gel column chromatography (0–70% EtOAc / heptane) to give the title compound (1.1 g) as a pale yellow solid. [M+H] + m / z = 530.5

[0607] tert-Butyl-(cis)-3-(aminomethyl)-2-({[1,1'-biphenyl]-3-yl}methyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}piperidine-1-carboxylate (intermediate 46)

[0608]

[0609] A solution of intermediate 45 (1.00 g, 1.89 mmol), iron (527 mg, 9.44 mmol), and ammonium hydrochloride (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 under vacuum. The crude substance was purified by silica gel column chromatography (0–10% methanol / DCM) to give the title compound (814 mg) as a white solid. [M+H] + m / z = 500.5

[0610] (cis)-3-amino-3-(aminomethyl)-2-({[1,1'-biphenyl]-3-yl}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 47)

[0611]

[0612] 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 adding saturated NaHCO3 aqueous solution (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 under vacuum to give the title compound (650 mg) as a colorless oil. [M+H]+ m / z = 396.4

[0613] (cis)-6-({[1,1'-biphenyl]-3-yl}methyl)-2,2-dioxo-2λ 6 -Thia-1,3,7-triazaspiro[4.5]decane-7-carboxylic acid tert-butyl ester (intermediate 48)

[0614]

[0615] Intermediate 47 (450 mg, 1.14 mmol) and sulfonamide (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 × 25 mL). The organic layers were combined, washed with 2 M HCl (50 mL) and brine (50 mL), dried over MgSO4, and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (20–100% EtOAc / heptane) to give the title compound (122 mg) as a creamy solid. [M+NH4] + m / z = 475.4

[0616] (cis)-6-({[1,1'-biphenyl]-3-yl}methyl)-2λ 6 -Thia-1,3,7-triazaspiro[4.5]decane-2,2-dione (intermediate 49)

[0617]

[0618] 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 adding saturated NaHCO3 aqueous solution (5 mL) and extracted with DCM (3 × 10 mL). The organic layers were combined, passed through a phase separator, and concentrated under vacuum to give the title compound (60 mg) as a creamy solid. [M+H] + m / z = 358.3

[0619] (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)

[0620]

[0621] Ethyl isocyanate (22 μL, 0.280 mmol) was added 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, and the solution was stirred at room temperature for 30 min. The solution was quenched by adding 2 M NaOH aqueous solution (5 mL) and extracted with DCM (3 × 10 mL). The organic layers were combined, passed through a phase separator, and concentrated. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (47 mg) as a white solid.

[0622] 1 H NMR (400MHz, CDCl3) δ7.59-7.53(m,2H),7.49-7.40(m,4H),7.41-7.29(m,2H),7.21(d,J=7.5Hz,1H),4.41(d ,J=10.0Hz,1H),4.27-4.14(m,1H),4.02(d,J=10.9Hz,1H),3.69(d,J=11.9Hz,1H),3.58(s,1H),3.31(dd,J=1 3.7 (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). NH4+ deletion may be due to solvent exchange. LCMS (Method A): [M+NH4+] + m / z 446.4, RT 3.09 minutes.

[0623] Example 31: (5R,6S)-6-({[1,1'-biphenyl]-3-yl}methyl)-N-ethyl-2,2-dioxo-2λ 6 -Thia-1,3,7-triazaspiro[4.5]decane-7-carboxamide and

[0624] 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

[0625]

[0626] Example 30 (35 mg) was subjected to chiral HPLC with a gradient of 85 heptane, 15% ethanol, Chiralcel OD-H, 4.6 × 250 mm, 5 μm, at a flow rate of 18 mL / min, yielding the title compound (peak 1, 12 mg, 100% ee; and peak 2, 6 mg, 100% ee). The absolute stereochemistry of the isolated compounds 31 and 32 was not definitively determined, but is assigned as follows.

[0627] Peak 1 (assigned as 5R, 6S in piperidine); 1 H NMR (400MHz, CDCl3) δ7.59-7.53(m,2H),7.48-7.40(m,4H),7.40-7.31(m,2H),7.20(dt,J=7.5,1.2Hz,1H),5.08(s, 1H),4.38(d,J=9.9Hz,1H),4.30(s,1H),4.02(d,J=11.2Hz,1H),3.67(d,J=11.8Hz,2H),3.29(dd,J=13.7,2.7Hz,1H ),3.23(d,J=11.9Hz,1H),3.03(td,J=13.3,2.8Hz,1H),2.94(dd,J=13.6,11.8Hz,1H),2.82(ddt,J=20.6,13.2,6.9 Hz,2H),2.09(td,J=13.5,4.6Hz,1H),1.83-1.70(m,2H),1.59(ddt,J=17.9,9.1,4.6Hz,1H),0.66(t,J=7.2Hz,3H). LCMS (Method A):[M+NH4] + m / z 446.4, RT 2.96 min. Chiral analysis (Chiralcel OD-H, 4.6 × 250 mm, 5 μm, 85:15 heptane: ethanol): RT 8.97 min.

[0628] Peak 2 (assigned as 5S, 6R at piperidine): 1H NMR (400MHz, CDCl3) δ7.60-7.52(m,2H),7.48-7.40(m,4H),7.39-7.31(m,2H),7.20(d,J=7.5Hz,1H),5 .08(s,1H),4.39(d,J=10.0Hz,1H),4.29(s,1H),4.01(d,J=9.8Hz,1H),3.67(d,J=11.8Hz,2H),3.29(d d,J=13.7,2.4Hz,1H),3.23(d,J=11.9Hz,1H),3.03(t,J=12.0Hz,1H),2.99-2.90(m,1H),2.82(ddt,J= 20.3,13.1,6.7Hz,2H),2.15-2.04(m,1H),1.87-1.70(m,2H),1.65-1.51(m,1H),0.67(t,J=7.2Hz,3H). LCMS (Method A):[M+NH4] + m / z 446.4, RT 2.97 min. Chiral analysis (Chiralcel OD-H, 4.6 × 250 mm, 5 μm, 85:15 heptane: ethanol): RT 29.24 min.

[0629] Example 33: rel-(6S,7R)-N-ethyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxamide

[0630]

[0631] tert-butyl-rel-(2R,3R)-3-nitro-3-(prop-2-en-1-yl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (intermediate 50):

[0632]

[0633] 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. Methanol (20 mL) containing intermediate 4 (92%, 1.73 g, 3.80 mmol) was added, and the solution was then degassed. Palladium diacetate (43 mg, 0.190 mmol) and triphenylphosphine (150 mg, 0.570 mmol) were added sequentially. The solution was heated to 45 °C and stirred for 5 minutes, then propen-2-en-1-yl acetate (0.45 mL, 4.18 mmol) was added. The reaction mixture was heated to 55 °C and held for 3 hours, then cooled to room temperature. Palladium diacetate (43 mg, 0.190 mmol), triphenylphosphine (150 mg, 0.570 mmol), and propen-2-en-1-yl acetate (0.45 mL, 4.18 mmol) were added sequentially again. The reaction mixture was heated to 55 °C and held for 1 hour, then concentrated under vacuum to obtain the crude product. The crude substance was purified by silica gel column chromatography (0-20% TBME / heptane) to give the title compound (1.44 g) as an oil. [M+H] + m / z459.4.

[0634] tert-butyl-rel-(2R,3R)-3-amino-3-(prop-2-en-1-yl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (intermediate 51):

[0635]

[0636] Zinc (1.9 g, 28.6 mmol) was added to a stirred intermediate 50 (1.31 g, 2.86 mmol) in a solution of ethanol (36 mL) and acetic acid (8 mL) at room temperature, and the mixture was stirred for 7 hours. The reaction mixture was filtered through a diatomaceous earth mat and washed with methanol. The solution volume was reduced by approximately half, then neutralized with a saturated aqueous solution of NaHCO3 (100 mL) and extracted with DCM (2 × 100 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give the crude substance. The crude substance was purified by alkaline silica gel column chromatography (0–100% EtOAc / DCM) to give the title compound (924 mg) as an oil. [M+H] + m / z 429.8

[0637] 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):

[0638] A solution of acrylonitrile chloride (0.16 mL, 1.94 mmol) was added to a solution of intermediate 51 (416 mg, 0.971 mmol) and triethylamine (0.27 mL, 1.94 mmol) in DCM (2 mL) under stirring at room temperature, and the mixture was stirred for 1 h. The reaction mixture was quenched with 2 M NaOH aqueous solution (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give the title compound (500 mg) as an orange gel. [M+H] + m / z 483.5

[0639] tert-butyl-rel-(6R,7R)-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-3-ene-8-carboxylate (intermediate 53):

[0640]

[0641] The solution of intermediate 52 (400 mg, 0.829 mmol) in anhydrous toluene (800 mL) was treated with N... 2(气体) Degas for 15 minutes, heat to 65°C, then add [1,3-bis(2,4,6-trimethylphenyl)imidazolium-2-yl]dichloro{[5-(dimethylaminosulfonyl)-2-(prop-2-yloxy)phenyl]methylene}ruthenium (30 mg, 0.0414 mmol), and heat the reaction mixture at 65°C for 2 h while bubbling nitrogen through the solution for 2 h. Then add [1,3-bis(2,4,6-trimethylphenyl)imidazolium-2-yl]dichloro{[5-(dimethylaminosulfonyl)-2-(prop-2-yloxy)phenyl]methylene}ruthenium (30 mg, 0.0414 mmol), and heat the mixture at 65°C for 2 h. Add [1,3-bis(2,4,6-trimethylphenyl)imidazolium-2-ylidene]dichloro{[5-(dimethylaminosulfonyl)-2-(prop-2-yloxy)phenyl]methylene}ruthenium (30 mg, 0.0414 mmol), and heat the mixture at 65 °C for 4 h. Concentrate the reaction mixture under vacuum and purify by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (134 mg). [M+H] + m / z 455.4

[0642] tert-butyl-rel-(6S,7R)-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxylate (intermediate 54):

[0643]

[0644] 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 at room temperature for 16 h under a hydrogen atmosphere. The reaction mixture was filtered through a diatomaceous earth mat and washed with methanol. The combined organic layers were concentrated under vacuum to give the title compound (21 mg). [M+H] + m / z = 457.4.

[0645] rel-(6S,7R)-N-ethyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxamide (33):

[0646]

[0647] 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 h. The reaction was quenched with saturated NaHCO3 (2 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to obtain crude material. The crude material was dissolved in DCM (1 mL) and cooled to 0 °C. Triethylamine (26 μL, 0.184 mmol) and isocyanate ethane (7.3 μL, 0.092 mmol) were added sequentially at 0 °C, and the mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with 2 M NaOH aqueous solution (2 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to obtain crude material. The crude substance was purified by reverse column chromatography (10-60% MeCN / water (0.1% NH3)) to give the title compound (10.4 mg) in solid form.

[0648] 1H NMR (400MHz, CDCl3) δ7.34-7.27(m,2H),7.23-7.15(m,3H),6.16(s,1H),4.34-4.22(m,1H),3.90(d,J= 12.5Hz,1H),3.81(dd,J=9.7,7.1Hz,1H),3.74(dd,J=9.7,3.3Hz,1H),3.65(p,J=3.0Hz,1H),3.30-3.16 (m,2H), 3.11-3.02(m,1H), 2.59-2.49(m,1H), 2.45(dt,J=17.8,4.3Hz,1H), 2.37-2.26(m,1H), 2.21(dt,J=13.7,4.0Hz,1H), 2.08-1.97(m,2H), 1.97-1.49(m,12H), 1.45-1.35(m,1H), 1.12(t,J=7.2Hz,3H). 1NH exchange.

[0649] LCMS (Method A): [M+H] + m / z 428.4, RT 3.21 minutes.

[0650] Example 34: (6R,7S)-N-ethyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxamide

[0651] Example 35: (6S,7R)-N-ethyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxamide

[0652]

[0653] Example 33 (5.3 mg) was purified chirally using a Waters 600, eluted with 70 / 30% v / v hexane / ethanol, Chiralpak AS-H (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (peak 1, 2.5 mg, 100% ee; and peak 2, 2.6 mg, 100% ee). The absolute stereochemistry of the isolated compounds 34 and 35 was not definitively determined, but is assigned as follows.

[0654] Example 34: Peak 1 (assigned as 6R, 7S at piperidine); 1H NMR (400MHz, CDCl3) δ7.36-7.28(m,2H),7.25-7.14(m,3H),5.96(s,1H),4.76(br s,1H),4.28(br d,J=4.4Hz,1H),3.93(brd,J=12.8Hz,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=12.6Hz,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=14.0Hz, 2H), 1.98-1.49 (m, 12H), 1.40 (ddd, J=13.8, 10.5, 5.3Hz, 1H), 1.12 (t, J=7.2Hz, 3H).

[0655] LCMS (Method C): [M+H] + m / z 428.5, RT 0.96 minutes.

[0656] Chiral analysis (Chiralpak AS-H, 25 × 0.46 cm, 5 μm, 70 / 30 n-hexane: ethanol): RT 5.0 min.

[0657] Example 35: Peak 2 (assigned as 6R, 7S at piperidine): 1 H NMR (400MHz, CDCl3) δ7.36-7.28(m,2H),7.25-7.14(m,3H),5.96(s,1H),4.76(br s,1H),4.28(br d,J=4.4Hz,1H),3.93(brd,J=12.8Hz,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=12.6Hz,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=14.0Hz, 2H), 1.98-1.49 (m, 12H), 1.40 (ddd, J=13.8, 10.5, 5.3Hz, 1H), 1.12 (t, J=7.2Hz, 3H).

[0658] CMS (Method C): [M+H] +m / z 428.5, RT 0.96 minutes.

[0659] Chiral analysis (Chiralpak AS-H, 25 × 0.46 cm, 5 μm, 70 / 30 n-hexane: ethanol): RT 9.4 min.

[0660] 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

[0661]

[0662] tert-butyl-rel-(2R,3S)-3-(chloromethanesulfonamide)-3-(hydroxymethyl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate ( Intermediate 55):

[0663]

[0664] At 0 °C, chloromethanesulfonyl chloride (65 μL, 0.717 mmol) was added to a solution of intermediate 6 (150 mg, 0.358 mmol) and N-ethyl-N-(propyl-2-yl)propyl-2-amine (0.19 mL, 1.08 mmol) in anhydrous DCM (5 mL). The reaction was stirred for 30 min 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 under vacuum to give the title compound (190 mg) as a yellow gel. [M+Na] + m / z 553.2

[0665] 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):

[0666]

[0667] Intermediate 55 (190 mg, 0.358 mmol) was dissolved in THF (5 mL) and potassium 2-methylprop-2-oxide (100 mg, 0.894 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL) and EtOAc (10 mL). The pH was adjusted to 7 with a saturated aqueous solution of NH4Cl (approximately 5 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (15 mL), passed through a phase separator, and concentrated under vacuum to obtain the crude substance. The crude substance was purified by silica gel column chromatography (0–100% EtOAc / heptane) to give the title compound (45 mg) as a solid. [M+Na] + m / z 517.3.

[0668] 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)

[0669]

[0670] 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 min. The reaction mixture was evaporated and dissolved in anhydrous DCM (0.5 mL) and cooled to 0 °C. Triethylamine (51 μL, 0.364 mmol) and isocyanate ethane (14 μL, 0.182 mmol) were added sequentially, and the reaction mixture was stirred at room temperature 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), and the organic layers were combined, washed with brine, passed through a phase separator, and concentrated under vacuum to obtain the crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% MeCN / water (0.1% NH3)) to give the title compound (15 mg) in solid form.

