Macrocyclic orexin receptor agonists and their use

Abstract

Provided herein is a compound of formula (I), (I), or a pharmaceutically acceptable salt thereof, wherein m, n, p, A 1 , A 2 , A 3 , A 4 , L, R 1 , R 2 , R 3 , R 4 , formula (II), (II), V, X, Y and Z are as defined herein. Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a method of using a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a disease or disorder treatable by, for example, administration of an orexin agonist. 【Chemical 1】 JPEG2025518216000522.jpg60158 【Chemical 2】 JPEG2025518216000523.jpg16158

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 347,708, filed on June 1, 2022, the entire disclosure of which is hereby incorporated by reference herein.

Background Art

[0002] Orexin is a neuropeptide specifically produced by specific neurons scattered in the lateral hypothalamus and its surrounding regions. Orexin consists of two subtypes, namely orexin A and orexin B. Both orexin A (OX - A) and orexin B (OX - B) are endogenous ligands of orexin receptors that mainly exist in the brain. Two orexin receptors have been cloned and characterized in mammals. They belong to the superfamily of G - protein - coupled receptors. The orexin - 1 receptor (OX or OX1R) is partially selective for OX - A, and the orexin - 2 receptor (OX2 or OX2R) can bind to both OX - A and OX - B with similar affinities. The physiological effects presumed to be involved by orexin are thought to be expressed as two subtypes of orexin receptors, via one or both of the OX1 receptor and the OX2 receptor.

[0003] Since orexin regulates the states of sleep and wakefulness, the orexin system has become a target for potential therapeutic approaches to treat sleep disorders. Orexin has been found to stimulate food intake in rats, suggesting that these peptides play a physiological role as mediators in the central feedback mechanism that regulates feeding behavior. Orexin has also been shown to play a role in wakefulness, emotion, energy homeostasis, reward, learning, and memory.

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

SUMMARY OF THE INVENTION

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

[0006] In one aspect, the present disclosure provides a compound of formula (I):

CHEMICAL

CHEMICAL

CHEMICAL

Chemical formula

[0007] In some embodiments, the present disclosure provides a compound of formula (IA):

Chemical formula

[0008] In some embodiments, the disclosure provides a compound of formula (IB):

Chemical formula

Chemical formula

Chemical formula

[0009] In some embodiments, the present disclosure provides a compound of formula (IC):

Chemical formula

[0010] In some embodiments, the present disclosure provides a compound of formula (ID): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, A 5 A 6 R 1 R 2 R b , [Chemical formula] V, X, Y, and Z are as defined herein.

[0011] In some embodiments, A 1 is -C(O)- or -S(O) 2 -. In some embodiments, A 1 is -C(O)-. In some embodiments, A 1 is -S(O) 2 -.

[0012] In some embodiments, A 2 is -O-, -NR 7 -, or -CR 5 R 6 -. In some embodiments, A 2 is a bond, -O-, or -CR 5 R 6 -. In some embodiments, A 2 is -CR 5 R 6 -. In some embodiments, A 2 is -O. In some embodiments, A 2 is a bond.

[0013] In some embodiments, A 3 is a bond, -O-, or -CR 5 R 6 -. In some embodiments, A 3 is -O- or -CR 5 R 6 -. In some embodiments, A 3 is -O-. In some embodiments, A 3 is -CR 5 R 6 -. In some embodiments, A 3 is a bond.

[0014] In some embodiments, A 4 is -CR 5 R 6 -.

[0015] In some embodiments, R 5 and R 6 are each independently H, halogen, or alkyl. In some embodiments, R 5 and R 6 are each independently H or alkyl. In some embodiments, the alkyl is methyl or ethyl.

[0016] In some embodiments, R 5 and R 6 are H. In some embodiments, R 5 and R 6 are halogen. In some embodiments, R 5 and R 6 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6 cycloalkyl. In some embodiments, the heterocyclic ring is a 3- or 6-membered heterocyclic ring. In some embodiments, the heterocyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0017] In some embodiments, R 7is H or alkyl.

[0018] In some embodiments, R 1 and R 2 are each independently H, halogen, or alkyl. In some embodiments, R 1 and R 2 are each independently H or alkyl. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, R 1 and R 2 are H. In some embodiments, R 1 and R 2 are H or halogen. In some embodiments, the halogen is fluoride. In some embodiments, R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6 cycloalkyl. In some embodiments, the heterocyclic ring is a 3- or 6-membered heterocyclic ring. In some embodiments, the heterocyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0019] In some embodiments, R 3 and R 4 are each independently H, halogen, or alkyl. In some embodiments, R 3 and R 4 are each independently H or alkyl. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, R 3 and R 4 are H. In some embodiments, R 3 and R 4 are halogen. In some embodiments, the halogen is fluoride. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6It is cycloalkyl. In some embodiments, the heterocyclic ring is a 3-membered or 6-membered heterocyclic ring. In some embodiments, the heterocyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0020] In some embodiments,

Chemical formula

[0021] In some embodiments, V is -O- or -CR 8 R 9 -. In some embodiments, V is -O- or -NR 10 -. In some embodiments, V is -O-. In some embodiments, V is -CR 8 R 9 -. In some embodiments, R 8 and R 9 are each independently H or alkyl. In some embodiments, R 8 and R 9 together with the atom to which they are attached form a C 3-6 cycloalkyl. In some embodiments, R 10 is H, alkyl, -(C=O)alkyl, or -S(O) 2 -alkyl. In some embodiments, R 10 is H or alkyl. In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the alkyl is methyl.

[0022] In some embodiments, Y is a bond or -CR 8 R 9 -. In some embodiments, R 8 and R 9 are each independently H or alkyl. In some embodiments, R 8 and R 9together with the atoms to which they are attached form a C 3-6 cycloalkyl.

[0023] In some embodiments, Z is -NR 10 - or -CR 8 R 9 -. In some embodiments, Z is -NR 10 -. In some embodiments, Z is -CR 8 R 9 -. In some embodiments, R 8 and R 9 are each independently H or alkyl. In some embodiments, R 8 and R 9 together with the atoms to which they are attached form a C 3-6 cycloalkyl. In some embodiments, R 10 is H, alkyl, -(C=O)alkyl, or -S(O) 2 -alkyl. In some embodiments, R 10 is H or alkyl. In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the alkyl is methyl.

[0024] In some embodiments, X is -CR 11 R 12 -. In some embodiments, R 11 and R 12 are each independently H or alkyl. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, R 11 and R 12 together with the atoms to which they are attached form a C 3-6 cycloalkyl.

[0025] In some embodiments,

Chemical formula

[0026] In some embodiments, m is 0 or 1. In some embodiments, m is 0.

[0027] In some embodiments, n is 0 or 1. In some embodiments, n is 1.

[0028] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0029] In some embodiments, L is a

Chemical formula

[0030] In some embodiments, L is

Chemical formula

Chemical formula

[0031] In some embodiments, L is a 5- or 6-membered heteroaryl linker. In some embodiments, L is a 5- or 6-membered heteroaryl linker having 1 or 2 nitrogen atoms. In some embodiments, L is [Chemical formula] wherein R b is halogen, alkyl, or alkoxy; and r is 0 or 1.

[0032] In some embodiments, the present disclosure provides the following: [Chemical formula] [Chemical formula] and provides a compound selected from the group consisting of.

[0033] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [Modes for Carrying Out the Invention]

[0034] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications are hereby incorporated by reference in their entirety for all purposes to more fully describe the state of the art known to those of ordinary skill in the art as of the date of this disclosure. In the event of any inconsistencies between the cited patents, patent applications, and publications and this disclosure, this disclosure shall control.

[0035] For convenience, certain terms used herein in the specification, examples, and claims are summarized here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0036] The term "about" immediately preceding a numerical value means a range (e.g., ±10% of that value). For example, unless otherwise indicated in the context of this disclosure or unless such an interpretation is inconsistent, "about 50" can mean 45 to 55, and "about 25,000" can mean 22,500 to 27,500, etc. For example, in a list of numerical values, e.g., "about 49, about 50, about 55,...", "about 50" means a range that extends less than half the interval(s) between the values before and after it, e.g., a range that exceeds 49.5 and is less than 50.5. Further, the expressions "about" a value "less than" or "about" a value "more than" should be understood in view of the definition of the term "about" provided herein. Similarly, the term "about" preceding a series of numerical values or a range of values (e.g., "about 10, 20, 30" or "about 10 - 30") refers to each of all the values in that series or the endpoints of that range.

[0037] As used herein, the terms "administer", "administering", or "administration" refer to the administration of a compound or a pharmaceutically acceptable salt of the compound, or a composition or formulation comprising the compound or a pharmaceutically acceptable salt of the compound to a patient.

[0038] The term "pharmaceutically acceptable salt" includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt, for example, salts such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Examples of base addition salts include ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, phenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine dicyclohexylamine, etc., but are not limited thereto. Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc. Examples of ammonium salts and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, etc. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting this compound with a suitable inorganic or organic acid by any of a number of known methods.

[0039] As used herein with respect to a patient, the term "treating" refers to ameliorating at least one symptom of the patient's disorder. Treatment can be ameliorating or at least partially ameliorating the disorder or a symptom associated with the disorder.

[0040] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in the present disclosure and refer to the amount of a compound, or a salt thereof, (or a pharmaceutical composition comprising the compound or salt) that, when administered to a patient, is capable of achieving the intended result. The "effective amount" may vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, as well as the age, weight, physical condition, and responsiveness of the mammal to be treated.

[0041] The term "therapeutically effective" as applied to a dosage or amount refers to an amount of a compound or pharmaceutical formulation that is sufficient to produce a desired clinical benefit upon administration to a patient in need thereof.

[0042] The term "carrier" or "vehicle", as used interchangeably herein, encompasses carriers, excipients, adjuvants, and diluents or any combination of the foregoing, and refers to a substance, composition, or vehicle involved in carrying or transporting a pharmaceutical from one organ, or part, of the body to another organ or part of the body, such as, by way of example, a liquid or solid filler, diluent, excipient, solvent, or encapsulating agent. In addition to adjuvants, excipients, and diluents known to those of skill in the art, carriers include organic and inorganic nanoparticles.

[0043] When a range of values is recited, it is intended that the range include each value and sub-range within the range. For example, "C 1 -C 6 alkyl" includes C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、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 、C3-4 , C 4-6 , C 4-5 , and C 5-6 is intended to include alkyl.

[0044] "Alkyl" or "alkyl group" refers to a fully saturated straight-chain or branched hydrocarbon chain having 1 to 12 carbon atoms, and is bonded to the remainder of the molecule by a single bond. Alkyl containing any number of carbon atoms from 1 to 12 is included. Alkyl containing a maximum of 12 carbon atoms is C 1 -C 12 alkyl, and alkyl containing a maximum of 10 carbon atoms is C 1 -C 10 alkyl, and alkyl containing a maximum of 6 carbon atoms is C 1 -C 6 alkyl, and alkyl containing a maximum of 5 carbon atoms is C 1 -C 5 alkyl. C 1 -C 5 alkyl includes, as alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl and C 1 alkyl (i.e., methyl). C 1 -C 6 alkyl includes all the parts described above for C 1 -C 5 alkyl, and further includes C 6 alkyl. C 1 -C 10 alkyl includes all the parts described above for C 1 -C 5 alkyl and C 1 -C 6 alkyl, and further includes C 7 , C 8 , C 9 and C 10 alkyl. Similarly, C 1 -C 12 alkyl includes all the parts described above, and further includes C 11 and C 12 alkyl. C1 -C 12 Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated herein, the alkyl group may be optionally substituted.

[0045] "Alkylene" or "alkylene chain" refers to a fully saturated, straight-chain or branched divalent hydrocarbon chain radical having 1 to 12 carbon atoms. C 1 -C 12 Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is bonded to the remainder of the molecule via a single bond and to a radical group (e.g., those described herein) via a single bond. The points of attachment of the alkylene chain to the remainder of the molecule and to the radical group may be via one carbon or any two carbons within the chain. Unless otherwise specifically stated herein, the alkylene chain may be optionally substituted.

[0046] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched hydrocarbon chain having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is bonded to the remainder of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. An alkenyl group containing up to 12 carbon atoms is C 2 -C 12 an alkenyl, an alkenyl containing up to 10 carbon atoms is C 2 -C 10 an alkenyl, an alkenyl group containing up to 6 carbon atoms is C 2 -C 6 an alkenyl, an alkenyl containing up to 5 carbon atoms is C 2 -C 5 an alkenyl. C 2 -C 5 Alkenyl is C 5 Alkenyl, C4 Alkenyl, C 3 Alkenyl, and C 2 Contains alkenyl. C 2 -C 6 The alkenyl is C 2 -C 5 The alkenyl includes all the parts described above, and further C 6 Also includes alkenyl. C 2 -C 10 The alkenyl is C 2 -C 5 Alkenyl and C 2 -C 6 The alkenyl includes all the parts described above, and further C 7 , C 8 , C 9 and C 10 Also includes alkenyl. Similarly, C 2 -C 12 The alkenyl includes all the parts described above, but further C 11 and C 12 Also includes alkenyl. C 2 -C 12Non-limiting examples of alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 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 herein, an alkyl group may be optionally substituted.

[0047] "Alkenylene" or "alkenylene chain" refers to an unsaturated, straight-chain or branched divalent hydrocarbon chain radical having one or more olefins and 2 to 12 carbon atoms. C 2 -C 12 Non-limiting examples of alkenylene include ethenylene, propenylene, n-butenylene, etc. The alkenylene chain is bonded to the remainder of the molecule via a single bond and to a radical group (e.g., those described herein) via a single bond. The points of attachment of the alkenylene chain to the remainder of the molecule and to the radical group may be via one carbon or any two carbons within the chain. Unless otherwise specifically stated herein, the alkenylene chain may be optionally substituted.

[0048] "Alkynyl" or "alkynyl group" refers to a straight-chain or branched hydrocarbon chain having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is bonded to the remainder of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. An alkynyl group containing up to 12 carbon atoms is C 2 -C 12 alkynyl, and an alkynyl containing up to 10 carbon atoms is C 2 -C 10 alkynyl, and an alkynyl group containing up to 6 carbon atoms is C 2 -C 6 alkynyl, and an alkynyl containing up to 5 carbon atoms is C 2 -C 5 alkynyl. C 2 -C 5 alkynyl is C 5 alkynyl, C 4 alkynyl, C 3 alkynyl, and C 2 alkynyl are included. C 2 -C 6 alkynyl is C 2 -C 5 alkynyl containing all of the portions described above, and further C 6 alkynyl is also included. C 2 -C 10 alkynyl is C 2 -C 5 alkynyl and C 2 -C 6 alkynyl containing all of the portions described above, and further C 7 , C 8 , C 9 and C 10 alkynyl are also included. Similarly, C 2 -C 12 alkynyl contains all of the portions described above, but further C 11 and C 12 alkynyl are also included. C 2 -C 12Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise specifically described herein, an alkyl group may be optionally substituted.

[0049] "Alkynylene" or "alkynylene chain" refers to an unsaturated, straight-chain or branched divalent hydrocarbon chain radical having one or more alkynes and 2 to 12 carbon atoms. C 2 -C 12 Non-limiting examples of alkynylene include ethylene, propylene, n-butylene, and the like. The alkynylene chain is bonded to the remainder of the molecule via a single bond and to a radical group (e.g., those described herein) via a single bond. The points of attachment of the alkynylene chain to the remainder of the molecule and to the radical group can be via any two carbons within the chain having appropriate valences. Unless otherwise specifically described herein, the alkynylene chain may be optionally substituted.

[0050] "Alkoxy" refers to a group of the formula -OR a wherein R a is alkyl, alkenyl or alkynyl as defined above containing 1 to 12 carbon atoms. Unless otherwise specifically described herein, an alkoxy group may be optionally substituted.

[0051] "Aryl" refers to a hydrocarbon ring system containing hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, and is bonded to the remainder of the molecule by a single bond. For the purposes of the present disclosure, aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused ring systems or bridged ring systems. Examples of aryl include, but are not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, preiadene, pyrene and triphenylene. Unless otherwise specifically described herein, "aryl" may be optionally substituted.

[0052] "Aralkyl" or "arylalkyl" refers to a radical of the formula -R b -R c wherein R b is an alkylene group as defined above, and R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl, etc. Unless otherwise specifically stated herein, the aralkyl group may be optionally substituted.

[0053] "Carbocyclic", "carbocyclic ring" or "carbocycle" refers to a ring structure, and the atoms forming the ring are each carbon and are bonded to the rest of the molecule by single bonds. The carbocyclic ring may contain 3 to 20 carbon atoms in the ring. Examples of the carbocyclic ring include aryl and cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein. Unless otherwise specifically stated herein, the carbocyclic group may be optionally substituted.

[0054] "Cycloalkyl" refers to a stable non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon consisting only of carbon and hydrogen atoms, and may include fused rings, bridged rings, or spiro ring systems, having 3 to 20 carbon atoms (for example, having 3 to 10 carbon atoms) and being bonded to the rest of the molecule by single bonds. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, etc. Unless otherwise specifically stated herein, the cycloalkyl group may be optionally substituted.

[0055] "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, capable of including a fused ring or a bridged ring system, having 3 to 20 carbon atoms, preferably having 3 to 10 carbon atoms, and being bonded to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Examples of polycyclic cycloalkenyl include bicyclo[2.2.1]hept-2-enyl, etc. Unless otherwise specifically described herein, the cycloalkenyl group may be optionally substituted.

[0056] "Cycloalkynyl" 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, capable of including a fused ring or a bridged ring system, having 3 to 20 carbon atoms, preferably having 3 to 10 carbon atoms, and being bonded to the rest of the molecule by a single bond. Examples of monocyclic cycloalkynyl include cycloheptynyl, cyclooctynyl, etc. Unless otherwise specifically described herein, the cycloalkynyl group may be optionally substituted.

[0057] "Haloalkyl" refers to an alkyl as defined above substituted by one or more halogen radicals, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specifically described herein, the haloalkyl group may be optionally substituted.

[0058] "Heterocyclyl", "heterocyclic ring" or "heterocycle" refers to a stable saturated or unsaturated 3- to 20-membered ring consisting of 2 to 19 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and bonded to the rest of the molecule by a single bond. Examples of heterocyclyl rings or heterocyclic rings include heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl. Unless otherwise specifically stated herein, heterocyclyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, can include fused rings, bridged rings, or spiro ring systems, and the nitrogen, carbon, or sulfur atoms of heterocyclyl may optionally be oxidized; the nitrogen atoms may optionally be quaternized; heterocyclyl may be partially saturated or fully saturated. Examples of such heterocyclyl include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated herein, heterocyclic groups can be optionally substituted.

[0059] "Heteroaryl" refers to a 5- to 20-membered ring system consisting of a hydrogen atom, 1 to 19 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring, and is bonded to the remainder of the molecule by a single bond. For the purposes of the present disclosure, heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms of heteroaryl can optionally be oxidized, and the nitrogen atoms can optionally be quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated herein, heteroaryl groups can be optionally substituted.

[0060] "Heterocyclylalkyl" refers to a radical of the formula -R b -R e wherein R b is an alkylene, alkenylene, or alkynylene group as defined above, and R e is a heterocyclyl radical as defined above. Unless otherwise specifically stated herein, the heterocyclylalkyl group may be optionally substituted.

[0061] As used herein, the term "substituted" means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and / or heteroaryl), where at least one hydrogen atom is replaced by a non-hydrogen atom, such as, but not limited to, halogen atoms such as F, Cl, Br, and I, oxygen atoms of groups such as hydroxyl, alkoxy, and ester groups, sulfur atoms of groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups, nitrogen atoms of groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine, silicon atoms of groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and by the attachment of other heteroatoms of various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher order bond (e.g., a double bond or a triple bond) to a heteroatom, such as oxygen of oxo, carbonyl, carboxy, and ester groups, and nitrogen of imine, oxime, hydrazone, and nitrile groups. For example, "substituted" includes one or more hydrogen atoms being replaced by -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NRg C(=O)OR h , -NR g SO 2 R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO 2 R g , -OSO 2 R g , -SO 2 OR g , =NSO 2 R g , and -SO 2 NR g R h "Substituted" also includes any of the above groups in which one or more hydrogen atoms have been replaced with -C(=O)R. g , -C(=O)OR g , -C(=O)NR g R h , -CH 2 SO 2 R g , -CH 2 SO 2 NR g R h In the above, R g and R hare the same or different and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N - heterocyclyl, heterocyclylalkyl, heteroaryl, N - heteroaryl and / or heteroarylalkyl. “Substituted” further means that one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N - heterocyclyl, heterocyclylalkyl, heteroaryl, N - heteroaryl group and / or heteroarylalkyl group. In addition, each of the aforementioned substituents may also be optionally substituted with one or more of the above - mentioned substituents.

[0062] As used herein,

Chemical formula

Chemical formula

Chemical formula

[0063] Compound The present disclosure provides macrocyclic compounds that are agonists of the orexin type 2 receptor, pharmaceutical compositions thereof, and their use in the treatment of various diseases and disorders.

[0064] In one aspect, the present disclosure provides a compound of formula (I):

Chemical formula

Chemical formula

[0065] In another aspect, the disclosure provides a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0066] In some embodiments, L is a linker selected from the group consisting of aryl, heteroaryl, -carbocyclyl-O-, and -heterocyclyl-O-, where -carbocyclyl-O- and -heterocyclyl-O- have the following orientations:

Chemical formula

[0067] In some embodiments, L is a linker selected from the group consisting of aryl, heteroaryl, -cycloalkyl-O-, and -heterocyclyl-O-, where -cycloalkyl-O- and -heterocyclyl-O- have the following orientations:

Chemical formula

[0068] In some embodiments, the present disclosure provides a compound of formula (I-1):

Chemical formula

Chem.

[0069] In some embodiments, the present disclosure provides a compound of formula (I-2):

Chem.

Chem.

[0070] In some embodiments, the present disclosure provides a compound of formula (IA):

Chem.

Chem.

[0071] In some embodiments, the disclosure provides a compound of formula (IA-1): [Chemical formula] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 1 , R 2 , R 3 , R 4 , [Chemical formula] , V, X, Y, and Z are as defined herein.

[0072] In some embodiments, the disclosure provides a compound of formula (IA-1-1): [Chemical formula] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, p, A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , [Chemical formula] , Y, and Z are as defined herein.

[0073] In some embodiments, the disclosure provides a compound of formula (IA-2): [Chemical formula] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A 1 、A 2 、A 3 、A 4 、A 5 、A 6 、R 1 、R 2 、R 3 、R 4 、

Chemical formula

[0074] In some embodiments, the disclosure provides a compound of formula (IA-2-1):

Chemical formula

Chemical formula

[0075] In some embodiments, the disclosure provides a compound of formula (IA-3):

Chemical formula

Chemical formula

[0076] In some embodiments, the disclosure provides a compound of formula (IA-4): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein m, p, A 1 , R 1 , R 5 , R 6 , [Chemical formula] X, Y, and Z are as defined herein.

[0077] In some embodiments, the disclosure provides a compound of formula (IA-5): [Chemical formula] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, p, A 1 , R 1 , R 5 , R 6 , [Chemical formula] X, Y, and Z are as defined herein.

[0078] In some embodiments, the disclosure provides a compound of formula (IB): [Chemical formula] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A 1 , A 2 , A 3 , A 4 , R 1 , R 2, R 3 , R 4 , Ar, [Chemistry] , V, X, Y, and Z are as defined herein.

[0079] In some embodiments, the disclosure provides a compound of formula (IB-1): [Chemistry] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , Ar, [Chemistry] , V, X, Y, and Z are as defined herein.

[0080] In some embodiments, the disclosure provides a compound of formula (IB-2): [Chemistry] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , Ar, [Chemistry] , V, X, Y, and Z are as defined herein.

[0081] In some embodiments, the present disclosure provides a compound of formula (IC):

Chemical formula

Chemical formula

[0082] In some embodiments, the present disclosure provides a compound of formula (IC-1):

Chemical formula

Chemical formula

[0083] In some embodiments, the present disclosure provides a compound of formula (IC-2):

Chemical formula

Chemical formula

[0084] In some embodiments, the disclosure provides a compound of formula (IC-3):

Chemical formula

Chemical formula

[0085] In some embodiments, the disclosure provides a compound of formula (IC-4):

Chemical formula

Chemical formula

[0086] In some embodiments, the disclosure provides a compound of formula (IC-5):

Chemical formula

Chemical formula

[0087] In some embodiments, the present disclosure provides a compound of formula (IC-6):

Chemical formula

[0088] In some embodiments, the present disclosure provides a compound of formula (ID):

Chemical formula

Chemical formula

[0089] In some embodiments, the present disclosure provides a compound of formula (ID-1):

Chemical formula

Chemical formula

[0090] In some embodiments, the disclosure provides a compound of formula (ID-2):

Chemical formula

Chemical formula

[0091] In some embodiments, the disclosure provides a compound of formula (IE):

Chemical formula

Chemical formula

[0092] In some embodiments, the disclosure provides a compound of formula (IF):

Chemical formula

Chemical formula

[0093] In some embodiments, the stereoisomers are diastereoisomers of the compound. In some embodiments, the stereoisomers are enantiomers of the compound.

[0094] In some embodiments, L is a linker selected from the group consisting of aryl, -carbocyclyl-O-, and -heterocyclyl-O-. In some embodiments, L is -carbocyclyl-O- or -heterocyclyl-O-. In some embodiments, L is -carbocyclyl-O-. In some embodiments, L is -heterocyclyl-O-. In some embodiments, the carbocyclyl is C 3-6 cycloalkyl. In some embodiments, the carbocyclyl is cyclohexyl. In some embodiments, the carbocyclyl is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0095] In some embodiments, A 1 is -C(O)- or -S(O) 2 -. In some embodiments, A 1 is -C(O)-. In some embodiments, A 1 is -S(O) 2 -. In some embodiments, A 1 is -C(H)(CF 3 ).

[0096] In some embodiments, A 2 , A 3 and A 4 are each independently -O-, -CR 5 R 6 -, -NR 7 -, or -S-, provided that A 2 , A 3 and A 4 are -O-O-, -O-S-, -S-S-, -O-NR 7 -, -S-NR 7 -, or -NR7 -NR 7 - does not contain. In some embodiments, A 2 , A 3 and A 4 are each independently, -O-, -CR 5 R 6 -, -NR 7 -, or -S-, provided that A 2 , A 3 and A 4 do not contain -O - O -, -O - NR 7 - or -NR 7 -NR 7 -. In some embodiments, A 2 , A 3 and A 4 are each independently, -O-, -CR 5 R 6 -, or -NR 7 -, provided that A 2 , A 3 and A 4 do not contain -O - O -, -O - NR 7 - or -NR 7 -NR 7 -. In some embodiments, A 2 and A 3 optionally together with a substituted carbon atom form a cyclopropyl ring having the structure:

Chemical formula

Chemical formula

[0097] In some embodiments, A 2 is -O-, -NR 7 -, or -CR 5 R 6- is. In some embodiments, A 2 is a bond, -O-, or -CR 5 R 6 -. In some embodiments, A 2 is -O- or -CR 5 R 6 -. In some embodiments, A 2 is -O- or -NR 7 -. In some embodiments, A 2 is -CR 5 R 6 -. In some embodiments, A 2 is -O-. In some embodiments, A 2 is a bond.

[0098] In some embodiments, A 3 is -O-, -NR 7 -, or -CR 5 R 6 -. In some embodiments, A 3 is a bond, -O-, or -CR 5 R 6 -. In some embodiments, A 3 is -O- or -CR 5 R 6 -. In some embodiments, A 3 is -O- or -NR 7 -. In some embodiments, A 3 is -O-. In some embodiments, A 3 is -CH 2 -. In some embodiments, A 3 is a bond.

[0099] In some embodiments, A 4 is a bond, -O-, -CR 5 R 6 -, -NR 7 -, -(CR 5 R 6 ) 2 -, -CR 5 R 6 -O-, -CR 5 R6 -N(R 7 )-, -O-CR 5 R 6 -, or -N(R 7 )-CR 5 R 6 -. In some embodiments, A 4 is a bond, -O-, -CR 5 R 6 -, -(CR 5 R 6 ) 2 -, -CR 5 R 6 -O-, or -O-CR 5 R 6 . In some embodiments, A 4 is -O-, -NR 7 -, or -CR 5 R 6 -. In some embodiments, A 4 is -O- or -NR 7 -. In some embodiments, A 4 is -O- or -CR 5 R 6 -. In some embodiments, A 4 is -CR 5 R 6 -. In some embodiments, A 4 is -O-.

[0100] In some embodiments, A 2 is -O-, -NR 7 -, or -S-, and A 3 and A 4 are each -CR 5 R 6 -. In some embodiments, A 2 is -O-, and A 3 and A 4 are each -CR 5 R 6 -. In some embodiments, A 2 is -O-, A 3 is -CR 5 R 6 -, and A 4is a bond. In some embodiments, A 2 is -CR 5 R 6 -. In some embodiments, A 3 is -O-. In some embodiments, A 4 is a bond. In some embodiments, A 3 is -O-, -NR 7 -, or -S-. In some embodiments, A 2 and A 4 are each -CR 5 R 6 -. In some embodiments, A 3 is -O-. In some embodiments, A 2 and A 4 are each -CR 5 R 6 -. In some embodiments, A 4 is -O-, -NR 7 -, or -S-. In some embodiments, A 2 and A 3 are each -CR 5 R 6 -. In some embodiments, A 4 is -O-. In some embodiments, A 2 and A 3 are each -CR 5 R 6 -.

[0101] In some embodiments, A 1 is -C(O)-, -S(O) 2 -, or -C(H)(CF 3 )-; A 2 is -O- or -CR 5 R 6 -; A 3 is -O- or -CR 5 R 6 -; A 4 is a bond or -CH 2 -. In some embodiments, A 1 is -C(O)- or -S(O) 2 -; A 2 is -O- or -CR 5 R 6 -; A 3is -O- or -CR 5 R 6 -; A 4 is a bond or -CH 2 -. In some embodiments, A 1 is -C(O)- or -S(O) 2 -; A 2 is -O-; A 3 is -CR 5 R 6 -; A 4 is a bond or -CH 2 -. In some embodiments, A 1 is -C(O)- or -S(O) 2 -; A 2 is -CR 5 R 6 -; A 3 is -O-; A 4 is a bond or -CH 2 -.

[0102] In some embodiments, the ring containing A 2 , A 3 , and A 4 does not contain -O-O-, -O-NR 7 - or -NR 7 -NR 7 -. In some embodiments, the ring containing A 2 , A 3 , and A 4 does not contain two adjacent heteroatoms.

[0103] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 11 , R 12 , and R 14 are each independently hydrogen, halogen, alkyl, or cycloalkyl. In some embodiments, R 1 , R 2 , R 3, R 4 , R 5 , R 6 , R 8 , R 9 , R 11 , R 12 , and R 14 are each independently hydrogen, halogen, or alkyl. In some embodiments, the alkyl is C 1-5 alkyl. In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the cycloalkyl is C 3-6 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl.