[0671] 1H NMR (400MHz, CDCl3) δ7.33-7.28(m,2H),7.23-7.15(m,3H),5.11(s,1H),4.79(d,J=11.4Hz,1H),4.73(dd,J=8.2 ,4.1Hz,1H),4.56(s,1H),4.53(d,J=11.4Hz,1H),4.29(d,J=12.2Hz,1H),4.22(d,J=11.7Hz,1H),4.06(dd,J=9. 4,4.2Hz,1H),3.79(t,J=8.8Hz,1H),3.74-3.67(m,1H),3.40(d,J=12.1Hz,1H),3.27(q,J=5.6Hz,2H),2.91(t,J =11.4Hz,1H),2.53(ddd,J=15.2,7.9,3.8Hz,1H),2.10-1.97(m,2H),1.88-1.48(m,10H),1.13(t,J=7.1Hz,3H).

[0672] LCMS (Method A): [M+H] + 466.4, RT = 3.43 min

[0673] 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

[0674]

[0675] tert-Butyl-rel-(2R,3R)-3-ethylenesulfonamido-3-(prop-2-en-1-yl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate (intermediate 57)

[0676]

[0677] At 0 °C, 2-chloroethanesulfonyl chloride (93 μL, 0.933 mmol) was added to a solution of intermediate 51 (200 mg, 0.467 mmol) and N-ethyl-N-(propyl-2-yl)propyl-2-amine (0.24 mL, 1.40 mmol) in anhydrous DCM (5 mL), and the mixture was stirred for 30 min. The reaction mixture was cooled to room temperature, quenched with saturated NH4Cl aqueous solution (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 under vacuum to give crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (130 mg) as a colorless gel. [M+Na] + m / z 541.3.

[0678] tert-butyl-rel-(6R,7R)-2,2-dioxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-3-ene-8-carboxylate (intermediate 58):

[0679]

[0680] The solution of intermediate 57 (120 mg, 0.231 mmol) in anhydrous toluene (200 mL) was heated to 65 °C and treated with N2. 2(气体)Degas for 15 min. Add [1,3-bis(2,4,6-trimethylphenyl)imidazolium-2-yl]dichloro{[5-(dimethylaminosulfonyl)-2-(prop-2-yloxy)phenyl]methylene}ruthenium (8.5 mg, 0.0116 mmol), and maintain the reaction mixture at 65 °C while bubbling nitrogen through the solution for 4 h. Add [1,3-bis(2,4,6-trimethylphenyl)imidazolium-2-yl]dichloro{[5-(dimethylaminosulfonyl)-2-(prop-2-yloxy)phenyl]methylene}ruthenium (8.5 mg, 0.0116 mmol), and heat the mixture for 4 h. The reaction mixture was cooled to room temperature and stirred for 16 h. Then, [1,3-bis(2,4,6-trimethylphenyl)imidazolium-2-methylene]dichloro{[5-(dimethylaminosulfonyl)-2-(prop-2-yloxy)phenyl]methylene}ruthenium (8.5 mg, 0.0116 mmol) was added, and the reaction mixture was heated for 4 h. Then, [1,3-bis(2,4,6-trimethylphenyl)imidazolium-2-yl]dichloro{[5-(dimethylaminosulfonyl)-2-(prop-2-yloxy)phenyl]methylene}ruthenium (8.5 mg, 0.0116 mmol) was added, and the mixture was heated for 4 h. The reaction mixture was concentrated under vacuum, and the crude product was purified by reversed-phase column chromatography (10-100% MeCN / water (0.1% NH3)) to give the title compound (56 mg) as an oil. [M+Na] + m / z 513.1

[0681] 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):

[0682]

[0683] Intermediate 58 (55 mg, 0.112 mmol) was dissolved in ethanol (10 mL) and the mixture was evacuated and backfilled three times with nitrogen. Palladium / carbon (10% w / w) (10%, 5.9 mg, 5.60 μmol) was added, and the reaction was evacuated and backfilled three times with hydrogen. The reaction was stirred for 16 h, evacuated, backfilled three times with nitrogen, filtered through diatomaceous earth, and eluted with ethanol (10 mL) and EtOAc (20 mL). The solution was concentrated under vacuum to give the title compound (55 mg) as a colorless gel, which was used without further purification. [M+Na] + m / z 515.1.

[0684] 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):

[0685]

[0686] 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 and dissolved in anhydrous DCM (0.5 mL) and cooled to 0 °C. Triethylamine (62 μL, 0.447 mmol) and isocyanate ethane (18 μL, 0.223 mmol) were added sequentially, 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 under vacuum to give crude material. The crude material was purified by reversed-phase column chromatography (10-100% MeCN / water (0.1% NH3)) to give the title compound (43 mg) as a white solid.

[0687] 1 H NMR (500MHz, CDCl3) δ7.34-7.25(m,2H),7.25-7.13(m,3H),5.13(s,1H),4.58(dd,J=8.6,3.5Hz,1H),4.31(s,1H),4.20(d,J=1 1.9Hz,1H),4.08(dd,J=9.4,3.9Hz,1H),3.78(t,J=9.1Hz,1H),3.74-3.67(m,1H),3.29-3.14(m,3H),2.98-2.82(m,2H),2.52( tt,J=11.6,3.8Hz,1H),2.39(tdd,J=15.0,7.6,3.3Hz,1H),2.31(dt,J=14.1,3.9Hz,1H),2.23(dp,J=14.2,4.5Hz,1H),2.10-1 .97(m,2H),1.78(pd,J=14.2,13.7,3.6Hz,3H),1.72-1.59(m,5H),1.59-1.48(m,2H),1.37-1.28(m,1H),1.11(t,J=7.2Hz,3H).

[0688] LCMS (Method A): [M+H] + m / z 464.4, RT 3.57 minutes.

[0689] 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

[0690]

[0691] tert-Butyl-rel-(1R,6S)-8,8-dioxo-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-8λ6-thia-2,7-diazaspiro[5.6]dodecane-2-carboxylate (intermediate 60)

[0692]

[0693] At 0 °C, 2-chloroethanesulfonyl chloride (71 μL, 0.717 mmol) was added to a solution of intermediate 6 (150 mg, 0.358 mmol) and N-ethyl-N-(propyl-2-yl)propyl-2-amine (0.19 mL, 1.08 mmol) in anhydrous DCM (3.75 mL), and the mixture was stirred for 30 min. The reaction mixture was heated to room temperature, quenched with saturated NH4Cl aqueous solution (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 under vacuum to give the title compound (110 mg) as a colorless oil, which was used in the next step without further purification. [M+H] + m / z 509.3.

[0694] 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)

[0695]

[0696] 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 mixture was evaporated and dissolved in anhydrous DCM (1.1 mL) and cooled to 0 °C. Triethylamine (110 μL, 0.786 mmol) and isocyanate ethane (31 μL, 0.393 mmol) were added sequentially, and the reaction 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 under vacuum to obtain the crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% MeCN / water (0.1% NH3)) to give the title compound (26 mg) as a solid.

[0697] 1 H NMR (400MHz, CDCl3) δ7.35-7.29(m,2H),7.24-7.14(m,3H),4.91(s,1H),4.57(d,J=1 3.2Hz,1H),4.46-4.35(m,1H),4.15(d,J=15.9Hz,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=11.5Hz,1H),2.55(tt,J=10.9,5.1Hz,1H),2.01(dd,J=10.0,4.1Hz,2H),1.89(s,1H),1.79-1.44(m,9H),1.13(t,J=7.2Hz,3H). NH protons are shielded.

[0698] LCMS (Method A): [M+H] + m / z 480.4, RT 3.60 minutes.

[0699] 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

[0700] 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

[0701]

[0702] 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)

[0703]

[0704] A solution of K₂CO₃ (99 mg, 0.717 mmol) in water (2 mL) was added to a solution of intermediate 6 (100 mg, 0.239 mmol) in THF (2 mL) under stirring at 0 °C. 2-Bromopropionyl 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 under vacuum to obtain the crude product. The residue was dissolved in anhydrous DMF (2 mL), and 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 HCl aqueous solution and saturated NaHCO₃ aqueous solution, 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 under vacuum to obtain the crude product. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane, then 0-20% methanol / EtOAc) to give the title compound (41 mg) as a colorless residue. This substance was used without further purification. [MH] - m / z 471.5.

[0705] (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

[0706] (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)

[0707]

[0708] 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 × 2 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give crude material. The residue was dissolved in DCM (2 mL), and triethylamine (24 μL, 0.174 mmol) and isocyanate ethane (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 NaOH aqueous solution (2 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give crude material. The crude material was attempted to be purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give a white solid. This was purified by chiral preparation using a Waters 600, eluted 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 the isolated compounds 39 and 40 was not definitively determined, but is assigned as follows.

[0709] Example 39: Peak 1 (assigned as 6R, 7S at piperidine); 1 H NMR (500MHz, CDCl3) δ7.34-7.28(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,4 H),3.70-3.62(m,1H),3.33-3.21(m,2H),3.13-2.96(m,1H),2.55(tt,J=11.3,4.2Hz ,1H),2.09-1.85(m,4H),1.82-1.53(m,8H),1.53-1.45(m,3H),1.14(t,J=7.2Hz,3H).

[0710] LCMS (Method C): [M+H] + m / z 444.3, RT 1.00 minutes.

[0711] Chiral analysis (Chiralcelpak AS-H, 25 × 0.46 cm, 5 μm, 75 / 25 n-hexane / ethanol + 0.1% isopropylamine): RT 5.0 min.

[0712] Example 40: Peak 2 (assigned as 6S, 7R at piperidine): 1 H NMR (500MHz, CDCl3) δ7.34-7.28(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,4 H),3.70-3.62(m,1H),3.33-3.21(m,2H),3.13-2.96(m,1H),2.55(tt,J=11.3,4.2Hz ,1H),2.09-1.85(m,4H),1.82-1.53(m,8H),1.53-1.45(m,3H),1.14(t,J=7.2Hz,3H).

[0713] LCMS (Method C): [M+H] + m / z 444.3, RT 1.00 minutes.

[0714] Chiral analysis (Chiralcelpak AS-H, 25 × 0.46 cm, 5 μm, 75 / 25 n-hexane / ethanol + 0.1% isopropylamine): RT 8.0 min.

[0715] 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

[0716]

[0717] 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)

[0718]

[0719] At 0 °C, a solution of 2-chloro-2-fluoro-acetyl chloride (282 mg, 2.15 mmol) in DCM (11 mL) was added to a solution of intermediate 6 (450 mg, 1.08 mmol) and N-ethyl-N-(propyl-2-yl)propyl-2-amine (0.56 mL, 3.23 mmol) in DCM (11 mL), 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 under vacuum to give a crude substance. 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. Sodium hydride (60%, 82 mg, 2.04 mmol) was added again at room temperature, and the reaction was stirred at 50 °C for 0.5 h. 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 under vacuum to give the title compound (450 mg). [MH] - m / z 457.4.

[0720] 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)

[0721]

[0722] A solution of trifluoroacetic acid (24 mL, 0.311 mol) 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 × 20 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to obtain the crude product. The crude mixture was dissolved in DCM (22 mL), and triethylamine (609 μL, 4.37 mmol) and isocyanate ethane (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 NaOH aqueous solution (15 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to obtain the crude product. The crude substance was purified by reverse column chromatography (10-60% MeCN / water (0.1% NH3)) to give the title compound (43 mg) as a white solid.

[0723] 1 H NMR (400MHz, CDCl3) δ7.33-7.27(m,2H),7.23-7.16(m,3H),6.49(s,1H),5.57(d,J=51. 8Hz,1H),4.78(t,J=5.3Hz,1H),4.51-4.46(m,1H),4.17(d,J=11.9Hz,1H),4.07-3.99(m ,1H),3.87-3.70(m,3H),3.64(p,J=2.9Hz,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 = 7.2Hz, 3H).

[0724] LCMS (Method A): [M+H] + m / z 448.4, RT 3.39 minutes.

[0725] 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

[0726] 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)

[0727]

[0728] Example 41 (39 mg) was purified by chiral preparation using a Waters 600, eluted with 80 / 20% v / v hexane / ethanol, Chiralpak AS-H (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (peak 1, 15.5 mg, 100% ee; and peak 2, 15.2 mg, 99.6% ee). The absolute stereochemistry of the isolated compounds 42 and 43 was not definitively determined, but is assigned as follows.

[0729] Example 42: Peak 1 (assigned as 6R, 7S at piperidine); 1H NMR (500MHz, CDCl3) δ7.34-7.29(m,2H),7.23-7.17(m,3H),5.94(br s,1H),5.59(d,J=51.9Hz,1H),4.72(br t,J=4.9Hz,1H),4.53(br d,J=3.4Hz,1H),4.17(br d,J=11.8Hz,1H),4.00(br d,J=10.6Hz,1H),3.87-3.78(m,2H),3.75(dd,J=9.9,2.7Hz,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=12.6Hz,1H),1.77-1.66(m,5H),1.64-1.56(m,3H),1.14(t,J=7.3Hz,3H).

[0730] LCMS (Method C): [M+H] + m / z 448.3, RT 1.01 minutes.

[0731] Chiral analysis (Chiralcelpak AS-H, 25 × 0.46 cm, 5 μm, 80 / 20 n-hexane:ethanol): RT 6.3 min.

[0732] Example 43: Peak 2 (assigned as 6S, 7R at piperidine); 1 H NMR (500MHz, CDCl3) δ7.34-7.28(m,2H),7.24-7.16(m,3H),6.07(br s,1H),5.59(d,J=51.9Hz,1H),4.74(br t,J=5.1Hz,1H),4.52(br d,J=4.0Hz,1H),4.17(br d,J=11.9Hz,1H),4.01(br d,J=11.8Hz,1H),3.90-3.79(m,2H),3.75(dd,J=9.9,2.7Hz,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=13.0Hz,1H),1.76-1.66(m,5H),1.66-1.58(m,3H),1.14(t,J=7.2Hz,3H).

[0733] LCMS (Method C): [M+H] + m / z 448.3, RT 1.01 minutes.

[0734] Chiral analysis (Chiralcelpak AS-H, 25 × 0.46 cm, 5 μm, 80 / 20 n-hexane:ethanol): RT 9.4 min.

[0735] Example 44: N-ethyl-8-oxo-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5.6]dodecane-2-carboxamide (44)

[0736]

[0737] 4,4-Difluoro-3-oxo-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 63)

[0738]

[0739] At -78°C, 10 mL of anhydrous THF containing intermediate 2 (1.63 g, 4.21 mmol) was added dropwise to a solution of 2 M 1,1,1,3,3,3-hexamethyldisilazane-2-oxide (2.5 mL, 5.05 mmol) in 10 mL of anhydrous THF, and the mixture was stirred for 30 min. Then, 10 mL of anhydrous THF containing N-(benzenesulfonyl)-N-fluorobenzenesulfonamide (1592 mg, 5.05 mmol) was added, and the mixture was stirred at this temperature for 3 h. The mixture was quenched with 20 mL of saturated NaHCO3 aqueous solution, diluted with 20 mL of water, and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (2.43 g) as crude material. [M+Na] + m / z 446.1

[0740] (3E / Z)-4,4-Difluoro-3-{[(R)-2-methylpropane-2-sulfinyl]imino}-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 64)

[0741]

[0742] Intermediate 63 (2.43 g, 5.74 mmol), (R)-2-methylpropane-2-sulfinamide (509 mg, 4.20 mmol), and (4+)tetraethanolamine (1.8 mL, 8.41 mmol) were dissolved in anhydrous THF (35 mL) and stirred overnight at 60 °C. The mixture was concentrated under vacuum, and the crude material was purified by silica gel column chromatography (0-60% TBME / heptane) to give the title compound (729 mg, 50% purity) as a yellow gel. [M+Na] + m / z 549.2

[0743] 3-(2-ethoxy-2-oxoethyl)-4,4-difluoro-3-{[(S)-2-methylpropane-2-sulfinyl]amino}-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester ( Intermediate 65 )

[0744]

[0745] At -78°C, a solution of anhydrous ethyl acetate (0.68 mL, 6.92 mmol) was added dropwise to a stirred solution of 2M dipropyl-2-yl-N-acetyl lithium (3.5 mL, 6.92 mmol) in 3 mL of THF, and the mixture was stirred for 30 min. Then, a solution of intermediate 64 (365 mg, 0.692 mmol) in 5 mL of anhydrous THF was added dropwise, and the mixture was stirred at -78°C for 1 h. The reaction mixture was cooled to room temperature, quenched with saturated NH4Cl aqueous solution (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 under vacuum to obtain the crude compound. The crude compound was purified by column chromatography (0-100% EtOAc / heptane) to give the title compound (200 mg) as a beige solid. [M+H] + m / z 615.3

[0746] 4,4-Difluoro-3-(2-hydroxyethyl)-3-{[(S)-2-methylpropane-2-sulfinyl]amino}-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 66)

[0747]

[0748] A solution of 4 M 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 then heated 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 under vacuum to give the title compound (155 mg) as a yellow gel. [M+H] + m / z 573.5

[0749] 3-Amino-4,4-difluoro-3-(2-hydroxyethyl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 67)

[0750]

[0751] Intermediate 66 (155 mg, 0.271 mmol) was dissolved in methanol (2.3 mL) and cooled to 0 °C. Dioxane containing 4 M HCl (0.070 mL, 0.279 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 3 h. Then, dioxane containing 4 M HCl (7.7 μL, 0.0310 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction was quenched at 0 °C by dropwise addition of a saturated aqueous solution of NaHCO3 (5 mL), and extracted with 10% methanol / DCM (3 × 5 mL). The combined organic layers were filtered through a phase separator and concentrated under vacuum to give the title compound (150 mg) as a pale yellow oil, which was used in the next step without purification. [M+H] + m / z 469.5

[0752] 11,11-Difluoro-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylic acid tert-butyl ester ( Intermediate 68 )

[0753]

[0754] At 0 °C, N-ethyl-N-(propyl-2-yl)propyl-2-amine (0.036 mL, 0.208 mmol) was added to a solution of intermediate 67 (65%, 150 mg, 0.208 mmol) and bis(trichloromethyl) carbonate (62 mg, 0.208 mmol) under stirring. The reaction mixture was stirred at 0 °C for 1.5 h, then quenched with a saturated aqueous solution of NaHCO3 (1 mL) and purged with N2 (gas) for 30 min using a 20% NaOH scrubber to quench excess phosgene gas. The solution was extracted with DCM (3 × 1 mL) and concentrated under vacuum through a phase separator to obtain a crude product. The crude product was purified by silica gel column chromatography (0–100% EtOAc) to give the title compound (60 mg) as a colorless gel. [M+H] + m / z 469.5

[0755] N-Ethyl-8-oxo-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5.6]dodecane-2-carboxamide (44)

[0756]

[0757] 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 under vacuum. The residue was dissolved in DCM (1 mL) and cooled to 0 °C. Triethylamine (68 μL, 0.485 mmol) and isocyanate ethane (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 NaOH aqueous solution (2 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give crude material. The crude material was purified by reversed column chromatography (10-60% MeCN / water (0.1% NH3)) to give the title compound (8.0 mg) as a white solid.

[0758] 1H NMR (400MHz, CDCl3) δ7.27-7.19(m,2H),7.14-7.06(m,3H),5.27(s,2H),4. 38(d,J=12.6Hz,1H),4.34-4.18(m,2H),4.12(d,J=9.3Hz,1H),3.75-3.58(m ,3H),3.17-3.05(m,2H),2.94(td,J=14.0,3.8Hz,1H),2.53-2.41(m,1H),1. 97(td,J=31.5,28.3,12.3Hz,6H),1.68-1.54(m,6H),1.01(t,J=7.2Hz,3H).

[0759] LCMS (Method A): [M+H] + m / z 466.4, RT 3.44 minutes

[0760] 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

[0761] 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

[0762]

[0763] Example 44 (4.3 mg) was purified chirally using a Waters 600, eluted with 80 / 20% v / v hexane / ethanol, Chiralpak AD-H (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (peak 1, 2.1 mg, 100% ee; and peak 2, 1.7 mg, 100% ee). The absolute stereochemistry of the isolated compounds 45 and 46 was not definitively determined, but is assigned as follows.

[0764] Example 45: Peak 1 (assigned as 6R, 7R at piperidine); 1H NMR (400MHz, CDCl3) δ7.34-7.28(m,2H),7.23-7.17(m,3H),5.38(s,1H),5.33(br t,J=5.1Hz,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=7.3Hz,3H).

[0765] LCMS (Method C): [M+H] + m / z 466.2, RT 1.03 minutes.

[0766] Chiral analysis (Chiralcelpak AD-H, 25×0.46cm, 5μm, 80:20 n-hexane:ethanol): RT 4.6 min.

[0767] Example 46: Peak 2 (assigned as 6S, 7S at piperidine): 1 H NMR (400MHz, CDCl3) δ7.34-7.28(m,2H),7.23-7.17(m,3H),5.38(s,1H),5.33(br t,J=5.1Hz,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=7.3Hz,3H).

[0768] LCMS (Method C): [M+H] + m / z 466.1, RT 1.03 minutes.

[0769] Chiral analysis (Chiralcelpak AD-H, 25×0.46cm, 5μm, 80:20 n-hexane:ethanol): RT 8.5 min.

[0770] 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

[0771]

[0772] Intermediate 69

[0773]

[0774] (3R)-3-{[(benzyloxy)carbonyl]({[methoxy(methyl)carbamoyl]methyl})amino}methyl butyrate

[0775] Potassium carbonate (71.3 g, 0.516 mol) was added to a solution of (3R)-3-aminobutyrate methyl hydrochloride (36.0 g, 0.234 mol) in acetonitrile (500 mL), followed by the addition of 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 under vacuum and the crude material was dissolved in DCM (500 mL), cooled to 0 °C, and then triethylamine (33 mL, 0.234 mol) and benzyl chloroformate (43 mL, 0.305 mol) were added dropwise, while the mixture was stirred at room temperature for 24 h. The solution was diluted with DCM (500 mL), washed with NaHCO3 (300 mL), passed through a phase separator, and concentrated under vacuum to obtain the crude material. The crude substance was purified (0-100% EtOAc / heptane) to give the title compound methyl (39.5 g) as a pale yellow oil. [M+H] + m / z353.3

[0776] Intermediate 70

[0777]

[0778] (2R)-2-methyl-4-oxopyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester

[0779] At -78°C, 2M sodium 1,1,1,3,3,3-hexamethyldisilazane-2-oxide (11 mL, 21.6 mmol) was added dropwise to a stirred solution of intermediate 69 (7.60 g, 21.6 mmol) in anhydrous THF (150 mL). After stirring the solution for 10 min at the same temperature, the reaction was quenched with 1M HCl aqueous solution (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 under vacuum to obtain the crude substance. The crude substance was purified by silica gel column chromatography (0–80% methanol / DCM) to give the title compound (4.40 g) as a yellow oil. [M+H] + m / z 292.2

[0780] Intermediate 71

[0781]

[0782] (2R)-2-methyl-4-oxo-5-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester

[0783] Paraformaldehyde (1.02 g, 34.0 mmol) was added to a solution of 4-phenylcyclohexanol (5.99 g, 34.0 mmol) in anhydrous DCM (50 mL), followed by the addition of chloro(trimethyl)silane (17 mL, 0.136 mol). The reaction was stirred at room temperature for 2 h, and the solution was concentrated under vacuum at 30 °C to give a pale yellow oily substance 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-(propyl-2-yl)propyl-2-amine (11 mL, 81.6 mmol) in anhydrous THF (37.438 mL) at 0 °C. The reaction was maintained at this temperature for 0.5 h. 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 under vacuum to give a crude substance. The crude substance was purified by silica gel column chromatography (0–40% methanol / DCM) to give the title compound (9.90 g) as a colorless oil. [M+H] + m / z480.3

[0784] Intermediates 72a and 72b

[0785]

[0786] Intermediate 72a: (2S,5R)-5-methyl-3-oxo-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylic acid benzyl ester and

[0787] Intermediate 72b: (2R,5R)-5-methyl-3-oxo-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylic acid benzyl ester

[0788] 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 and maintained 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) and brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give the crude substance. The crude substance was purified by silica gel column chromatography (0–70% EtOAc / 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

[0789] Intermediate 73

[0790]

[0791] Benzyl-(2R,5R)-3-(hydroxyimino)-5-methyl-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate.

[0792] 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 and maintained for 1 h. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (3.30 g) as a colorless oil. [M+H] + m / z = 437.3

[0793] Intermediate 74

[0794]

[0795] (2R,5R)-5-methyl-3-nitro-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylic acid benzyl ester

[0796] At 0 °C, 6.7 mL of anhydrous acetonitrile containing 1.4 mL (10.4 mmol) trifluoroacetic anhydride was added to a stirred solution of hydrogen peroxide-urea (1:1) (1.37 g, 14.6 mmol) in 6.7 mL of anhydrous acetonitrile. The reaction was stirred at 0 °C for 2 h. The resulting solution was added dropwise at 80 °C to a mixture of intermediate 73 (2.49 g, 4.16 mmol) and sodium bicarbonate (1.75 g, 20.8 mmol) in 9.6184 mL of anhydrous acetonitrile, and the mixture was stirred at 80 °C for 1 h. The reaction was cooled to room temperature and quenched with a saturated aqueous solution of Na₂SO₃, diluted with water (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO₄, filtered, and concentrated under vacuum to give the crude product. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title (1.20 g) as a white solid. [M+H] + m / z = 453.3

[0797] Intermediate 75

[0798]

[0799] (2R,3S,5R)-3-(hydroxymethyl)-5-methyl-3-nitro-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylic acid benzyl ester

[0800] Formaldehyde (37% in water, 1.9 mL, 26.1 mmol) was added to 13 mL of THF containing intermediate 74 (1.27 g, 2.90 mmol) and triethylamine (0.48 mL, 3.48 mmol) at room temperature, and the solution was heated to 70 °C and maintained for 18 h. After cooling, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (1.42 g) as a colorless oil. [M+H] + m / z 483.3

[0801] Intermediate 76

[0802]

[0803] (2R,3S,5R)-3-amino-3-(hydroxymethyl)-5-methyl-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)pyrrolidine-1-carboxylic acid benzyl ester

[0804] 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 h. Zinc (1.55 g, 24.0 mmol) was then added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a diatomaceous earth mat and washed with methanol. The filtrate was neutralized with a saturated aqueous solution of NaHCO3 and extracted with DCM (3 × 50 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum to give the title compound (1.22 g) as a white solid. [M+H] + m / z 453.4

[0805] Intermediate 77

[0806]

[0807] (1R,3R,5S)-3-methyl-7-oxo-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid benzyl ester

[0808] Potassium dicarbonate (183 mg, 1.33 mmol) and water (2 mL) were added sequentially to a solution of intermediate 76 (200 mg, 0.442 mmol) in THF (2 mL) at 0 °C. Chloroacetyl chloride (49 μL, 0.619 mmol) was added dropwise to this mixture at 0 °C. The reaction was stirred at 0 °C for 2 h. 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 under vacuum. The intermediate was dissolved in DCM (4 mL) and IPA (4 mL) and cooled to 0 °C. Potassium 2-methylprop-2-ol (198 mg, 1.77 mmol) was added, and the reaction was stirred at 0 °C for 1 h, then heated to room temperature and stirred overnight. The reaction mixture was quenched with water (5 mL). The mixture was poured onto a saturated aqueous solution of NaHCO3 (10 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain a crude substance. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (80 mg) as a colorless oil. [M+H] + m / z 493.2

[0809] Intermediate 78

[0810]

[0811] (1R,3R,5S)-3-methyl-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]dec-7-one

[0812] Intermediate 77 (80 mg, 0.162 mmol) was dissolved in ethanol (8 mL), and the mixture was evacuated to atmospheric pressure and backfilled with nitrogen three times. Palladium / carbon (10%) (20 mg, 0.162 mmol) was added, and the mixture was evacuated to atmospheric pressure and backfilled with hydrogen three times. The reaction was stirred for 2 h, then filtered through a diatomaceous earth pad and washed with EtOAc. The filtrate was concentrated under vacuum to give the title compound (58 mg) as a white gel. [M+H] + m / z 359.3

[0813] (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)

[0814]

[0815] At room temperature, isocyanate ethane (26 μL, 0.324 mmol) was added to a solution of triethylamine (45 μL, 0.324 mmol) and intermediate 78 in anhydrous DCM (1.2 mL). The reaction was stirred for 1 h. The reaction mixture was quenched with 2 M NaOH aqueous solution and extracted with DCM (3 × 10 mL). The organic layers were combined, washed with brine (25 mL), passed through a phase separator, and concentrated under vacuum. The crude substance was purified by reversed-phase rapid column chromatography (10–100% MeCN / H2O (0.1% NH3)) to give the title compound (24 mg) as a white powder.

[0816] 1H NMR (400MHz, CDCl3) δ7.34-7.27(m,2H),7.24-7.15(m,3H),6.36(s,1H),5.14(s,1H),4.24(d,J=16.8Hz,1H),4 .17-4.07(m,2H),3.94-3.83(m,1H),3.78-3.68(m,3H),3.49(dd,J=9.4,6.9Hz,1H),3.43(d,J=11.7Hz,1H),3. 33-3.18(m,2H),2.57(tt,J=10.6,4.9Hz,1H),2.27(dd,J=13.0,7.4Hz,1H),2.12-2.00(m,2H),1.81(dd,J=13. 0,9.6Hz,1H),1.73(td,J=9.0,8.1,3.5Hz,4H),1.65-1.55(m,2H),1.37(d,J=5.9Hz,3H),1.13(t,J=7.3Hz,3H).

[0817] LCMS (Method A): [M+H] + m / z 430.4, RT 3.35 minutes

[0818] 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

[0819]

[0820] Example 48 was synthesized using intermediate 72b following the same procedure used to synthesize Example 47. The substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give Example 48 (44 mg) as a white powder. [M+H] + m / z 430.3

[0821] 1H NMR (500MHz, CDCl3) δ7.31(t,J=7.6Hz,2H),7.20(dd,J=13.4,7.1Hz,3H),6.27(s,1H),4.24(d,J=16 .7Hz,2H),4.12-4.05(m,3H),4.03-3.90(m,2H),3.65-3.59(m,1H),3.56(d,J=11.6Hz,1H),3.52(dd, J=10.5,1.7Hz,1H),3.34-3.21(m,2H),2.65-2.48(m,2H),2.04-1.95(m,2H),1.81(d,J=13.1Hz,1H) ,1.72(td,J=10.9,10.0,3.0Hz,2H),1.69-1.42(m,5H),1.29(d,J=6.4Hz,3H),1.11(t,J=7.2Hz,3H).