[0104] In some embodiments, R 1 and R 2 are each independently H, halogen, or alkyl. In some embodiments, R 1 and R 2 are each independently H or alkyl. In some embodiments, R 1 and R 2 are alkyl. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, the alkyl is methyl. In some embodiments, R 1 is methyl and R 2 is H. In some embodiments, R 1 and R 2 are H. In some embodiments, R 1 and R 2 are each independently H or halogen. In some embodiments, the halogen is fluoride. In some embodiments, R 1 and R 2 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cyclopropyl. In some embodiments, the heterocycle is a 3- or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0105] In some embodiments, R 3 and R 4 are each independently H, halogen, or alkyl. In some embodiments, R 3 and R 4 are each independently H or alkyl. In some embodiments, R 3 and R 4 is alkyl. In some embodiments, alkyl is methyl or ethyl. In some embodiments, R 3 and R 4 are each independently H or halogen. In some embodiments, R 3 and R 4 is H. In some embodiments, R 3 and R 4 is a halogen. In some embodiments, the halogen is a fluoride. In some embodiments, R 3 and R 4 taken together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, a carbocyclic ring is 3-6 In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cyclopropyl. In some embodiments, the heterocycle is a 3- or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0106] In some embodiments, R 5 and R 6 are each independently H, halogen, or alkyl. In some embodiments, R 5 and R 6 are each independently H or alkyl. In some embodiments, R5 and R 6 is alkyl. In some embodiments, R 5 and R 6 are each independently H or halogen. In some embodiments, the alkyl is haloalkyl. In some embodiments, the haloalkyl is CF 3 . In some embodiments, the alkyl is methyl or ethyl. In some embodiments, R 5 and R 6 are each independently H, F, or CF 3 . In some embodiments, R 5 and R 6 are H. In some embodiments, R 5 and R 6 are halogen. In some embodiments, the halogen is fluoride. In some embodiments, R 5 and R 6 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6 cycloalkyl. In some embodiments, the carbocyclic ring is cyclopropyl. In some embodiments, the heterocyclic ring is a 3- or 6-membered heterocyclic ring. In some embodiments, the heterocyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0107] In some embodiments, R 7 , R 10 , and R 13 are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -S(O) 2 -alkyl, or -S(O) 2 -cycloalkyl. In some embodiments, R 7 , R 10 , R 13 , and R 14is, independently of each other, hydrogen, alkyl, cycloalkyl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -S(O) 2 -alkyl, -S(O) 2 -cycloalkyl, or -S(O) 2 -heterocyclyl. In some embodiments, R 7 , R 10 , R 13 , and R 14 are, independently of each other, hydrogen, alkyl, -(C=O)-O-alkyl, or -S(O) 2 -alkyl. In some embodiments, the alkyl is C 1-5 alkyl. In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the cycloalkyl is C 3-6 cycloalkyl. In some embodiments, the aryl is phenyl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.

[0108] In some embodiments, R 7 is H, alkyl, cycloalkyl, -(C=O)-O-alkyl, -S(O) 2 -alkyl. In some embodiments, R 7 is H, alkyl, cycloalkyl, -(C=O)-O-alkyl, or -S(O) 2 -alkyl. In some embodiments, R 7 is H, alkyl, -(C=O)-O-alkyl, or -S(O) 2 -alkyl. In some embodiments, R 7 is H, alkyl, or cycloalkyl. In some embodiments, R 7 is H or alkyl. In some embodiments, R7 is alkyl. In some embodiments, the alkyl is C 1-5 alkyl. In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the alkyl is methyl. In some embodiments, the cycloalkyl is C 3-6 cycloalkyl.

[0109] In some embodiments, V is -O- or -CR 8 R 9 -. In some embodiments, V is -O- or -NR 10 -. In some embodiments, V is -O-. In some embodiments, V is -CR 8 R 9 -. In some embodiments, R 8 and R 9 are each independently H or alkyl.

[0110] In some embodiments, X is -O- or -NR 13 -. In some embodiments, X is -O- or -CR 11 R 12 -. In some embodiments, X is -CR 11 R 12 - or -NR 13 -. In some embodiments, X is -CR 11 R 12 -.

[0111] In some embodiments, Y is a bond, -CR 8 R 9 -, or -NR 10 -. In some embodiments, Y is a bond, -O-, or -CR 8 R 9 -. In some embodiments, Y is a bond or -CR 8 R 9 -. In some embodiments, Y is a bond. In some embodiments, Y is -CR 8 R 9- is. In some embodiments, R 8 and R 9 together with the atom to which they are attached form a C 3-6 cycloalkyl. In some embodiments, R 8 and R 9 together with the atom to which they are attached form a cyclopropyl.

[0112] In some embodiments, Z is -NR 10 - or -CR 8 R 9 -. In some embodiments, Z is -NR 10 -. In some embodiments, R 8 and R 9 are each independently H or alkyl. In some embodiments, R 8 and R 9 together with the atom to which they are attached form a C 3-6 cycloalkyl. In some embodiments, R 8 and R 9 together with the atom to which they are attached form a cyclopropyl. In some embodiments, R 10 is H, alkyl, -(C=O)alkyl, or -S(O) 2 -alkyl. In some embodiments, R 10 is H or alkyl. In some embodiments, alkyl is methyl, ethyl, or isopropyl. In some embodiments, alkyl is methyl.

[0113] In some embodiments, V-(X) p -Y-Z is -O-(CH 2 ) p -CH 2 -CR 8 R 9 -, -O-(CH 2 ) p CR 8 R 9 -, or -O-(CH 2 ) p -CR 8R 9 is -O-, where p is 0, 1, or 2. In some embodiments, V-(X) p -Y-Z is -O-(CH 2 ) p -CH 2 -CR 8 R 9 - or -O-(CH 2 ) p -CR 8 R 9 - and where p is 0, 1, or 2. In some embodiments, V-(X) p -Y-Z is -O-(CH 2 ) p -CH 2 -CR 8 R 9 - or -O-(CH 2 ) p -CR 8 R 9 - and where p is 0 or 1. In some embodiments, V-(X) p -Y-Z is -O-(CH 2 ) p -CH 2 -CH 2 - or -O-(CH 2 ) p -CH 2 - and where p is 0 or 1. In some embodiments, V-(X) p -Y-Z is -O-(CH 2 ) p -CH 2 -O- and where p is 1. In some embodiments, V-(X) p -Y-Z is -O-CH 2 -CH 2 -CH 2 -CH 2 -, -O-CH 2 -CH 2 -CH 2 -, -O-CH 2 -CH 2 -, -O-CH 2 -, -O-CH(CH 3 )-, -O-CH 2 -CH 2 -CH2 -O-, -O-CH 2 -CH 2 is -O-. In some embodiments, V-(X) p -Y-Z is -O-CH 2 -CH 2 is -O-. In some embodiments, V-(X) p -Y-Z is -O-CH 2 is -O-. In some embodiments, V-(X) p -Y-Z is -O-CH 2 -. In some embodiments, V-(X) p -Y-Z is -O-CH 2 -CH 2 is

[0114] In some embodiments, V-(X) p -Y-Z does not contain an -O-O- or -N-N- bond.

[0115] In some embodiments, R 8 and R 9 are each independently H, halogen, or alkyl. In some embodiments, R 8 and R 9 are each independently H or alkyl. In some embodiments, R 8 and R 9 are alkyl. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, R 8 and R 9 are each independently H or halogen. In some embodiments, R 8 and R 9 are H. In some embodiments, R 8 and R 9 are halogen. In some embodiments, the halogen is fluoride. In some embodiments, R 8 and R 9 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6It is cycloalkyl. In some embodiments, the carbocyclic ring is cyclopropyl. In some embodiments, the heterocyclic ring is a 3- or 6-membered heterocyclic ring. In some embodiments, the heterocyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0116] In some embodiments, R 10 is H, alkyl, cycloalkyl, -(C=O)-O-alkyl, -S(O) 2 -alkyl. In some embodiments, R 10 is H, alkyl, cycloalkyl, -(C=O)-O-alkyl, or -S(O) 2 -alkyl. In some embodiments, R 10 is H, alkyl, -(C=O)-O-alkyl, or -S(O) 2 -alkyl. In some embodiments, R 10 is H, alkyl, or cycloalkyl. In some embodiments, R 10 is H or alkyl. In some embodiments, R 10 is alkyl. In some embodiments, the alkyl is C 1-5 alkyl. In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the alkyl is methyl. In some embodiments, the cycloalkyl is C 3-6 cycloalkyl.

[0117] In some embodiments, R 11 and R 12 are each independently H, halogen, or alkyl. In some embodiments, R 11 and R 12 are each independently H or alkyl. In some embodiments, R 11 and R 12 are alkyl. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, R 11 and R 12Each is independently H or halogen. In some embodiments, R 11 and R 12 are H. In some embodiments, R 11 and R 12 are halogen. In some embodiments, the halogen is fluoride. In some embodiments, R 11 and R 12 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6 cycloalkyl. In some embodiments, the carbocyclic ring is cyclopropyl. In some embodiments, the heterocyclic ring is a 3- or 6-membered heterocyclic ring. In some embodiments, the heterocyclic ring contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0118] In some embodiments,

Chemical formula

[0119] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0120] In some embodiments,

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

[0121] In some embodiments,

Chemical formula

Chemical formula

[0122] In some embodiments,

Chemical formula

Chemical formula

[0123] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0124] In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0.

[0125] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0126] In some embodiments, L is a -carbocyclic-O- or -heterocyclic-O-linker having the structure

Chemical formula

[0127] In some embodiments, L is an aryl linker having the structure

Chemical formula

Chemical formula

[0128] In some embodiments, L is a 5- or 6-membered heteroaryl linker. In some embodiments, L is a 5- or 6-membered heteroaryl linker having 1 or 2 nitrogen atoms. In some embodiments, linker L has the structure

Chemical formula

[0129] In some embodiments, A 1 is -C(O)- or -S(O) 2 -, A 2 is -CR 5 R 6 -, A 3 is -O-, R 1 and R 2 are each independently H or alkyl, R 3 and R 4 are H, X is -CH 2 -, V is -O-, Y is a bond or -CR 8 R 9 -, Z is -O- or -CR 8 R 9 -, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0130] In some embodiments, A 1 is -C(O)- or -S(O) 2 -, A 2 is -O-, A 3 is -CR 5 R 6 -, R 1 and R 2 are each independently H or alkyl, R 3 and R 4 are H, X is -CH2 - and V is -O- and Y is a bond or -CR 8 R 9 - and Z is -O- or -CR 8 R 9 - m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0131] In some embodiments, A 1 is -C(O)-, A 3 is -O-, R 1 and R 2 are each independently H or alkyl, R 3 and R 4 is H, X is -CH 2 -, V is -O-, Y is a bond or -CH 2 -, Z is -O-, -CH 2 -, or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0132] In some embodiments, A 1 is -C(O)-, A 2 and A 4 is -CH 2 -, A 3 is -O-, R 1 and R 2 are each independently H or alkyl, R 3 and R 4 is H, X is -CH 2 -, V is -O-, Y is a bond or -CH 2 -, Z is -O-, -CH 2 -, -CH(Me)-, or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0133] In some embodiments, A 1 is -C(O)-, A 2 and A 4 is -CH 2 -, A3 is -O-, L is -carbocyclic-O- or -heterocyclic-O-, R 1 and R 2 are each independently H or alkyl, R 3 and R 4 is H, X is -CH 2 -, V is -O-, Y is a bond or -CH 2 -, Z is -O-, -CH 2 -, -CH(Me)-, or -N(alkyl)-, m is 0 or 1, n is 0 or 1, p is 0 or 1.

[0134] In some embodiments, A 1 is -C(O)-, A 2 and A 4 is -CH 2 -, A 3 is -O-, L is

Chemical formula

[0135] In some embodiments, A 1 is -C(O)-, A 2 is -O-, A 3 and A 4 is -CH 2 -, L is [Chemical formula] wherein A 5 and A 6 are each independently -CH 2 - or -O-, R 1 and R 2 are each independently H or alkyl, R 3 and R 4 are H, X is -CH 2 -, V is -O-, Y is a bond or -CH 2 -, Z is -O-, -CH 2 -, -CH(Me)-, or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0136] In some embodiments, A 1 is -C(O)-, A 2 and A 4 are -CH 2 -, A 3 is -O-, [Chemical formula] is optionally substituted phenyl or optionally substituted heteroaryl having one or two N atoms, and L is [Chemical formula] wherein A 5 and A 6 are each independently -CH 2 - or -O-, R 1 and R 2 are each independently H or alkyl, R 3 and R 4 are H, X is -CH 2 -, V is -O-, Y is a bond or -CH 2 -, Z is -O-, -CH 2is -CH(Me)- or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0137] In some embodiments, A 1 is -C(O)-, A 2 is -O-, A 3 and A 4 is -CH 2 -,

Chemical Structure

Chemical Structure

[0138] In some embodiments, A 1 is -C(O)-, A 2 and A 4 are -CH 2 -, A 3 is -O-,

Chemical Structure

Chemical formula

[0139] In some embodiments, A 1 is -C(O)-, A 2 and A 4 are -CH 2 -, A 3 is -O-,

Chemical formula

Chemical formula

[0140] In some embodiments, the compounds of the present disclosure have one of the following structures:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0141] In some embodiments, the present disclosure provides the following:

Chem.

Chem.

[0142] In some embodiments, the compounds disclosed herein are racemic mixtures. In some embodiments, one enantiomer of the compounds disclosed herein is enriched. In some embodiments, the compounds disclosed herein have one enantiomer enriched and substantially no other enantiomer. In some embodiments, the compounds disclosed herein have an enantiomeric excess of about 55% or greater, about 60% or greater, about 65% or greater, about 70% or greater, about 75% or greater, about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 98.5% or greater, about 99% or greater, about 99.5% or greater, or higher, including all subranges and values therebetween. In some embodiments, the compounds of the present disclosure are provided as mixtures of diastereomers. In some embodiments, the diastereomers of the compounds of the present disclosure are provided substantially free of other possible diastereomers. The present disclosure includes tautomers of any of the compounds described herein.

[0143] In some embodiments, provided herein is one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

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

[0145] In some embodiments, provided herein is one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a diastereomer thereof, or a mixture of diastereomers.

[0146] In some embodiments, provided herein is one or more compounds selected from Table 1.

[0147] In some embodiments, provided herein are one or more pharmaceutically acceptable salts of a compound selected from Table 1. [Table 1-1] [Table 1-2]

[0148] In some embodiments, the present disclosure provides a compound provided in Table 2 or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound provided in Table 2 or a pharmaceutically acceptable salt thereof having A or B activity. In some embodiments, the present disclosure provides a compound provided in Table 2 or a pharmaceutically acceptable salt thereof having A activity.

[0149] Composition The present disclosure provides a pharmaceutical composition for modulating an orexin receptor (e.g., orexin type 2 receptor) in a subject. In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2) or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments of the present disclosure, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the present disclosure (e.g., compounds of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-2), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (ID), formula (ID1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2) or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the pharmaceutical composition comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as described herein.

[0152] In some embodiments, the pharmaceutical composition comprises one or more compounds selected from Table 2, or a pharmaceutically acceptable salt thereof, as described herein.

[0153] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2) or a pharmaceutically acceptable salt thereof disclosed herein; and one or more pharmaceutically acceptable excipients.

[0154] In some embodiments of the present disclosure, there is provided a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., compounds of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or adjuvant. Pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for various purposes. In some embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable excipient, binder, and / or diluent. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, saline, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0155] For the purposes of the present disclosure, the compounds of the present disclosure can be formulated for administration by various means including oral, parenteral, by inhalation spray, topical, or rectal in a formulation containing a pharmaceutically acceptable carrier, adjuvant, and vehicle. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, and intraarterial injection using various injection techniques. Intraarterial and intravenous injection as used herein includes administration via a catheter.

[0156] In general, the compounds of the present disclosure are administered in a therapeutically effective amount. The amount of the compound actually administered is usually determined by a physician in light of relevant circumstances including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0157] Method of treatment The compounds of the present disclosure are used in many ways. For example, in some embodiments, the compounds are useful in methods for modulating orexin receptors, such as orexin type 2 receptor. Thus, in some embodiments, the present disclosure provides for the use of any one of the foregoing compounds of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2, or a pharmaceutically acceptable salt thereof, for modulating orexin receptor (such as orexin type 2 receptor) activity. For example, in some embodiments, the modulation of orexin receptor (such as orexin type 2 receptor) activity is in mammalian cells. The modulation of orexin receptor (such as orexin type 2 receptor) activity is for the treatment of any of the above conditions or diseases in a subject (such as a mammalian subject, for example, a human) in need thereof.

[0158] In some embodiments, the modulation of orexin receptor (such as orexin type 2 receptor) activity is by binding. In some embodiments, the modulation of orexin receptor (such as orexin type 2 receptor) activity is by agonizing or stimulating the orexin receptor.

[0159] In some embodiments, the present disclosure provides a method of treating a disease or disorder treatable by administration of an orexin agonist, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2).

[0160] In some embodiments, the present disclosure provides a method of treating a disease or disorder treatable by administration of an orexin agonist, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2).

[0161] In some embodiments, the compounds of the present disclosure are used to treat, prevent, improve, control or reduce the risk of one or more of the following conditions or diseases: narcolepsy, narcolepsy syndrome with narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, endogenous hypersomnia, hypersomnia with daytime hypersomnia, fragmented sleep, sleep apnea, hypersomnia with sleep apnea, nocturnal myoclonus, disorders of consciousness, such as coma, REM sleep disruption, jet lag, excessive daytime sleepiness, shift work sleep disorder, abnormal sleep, sleep disorder, sleep disturbance, depression, mood / affective disorders, drug use, Alzheimer's disease or cognitive impairment, Parkinson's disease, Guillain-Barré syndrome, hypersomnia associated with Kleine-Levin syndrome, and sleep disorders associated with aging, muscular dystrophy, immune-mediated diseases; sundowning in Alzheimer's disease; circadian rhythms associated with travel to a time zone with a time difference and shift work schedules and conditions associated with mental and physical disorders; fibromyalgia; heart failure; diseases associated with bone loss; sepsis; syndromes with sleep and muscle pain without recovery of physical strength or sleep apnea with respiratory disorders during sleep; conditions resulting from poor sleep quality; and other diseases associated with general orexin system dysfunction. In some embodiments, the compounds of the present disclosure are useful for the treatment, prevention, improvement, control or reduction of the risk of various narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime hypersomnia (e.g., Parkinson's disease, Guillain-Barré syndrome and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness such as coma, anesthesia, etc., or side effects and complications resulting from anesthetic agents or anesthetic antagonists.

[0162] In some embodiments, the compounds of the present disclosure (e.g., the compounds of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2), their pharmaceutically acceptable salts, or compositions thereof are used to treat a disease or disorder or symptom associated with excessive sleepiness in a subject in need thereof. In some embodiments, the excessive sleepiness is caused by any one of the following: lack of quality or quantity of nighttime sleep; environmental disruption of the body's circadian pacemaker (e.g., work, e.g., shift work or personal obligations, such as having to get up at night for care of a sick, minor, or elderly family member), such as 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, highly probable narcolepsy), sleep apnea (e.g., obstructive sleep apnea, obstructive sleep apnea with the use of continuous positive airway pressure therapy), idiopathic hypersomnia, idiopathic excessive sleepiness, and restless legs syndrome; disorders such as clinical depression or atypical depression; tumors; head trauma; anemia; kidney failure; hypothyroidism; central nervous system injury; drug abuse; genetic vitamin deficiencies, such as biotin deficiency; and certain classes of prescription and over-the-counter medications.

[0163] In some embodiments, the compounds of the present disclosure (e.g., the compounds of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2), their pharmaceutically acceptable salts, or compositions thereof are used to treat any of the following: shift work disorder; shift work sleep disorder; and jet lag syndrome. In some embodiments, the methods and uses herein are used for the treatment of any one of the following: narcolepsy type 1, narcolepsy type 2, almost certain narcolepsy, idiopathic hypersomnia, idiopathic excessive sleepiness, hypersomnia, hypnagogic hypersomnia, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with the use of continuous positive airway pressure therapy); or disorders of consciousness such as coma; and narcolepsy syndrome with narcolepsy-like symptoms; hypnagogic hypersomnia or hypersomnia syndrome with daytime hypersomnia (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome); Parkinson's disease, Prader-Willi syndrome, depression (depression, atypical depression, major depressive disorder, treatment-resistant depression), ADHD, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with the use of continuous positive airway pressure therapy), and excessive daytime sleepiness in other arousal disorders; excessive residual sleepiness during the day in sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with the use of continuous positive airway pressure therapy); etc. Narcolepsy (e.g., narcolepsy type 1, narcolepsy type 2, almost certain narcolepsy) can be diagnosed according to generally used diagnostic criteria in the art, such as the International Classification of Sleep Disorders, 3rd edition (ICSD-3) and the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).In some embodiments, excessive sleepiness is excessive sleepiness during the day or during working hours, or excessive sleepiness or a decrease in the amount of sleep due to having to wake up at night for work (e.g., shift work) or personal obligations (e.g., caring for a sick, minor, or elderly family member). In some embodiments, the subject has a disease or disorder or symptom associated with excessive sleepiness. In some embodiments, the subject is a sleep-deprived subject, a subject with excessive sleepiness, a subject with a disrupted regular sleep cycle, or a subject in need of reducing sleepiness. In some embodiments, the present disclosure provides a method for reducing or treating excessive sleepiness. In some embodiments, excessive sleepiness is caused by narcolepsy type 1, narcolepsy type 2, or idiopathic hypersomnia. In some embodiments, excessive sleepiness is caused by obstructive sleep apnea despite the use of continuous positive airway pressure therapy (CPAP). In some embodiments, a method is provided for increasing the state of wakefulness in a subject in need of an increased state of wakefulness. In some embodiments, the orexin level in the subject is not impaired or is not partially impaired.

[0164] In some embodiments of the present disclosure, a method for the treatment of sleep disorders in a subject in need thereof (e.g., as disclosed herein), the method comprising administering to the subject a compound of the present disclosure (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2), a pharmaceutically acceptable salt thereof, or a composition thereof. In some embodiments, a compound of the present disclosure (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2), or a pharmaceutically acceptable salt thereof is used to treat a subject having a sleep disorder, to treat a sleep disorder, or to treat symptoms of a sleep disorder.

[0165] In some embodiments of the present disclosure, a method for the treatment of narcolepsy in a subject in need thereof, the method comprising administering to the subject in need thereof a compound of the present disclosure (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2), or a pharmaceutically acceptable salt thereof is used to treat a subject having narcolepsy, to treat narcolepsy, or to treat the symptoms of narcolepsy.

[0166] In some embodiments of the present disclosure, a method for the treatment of idiopathic hypersomnia (IH) in a subject in need thereof, comprising administering to the subject in need thereof a compound of the present disclosure (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure (e.g., a compound of formula (I), formula (I-1), formula (I-2), formula (IA), formula (IA-1), formula (IA-1-1), formula (IA-2), formula (IA-2-1), formula (IA-3), formula (IA-4), formula (IA-5), formula (IB), formula (IB-1), formula (IB-2), formula (IC), formula (IC-1), formula (IC-2), formula (IC-3), formula (IC-4), formula (IC-5), formula (IC-6), formula (ID), formula (ID-1), formula (ID-2), formula (IE), formula, (IF), Table 1, or Table 2), or a pharmaceutically acceptable salt thereof is used to treat a subject having IH, to treat IH, or to treat the symptoms of IH.

Examples

[0167] Although the present disclosure is generally described at present, it will be more readily understood by reference to the following examples. These examples are included only for the purpose of illustrating certain aspects and embodiments of the present disclosure and are not intended to limit the present disclosure.

[0168] The compounds of the present disclosure can be synthesized using synthetic methods known in the field of synthetic organic chemistry or modifications thereof recognized by those skilled in the art, together with the methods described below.

[0169] The preparation of the compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th. Ed., Wiley and Sons, 2006, in addition to Jerry March, Advanced Organic Chemistry, 4 th edition, John Wiley and Sons, publisher, New York, 1992, which is hereby incorporated by reference in its entirety. Abbreviations AcOH Acetic acid DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMPU N,N’-Dimethylpropyleneurea DMSO Dimethyl sulfoxide EtOAc Ethyl acetate IPA Isopropyl alcohol LDA Lithium diisopropylamide NMO N-Methylmorpholine-N-oxide TEA Triethylamine TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran

[0170] General synthesis The compounds of the present disclosure can be synthesized using the following methods. General reaction conditions are provided, and the reaction products can be purified by generally known methods including silica gel chromatography or preparative reverse-phase high-pressure liquid chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol, etc.

[0171] Analysis conditions:

[0172] Method A: · Column: Waters UPLC® BEH® C18, part number 186002352, 2.1 x 100 mm, 1.7 μm · Column temperature: 40 °C · Mobile phase A: 2 mM ammonium bicarbonate, pH 10 buffer · Mobile phase B: Acetonitrile · Injection volume: 1 μL · Gradient program: Flow rate 0.6 mL / min Time A% B% 0.00 95.00 5.00 5.30 0 100 5.80 0 100 5.82 95.00 5.00 7.00 95.00 5.00 · UV 215 nm, PDA spectrum 200 - 400 nm, step: 1 nm · MSD scan Positive: 100 - 1000, scan Positive Negative: 150 - 850, scan Neg: 100 - 1000

[0173] Method B: · Column: Phenomenex, Kinetex-XB C18, part number 00D-4498-AN, 2.1 mm × 100 mm, 1.7 μm · Column temperature: 40 °C · Mobile phase A: 0.1% formic acid in water · Mobile phase B: 0.1% formic acid in acetonitrile · Injection volume: 1 μL · Gradient program: Flow rate 0.6 mL / min Time A% B% 0.00 95 5 5.30 0 100 5.80 0 100 5.82 95 5 7.00 95 5 · UV 215 nm, PDA spectrum 200 - 400 nm, step: 1 nm · MSD scan Positive: 100 - 1000, scan Positive Negative: 150 - 850

[0174] Method C: · Column: Acquity UPLC CSH C18 (5.0 mm x 2.1 mm I.d., 1.7 μm) column · Column temperature: 40 °C · Mobile phase A: 0.1% formic acid in water · Mobile phase B: 0.1% formic acid in acetonitrile · Gradient program: Flow rate 1 mL / min Time A% B% 0.00 97.00 3.00 1.50 0.10 99.90 1.90 0.10 99.90 2.00 97.0 3.00

[0175] Method D: · Column: Kintex EVO C18 (1.7 μm, 2.1 × 50 mm) column · Column temperature: 40 °C · Mobile phase A: 10 mM aqueous ammonium bicarbonate solution, adjusted to pH 10 with NH 3 · Mobile phase B: Acetonitrile · Gradient program: Flow rate 1 mL / min Time A% B% 0.00 97.00 3.00 1.50 0.10 99.90 1.90 0.10 99.90 2.00 97.0 3.00

[0176] Synthesis of spirocyclic core

Chemical formula

[0177] Intermediate 1

Chemical formula

[0178] ​1-tert-Butyl 3-ethyl 4-oxo-5-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1,3-dicarboxylate

[0179] In a flask, 2.4 M butyllithium (49 mL, 0.117 mol) was added to a stirred solution of N-(propan-2-yl)propan-2-amine (16 mL, 0.116 mol) in anhydrous THF (58 mL) at -78 °C. The reaction was maintained at this temperature for 40 minutes. This newly prepared LDA was added via an addition funnel over 0.5 hour to a stirred solution of 1-tert-butyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (13.70 g, 53.2 mmol) and 1,3-dimethylhexahydropyrimidin-2-one (27.20 g, 0.212 mol) in anhydrous THF (154 mL) at -78 °C, and the reaction temperature did not rise above -65 °C. The solution was maintained at this temperature for 20 minutes. A solution of 1-benzyloxy-2-[4-(chloromethoxy)cyclohexyl]benzene (17.60 g, 53.2 mmol) in anhydrous THF (37 mL) was added to the reaction mixture over 20 minutes. The reaction mixture was stirred at -78 °C for 1 hour, warmed to room temperature and stirred for 2 hours. The reaction was quenched with NH 4 Cl, diluted with water (100 mL), and extracted with EtOAc (3 × 300 mL). The combined organic layers were dried over MgSO 4 and filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0 - 25% EtOAc in heptane) to give the title compound (17.50 g) as a yellow oil. (M+Na) + m / z: 574.3

[0180] Intermediate 2

Chemical Structure

[0181] tert-Butyl 3-oxo-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0182] Sodium chloride (3.50 g, 59.9 mmol) and water (15 mL) were added to a solution of Intermediate 1 (17.70 g, 32.1 mmol) in DMSO (148 mL), and the reaction mixture was heated to 125 °C for 2.5 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (2 × 50 mL), brine (50 mL), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude material. The crude material was purified by column chromatography (0 - 40% EtOAc in heptane) to give the title compound (10.00 g) as a yellow oil. [M+Na] + m / z 502.3.

[0183] Intermediate 3

Chemical formula

[0184] tert-Butyl (3E / Z)-3-(hydroxyimino)-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0185] A solution of N,N-diethylethanamine (8.0 mL, 57.4 mmol), hydroxylamine hydrochloride (1:1) (3.99 g, 57.4 mmol), and Intermediate 2 (92%, 10.00 g, 19.2 mmol) in ethanol (38.818 mL) was heated at 90 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 75 mL). The organic extract was dried over magnesium sulfate and concentrated in vacuo to give the title compound (10 g) as a yellow gum. [M+Na] + m / z = 517.3.

[0186] Intermediate 4 [Chemical]

[0187] tert-Butyl 3-nitro-2-({[(1S,4S)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0188] A solution of trifluoroacetic anhydride (7.0 mL, 50.5 mmol) in acetonitrile (36 mL) was added to a stirred solution of hydrogen peroxide-urea (1:1) (6.60 g, 70.2 mmol) in acetonitrile (36 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The resulting solution was added dropwise to a mixture of intermediate 3 (10.00 g, 20.2 mmol) and sodium hydrogen carbonate (8.50 g, 0.101 mol) in acetonitrile (36 mL) at 80 °C over 1 h. The reaction mixture was cooled to room temperature, quenched with saturated Na 2 SO 3 (50 mL), stirred for 10 min, and then extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0 - 40% EtOA in heptane) to give the title compound (6.70 g) as a yellow gum. [M+H] + m / z = 511.3.

[0189] Intermediate 5 [Chemical]

[0190] tert-Butyl-rel-(2R,3S)-3-(hydroxymethyl)-3-nitro-2-({[(1S,4S)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0191] Formaldehyde (in water) (37%, 8.8 mL, 0.118 mol) was added to Intermediate 5 (6.70 g, 13.1 mmol) and triethylamine (2.2 mL, 15.8 mmol) in THF (66 mL) at room temperature. The solution was heated to 70 °C for 18 h. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 75 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO 4 ), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0 - 60% EtOAc in heptane) to afford the title compound (5.80 g) as a yellow solid. [M+H] + m / z = 541.4

[0192] Intermediate 6

Chem.