[0822] LCMS (Method A): [M+H] + m / z 430.3, RT 3.28 minutes.

[0823] Example 49: (1R,3R,5S)-2-(2-hydroxy-2-methylpropionyl)-3-methyl-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]dec-7-one

[0824]

[0825] At room temperature, a solution of intermediate 78 in anhydrous DMF (0.2 mL) was added to a stirred solution of 2-hydroxy-2-methylpropionic acid (19 mg, 0.181 mmol), HATU (80 mg, 0.209 mmol), and DIPEA (49 μL, 0.279 mmol) in anhydrous DMF (1 mL), 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 under vacuum to give a crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give the title compound (8.3 mg) as a beige solid.

[0826] 1H NMR (400MHz, CDCl3) δ7.32(t,J=7.4Hz,2H),7.27-7.18(m,3H),6.34(s,1H),4.95-4.84(m,1H),4.29(d,J=16. 8Hz,1H),4.23-4.14(m,2H),3.86(dd,J=10.0,3.1Hz,1H),3.77-3.73(m,1H),3.71-3.62(m,2H),3.43(d,J=11 .8Hz,1H),2.60(tt,J=10.8,5.0Hz,1H),2.21(dd,J=13.1,8.5Hz,1H),2.11(d,J=12.0Hz,2H),1.87(dd,J=12. 9,9.0Hz,1H),1.77(dd,J=7.6,4.5Hz,4H),1.70-1.55(m,4H),1.55(s,3H),1.49(s,3H),1.44(d,J=6.2Hz,3H).

[0827] LCMS (Method A): [M+H] + m / z 445.4, RT 3.46 minutes.

[0828] 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

[0829]

[0830] A solution of 2,2-difluoroethylamine (22 μL, 0.307 mmol) and N-ethyl-N-isopropyl-prop-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 the mixture was stirred at room temperature for 2 h. This mixture was then 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 h. Carbonyl dichloride (20%, 0.15 mL, 0.279 mmol) was added, and the reaction was stirred at room temperature for 15 min. 2,2-difluoroethylamine (22 μL, 0.307 mmol) was then added, and the reaction was stirred overnight at room temperature. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (5 mL) and purged with N2 (gas) (using 20% ​​NaOH aqueous solution as a scrubber) for 30 min. The reaction mixture was extracted with DCM (3 × 3 mL), and the combined organic layers were passed through a phase separator and concentrated under vacuum to obtain a crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give the title compound (23 mg) as a white powder.

[0831] 1 H NMR (400MHz, CDCl3) δ7.33-7.27(m,2H),7.23-7.14(m,3H),6.41(s,1H),6.06-5.63(m,2H ),4.25(d,J=16.9Hz,1H),4.18-4.10(m,2H),3.92(dt,J=9.6,7.0Hz,1H),3.82-3.59(m,4H ),3.55-3.36(m,3H),2.57(p,J=8.7,8.2Hz,1H),2.27(dd,J=13.1,7.4Hz,1H),2.11-1.99( m,2H),1.79(dd,J=13.1,9.8Hz,1H),1.76-1.66(m,4H),1.64(s,2H),1.37(d,J=6.0Hz,3H)

[0832] LCMS (Method A): [M+H] + m / z 466.4, RT 3.34 minutes.

[0833] 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

[0834]

[0835] A solution of 1-isocyano-2-methoxyethane (12 μL, 0.112 mmol) was added dropwise to a solution of intermediate 78 (20 mg, 0.0558 mmol) and triethylamine (16 μL, 0.112 mmol) in anhydrous DCM (0.5 mL) while stirring at room temperature, and the mixture was stirred for 1 h. The reaction mixture was quenched with 2 M NaOH aqueous solution (1 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give a crude substance. The crude substance was purified by reversed-phase column chromatography (10–100% acetonitrile / water (0.1% NH3)) to give the title compound (17 mg) as a white solid.

[0836] 1 H NMR (500MHz, CDCl3) δ7.35-7.29(m,2H),7.26-7.18(m,3H),6.29(s,1H),5.24(s,1H),4.26(d,J=16.8Hz,1 H),4.19-4.13(m,2H),3.90-3.81(m,1H),3.79(dd,J=9.7,2.3Hz,1H),3.75-3.65(m,1H),3.57(dd,J=9.7, 5.2Hz,1H),3.51-3.37(m,5H),3.35(s,3H),2.59(tt,J=11.5,4.0Hz,1H),2.32(dd,J=13.0,7.5Hz,1H),2. 16-2.03(m,2H),1.91(dd,J=13.0,9.5Hz,1H),1.86-1.68(m,4H),1.68-1.63(m,2H),1.41(d,J=6.0Hz,3H).

[0837] LCMS (Method B): [M+H] + m / z 460.4, RT 2.96 minutes.

[0838] Example 52: (1R,3R,5S)-2-(3,3-difluoroazacyclobutane-1-carbonyl)-3-methyl-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]dec-7-one

[0839]

[0840] At room temperature, 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-prop-2-amine (31 μL, 0.179 mmol) in anhydrous DCM (1.4 mL), and the mixture was stirred for 3 h. At room temperature, a solution of 3,3-difluoroazacyclobutane-1-onium chloride (22 μL, 0.245 mmol) in anhydrous DCM (1.4 mL) and N-ethyl-N-isopropyl-prop-2-amine (31 μL, 0.179 mmol) was added dropwise to the reaction mixture, and the reaction was stirred for 18 h. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (5 mL) and purged with N2 (20% NaOH aqueous solution as a scrubber) for 30 min. The reaction mixture was extracted with DCM (3 × 3 mL), and the combined organic layers were passed through a phase separator and concentrated under vacuum to obtain a crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give the title compound (16 mg) as a white powder.

[0841] 1 H NMR (400MHz, CDCl3) δ7.38-7.28(m,2H),7.25-7.15(m,3H),6.32(s,1H),4.46-4.35(m,2H), 4.24(d,J=16.7Hz,1H),4.21-4.11(m,3H),4.00(s,1H),3.93(dd,J=10.5,2.2Hz,1H),3.82- 3.72(m,1H),3.72-3.64(m,3H),3.47(d,J=11.7Hz,1H),2.64-2.52(m,1H),2.27(dd,J=12.8 ,7.8Hz,1H),2.13-2.00(m,3H),1.83-1.70(m,4H),1.68-1.57(m,2H),1.41(d,J=6.1Hz,3H).

[0842] LCMS (Method B): [M+H] + m / z 478.4, RT 3.50 minutes.

[0843] 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

[0844]

[0845] Intermediate 79

[0846]

[0847] (2R)-2-methyl-4-oxopyrrolidine-1-carboxylic acid benzyl ester

[0848] Sodium chloride (1.18 g, 20.3 mmol) and water (5.5 mL) were added to DMSO (55 mL) containing intermediate 70 (3.10 g, 10.6 mmol), and the reaction mixture was heated to 130 °C and maintained 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) and 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 / z234.2

[0849] Intermediate 80

[0850]

[0851] (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-5-methyl-3-oxopyrrolidine-1-carboxylic acid benzyl ester

[0852] 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 and held for 1.5 h using a Dean-Stark water separator. The reaction mixture was cooled to room temperature and evaporated to dryness to give crude material. It was dissolved in acetonitrile (18 mL) and treated with acetonitrile (9 mL) containing 1-bromo-3-(bromomethyl)-2-fluorobenzene (2.85 g, 10.6 mmol) 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 crude material. It was dissolved in water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated to dryness to give crude material. The crude substance was purified by silica gel column chromatography (0-85% EtOAc / heptane) to give the title compound (2.8 g) as an orange oil. [M+H] + m / z 420.2 / 422.1

[0853] Intermediate 81

[0854]

[0855] (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxyimino)-5-methylpyrrolidine-1-carboxylic acid benzyl ester

[0856] 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 and maintained 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 under vacuum to give the title compound (1.1 g) as a yellow oil. [M+H] + m / z 435.1 / 437.1

[0857] Intermediate 82

[0858]

[0859] (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-5-methyl-3-nitropyrrolidine-1-carboxylic acid benzyl ester

[0860] At 0 °C, anhydrous acetonitrile (7.2916 mL) containing trifluoroacetic anhydride (1.6 mL, 11.3 mmol) was added to a stirred solution of hydrogen peroxide-urea (1:1) (1.48 g, 15.8 mmol) in anhydrous acetonitrile (7.3 mL). The reaction was stirred at 0 °C for 2 h. At room temperature, 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). The mixture was then heated to 80 °C and stirred for 1 h. The reaction was cooled to room temperature and quenched with a saturated aqueous solution of Na₂SO₃, diluted with water (50 mL), and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO₄, filtered, and concentrated under vacuum to give the crude substance. The crude substance was purified by silica gel column chromatography (0-97% EtOAc / heptane) to give the title compound (0.19 g) as a colorless gel. [M+H] + m / z 451.1 / 453.1

[0861] Intermediate 83

[0862]

[0863] (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-5-methyl-3-nitropyrrolidine-1-carboxylic acid benzyl ester

[0864] Formaldehyde (37% in water, 1.9 mL, 26.1 mmol) was added to THF (1.249 mL) containing intermediate 82 (1.27 g, 2.90 mmol) and triethylamine (0.48 mL, 3.48 mmol). The solution was heated to 70 °C and held for 6 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 under vacuum to give a crude substance. The crude substance was purified by silica gel column chromatography (0–100% EtOAc / heptane) to give the title compound (100 mg) as a colorless oil. [M+H] + m / z 481.9 / 482.9

[0865] Intermediate 84

[0866]

[0867] (5R)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylic acid benzyl ester

[0868] 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 h. Zinc (326 mg, 4.99 mmol) was then added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a diatomaceous earth mat and washed with methanol. The filtrate was neutralized with a saturated aqueous solution of NaHCO3 and extracted with DCM (3 × 20 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum to give the title compound (220 mg) as a colorless oil. [M+H] + m / z 453.1

[0869] Intermediate 85

[0870]

[0871] (3R)-1-[(3-bromo-2-fluorophenyl)methyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid benzyl ester

[0872] Potassium dicarbonate (202 mg, 1.46 mmol) and water (2.2 mL) were added sequentially to a solution of intermediate 84 (220 mg, 0.487 mmol) in THF (2.2 mL) at 0 °C. Chloroacetyl chloride (54 μL, 0.682 mmol) was added dropwise to this mixture at 0 °C and the mixture was stirred for 1 h. 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 an oily residue intermediate. The intermediate was dissolved in DCM (5 mL) and IPA (5 mL) and cooled to 0 °C. Potassium 2-methylprop-2-ol (219 mg, 1.95 mmol) was added, and the reaction was stirred at 0 °C for 1 h. The mixture was quenched with water (10 mL). The mixture was poured onto a saturated aqueous solution of NaHCO3 (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain a crude substance. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (140 mg) as a colorless oil. [M+NH4] + m / z = 510.2

[0873] Intermediate 86

[0874]

[0875] (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-carboxylic acid benzyl ester

[0876] A mixture of intermediate 85 (120 mg, 0.244 mmol), 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (78 mg, 0.488 mmol), 1M tripotassium phosphate aqueous solution (0.73 mL, 0.733 mmol), and THF (2.4 mL) was prepared using N... 2(气体) Degas for 15 minutes. Add XPhos Pd G3 (21 mg, 0.0244 mmol), and stir the reaction mixture at 70 °C for 1 h under a nitrogen atmosphere. Cool the reaction mixture to room temperature, quench with a saturated aqueous solution of NaHCO3 (3 mL), and extract with ethyl acetate (3 × 3 mL). Separate the combined organic layers and concentrate under vacuum using a phase separator to obtain the crude product. Purify the crude product by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (90 mg) as a black oil. [M+H] + m / z 525.2

[0877] Intermediate 87

[0878]

[0879] (3R)-3-methyl-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4,5]dec-7-one

[0880] Intermediate 86 (90 mg, 0.172 mmol) was dissolved in ethanol (8.2 mL), and the mixture was evacuated to atmospheric pressure and backfilled with nitrogen three times. Palladium / carbon (10%) (20 mg, 0.172 mmol) was added, and the mixture was evacuated to atmospheric pressure and backfilled with hydrogen three times. The reaction was stirred for 2 h, filtered through a diatomaceous earth pad, washed with EtOAc, and concentrated under vacuum to give the title compound (65 mg) as a pale yellow oil. [M+H] + m / z 391.2

[0881] (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)

[0882]

[0883] Ethyl isocyanate (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 NaOH aqueous solution and extracted with DCM (3 × 10 mL). The organic layers were combined, washed with brine (25 mL), passed through a phase separator, and concentrated under vacuum to obtain the crude substance. The crude substance was purified by reversed-phase rapid column chromatography (10-60% MeCN / aqueous solution) to give the title compound (12 mg) as a white solid.

[0884] 1H NMR (400MHz, CDCl3) δ7.39-7.30(m,2H),7.25-7.17(m,1H),7.09-7.02(m,2H),6.84(tt,J=8.9,2.3H z,1H),6.35(s,1H),4.24-4.05(m,3H),4.04-3.93(m,1H),3.66(d,J=11.8Hz,1H),3.51(s,1H),3.41( d,J=11.8Hz,1H),3.13(dd,J=13.4,4.8Hz,1H),3.04-2.85(m,2H),2.76(dd,J=13.0,10.1Hz,1H),2.2 8(dd,J=13.4,7.6Hz,1H), 1.75(dd,J=13.4,9.8Hz,1H), 1.40(d,J=6.1Hz,3H), 0.78(t,J=7.2Hz,3H).

[0885] LCMS (Method A) [M+H] + m / z 462.3, RT 3.31 minutes

[0886] Example 54: (1S,3R,5S)-2-(2-hydroxy-2-methylpropionyl)-3-methyl-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4,5]dec-7-one

[0887]

[0888] Intermediate 87 (40 mg, 0.102 mmol) was added to a stirred solution of 2-hydroxy-2-methylpropionic 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), and the mixture was stirred for 24 h. The reaction mixture was filtered and purified directly by preparative HPLC acidic early elution: Waters Sunfire C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature). The injection volume was 1500 μL, and the flow rate was 40 mL / min. 10% B (A = 0.1% formic acid / water; B = 0.1% formic acid / acetonitrile) was applied for 1.90 min, followed by a 10-95% B gradient for 14.1 min and held for 1.9 min. A second gradient of 95-10% B was then applied over 0.3 min and held for another 0.9 min. The ultraviolet spectrum was recorded at 215 nm using a Gilson detector, yielding the title compound (7.8 mg) as a beige solid.

[0889] 1 H NMR (400MHz, CDCl3) δ7.61-7.48(m,1H),7.23-7.07(m,4H),6.82(ddd,J=11.2,5.6,2.3Hz,1H), 6.00(s,1H),5.08(d,J=8.7Hz,1H),4.17(s,1H),3.96(d,J=17.0Hz,1H),3.86(d,J=17.6Hz,1H) ,3.61(d,J=11.7Hz,1H),3.33(d,J=11.8Hz,1H),3.19(dd,J=14.6,10.4Hz,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 = 6.0Hz, 3H).

[0890] LCMS (Method A): [M+H] + m / z 477.3, RT 3.29 minutes.

[0891] 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

[0892]

[0893] Intermediate 88

[0894]

[0895] 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

[0896] Methyl propargyl 2-acetylacetate (77 μL, 0.869 mmol) was added to a 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) and stirred for 3 days at room temperature. The reaction was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (257 mg) as a colorless gel. [M+NH4] + m / z 550.4

[0897] Intermediate 89

[0898]

[0899] tert-butyl-rel-(2R,3S)-3-[(3-methoxy-3-oxopropoxy)methyl]-3-nitro-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0900] 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 h. The reaction mixture was filtered through a diatomaceous earth pad and washed with EtOAc. The filtrate was concentrated under vacuum to give the title compound (206 mg) as a colorless gel. [M+H] + m / z535.5

[0901] Intermediate 90

[0902]

[0903] tert-butyl-rel-(2R,3S)-3-amino-3-[(3-methoxy-3-oxopropoxy)methyl]-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0904] At 0 °C, zinc (462 mg, 7.07 mmol) was added to a stirred intermediate 89 (189 mg, 0.354 mmol) in ethanol (5 mL) and acetic acid (1.5 mL). The reaction was heated to room temperature and stirred for 1 h. The reaction was then heated to reflux and continued for 1 h. The reaction mixture was filtered through a diatomaceous earth mat and washed with methanol. The filtrate was concentrated under vacuum, neutralized with a saturated aqueous solution of NaHCO3 (25 mL), and extracted with DCM (3 × 25 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give the title compound (179 mg) as a colorless gel. [M+H] + m / z 505.7

[0905] Intermediate 91

[0906]

[0907] 3-{[rel-(2R,3S)-3-amino-1-[(tert-butoxy)carbonyl]-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidin-3-yl]methoxy}propionic acid

[0908] 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) and brine (10 mL) and extracted with diethyl ether (2 × 20 mL). The aqueous layer was acidified to pH 1 with 2M aqueous HCl and extracted again with EtOAc (2 × 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (138 mg) as a colorless, glassy substance. [MH] - m / z 489.5.

[0909] Intermediate 92

[0910]

[0911] tert-butyl-rel-(1R,6S)-8-oxo-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5,6]dodecane-2-carboxylate

[0912] A solution of T3P (50% in EtOAc) (0.38 mL, 0.637 mmol) was added to a solution of intermediate 91 (125 mg, 0.255 mmol) and triethylamine (0.12 mL, 0.892 mmol) in 1,4-dioxane (25 mL) under stirring at room temperature, and the mixture was stirred for 1 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (25 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (132 mg) as a colorless gel. [M+Na] + m / z 495.4

[0913] Intermediate 93

[0914]

[0915] rel-(1R,6S)-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5.6]dodecyl-8-one

[0916] Intermediate 92 (132 mg, 0.279 mmol) was stirred in TFA (0.5 mL) and DCM (1 mL) at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 aqueous solution (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give the title compound (65 mg) as a colorless gel. [M+H] + m / z 373.4

[0917] rel-(1R,6S)-N-ethyl-8-oxo-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-11-oxa-2,7-diazaspiro[5,6]dodecane-2-carboxamide (55)

[0918]

[0919] A solution of isocyanate ethane (14 μL, 0.172 mmol) was added to a solution of intermediate 93 (32 mg, 0.086 mmol) and triethylamine (24 μL, 0.172 mmol) in DCM (1 mL) under stirring at room temperature, and the mixture was stirred for 0.5 h. The reaction mixture was quenched with 2 M NaOH aqueous solution (2 mL), and the reaction mixture was passed through a phase separator and washed with DCM (3 × 5 mL). The combined organic layers were subjected to vacuum to give a crude substance. The crude substance was purified by reversed-phase column chromatography (10–100% acetonitrile / water (0.1% NH3)) to give the title compound (20.2 mg) as a white solid.

[0920] 1H NMR (500MHz, CDCl3) δ7.32-7.27(m,2H),7.25-7.22(m,2H),7.20-7.15(m,1H),6.20(s,1H),4.56(t,J=5.2Hz,1H),4.14(d ,J=12.8Hz,1H),4.08-3.97(m,2H),3.83(dd,J=9.7,5.7Hz,1H),3.75(ddd,J=12.2,10.3,1.5Hz,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 shielded.

[0921] LCMS (Method B): [M+H] + m / z 444.4, RT 2.95 minutes.

[0922] 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

[0923]

[0924] Intermediate 94

[0925]

[0926] tert-butyl-rel-(2R,3R)-3-[(2-methylpropane-2-sulfinyl)amino]-3-(nitromethyl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0927] At room temperature, a solution of 1 M N,N,N-tributylbut-1-ammonium 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), and the mixture was stirred for 4 h. The reaction mixture was concentrated under vacuum, diluted with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under vacuum to give the crude substance. The crude substance was purified by silica gel column chromatography (0–100% EtOAc / heptane) to give the title compound (1.25 g) as a white solid. [M+H] + m / z 552.5

[0928] Intermediate 95

[0929]

[0930] tert-butyl-rel-(2R,3R)-3-[(2-methylpropane-2-sulfinyl)amino]-3-(nitromethyl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0931] Zinc (1.48 g, 22.7 mmol) was added to a stirred intermediate 94 (1.25 g, 2.27 mmol) in a solution of acetic acid (7 mL) and ethanol (25 mL) at room temperature, and the mixture was stirred for 16 h. The reaction mixture was quenched and neutralized with a saturated aqueous solution of NaHCO3 (30 mL), filtered through diatomaceous earth (washed with EtOAc), and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (1.03 g). [M+H] + m / z 522.4

[0932] Intermediate 96

[0933]

[0934] tert-butyl-rel-(2R,3R)-3-(aminomethyl)-3-[(2-methylpropane-2-sulfinyl)amino]-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0935] 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), and the mixture was stirred for 16 h. 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 MgSO4, filtered, and concentrated under vacuum to give a crude product. The crude product was purified by silica gel column chromatography (0–100% EtOAc / heptane, then 0–20% methanol / DCM) to give the title compound (1 g) as a colorless oil. [M+H] + m / z 608.4

[0936] Intermediate 97

[0937]

[0938] 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

[0939] At 0 °C, a solution of 4 M hydrogen chloride (4 M 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), and the mixture was stirred for 16 h. The reaction mixture was heated to room temperature, quenched with a saturated aqueous solution of NaHCO3 (25 mL), and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under vacuum to give a crude substance (600 mg) as a yellow oil, which was used without further purification. [M+H] + m / z 504.5

[0940] Intermediate 98

[0941]

[0942] tert-butyl-rel-(6R,7R)-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-1,4,8-triazaspiro[5.5]undecane-8-carboxylate

[0943] A solution of lithium hydroxide (2M in water) (1.5 mL, 3.0 mmol) was added to a solution of intermediate 97 (600 mg, 1.49 mmol) in THF (10 mL) under stirring 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 × 25 mL). The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give the title compound (48 mg) as a white solid. [M+H] + m / z458.4

[0944] Intermediate 99

[0945]

[0946] tert-butyl-rel-(6R,7R)-4-methyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-1,4,8-triazaspiro[5.5]undecane-8-carboxylate

[0947] A solution of formaldehyde (37% in water) (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), and the mixture was stirred for 1 h. Sodium triacetoxyborohydride (28 mg, 0.131 mmol) was added, and the reaction was stirred for another hour. 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 under vacuum to give the title compound (15 mg) as a colorless oil. [M+H] + m / z 472.5

[0948] 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)

[0949]

[0950] Intermediate 99 (20 mg, 0.0424 mmol) was stirred for 30 minutes at room temperature in a mixture of anhydrous DCM (0.25 mL) and TFA (0.25 mL). The reaction mixture was quenched with NaHCO3 solution (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give crude material. A solution of 2,2-difluoroethyl chloroformate (5.3 μL, 0.0509 mmol) was added dropwise to the stirred crude material and a solution of triethylamine (14 μL, 0.102 mmol) in anhydrous DCM (0.5 mL) at 0 °C, and the mixture was stirred for 30 minutes. Then, 2,2-difluoroethyl chloroformate (5.3 μL, 0.0509 mmol) was added, and the reaction was stirred for another 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 under vacuum to obtain the crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% ammonia)) to give the title compound (8.6 mg) as a white solid.

[0951] 1 H NMR (400MHz, DMSO) δ7.75(s,1H),7.27(dd,J=8.0,7.0Hz,2H),7.22-7.12(m,3H),6.17(tdd,J=54.8,7. 4,3.8Hz,1H),4.81-4.73(m,1H),4.48-4.05(m,3H),3.95-3.84(m,1H),3.72(t,J=10.3Hz,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). Two rotational isomers, and the peak at 2.44–2.50 is obscured by the DMSO peak.

[0952] LCMS (Method B): [M+H] + m / z 480.1, RT 3.11 minutes.

[0953] 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

[0954]

[0955] Intermediate 100

[0956]

[0957] tert-butyl-rel-(2R,3R)-3-nitro-3-(2-oxoethyl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0958] Potassium dioxane hydrate (2:1:2) (40 mg, 0.109 mmol) was added to THF (25 mL) and water (6.25 mL) containing intermediate 50 (1.00 g, 2.18 mmol) in a mixture of dioxane-bridged (dioxo)osmium (2:1:2) and stirred for 10 min at room temperature. Sodium periodate (1.40 g, 6.54 mmol) was added, and the reaction was stirred for 20 h. Sodium periodate (1.40 g, 6.54 mmol) was added again, and the reaction was stirred for 4 h. The reaction was quenched by adding sodium sulfite solution (20 mL) and water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried (MgSO4), filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (0–60% EtOAc / heptane) to give the title compound (660 mg) as a colorless oil. [M+H-Boc] + m / z 361.3

[0959] Intermediate 101

[0960]

[0961] tert-butyl-rel-(2R,3R)-3-(2-hydroxyethyl)-3-nitro-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0962] Sodium tetrahydroborate (80 mg, 2.12 mmol) was added to a stirred intermediate 100 (650 mg, 1.41 mmol) in anhydrous methanol (15 mL) at 0 °C, and the mixture was stirred for 1 h. The reaction mixture was concentrated under vacuum, 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 under vacuum to give the crude substance. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (615 mg) as a white solid. [M+H-Boc] + m / z 363.3

[0963] Intermediate 102

[0964]

[0965] tert-butyl-rel-(2R,3R)-3-[2-(methanesulfonyloxy)ethyl]-3-nitro-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0966] At 0 °C, a solution of methanesulfonyl chloride (125 μL, 1.62 mmol) was added dropwise to a solution of intermediate 101 (600 mg, 1.30 mmol) and triethylamine (226 μL, 1.62 mmol) in anhydrous DCM (10 mL), and the mixture was stirred for 3 h. The reaction mixture was heated to room temperature, quenched with water (25 mL), and extracted with DCM (3 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give the crude compound. The crude compound was purified by silica gel column chromatography (0–50% EtOAc / heptane) to give the title compound (560 mg) as a colorless gel. [M+Na] + m / z 563.3

[0967] Intermediate 103

[0968]

[0969] tert-butyl-rel-(2R,3R)-3-[2-(methylamino)ethyl]-3-nitro-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0970] A solution of methylamine (33% in EtOH) (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), and the mixture was heated at 65 °C for 16 h. The reaction mixture was cooled to room temperature, concentrated under vacuum, diluted with saturated aqueous NaHCO3 solution (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give a crude product. The crude product was used without further purification to give the title compound (430 mg) as a yellow oil. [M+H] + m / z 476.8

[0971] Intermediate 104

[0972]

[0973] tert-butyl-rel-(2R,3R)-3-amino-3-[2-(methylamino)ethyl]-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[0974] Zinc (591 mg, 9.04 mmol) was added to a solution of intermediate 103 (430 mg, 0.904 mmol) in acetic acid (3 mL) and ethanol (11 mL) under stirring at room temperature, and the mixture was stirred for 16 h. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (10 mL), filtered through diatomaceous earth (washed with EtOAc), and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give crude material. The crude material (135 mg) was used without further purification. [M+H] + m / z 446.3

[0975] Intermediate 105

[0976]

[0977] tert-butyl-rel-(6R,7R)-3-methyl-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-1,3,8-triazaspiro[5.5]undecane-8-carboxylate

[0978] At room temperature, CDI (18 mg, 0.112 mmol) was added to a solution of intermediate 104 (100 mg, 0.224 mmol) in anhydrous DMF (2.5 mL) and the mixture was stirred for 30 min. Then, di-1H-imidazol-1-yl ketone (18 mg, 0.112 mmol) was added and the reaction was stirred for 30 min. 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 under vacuum to give the crude compound. The crude compound was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% formic acid)) to give the title compound (41 mg) as a white solid. [M+H] + m / z 472.4

[0979] 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)

[0980]

[0981] Intermediate 105 (40 mg, 0.0848 mmol) was stirred for 30 minutes in a mixture of anhydrous DCM (0.5 mL) and TFA (0.5 mL) at room temperature. The reaction mixture was quenched with NaHCO3 solution (1 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain crude material. A solution of 2,2-difluoroethyl chloroformate (8.8 μL, 0.0848 mmol) was added dropwise to the stirred crude material and a solution of 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 sequentially with methanol (0.5 mL) and 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 under vacuum to obtain crude material. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% formic acid)) to give the title compound (23 mg) as a white solid.

[0982] 1H NMR (400MHz, DMSO) δ7.29-7.23(m,2H),7.22-7.18(m,2H),7.18-7.12(m,1H),6.17(tt,J=54.7,3.4Hz,1 H),5.88(s,1H),4.32(s,3H),3.90(d,J=12.9Hz,1H),3.76(dd,J=10.5,8.8Hz,1H),3.66(dd,J=10.6,4. 7Hz,1H),3.60(s,1H),3.33(td,J=11.9,4.4Hz,1H),3.14(ddd,J=12.5,5.7,3.3Hz,1H),2.95(d,J=15.1 Hz, 1H), 2.80 (s, 3H), 2.59-2.52 (m, 1H), 2.05 (d, J = 14.4Hz, 1H), 2.01-1.83 (m, 3H), 1.81-1.40 (m, 10H).

[0983] LCMS (Method B): [M+H] + m / z 480.4, RT 3.64 minutes.

[0984] Example 58: (1R,3R,5S)-2-cyclobutanecarbonyl-3-methyl-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]dec-7-one

[0985]

[0986] At room temperature, 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), 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 under vacuum to give a crude substance. The crude substance was purified by reversed-phase column chromatography (10–100% acetonitrile / water (0.1% formic acid)) to give the title compound (1.8 mg) as a colorless gel.

[0987] 1H NMR(400MHz, CDCl3)δ7.30(t,J=7.6Hz,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=6.1Hz,3H).

[0988] LCMS (Method B): [M+H] + m / z 441.4, RT 3.58 minutes.

[0989] 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]dec-7-one

[0990]

[0991] At room temperature, 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), 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 under vacuum to give a crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give the title compound (5.1 mg) as a beige solid.