[0193] tert-Butyl-rel-(2R,3S)-3-amino-3-(hydroxymethyl)-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0194] A suspension of Intermediate 5 (5.80 g, 10.7 mmol) and zinc (7.00 g, 0.107 mol) in acetic acid (49 mL) and ethanol (371 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was neutralized with NaHCO 3 and extracted with DCM (3 × 75 mL). The combined organic layers were dried (MgSO 4 ), concentrated under vacuum to afford the title compound (5.49 g) as a yellow oil. [M+H] + m / z 511.4.

[0195] Intermediate 7

Chem.

[0196] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0197] To a solution of Intermediate 6 (3.00 g, 5.87 mmol) in THF (25 mL) was added potassium carbonate (2.43 g, 17.6 mmol) at 0 °C, and then water (25 mL) was added. To this mixture was added chloroacetyl chloride (0.65 mL, 8.15 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h. The mixture was quenched with water and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO 4 ), filtered, and concentrated to give an oily residue. The intermediate was dissolved in DCM (53 mL) and IPA (82 mL) and cooled to 0 °C. Potassium 2-methylpropane-2-olate (2.63 g, 23.4 mmol) was added and the reaction was stirred at 0 °C for 1 h. The reaction was quenched by the addition of water (20 mL). The mixture was poured into saturated NaHCO 3 aqueous solution (30 ml). After extraction with DCM (3 × 50 mL), the combined organic extracts were washed with brine (20 mL), dried (MgSO 4 ), filtered, and concentrated to give the title compound (3.12 g) as a yellow solid. [M+H] + m / z 551.4.

[0198] Intermediate 8

Chemical formula

[0199] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0200] Intermediate 7 (1.00 g, 1.62 mmol) was dissolved in ethanol (77 mL), the atmosphere was evacuated and filled with nitrogen three times. Palladium carbon (10%) (5.0%, 344 mg, 0.161 mmol) was added, the atmosphere was evacuated and filled with hydrogen three times. The reaction mixture was stirred for 6 hours, filtered through celite, washed with EtOAc, and concentrated in vacuo to give the title compound (680 mg) as a white solid. [M+H] + m / z 461.4

Chemical Structure

[0201] Intermediate 9

Chemical Structure

[0202] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-(2-{[3-ethoxy-3-oxoprop-1-en-1-yl]oxy}phenyl)cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0203] A solution of ethyl prop-2-ynoate (98%, 44 mg, 0.44 mmol) and 1,4-diazabicyclo[2.2.2]octane (4.1 mg, 0.0366 mmol) in THF (1.68 mL) was added to a solution of Intermediate 8 (84%, 200 mg, 0.365 mmol) in THF (8.4 mL) at ℃ under a nitrogen atmosphere, and the solution was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×15 mL). The organic phase was washed with brine and dried over MgSO 4 and concentrated in vacuo to give the title compound (160 mg) as a yellow oil. [M+H] + m / z 559.4

[0204] Intermediate 10

Chemical Structure

[0205] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-[2-(3-ethoxy-3-oxopropoxy)phenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0206] Intermediate 9 (64%, 160 mg, 0.183 mmol) and ammonium formate (114 mg, 1.84 mmol) were dissolved in IPA (2.6 mL), and then palladium(2+) dihydroxide (20%, 129 mg, 0.184 mmol) was added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 5 h, cooled to room temperature, filtered through celite, washed with IPA, and concentrated in vacuo to afford the title compound (120 mg) as a yellow oil. [M+H] + m / z 561.4

[0207] Intermediate 11

Chemical Structure

[0208] 3-{2-[(1s,4s)-4-{[rel-(1R,5S)-2-[(tert-butoxy)carbonyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decan-1-yl]methoxy}cyclohexyl]phenoxy}propanoic acid

[0209] To a solution of Intermediate 10 (72%, 120 mg, 0.154 mmol) in THF (4.4 mL) and water (1.25 mL) was added 2M aqueous lithium hydroxide solution (0.77 mL, 1.54 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. The mixture was diluted with water (5 mL), neutralized to pH 7 with 1M aqueous HCl solution, and then extracted with 10% MeOH in DCM (3×10 mL). The organic layer was dried over MgSO 4 and concentrated in vacuo to afford the title compound (110 mg) as a colorless oil. [M+H] + m / z: 533.4

[0210] Intermediate 12

Chem.

[0211] 3-{2-[(1s,4s)-4-{[rel-(1R,5S)-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methoxy}cyclohexyl]phenoxy}propanoic acid

[0212] 4M hydrogen chloride in dioxane (0.20 mL, 0.805 mmol) was added to Intermediate 11 (50 mg, 0.109 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The aqueous phase was neutralized with a few drops of 1M K 2 CO 3 aqueous solution, washed with DCM (2 × 2 mL), and concentrated in vacuo to give the title compound (60 mg) as a yellow solid. [M+H] + m / z: 433.3

[0213] Example 1

Chem.

[0214] rel-(1’s,3S,16’R,19’s)-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0215] To a stirred solution of HATU (49 mg, 0.129 mmol) and DIPEA (45 μL, 0.255 mmol) in acetonitrile (40 mL) was added intermediate 12 (62%, 60 mg, 0.0860 mmol) in acetonitrile (3.6 mL) using a syringe pump over 2 h. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo to afford the crude material. The mixture was diluted with water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated to afford the crude material as a solid. The crude material was purified by basic reverse-phase column chromatography (10 - 55% acetonitrile in water (0.1% ammonia)) to afford the title compound (33 mg) as a white solid.

[0216] LCMS (Method A): [M + H] + m / z 415.3, RT 2.87 min

[0217] 1 H NMR (500 MHz, CDCl 3 ) δ 7.20 - 7.11 (m, 2H), 7.09 (dd, J = 7.5, 1.7 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.93 - 6.86 (m, 1H), 6.42 (s, 1H), 4.57 - 4.32 (m, 2H), 4.29 (d, J = 2.4 Hz, 1H), 4.29 - 4.10 (m, 3H), 4.07 - 3.95 (m, 1H), 3.83 (s, 1H), 3.78 (d, J = 11.6 Hz, 1H), 3.65 - 3.53 (m, 2H), 3.30 (d, J = 9.4 Hz, 1H), 3.18 - 3.06 (m, 1H), 2.55 - 2.36 (m, 3H), 2.37 - 2.25 (m, 1H), 2.22 - 2.06 (m, 3H), 1.88 - 1.78 (m, 1H), 1.60 - 1.50 (m, 1H), 1.51 - 1.45 (m, 1H), 1.43 - 1.30 (m, 1H).

[0218] Example 1a and 1b [Chemical formula]

[0219] Example 1a: (1’s,3S,16’R,19’s)-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0220] Example 1b: (1’s,3R,16’S,19’s)-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0221] Example 1 (33 mg) was subjected to chiral preparative purification using Waters 600, eluting with 30 / 70% v / v n-hexane / (ethanol / methanol 1:1 + 0.1% isopropylamine), Chiralpak IC (25×2.0 cm), 5 μm, flow rate 17 mL / min to obtain the title compound (peak 1, 11.1 mg, 100% ee; and peak 2, 10.9 mg, 100% ee).

[0222] Example 1a: Peak 1 (stereochemistry arbitrarily assigned to pyrrolidine)

[0223] LCMS (method C): [M+H] + m / z 415.3, RT 1.00 min.

[0224] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 30:70 n-hexane:(ethanol / methanol 1:1 + 0.1% isopropylamine)): RT 9.2 min

[0225] 1 HNMR (500 MHz, CDCl 3 ) δ 7.21 - 7.13 (m, 1H), 7.09 (dd, J=7.5, 1.6 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.89 (td, J=7.4, 1.0 Hz, 1H), 6.26 (s, 1H), 4.47 - 4.44 (m, 1H), 4.45 - 4.42 (m, 1H), 4.29 (d, J=2.2 Hz, 1H), 4.25 (d, J=16.9 Hz, 1H), 4.26 - 4.21 (m, 1 H), 4.18 (d, J=16.9 Hz, 1H), 4.01 (td, J=10.0, 3.2 Hz, 1H), 3.83 (br s, 1H), 3.78 (d, J=11.7 Hz, 1H), 3.59 (d, J=11.7 Hz, 1H), 3.59 - 3.53 (m, 1H), 3.30 (d, J=9.5 Hz, 1H), 3.12 (ddd, J=14.2, 12.2, 4.2 Hz, 1H), 2.50 - 2.40 (m, 2H), 2.42 - 2.36 (m, 1H), 2.30 (qd, J=12.8, 3.7 Hz, 1H), 2.22 - 2.16 (m, 1H), 2.19 - 2.11 (m, 1H), 2.15 - 2.08 (m, 1H), 1.84 - 1.77 (m, 1H), 1.60 - 1.51 (m, 1H), 1.48 (br d, J=12.2 Hz, 1H), 1.43 - 1.30 (m, 2H).

[0226] Example 1b: Peak 2 (stereochemistry arbitrarily assigned to pyrrolidine)

[0227] LCMS (Method C): [M+H] + m / z 415.3, RT 1.00 min.

[0228] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 30:70 n - hexane:(ethanol / methanol 1:1 + 0.1% isopropylamine)): RT 15.9 min

[0229] 1 HNMR (500 MHz, CDCl 3 ) δ 7.21 - 7.13 (m, 1H), 7.09 (dd, J = 7.5, 1.6 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.89 (td, J = 7.4, 1.0 Hz, 1H), 6.26 (s, 1H), 4.47 - 4.44 (m, 1H), 4.45 - 4.42 (m, 1H), 4.29 (d, J = 2.2 Hz, 1H), 4.25 (d, J = 16.9 Hz, 1H), 4.26 - 4.21 (m, 1 H), 4.18 (d, J = 16.9 Hz, 1H), 4.01 (td, J = 10.0, 3.2 Hz, 1H), 3.83 (br s, 1H), 3.78 (d, J = 11.7 Hz, 1H), 3.59 (d, J = 11.7 Hz, 1H), 3.59 - 3.53 (m, 1H), 3.30 (d, J = 9.5 Hz, 1H), 3.12 (ddd, J = 14.2, 12.2, 4.2 Hz, 1H), 2.50 - 2.40 (m, 2H), 2.42 - 2.36 (m, 1H), 2.30 (qd, J = 12.8, 3.7 Hz, 1H), 2.22 - 2.16 (m, 1H), 2.19 - 2.11 (m, 1H), 2.15 - 2.08 (m, 1H), 1.84 - 1.77 (m, 1H), 1.60 - 1.51 (m, 1H), 1.48 (br d, J = 12.2 Hz, 1H), 1.43 - 1.30 (m, 2H).

Chem.

[0230] Intermediate 13

Chem.

[0231] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-[2-(4-ethoxy-4-oxobutoxy)phenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0232] To a solution of Intermediate 8 (200 mg, 0.434 mmol) and ethyl 4-bromobutanoate (0.12 mL, 0.866 mmol) in acetone (2.7 mL) was added potassium carbonate (180 mg, 1.30 mmol), and the solution was heated at 50 °C for 24 h. The solid was removed by filtration, the filtrate was concentrated in vacuo, suspended in water (5 mL), and extracted with DCM (3 × 5 mL). The solvent was removed in vacuo to afford the title compound (202 mg) as a colorless oil. [M+H] + m / z 575.4

[0233] Intermediate 14

Chemical Structure

[0234] 4-{2-[(1s,4s)-4-{[rel-(1R,5S)-2-[(tert-butoxy)carbonyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decan-1-yl]methoxy}cyclohexyl]phenoxy}butanoic acid

[0235] To a solution of Intermediate 13 (64%, 202 mg, 0.225 mmol) in THF (6.4 mL) and water (1.8 mL) was added 2 M aqueous lithium hydroxide (1.1 mL, 2.25 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with water (5 mL), neutralized to pH 7 with 1 M aqueous HCl, and the aqueous phase was extracted with 10% methanol in DCM (3 × 10 mL). The combined organic layers were dried (MgSO 4 ) and concentrated in vacuo to afford the title compound (200 mg) as a colorless oil. [M+H] +m / z: 547.4

[0236] Intermediate 15

Chem.

[0237] 4-{2-[(1s,4s)-4-{[rel-(1R,5S)-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-1-yl]methoxy}cyclohexyl]phenoxy}butanoic acid

[0238] 4M hydrogen chloride (0.45 mL, 1.80 mmol) was added to Intermediate 14 (50 mg, 0.109 mmol) at room temperature and the reaction mixture was stirred for 30 minutes. The aqueous phase was washed with DCM (2 × 2 mL) and concentrated in vacuo to give the title compound (80 mg) as a yellow solid. [M+H] + 447.4

[0239] Example 2

Chem.

[0240] rel-(1’s,3S,17’R,20’s)-8’,19’-dioxa-13’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2,7 .0 13,17 tetracosane]-2’(7’),3’,5’-triene-5,12’-dione

[0241] To a stirred solution of HATU (75 mg, 0.199 mmol) and DIPEA (68 μL, 0.391 mmol) in acetonitrile (63.5 mL) was added Intermediate 15 (74%, 80 mg, 0.133 mmol) in acetonitrile (2.6 mL) using a syringe pump over 2 hours. The resulting solution was stirred for 1 hour. The reaction mixture was concentrated in vacuo to give a crude material. The mixture was diluted with water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO 4) It was filtered, concentrated to obtain a solid residue. The crude substance was purified by basic reverse-phase column chromatography (10 - 50% acetonitrile (0.1% ammonia) in water) to obtain the title compound (31 mg) as a white solid.

[0242] LCMS (Method A): [M + H] + m / z 429.3, RT 2.98 min

[0243] 1 H NMR (500 MHz, CDCl 3 ) δ 7.77 (s, 1H), 7.19 - 7.12 (m, 1H), 7.08 (dd, J = 7.4, 1.6 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 4.38 (dd, J = 10.7, 2.7 Hz, 1H), 4.28 (d, J = 17.1 Hz, 1H), 4.23 - 4.18 (m, 1H), 4.13 (d, J = 17.1 Hz, 1H), 4.06 - 3.92 (m, 1H), 3.86 - 3.77 (m, 1H), 3.77 - 3.72 (m, 1H), 3.73 - 3.69 (m, 1H), 3.64 (dd, J = 9.4, 2.9 Hz, 1H), 3.58 (s, 1H), 3.57 - 3.50 (m, 1H), 3.49 - 3.45 (m, 1H), 3.39 (d, J = 11.8 Hz, 1H), 2.56 - 2.48 (m, 3H), 2.40 (ddd, J = 16.4, 9.6, 5.1 Hz, 1H), 2.26 - 2.12 (m, 1H), 2.11 - 2.04 (m, 2H), 2.03 - 1.89 (m, 3H), 1.51 - 1.40 (m, 4H).

[0244] Example 3

Chemical Structure

[0245] rel-(1’s,3S,15’R,18’s)-8’,17’-dioxa-11’-azaspiro[morpholine-3,14’-tetracyclo[16.2.2.0 2 , 7 .0 11 , 15 docosane]-2’(7’),3’,5’-triene-5,10’-dione

[0246] Example 3 was prepared according to the procedure described for Example 2 using Intermediate 8, and the title compound (2.4 mg) was obtained as an off-white solid.

[0247] LCMS (Method A): [M+H] + m / z 401.2, RT 2.88 min.

[0248] 1 H NMR (500 MHz, CDCl 3 ) δ 7.23 - 7.16 (m, 1H), 7.10 (dd, J = 7.5, 1.7 Hz, 1H), 6.93 (td, J = 7.4, 1.1 Hz, 1H), 6.78 (dd, J = 8.0, 0.9 Hz, 1H), 6.38 (s, 1H), 5.00 (d, J = 10.4 Hz, 1H), 4.42 - 4.37 (m, 1H), 4.36 (dd, J = 10.2, 3.4 Hz, 1H), 4.33 - 4.25 (m, 3H), 4.20 (d, J = 16.7 Hz, 1H), 3.87 (s, 1H), 3.83 (d, J = 11.7 Hz, 1H), 3.64 (d, J = 11.7 Hz, 1H), 3.62 - 3.53 (m, 1H), 3.34 (d, J = 9.8 Hz, 1H), 2.62 - 2.54 (m, 1H), 2.54 - 2.48 (m, 1H), 2.49 - 2.39 (m, 1H), 2.21 - 2.12 (m, 2H), 2.11 - 2.00 (m, 1H), 1.87 - 1.80 (m, 1H), 1.58 - 1.49 (m, 2H), 1.44 - 1.32 (m, 2H). [Chemistry]

[0249] Intermediate 16 [Chemistry]

[0250] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-(2-{[4-ethoxy-4-oxobuta-2-en-2-yl]oxy}phenyl)cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0251] To a solution of Intermediate 8 (84%, 200 mg, 0.365 mmol) in acetonitrile (3 mL) was added 1,4-diazabicyclo[2.2.2]octane (41 mg, 0.365 mmol) at room temperature under a nitrogen atmosphere, and the solution was heated to 70 °C. Ethyl but-2-ynoate (0.047 mL, 0.401 mmol) was added to the reaction mixture, and the solution was stirred at 70 °C for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 15 mL). The organic phase was washed with brine and dried over MgSO 4 and concentrated. The crude material was purified by column chromatography (0 - 100% EtOAc in heptane) to give the title compound (198 mg) as a yellow oil. [M+H] + m / z 573.4

[0252] Intermediate 17 [Chemistry]

[0253] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-{2-[(4-ethoxy-4-oxobutan-2-yl)oxy]phenyl}cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0254] Intermediate 16 (89%, 198 mg, 0.308 mmol) and ammonium formate (191 mg, 3.08 mmol) were dissolved in IPA (4.4 mL). Palladium(II) dihydroxide (20%, 216 mg, 0.308 mmol) was added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 5 h, filtered through celite, washed with isopropanol, and concentrated in vacuo to afford the title compound (168 mg) as a yellow oil. [M+H] + m / z 575.3

[0255] Intermediate 18

Chemical formula

[0256] 3-{2-[(1s,4s)-4-{[rel-(1R,5S)-2-[(tert-butoxy)carbonyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methoxy}cyclohexyl]phenoxy}butanoic acid

[0257] To a solution of Intermediate 17 (76%, 168 mg, 0.222 mmol) in THF (6.4 mL) and water (1.8 mL) was added 2M aqueous lithium hydroxide solution (5.6 mL, 11.1 mmol) at room temperature. The mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (5 mL), washed with DCM (2×3 mL), neutralized to pH 7 with 1M aqueous HCl, and the aqueous layer was extracted with 10% MeOH in DCM (3×10 mL). The combined organic layers were dried (MgSO 4 ) and concentrated in vacuo to afford the title compound (90 mg) as a colorless oil. [M+H] + m / z 547.4

[0258] Intermediate 19

Chemical formula

[0259] 3-{2-[(1s,4s)-4-{[rel-(1R,5S)-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methoxy}cyclohexyl]phenoxy}butanoic acid

[0260] 4M hydrogen chloride in dioxane (2.0 mL, 7.82 mmol) was added to Intermediate 18 (90 mg, 0.109 mmol) at room temperature and the reaction was stirred for 30 minutes. The aqueous phase was washed with DCM (2 x 2 mL) and concentrated in vacuo to afford the title compound (74 mg) as a yellow solid. [M+H] + m / z 447.3

[0261] Example 4

Chemical Structure

[0262] rel-(1’s,3S,16’R,19’s)-9’-methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0263] To a stirred solution of HATU (76 mg, 0.200 mmol) and DIPEA (69 μL, 0.395 mmol) in acetonitrile (33 mL) was added Intermediate 19 (80%, 74 mg, 0.133 mmol) in acetonitrile (2.9 mL) using a syringe pump over 2 hours. The resulting solution was stirred for 1 hour. The reaction mixture was concentrated in vacuo to give a crude material. The mixture was diluted with water and extracted with DCM (3 x 5 mL). The combined organic extracts were dried (MgSO 4 )), filtered and concentrated to give a solid residue. The crude material was purified by basic reverse phase column chromatography (10 - 60% acetonitrile in water (0.1% ammonia)) to afford the title compound (26 mg) as a white solid. [M+H] + m / z 429.3

[0264] LCMS (Method A): [M+H] + m / z 429.3, RT 2.98 minutes

[0265] 1 H NMR (400 MHz, CDCl 3 ) δ 7.08 - 6.98 (m, 2H), 6.88 - 6.76 (m, 2H), 6.42 (s, 1H), 4.69 - 4.53 (m, 1H), 4.40 (dd, J = 9.6, 3.3 Hz, 1H), 4.20 - 4.06 (m, 3H), 3.74 (s, 1H), 3.73 - 3.64 (m, 1H), 3.52 (d, J = 11.7 Hz, 1H), 3.24 - 3.16 (m, 1H), 2.99 - 2.83 (m, 1H), 2.46 - 2.33 (m, 3H), 2.32 - 2.21 (m, 2H), 2.17 - 2.07 (m, 2H), 2.06 - 1.95 (m, 2H), 1.78 - 1.68 (m, 3H), 1.41 - 1.33 (m, 5H).

[0266] Examples 4a, 4b, 4c and 4d

Chemical Structure

[0267] Example 4a: (1’s,3R,9’S,16’S,19’s)-9’-Methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0268] Example 4b: (1’s,3S,9’S,16’R,19’s)-9’-Methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 ,7 .0 12 , 16 Tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0269] Example 4c: (1’s,3S,9’R,16’R,19’s)-9’-Methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 Tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0270] Example 4d: (1’s,3R,9’R,16’S,19’s)-9’-Methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 Tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0271] Example 4 (24 mg) was subjected to chiral preparative purification using Waters 600, eluting with 50 / 50% v / v n-hexane / ethanol + 0.1% isopropylamine, Chiralpak AD-H (25 × 2.0 cm), 5 μm, flow rate 17 mL / min to give the title compound (peak 1, 1 mg; peak 2, 3.7 mg, 99% ee; peak 3, 3.2 mg; peak 4, 4.5 mg, 100% ee).

[0272] Example 4a: Peak 1 (stereochemistry arbitrarily assigned at the pyrrolidine and methyl centers)

[0273] LCMS (method C): [M+H]+ m / z 429.3, RT 0.96, 0.99 min.

[0274] Chiral analysis (Chiralpak AD-H, 25 × 0.46 cm, 5 μm, 50:50 n-hexane:(ethanol + 0.1% isopropylamine): RT 9.0 min

[0275] 1 H NMR (400 MHz, CDCl 3 ) δ 7.21 - 7.14 (m, 1H), 7.09 (d, J = 7.5 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.22 (s, 1H), 5.09 - 4.97 (m, 1H), 4.35 (br d, J = 9.4 Hz, 1H), 4.32 (s, 1H), 4.29 - 4.12 (m, 2H), 4.03 (br t, J = 10.0 Hz, 1H), 3.83 (br s, 1H), 3.80 - 3.74 (m, 1H), 3.56 (d, J = 11.6 Hz, 1H), 3.55 - 3.46 (m, 1H), 3.37 - 3.31 (m, 1H), 3.24 (dd, J = 13.6, 5.3 Hz, 1H), 2.57 - 2.41 (m, 2H), 2.34 (d, J = 13.6 Hz, 1H), 2.15 - 2.00 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H), 2.25 - 1.15 (m, 8H).

[0276] Example 4b: Peak 2 (stereochemistry arbitrarily assigned at the pyrrolidine and methyl centers))

[0277] LCMS (Method C): [M + H]+ m / z 429.3, RT 0.97 min.

[0278] Chiral analysis (Chiralpak AD - H, 25×0.46 cm, 5 μm, 50:50 n - hexane:(ethanol + 0.1% isopropylamine): RT 18.4 min

[0279] 1 HNMR (400 MHz, CDCl 3) δ 7.16 - 7.05 (m, 2H), 6.96 - 6.86 (m, 2H), 6.47 - 6.36 (m, 1H), 4.75 - 4.63 (m, 1H), 4.49 (dd, J=9.6, 3.1 Hz, 1H), 4.29 - 4.15 (m, 3H), 4.09 (td, J=9.8, 3.9 Hz, 1H), 3.82 (br s, 1H), 3.75 (d, J=11.6 Hz, 1H), 3.61 (d, J=11.6 Hz, 1H), 3.58 - 3.48 (m, 1H), 3.28 (d, J=9.6 Hz, 1H), 2.98 (dd, J=14.5, 9.9 Hz, 1H), 2.54 - 2.41 (m, 2H), 2.40 - 2.27 (m, 2H), 2.24 - 2.16 (m, 1H), 2.09 (td, J=8.3, 3.7 Hz, 1H), 2.08 - 1.96 (m, 1H), 1.82 (br d, J=13.6 Hz, 1H), 1.59 - 1.47 (m, 1H), 1.45 (d, J=5.9 Hz, 3H), 1.50 - 1.39 (m, 2H), 1.42 - 1.23 (m, 1H).

[0280] Example 4c: Peak 3 (stereochemistry arbitrarily assigned at the pyrrolidine and methyl centers))

[0281] LCMS (Method C): [M+H]+ m / z 429.3, RT 0.96, 0.99 min.

[0282] Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 50:50 n-hexane:(ethanol + 0.1% isopropylamine): RT 21.8 min

[0283] 1 HNMR (400 MHz, CDCl 3) δ 7.21 - 7.14 (m, 1H), 7.09 (d, J=7.5 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.22 (s, 1H), 5.09 - 4.97 (m, 1H), 4.35 (br d, J=9.4 Hz, 1H), 4.32 (s, 1H), 4.29 - 4.12 (m, 2H), 4.03 (br t, J=10.0 Hz, 1H), 3.83 (br s, 1H), 3.80 - 3.74 (m, 1H), 3.56 (d, J=11.6 Hz, 1H), 3.55 - 3.46 (m, 1H), 3.37 - 3.31 (m, 1H), 3.24 (dd, J=13.6, 5.3 Hz, 1H), 2.57 - 2.41 (m, 2H), 2.34 (d, J=13.6 Hz, 1H), 2.15 - 2.00 (m, 1H), 1.44 (d, J=6.4 Hz, 3H), 2.25 - 1.15 (m, 8H).

[0284] Example 4d: Peak 4 (stereochemistry arbitrarily assigned at the pyrrolidine and methyl centers))

[0285] LCMS (Method C): [M+H]+ m / z 429.3, RT 0.97 min.

[0286] Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 50:50 n-hexane:(ethanol + 0.1% isopropylamine): RT 27.4 min

[0287] 1 H NMR (400 MHz, CDCl 3) δ 7.16 - 7.05 (m, 2H), 6.96 - 6.86 (m, 2H), 6.47 - 6.36 (m, 1H), 4.75 - 4.63 (m, 1H), 4.49 (dd, J=9.6, 3.1 Hz, 1H), 4.29 - 4.15 (m, 3H), 4.09 (td, J=9.8, 3.9 Hz, 1H), 3.82 (br s, 1H), 3.75 (d, J=11.6 Hz, 1H), 3.61 (d, J=11.6 Hz, 1H), 3.58 - 3.48 (m, 1H), 3.28 (d, J=9.6 Hz, 1H), 2.98 (dd, J=14.5, 9.9 Hz, 1H), 2.54 - 2.41 (m, 2H), 2.40 - 2.27 (m, 2H), 2.24 - 2.16 (m, 1H), 2.09 (td, J=8.3, 3.7 Hz, 1H), 2.08 - 1.96 (m, 1H), 1.82 (br d, J=13.6 Hz, 1H), 1.59 - 1.47 (m, 1H), 1.45 (d, J=5.9 Hz, 3H), 1.50 - 1.39 (m, 2H), 1.42 - 1.23 (m, 1H). [Chemical formula]

[0288] Intermediate 20 [Chemical formula]

[0289] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-[2-(3-methoxy-2-methylidene-3-oxopropoxy)phenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0290] A solution of intermediate 8 (200 mg, 0.434 mmol) and methyl 2-(bromomethyl)prop-2-enoate (98%, 0.080 mL, 0.651 mmol) in THF (2.5 mL) was added with potassium carbonate (181 mg, 1.31 mmol), and the solution was stirred at room temperature overnight. The reaction mixture was heated to 60 °C and stirred at that temperature for 5 hours. The reaction mixture was cooled to room temperature, the solid was filtered off, the filtrate was concentrated in vacuo, suspended in water (5 mL), and extracted with DCM (3 × 5 mL). The solvent was removed in vacuo to obtain the crude material. The crude material was purified by silica gel column chromatography (0 - 100% EtOAc in heptane) to give the title compound (200 mg) as a colorless oil. [M+H] + m / z = 559.4

[0291] Intermediate 21

Chemical Structure

[0292] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-[2-(3-methoxy-2-methyl-3-oxopropoxy)phenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0293] Intermediate 20 (200 mg, 0.358 mmol) was dissolved in ethanol (15 mL), the atmosphere was evacuated and filled with nitrogen three times. Palladium on carbon (10%, 38 mg, 0.0358 mmol) was added, the atmosphere was evacuated and filled with hydrogen three times. The reaction mixture was stirred for 5 hours, then filtered through celite, washed with EtOAc, and concentrated in vacuo to give the title compound (200 mg) as a colorless oil. [M+H] + m / z = 561.4

[0294] Intermediate 22

Chemical Structure

[0295] 2-Methyl-3-{2-[(1s,4s)-4-{[rel-(1R,5S)-2-[(tert-butoxy)carbonyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decan-1-yl]methoxy}cyclohexyl]phenoxy}propanoic acid

[0296] To a solution of Intermediate 21 (200 mg, 0.357 mmol) in THF (10 mL) and water (3 mL) was added 2M aqueous lithium hydroxide (8.9 mL, 17.8 mmol) at room temperature. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water (5 mL), neutralized to pH 7 with 1M HCL, and the aqueous phase was extracted with 10% MeOH in DCM (3×10 mL). The combined organic layers were dried (MgSO 4 ), concentrated in vacuo to afford the title compound (200 mg) as a colorless oil. [M+H] + m / z = 547.4

[0297] Intermediate 23

Chemical formula

[0298] 2-Methyl-3-{2-[(1s,4s)-4-{[rel-(1R,5S)-7-oxo-9-oxa-2,6-diazaspiro[4.5]decan-1-yl]methoxy}cyclohexyl]phenoxy}propanoic acid

[0299] 4M hydrogen chloride in dioxane (0.37 mL, 1.46 mmol) was added to Intermediate 22 (200 mg, 0.366 mmol) at room temperature and the reaction was stirred for 30 min. The aqueous phase was neutralized with a few drops of K 2 CO 3 (1M), washed with DCM (2×2 mL), and concentrated in vacuo to afford the title compound (200 mg) as an off-white solid. [M+H] + m / z = 447.3

[0300] Example 5

Chemical formula

[0301] (1’S,3S,16’R,19’S)-10’-Methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2,7 .0 12,16 tricosan]-2’(7’),3’,5’-triene-5,11’-dione

[0302] To a stirred solution of HATU (255 mg, 0.671 mmol) and DIPEA (232 μL, 1.33 mmol) in acetonitrile (112 mL) was added intermediate 22 (200 mg, 0.448 mmol) in acetonitrile (9.8 mL) using a syringe pump over 2 hours. The resulting solution was stirred for 1 hour. The reaction mixture was concentrated in vacuo to give a crude material. The mixture was diluted with water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO 4 ) and filtered and concentrated to give a solid residue. The crude material was purified by basic reverse phase column chromatography (10 - 50% acetonitrile in water (0.1% ammonia)) to give the title compound (18 mg) as a white solid.