[0992] 1H NMR(400MHz, CDCl3)δ7.30(t,J=7.6Hz,2H),7.25-7.16(m,3H),6.40(s,0.5H),6.12(s,0.5H),4.93(ddd,J=55 .5,15.3,8.3Hz,1H),4.36(s,0.5H),4.28-4.08(m,2H),4.02(d,J=3.1Hz,1H),3.92-3.79(m,1H),3.67(dd,J= 8.4,4.1Hz,2.5H),3.59(d,J=11.7Hz,1H),3.43(dd,J=22.9,11.8Hz,1H),2.80-2.34(m,6H),2.19(dd,J=12.9 ,8.1Hz,1H),2.10-2.01(m,2H),1.94(dd,J=13.0,9.5Hz,1H),1.83-1.60(m,6H),1.43(dd,J=6.1,1.8Hz,3H).

[0993] LCMS (Method A): [M+H] + m / z 459.5, RT 3.65 minutes.

[0994] 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]dec-7-one

[0995] Example 60

[0996]

[0997] At room temperature, 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), 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 under vacuum to give a crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give the title compound (10 mg) as a white powder.

[0998] 1H NMR (400MHz, CDCl3) δ7.35-7.28(m,2H),7.24-7.16(m,3H),6.25(s,1H),4.37(s,1H),4.26(d, J=16.7Hz,1H),4.21-4.10(m,1H),4.05-3.87(m,1H),3.75(dd,J=10.1,2.6Hz,1H),3.72-3.64 (m,2H),3.60(d,J=11.6Hz,1H),3.43(d,J=11.6Hz,1H),2.63-2.52(m,1H),2.50(s,1H),2.26- 2.03(m,9H),1.92(dd,J=12.9,9.3Hz,1H),1.84-1.69(m,4H),1.61(s,2H),1.52-1.36(m,3H).

[0999] LCMS (Method A): [M+H] + m / z 453.4, RT 3.62 minutes.

[1000] Example 61: (1R,3R,5S)-3-methyl-7-oxo-1-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid 2,2-difluoroethyl ester

[1001]

[1002] At 0 °C, a solution of 2,2-difluoroethyl chloroformate (8.6 μL, 0.0837 mmol) was added dropwise to a solution of intermediate 78 (20 mg, 0.0558 mmol) and triethylamine (19 μL, 0.134 mmol) in anhydrous DCM (0.5 mL), and the mixture was stirred for 1 h. The reaction mixture was quenched with methanol (1 mL) and concentrated under vacuum to give a crude substance. The crude substance was purified by reversed-phase column chromatography (10–100% acetonitrile / water (0.1% NH3)) to give the title compound (11 mg) as a white solid.

[1003] 1H NMR (400MHz, CDCl3) δ7.30 (t, J = 7.4Hz, 2H), 7.25-7.16 (m, 3H), 6.29 (d, J = 26.4Hz, 1H), 5.9 6(t,J=54.7Hz,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=10.4Hz,1H),3.49(dd,J=11.6,4.0Hz,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, 5.9Hz, 3H).

[1004] LCMS (Method B): [M+H] + m / z 467.3, RT 3.69 minutes.

[1005] 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

[1006]

[1007] At room temperature, 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-prop-2-amine (62 μL, 0.357 mmol) in N-ethyl-N-isopropyl-prop-2-amine (62 μL, 0.357 mmol), and the mixture was stirred for 3 h. At room temperature, a solution of 2,2,2-trifluoroethylamine (24 mg, 0.245 mmol) was added dropwise to the reaction mixture, and the reaction was stirred for 18 h. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (5 mL) and N... 2(气体) The mixture was purged for 30 minutes (using 20% ​​NaOH aqueous solution as a washer). The reaction mixture was extracted with DCM (3 × 3 mL), and the combined organic layers were passed through a phase separator and concentrated under vacuum to obtain the crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give the title compound (10 mg) as a white powder.

[1008] 1H NMR(400MHz, CDCl3) δ7.34-7.26(m,2H),7.19(dd,J=7.3,4.2Hz,3H),6.23(s,1H),5.91(s,1 H),4.27(d,J=16.9Hz,1H),4.19-4.10(m,2H),4.10-4.02(m,1H),3.96(dt,J=9.8,7.0Hz,1H) ,3.79-3.69(m,3H),3.63(ddd,J=14.9,9.0,5.8Hz,1H),3.49-3.41(m,2H),2.61-2.51(m,1H ), 2.28 (dd, J = 13.1, 7.4Hz, 1H), 2.09-2.00 (m, 2H), 1.82-1.58 (m, 7H), 1.37 (d, J = 6.0Hz, 3H).

[1009] LCMS (Method B): [M+H] + m / z 484.4, RT 3.36 minutes.

[1010] 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]dec-7-one

[1011]

[1012] 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 under vacuum to give a crude product. The crude product was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) followed by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% formic acid)) to give the impure title product (5 mg, 50%). This substance was purified by a preparative HPLC standard column: XBridge™ Prep.C18 10um OBD™, 30×100mm, mobile phase: 5-95% acetonitrile (0.2% ammonium hydroxide) / water (0.2% ammonium hydroxide) for 10 min, flow rate: 40 mL / min, UV: 215 and 254 nm, to give the title compound (0.5 mg) as a colorless oil.

[1013] 1H NMR (500MHz, CDCl3) δ8.04-7.88(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=16.7,4.6Hz,1H),3.98-3.90(m,1H),3.87-3.81(m, 4H),3.65(d,J=2.7Hz,1H),3.59-3.49(m,1H),3.42-3.34(m,1H),2.52(dt,J=15.4,8.7Hz,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=3.6Hz,3H).

[1014] LCMS (Method A): [M+H] + m / z 466.4, RT 4.30 minutes.

[1015] 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]dec-7-one

[1016]

[1017] At room temperature, 5-chloro-1-methyltetrazolium (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), and the stirred mixture was heated at 140 °C for 48 hours. 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 under vacuum to give the crude product. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to obtain a mixture of compounds, which was then purified by acidic preparative HPLC (Waters CSHC18 column (19 mm × 100 mm, 5 μm; temperature: room temperature). The injection volume was 1500 μL, and the flow rate was 20 mL / min. 5% B (A = 0.2% formic acid / water; B = acetonitrile) was applied for 2.0 min, followed by a gradient of 5-95% B for 18.0 min and held for 2.0 min. A second gradient of 95-10% B was then applied for 0.2 min and held for 0.9 min. The UV spectrum was recorded at 215 nm using a Gilson detector, yielding the title compound (4 mg) as a white powder.

[1018] 1 H NMR (400MHz, CDCl3) δ7.36-7.27(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=10.4,2.8Hz,1H ),3.80-3.67(m,3H),3.56(d,J=11.9Hz,1H),2.57(p,J=7.7Hz,1H),2.37(dd,J =12.9,7.4Hz,1H),2.13-1.98(m,3H),1.78-1.55(m,6H),1.37(d,J=6.0Hz,3H).

[1019] LCMS (Method B): [M+H] + m / z 441.3, RT 3.05 minutes.

[1020] 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

[1021]

[1022] Intermediate 106

[1023]

[1024] tert-butyl-rel-(2R,3R)-3-amino-3-(2-hydroxyethyl)-2-({[(cis)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

[1025] Zinc (1.84 g, 28.1 mmol) was added to a stirred 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 h while being heated to room temperature. The reaction mixture was filtered through a diatomaceous earth mat, washed with methanol (2 × 10 mL), and concentrated under vacuum. The reaction mixture 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 under vacuum to give the title compound (605 mg) as a colorless gel. [M+H] + m / z 433.5

[1026] Intermediate 107

[1027]

[1028] tert-butyl-rel-(6R,7R)-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1029] At 0 °C, a solution of N-ethyl-N-(prop-2-yl)prop-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), and the mixture was stirred for 30 min. The reaction mixture was heated to room temperature and purged with N2 through a 5N NaOH solution for 30 min (to quench any excess phosgene). The reaction was then quenched with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under vacuum to give the crude substance. The crude substance was purified by reversed-phase column chromatography (10–100% acetonitrile / water (0.1% NH3)) to give the title compound (524 mg) as a white solid. [M+H] + m / z 459.5

[1030] Intermediate 108

[1031]

[1032] rel-(6R,7R)-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-2-one

[1033] Intermediate 107 (100 mg, 0.218 mmol) was dissolved in DCM (0.5 mL), followed by dropwise addition of TFA (0.5 mL) solution, and the mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness to give the title compound (80 mg) as a colorless, viscous solid. [M+H] + m / z359.3

[1034] Example 65

[1035]

[1036] 2,2-Difluoroethyl-rel-(6R,7R)-2-oxo-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1037] A solution of 2,2-difluoroethyl chloroformate (8.6 μL, 0.0837 mmol) was added dropwise to a solution of intermediate 108 (20 mg, 0.0558 mmol) and triethylamine (19 μL, 0.134 mmol) in anhydrous DCM (0.5 mL) under stirring 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 under vacuum to give a crude substance. The crude substance was purified by reversed-phase column chromatography (10–100% acetonitrile / water (0.1% NH3)) to give the title compound (10 mg) as a white solid.

[1038] 1 H NMR (400MHz, CDCl3) δ7.34-7.27(m,2H),7.23-7.15(m,3H),5.93(tt,J=55.1,3.8Hz,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).

[1039] LCMS (Method A): [M+H] + m / z 467.4, RT 3.60 minutes.

[1040] Example 66: (6R,7R)-8-[(cis)-3-fluorocyclobutanecarbonyl]-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-2-one and

[1041] Example 67: (6S,7S)-8-[(cis)-3-fluorocyclobutanecarbonyl]-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-2-one

[1042]

[1043] At room temperature, 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), 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 under vacuum to give a crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give a compound (47 mg) as a grayish-white solid. Purification was performed by basic preparative HPLC (Waters XSelect CSH column (30 mm × 100 mm, 3 μm; temperature: room temperature). The injection volume was 1000 μL, and the flow rate was 40 mL / min. [A1: water + 0.1% NH3OH]; [B1: MeCN + 0.1% NH3OH]. Gradient: from 3% B1 to 99.9% B1 over 1.5 min (flow rate: 1.00 mL / min). Chiral preparative purification was then performed using a Waters 600, eluted with 65 / 35% v / v n-hexane / ethanol, Chiralpak AS-H (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (peak 1, 14.1 mg, 100% ee; peak 2, 14.3 mg, 100% ee). The absolute stereochemistry of the isolated compounds 66 and 67 was not definitively determined, but is assigned as follows.

[1044] Example 66: Peak 1 (assigned as 6R, 7R at piperidine); 1H NMR (400MHz, CDCl3) δ7.34-7.28(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).

[1045] LCMS (Method C): [M+H] + m / z 459.4, RT 1.07 minutes.

[1046] Chiral analysis (Chiralcelpak AS-H, 25 × 0.46 cm, 5 μm, 40:60 n-hexane:ethanol): RT 8.5 min.

[1047] Example 67: Peak 2 (assigned as 6S, 7S at piperidine): 1 H NMR (400MHz, CDCl3) δ7.34-7.28(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).

[1048] LCMS (Method C): [M+H] + m / z 459.4, RT 1.07 minutes.

[1049] Chiral analysis (Chiralcelpak AS-H, 25 × 0.46 cm, 5 μm, 40:60 n-hexane:ethanol): RT 13.9 min.

[1050] Example 68: rel-(6R,7R)-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-8-(2,2,2-trifluoroethyl)-3-oxa-1,8-diazaspiro[5.5]undecane-2-one

[1051]

[1052] rel-(6R,7R)-7-({[(cis)-4-phenylcyclohexyl]oxy}methyl)-8-(2,2,2-trifluoroethyl)-3-oxa-1,8-diazaspiro[5.5]undecane-2-one.

[1053] A solution of 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (24 μL, 0.167 mmol) was added to a solution of intermediate 108 (41 mg, 0.110 mmol) and DIPEA (45 μL, 0.258 mmol) in anhydrous THF (1 mL) while stirring 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 under vacuum to give a crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give the title compound (13 mg) as a white powder.

[1054] LCMS (Method A): [M+H] + m / z 441.5, RT 4.30 minutes.

[1055] 1H NMR (400MHz, CDCl3) δ7.35-7.27(m,2H),7.23-7.16(m,3H),5.61(s,1H),4.38-4.27(m ,2H),3.82(dd,J=10.3,6.9Hz,1H),3.72(dd,J=10.3,3.4Hz,1H),3.62(s,1H),3.43(d q,J=19.2,9.4Hz,1H),3.30(dq,J=18.1,9.1Hz,1H),3.05-2.92(m,2H),2.76-2.66(m, 1H),2.60-2.47(m,2H),2.03(d,J=14.3Hz,2H),1.87-1.64(m,8H),1.62-1.52(m,3H).

[1056] 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

[1057] 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

[1058]

[1059] Intermediate 109

[1060]

[1061] 5-[(3-bromo-2-fluorophenyl)methyl]-3-methyl-4-oxopyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

[1062] At -78 °C, a solution of 0.6 M sodium 1,1,1,3,3,3-hexamethyldisilazane-2-oxide (14 mL, 8.11 mmol) was added to a stirred solution of 1-tert-butyl 3-ethyl 3-methyl-4-oxopyrrolidine-1,3-dicarboxylic acid (2.00 g, 7.37 mmol) in anhydrous THF (28 mL), and the mixture was stirred for 15 min. Anhydrous THF (9 mL) containing 1-bromo-3-(bromomethyl)-2-fluorobenzene (2.17 g, 8.11 mmol) was added, and the reaction mixture was heated to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to obtain the crude product. The crude substance was purified by silica gel column chromatography (0-10% EtOAc / heptane) to give the title compound (diastereomer ratio 2:1) (1.8 g) as a pale yellow oil. [M-Boc+H] + m / z 358.0 and 360.0

[1063] Intermediate 110

[1064]

[1065] 2-[(3-bromo-2-fluorophenyl)methyl]-4-methyl-3-oxopyrrolidine-1-carboxylic acid tert-butyl ester

[1066] A suspension of intermediate 109 (99%, 2.89 g, 6.24 mmol) in 3M hydrogen chloride (42 mL, 0.125 mol) was heated to 105 °C and maintained for 6 h. The reaction was quenched with saturated Na₂CO₃ aqueous solution (20 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under vacuum to give a crude substance as a brown liquid. The crude substance 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 × 50 mL). The combined organic extracts were dried over MgSO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-40% EtOAc / heptane) to give the title compound (1.13 g) as a yellow oil. (M-tBu+H) + m / z 330.3 and 332.3

[1067] Intermediate 111

[1068]

[1069] tert-butyl-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxyimino)-4-methylpyrrolidine-1-carboxylate

[1070] 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 and maintained for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 75 mL). The organic extract was dried over magnesium sulfate and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (0–100% EtOAc / heptane) to give the title compound (2 g) as a colorless gel. [M-tert-butyl + H] + m / z 345.0 and 347.0

[1071] Intermediate 112

[1072]

[1073] 2-[(3-bromo-2-fluorophenyl)methyl]-4-methyl-3-nitropyrrolidine-1-carboxylic acid tert-butyl ester

[1074] 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), and the mixture was stirred at 0 °C for 2 h. The resulting solution was added dropwise at 80 °C 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) for 1 h. The reaction mixture was cooled to room temperature, quenched with saturated Na₂SO₃ aqueous solution (10 mL), and stirred for 10 min, followed by extraction with EtOAc (2 × 25 mL). The combined organic extracts were dried over MgSO₄, filtered, and concentrated under vacuum to obtain the crude product. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (1.24 g) as a pale yellow oil. [M-tert-butyl + H] + m / z 361.2 and 363.1