[0303] LCMS (Method A): [M + H] + m / z 429.3, RT 3.12 and 3.17 min

[0304] 1 H NMR (500 MHz, CDCl 3) δ 7.17 - 6.76 (m, 4H), 6.18 (s, 1H), 4.72 - 4.42 (m, 1.5H), 4.35 - 4.14 (m, 3H), 4.03 - 3.90 (m, 1H), 3.87 - 3.80 (m, 1.5H), 3.75 (t, J = 11.5 Hz, 1H), 3.70 - 3.59 (m, 1H), 3.60 - 3.40 (m, 3H), 3.31 - 3.19 (m, 1H), 2.59 - 2.25 (m, 3H), 2.22 - 1.74 (m, 4H), 1.50 - 1.24 (m, 4H), 1.16 (dd, J = 20.8, 7.1 Hz, 3H).

[0305] Examples 5a, 5b and 5c [Chemical formula]

[0306] Example 5a: (1’s,3S,10’R,16’R,19’s)-10’-Methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0307] Example 5b: (1’s,3R,10’S,16’S,19’s)-10’-Methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0308] Example 5c: (1’s,3R,10’R,16’S,19’s)-10’-Methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.02 , 7 .0 12 , 16 Tricosane]-2’(7’),3’,5’-triene-5,11’-dione and (1’s,3S,10’S,16’R,19’s)-10’-methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 Tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0309] Example 5 (16 mg) was subjected to chiral preparative purification using Waters 600, eluting with 55 / 45% v / v n-hexane / (ethanol + 0.1% isopropylamine), Chiralpak IC (25×2.0 cm), 5 μm, flow rate 17 mL / min to obtain the title compound (Peak 1, 3.8 mg, 100% ee; Peak 2, 3.45 mg, 100% ee; Peak 3, 8 mg).

[0310] Example 5a Peak 1 (stereochemistry is arbitrarily assigned); 1 H NMR (500 MHz, CDCl 3) δ 7.17 - 7.10 (m, 1H), 7.03 (dd, J=7.3, 1.2 Hz, 1H), 6.86 - 6.76 (m, 3H), 4.67 (dd, J=10.2, 7.8 Hz, 1H), 4.47 (dd, J=9.7, 2.0 Hz, 1H), 4.35 - 4.28 (m, 1H), 4.21 - 4.14 (m, 1H), 3.90 - 3.82 (m, 1H), 3.81 (dd, J=9.1, 2.1 Hz, 1H), 3.74 (d, J=11.9 Hz, 1H), 3.68 (br s, 1H), 3.62 (dd, J=7.6, 2.8 Hz, 1H), 3.60 - 3.53 (m, 1H), 3.52 - 3.49 (m, 1H), 3.48 - 3.43 (m, 1H), 3.43 - 3.38 (m, 1H), 2.61 - 2.44 (m, 1H), 2.11 - 1.94 (m, 2H), 2.70 - 1.21 (m, 8H), 1.15 (d, J=7.3 Hz, 3H).

[0311] LCMS (Method C): [M+H]+ m / z 429.2, RT 0.98 min.

[0312] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 55:45 n-hexane (ethanol + 0.1% isopropylamine)): RT 6.3 min

[0313] Example 5b Peak 2 (stereochemistry is arbitrarily assigned); 1 H NMR (500 MHz, CDCl 3) δ 7.17 - 7.10 (m, 1H), 7.03 (dd, J=7.3, 1.2 Hz, 1H), 6.86 - 6.76 (m, 3H), 4.67 (dd, J=10.2, 7.8 Hz, 1H), 4.47 (dd, J=9.7, 2.0 Hz, 1H), 4.35 - 4.28 (m, 1H), 4.21 - 4.14 (m, 1H), 3.90 - 3.82 (m, 1H), 3.81 (dd, J=9.1, 2.1 Hz, 1H), 3.74 (d, J=11.9 Hz, 1H), 3.68 (br s, 1H), 3.62 (dd, J=7.6, 2.8 Hz, 1H), 3.60 - 3.53 (m, 1H), 3.52 - 3.49 (m, 1H), 3.48 - 3.43 (m, 1H), 3.43 - 3.38 (m, 1H), 2.61 - 2.44 (m, 1H), 2.11 - 1.94 (m, 2H), 2.70 - 1.21 (m, 8H), 1.15 (d, J=7.3 Hz, 3H).

[0314] LCMS (Method C): [M+H] + m / z 429.2, RT 0.98 min.

[0315] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 55:45 n - hexane: (ethanol + 0.1% isopropylamine)): RT 8.8 min

[0316] Example 5c Peak 3 / Peak 4 (stereochemistry is arbitrarily assigned); 1 H NMR (500 MHz, CDCl 3) δ 7.18 - 7.13 (m, 1H), 7.10 - 7.05 (m, 1H), 6.97 (d, J=8.1 Hz, 1H), 6.87 (t, J=7.3 Hz, 1H), 6.27 (s, 1H), 4.48 (dd, J=9.5, 2.8 Hz, 1H), 4.29 - 4.22 (m, 2H), 4.21 - 4.13 (m, 2H), 4.04 - 3.92 (m, 2H), 3.88 - 3.81 (m, 1H), 3.77 (d, J=11.7 Hz, 1H), 3.59 (d, J=11.7 Hz, 1H), 3.57 - 3.51 (m, 1H), 3.30 (d, J=9.5 Hz, 1H), 3.23 (ddd, J=10.8, 6.9, 4.2 Hz, 1H), 2.52 - 2.28 (m, 2H), 2.24 - 2.08 (m, 1H), 2.57 - 1.27 (m, 8H), 1.19 (d, J=7.0 Hz, 3H).

[0317] LCMS (Method C): [M+H] + m / z 429.2, RT 0.99 min.

[0318] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 55:45 n - hexane: (ethanol + 0.1% isopropylamine)): RT 13.3, 13.8 min

Chem.

[0319] Intermediate 24

Chem.

[0320] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-(2-{[(2E)-4-ethoxy-1,1,1-trifluoro-4-oxobuta-2-en-2-yl]oxy}phenyl)cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0321] To a solution of intermediate 8 (78%, 125 mg, 0.212 mmol) in acetonitrile (1.74 mL) was added 1,4-diazabicyclo[2.2.2]octane (24 μL, 0.214 mmol) and ethyl 4,4,4-trifluorobut-2-inoate (36 μL, 0.253 mmol) at room temperature under a nitrogen atmosphere, and the solution was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2 × 5 mL). The organic phase was washed with brine and dried over MgSO 4 and concentrated in vacuo to afford the title compound (140 mg) as a yellow oil. [M+H] + m / z 627.5

[0322] Intermediate 25

Chemical formula

[0323] 4,4,4-Trifluoro-3-{2-[(1s,4s)-4-{[rel-(1R,5S)-2-[(tert-butoxy)carbonyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-1-yl]methoxy}cyclohexyl]phenoxy}but-2-enoic acid

[0324] To a solution of intermediate 24 (82%, 140 mg, 0.183 mmol) in THF (5.2 mL) and water (1.5 mL) was added 2 M aqueous lithium hydroxide (4.6 mL, 9.16 mmol) at room temperature. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (5 mL), neutralized to pH 7 with 1 M HCl, and the aqueous phase was extracted with 10% MeOH in DCM (3 × 10 mL). The combined organic layers were dried (MgSO 4) Concentrated in vacuo to afford the title compound (130 mg) as a white oil. [M+Na] + 621.2

[0325] Intermediate 26

Chem.

[0326] 4,4,4-Trifluoro-3-{2-[(1s,4s)-4-{[rel-(1R,5S)-2-[(tert-butoxy)carbonyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methoxy}cyclohexyl]phenoxy}butanoic acid

[0327] Intermediate 25 (78%, 130 mg, 0.169 mmol) was dissolved in ethanol (32 mL), the atmosphere was evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 90 mg, 0.0847 mmol) was added, the atmosphere was evacuated and backfilled with hydrogen three times. The reaction mixture was stirred overnight, then filtered through Celite, washed with EtOAc and concentrated in vacuo to afford (100 mg) as a colorless oil. [M+H] + m / z 601.35

[0328] Intermediate 27

Chem.

[0329] 4,4,4-Trifluoro-3-{2-[(1s,4s)-4-{[rel-(1R,5S)-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methoxy}cyclohexyl]phenoxy}butanoic acid

[0330] 4M Hydrogen chloride in dioxane (1.8 mL, 7.16 mmol) was added to Intermediate 26 (86%, 100 mg, 0.143 mmol) at room temperature and the reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo to afford the title compound (97 mg) as a yellow solid. [M+H] +m / z 501.3

[0331] Example 6 [Chemical formula]

[0332] rel-(1’S,3S,16’R,19’S)-9’-(trifluoromethyl)-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0333] To a stirred solution of HATU (82 mg, 0.216 mmol) and DIPEA (74 μL, 0.426 mmol) in acetonitrile (36 mL) was added intermediate 28 (72 mg, 0.144 mmol) in acetonitrile (3.1 mL) using a syringe pump over 2 h. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo to give a crude material. The mixture was diluted with water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated to give a solid residue. The crude material was purified by basic reverse-phase column chromatography (10 - 65% acetonitrile in water (0.1% ammonia)) to give a diastereomeric mixture (1:1) of the title compound (38 mg) as a white solid.

[0334] LCMS (Method A): [M + H] + m / z 483.3, RT = 3.35 and 3.39 min.

[0335] Isomer 1:1H NMR (500 MHz, CDCl 3) δ 8.09 (s, 1H), 7.17 - 7.11 (m, 1H), 7.11 - 7.03 (m, 1H), 7.02 - 6.94 (m, 1H), 6.89 - 6.83 (m, 1H), 5.65 - 5.30 (m, 1H), 4.30 - 4.10 (m, 3H), 4.03 - 3.92 (m, 1H), 3.65 - 3.59 (m, 3H), 3.58 - 3.53 (m, 1H), 3.43 - 3.33 (m, 2H), 2.63 (d, J = 15.7 Hz, 1H), 2.41 - 2.30 (m, 2H), 2.18 (d, J = 14.6 Hz, 1H), 2.11 - 2.03 (m, 2H), 1.99 - 1.77 (m, 3H), 1.62 - 1.25 (m, 4H).

[0336] Isomer 2: 1H NMR (500 MHz, CDCl 3 ) δ 7.17 - 7.11 (m, 2H), 7.11 - 7.03 (m, 1H), 7.02 - 6.94 (m, 1H), 6.89 - 6.83 (m, 1H), 5.07 - 4.95 (m, 1H), 4.50 - 4.42 (m, 2H), 4.31 - 4.08 (m, 3H), 3.83 - 3.79 (m, 2H), 3.76 (d, J = 11.5 Hz, 2H), 3.70 (d, J = 11.8 Hz, 1H), 3.29 (d, J = 9.5 Hz, 1H), 3.21 - 3.11 (m, 1H), 3.05 - 2.89 (m, 1H), 2.83 - 2.74 (m, 1H), 2.58 - 2.49 (m, 2H), 1.98 - 1.75 (m, 3H), 1.65 - 1.24 (m, 4H).

[0337] Example 7 [Chemical formula]

[0338] Rel-(1’s,15’S,16’R,19’s)-Dispiro[cyclopropane-1,10’-[8,18]dioxa-

[12] azatetracyclo[17.2.2.0 2,7 .0 12,16 tricosan-15’,3”-morpholine]-2’(7’),3’,5’-triene-5”,11’-dione

[0339] Example 7 was prepared using Intermediate 8 according to the procedure described for Example 2, and the title compound (28 mg) was obtained as a white solid.

[0340] LCMS (Method A): [M+H] + m / z 441.3, RT 3.14 min.

[0341] 1 H NMR (500 MHz, CDCl 3 ) δ 7.18 - 7.12 (m, 1H), 7.10 (dd, J = 7.5, 1.5 Hz, 1H), 6.97 - 6.89 (m, 2H), 6.36 (s, 1H), 4.45 (dd, J = 9.8, 2.1 Hz, 1H), 4.38 (td, J = 10.5, 2.6 Hz, 1H), 4.33 (d, J = 10.2 Hz, 1H), 4.26 -4.21 (m, 2H), 4.16 (d, J = 16.7 Hz, 1H), 3.81 (s, 1H), 3.72 - 3.64 (m, 2H), 3.62 (d, J = 10.2 Hz, 1H), 3.55 (d, J = 11.7 Hz, 1H), 3.31 (d, J = 9.6 Hz, 1H), 2.54 - 2.40 (m, 2H), 2.34 (qd, J = 13.1, 3.3 Hz, 1H), 2.25 - 2.18 (m, 1H), 2.13 - 2.01 (m, 2H), 1.86 - 1.79 (m, 1H), 1.56 - 1.41 (m, 3H), 1.37 - 1.24 (m, 1H), 1.20 - 1.06 (m, 3H), 0.76 - 0.66 (m, 1H).

Chem.

[0342] Intermediate 28

Chem.

[0343] tert-Butyl-rel-(1R,5S)-8-fluoro-7-oxo-1-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0344] A solution of 2-chloro-2-fluoro-acetyl chloride (64 mg, 0.489 mmol) in DCM (4.7 mL) was added to a solution of Intermediate 6 (91%, 250 mg, 0.446 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (0.30 mL, 1.71 mmol) in DCM (4.7 mL) at 0 °C, and the mixture was stirred for 0.5 h. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography (0 - 60% EtOAc in heptane) to give the corresponding amide intermediate. The residue was dissolved in THF-anhydrous (2.6 mL), sodium hydride (60%, 91 mg, 2.28 mmol) was slowly added at 0 °C, the mixture was stirred at this temperature for 30 min and then heated at 50 °C for 2 h. The reaction mixture was quenched with water (5 ml) and extracted with DCM (2 × 5 ml). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated to give the title compound (225 mg) as a colorless oil. [M+H] + m / z 569.4

[0345] Intermediate 29

Chem.

[0346] tert-butyl rel-(1R,5S)-8-fluoro-7-oxo-1-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0347] Intermediate 28 (99%, 400 mg, 0.696 mmol) was dissolved in ethanol (33 mL), the atmosphere was evacuated, and the flask was filled with nitrogen three times. Palladium on carbon (10%) (5.0%, 592 mg, 0.278 mmol) was added, the atmosphere was evacuated, and the flask was filled with hydrogen three times. The reaction mixture was stirred for 16 h, then filtered through Celite, washed with EtOAc, and concentrated in vacuo to afford the title compound (300 mg) as a colorless oil. [M+H] + m / z 479.3

[0348] Intermediate 30

Chemical formula

[0349] tert-butyl rel-(1R,5S)-8-fluoro-7-oxo-1-({[(1s,4s)-4-(2-{[3-(tert-butoxy)-3-oxoprop-1-en-1-yl]oxy}phenyl)cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0350] To a solution of tert-butyl prop-2-ynoate (86 mg, 0.680 mmol) and 1,4-diazabicyclo[2.2.2]octane (25 mg, 0.226 mmol) in THF (13 mL) was added Intermediate 29 (90%, 300 mg, 0.564 mmol) in THF (2.6 mL) at 0 °C under a nitrogen atmosphere, and the solution was stirred at room temperature for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2 × 5 mL). The organic layer was washed with brine, MgSO 4It was dried above and concentrated in vacuo to obtain the crude substance. The crude substance was purified by column chromatography (0 - 80% EtOAc in heptane) to give the title compound (215 mg) as a colorless oil. [M+H] + m / z 605.5

[0351] Intermediate 31

Chem.

[0352] tert-Butyl-rel-(1R,5S)-8-fluoro-7-oxo-1-({[(1s,4s)-4-{2-[3-(tert-butoxy)-3-oxopropoxy]phenyl}cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0353] Intermediate 30 (91%, 215 mg, 0.324 mmol) was dissolved in ethanol (61 mL), the atmosphere was evacuated and filled with nitrogen three times. Palladium on carbon (10%, 69 mg, 0.0647 mmol) was added, the atmosphere was evacuated and filled with hydrogen three times. The reaction mixture was stirred for 5 h, then filtered through celite, washed with EtOAc and concentrated in vacuo to give the title compound (240 mg, 0.306 mmol) as a colorless oil. [M+Na] + m / z 624.6

[0354] Intermediate 32

Chem.

[0355] 3-{2-[(1s,4s)-4-{[rel-(1R,5S)-8-fluoro-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-1-yl]methoxy}cyclohexyl]phenoxy}propanoic acid

[0356] 4M hydrogen chloride in dioxane (3.7 mL, 14.8 mmol) was added to Intermediate 31 (99%, 180 mg, 0.294 mmol) at room temperature, and the reaction mixture was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo to afford the title compound (130 mg) as a white solid. [M+H] + m / z 451.3

[0357] Example 8

Chemical Structure

[0358] rel-(1’s,3S,16’R,19’s)-6-Fluoro-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0359] To a stirred solution of HATU (162 mg, 0.426 mmol) and DIPEA (147 μL, 0.843 mmol) in acetonitrile (72 mL) was added Intermediate 32 (99%, 130 mg, 0.286 mmol) in acetonitrile (6.2 mL) using a syringe pump over 2 hours. The resulting solution was stirred for 1 hour. The reaction mixture was concentrated in vacuo to afford a crude material. The mixture was diluted with water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated to afford a solid residue. The crude material was purified by basic reverse-phase column chromatography (10 - 65% acetonitrile (0.1% ammonia) in water) to afford the title compound (57 mg) as a yellow solid.

[0360] LCMS (Method A): [M+H] + m / z 433.3, RT 3.14 and 3.22 minutes.

[0361] 1 H NMR (500 MHz, CDCl3 ) δ 7.12 - 7.05 (m, 1H), 7.03 - 6.98 (m, 1H), 6.96 - 6.90 (m, 1H), 6.85 - 6.78 (m, 1H), 6.57 (s, 1H), 5.49 (dd, J = 51.8, 7.1 Hz, 1H), 4.44 - 4.40 (m, 1H), 4.41 - 4.34 (m, 1H), 4.33 (dd, J = 9.4, 2.9 Hz, 1H), 4.19 - 4.10 (m, 1H), 3.96 (d, J = 11.8 Hz, 1H), 3.77 - 3.70 (m, 2H), 3.53 - 3.43 (m, 1H), 3.15 (d, J = 9.5 Hz, 1H), 3.01 (dd, J = 11.3, 7.0 Hz, 1H), 2.39 - 2.33 (m, 2H), 2.33 - 2.25 (m, 1H), 2.18 (td, J = 12.7, 3.7 Hz, 1H), 2.12 - 2.05 (m, 2H), 1.97 - 1.90 (m, 1H), 1.78 - 1.70 (m, 1H), 1.52 - 1.44 (m, 1H), 1.44 - 1.37 (m, 1H), 1.29 (t, J = 14.1 Hz, 3H).

[0362] Example 9 [Chemical formula]

[0363] Rel-(1’s,3S,16’R,19’s)-8’,18’-Dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2,7 .0 12,16 tricosane]-2’,4’,6’-triene-11’-one

[0364] To a stirred solution of HATU (481 mg, 1.27 mmol) and DIPEA (442 μL, 2.53 mmol) in acetonitrile (58 mL) was added intermediate 37 (415 mg) in DMF (5.8 mL) using a syringe pump over 2 hours. The resulting solution was stirred for 1 hour. The reaction mixture was concentrated in vacuo to give a crude material. The mixture was diluted with water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give a solid residue. The crude material was purified by basic reverse-phase column chromatography (20 - 60% acetonitrile in water (0.1% ammonia)) to give the title compound (136 mg) as a yellow solid.

[0365] LCMS (Method A): [M+H] + m / z 401.4, RT 3.17 min

[0366] 1 H NMR (500 MHz, CDCl 3 ) δ 7.21 - 7.09 (m, 1H), 7.09 - 7.03 (m, 1H), 7.02 - 6.95 (m, 1H), 6.91 - 6.83 (m, 1H), 4.46 - 4.38 (m, 1H), 4.38 - 4.30 (m, 1H), 4.26 - 4.17 (m, 2H), 4.03 - 3.92 (m, 1H), 3.79 (s, 1H), 3.77 - 3.71 (m, 2H), 3.56 - 3.48 (m, 2H), 3.45 (d, J = 11.2 Hz, 1H), 3.32 (d, J = 9.4 Hz, 1H), 3.22 - 3.06 (m, 1H), 3.03 - 2.92 (m, 2H), 2.47 - 2.29 (m, 3H), 2.32 - 2.23 (m, 1H), 2.21 - 2.10 (m, 3H), 1.85 - 1.78 (m, 2H), 1.53 - 1.41 (m, 2H), 1.37 - 1.21 (m, 2H).

Chemical Structure

[0367] Intermediate 38

Chem.

[0368] 1-tert-butyl 3-ethyl 5-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-4-oxopyrrolidine-1,3-dicarboxylate

[0369] Paraformaldehyde (3.40 g, 0.113 mol) was added to a solution of 4-benzyloxycyclohexanol (23.50 g, 0.114 mol) in anhydrous DCM (134 mL), followed by the addition of chloro(trimethyl)silane (20 mL, 0.155 mol). The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was concentrated in vacuo at 30 °C to afford a pale yellow oil of the chloro intermediate. In a separate flask, 2.4 M butyllithium in THF (87 mL, 0.209 mol) was added to a stirred solution of N-(propan-2-yl)propan-2-amine (29 mL, 0.207 mol) in anhydrous THF (104 mL) at -78 °C. The reaction was maintained at this temperature for 40 min. In a third flask, this freshly prepared LDA was added via an addition funnel over 0.5 h to a stirred solution of 1,3-dimethylhexahydropyrimidin-2-one (48.70 g, 0.380 mol) and 1-tert-butyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (24.50 g, 95.2 mmol) in anhydrous THF (276 mL) at -78 °C, keeping the reaction temperature from rising above -65 °C. The solution was maintained at this temperature for 20 min. The oil containing [4-(chloromethoxy)cyclohexyl]benzene was dissolved in anhydrous THF (67 mL) and added to the reaction mixture via an addition funnel over 20 min, keeping the reaction temperature from rising above -65 °C. The reaction mixture was stirred at -78 °C for 2 h. The reaction was quenched with saturated NH 4 Cl aqueous solution. The crude mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 300 mL). The combined organic extracts were dried over MgSO 4It was dried, filtered, and concentrated in vacuo to obtain the crude substance. The crude substance was purified by silica gel column chromatography (0 - 20% EtOAc in heptane) to give the title compound (4.00 g) as a yellow oil. [M+Na] + : m / z 498.3

[0370] Intermediate 39

Chem.

[0371] tert-Butyl 2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-oxopyrrolidine-1-carboxylate

[0372] To a solution of Intermediate 38 (13.50 g) in DMSO (131 mL) were added sodium chloride (3.10 g, 53.0 mmol) and water (13 mL), and the reaction mixture was heated at 125 °C for 2.5 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with water (2 × 50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude substance. The crude substance was purified by column chromatography (0 - 100% EtOAc in heptane) to give the title compound (13.5 g) as a yellow oil. [M+Na] + m / z 426.3

[0373] Intermediate 40

Chem.

[0374] tert-Butyl 2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(hydroxyimino)pyrrolidine-1-carboxylate

[0375] A solution of N,N - diethylethanamine (8.7 mL, 62.3 mmol), hydroxylamine hydrochloride (1:1) (4.30 g, 61.9 mmol), and Intermediate 39 (8.40 g) in ethanol (42 mL) was heated at 90 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 75 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford the title compound (8.6 g) as a yellow oil. [M+Na] + m / z 441.3

[0376] Intermediate 41

Chemical Structure

[0377] tert - Butyl 2 - ({[4 - (benzyloxy)cyclohexyl]oxy}methyl)-3 - nitropyrrolidine - 1 - carboxylate

[0378] A solution of trifluoroacetic anhydride (7.1 mL, 51.4 mmol) in acetonitrile (37 mL) was added to a stirred solution of hydrogen peroxide - urea (1:1) (6.8 g, 71.9 mmol) in acetonitrile (37 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 hours. The resulting solution was added dropwise to a mixture of Intermediate 40 (8.60 g) and sodium hydrogen carbonate (8.6 g, 0.103 mol) in acetonitrile (37 mL) at 80 °C over 1 hour. The reaction mixture was cooled to room temperature, quenched with saturated Na 2 SO 3 aqueous solution (50 mL), stirred for 10 minutes, and then extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over MgSO 4 and filtered, and concentrated in vacuo to afford a crude material. The crude material was purified by silica gel column chromatography (0 - 70% EtOAc in heptane) to afford the title compound (4.80 g) as a pale yellow oil. [M+H] + m / z 435.3

[0379] Intermediate 42

Chemical Structure

[0380] tert-butyl-rel-(2R,3S)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(hydroxymethyl)-3-nitropyrrolidine-1-carboxylate

[0381] Formaldehyde (37% in water, 7.4 mL, 0.10 mol) was added to a solution of Intermediate 41 (4.80 g) and triethylamine (1.9 mL, 13.3 mmol) in THF (56 mL) at room temperature. The solution was heated to 70 °C for 18 h. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 75 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO 4 ), filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0 - 90% EtOAc in heptane) to afford the title compound (4.0 g) as a colorless oil. [M+H] + m / z 465.5

[0382] Intermediate 43

Chemical Structure

[0383] tert-butyl-rel-(2R,3S)-3-amino-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(hydroxymethyl)pyrrolidine-1-carboxylate

[0384] A suspension of Intermediate 42 (4.00 g) and zinc (5.60 g, 85.6 mmol) in acetic acid (39 mL) and ethanol (298 mL) was stirred at room temperature for 6 h. The reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was neutralized with saturated NaHCO 3 aqueous solution and extracted with DCM (3 × 75 mL). The combined organic extracts were dried (MgSO 4) Concentrated under vacuum to obtain the title compound (3.63 g) as a colorless oil. [M+H] + m / z 435.3.

[0385] Intermediate 44

Chemical formula

[0386] tert-Butyl-rel-(1R,5S)-1-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0387] To a solution of Intermediate 43 (3.63 g) in THF (36 mL) was added potassium carbonate (3.46 g, 25.0 mmol) at 0 °C, and then water (36 mL) was added. To this mixture, chloroacetyl chloride (0.93 mL, 11.7 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was quenched with water and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO 4 ), filtered, and concentrated to obtain an oily residue. This intermediate was dissolved in DCM (75 mL) and IPA (117 mL), cooled to 0 °C, potassium 2-methylpropane-2-olate (3.75 g, 33.4 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hour. The reaction was quenched by the addition of water (20 mL). The mixture was poured into saturated NaHCO 3 aqueous solution (30 ml). After extraction with DCM (3 × 50 mL), the combined organic extracts were washed with brine (20 mL), dried (MgSO 4 ), filtered, and concentrated to obtain the title compound (3.72 g) as a yellow oil. [M+H]+ m / z 475.4.

[0388] Intermediate 45

Chemical formula

[0389] tert-butyl-rel-(1R,5S)-1-{[(4-hydroxycyclohexyl)oxy]methyl}-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0390] Intermediate 44 (2.43 g) was dissolved in ethanol (95 mL), the atmosphere was evacuated, and nitrogen was charged three times. Palladium C (5.0%, 1013 mg, 0.476 mmol) was added, the atmosphere was evacuated, and hydrogen was charged three times. The reaction mixture was stirred for 6 hours, then filtered through celite, washed with EtOAc, and concentrated in vacuo to give the title compound (1.95 g) as a white solid. [M+H]+ m / z: 385.3

[0391] Intermediate 46

Chemical formula

[0392] tert-butyl-rel-(1R,5S)-7-oxo-1-{[(4-oxocyclohexyl)oxy]methyl}-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0393] To a solution of Intermediate 45 (1.90 g) in DCM (10 mL) at 0 °C was added Dess-Martin periodinane (2.73 g, 6.43 mmol) portionwise. The mixture was stirred at room temperature for 40 minutes, quenched by addition of saturated aqueous solutions of Na 2 S 2 O 3 (10 mL) and NaHCO 3 (10 mL), and extracted with DCM (3 × 10 mL). The crude material was purified by silica gel column chromatography (0 - 100% EtOAc in heptane) to give the title compound (1 g) as a white solid. [M+H]+ m / z: 383.3

[0394] Intermediate 47

Chemical formula

[0395] tert-butyl-rel-(1R,5S)-1-[({4-[(4-methylbenzenesulfonamido)imino]-cyclohexyl}oxy)methyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0396] To a stirred solution of intermediate 46 (1.00 g) in ethanol (20 mL) was added 4-methylbenzenesulfonohydrazide (528 mg, 2.83 mmol), and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 10 mL). The organic phase was dried (MgSO 4 ), filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0 - 100% EtOAc in heptane) to afford the title compound (1.1 g) as a white oil. [M+H] + m / z 551.4

[0397] Intermediate 48

Chemical Structure

[0398] tert-butyl-rel-(1R,5S)-1-[({4-[2-(benzyloxy)-6-fluorophenyl]cyclohex-3-en-1-yl}oxy)methyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0399] A solution of intermediate 47 (600 mg), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (50 mg, 0.0545 mmol), dicyclohexyl[2’,4’,6’-tri(propane-2-yl)biphenyl-2-yl]phosphane (52 mg, 0.109 mmol), lithium tert-butoxide (218 mg, 2.72 mmol) and 1-benzyloxy-2-bromo-3-fluorobenzene (368 mg, 1.31 mmol) in anhydrous 1,4-dioxane (10 mL) was heated at 110 °C for 18 h under a nitrogen atmosphere. The mixture was cooled to room temperature, filtered through celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the crude material. The latter was purified by column chromatography (0 - 100% EtOAc in heptane) to give the title compound (452 mg) as an off-white solid. [M+H] + m / z 567.4

[0400] Intermediate 49

Chem.

[0401] tert-butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-(2-fluoro-6-hydroxyphenyl)-cyclohexyl]oxy}methyl)-9-oxa-2,6-

[0402] diazaspiro[4.5]decane-2-carboxylate

[0403] Intermediate 48 (450 mg) was dissolved in ethanol (20 mL), the atmosphere was evacuated and the flask was filled with nitrogen three times. Palladium on carbon (10%, 169 mg, 0.159 mmol) was added, the atmosphere was evacuated and the flask was filled with hydrogen three times. The reaction mixture was stirred for 18 h, then filtered through celite, washed with EtOAc and the filtrate was concentrated in vacuo to give the title compound (330 mg) as an off-white solid. [M+H] + m / z479.3

[0404] Intermediate 50 [Chemistry]

[0405] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-(2-{[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]oxy}-6-fluorophenyl)cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0406] A solution of tert-butyl prop-2-ynoate (138 μL, 1.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (16 mg, 0.143 mmol) in THF (0.5 mL) was added with intermediate 49 (330 mg) in THF (3 mL) at 0 °C under nitrogen, and the solution was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine and dried over MgSO 4 and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography (0 - 100% EtOAc in heptane) to afford the title compound (352 mg) as a colorless gum. [M+H] + m / z 605.4.

[0407] Intermediate 51 [Chemistry]

[0408] tert-Butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-{2-[3-(tert-butoxy)-3-oxopropoxy]-6-fluorophenyl}cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0409] Intermediate 50 (350 mg) was dissolved in ethanol (15 mL), the atmosphere was evacuated, and the flask was filled with nitrogen three times. Palladium on carbon (10%, 123 mg, 0.12 mmol) was added, the atmosphere was evacuated, and the flask was filled with hydrogen three times. The reaction mixture was stirred for 5 h, then filtered through Celite, washed with EtOAc, and the filtrate was concentrated in vacuo to afford the title compound (303 mg) as a colorless gum. [M+H] + m / z 607.4

[0410] Intermediate 52

Chemical Structure

[0411] Rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-[2-(2-carboxyethoxy)-6-fluorophenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-ium chloride

[0412] 4M Hydrogen chloride in dioxane (3.5 mL, 14.0 mmol) was added to Intermediate 51 (300 mg) at room temperature and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo to afford the title compound (254 mg). [M+H] + m / z 451.3

[0413] Example 10

Chemical Structure

[0414] Rel-(1’s,3S,16’R,19’s)-3’-fluoro-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2,7 .0 12,16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0415] A solution of intermediate 52 (240 mg) in anhydrous DMF (6 mL) was added dropwise to a stirred solution of HATU (281 mg, 0.739 mmol) and DIPEA (430 μL, 2.46 mmol) in acetonitrile (85 mL) at room temperature under nitrogen over 2 hours. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to afford the crude material. The crude material was diluted with water and extracted with DCM (3 × 20 mL). The combined organic extracts were dried (MgSO 4 )), filtered, and concentrated to give a solid residue. The crude material was purified by basic reverse-phase column chromatography (20 - 50% acetonitrile in water (0.1% ammonia)) to afford the title compound (99 mg) as a white solid.

[0416] LCMS (Method B): [M + H] + m / z 433.3, RT 2.80 min

[0417] 1 H NMR (500 MHz, CDCl 3 ) δ 7.11 - 7.03 (m, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.71 - 6.65 (m, 1H), 6.29 (s, 1H), 4.44 (dd, J = 9.6, 3.1 Hz, 1H), 4.42 - 4.37 (m, 1H), 4.29 - 4.14 (m, 4H), 3.95 (td, J = 9.9, 3.6 Hz, 1H), 3.86 - 3.81 (m, 1H), 3.77 (d, J = 11.7 Hz, 1H), 3.60 - 3.53 (m, 2H), 3.28 (dd, J = 9.5, 0.9 Hz, 1H), 3.14 - 3.00 (m, 2H), 2.46 - 2.34 (m, 2H), 2.27 (qd, J = 12.9, 3.7 Hz, 1H), 2.20 - 2.07 (m, 3H), 1.81 (dt, J = 14.0, 3.1 Hz, 1H), 1.64 - 1.60 (m, 1H), 1.46 - 1.33 (m, 2H), 1.32 - 1.23 (m, 1H).

[0418] Examples 10a and 10b [Chem.]

[0419] Example 10a: (1’s,3S,16’R,19’s)-3’-fluoro-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0420] Example 10b: (1’s,3R,16’S,19’s)-3’-fluoro-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0421] Example 10 (95 mg, 0.220 mmol) was subjected to chiral preparative purification using a Chiralcel OD-H, 20 × 250 mm, 5 μm column, eluting with 85:15 heptane:ethanol to give the title compound (peak 1, 35 mg, 100% ee; and peak 2, 30 mg, 100% ee).

[0422] Example 10a: Peak 1 (stereochemistry tentatively assigned to pyrrolidine)

[0423] LCMS (Method B): [M+H] + m / z 433.3, RT 2.80 min

[0424] Chiral analysis (Chiralcel OD-H, 4.6 × 250 mm, 5 μm, 85:15 n-hexane:ethanol: RT 14.0 min

[0425] 11H NMR (500 MHz, CDCl 3 ) δ 7.10 - 7.04 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.71 - 6.65 (m, 1H), 6.30 (s, 1H), 4.44 (dd, J = 9.6, 3.1 Hz, 1H), 4.42 - 4.37 (m, 1H), 4.30 - 4.15 (m, 4H), 3.95 (td, J = 9.9, 3.6 Hz, 1H), 3.85 - 3.81 (m, 1H), 3.77 (d, J = 11.6 Hz, 1H), 3.61 - 3.53 (m, 2H), 3.28 (dd, J = 9.5, 0.9 Hz, 1H), 3.14 - 3.00 (m, 2H), 2.46 - 2.34 (m, 2H), 2.27 (qd, J = 12.8, 3.7 Hz, 1H), 2.20 - 2.08 (m, 3H), 1.81 (dt, J = 13.7, 3.1 Hz, 1H), 1.64 - 1.60 (m, 1H), 1.45 - 1.33 (m, 2H), 1.31 - 1.25 (m, 1H).

[0426] Example 10b: Peak 2 (Provisionally assigned stereochemistry to pyrrolidine)

[0427] LCMS (Method B): [M+H] + m / z 433.3, RT 2.79 min

[0428] Chiral analysis (Chiralcel OD-H, 4.6×250 mm, 5 μm, 85:15 n-hexane:ethanol: RT 22.4 min

[0429] 1 1H NMR (500 MHz, CDCl 3) δ 7.11 - 7.03 (m, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.72 - 6.64 (m, 1H), 6.32 (s, 1H), 4.44 (dd, J = 9.6, 3.2 Hz, 1H), 4.42 - 4.37 (m, 1H), 4.28 - 4.15 (m, 4H), 3.95 (td, J = 9.9, 3.6 Hz, 1H), 3.84 - 3.81 (m, 1H), 3.77 (d, J = 11.6 Hz, 1H), 3.61 - 3.53 (m, 2H), 3.28 (dd, J = 9.5, 0.9 Hz, 1H), 3.13 - 3.00 (m, 2H), 2.46 - 2.34 (m, 2H), 2.27 (qd, J = 12.9, 3.7 Hz, 1H), 2.20 - 2.06 (m, 3H), 1.81 (dt, J = 13.6, 3.1 Hz, 1H), 1.59 - 1.54 (m, 1H), 1.44 - 1.33 (m, 2H), 1.31 - 1.26 (m, 1H).

Chem.

[0430] Intermediate 53

Chem.

[0431] tert-Butyl-rel-(1R,5S)-1-[({4-[2-(Benzyloxy)-3,5-difluorophenyl]cyclohex-3-en-1-yl}oxy)methyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0432] Intermediate 47 (561 mg), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one: palladium (47 mg, 0.0509 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (49 mg, 0.102 mmol), lithium tert-butoxide (0.23 mL, 2.55 mmol) and 2-benzyloxy-1-bromo-3,5-difluorobenzene (274 mg, 0.917 mmol) in anhydrous 1,4-dioxane (6 mL) were heated at 110 °C for 4 h under a nitrogen atmosphere. The mixture was cooled to room temperature, filtered through celite and washed with EtOAc (10 mL). The filtrate was concentrated in vacuo. The residue was resuspended in EtOAc (20 mL) and water (20 mL). The organic phase was separated and the aqueous phase was further extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo to give the crude material. The crude material was purified by flash column chromatography (0 - 100% EtOAc in heptane) to give the title compound (250 mg) as a yellow oil. [M+H] + m / z: 585.3

[0433] Intermediate 54 [Chemical Structure]

[0434] tert-butyl-rel-(1R,5S)-1-({[(1R)-4-(3,5-difluoro-2-hydroxyphenyl)cyclohex-3-en-1-yl]oxy}methyl)-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0435] Intermediate 53 (300 mg) was dissolved in ethanol (10 mL), the atmosphere was evacuated, and the flask was filled with nitrogen three times. Palladium on carbon (10%, 33 mg, 0.0313 mmol) was added, the atmosphere was evacuated, and the flask was filled with hydrogen three times. The reaction mixture was stirred for 6 hours, then filtered through celite, washed with EtOAc, and the filtrate was concentrated in vacuo to afford the title compound (278 mg) as an orange oil. [M+H] + m / z 495.3.

[0436] Intermediate 55

Chemical Structure

[0437] tert-Butyl-rel-(1R,5S)-1-({[(1R)-4-(2-{[(1E)-3-(tert-Butoxy)-3-oxoprop-1-en-1-yl]oxy}-3,5-difluorophenyl)cyclohex-3-en-1-yl]oxy}methyl)-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0438] To a solution of tert-butyl prop-2-ynoate (63 mg, 0.496 mmol) and 1,4-diazabicyclo[2.2.2]octane (18 mg, 0.164 mmol) in THF (9 mL) was added Intermediate 54 (278 mg) in THF (2 mL) at 0 °C under nitrogen, and the solution was stirred at room temperature for 16 hours. Further, tert-butyl prop-2-ynoate (63 mg, 0.496 mmol) and 1,4-diazabicyclo[2.2.2]octane (18 mg, 0.164 mmol) in THF (2 mL) were added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO 4 and filtered, and concentrated in vacuo to afford a crude material. The crude material was purified by column chromatography (0 - 100% EtOAc in heptane) to afford the title compound (206 mg) as a yellow solid. [M+H] + m / z: 621.3

[0439] Intermediate 56

Chem.

[0440] tert-Butyl-rel-(1R,5S)-1-({[(1R)-4-{2-[3-(tert-Butoxy)-3-oxopropoxy]-3,5-difluorophenyl}cyclohex-3-en-1-yl]oxy}methyl)-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0441] Intermediate 55 (200 mg) was dissolved in ethanol (5 mL), the atmosphere was evacuated and filled with nitrogen three times. Palladium carbon (10%, 61 mg, 0.0576 mmol) was added, the atmosphere was evacuated and filled with hydrogen three times. The reaction mixture was stirred for 4 hours, then filtered through celite, washed with EtOAc, and the filtrate was concentrated in vacuo to give the title compound (195 mg) as a yellow foam. [M+Na] + m / z 645.3

[0442] Intermediate 57

Chem.

[0443] Rel-(1R,5S)-1-[({4-[2-(2-Carboxyethoxy)-3,5-difluorophenyl]cyclohex-3-en-1-yl}oxy)methyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-ium chloride

[0444] 4M Hydrogen chloride (2.7 mL, 11.0 mmol) was added to Intermediate 56 (136 mg) at room temperature and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound (160 mg) as a yellow solid. [M+H] + :m / z 467.2

[0445] Intermediate 58 [Chemical formula]

[0446] Rel-(3S,16’R)-4’,6’-Difluoro-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-1’(21’),2’,4’,6’-tetraene-5,11’-dione

[0447] To a stirred solution of HATU (136 mg, 0.359 mmol) and DIPEA (168 μL, 0.960 mmol) in acetonitrile (60 mL) was added intermediate 57 (112 mg) in anhydrous DMF (5 mL) using a syringe pump over 2 h. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo to give the crude material. The crude material was diluted with water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated to give a solid residue. The crude material was purified by basic reverse-phase column chromatography (10 - 100% acetonitrile in water (0.1% ammonia)) to give the title compound (60 mg) as a yellow solid. [M+H] + m / z 449.5

[0448] Example 11 [Chemical formula]

[0449] Rel-(1’s,3S,16’R,19’s)-4’,6’-Difluoro-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2,7 .0 12,16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0450] Intermediate 58 (60 mg) was dissolved in ethanol (2.75 mL), the atmosphere was evacuated, and the flask was filled with nitrogen three times. Palladium on carbon (10%, 5.5 mg, 5.17 μmol) was added, the atmosphere was evacuated, and the flask was filled with hydrogen three times. The reaction mixture was stirred for 16 h, then filtered through Celite, washed with EtOAc, and the filtrate was concentrated in vacuo to give the crude product. The crude material was purified by basic reverse-phase column chromatography (10 - 45% acetonitrile in water (0.1% ammonia)) to give the title compound (3 mg) as a white solid.

[0451] LCMS (Method A): [M+H] + m / z 451.3, RT 3.13 min

[0452] 1 H NMR (500 MHz, DMSO) δ 8.15 (s, 1H), 7.28 - 7.02 (m, 1H), 6.97 - 6.81 (m, 1H), 4.52 - 4.38 (m, 1H), 4.26 - 3.91 (m, 5H), 3.89 - 3.71 (m, 2H), 3.67 (s, 1H), 3.64 - 3.54 (m, 2H), 3.49 - 3.37 (m, 1H), 3.18 - 3.14 (m, 1H), 3.08 - 2.98 (m, 1H), 2.41 - 2.24 (m, 2H), 2.17 - 1.81 (m, 5H), 1.44 - 1.21 (m, 4H).

[0453] Examples 12a and 12b

Chemical Structure

[0454] Example 12a: (1’s,3S,12’R,15’R,18’s)-12’-Methyl-8’,17’-dioxa-11’-azaspiro[morpholine-3,14’-tetracyclo[16.2.2.0 2 , 7 .0 11 , 15Docosane]-2’(7’),3’,5’-triene-5,10’-dione

[0455] Example 12b: (1’s,3R,12’R,15’S,18’s)-12’-Methyl-8’,17’-dioxa-11’-azaspiro[morpholine-3,14’-tetracyclo[16.2.2.0 2 , 7 .0 11 , 15 Docosane]-2’(7’),3’,5’-triene-5,10’-dione

[0456] The above Examples 12a and 12b were prepared according to the same procedure as described in Example 3. The crude material was purified by acidic reverse-phase column chromatography (20 - 40% acetonitrile (0.1% formic acid) in water) to obtain Example 12a (11 mg) of the title compound as an orange solid and 12b (16 mg) as a yellow solid.

[0457] Example 12a: LCMS (Method B): [M + H] + 415.3, RT = 2.76 minutes

[0458] 1 H NMR (500 MHz, CDCl 3 ) δ 7.47 (s, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.77 (s, 1H), 4.98 (d, J = 8.4 Hz, 1H), 4.44 - 4.11 (m, 6H), 3.88 (s, 1H), 3.71 - 3.62 (m, 2H), 3.23(d, J = 9.0 Hz, 1H), 2.79 (s, 1H), 2.56 (s, 1H), 2.41 - 2.28 (m, 1H), 2.25 - 2.06 (m, 3H), 1.63 (s, 4H), 1.53 - 1.41 (m, 3H), 1.39 - 1.30 (m, 2H).

[0459] Example 12b: LCMS (Method B): [M+H] + 415.3, RT = 2.99 minutes

[0460] 1 H NMR (500 MHz, CDCl 3 ) δ 7.21 - 7.14 (m, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.17 (s, 1H), 5.09 (d, J = 10.5 Hz, 1H), 4.70 (dt, J = 13.5, 6.6 Hz, 1H), 4.55 (s, 1H), 4.35 - 4.22 (m, 3H), 4.13 (d, J = 16.7 Hz, 1H), 4.04 (d, J = 11.5 Hz, 1H), 3.84 (s, 1H), 3.61 (d, J = 11.6 Hz, 1H), 3.24 (d, J = 9.8 Hz, 1H), 2.64 (dd, J = 12.9, 9.9 Hz, 1H), 2.59 - 2.43 (m, 2H), 2.16 - 2.01 (m, 2H), 1.87 - 1.73 (m, 2H), 1.55 - 1.45 (m, 2H), 1.42 - 1.32 (m, 5H).

[0461] Example 13

Chemical Structure

[0462] rel-(1’s,3S,13’R,16’R,19’s)-13’-methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2,7 .0 12,16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0463] Example 13 was prepared according to the same procedure as described in Example 1 using the known starting material 1-tert-butyl 3-ethyl (2R)-2-methyl-4-oxopyrrolidine-1,3-dicarboxylate, and the title compound (38 mg) was obtained as an off-white solid.

[0464] LCMS (Method A): [M+H] + m / z 429.3, RT 3.08 and 3.17 minutes

[0465] 1 H NMR (500 MHz, CDCl 3 ) δ 7.18 - 7.10 (m, 1H), 7.10 - 7.01 (m, 1H), 6.99 - 6.91 (m, 1H), 6.90 - 6.76 (m, 1H), 6.46 - 5.98 (m, 1H), 4.88 - 4.41 (m, 2H), 4.38 - 4.09 (m, 4H), 4.04 - 3.77 (m, 2H), 3.73 - 3.55 (m, 1H), 3.54 - 3.33 (m, 1H), 3.26 - 2.97 (m, 1H), 2.68 - 2.38 (m, 3H), 2.38 - 2.08 (m, 2H), 1.97 - 1.77 (m, 2H), 1.63 - 1.50 (m, 3H), 1.42 - 1.21 (m, 6H).

[0466] Examples 13a and 13b

Chemical formula

[0467] Example 13a: (1’s,3S,13’R,16’R,19’s)-13’-methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0468] Example 13b: (1’S,3R,13’R,16’S,19’S)-13’-Methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0469] Example 13 (35 mg) was subjected to chiral preparative purification using Waters 600, eluting with 70 / 30% v / v n-hexane / (ethanol + 0.1% isopropylamine), Chiralpak OD-H (25 × 2.0 cm), 5 μm, flow rate 17 mL / min to give the title compound (peak 1, 11.8 mg, 100% ee; peak 2, 6.4 mg, 100% ee).

[0470] Example 13a: Peak 1 (stereochemistry arbitrarily assigned to the pyrrolidine); 1 HNMR (500 MHz, CDCl 3 ) δ 7.19 - 7.12 (m, 1H), 7.06 (ddd, J = 14.5, 7.4, 1.5 Hz, 1H), 7.00 - 6.78 (m, 2H), 7.38 - 6.00 (m, 1H), 4.92 - 4.36 (m, 1H), 4.56 - 3.79 (m, 6H), 3.96 - 3.34 (m, 3H), 3.51 - 3.12 (m, 1H), 3.55 - 2.41 (m, 1H), 3.12 - 2.31 (m, 1H), 2.38 - 2.24 (m, 1H), 2.72 - 2.12 (m, 1H), 2.73 - 1.82 (m, 4H), 2.23 - 1.59 (m, 1H), 1.60 - 1.27 (m, 7H).

[0471] LCMS (method C): [M+H]+ m / z 429.3, RT 0.97 min.

[0472] Chiral analysis (Chiralpak OD-H, 25×0.46 cm, 5 μm, 70:30 n-hexane:(ethanol + 0.1% isopropylamine)): RT 6.6 min.

[0473] Example 13b: Peak 2 (stereochemistry arbitrarily assigned to pyrrolidine); 1 HNMR (500 MHz, CDCl 3 ) δ 7.19 - 7.12 (m, 1H), 7.10 - 7.04 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.86 (t, J=7.3 Hz, 1H), 6.03 (s, 1H), 4.56 (dd, J=9.6, 2.6 Hz, 1H), 4.45 (d, J=1.6 Hz, 1H), 4.41 - 4.29 (m, 3H), 4.29 - 4.20 (m, 1H), 4.18 - 4.08 (m, 1H), 4.02 (d, J=11.5 Hz, 1H), 3.84 (br s, 1H), 3.60 (d, J=11.5 Hz, 1H), 3.19 (d, J=9.5 Hz, 1H), 3.09 (ddd, J=15.0, 11.4, 4.0 Hz, 1H), 2.61 (dd, J=12.9, 9.7 Hz, 1H), 2.52 - 2.34 (m, 3H), 2.22 - 2.04 (m, 2H), 1.85 (d, J=13.0 Hz, 1H), 1.79 (br d, J=13.3 Hz, 1H), 1.57 - 1.40 (m, 2H), 1.38 - 1.24 (m, 5H).

[0474] LCMS (Method C): [M+H] + m / z 429.2, RT 0.99 min

[0475] Chiral analysis (Chiralpak OD-H, 25×0.46 cm, 5 μm, 70:30 n-hexane:(ethanol + 0.1% isopropylamine)): RT 9.5 min

[0476] Example 14

Chemical formula

[0477] Example 14: (1’s,14’R,20’s)-14’-Methyl-8’,19’-dioxa-13’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2 , 7 .0 13 , 17 tetracosan]-2’(7’),3’,5’-triene-5,12’-dione

[0478] Example 14 was prepared according to the same procedure as described in Example 2 using the known starting material 1-tert-butyl 3-ethyl (2R)-2-methyl-4-oxopyrrolidine-1,3-dicarboxylate, and the title compound (15 mg) was obtained as a yellow solid.

[0479] 1 H NMR (500 MHz, CDCl 3 ) δ 7.18 - 7.12 (m, 1H), 7.07 (dd, J = 7.4, 1.9 Hz, 1H), 6.90 - 6.78 (m, 2H), 6.46 - 5.99 (m, 1H), 4.61 - 3.06 (m, 11H), 2.88 - 1.61 (m, 11H), 1.52 - 1.38 (m, 4H), 1.38 - 1.24 (m, 3H).

[0480] LCMS (Method B): [M+H] + m / z 443.3, RT 3.05 min.

Chem.

[0481] Intermediate 59

Chem.

[0482] tert-butyl (3R)-3-methyl-1-[({4-[(4-methylbenzenesulfonamido)imino]cyclohexyl}oxy)methyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0483] Intermediate 59 was prepared using the known starting material 1-tert-butyl 3-ethyl (2R)-2-methyl-4-oxopyrrolidine-1,3-dicarboxylate according to the same procedure as described for Intermediate 47, and the title compound (6.80 g) was obtained as a white solid. [M+H] + m / z 565.3

[0484] Intermediate 60

Chemical Structure

[0485] tert-butyl-(3R)-1-[({4-[2-(benzyloxy)-3-fluorophenyl]cyclohex-3-en-1-yl}oxy)methyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0486] Intermediate 59 (2.85 g), 2-benzyloxy-1-bromo-3-fluorobenzene (1.50 g, 5.34 mmol), (1{E},4{E})-1,5-diphenylpenta-1,4-dien-3-one; palladium (231 mg, 0.252 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (241 mg, 0.505 mmol), and lithium tert-butoxide (1.1 mL, 12.6 mmol) in anhydrous 1,4-dioxane (30 mL) were degassed for 10 minutes and then heated at 110 °C for 21 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated in vacuo to give a crude material. The crude material was purified by silica gel column chromatography (0 - 100% EtOAc in heptane) to give the title compound (2.32 g) as an orange oil. [M+Na]+ m / z 603.3

[0487] Intermediate 61

Chem.

[0488] tert-Butyl-(3R)-1-({[4-(3-Fluoro-2-hydroxyphenyl)cyclohex-3-en-1-yl]oxy}methyl)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0489] Intermediate 60 (2.32 g) was dissolved in ethanol (78 mL). The atmosphere was evacuated and filled with nitrogen three times. Palladium carbon (10%, 850 mg, 0.799 mmol) was added. The atmosphere was evacuated and filled with hydrogen three times. The reaction mixture was stirred for 2 hours, then filtered through celite, washed with EtOAc, and the filtrate was concentrated in vacuo to give the title compound (2.1 g) as a pale yellow gum. [M+H]+ m / z 491.4.

[0490] Intermediate 62

Chem.

[0491] tert-Butyl-(3R)-1-{[(4-{2-[2-(tert-Butoxy)-2-oxoethoxy]-3-fluorophenyl}cyclohex-3-en-1-yl)oxy]methyl}-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0492] To a solution of intermediate 61 (0.80 g) and tert-butyl bromoacetate (0.37 mL, 2.45 mmol) in acetone (8.6 mL) was added potassium carbonate (676 mg, 4.89 mmol), and the solution was heated at 50 °C overnight. The solid was filtered off, and the filtrate was concentrated in vacuo. The residue was suspended in water (15 mL) and extracted with DCM (3 × 20 mL). The combined organic extracts were concentrated in vacuo to give the title compound (1.2 g) as a yellow oil. [M+H] + m / z 605.4.

[0493] Intermediate 63

Chemical formula

[0494] (3R)-1-[({4-[2-(Carboxymethoxy)-3-fluorophenyl]cyclohex-3-en-1-yl}oxy)methyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-nium chloride

[0495] 4M hydrogen chloride in dioxane (11 mL, 42.3 mmol) was added to intermediate 62 (1.28 g) at room temperature, and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo to give the title compound (1.31 g) as a yellow solid. [M+H] + m / z 449.3.

[0496] Intermediate 64

Chemical formula

[0497] (12’R)-6’-Fluoro-12’-methyl-8’,17’-dioxa-11’-azaspiro[morpholine-3,14’tetracyclo[16.2.2.0 2,7 .0 11,15 docosane]-1’(20’),2’,4’,6’-tetraene-5,10’-dione

[0498] To a stirred solution of HATU (1.65 g, 4.35 mmol) and DIPEA (1.50 mL, 8.59 mmol) in acetonitrile (150 mL) was added intermediate 63 (1.31 g) in DMF (10 mL) via syringe pump over 2 h. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo to afford the crude material. The crude material was diluted with water and extracted with DCM (3 × 20 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated to afford a solid residue. The crude material was purified by basic reverse phase column chromatography (10 - 50% acetonitrile in water (0.1% ammonia)) to afford the title compound (350 mg) as a yellow oil. [M+H] + m / z 431.3.

[0499] Examples 15a and 15b

Chemical Structure

[0500] Example 15a: (1’s,3S,12’R,15’R,18’s)-6’-fluoro-12’-methyl-8’,17’-dioxa-11’-azaspiro[morpholine-3,14’-tetracyclo[16.2.2.0 2 , 7 .0 11 , 15 docosane]-2’,4’,6’-triene-5,10’-dione

[0501] Example 15b: (1’s,3R,12’R,15’S,18’s)-6’-fluoro-12’-methyl-8’,17’-dioxa-11’-azaspiro[morpholine-3,14’-tetracyclo[16.2.2.0 2 , 7 .0 11 , 15 docosane]-2’,4’,6’-triene-5,10’-dione

[0502] Intermediate 64 (300 mg) was dissolved in ethanol (24 mL), the atmosphere was evacuated, and the flask was filled with nitrogen three times. Palladium on carbon (10%, 345 mg, 0.324 mmol) was added, the atmosphere was evacuated, and the flask was filled with hydrogen three times. The reaction mixture was stirred for 24 h, then filtered through Celite, washed with EtOAc, and the filtrate was concentrated in vacuo to give a crude mixture. The crude material was purified by basic reverse-phase column chromatography (15 - 50% acetonitrile in water (0.1% ammonia)) to give the title compound as a white solid (peak 1, 53 mg) and also as a white solid (peak 2, 30 mg).

[0503] Example 15a: Peak 1

[0504] LCMS (Method A): [M+H] + m / z 433.3, RT 2.99 min

[0505] 1 H NMR (500 MHz, CDCl 3 ) δ 7.42 (s, 1H), 6.96 - 6.90 (m, 1H), 6.87 - 6.79 (m, 2H), 5.22 (d, J = 11.2 Hz, 1H), 4.52 - 4.13 (m, 6H), 3.88 (s, 1H), 3.75 - 3.59 (m, 2H), 3.25 (d, J = 9.4 Hz, 1H), 2.87 - 2.71 (m, 1H), 2.66 - 2.50 (m, 1H), 2.35 (dd, J = 13.4, 8.3 Hz, 1H), 2.24 - 2.12 (m, 2H), 2.07 - 2.01 (m, 1H), 1.99 - 1.94 (m, 1H), 1.68 (d, J = 6.9 Hz, 3H), 1.50 - 1.37 (m, 3H), 1.37 - 1.29 (m, 1H).

[0506] Example 15b: Peak 2

[0507] LCMS (Method A): [M+H] + m / z 433.3, RT 3.99 min

[0508] 1 H NMR (500 MHz, CDCl 3 ) δ 7.01 - 6.82 (m, 3H), 6.22 (s, 1H), 5.36 (dd, J = 12.7, 3.7 Hz, 1H), 4.87 (ddt, J = 12.3, 7.7, 3.8 Hz, 1H), 4.53 (d, J = 2.4 Hz, 1H), 4.32 (dd, J = 9.9, 2.8 Hz, 1H), 4.26 (d, J = 16.7 Hz, 1H), 4.22 (dd, J = 12.7, 2.3 Hz, 1H), 4.14 (d, J = 16.7 Hz, 1H), 4.02 (d, J = 11.6 Hz, 1H), 3.84 (s, 1H), 3.62 (d, J = 11.6 Hz, 1H), 3.25 (dd, J = 9.8, 1.1 Hz, 1H), 2.66 - 2.39 (m, 3H), 2.15 (d, J = 14.7 Hz, 1H), 1.92 - 1.72 (m, 3H), 1.49 (d, J = 12.3 Hz, 3H), 1.43 (d, J = 6.6 Hz, 3H), 1.34 (td, J = 14.2, 3.9 Hz, 1H).

[0509] The following examples were prepared according to the same procedure as described for Examples 15a and 15b using appropriate reagents followed by purification. [Table 2] [Chemical formula]

[0510] Intermediate 65 [Chemical formula]

[0511] tert-Butyl-(3R)-1-[({4-[2-(Benzyloxy)-6-fluorophenyl]cyclohex-3-en-1-yl}oxy)methyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0512] Intermediate 65 was prepared using Intermediate 59 and the known starting material 1-(benzyloxy)-2-bromo-3-fluorobenzene according to the same procedure as described for Intermediate 60, and the title compound (2.75 g) was obtained as a yellow oil. [M+H] + m / z 581.6.

[0513] Intermediate 66

Chemical Structure

[0514] tert-Butyl-(3R)-3-methyl-7-oxo-1-({[(1s,4s)-4-(2-fluoro-6-hydroxyphenyl)cyclohexyl]-oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0515] Intermediate 65 (330 mg) was dissolved in ethanol (11.095 mL), the atmosphere was evacuated and filled with nitrogen three times. Palladium on carbon (10%, 242 mg, 0.227 mmol) was added, the atmosphere was evacuated and filled with hydrogen three times. The reaction mixture was stirred for 16 hours, then filtered through celite, washed with EtOAc, and the filtrate was concentrated in vacuo to give the title compound (270 mg) as a yellow oil. [M+H]+ m / z 493.4.

[0516] Intermediate 67

Chemical Structure

[0517] tert-Butyl (3R)-3-methyl-7-oxo-1-({[(1s,4s)-4-{2-[2-(tert-butoxy)-2-oxoethoxy]-6-fluorophenyl}cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0518] To a solution of Intermediate 66 (270 mg) and tert-butyl 2-bromoacetate (209 mg, 1.05 mmol) in acetonitrile (6.7 mL) was added potassium carbonate (145 mg, 1.05 mmol), and the solution was heated at 50 °C for 3 hours. The solid was filtered off, and the filtrate was concentrated in vacuo. The residue was suspended in water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were concentrated in vacuo to give the title compound (250 mg) as a yellow oil. [M+H] + m / z 607.5.

[0519] Intermediate 68

Chemical formula

[0520] (3R)-3-Methyl-7-oxo-1-({[(1s,4s)-4-[2-(carboxymethoxy)-6-fluorophenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decan-2-ium chloride

[0521] 4M Hydrogen chloride in dioxane (1.6 mL, 6.59 mmol) was added to Intermediate 67 (250 mg) at room temperature, and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (250 mg) as a yellow solid. [M+H] + m / z 451.3

[0522] Examples 17a and 17b

Chemical formula

[0523] Example 17a: (1’S,3S,12’R,15’R,18’S)-3’-fluoro-12’-methyl-8’,17’-dioxa-11’-azaspiro[morpholine-3,14’-tetracyclo[16.2.2.0 2 , 7 .0 11 , 15 docosane]-2’,4’,6’-triene-5,10’-dione

[0524] Example 17b: (1’S,3R,12’R,15’S,18’S)-3’-fluoro-12’-methyl-8’,17’-dioxa-11’-azaspiro[morpholine-3,14’-tetracyclo[16.2.2.0 2 , 7 .0 11 , 15 docosane]-2’,4’,6’-triene-5,10’-dione

[0525] To a stirred solution of HATU (201 mg, 0.529 mmol) and DIPEA (182 μL, 1.04 mmol) in acetonitrile (24.3 mL) was added intermediate 68 (250 mg) in DMF (2.4 mL) using a syringe pump over 2 h. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo to give a crude material. The mixture was diluted with water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated to give a solid residue. The crude material was purified by basic reverse-phase column chromatography (15 - 45% acetonitrile in water (0.1% ammonia)) to give the title compound (peak 1, 8.6 mg) as a white solid and (peak 2, 11.3 mg) as a white solid.