[1075] Intermediate 113

[1076]

[1077] tert-butyl-rel-(2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-4-methyl-3-nitropyrrolidine-1-carboxylate

[1078] Formaldehyde (in water) (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 and held for 18 h. After cooling, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 25 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered, concentrated under vacuum, and subjected to silica gel column chromatography (0–90% EtOAc / heptane) to give the title compound (1.03 g) as a yellow oil. [M-tBu+H] + m / z 393.1 and 391.1

[1079] Intermediate 114

[1080]

[1081] tert-butyl-rel-(2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate

[1082] 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 h. The reaction mixture was filtered through a diatomaceous earth mat and washed with methanol. The filtrate was neutralized with NaHCO3, extracted with DCM (3 × 25 mL), and the organic layer was dried over MgSO4 and concentrated under vacuum to give the title compound (850 mg) as a colorless oil. [M+H] + m / z = 417.2 and 419.2

[1083] Intermediate 115

[1084]

[1085] 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

[1086] At 0 °C, potassium dicarbonate (325 mg, 2.35 mmol) and water (3.3 mL) were added sequentially to a solution of intermediate 114 (77%, 425 mg, 0.784 mmol) in THF (3.3 mL). Chloroacetyl chloride (0.087 mL, 1.10 mmol) was added dropwise to this mixture 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 substance was dissolved in DCM (7 mL) and IPA (11 mL) and cooled to 0 °C. Potassium 2-methylprop-2-ol (351 mg, 3.13 mmol) was added, and the reaction was stirred at 0 °C for 1 h. The reaction was quenched by adding water (2 mL). The mixture was poured onto a saturated aqueous solution of NaHCO3 (10 mL). After extraction with DCM (3 × 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 substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (274 mg) as a white solid. [MH] - m / z 455.3 and 457.3

[1087] Intermediate 116

[1088]

[1089] 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

[1090] A mixture of intermediate 115 (95%, 260 mg, 0.541 mmol), 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (259 mg, 1.08 mmol), 1M tripotassium phosphate (1 M in H₂O) (1.6 mL, 1.62 mmol), and THF (5.3 mL) was degassed for 15 min (N₂ purging). XPhos Pd G₃ (46 mg, 0.0548 mmol) was added, and the reaction mixture was stirred at 70 °C for 1 h under a nitrogen atmosphere. The reaction mixture was poured into a saturated aqueous solution of 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 substance was purified by silica gel column chromatography (0–100% EtOAc / heptane) to give the title compound (172 mg) as a yellow oil. [MH] - m / z 489.4

[1091] Intermediate 117

[1092]

[1093] rel-(1S,5S)-4-methyl-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4,5]dec-7-one

[1094] At room temperature, tert-butyl intermediate 116 (97%, 177 mg, 0.350 mmol) was stirred for 30 minutes in a mixture of TFA (0.4 mL) and anhydrous DCM (0.4 mL). The reaction mixture was quenched with NaHCO3 solution (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (129 mg) as a white solid. [M+H] + m / z 391.3

[1095] 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

[1096] 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)

[1097]

[1098] At room temperature, isocyanate ethane (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). 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 under vacuum. The crude material was purified by alkaline 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).

[1099] Example 69: 1 H NMR (400MHz, CDCl3) δ7.41(t,J=6.3Hz,1H),7.35-7.30(m,1H),7.20(t,J=7.6Hz,1H),7.11(d,J=7.5Hz,2H),6.8 4(tt,J=8.9,2.3Hz,1H),6.63(s,1H),4.27(dd,J=8.7,5.3Hz,1H),4.14(t,J=5.3Hz,1H),4.07(d,J=16.7Hz,1H), 3.86-3.71(m,2H),3.52(d,J=11.9Hz,1H),3.41-3.32(m,2H),3.23(ddd,J=12.9,7.3,5.7Hz,2H),3.08(dd,J=10 .4, 8.7Hz, 1H), 3.00 (dd, J=14.0, 8.8Hz, 1H), 2.23 (q, J=7.9Hz, 1H), 1.19 (d, J=7.0Hz, 3H), 1.09 (t, J=7.2Hz, 3H). LCMS(Method A)(ESI+)(M+H) +:462.3,rt=3.09.

[1100] LCMS (Method A): [MH] - m / z 462.3, RT 3.09 minutes.

[1101] Example 70: 1 H NMR(400MHz, CDCl3)δ7.43(t,J=6.3Hz,1H),7.28-7.25(m,1H),7.24-7.19(m,1H),7 .12(d,J=7.5Hz,2H),6.84(tt,J=8.9,2.3Hz,1H),6.30(s,1H),4.45(t,J=6.9Hz,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.

[1102] LCMS (Method A): [MH] - m / z 462.3, RT 3.0 minutes.

[1103] 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]dec-7-one

[1104]

[1105] Intermediate 118

[1106]

[1107] 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylic acid benzyl ester

[1108] At room temperature, 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), and the mixture was heated at 140 °C (external temperature) using a Dean-Stark water separator for 1.5 h. The reaction mixture was cooled to room temperature and evaporated to dryness to give a crude substance. This crude substance was dissolved in anhydrous acetonitrile (67 mL) and treated at room temperature with acetonitrile (34 mL) containing 1-bromo-3-(bromomethyl)-2-fluorobenzene (12.34 g, 46.1 mmol), and the mixture was heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under vacuum to give a crude substance. This crude substance was dissolved in water (50 mL) and acidified to pH 1 with 1 M HCl, and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude substance. The crude substance was purified by silica gel column chromatography (0-40% EtOAc / heptane) to give the title compound (6.74 g) as a pale yellow, viscous oil. [M+H] + m / z 406.1 and 408.1

[1109] Intermediate 119

[1110]

[1111] Benzyl-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxyimino)pyrrolidine-1-carboxylate

[1112] 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 and maintained for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 75 mL). The organic extract was dried over magnesium sulfate and concentrated under vacuum. The crude substance was purified by column chromatography (0–100% EtOAc / heptane) to give the title compound (6.60 g) as a colorless gel. [M+H] + m / z = 421.1 / 423.1

[1113] Intermediate 120

[1114]

[1115] 2-[(3-bromo-2-fluorophenyl)methyl]-3-nitropyrrolidine-1-carboxylic acid benzyl ester

[1116] At 0 °C, 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), and the mixture was stirred at 0 °C for 2 h. The resulting solution was added dropwise at 80 °C 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) for 1 h. The reaction mixture was cooled to room temperature, quenched with saturated Na₂SO₃ aqueous solution (10 mL), and stirred for 10 min, followed by extraction with EtOAc (2 × 25 mL). The combined organic extracts were dried over MgSO₄, filtered, and concentrated under vacuum to give the crude product. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (5.20 g) as a pale yellow oil. [M+H] + m / z 437.2 / 440.2

[1117] Intermediate 121

[1118]

[1119] Benzyl-rel-(2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-3-nitropyrrolidine-1-carboxylate

[1120] Formaldehyde (in water) (37%, 6.2 mL, 83.8 mmol) was added to 47 mL of THF containing intermediate 120 (78%, 5.20 g, 9.28 mmol) and triethylamine (1.6 mL, 11.2 mmol). The solution was heated to 70 °C and held for 18 h. 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 under vacuum to give a crude substance. The crude substance was purified by silica gel column chromatography (EtOAc / heptane) to give the title compound (4.67 g) as a yellow oil. [M+H] + m / z 467.1 and 469.1

[1121] Intermediate 122

[1122]

[1123] rel-(2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)pyrrolidine-1-carboxylic acid benzyl ester

[1124] 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 diatomaceous earth mat and washed with methanol. The filtrate was neutralized with NaHCO3, extracted with DCM (3 × 75 mL), the organic layer was dried (MgSO4) and concentrated under vacuum to give the title compound (4.30 g) as a colorless oil. [M+H] + m / z 437.2 and 439.2 Intermediate 123

[1125]

[1126] rel-(1S,5S)-1-[(3-bromo-2-fluorophenyl)methyl]-7-oxo-9-oxa-2,6-diazaspiro[4,5]decane-2-carboxylic acid benzyl ester

[1127] At 0 °C, potassium dicarbonate (825 mg, 5.97 mmol) and water (8.5 mL) were added sequentially to a solution of intermediate 122 (0.87 g, 1.99 mmol) in THF (8.5 mL). Chloroacetyl chloride (0.22 mL, 2.78 mmol) was added dropwise to this mixture at 0 °C. The reaction was stirred at 0 °C for 1 h. 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. The intermediate was dissolved in DCM (18 mL) and IPA (28 mL) and cooled to 0 °C. Potassium 2-methylprop-2-ol (893 mg, 7.96 mmol) was added, and the reaction was stirred at 0 °C for 1 h. The reaction was quenched by adding water (20 mL). The mixture was poured onto a saturated aqueous solution of NaHCO3 (30 mL). After extraction with DCM (3 × 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 substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (430 mg) as a white solid. [M+H] + m / z 475.2 and 477.2

[1128] Intermediate 124

[1129]

[1130] 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

[1131] A mixture of intermediate 123 (250 mg, 0.524 mmol), 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (251 mg, 1.05 mmol), 1 M tripotassium phosphate aqueous solution (1.6 mL, 1.57 mmol), and THF (5.1 mL) was degassed for 15 min (N2 purging). XPhos Pd G3 (45 mg, 0.0531 mmol) was added, and the reaction mixture was stirred at 70 °C for 1 h under a nitrogen atmosphere. The reaction mixture was poured into a saturated NaHCO3 aqueous solution (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 substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (180 mg) as a yellow oil. [M+H] + m / z 511.3

[1132] Intermediate 125

[1133]

[1134] rel-(1S,5S)-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4,5]dec-7-one

[1135] Intermediate 124 (240 mg, 0.465 mmol) was dissolved in ethanol (22 mL), and the mixture was evacuated to atmospheric pressure and backfilled with nitrogen three times. Palladium / carbon (10%) (5.0%, 99 mg, 0.0465 mmol) was added, and the mixture was evacuated to atmospheric pressure and backfilled with hydrogen three times. The reaction was stirred for 2 hours, then filtered through diatomaceous earth, washed with EtOAc, and concentrated under vacuum to give the title compound (163 mg) as an orange solid. [M+H] + m / z 377.2

[1136] 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]dec-7-one (71):

[1137]

[1138] At room temperature, 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), and the mixture was stirred for 2 h. The reaction mixture was filtered. The crude material was purified by a preparative HPLC standard column: XBridge™ Prep.C18 10 μm OBD™, 30 × 100 mm, mobile phase: 30-95% acetonitrile (0.2% ammonium hydroxide) / 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.

[1139] 1 H NMR (400MHz, CDCl3) δ7.49-7.29(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).

[1140] LCMS (Method B): [M+H] + m / z 477.2, RT 3.07 minutes.

[1141] 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]dec-7-one (Example 72) and

[1142] 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]dec-7-one (Example 73)

[1143] Examples 72 and 73

[1144]

[1145] Example 71 (6 mg) was purified by chiral preparation using a Waters 600, eluted with 75 / 25% v / v n-hexane / (ethanol + 0.1% isopropylamine), Chiralpak IC (25 × 2.0 cm), 5 μm, at a flow rate of 17 mL / min, to give the title compound (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 definitively determined, but is assigned as follows.

[1146] Example 72: Peak 1 (assigned as 1S, 5S at pyrrolidine); 1 H NMR (500MHz, CDCl3) δ7.45-7.16(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).

[1147] LCMS (Method C): [M+H] + m / z 477.3, RT 0.98 minutes.

[1148] Chiral analysis (Chiralpak IC, 25 × 0.46 cm, 5 μm, 75:25 n-hexane / (ethanol + 0.1% isopropylamine)): RT 10.0 min.

[1149] Example 73: Peak 2 (assigned as 1R, 5R at pyrrolidine): 1 H NMR (500MHz, CDCl3) δ7.45-7.16(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).

[1150] LCMS (Method C): [M+H] + m / z 477.3, RT 0.98 minutes.

[1151] Chiral analysis (Chiralpak IC, 25 × 0.46 cm, 5 μm, 75:25 n-hexane / (ethanol + 0.1% isopropylamine)): RT 12.1 min.

[1152] Example 74: (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-carboxylic acid 2,2-difluoroethyl ester and

[1153] Example 75: (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-carboxylic acid 2,2-difluoroethyl ester

[1154]

[1155] Intermediate 126

[1156]

[1157] Benzyl-rel-(1S,5S)-1-[(3-bromo-2-fluorophenyl)methyl]-8-fluoro-7-oxo-9-oxa-2,6-diazaspiro[4,5]decane-2-carboxylate

[1158] At 0 °C, a solution of 2-chloro-2-fluoro-acetyl chloride (125 mg, 0.956 mmol) in DCM (5 mL) was added to a solution of intermediate 122 (200 mg, 0.478 mmol) and N-ethyl-N-(propyl-2-yl)propyl-2-amine (250 μL, 1.44 mmol) in DCM (5 mL), 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 under vacuum to give crude material. The residue was dissolved in anhydrous THF (21 mL) and slowly added at 0 °C to anhydrous THF (11.5 mL) containing sodium hydride (60%, 0.16 g, 4.00 mmol). The mixture was stirred at this temperature for 30 min, then heated at 50 °C for 5 h, and then heated at room temperature for 16 h. The crude substance was purified by silica gel chromatography (0-100% EtOAc / heptane) to give the title compound (150 mg) as a colorless oil. [M+H] + m / z 495.2 and 497.2

[1159] Intermediate 127

[1160]

[1161] 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

[1162] A mixture of intermediate 126 (46%, 150 mg, 0.139 mmol), 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (66 mg, 0.275 mmol), 1M tripotassium phosphate (1M in H2O) (0.42 mL, 0.420 mmol), and THF (1.35 mL) was degassed for 15 min (N2 purging). XPhos Pd G3 (5.9 mg, 6.96 μmol) was added, and the reaction mixture was stirred at 50 °C for 1 h under a nitrogen atmosphere. The reaction mixture was poured into a saturated aqueous solution of 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 substance was purified by silica gel chromatography (0–100% EtOAc / heptane) to give the title compound (148 mg) as a yellow oil. [M+H] + m / z529.4

[1163] Intermediate 128

[1164]

[1165] rel-(1S,5S)-8-fluoro-1-({2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4,5]dec-7-one

[1166] Intermediate 127 (49%, 148 mg, 0.137 mmol) was dissolved in ethanol (6.5 mL), and the mixture was evacuated to atmospheric pressure and backfilled with nitrogen three times. Palladium / carbon (10%) (5.0%, 29 mg, 0.0137 mmol) was added, and the mixture was evacuated to atmospheric pressure and backfilled with hydrogen three times. The reaction was stirred for 3 hours, then filtered through diatomaceous earth, washed with EtOAc, and concentrated under vacuum to give the title compound (80 mg) as a yellow oil. [M+H] + m / z 395.2

[1167] (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-carboxylic acid 2,2-difluoroethyl ester (74) and

[1168] (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-carboxylic acid 2,2-difluoroethyl ester (75)

[1169]

[1170] At 0 °C, a solution of 2,2-difluoroethyl chloroformate (16 μL, 0.155 mmol) in anhydrous DCM (0.45 mL) was added dropwise to a solution of intermediate 128 (50%, 80 mg, 0.101 mmol) and triethylamine (34 μL, 0.244 mmol) in anhydrous DCM (0.45 mL), and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with methanol (1 mL) and concentrated under vacuum to give a crude product. The crude product was purified by reversed-phase column chromatography (10–100% acetonitrile / water (0.1% NH3)) to give a mixture of products (16 mg) as a white solid. [MH] - m / z 501.3. The latter was purified using a Waters 600 via chiral preparation, eluted with 75 / 25% v / v n-hexane / ethanol, Chiralcel OD-H (25 × 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). The absolute stereochemistry of compounds 74 and 75 in each peak was not definitively determined, but was assigned as follows.