[0526] Example 17a: Peak 1

[0527] LCMS (Method A): [M + H] + m / z 433.3, RT 3.03 min

[0528] 1 H NMR (500 MHz, CDCl 3) δ 7.47 (s, 1H), 7.12 - 7.05 (m, 1H), 6.74 - 6.65 (m, 1H), 6.60 - 6.49 (m, 1H), 5.02 - 4.91 (m, 1H), 4.41 - 4.15 (m, 5H), 3.88 (s, 1H), 3.76 - 3.56 (m, 2H), 3.29 - 3.11 (m, 2H), 2.80 - 2.62 (m, 1H), 2.44 - 2.25 (m, 2H), 2.21 - 2.07 (m, 3H), 2.00 - 1.88 (m, 1H), 1.44 - 1.37 (m, 3H), 1.32 - 1.28 (m, 4H).

[0529] Example 17b: Peak 2

[0530] LCMS (Method A): [M+H] + m / z 433.3, RT 3.23 min

[0531] 1 1H NMR (500 MHz, CDCl 3 ) δ 7.17 - 7.02 (m, 1H), 6.71 (t, J = 8.8 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.28 (s, 1H), 5.06 (d, J = 10.3 Hz, 1H), 4.73 - 4.60 (m, 1H), 4.55 (s, 1H), 4.39 - 4.21 (m, 3H), 4.13 (d, J = 16.8 Hz, 1H), 4.03 (d, J = 11.5 Hz, 1H), 3.91 - 3.74 (m, 1H), 3.60 (d, J = 11.6 Hz, 1H), 3.24 (d, J = 9.8 Hz, 1H), 3.19 - 3.07 (m, 1H), 2.74 - 2.59 (m, 1H), 2.55 - 2.33 (m, 1H), 2.17 - 2.01 (m, 2H), 1.90 - 1.75 (m, 2H), 1.59 - 1.48 (m, 1H), 1.47 - 1.29 (m, 6H).

[0532] The following examples were prepared using appropriate reagents according to the same procedures as described for Examples 17a and 17b.

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Chemical formula

[0533] Intermediate 69

Chemical formula

[0534] tert-Butyl (3R)-1-({[4-(2-{[(1E)-3-(tert-Butoxy)-3-oxoprop-1-en-1-yl]oxy}-3-fluorophenyl)cyclohex-3-en-1-yl]oxy}methyl)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0535] To a solution of tert-butyl prop-2-ynoate (436 μL, 3.18 mmol) and 1,4-diazabicyclo[2.2.2]octane (117 mg, 1.04 mmol) in THF (2.1 mL) was added intermediate 61 (1.30 g) in THF (11 mL) at 0 °C under nitrogen, and the solution was stirred at room temperature for 5 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with brine and dried over MgSO 4 and concentrated in vacuo to afford a crude product. The crude product was purified by silica gel column chromatography (0 - 80% EtOAc in heptane) to give the title compound (1.48 g) as a yellow oil. [M + H] + m / z 617.5.

[0536] Intermediate 70

Chem.

[0537] tert-butyl (3R)-3-methyl-7-oxo-1-({[(1s,4s)-4-{2-[3-(tert-butoxy)-3-oxopropoxy]-3-fluorophenyl}cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0538] Intermediate 69 (1.48 g) was dissolved in ethanol (40 mL), the atmosphere was evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 255 mg, 0.240 mmol) was added, the atmosphere was evacuated and backfilled with hydrogen three times. The reaction was stirred for 16 h, then filtered through Celite, washed with EtOAc, and the filtrate was concentrated in vacuo to afford a crude product. The crude material was purified by silica gel column chromatography (0 - 80% EtOAc in heptane) to give the title compound (1.2 g) as a colorless oil. [M + H] + m / z 621.5.

[0539] Intermediate 71

Chem.

[0540] (3R)-3-Methyl-7-oxo-1-({[(1s,4s)-4-[2-(2-carboxyethoxy)-3-fluorophenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-ium chloride

[0541] 4M hydrogen chloride in dioxane (4.8 mL, 19.3 mmol) was added to Intermediate 70 (1.20 g) at room temperature and the reaction was stirred for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound (1.0 g) as an orange solid. [M+H] + m / z 463.4

[0542] Example 24a and 24b

Chemical Structure

[0543] Example 24a: (1’s,3S,13’R,16’R,19’s)-6’-Fluoro-13’-methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0544] Example 24b: (1’s,3R,13’R,16’S,19’s)-6’-Fluoro-13’-methyl-8’,18’-dioxa-12’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 12 , 16 tricosane]-2’(7’),3’,5’-triene-5,11’-dione

[0545] To a stirred solution of HATU (908 mg, 2.39 mmol) and DIPEA (822 μL, 4.70 mmol) in acetonitrile (110 mL) was added intermediate 71 (0.74 g) in DMF (11 mL) using a syringe pump over 2 h. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo to afford the crude material. The crude material was diluted with water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a solid residue. The crude material was purified by basic reverse-phase column chromatography (15 - 45% acetonitrile in water (0.1% ammonia)) to afford the title compound (245 mg) as a mixture of diastereoisomers as a yellow solid. The mixture of diastereoisomers (245 mg) was subjected to chiral preparative purification and eluted with 5 - 95% acetonitrile in water (0.2% ammonia), X-Bridge (100 × 30 mm), 5 μm, flow rate 40 mL / min to afford the title compound (peak 1, 43 mg) as a white solid and (peak 2, 26 mg) as a white solid.

[0546] Example 24a: Peak 1

[0547] LCMS (Method A): [M+H] + m / z 447.3, RT 3.15 min

[0548] 1 H NMR (500 MHz, CDCl 3 ) δ 7.46 (s, 1H), 6.98 - 6.74 (m, 3H), 5.87 (s, 1H), 5.27 (s, 0H), 4.78 - 4.57 (m, 1H), 4.45 - 3.96 (m, 5H), 3.99 - 3.60 (m, 4H), 3.56 - 3.35 (m, 1H), 3.22 - 3.06 (m, 1H), 2.54 - 2.43 (m, 1H), 2.40 - 1.88 (m, 7H), 1.60 (d, J = 6.9 Hz, 2H), 1.50 - 1.41 (m, 2H), 1.38 (d, J = 6.3 Hz, 1H), 1.34 - 1.28 (m, 1H).

[0549] Example 24b: Peak 2

[0550] LCMS (Method A): [M+H] + m / z 447.3, RT 3.27 min

[0551] 1 1H NMR (500 MHz, CDCl 3 ) δ 6.97 - 6.88 (m, 2H), 6.88 - 6.83 (m, 1H), 6.14 (s, 1H), 4.63 (dd, J = 9.7, 2.4 Hz, 1H), 4.56 (ddd, J = 8.8, 4.9, 2.5 Hz, 1H), 4.46 (dq, J = 9.4, 6.6 Hz, 1H), 4.39 (d, J = 1.9 Hz, 1H), 4.28 - 4.19 (m, 2H), 4.12 (d, J = 16.7 Hz, 1H), 4.06 - 3.98 (m, 1H), 3.79 (s, 1H), 3.62 (d, J = 11.6 Hz, 1H), 3.21 (ddd, J = 13.9, 11.0, 2.6 Hz, 1H), 3.15 (dd, J = 9.7, 1.5 Hz, 1H), 2.67 - 2.55 (m, 1H), 2.52 - 2.39 (m, 2H), 2.26 - 2.15 (m, 2H), 2.09 - 1.97 (m, 1H), 1.85 (d, J = 12.9 Hz, 1H), 1.82 - 1.76 (m, 1H), 1.54 - 1.45 (m, 2H), 1.40 (d, J = 6.6 Hz, 3H), 1.37 (d, J = 2.4 Hz, 1H), 1.35 - 1.27 (m, 1H).

[0552] The following examples were prepared according to the same procedures as described for Examples 24a and 24b using appropriate reagents.

Table 4

[0553] Intermediate 72 [Chemistry]

[0554] Benzyl (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-5-methyl-3-oxopyrrolidine-1-carboxylate

[0555] To a mixture of benzyl (2R)-2-methyl-4-oxo-pyrrolidine-1-carboxylate (52.24 g, 223.95 mmol) and toluene (200 mL) was added pyrrolidine (19.16 mL, 233.28 mmol) at room temperature. The mixture was heated under reflux for 3 hours using a Dean-Stark apparatus and then the mixture was concentrated under reduced pressure. The residue was co-evaporated twice with anhydrous MeCN (2 × 100 mL) and then dissolved in anhydrous MeCN (200 mL) under nitrogen. A solution of 1-bromo-3-(bromomethyl)-2-fluoro-benzene (50.0 g, 186.62 mmol) in anhydrous MeCN (100 mL) was added dropwise and then the mixture was heated under reflux for 2 hours. The mixture was concentrated under reduced pressure and then partitioned between water (50 mL) and EtOAc (400 mL). The mixture was acidified with 2N aqueous HCl (150 mL) and stirred at room temperature for 1 hour. The biphasic mixture was separated and the aqueous layer was further extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with water (400 mL), brine (200 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel column chromatography (5 - 25% EtOAc in cyclohexane) to give the title compound (71 g) as an orange oil. [M+H] + m / z 420.3, 422.3

[0556] Intermediate 73 [Chemistry]

[0557] Benzyl (3E,5R)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxyimino)-5-methylpyrrolidine-1-carboxylate

[0558] To a solution of Intermediate 72 (71 g) and hydroxylamine hydrochloride (12.0 g, 172.69 mmol) in ethanol (300 mL) was added triethylamine (30 mL, 215.24 mmol). The solution was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (250 mL) and extracted with EtOAc (3 × 100 ml). The combined organic phases were washed with water (150 mL) and brine (150 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to afford the title compound (79 g) as a yellow oil. [M+H] + m / z 435.3, 437.3

[0559] Intermediate 74

Chemical Structure

[0560] Benzyl (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-5-methyl-3-nitropyrrolidine-1-carboxylate

[0561] A solution of trifluoroacetic anhydride (54.7 mL, 393.35 mmol) was added dropwise to a stirred solution of hydrogen peroxide-urea (1:1) (47.62 g, 506.23 mmol) in acetonitrile (280 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The resulting solution was added dropwise to a mixture of Intermediate 73 (75.0 g) and sodium hydrogen carbonate (70.55 g, 829.9 mmol) in anhydrous acetonitrile (280 mL) at 80 °C over 1 h. The reaction mixture was cooled to room temperature and saturated Na 2 SO 3Quenched with aqueous solution (200 mL), stirred for 10 minutes, and then extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with brine (250 mL), dried over Na 2 SO 4 filtered, and concentrated in vacuo to afford the crude material. The crude material was purified by silica gel column chromatography (5 - 30% EtOAc in cyclohexane) to give the title compound (73.6 g) as a yellow oil. [M + H] + m / z 451.3, 453.3

[0562] Intermediate 75

Chem.

[0563] Benzyl (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-5-methyl-3-nitropyrrolidine-1-carboxylate

[0564] Formaldehyde (37% in water, 73.0 mL, 980.4 mmol) was added to Intermediate 74 (73.6 g) and triethylamine (25 mL, 179.37 mmol) in THF (280 mL) at room temperature. The solution was heated to 70 °C for 3 hours. After cooling, the reaction mixture was diluted with water (400 mL) and extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with saturated NH 4 Cl aqueous solution (300 mL), water (200 mL), and brine (100 mL), dried over Na 2 SO 4 filtered, and concentrated in vacuo to give the title compound (44 g) as a yellow oil. [M + H] + m / z 481.3, 483.3

[0565] Intermediate 76

Chem.

[0566] Benzyl (5R)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate

[0567] A suspension of intermediate 75 (44.0 g) and zinc (28.09 g, 429.66 mmol) in acetic acid (50 mL) and ethanol (140 mL) was stirred at room temperature for 1 hour. Next, the mixture was heated to 60 °C for 1 hour. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and washed with methanol. The filtrate was diluted with toluene (100 mL) and concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated K 2 CO 3 aqueous solution. The resulting white slurry was filtered through celite and washed with EtOAc. The filtrate was separated and the aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to afford the title compound (40 g) as a yellow oil. [M+H] + m / z 451.3, 453.3.

[0568] Intermediate 77

Chemical Structure

[0569] Benzyl (3R)-1-[(3-bromo-2-fluorophenyl)methyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0570] To a solution of intermediate 76 (9.2 g) in THF (45 mL) was added potassium carbonate (8.45 g, 61.15 mmol) at 0 °C, followed by water (45 mL). To this mixture was added chloroacetyl chloride (2.27 mL, 28.54 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was saturated with NaHCO 3It was quenched with aqueous solution (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine (40 mL), dried (Na 2 SO 4 ), filtered, and concentrated to obtain an oily residue. The intermediate was dissolved in DCM (45 mL) and IPA (45 mL) and cooled to 0 °C. Potassium 2-methylpropane-2-olate (9.15 g, 81.54 mmol) was added and the reaction mixture was stirred at 0 °C for 30 minutes. The mixture was poured into saturated NaHCO 3 aqueous solution (100 ml), then concentrated to remove DCM and IPA. The aqueous suspension was extracted with EtOAc (2 × 100 mL), the combined organic extracts were washed with brine (50 mL), dried (Na 2 SO 4 ), filtered, and concentrated to obtain the title compound (9.6 g) as a colorless oil. [M+H] + m / z 491.3, 493.3.

[0571] Intermediate 78

Chemical Structure

[0572] Benzyl (3R)-1-({2-fluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl}methyl)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0573] XPHOS Pd G3 (258.4 mg, 0.310 mmol), Intermediate 77 (1.5 g), 1 M aqueous potassium phosphate solution (12.21 ml, 12.21 mmol), THF (30 mL), and 2 M aqueous solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (767.8 μL, 3.66 mmol) were added to a microwave vial, which was purged with nitrogen for 10 minutes. The reaction mixture was heated at 70 °C for 18 hours. After cooling the mixture to room temperature, it was filtered through celite and washed with EtOAc. The mixture was washed with water (20 mL), brine (20 mL), and Na 2 SO4 It was dried, filtered, and concentrated under reduced pressure to obtain a crude substance. The crude substance was purified by silica gel column chromatography (0 - 100% EtOAc in DCM) to obtain the title compound (1.16 g) as a white solid. [M+H] + m / z 505.2

[0574] Intermediate 79

Chemical Structure

[0575] Benzyl (3R)-1-({2’-[(3-ethoxy-3-oxoprop-1-en-1-yl)oxy]-2-fluoro-[1,1’-biphenyl]-3-yl}methyl)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0576] To a solution of ethyl prop-2-ynoate (33.2 μL, 0.330 mmol) and 1,4-diazabicyclo[2.2.2]octane (13 mg, 0.120 mmol) in THF (7.4 mL), intermediate 78 (150 mg) in THF (2.5 mL) was added at 0 °C under a nitrogen atmosphere, and the solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 15 mL). The organic phase was washed with brine and dried over Na 2 SO 4 It was dried and concentrated in vacuo to obtain the title compound (160 mg) as a yellow solid. [M+H] + m / z 603.3

[0577] Intermediate 80

Chemical Structure

[0578] 3-[(3’-{[(3R)-2-[(Benzyloxy)carbonyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decan-1-yl]methyl}-2’-fluoro-[1,1’-biphenyl]-2-yl)oxy]prop-2-enoic acid

[0579] To a solution of intermediate 79 (153 mg) in 2-propanol (3.3 mL) and water (3.3 mL) was added 2M aqueous lithium hydroxide (54.55 mg, 1.27 mmol) at room temperature, and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water (5 mL), neutralized to pH 4 with 2M aqueous HCl, and then extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over Na 2 SO 4 and concentrated in vacuo to afford the title compound (152 mg) as an off-white solid. [M+H] + m / z: 575.2

[0580] Intermediate 81

Chemical Structure

[0581] 3-[(2’-Fluoro-3’-{[(3R)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decan-1-yl]methyl}-[1,1’-biphenyl]-2-yl)oxy]propanoic acid

[0582] Intermediate 80 (128 mg) was dissolved in methanol (5 mL), the atmosphere was evacuated and backfilled with nitrogen three times. Palladium on carbon (23.71 mg, 0.020 mmol) was added, the atmosphere was evacuated and backfilled with hydrogen three times. The reaction was stirred for 18 h, filtered through celite, washed with methanol and concentrated in vacuo to afford the title compound (91 mg) as a white solid. [M+H] + m / z 443.3

[0583] Example 26

Chemical Structure

[0584] (13’R)-22’-fluoro-13’-methyl-8’-oxa-12’-azaspiro[morpholine-3,15’-tetracyclo[16.3.1.0 2,7 .0 12,16 docosane]-1’(22’),2’(7’),3’,5’,18’,20’-hexaene-5,11’-dione

[0585] A solution of intermediate 81 (77 mg) in DMA (8 mL) was added dropwise to a stirred solution of HATU (53.6 mg, 0.140 mmol) and DIPEA (32.74 μL, 0.190 mmol) in MeCN (200 mL) under nitrogen at 25 °C over 2 h via a syringe pump. After an additional 30 min, the reaction mixture was concentrated under reduced pressure. The crude mixture was dissolved in diethyl ether and then washed with water:brine 1:1 (×3). The aqueous phase was back-extracted with diethyl ether (×2). The combined organic extracts were then filtered through a phase separator and concentrated under reduced pressure to give a crude material, which was purified by reverse-phase column chromatography (0 - 55% MeCN in water) to give a crude residue, which was further purified using silica gel column chromatography (0 - 5% methanol in DCM) to give a crude product. The crude product was purified by preparative HPLC: mass spectrometry detection (MS: ZQ2000) on MDAP Waters. Column: CSH C18 (30 × 100 mm, 3 - μm). Conditions: [A1: water + 0.1% HCOOH]; [B1: MeCN]. Gradient: 34.0% B1 - 35.0% B1, 10 min (flow rate: 40.00 mL / min). Detection: UV / Vis detection range 210 nm - 350 nm, MS (ES+ / ES-) scan range 100 - 1000 AMU, to give the title compound (1.8 mg) as a white foam.

[0586] LCMS (method C): [M + H] + m / z 425.3, RT 0.84 min

[0587] 1 H NMR (400 MHz, CDCl 3) δ 7.28 - 7.47 (m, 3 H), 7.10 - 7.24 (m, 4 H), 6.21 (s, 1 H), 4.72 (dd, J=12.5, 3.1 Hz, 1 H), 4.26 - 4.35 (m, 1 H), 4.12 - 4.23 (m, 2 H), 3.81 - 4.02 (m, 1 H), 3.59 - 3.76 (m, 2 H), 3.49 (d, J=11.6 Hz, 1 H), 2.79 - 3.05 (m, 3 H), 2.52 - 2.65 (m, 1 H), 2.07 (dt, J=13.0, 3.1 Hz, 1 H), 1.95 (dd, J=13.7, 8.7 Hz, 1 H), 1.72 (d, J=6.2 Hz, 3 H)

Chem.

[0588] Intermediate 82

Chem.

[0589] Benzyl (3R)-3-methyl-7-oxo-1-({2,3’,5’-trifluoro-[1,1’-biphenyl]-3-yl}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0590] To a solution of intermediate 78 (150 mg) in THF (3.0 mL), 4-hydroxybutyric acid tert-butyl ester (73.2 μL, 0.450 mmol), and triphenylphosphine (116.97 mg, 0.450 mmol) was added diisopropyl azodicarboxylate (87.55 μL, 0.450 mmol) at 0 °C under a nitrogen atmosphere. The ice bath was removed and the reaction mixture was heated at 70 °C overnight. Next, the crude mixture was cooled, diluted with EtOAc, and quenched with water. Then, the aqueous phase was back-extracted with EtOAc (×2), the combined organic extracts were filtered through a phase separator, and concentrated under reduced pressure. The crude material was purified by reverse-phase column chromatography (0 - 100% MeCN in water) to afford the title compound (143 mg) as a white solid. [M+H] + m / z 647.3

[0591] Intermediate 83

Chem.

[0592] 4-[(3’-{[(3R)-2-[(Benzyloxy)carbonyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-1-yl]methyl}-2’-fluoro-[1,1’-biphenyl]-2-yl)oxy]butanoic acid

[0593] To a stirred solution of intermediate 82 (143 mg) in DCM (2.211 mL) at 25 °C was added trifluoroacetic acid (851.72 μL, 11.06 mmol). The mixture was stirred for 2 hours, then the reaction was quenched with water and diluted with DCM. The organic phase was washed with water (×2), filtered through a phase separator, diluted with 10 mL of toluene, and then concentrated under reduced pressure to afford the title compound (150 mg) as a pale yellow solid. [M+H] + m / z 591.2

[0594] Intermediate 84

Chem.

[0595] 4-[(2’-Fluoro-3’-{[(3R)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-1-yl]methyl}-[1,1’-biphenyl]-2-yl)oxy]butanoic acid

[0596] To a stirred solution of Intermediate 83 (162.5 mg) in ethanol (8.07 mL) was added Pd / C 10% wt. (25.77 mg, 0.020 mmol), and then the reaction mixture was stirred at 25 °C overnight under 1 atm of molecular hydrogen (0.49 mg, 0.240 mmol). The reaction was filtered through cellulose paper, washed with methanol in vacuo, and the filtrate was concentrated under reduced pressure to afford the title compound (113 mg) as a white solid. [M+H] + m / z 457.3

[0597] Example 27

Chemical formula

[0598] (14’R)-23’-Fluoro-14’-methyl-8’-oxa-13’-azaspiro[morpholine-3,16’-tetracyclo[17.3.1.0 2,7 .0 13,17 tricosane]-1’(23’),2’(7’),3’,5’,19’,21’-hexaene-5,12’-dione

[0599] Under nitrogen, a solution of intermediate 84 (102 mg) in DMA (8 mL) was added dropwise to a solution of HATU (127.43 mg, 0.340 mmol) and DIPEA (77.83 μL, 0.450 mmol) in MeCN (89.16 mL) at 25 °C over 2 hours using a syringe pump. After an additional 30 minutes, the reaction mixture was concentrated under reduced pressure. The crude mixture was dissolved in ethyl acetate and then washed with water (×3). The aqueous phase was back-extracted with diethyl ether (×2), and then the combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase column chromatography (0 - 40% MeCN in water) to give the title compound (83.2 mg) as a white foam.

[0600] LCMS (Method C): [M + H] + m / z 463.2, RT 0.92 min.

[0601] 1 H NMR (500 MHz, CDCl 3 ) δ 7.23 - 7.41 (m, 2 H), 7.02 - 7.26 (m, 4 H), 6.83 - 7.02 (m, 1 H), 6.36 - 6.78 (m, 1 H), 4.15 - 4.81 (m, 1 H), 4.14 - 4.38 (m, 2 H), 3.81 - 4.21 (m, 1 H), 3.66 - 4.16 (m, 2 H), 3.29 - 3.67 (m, 2 H), 2.74 - 3.11 (m, 2 H), 1.63 - 2.70 (m, 6 H), 1.37 - 1.61 (m, 3 H)

Chem.

[0602] Intermediate 85

Chem.

[0603] (3E)-4-(2-Bromophenyl)but-3-enoic acid

[0604] A suspension of 2-carboxyethyl(triphenyl)phosphonium bromide (4.94 g, 11.89 mmol) in THF (30 mL) and DMSO (10 mL) was added with sodium hydride (951 mg, 23.78 mmol) at room temperature. After 10 minutes, 2-bromobenzaldehyde (1.26 mL, 10.81 mmol) in THF (1.26 mL) was added dropwise. The resulting mixture was stirred at room temperature for 18 hours. Next, the reaction mixture was acidified to about pH 4 with 1 M aqueous HCl and extracted with EtOAc (20 mL). The organic phase was washed with basic water (NaOH) to about pH 8. Next, the aqueous washings were acidified to about pH 4 with 1 M aqueous HCl and extracted with EtOAc (20 mL). The combined organics were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude material. The crude material was purified by silica gel column chromatography (10% methanol in DCM) to obtain the title compound (1.45 g) as a yellow solid. [M+H] + m / z 241.0, 243.0

[0605] Intermediate 86

Chemical formula

[0606] (3E)-4-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]but-3-enoic acid

[0607] Potassium acetate (1.33 g, 13.58 mmol), [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (199.4 mg, 0.270 mmol), Intermediate 85 (1.31 g), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dioxaborolane (2.07 g, 8.15 mmol), CPME (23 mL) were added with N 2It was degassed for 10 minutes. While stirring the mixture, it was heated at 100 °C for 18 hours. The reaction product was cooled to room temperature, filtered through a Celite pad, washed with diethyl ether, and concentrated under reduced pressure to obtain the title compound (3.1 g) as a yellow solid. [M+H] + m / z 289.2

[0608] Intermediate 87

Chem.

[0609] Methyl (3E)-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]but-3-enoate

[0610] To a mixture of Intermediate 86 (3.0 g) and methanol (15 mL), trimethylsilyldiazomethane (ca. 10% in hexane, ca. 0.6 mol / L) (34.7 mL, 20.82 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was warmed to room temperature and concentrated under reduced pressure to obtain a crude substance. The crude substance was purified by silica gel column chromatography (0 - 10% EtOAc in cyclohexane) to obtain the title compound (1.35 g) as a yellow solid. [M+H] + m / z 303.3

[0611] Intermediate 88

Chem.

[0612] Methyl 4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate

[0613] The mixture of Intermediate 87 (1.3 g) was dissolved in methanol (30 mL), the atmosphere was evacuated, and the vessel was filled with nitrogen three times. Palladium on carbon (10%, 475 mg, 0.450 mmol) was added, the atmosphere was evacuated, and the vessel was filled with hydrogen three times. The reaction mixture was stirred for 1 hour, filtered through celite, washed with methanol, and concentrated in vacuo to afford the title compound (721 mg) as an off-white solid. [M+H] + m / z 305.2

[0614] Intermediate 89

Chem.

[0615] Benzyl (3R)-1-{[2-fluoro-2'-(4-methoxy-4-oxobutyl)-[1,1'-biphenyl]-3-yl]methyl}-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0616] XPHOS Pd G3 (137.8 mg, 0.160 mmol), Intermediate 77 (400 mg), 0.6 M aqueous tripotassium phosphate solution (4.07 ml, 2.44 mmol), THF (10 mL), and Intermediate 88 (619 mg) were added to a microwave vial, which was purged with nitrogen for 10 minutes. The reaction mixture was heated at 70 °C for 1 hour. After the mixture was cooled to room temperature, it was filtered through celite and washed with EtOAc. The mixture was washed with water (20 mL) and brine (20 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a crude material. The crude material was purified by silica gel column chromatography (0 - 5% methanol in DCM) to afford the title compound (444 mg) as an orange oil. [M+H] + m / z 589.3.

[0617] Intermediate 90

Chem.

[0618] 4-(3’-{[(3R)-2-[(Benzyloxy)carbonyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-1-yl]methyl}-2’-fluoro-[1,1’-biphenyl]-2-yl)butanoic acid

[0619] To a solution of intermediate 89 (444 mg) in THF (10 mL) and water (10 mL) was added lithium hydroxide hydrate (124.8 mg, 2.9 mmol) at room temperature, and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water (5 mL), neutralized to pH 4 with 1 M aqueous HCl, and then extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over Na 2 SO 4 and concentrated in vacuo to afford the title compound (468 mg) as an orange oil. [M+H] + m / z: 575.4

[0620] Intermediate 91

Chemical formula

[0621] 4-(2’-Fluoro-3’-{[(3R)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-1-yl]methyl}-[1,1’-biphenyl]-2-yl)butanoic acid

[0622] Intermediate 90 (468 mg) was dissolved in methanol (10 mL), the atmosphere was evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 39 mg, 0.040 mmol) was added, the atmosphere was evacuated and backfilled with hydrogen three times. The reaction mixture was stirred for 18 h, filtered through celite, washed with methanol and concentrated in vacuo to afford the title compound (354 mg) as a yellow oil. [M+H] + m / z 441.3

[0623] Example 28

Chemical formula

[0624] (13’R)-22’-fluoro-13’-methyl-12’-azaspiro[morpholine-3,15’-tetracyclo-[16.3.1.0 2,7 .0 12,16 docosane]-1’(22’),2’(7’),3’,5’,18’,20’-hexaene-5,11’-dione

[0625] Under nitrogen, a solution of intermediate 91 (354 mg) in DMA (15 mL) was added dropwise to a solution of HATU (307 mg, 0.810 mmol) and DIPEA (187.46 μL, 1.08 mmol) in MeCN (650 mL) at 25 °C over 2 hours via a syringe pump. After an additional 30 minutes, the reaction mixture was concentrated under reduced pressure. The crude mixture was dissolved in diethyl ether and then washed with water:brine 1:1 (×3). The aqueous phase was back-extracted with diethyl ether (×2), and then the combined organic phases were filtered through a phase separator and concentrated under reduced pressure to obtain the crude material. The crude material was purified by silica gel column chromatography (0 - 5% methanol in DCM) to obtain the crude product. The crude product was purified by preparative HPLC: mass spectrometry detection (MS: ZQ2000) on MDAP Waters. Column: CSH C18 (30 × 100 mm, 3 - m). Conditions: [A1: water + 0.1% HCOOH]; [B1: MeCN]. Gradient: 34.0% B1 - 35.0% B1, 10 minutes (flow rate: 40.00 mL / min). Detection: UV / Vis detection range 210 nm - 350 nm, MS (ES+ / ES-) scan range 100 - 1000 AMU, to obtain the title compound (23 mg) as a white solid.

[0626] LCMS (method C): [M + H] + m / z 423.2, RT 0.92 minutes

[0627] 1 H NMR (500 MHz, CDCl 3) δ 7.24 - 7.40 (m, 5H), 6.96 - 7.21 (m, 2H), 6.28 - 6.59 (m, 1H), 4.57 - 4.84 (m, 1H), 4.07 - 4.36 (m, 2H), 3.74 - 4.00 (m, 1H), 3.66 (br d, J = 11.8 Hz, 1H), 3.47 (d, J = 11.8 Hz, 1H), 2.42 - 3.43 (m, 2H), 2.42 - 2.57 (m, 2H), 2.34 - 2.42 (m, 2H), 1.96 - 2.07 (m, 1H), 1.85 - 1.97 (m, 2H), 1.70 - 1.84 (m, 1H), 1.31 - 1.48 (m, 3H). [Chemistry]

[0628] Intermediate 92 [Chemistry]

[0629] Benzyl (3R)-1-{[2-fluoro-2'-(trifluoromethanesulfonyloxy)-[1,1'-biphenyl]-3-yl]methyl}-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0630] To a mixture of Intermediate 78 (300 mg) and DCM (12 mL) was added triethylamine (100.0 μL, 0.720 mmol) and trifluoromethylsulfonyloxy trifluoromethanesulfonate (100.03 μL, 0.590 mmol) at -20 °C. The reaction mixture was stirred at -20 °C for 1 h. Additional trifluoromethylsulfonyloxy trifluoromethanesulfonate (17.0 μL, 0.100 mmol) was added and the mixture was stirred at room temperature overnight. Additional triethylamine (16.57 μL, 0.120 mmol) and trifluoromethylsulfonyloxy trifluoromethanesulfonate (20.01 μL, 0.120 mmol) were added. Stirring was continued for 2 h and the mixture was diluted with EtOAc and washed with saturated NaHCO 3 aqueous solution. The combined organic extracts were dried through a phase separator and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0 - 50% EtOAc in DCM) to give the title compound (359 mg) as a colorless oil. [M+H] + m / z 637.4

[0631] Intermediate 93

Chemical Structure

[0632] Benzyl (3R)-1-{[2-fluoro-2'-(5-methoxy-5-oxopent-1-yn-1-yl)-[1,1'-biphenyl]-3-yl]methyl}-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0633] Dicyclohexyl-[2-[2,4,6-tri(propane-2-yl)phenyl]phenyl]phosphine (40.21 mg, 0.080 mmol), palladium dichlorobis(acetonitrile) (7.35 mg, 0.030 mmol), cesium carbonate (549.68 mg, 1.69 mmol) were charged into a microwave vial and sealed. The vial was purged with nitrogen for 10 minutes, then a solution of intermediate 92 (358 mg) in anhydrous MeCN (5.5 mL) (previously sparged with a nitrogen stream for 15 minutes) was added, followed by methyl pent-4-ynoate (126.11 mg, 1.12 mmol). The reaction mixture was further purged for 5 minutes and then heated to 80 °C for 2 hours. The mixture was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in EtOAc and washed with water and brine. The organic phase was filtered through a phase separator and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel column chromatography (0 - 100% EtOAc in DCM) to give the title compound (274 mg) as a pale yellow foam. [M+H] + m / z 599.12

[0634] Intermediate 94 [Chemical formula]

[0635] 5-(3’-{[(3R)-2-[(benzyloxy)carbonyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-1-yl]methyl}-2’-fluoro-[1,1’-biphenyl]-2-yl)penta-4-ynoic acid

[0636] To a solution of intermediate 93 (274 mg) in THF (6 mL) and water (6 mL), lithium hydroxide hydrate (98.33 mg, 2.29 mmol) was added as a solid all at once at 25 °C. The reaction mixture was stirred for 20 minutes and concentrated under reduced pressure to remove THF. The pH of the aqueous phase was adjusted to 2 - 3 with 0.1 M aqueous HCl, and then the aqueous phase was extracted with EtOAc (×3). The combined organic phases were filtered through a phase separator and concentrated under reduced pressure, and triturated with diethyl ether to afford the title compound (264 mg) as a pale yellow foam. [M+H] + m / z 505.3

[0637] Intermediate 95

Chemical Structure

[0638] 5-(2’-Fluoro-3’-{[(3R)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methyl}-[1,1’-biphenyl]-2-yl)pentanoic acid

[0639] To a stirred solution of intermediate 94 (264 mg) in ethanol (15.11 mL), 10% wt. Pd / C (48.06 mg, 0.050 mmol) was added, and then the reaction mixture was stirred at 25 °C for 24 hours under 1 atm of molecular hydrogen (0.91 mg, 0.450 mmol). The reaction mixture was filtered through a cellulose filter, washed with methanol under vacuum, and the filtrate was concentrated under reduced pressure to afford the title compound (197 mg) as an off-white solid. [M+H] + m / z 455.3

[0640] Example 29

Chemical Structure

[0641] (14’R)-23’-Fluoro-14’-methyl-13’-azaspiro[morpholine-3,16’tetracyclo-[17.3.1.0 2,7 .013,17 Tricosane]-1’(23’),2’(7’),3’,5’,19’,21’-hexaene-5,12’-dione

[0642] Under nitrogen, a solution of intermediate 95 (197 mg) in DMA (16 mL) was added dropwise to a solution of HATU (247.2 mg, 0.650 mmol) and DIPEA (151 μL, 0.870 mmol) in MeCN (179.58 mL) at 25 °C over 2 hours using a syringe pump. After an additional 30 minutes, the reaction mixture was concentrated under reduced pressure. The crude mixture was dissolved in diethyl ether and then washed with water (×3). The aqueous phase was back-extracted with diethyl ether (×2), and then the combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to obtain the crude material. The crude material was purified by reverse-phase column chromatography (0 - 40% MeCN in water) to give the title compound (120 mg) as a pale yellow foam.

[0643] LCMS (Method C): [M + H] + m / z 437.3, RT 0.99 min

[0644] 1 H NMR (500 MHz, CDCl 3 ) δ 7.04 - 7.43 (m, 7 H), 6.25 - 6.65 (m, 1 H), 4.14 - 4.38 (m, 2 H), 4.06 - 4.94 (m, 1 H), 3.75 - 4.23 (m, 1 H), 3.52 - 3.67 (m, 1 H), 3.32 - 3.48 (m, 1 H), 2.82 - 3.12 (m, 2 H), 2.53 - 2.73 (m, 1 H), 2.19 - 2.33 (m, 1 H), 2.18 - 2.54 (m, 1 H), 1.76 - 1.94 (m, 1 H), 1.43 - 1.57 (m, 3 H), 1.11 - 1.43 (m, 1 H), 1.01 - 2.08 (m, 4 H), 0.76 - 1.38 (m, 1 H)

Chemical Structure

[0645] Intermediate 96

Chem.

[0646] Benzyl (3R)-1-{[2’-(2-{[(tert-Butoxy)carbonyl](methyl)amino}ethoxy)-2-fluoro-[1,1’-biphenyl]-3-yl]methyl}-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0647] Tripotassium phosphate (610.56 μL, 1.22 mmol), [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.030 mmol), Intermediate 77 (200 mg), THF (1.357 mL), and a 2 M aqueous solution of tert-Butyl N-methyl-N-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (230.35 mg, 0.610 mmol) were added to a microwave tube. The tube was sealed, then evacuated, filled with nitrogen three times, and then transferred to a metal block preheated to 70 °C and stirred for 5 hours. The mixture was cooled and concentrated under reduced pressure to obtain a crude material. The crude material was purified by silica gel column chromatography (0 - 100% EtOAc in cyclohexane) to obtain the title compound (198 mg) as an orange oil. [M+H] + m / z 662.4

[0648] Intermediate 97

Chem.

[0649] tert-Butyl N-{2-[(2’-Fluoro-3’-{[(3R)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-1-yl]methyl}-[1,1’-biphenyl]-2-yl)oxy]ethyl}-N-methylcarbamate

[0650] To a solution of intermediate 96 (194 mg) in methanol (19.54 mL) was added palladium carbon (10%, 106.42 mg, 0.100 mmol), and the reaction mixture was stirred for 4 hours under an atmosphere of molecular hydrogen (5 atm.). The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under vacuum to give the title compound (274 mg) as a yellow oil. [M+H] + m / z 528.2

[0651] Intermediate 98

Chemical Structure

[0652] (3R)-1-({2-Fluoro-2’-[2-(methylamino)ethoxy]-[1,1’-biphenyl]-3-yl}methyl)-3-methyl-9-oxa-2,6-diazaspiro[4.5]decan-7-one dihydrochloride

[0653] Intermediate 97 (260.19 mg) was dissolved in 4M hydrogen chloride in dioxane (3.21 mL, 12.82 mmol). The reaction mixture was stirred at 25 °C for 2 hours and then concentrated under vacuum to give the title compound (244 mg) as a white solid. [M+H] + m / z 428.2

[0654] Example 30

Chemical Structure

[0655] (14’R)-23’-Fluoro-11’,14’-dimethyl-8’-oxa-11’,13’-diazaspiro[morpholine-3,16’-tetracyclo[17.3.1.0 2,7 .0 13,17 tricosane]-1’(23’),2’(7’),3’,5’,19’,21’-hexaene-5,12’-dione

[0656] Bis(trichloromethyl) carbonate (8.8 mg, 0.030 mmol) was added to a solution of intermediate 98 (115 mg) in DCM (20 mL). The reaction mixture was stirred at 60 °C for 12 h and then concentrated in vacuo to afford the crude reaction mass. The crude material was purified by preparative HPLC: UPLC Waters with a mass spectrometric detector (MS: SQD2). Column: CSH C18 (2.1×50 mm, 1.7-μm). Conditions: [A1: water + 0.1% HCOOH]; [B1: MeCN + 0.1% HCOOH]. Gradient: 3% B1 to 99.9% B1, 1.4 min (flow rate: 0.90 mL / min). Detection: UV / Vis detection range 210 nm to 350 nm, MS (ES+ / ES−) scan range 100 to 1000 AMU, the title compound (3.5 mg) was obtained as a white solid.

[0657] LCMS (Method C): [M + H] + m / z 454.2, RT 0.89 min

[0658] 1 H NMR (400 MHz, CDCl 3) δ 7.39 - 7.28 (m, 2H), 7.25 - 7.17 (m, 1H), 7.16 - 7.08 (m, 2H), 7.08 - 7.02 (m, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.46 (br s, 1H), 4.48 - 4.39 (m, 1H), 4.33 (d, J = 16.9 Hz, 1H), 4.24 (d, J = 16.8 Hz, 1H), 4.21 - 4.15 (m, 1H), 4.05 - 3.97 (m, 1H), 3.91 (br d, J = 11.5 Hz, 1H), 3.74 (br d, J = 11.5 Hz, 1H), 3.74 - 3.68 (m, 2H), 3.66 - 3.56 (m, 1H), 3.19 - 3.01 (m, 1H), 2.87 (s, 3H), 2.71 (br d, J = 13.0 Hz, 1H), 2.23 (dd, J = 13.5, 8.0 Hz, 1H), 1.77 (dd, J = 13.6, 3.9 Hz, 1H), 1.49 (br d, J = 6.7 Hz, 3H)

[0659] Example 31 [Chemical formula]

[0660] (15’R)-24’-fluoro-12’,15’-dimethyl-8’-oxa-12’,14’-diazaspiro[morpholine-3,17’-tetracyclo[18.3.1.0 2,7 .0 14,18 tetracosane]-1’(24’),2’(7’),3’,5’,20’,22’-hexaene-5,13’-dione

[0661] Example 31 was prepared according to the same procedure as described in Example 30 using Intermediate 77 and tert-butyl N-methyl-N-{3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propyl}carbamate, and the title compound (13.1 mg) was obtained as a pink solid.

[0662] LCMS (Method C): [M+H + m / z 468.2, RT 0.97 min

[0663] 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 6.2 Hz, 2H), 7.09 (dt, J = 24.9, 7.3 Hz, 3H), 6.92 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 20.1 Hz, 1H), 4.69 (d, J = 10.2 Hz, 1H), 4.36 - 4.15 (m, 2H), 4.06 - 3.68 (m, 6H), 3.57 (d, J = 11.6 Hz, 1H), 3.24 - 2.98 (m, 3H), 2.65 (s, 3H), 2.48 - 2.29 (m, 2H), 1.90 (s, 1H), 1.70 (dd, J = 13.7, 5.3 Hz, 1H), 1.55 (bs, 3H).

[0664] Example 32

Chemical Structure

[0665] Rel-(1’s,3S,16’R,19’s)-8’,18’-Dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo-[17.2.2.0 2,7 .0 11,16 tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0666] Example 32 was prepared according to the same procedure as described for Example 3 using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate, and the title compound (28 mg) was obtained as a white solid.

[0667] LCMS (Method A): [M+H] + m / z 415.3, RT 2.93 min

[0668] 1 H NMR (500 MHz, CDCl 3 ) δ 7.16 (td, J = 7.8, 1.6 Hz, 1H), 7.11 - 7.06 (m, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.20 (s, 1H), 5.36 (dd, J = 10.1, 3.9 Hz, 1H), 5.10 (d, J = 10.6 Hz, 1H), 4.35 - 4.23(m, 2H), 4.17 - 4.08 (m, 2H), 3.91 - 3.81 (m, 1H), 3.77 - 3.67 (m, 2H), 3.60 - 3.47 (m, 2H), 3.40 (d, J = 11.7 Hz, 1H), 2.60 (dtd, J = 28.3, 12.4, 5.5 Hz, 2H), 2.31 - 2.17 (m, 1H), 2.13 - 2.01 (m, 1H), 1.94 - 1.80 (m,2H), 1.80 - 1.71 (m, 2H), 1.52 - 1.46 (m, 2H), 1.40 - 1.34 (m, 3H).

[0669] Examples 32a and 32b

Chemical formula

[0670] Example 32a: (1’s,3S,16’R,19’s)-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2,7.0 11,16 Tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0671] Example 32b: (1’s,3R,16’S,19’s)-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2,7 .0 11,16 Tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0672] Example 32 (25 mg) was subjected to chiral preparative purification using Waters 600, eluting with 60 / 40% v / v n-hexane / (ethanol + 0.1% isopropylamine), Chiralpak IC (25 × 2.0 cm), 5 μm, flow rate 17 mL / min to obtain the title compound (peak 1, 12.3 mg, 96.6% ee; peak 2, 5.6 mg, 99% ee).

[0673] Example 32a: Peak 1 (tentatively assigned stereochemistry)

[0674] LCMS (method C): [M+H]+ m / z 415.2, RT 0.92 min.

[0675] Chiral analysis (Chiralpak IC, 25 × 0.46 cm, 5 μm, 60:40 n-hexane:(ethanol + 0.1% isopropylamine): RT 9.9 min

[0676] 1 HNMR (500 MHz, CDCl 3) δ 7.17 (td, J = 7.7, 1.6 Hz, 1H), 7.10 (dd, J = 7.4, 1.5 Hz, 1H), 6.93 - 6.88 (m, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.96 (s, 1H), 5.37 (dd, J = 10.0, 3.8 Hz, 1H), 5.11 (d, J = 10.6 Hz, 1H), 4.33 (d, J = 10.6 Hz, 1H), 4.31 (d, J = 16.7 Hz, 1H), 4.15 (d, J = 11.5 Hz, 1H), 4.14 - 4.09 (m, 1H), 3.89 - 3.84 (m, 1H), 3.77 - 3.70 (m, 2H), 3.58 (dd, J = 8.5, 4.1 Hz, 1H), 3.58 - 3.50 (m, 1H), 3.42 (d, J = 11.8 Hz, 1H), 2.70 - 2.60 (m, 1H), 2.62 - 2.53 (m, 1H), 2.30 - 2.20 (m, 1H), 2.09 - 2.03 (m, 1H), 1.92 (br d, J = 13.3 Hz, 1H), 1.89 - 1.83 (m, 1H), 1.81 - 1.76 (m, 1H), 1.77 - 1.69 (m, 1H), 1.67 - 1.59 (m, 1H), 1.54 - 1.48 (m, 1H), 1.46 - 1.33 (m, 3H).

[0677] Example 32b: Peak 2 (tentatively assigned stereochemistry)

[0678] LCMS (Method C): [M+H] + m / z 415.2, RT 0.92 min.

[0679] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 60:40 n - hexane:(ethanol + 0.1% isopropylamine): RT 14.1 min

[0680] 1 HNMR (500 MHz, CDCl3 ) δ 7.17 (td, J = 7.7, 1.6 Hz, 1H), 7.10 (dd, J = 7.4, 1.5 Hz, 1H), 6.93 - 6.88 (m, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.96 (s, 1H), 5.37 (dd, J = 10.0, 3.8 Hz, 1H), 5.11 (d, J = 10.6 Hz, 1H), 4.33 (d, J = 10.6 Hz, 1H), 4.31 (d, J = 16.7 Hz, 1H), 4.15 (d, J = 11.5 Hz, 1H), 4.14 - 4.09 (m, 1H), 3.89 - 3.84 (m, 1H), 3.77 - 3.70 (m, 2H), 3.58 (dd, J = 8.5, 4.1 Hz, 1H), 3.58 - 3.50 (m, 1H), 3.42 (d, J = 11.8 Hz, 1H), 2.70 - 2.60 (m, 1H), 2.62 - 2.53 (m, 1H), 2.30 - 2.20 (m, 1H), 2.09 - 2.03 (m, 1H), 1.92 (br d, J = 13.3 Hz, 1H), 1.89 - 1.83 (m, 1H), 1.81 - 1.76 (m, 1H), 1.77 - 1.69 (m, 1H), 1.67 - 1.59 (m, 1H), 1.54 - 1.48 (m, 1H), 1.46 - 1.33 (m, 3H).

[0681] Example 33 [Chemical Structure]

[0682] Rel-(1’s,3S,17’R,20’s)-8’,19’-Dioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2,7 .0 12,17 tetracosane]-2’(7’),3’,5’-triene-5,11’-dione

[0683] Example 33 was prepared according to the same procedure as described for Example 1 using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate, and the title compound (48 mg) was obtained as a white solid.

[0684] LCMS (Method A): [M+H] + m / z 429.3, RT 2.99 min

[0685] 1 H NMR (500 MHz, CDCl 3 ) δ 8.16 (s, 1H), 7.05 (t, J = 7.1 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.77 - 6.67 (m, 2H), 4.70 (dd, J = 13.8, 4.2 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.23 (d, J = 17.0 Hz, 1H), 4.07 (d, J = 11.9 Hz, 1H), 4.02 (d, J = 16.9 Hz, 1H), 3.97 - 3.91 (m, 1H), 3.81 (t, J = 9.8 Hz, 1H), 3.75 - 3.68 (m, 1H), 3.57 (s, 1H), 3.43 (t, J = 12.2 Hz, 1H), 3.16 (d, J = 12.0 Hz, 1H), 2.70 - 2.57 (m, 1H), 2.58 - 2.49 (m, 1H), 2.44 - 2.31 (m, 2H), 2.19 (d, J = 15.5 Hz, 1H), 1.84 (s, 1H), 1.73 (d, J = 13.8 Hz, 1H), 1.66 (d, J = 4.6 Hz, 2H), 1.44 - 1.34 (m, 2H), 1.33 - 1.19 (m, 4H).

[0686] Examples 33a and 33b

Chemical Structure

[0687] Example 33a: (1’s,3S,17’R,20’s)-8’,19’-Dioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2 , 7 .0 12 , 17 tetracosane]-2’(7’),3’,5’-triene-5,11’-dione

[0688] Example 33b: (1’s,3R,17’S,20’s)-8’,19’-Dioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2 , 7 .0 12 , 17 tetracosane]-2’(7’),3’,5’-triene-5,11’-dione

[0689] Example 33 (44 mg) was subjected to chiral preparative purification using Waters 600, eluting with 75 / 25% v / v n-hexane / (ethanol + 0.1% isopropylamine), Chiralpak OD-H (25×2.0 cm), 5 μm, at a flow rate of 17 mL / min to obtain the title compounds (peak 1, 10.3 mg, 100% ee; and peak 2, 10.4 mg, 100% ee).

[0690] Example 32b: Peak 1 (provisionally assigned stereochemistry)

[0691] LCMS (Method C): [M+H] + m / z 429.4, RT 0.91 min.

[0692] Chiral analysis (Chiralpak OD-H, 25×0.46 cm, 5 μm, 75:25 n-hexane:(ethanol + 0.1% isopropylamine): RT 7.4 min

[0693] 1 HNMR (500 MHz, CDCl 3) δ 7.13 (td, J = 7.7, 1.6 Hz, 1H), 7.03 (br dd, J = 7.4, 1.5 Hz, 1H), 7.02 (br s, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.81 - 6.77 (m, 1H), 4.80 (br dd, J = 14.1, 4.7 Hz, 1H), 4.77 - 4.69 (m, 2H), 4.33 (d, J = 17.0 Hz, 1H), 4.16 (d, J = 11.9 Hz, 1H), 4.12 (d, J = 17.0 Hz, 1H), 4.02 (dt, J = 7.7, 2.7 Hz, 1H), 3.88 (br t, J = 9.7 Hz, 1H), 3.77 (dd, J = 9.3, 2.6 Hz, 1H), 3.66 (br s, 1H), 3.56 - 3.46 (m, 1H), 3.26 (d, J = 11.9 Hz, 1H), 2.78 - 2.68 (m, 1H), 2.63 (qd, J = 12.6, 3.8 Hz, 1H), 2.54 - 2.45 (m, 1H), 2.46 - 2.36 (m, 1H), 2.28 (br dd, J = 15.5, 1.2 Hz, 1H), 1.92 (br d, J = 13.3 Hz, 1H), 1.85 - 1.78 (m, 1H), 1.77 - 1.63 (m, 3H), 1.57 - 1.48 (m, 1H), 1.49 - 1.24 (m, 4H).

[0694] Example 33b: Peak 2 (Provisionally Assigned Stereochemistry)

[0695] LCMS (Method C): [M+H] + m / z 429.5, RT 0.91 min.

[0696] Chiral analysis (Chiralpak OD-H, 25×0.46 cm, 5 μm, 75:25 n-hexane:(ethanol + 0.1% isopropylamine): RT 10.7 min

[0697] 1HNMR (500 MHz, CDCl 3 ) δ 7.13 (td, J = 7.7, 1.6 Hz, 1H), 7.03 (br dd, J = 7.4, 1.5 Hz, 1H), 7.02 (br s, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.81 - 6.77 (m, 1H), 4.80 (br dd, J = 14.1, 4.7 Hz, 1H), 4.77 - 4.69 (m, 2H), 4.33 (d, J = 17.0 Hz, 1H), 4.16 (d, J = 11.9 Hz, 1H), 4.12 (d, J = 17.0 Hz, 1H), 4.02 (dt, J = 7.7, 2.7 Hz, 1H), 3.88 (br t, J = 9.7 Hz, 1H), 3.77 (dd, J = 9.3, 2.6 Hz, 1H), 3.66 (br s, 1H), 3.56 - 3.46 (m, 1H), 3.26 (d, J = 11.9 Hz, 1H), 2.78 - 2.68 (m, 1H), 2.63 (qd, J = 12.6, 3.8 Hz, 1H), 2.54 - 2.45 (m, 1H), 2.46 - 2.36 (m, 1H), 2.28 (br dd, J = 15.5, 1.2 Hz, 1H), 1.92 (br d, J = 13.3 Hz, 1H), 1.85 - 1.78 (m, 1H), 1.77 - 1.63 (m, 3H), 1.57 - 1.48 (m, 1H), 1.49 - 1.24 (m, 4H).

[0698] Example 34

Chemical Structure

[0699] Rel-(1’s,3S,18’R,21’s)-8’,20’-Dioxa-13’-azaspiro[morpholine-3,17’-tetracyclo[19.2.2.0 2,7 .0 13,18 pentacosan]-2’(7’),3’,5’-triene-5,12’-dione

[0700] Example 34 was prepared using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate according to the same procedure as described for Example 2, and the title compound (36 mg) was obtained as a white solid.

[0701] LCMS (Method A): [M+H] + m / z 443.3, RT 3.11 min.

[0702] 1 H NMR (500 MHz, CDCl 3 ) δ 7.17 - 7.11 (m, 1H), 7.05 (dd, J = 7.4, 1.6 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.82 (t, J = 7.3 Hz, 1H), 6.01 (s, 1H), 4.73 - 4.65 (m, 1H), 4.65 - 4.59 (m, 1H), 4.32 (d, J = 17.0 Hz, 1H),4.24 - 4.18 (m, 2H), 4.10 (d, J = 17.0 Hz, 1H), 4.02 (td, J = 8.8, 3.4 Hz, 1H), 3.87 - 3.80 (m, 1H), 3.70 - 3.55 (m, 3H), 3.25 (d, J = 11.9 Hz, 1H), 2.71 - 2.61 (m, 1H), 2.49 - 2.32 (m, 4H), 2.26 - 2.16 (m, 1H), 2.08 -1.97 (m, 2H), 1.85 (d, J = 14.3 Hz, 1H), 1.78 - 1.65 (m, 2H), 1.64 - 1.57 (m, 1H), 1.52 - 1.37 (m, 5H).

[0703] Example 35

Chemical Structure

[0704] Rel-(1’s,3S,16’R,19’s)-9’-Methyl-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2,7 .0 11,16 tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0705] Example 35 was prepared using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate according to the same procedure as described for Example 3, and the title compound (20 mg) was obtained as a pale yellow solid.

[0706] LCMS (Method A): [M+H] + m / z 429.5, RT 2.81 min

[0707] 1 H NMR (400 MHz, CDCl 3 ) δ 7.18 - 7.13 (m, 1H), 7.12 - 7.08 (m, 1H), 6.95 (s, 1H), 6.90 - 6.83 (m, 1H), 6.81 - 6.78 (m, 1H), 5.52 (dd, J = 11.4, 3.8 Hz, 1H), 5.26 (q, J = 6.0 Hz, 1H), 4.28 (d, J = 16.9 Hz, 1H), 4.15 (d, J = 11.7 Hz, 1H), 4.08 (d, J = 16.9 Hz, 1H), 3.88 (dd, J = 11.5, 8.5 Hz, 1H), 3.79 - 3.60 (m, 2H), 3.52 - 3.42 (m, 2H), 3.41 - 3.33 (m, 2H), 2.73 - 2.47 (m, 2H), 2.38 - 2.18 (m, 1H), 2.12 - 2.06 (m, 1H), 1.92 - 1.84 (m, 1H), 1.80 - 1.75 (m, 1H), 1.74 - 1.62 (m, 3H), 1.52 (d, J = 6.0 Hz, 3H), 1.43 - 1.32 (m, 3H).

[0708] Examples 35a and 35b

Chemical Formula

[0709] Example 35a: (1’s,3S,16’R,19’s)-9’-Methyl-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 11 , 16 tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0710] Example 35b: (1’s,3R,16’S,19’s)-9’-Methyl-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 11 , 16 tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0711] Example 35 (15.4 mg) was subjected to chiral preparative purification using Waters 600, eluting with 65 / 35% v / v n-hexane / (ethanol / methanol 1:1 + 0.1% isopropylamine), Chiralpak AD-H (25×2.0 cm), 5 μm, at a flow rate of 17 mL / min to obtain the title compound (peak 1, 3.32 mg, 100% ee; and peak 2, 4.06 mg, 100% ee).

[0712] Example 35a: Peak 1 (tentatively assigned stereochemistry)

[0713] LCMS (Method C): [M+H] + m / z 429.3, RT 0.95 min.

[0714] Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 65:35 n-hexane:(ethanol + 0.1% isopropylamine)): RT 4.3 min

[0715] 1 H NMR (500 MHz, CDCl 3 ) δ 7.16 (td, J = 7.7, 1.7 Hz, 1H), 7.10 (dd, J = 7.4, 1.6 Hz, 1H), 6.87 (td, J = 7.4, 1.0 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.98 (br s, 1H), 5.51 (dd, J = 11.3, 3.6 Hz, 1H), 5.26 (q, J = 6.0 Hz, 1H), 4.30 (d, J = 16.9 Hz, 1H), 4.14 (d, J = 11.7 Hz, 1H), 4.11 (d, J = 17.0 Hz, 1H), 3.86 (dd, J = 11.4, 8.4 Hz, 1H), 3.71 - 3.75 (m, 1H), 3.68 (br dd, J = 14.1, 3.7 Hz, 1H), 3.47 (dd, J = 8.3, 3.9 Hz, 1H), 3.35 - 3.44 (m, 2H), 2.49 - 2.69 (m, 2H), 2.24 - 2.39 (m, 1H), 2.02 - 2.13 (m, 1H), 1.86 - 1.93 (m, 1H), 1.79 - 1.86 (m, 1H), 1.63 - 1.76 (m, 2H), 1.56 (s, 1H), 1.53 (s, 3H), 1.27 - 1.45 (m, 4H).

[0716] Example 35b: Peak 2 (tentatively assigned stereochemistry)

[0717] LCMS (Method C): [M+H] + m / z 429.3, RT 0.95 min.

[0718] Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 65:35 n-hexane:(ethanol + 0.1% isopropylamine)): RT 7.3 min

[0719] 1 H NMR (500 MHz, CDCl 3 ) δ 7.16 (td, J = 7.7, 1.7 Hz, 1H), 7.10 (dd, J = 7.4, 1.6 Hz, 1H), 6.87 (td, J = 7.4, 1.0 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.98 (br s, 1H), 5.51 (dd, J = 11.3, 3.6 Hz, 1H), 5.26 (q, J = 6.0 Hz, 1H), 4.30 (d, J = 16.9 Hz, 1H), 4.14 (d, J = 11.7 Hz, 1H), 4.11 (d, J = 17.0 Hz, 1H), 3.86 (dd, J = 11.4, 8.4 Hz, 1H), 3.71 - 3.75 (m, 1H), 3.68 (br dd, J = 14.1, 3.7 Hz, 1H), 3.47 (dd, J = 8.3, 3.9 Hz, 1H), 3.35 - 3.44 (m, 2H), 2.49 - 2.69 (m, 2H), 2.24 - 2.39 (m, 1H), 2.02 - 2.13 (m, 1H), 1.86 - 1.93 (m, 1H), 1.79 - 1.86 (m, 1H), 1.63 - 1.76 (m, 2H), 1.56 (s, 1H), 1.53 (s, 3H), 1.27 - 1.45 (m, 4H).

[0720] Example 36

Chemical Structure

[0721] Rel-(1’s,3S,16’R,19’s)-9’,9’-dimethyl-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.02,7 .0 11,16 Tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0722] Example 36 was prepared using the commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate according to the same procedure as described for Example 3, and the title compound (1 mg) was obtained as a white solid.

[0723] LCMS (Method B): [M+H] + m / z 443.3, RT 3.21 min

[0724] 1 H NMR (400 MHz, CDCl 3 ) δ 7.16 - 7.06 (m, 2H), 7.03 (dd, J = 8.2, 1.3 Hz, 1H), 6.92 (td, J = 7.4, 1.3 Hz, 1H), 6.09 (s, 1H), 5.49 (dd, J = 10.8, 4.0 Hz, 1H), 4.52 (d, J = 14.5 Hz, 1H), 4.28 (d, J = 16.9 Hz, 1H), 4.16 - 4.05 (m, 2H), 3.84 (dd, J = 10.8, 8.3 Hz, 1H), 3.74 (s, 1H), 3.54 (dd, J = 8.3, 4.0 Hz, 1H), 3.49 - 3.34 (m, 2H), 2.66 - 2.41 (m, 2H), 2.23 - 2.04 (m, 2H), 1.97 - 1.82 (m, 4H), 1.78 - 1.64 (m, 3H), 1.53 (s, 3H), 1.45 - 1.32 (m, 5H).

[0725] Example 37

Chemical Structure

[0726] Rel-(1’s,16’S,17’R,20’s)-Dispiro[cyclopropane-1,10’-[8,19]dioxa-

[12] azatetracyclo[18.2.2.0 2,7 .0 12,17 tetracosan-16’,3”-morpholin]-2’(7’),3’,5’-triene-5”,11’-dione

[0727] Example 37 was prepared using the commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate according to the same procedure as described for Example 7, and the title compound (9.4 mg) was obtained as a white solid.