[1171] Example 74: Peak 1+2 (assigned as 1S, 5S at pyrrolidine and racemic at morpholinone); 1 H NMR (400MHz, CDCl3) δ7.38-7.28(m,1H),7.20(q,J=7.6Hz,2H),7.07(d,J=8.6Hz,2H),6.83(d,J=9.7Hz,1H),6.23(d,J=34.9Hz,1H),5.95-5.06(m, 2H),4.55(d,J=28.3Hz,1H),4.37-4.03(m,2H),3.97(s,1H),3.70(t,J=1 3.7Hz, 1H), 3.49 (d, J = 45.0Hz, 2H), 3.13-2.77 (m, 2H), 2.49-1.94 (m, 2H).

[1172] LCMS (Method C): [M+H] + m / z 503.2, RT 1.09-1.10 minutes.

[1173] Chiral analysis (Chiralcel OD-H, 25×0.46cm, 5μm, 75:25 n-hexane:ethanol): RT peak 1 6.9 min, peak 2 7.7 min.

[1174] Example 75: Peak 3+4 (assigned as 1R, 5R at pyrrolidine, and as racemic at morpholinone): 1 H NMR (400MHz, CDCl3) δ7.38-7.28(m,1H),7.19(q,J=7.5Hz,2H),7.14-7.03(m,2H),6.83(d,J=9.5Hz,1H),6.34(t,J=36.0Hz,1H),6.06-5.08(m,2H), 4.55(d,J=29.1Hz,1H),4.35-4.03(m,2H),3.98(d,J=12.6Hz,1H),3.69(t ,J=13.8Hz,1H),3.62-3.33(m,2H),3.14-2.78(m,2H),2.48-1.96(m,2H).

[1175] LCMS (Method C): [M+H] + m / z 503.2, RT 1.09-1.10 minutes.

[1176] Chiral analysis (Chiralcel OD-H, 25×0.46cm, 5μm, 75:25 n-hexane:ethanol): RT peak 3 at 10.7 min, peak 4 at 12.1 min.

[1177] 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

[1178]

[1179] Intermediate 129

[1180]

[1181] 1-tert-butyl-4-ethyl-2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-oxopiperidine-1,4-dicarboxylate

[1182] Under nitrogen atmosphere, a solution of diisopropylamine (23.74 mL, 169.4 mmol) in anhydrous THF (70 mL) was added to a 500 mL RBF equipped with a stir bar, a rubber septum, and a syringe connected to a vacuum / nitrogen inlet. The mixture was cooled to -5 °C, and a solution of 2.5 M nBuLi in hexane (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 minutes. A solution of ethyl 1-N-boc-3-oxopiperidine-4-carboxylate (20.89 g, 77 mmol) and 1,3-dimethyl-1,3-diazacyclohexane-2-one (37.1 mL, 308 mmol) in anhydrous THF (160 mL) was added to a separate 1 L three-necked RBF equipped with a stir bar, a rubber septum, a vacuum / nitrogen valve, and a thermometer. The mixture was cooled to below -65°C using an acetone / dry ice bath, and the previously prepared LDA solution was added dropwise to the substrate mixture over 20 minutes while maintaining the internal temperature below -65°C. After addition, the mixture was stirred at the same temperature for 30 minutes. A solution of 4-(chloromethoxy)piperidine-1-carboxylic acid benzyl ester (24.03 g, 84.7 mmol) in anhydrous THF (70 mL) was loaded into a separate 25 mL RBB equipped with a stir bar, a rubber septum, and connected via a syringe to a vacuum / nitrogen inlet. This solution was pre-cooled at 0°C and then added dropwise to the lithium-ionized piperidinone substrate mixture while maintaining the internal temperature below -65°C. The mixture was stirred at this temperature for 1 hour. The mixture was then slowly heated to 0°C, and the reaction was quenched with a saturated aqueous solution of NH4Cl (250 mL) and water (150 mL). The mixture was extracted with EtOAc (200 mL), the organic phase was then separated and washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a yellow oil. The crude substance was purified by silica gel column chromatography (0-26% EtOAc / cHex) to give the title compound (32 g) as a colorless oil. [M+H] + m / z 419.4

[1183] Intermediate 130

[1184]

[1185] 2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-oxopiperidin-1-carboxylic acid tert-butyl ester

[1186] 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) and maintained for 6 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with diethyl ether (3 × 50 mL). The combined organic layers were washed with water (400 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated under vacuum to give the crude substance. The crude substance was purified by column chromatography (0-80% EtOAc / heptane) to give the title compound (1.75 g) as a yellow oil. [M+H] + m / z 447.4

[1187] Intermediate 131

[1188]

[1189] 2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-(hydroxyimino)piperidin-1-carboxylic acid tert-butyl ester

[1190] 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), and the mixture was heated at 80 °C for 1 h. The reaction mixture was cooled to room temperature, concentrated under vacuum, diluted with water (25 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under vacuum to give a crude product. The crude product was purified by silica gel column chromatography (0–100% EtOAc / heptane) to give the title compound (1.88 g) as a yellow oil. [M+H] + m / z 462.5

[1191] Intermediate 132

[1192]

[1193] 2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-nitropiperidin-1-carboxylic acid tert-butyl ester

[1194] At 0 °C, 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), and the mixture was stirred at 0 °C for 2 h. The resulting solution was added dropwise at 80 °C 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), and the mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature, quenched with saturated Na₂SO₃ aqueous solution (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 MgSO₄, filtered, and concentrated under vacuum to obtain the crude substance. The crude substance was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (1.4 g) as a colorless oil. [M+H] + m / z 478.3

[1195] Intermediate 133

[1196]

[1197] rel-(2R,3S)-2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-(hydroxymethyl)-3-nitropiperidin-1-carboxylic acid tert-butyl ester

[1198] A solution of formaldehyde (in water) (37%, 1.1 mL, 14.7 mmol) was added to a solution of intermediate 132 (1.40 g, 2.93 mmol) in THF (15 mL) under stirring 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 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under vacuum to give a crude substance. The crude substance was purified by silica gel column chromatography (0–60% EtOAc / heptane) to give the title compound (1.03 g) as a colorless oil. [M+Na] + m / z 530.3

[1199] Intermediate 134

[1200]

[1201] tert-butyl-rel-(2R,3S)-3-amino-2-[({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methyl]-3-(hydroxymethyl)piperidin-1-carboxylate

[1202] Zinc (1.29 g, 19.7 mmol) was added to a stirred 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 h. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (10 mL), filtered through diatomaceous earth (washed with EtOAc), and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give crude material. The crude material (700 mg) was used without further purification as a colorless gel. [M+H] + m / z 478.4

[1203] Intermediate 135

[1204]

[1205] 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

[1206] At 0 °C, a solution of chloroacetyl chloride (163 μL, 2.05 mmol) was added dropwise to a 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), 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 MgSO4, filtered, and concentrated under vacuum to give a crude intermediate. The crude intermediate was dissolved in DCM (12 mL) and IPA (20 mL), cooled to 0 °C, and potassium 2-methylprop-2-ol (658 mg, 5.86 mmol) was added, and the reaction was stirred at 0 °C for 16 h. The reaction was quenched by adding water (20 mL). The mixture was poured onto a saturated aqueous solution of NaHCO3 (30 mL). After extraction with DCM (3 × 15 mL), the combined organic extracts were washed with brine (20 mL), dried over MgSO4, and filtered to obtain the crude substance. The crude substance was purified by reversed-phase column chromatography (10-100% acetonitrile / water (0.1% NH3)) to give the title compound (350 mg) as a colorless oil. [M+Na] + m / z 540.3

[1207] Intermediate 136

[1208]

[1209] tert-butyl-rel-(6S,7R)-2-oxo-7-[(piperidin-4-yloxy)methyl]-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1210] Intermediate 135 (350 mg, 0.676 mmol) was dissolved in ethanol (25 mL), and the mixture was evacuated to atmospheric pressure and backfilled with nitrogen three times. Palladium / carbon (10%) (10%, 72 mg, 0.0676 mmol) was added, and the mixture was evacuated to atmospheric pressure and backfilled with hydrogen three times. The reaction was stirred for 2 hours, then filtered through diatomaceous earth, washed with EtOAc, and concentrated under vacuum to give the title compound (250 mg) as a beige solid. [M+H] + m / z 384.4

[1211] Intermediate 137

[1212]

[1213] tert-butyl-rel-(6S,7R)-7-({[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]oxy}methyl)-2-oxo-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1214] 2-Chloro-5-fluoropyrimidine (72 μL, 0.782 mmol) was added to a stirred solution of N-ethyl-N-(prop-2-yl)prop-2-amine (1.1 mL, 6.52 mmol) and intermediate 136 (250 mg, 0.652 mmol) in anhydrous acetonitrile (10 mL), and the mixture was heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature, quenc...

Claims

1. A compound of formula (I): Or its pharmaceutically acceptable salt. in n and m are independently 0 or 1; A1 is a -CR4R5- OR key; A2 is -C(O)- or -S(O)2-; A3 and A4 are independently -O-, -CR4R5-, -NR6, -S-, or bonds; A5 and A6 are independently -O-, -CR4R5-, -NR6, -S- or bonds; the condition is that the ring including A2, A3, A4, A5 and A6 does not contain -OO-, -NR6-NR6- or -O-NR6-. L1 is an -O- OR bond; L2 is -CR4R5; R1 is C 1-6 Alkyl, 5- or 6-membered heteroaryl, -(C=O)NR7R8, -(C=O)-OC 1-6 Alkyl group, -(C=O)C 3-6 cycloalkyl, -(C=O)C 1-6 Alkyl group, -(C=O)C 4-6 Saturated heterocyclic groups or -S(O)2-C 1-6 Alkyl, wherein each C 1-6 Alkyl, C 3-6 cycloalkyl, C 4-6 Saturated heterocyclic groups and heteroaryl groups are independently and optionally separated by one or more hydroxyl groups, -C 1-6 Alkyl, -OC 1-6 Alkyl or fluorine-substituted; R2and R3are independently hydrogen or C 1-5 alkyl; wherein C 1-5 alkyl is optionally substituted with one or more fluorines; R4and R5are independently hydrogen, halo, or C 1-5 alkyl; R6is hydrogen or C 1-5 alkyl, R7 and R8 are independently hydrogen or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups are optionally fluorinated by one or more fluorine molecules or -OC 1-6 Alkyl substitution, or R7 and R8 together with the atoms they are attached to form an azahexacyclic butane-1-yl group optionally substituted with one or more fluorine atoms; Y is a 3-7 membered monocycloalkyl, 4-7 membered saturated heterocyclic, or phenyl; wherein the phenyl is optionally substituted with one or more fluorine molecules; and Z is a 6-membered heteroaryl or phenyl group; wherein the 6-membered heteroaryl or phenyl group is optionally substituted by one or more fluorine molecules independently.

2. The compound of claim 1, wherein Y and Z are phenyl groups.

3. The compound of claim 1, wherein Y is cyclohexyl and Z is phenyl.

4. The compound of claim 1, wherein Y is phenyl or cyclohexyl and Z is: or wherein each R B is fluorine, and o is 0, 1 or 2.

5. The compound according to any one of claims 1 to 3, wherein m and n are 0.

6. The compound according to any one of claims 1 to 3, wherein m is 1 and n is 0.

7. The compound according to any one of claims 1 to 3, wherein m is 0 and n is 1.

8. The compound according to any one of claims 1 to 3, wherein m is 1 and n is 1.

9. The compound according to any one of claims 1 to 3, wherein A1 is -CR4R5-.

10. The compound according to any one of claims 1 to 3, wherein A2 is -C(O)-.

11. The compound according to any one of claims 1 to 3, wherein A2 is -S(O)2-.

12. The compound according to any one of claims 1 to 3, wherein A2, A3, A4, A5 and A6 together with the atoms to which they are attached form a 5-membered heterocycle.

13. The compound according to any one of claims 1 to 3, wherein A2, A3, A4, A5 and A6 together with the atoms to which they are attached form a 6-membered heterocycle.

14. The compound according to any one of claims 1 to 3, wherein A2, A3, A4, A5 and A6 together with the atoms to which they are attached form a 7-membered heterocycle.

15. The compound according to any one of claims 1 to 3, wherein L1 is -O-.

16. The compound according to any one of claims 1 to 3, wherein L1 is a bond.

17. A compound of formula (II), or a pharmaceutically acceptable salt thereof, Wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3, Y, and Z have the definitions provided in any one of claims 1 to 3.

18. The compound of claim 17, wherein Y is cyclohexyl and Z is phenyl.

19. The compound of claim 17, wherein Y is phenyl and Z is phenyl.

20. The compound of claim 17, wherein Y is phenyl or cyclohexyl and Z is: or , where each R B It is fluorine, and o is 0, 1, or 2.

21. A compound of formula (III), or a pharmaceutically acceptable salt thereof, Wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3 and Z have the definitions provided in any one of claims 1 to 3.

22. A compound of formula (IV), Or its pharmaceutically acceptable salt. wherein R A is halo; and p is 0, 1, 2, 3 or 4; Wherein n, m, A1, A2, A3, A4, A5, A6, L1, L2, R1, R2, R3 and Z have the definitions provided in any one of claims 1 to 3.

23. The compound of claim 21 or 22, wherein Z is phenyl.

24. The compound of claim 1, wherein the compound of formula (I) is selected from the group consisting of the compounds in Table 1. Table 1 。 25. A pharmaceutical composition comprising the compound as described in any one of claims 1 to 22 and a pharmaceutically acceptable excipient.

26. Use of a therapeutically effective amount of the compound of any one of claims 1 to 24 or the composition of claim 25 in the preparation of a medicament for treating a disease or condition that can be treated by administration of an orexin-2 receptor agonist.

27. Use in the preparation of a medicament in a therapeutically effective amount of any one of claims 1 to 24 or of any one of claims 25, the medicament being used in a subject in need to treat a sleep disorder that can be treated by administration of an orexin-2 receptor agonist.

28. Use in the preparation of a medicament in an effective amount of any one of claims 1 to 24 or of a composition as described in claim 25, the medicament being used in a subject in need to treat narcolepsy that can be treated by administration of an orexin-2 receptor agonist.

29. Use in the preparation of a medicament in an effective amount of any one of claims 1 to 24 or of any one of claims 25, the medicament being used in a subject in need to treat narcolepsy that can be treated by administration of an orexin-2 receptor agonist.

30. Use in the preparation of a medicament in an effective amount of any one of claims 1 to 24 or of any one of claims 25, the medicament being used in a subject in need to reduce or treat excessive somnolence that can be treated by administration of an orexin-2 receptor agonist.

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