[0728] LCMS (Method A): [M+H] + m / z 455.32, RT 3.01 min

[0729] 1 H NMR (400 MHz, CDCl 3) δ 7.76 (s, 1H), 7.19 - 7.05 (m, 2H), 6.99 - 6.83 (m, 2H), 5.40 (dd, J = 10.1, 3.9 Hz, 1H), 4.54 (dd, J = 14.2, 3.4 Hz, 1H), 4.27 (d, J = 17.0 Hz, 1H), 4.17 (d, J = 10.0 Hz, 1H), 4.08 (d, J = 17.0 Hz, 1H), 3.96 - 3.87 (m, 2H), 3.83 (d, J = 10.1 Hz, 1H), 3.76 - 3.70 (m, 1H), 3.62 (dd, J = 8.8, 4.0 Hz, 1H), 3.45 - 3.34 (m, 1H), 3.31 (d, J = 11.7 Hz, 1H), 2.53 - 2.34 (m, 2H), 2.31 - 2.19 (m, 1H), 2.18 - 2.12 (m, 1H), 2.02 - 1.97 (m, 1H), 1.91 - 1.69 (m, 3H), 1.57 - 1.39 (m, 5H), 1.34 - 1.22 (m, 1H), 1.14 - 1.07 (m, 1H), 1.07 - 0.96 (m, 1H), 0.87 - 0.79 (m, 1H).

[0730] Examples 37a and 37b [Chemical formula]

[0731] Example 37a: (1’s,16’S,17’R,20’s)-Dispiro[cyclopropane-1,10’-[8,19]dioxa-

[12] azatetracyclo[18.2.2.0 2 , 7 .0 12 , 17 tetracosan-16’,3”-morpholin]-2’(7’),3’,5’-triene-5”,11’-dione

[0732] Example 37b: (1’s,16’R,17’S,20’s)-Dispiro[cyclopropane-1,10’-[8,19]dioxa-

[12] azatetracyclo[18.2.2.0 2 , 7 .0 12 , 17 tetracosan-16’,3”-morpholin]-2’(7’),3’,5’-triene-5”,11’-dione

[0733] Example 37 (6.1 mg) was subjected to chiral preparative purification using Waters 600, eluting with 70 / 30% v / v n-hexane / (ethanol / methanol 1:1 + 0.1% isopropylamine), Whelk O1 (R,R) (25 × 2.0 cm), 5 μm, flow rate 17 mL / min to give the title compound (peak 1, 1.4 mg, 100% ee; peak 2, 2.6 mg, 98.7% ee).

[0734] Example 37a: Peak 1 (tentatively assigned stereochemistry)

[0735] LCMS (method C): [M+H] + m / z 455.3, RT 0.92 min.

[0736] Chiral analysis (Whelk O1 (R,R), 25 × 0.46 cm, 5 μm, 70:30 n-hexane:(ethanol / methanol 1:1 + 0.1% isopropylamine)): RT 13.2 min

[0737] 1 H NMR (500 MHz, CDCl 3) δ 7.15 (td, J = 7.8, 1.8 Hz, 1H), 7.10 (dd, J = 7.8, 1.8 Hz, 1H), 6.90 - 6.97 (m, 2H), 5.78 (s, 1H), 5.31 (dd, J = 8.9, 4.0 Hz, 1H), 4.57 (br dd, J = 14.3, 3.8 Hz, 1H), 4.27 (d, J = 16.7 Hz, 1H), 4.21 (d, J = 10.2 Hz, 1H), 4.10 (d, J = 17.0 Hz, 1H), 3.89 (d, J = 11.8 Hz, 1H), 3.83 (t, J = 8.8 Hz, 1H), 3.77 (d, J = 10.2 Hz, 1H), 3.72 (br s, 1H), 3.68 - 3.72 (m, 1H), 3.44 (td, J = 13.6, 3.0 Hz, 1H), 3.34 (d, J = 11.8 Hz, 1H), 2.42 - 2.54 (m, 1H), 1.21 - 2.41 (m, 12H), 0.76 - 1.32 (m, 4H).

[0738] Example 37b: Peak 2 (tentatively assigned stereochemistry)

[0739] LCMS (Method C): [M+H] + m / z 455.3, RT 0.92 min.

[0740] Chiral analysis (Whelk O1 (R,R), 25×0.46 cm, 5 μm, 70:30 n-hexane: (ethanol / methanol 1:1 + 0.1% isopropylamine)): RT 15.3 min

[0741] 1 H NMR (500 MHz, CDCl 3) δ 7.15 (td, J = 7.8, 1.8 Hz, 1H), 7.10 (dd, J = 7.8, 1.8 Hz, 1H), 6.90 - 6.97 (m, 2H), 5.78 (s, 1H), 5.31 (dd, J = 8.9, 4.0 Hz, 1H), 4.57 (br dd, J = 14.3, 3.8 Hz, 1H), 4.27 (d, J = 16.7 Hz, 1H), 4.21 (d, J = 10.2 Hz, 1H), 4.10 (d, J = 17.0 Hz, 1H), 3.89 (d, J = 11.8 Hz, 1H), 3.83 (t, J = 8.8 Hz, 1H), 3.77 (d, J = 10.2 Hz, 1H), 3.72 (br s, 1H), 3.68 - 3.72 (m, 1H), 3.44 (td, J = 13.6, 3.0 Hz, 1H), 3.34 (d, J = 11.8 Hz, 1H), 2.42 - 2.54 (m, 1H), 1.21 - 2.41 (m, 12H), 0.76 - 1.32 (m, 4H).

[0742] Examples 38a and 38b [Chemical formula]

[0743] Example 38a: (1’s,3S,16’R,19’s)-6’-fluoro-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 11 , 16 tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0744] Example 38b: (1’s,3R,16’S,19’s)-6’-fluoro-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 11 , 16Tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0745] Examples 38a and 38b were prepared using the commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate according to the same procedure as described for Examples 17a and 17b. The racemic mixture (8.6 mg) was subjected to chiral preparative purification using Waters 600, eluting with 45 / 55% v / v n-hexane / (ethanol + 0.1% isopropylamine), Chiralpak OJ-C (25 × 2.0 cm), 5 μm, flow rate 17 mL / min to afford the title compound (peak 1, 1.5 mg, 100% ee; and peak 2, 1.72 mg, 100% ee).

[0746] Example 38a: Peak 1 (tentatively assigned stereochemistry)

[0747] LCMS (Method C): [M+H] + m / z 433.3, RT 0.94 min.

[0748] Chiral analysis (ChiralcelpakOJ-H, 25 × 0.46 cm, 5 μm, 45:55 n-hexane:ethanol + 0.1% isopropylamine): RT 5.9 min

[0749] 1 H NMR (500 MHz, CDCl 3) δ 6.80 - 7.01 (m, 3H), 5.99 (br s, 1H), 5.32 - 5.50 (m, 2H), 4.35 (dd, J = 12.5, 1.4 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.13 - 4.17 (m, 1H), 4.11 (d, J = 17.0 Hz, 1H), 3.92 - 4.00 (m, 1H), 3.84 (dd, J = 10.0, 8.5 Hz, 1H), 3.74 - 3.79 (m, 1H), 3.55 - 3.60 (m, 1H), 3.47 - 3.55 (m, 1H), 3.40 (d, J = 11.7 Hz, 1H), 2.63 - 2.73 (m, 1H), 2.53 - 2.64 (m, 1H), 1.20 - 2.16 (m, 11H).

[0750] Example 38b: Peak 2 (tentatively assigned stereochemistry)

[0751] LCMS (Method C): [M+H] + m / z 433.3, RT 0.94 min.

[0752] Chiral analysis (Chiralcelpak OJ-H, 25×0.46 cm, 5 μm, 45:55 n-hexane:ethanol + 0.1% isopropylamine): RT 10.0 min

[0753] 1 H NMR (500 MHz, CDCl 3) δ 6.80 - 7.01 (m, 3H), 5.99 (br s, 1H), 5.32 - 5.50 (m, 2H), 4.35 (dd, J = 12.5, 1.4 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.13 - 4.17 (m, 1H), 4.11 (d, J = 17.0 Hz, 1H), 3.92 - 4.00 (m, 1H), 3.84 (dd, J = 10.0, 8.5 Hz, 1H), 3.74 - 3.79 (m, 1H), 3.55 - 3.60 (m, 1H), 3.47 - 3.55 (m, 1H), 3.40 (d, J = 11.7 Hz, 1H), 2.63 - 2.73 (m, 1H), 2.53 - 2.64 (m, 1H), 1.20 - 2.16 (m, 11H).

[0754] The following examples were prepared according to the same procedures as described for Examples 38a and 38b using appropriate reagents. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Chemical formula]

[0755] Intermediate 99 [Chemical formula]

[0756] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(3-fluoro-2-hydroxyphenyl)cyclohexyl]-oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0757] Intermediate 99 was prepared using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate according to the same procedure as described for Examples 17a and 17b, and the title compound (1.80 g) was obtained as a yellow oil. M+H] + m / z 493.4.

[0758] Intermediate 100 [Chemical formula]

[0759] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(2-{[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]oxy}-3-fluorophenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0760] To a solution of tert-butyl prop-2-ynoate (334 μL, 2.43 mmol) and 1,4-diazabicyclo[2.2.2]octane (89 mg, 0.793 mmol) in THF (1.6 mL) was added intermediate 99 (1.00 g) in THF (8.4 mL) at 0 °C under nitrogen, and the solution was stirred at room temperature for 5 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with brine and dried over MgSO 4 and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography (0 - 100% EtOAc in heptane) to give the title compound (1.00 g) as a yellow oil. [M+H] + m / z 619.5

[0761] Intermediate 101

Chemical Structure

[0762] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-{2-[3-(tert-butoxy)-3-oxopropoxy]-3-fluorophenyl}cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0763] Intermediate 100 (1.00 g) was dissolved in ethanol (27 mL), the atmosphere was evacuated, and the flask was filled with nitrogen three times. Palladium on carbon (10%, 516 mg, 0.485 mmol) was added, the atmosphere was evacuated, and the flask was filled with hydrogen three times. The reaction mixture was stirred for 16 h, then filtered through celite, washed with EtOAc, and the filtrate was concentrated in vacuo to give the crude product. The crude material was purified by flash column chromatography (0 - 100% EtOAc in heptane) to afford the title compound (800 g) as a yellow oil. [M+H] + m / z 621.5.

[0764] Intermediate 102

Chem.

[0765] Rel-(6S,7R)-2-Oxo-7-({[(1s,4s)-4-[2-(2-Carboxyethoxy)-3-fluorophenyl]cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecan-8-ium chloride

[0766] 4M Hydrogen chloride in dioxane (3.2 mL, 12.8 mmol) was added to Intermediate 101 (800 mg) at room temperature and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo to afford the title compound (650 mg) as an orange solid. [M+H] + m / z 465.4

[0767] Example 48

Chem.

[0768] Rel-(1’s,3S,17’R,20’s)-6’-Fluoro-8’,19’-dioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2 , 7 .0 12 , 17Tetracosan]-2’,4’,6’-triene-5,11’-dione

[0769] To a stirred solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide (50%, 1.7 mL, 2.96 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (460 mg, 3.56 mmol) in acetonitrile (110.15 mL) was added intermediate 102 (550 mg) in anhydrous DMF (4.2367 mL) using a syringe pump over 2 h. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo to afford the crude material. The crude material was diluted with water and extracted with DCM (3 × 20 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated to give a solid residue. The crude material was purified by basic reverse-phase column chromatography (20 - 50% acetonitrile (0.1% ammonia) in water) to afford the title compound (75 mg) as a white solid. [M+H] + m / z 447.4

[0770] Examples 48a and 48b

Chemical Structure

[0771] Example 48a: (1’s,3S,17’R,20’s)-6’-fluoro-8’,19’-dioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2 , 7 .0 12 , 17 tetracosan]-2’(7’),3’,5’-triene-5,11’-dione

[0772] Example 48b: (1’s,3R,17’S,20’s)-6’-fluoro-8’,19’-dioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2 , 7 .0 12 , 17Tetracosan]-2’(7’),3’,5’-triene-5,11’-dione

[0773] Example 48 (75 mg) was subjected to chiral preparative purification using Waters 600, eluting with 40 / 60% v / v n-hexane / (ethanol + 0.1% isopropylamine), Chiralpak IC (25×2.0 cm), 5 μm, flow rate 17 mL / min to obtain the title compound (peak 1, 1.29 mg, 100% ee; peak 2, 3.31 mg, 96.7% ee).

[0774] Example 48a: Peak 1 (tentatively assigned stereochemistry)

[0775] LCMS (Method C): [M+H] + m / z 447.4, RT 0.93 min.

[0776] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 40:60 n-hexane:ethanol + 0.1% isopropylamine): RT 7.4 min

[0777] 1 H NMR (600 MHz, CDCl 3 ) δ 6.98 - 6.71 (m, 3H), 6.26 - 6.08 (m, 1H), 5.47 - 4.65 (m, 1H), 5.19 - 4.48 (m, 1H), 4.37 - 4.24 (m, 2H), 4.84 - 4.04 (m, 1H), 4.19 - 4.02 (m, 2H), 3.84 (dt, J = 12.6, 9.4 Hz, 1H), 3.77 - 3.66 (m, 1H), 3.72 - 3.62 (m, 1H), 3.60 - 3.31 (m, 1H), 3.39 - 3.25 (m, 1H), 3.43 - 2.66 (m, 1H), 2.56 - 2.32 (m, 2H), 2.55 - 1.22 (m, 12H).

[0778] Example 48b: Peak 2 (tentatively assigned stereochemistry)

[0779] LCMS (Method C): [M+H] + m / z 447.4, RT 0.93 minutes.

[0780] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 40:60 n-hexane:ethanol + 0.1% isopropylamine): RT 8.6 minutes

[0781] 1 H NMR (600 MHz, CDCl 3 ) δ 6.98 - 6.71 (m, 3H), 6.26 - 6.08 (m, 1H), 5.47 - 4.65 (m, 1H), 5.19 - 4.48 (m, 1H), 4.37 - 4.24 (m, 2H), 4.84 - 4.04 (m, 1H), 4.19 - 4.02 (m, 2H), 3.84 (dt, J = 12.6, 9.4 Hz, 1H), 3.77 - 3.66 (m, 1H), 3.72 - 3.62 (m, 1H), 3.60 - 3.31 (m, 1H), 3.39 - 3.25 (m, 1H), 3.43 - 2.66 (m, 1H), 2.56 - 2.32 (m, 2H), 2.55 - 1.22 (m, 12H).

[0782] The following examples were prepared according to the same procedure as described for Examples 48a and 48b using appropriate reagents.

Table 6-1

Table 6-2

Table 6-3

Chemical formula

[0783] Intermediate 103 [Chem.]

[0784] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0785] Intermediate 103 was prepared using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate according to the same procedure as described for Example 3, and the title compound (1.6 g) was obtained as a white solid. [M+H] + m / z 475.3

[0786] Intermediate 104 [Chem.]

[0787] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-[2-(trifluoromethanesulfonyloxy)-phenyl]cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0788] Trifluoromethylsulfonyl trifluoromethanesulfonate (0.38 mL, 2.02 mmol) in DCM (2 mL) was added dropwise to a stirred solution of Intermediate 103 (800 mg) and pyridine (0.41 mL, 5.06 mmol) in DCM (20 mL) at 0 °C. The mixture was stirred at 0 °C for 4 h. The reaction mixture was diluted with DCM (20 mL) and water (20 mL), the organic layer was separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic extracts were dried (Na 2 SO 4) It was filtered. The filtrate was concentrated in vacuo to obtain a crude substance. The crude substance was purified by column chromatography (0 - 100% EtOAc in heptane) to obtain the title compound (742 mg) as a yellow solid. [M + H] + m / z 607.1

[0789] Intermediate 105

Chem.

[0790] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(2-ethenylphenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0791] Intermediate 104 (740 mg), potassium ethenyl(trifluoro)borate(1-) (245 mg, 1.83 mmol) and cesium carbonate (795 mg, 2.44 mmol) were stirred in 1,4-dioxane (18 mL) and water (3 mL), and degassed with N 2 Bis(triphenylphosphine)palladium(II) dichloride (43 mg, 0.0610 mmol) was added to the reaction solution, and then this was further degassed with N 2 sealed and heated at 80 °C for 16 h. The reaction mixture was concentrated in vacuo. The crude reaction mixture was diluted with EtOAc (30 mL) and water (30 mL), the organic layer was separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na 2 SO 4 ) filtered. The filtrate was concentrated in vacuo to obtain a crude substance. The crude substance was purified by column chromatography (0 - 100% EtOAc in heptane) to obtain the title compound (606 mg) as a pale yellow gum. [M + H] + m / z 485.4

[0792] Intermediate 106

Chem.

[0793] Rel-(6S,7R)-7-({[(1s,4s)-4-(2-ethenylphenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecan-2-one hydrochloride

[0794] 4M hydrogen chloride in dioxane (6.0 mL, 24.0 mmol) was added to Intermediate 105 (600 mg) at room temperature and the reaction was stirred for 4 h. The solvent was removed in vacuo to afford the title compound (504 mg) as a white solid. [M+H] + m / z 385.3

[0795] Intermediate 107

Chemical Structure

[0796] Ethenyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(2-ethenylphenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0797] Ethenyl carbonochloridate (52 μL, 0.570 mmol) in DCM-anhydrous (1 mL) was added dropwise to a stirred solution of Intermediate 106 (200 mg) and triethylamine (331 μL, 2.38 mmol) in anhydrous DCM (5 mL) at 0 °C and the mixture was stirred for 2 h. The reaction mixture was diluted with DCM and then water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (2×20 mL), the organic fractions were combined, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography (0-100% EtOAc in heptane) to afford the title compound (198 mg) as a colorless gum. [M+H] + m / z 455.3

[0798] Intermediate 108

Chemical Structure

[0799] Rel-(1’s,3S,8’Z,17’R,20’s)-10’,19’-Dioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2 , 7 .0 12 , 17 tetracosan]-2’,4’,6’,8’-tetraene-5,11’-dione

[0800] A solution of intermediate 107 (150 mg) in anhydrous DCE (60 mL) was degassed with N 2 for 15 minutes. Next, [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene](dichloro)[2-(propan-2-yloxy)benzylidene]ruthenium (62 mg, 0.0990 mmol) was added, and then the reaction mixture was heated at 65 °C for 16 hours. Another 0.3 equivalent of [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene](dichloro)[2-(propan-2-yloxy)benzylidene]ruthenium was added and the reaction was heated at 65 °C for a further 16 hours. The solvent was removed under reduced pressure. The resulting residue was diluted with DCM, then water (15 mL) was added and the organic layer was separated. The aqueous layer was extracted with DCM (2 × 20 ml), the organic fractions were combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (0 - 100% EtOAc in heptane, then 0 - 20% methanol in DCM) to give the crude product, which was further purified by basic reverse-phase column chromatography (10 - 100% MeCN in water (0.1% ammonia)) to give the title compound (19 mg) as a brown solid. [M+H] + m / z 427.4

[0801] Example 52

Chemical Structure

[0802] Rel-(1’s,3S,17’R,20’s)-10’,19’-Dioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2,7 .0 12,17 tetracosane]-2’(7’),3’,5’-triene-5,11’-dione

[0803] Intermediate 108 (19 mg) was dissolved in ethanol (4 mL). The atmosphere was evacuated and filled with nitrogen three times. Palladium on carbon (10%, 9.5 mg, 8.91 μmol) was added. The atmosphere was evacuated and filled with hydrogen three times. The reaction mixture was stirred for 5 hours, then filtered through celite, washed with EtOAc, and the filtrate was concentrated in vacuo to give the crude product, which was purified by Gilson 9 gradient methanol / water (+0.2% ammonium hydroxide) 5% - 95% to give the title compound (1.2 mg) as a white solid.

[0804] LCMS (Method B): [M+H] + m / z 429.4, RT 3.19 min

[0805] 1 H NMR (500 MHz, CDCl 3 ) δ 7.23 - 7.08 (m, 4H), 6.24 (s, 1H), 4.66 (dd, J = 13.7, 4.8 Hz, 1H), 4.40 (dd, J = 7.3, 3.3 Hz, 1H), 4.28 (dd, J = 27.5, 16.8 Hz, 1H), 4.18 - 4.07 (m, 2H), 3.89 - 3.79 (m, 2H), 3.78 - 3.70 (m, 1H), 3.66 (s, 1H), 3.45 - 3.29 (m, 1H), 2.89 - 2.73 (m, 2H), 2.71 - 2.62 (m, 2H), 2.29 - 2.21 (m, 1H), 2.09 - 1.90 (m, 3H), 1.85 - 1.65 (m, 5H), 1.27 - 1.16 (m, 4H).

Chem.

[0806] Intermediate 109

Chem.

[0807] tert-Butyl-rel-(6S,7R)-7-[({4-[(4-Methylbenzenesulfonamido)imino]cyclohexyl}oxy)methyl]-2-oxo-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0808] Intermediate 109 was prepared using the known starting material tert-butyl 2-oxo-7-{[(4-oxocyclohexyl)oxy]methyl}-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate according to the same procedure as described for Intermediate 47, and the title compound (22.6 g) was obtained as a white solid. [M+H] + m / z 565.3.

[0809] Intermediate 110

Chem.

[0810] tert-Butyl-rel-(6S,7R)-7-[({4-[3-(Benzyloxy)phenyl]cyclohex-3-en-1-yl}oxy)methyl]-2-oxo-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0811] Intermediate 110 was prepared using the commercially available starting material 1-iodo-3-(phenoxymethyl)benzene and Intermediate 110 according to the same procedure as described for Intermediate 60, and the title compound (1.15 g) was obtained as a yellow solid. [M+H] + m / z 563.4

[0812] Intermediate 111

Chem.

[0813] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(3-hydroxyphenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0814] Intermediate 111 was prepared according to the same procedure as described for Intermediate 8 to give the title compound (952 mg). [M+H] + m / z 475.4

[0815] Intermediate 112

Chemical Structure

[0816] Rel-(6S,7R)-7-({[(1s,4s)-4-(3-hydroxyphenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecan-2-one hydrochloride

[0817] Intermediate 112 was prepared according to the same procedure as described for Intermediate 12 to give the title compound (134 mg). [M+H] + m / z 375.2

[0818] Intermediate 113

Chemical Structure

[0819] 2-Chloroethyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(3-{[(2-chloroethoxy)-carbonyl]oxy}phenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0820] To a solution of Intermediate 112 (134 mg) in DCM (3.5 mL) was added triethylamine (0.2 mL, 1.43 mmol), followed by 2-chloroethyl carbonochloridate (0.07 mL, 0.720 mmol). After 30 minutes at room temperature, the reaction was concentrated under vacuum to afford the title compound (275 mg). [M+H] + m / z 587.3

[0821] Intermediate 114

Chemical Structure

[0822] 2-chloroethyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(3-hydroxyphenyl)-cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0823] To a solution of Intermediate 113 (253 mg) in methanol (2 mL) / THF (2 mL) was added LiOH (52 mg, 2.15 mmol). After 30 minutes at room temperature, the reaction mixture was acidified with 2M aqueous HCl, water was added, and the crude product was extracted with EtOAc. The combined organic fractions were washed with brine and dried over Na 2 SO 4 and evaporated in vacuo to afford the title compound (170 mg). [M+H] + m / z 481.3

[0824] Example 53

Chemical Structure

[0825] Rel-(1’s,3S,17’R,20’s)-7’,10’,19’-trioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.1 2,6 .0 12,17 pentacosan]-2’(25’),3’,5’-triene-5,11’-dione

[0826] To a solution of intermediate 114 (170 mg) in DMF (88 mL) was added cesium carbonate (691 mg, 2.12 mmol), and the reaction mixture was stirred at 60 °C for 15 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by the first reverse-phase column chromatography (H 2 O + 0 - 100% acetonitrile + 0.1% formic acid in 0.1% formic acid), followed by purification by the second column chromatography (30 - 60% EtOAc + 20% EtOH in cyclohexane) to afford the title compound (17.5 mg).

[0827] LCMS (Method C): [M+H] + m / z 445.3, RT 0.99 min

[0828] 1 H NMR (500 MHz, CDCl 3 ) δ 7.11 (br t, J = 7.8 Hz, 1H), 6.85 (br s, 1H), 6.70 - 6.78 (m, 2H), 5.85 (br s, 1H), 5.00 - 5.17 (m, 1H), 4.79 (br d, J = 12.8 Hz, 1H), 4.64 (br dd, J = 14.1, 10.0 Hz, 1H), 4.32 (br d, J = 17.0 Hz, 1H), 4.27 (br d, J = 14.4 Hz, 1H), 4.07 - 4.21 (m, 4H), 3.85 (br t, J = 9.7 Hz, 1H), 3.74 (br s, 1H), 3.65 (br dd, J = 8.9, 3.1 Hz, 1H), 3.35 (br d, J = 11.8 Hz, 1H), 2.92 - 3.05 (m, 1H), 2.50 - 2.64 (m, 1H), 1.91 - 2.12 (m, 4H), 1.36 - 1.87 (m, 8H).

[0829] Examples 53a and 53b

Chemical formula

[0830] Example 53a: (1’r,3R,17’S,20’r)-7’,10’,19’-Trioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.1 2 , 6 .0 12 , 17 pentacosan]-2’(25’),3’,5’-triene-5,11’-dione;

[0831] Example 53b: (1’s,3R,17’S,20’s)-7’,10’,19’-Trioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.1 2,6 .0 12,17 pentacosan]-2’(25’),3’,5’-triene-5,11’-dione

[0832] Example 53 (15.4 mg) was subjected to chiral preparative purification using Waters 600, eluting with 50 / 50% v / v n-hexane / ethanol + 0.1% isopropylamine, Chiralpak AS-H (25 × 2.0 cm), 5 μm, flow rate 17 mL / min to give the title compound (peak 1, 4.18 mg, 100% ee; and peak 2, 4.61 mg, 100% ee).

[0833] Example 53a: Peak 1 (tentatively assigned stereochemistry)

[0834] LCMS (method C): [M+H] + m / z 445.3, RT 0.99 min

[0835] Chiral analysis (Chiralcelpak AS-H, 25 × 0.46 cm, 5 μm, 50:50 n-hexane:ethanol + 0.1% isopropylamine): RT 6.2 min

[0836] 1 H NMR (400 MHz, CDCl 3) δ 7.11 (br t, J = 7.8 Hz, 1H), 6.85 (br s, 1H), 6.70 - 6.78 (m, 2H), 5.85 (br s, 1H), 5.00 - 5.17 (m, 1H), 4.79 (br d, J = 12.8 Hz, 1H), 4.64 (br dd, J = 14.1, 10.0 Hz, 1H), 4.32 (br d, J = 17.0 Hz, 1H), 4.27 (br d, J = 14.4 Hz, 1H), 4.07 - 4.21 (m, 4H), 3.85 (br t, J = 9.7 Hz, 1H), 3.74 (br s, 1H), 3.65 (br dd, J = 8.9, 3.1 Hz, 1H), 3.35 (br d, J = 11.8 Hz, 1H), 2.92 - 3.05 (m, 1H), 2.50 - 2.64 (m, 1H), 1.91 - 2.12 (m, 4H), 1.36 - 1.87 (m, 8H).

[0837] Example 53b: Peak 2 (tentatively assigned stereochemistry)

[0838] LCMS (Method C): [M+H] + m / z 445.3, RT 0.99 min

[0839] Chiral analysis (Chiralcelpak AS-H, 25×0.46 cm, 5 μm, 50:50 n-hexane:ethanol + 0.1% isopropylamine): RT 10.2 min

[0840] 1 1H NMR (400 MHz, CDCl 3) δ 7.11 (broad triplet, J = 7.8 Hz, 1H), 6.85 (broad singlet, 1H), 6.70 - 6.78 (multiplet, 2H), 5.85 (broad singlet, 1H), 5.00 - 5.17 (multiplet, 1H), 4.79 (broad doublet, J = 12.8 Hz, 1H), 4.64 (broad doublet of doublets, J = 14.1, 10.0 Hz, 1H), 4.32 (broad doublet, J = 17.0 Hz, 1H), 4.27 (broad doublet, J = 14.4 Hz, 1H), 4.07 - 4.21 (multiplet, 4H), 3.85 (broad triplet, J = 9.7 Hz, 1H), 3.74 (broad singlet, 1H), 3.65 (broad doublet of doublets, J = 8.9, 3.1 Hz, 1H), 3.35 (broad doublet, J = 11.8 Hz, 1H), 2.92 - 3.05 (multiplet, 1H), 2.50 - 2.64 (multiplet, 1H), 1.91 - 2.12 (multiplet, 4H), 1.36 - 1.87 (multiplet, 8H).

[0841] Example 54 [Chemical Structure]

[0842] Rel-(1’s,3S,18’R,21’s)-7’,11’,20’-Trioxa-13’-azaspiro[morpholine-3,17’-tetracyclo[19.2.2.1 2,6 .0 13,18 hexacosane]-2’(26’),3’,5’-triene-5,12’-dione

[0843] Example 54 was prepared using Intermediate 113 according to the same procedure as described for Example 53 to give the title compound (10.9 mg).

[0844] LCMS (Method C): [M+H] + m / z 459.3, RT 1.01 min

[0845] 11H NMR (400 MHz, CDCl 3 ) δ 7.12 (t, J = 7.7 Hz, 1H), 6.81 - 6.68 (m, 3H), 6.30 (br s, 1H), 4.96 - 4.85 (m, 1H), 4.78 - 4.68 (m, 1H), 4.45 - 4.34 (m, 1H), 4.33 - 4.22 (m, 2H), 4.21 - 4.06 (m, 3H), 4.00 - 3.90 (m, 1H), 3.87 - 3.78 (m, 1H), 3.76 - 3.67 (m, 2H), 3.35 (br d, J = 11.7 Hz, 1H), 3.30 - 3.16 (m, 1H), 2.60 - 2.47 (m, 1H), 2.23 (td, J = 14.1, 7.8 Hz, 1H), 1.96 - 1.89 (m, 1H), 2.14 - 1.38 (m, 12H).

[0846] Examples 54a and 54b [Chemical formula]

[0847] Example 54a: (1’s,3S,18’R,21’s)-7’,11’,20’-trioxa-13’-azaspiro[morpholine-3,17’-tetracyclo[19.2.2.1 2,6 .0 13,18 hexacosane]-2’(26’),3’,5’-triene-5,12’-dione

[0848] Example 54b: (1’s,3R,18’S,21’s)-7’,11’,20’-trioxa-13’-azaspiro[morpholine-3,17’-tetracyclo[19.2.2.1 2,6 .0 13,18 hexacosane]-2’(26’),3’,5’-triene-5,12’-dione

[0849] Example 54 (9.3 mg) was subjected to chiral preparative purification using Waters 600, eluting with 50 / 50% v / v n-hexane / ethanol + 0.1% isopropylamine, Chiralpak IC (25×2.0 cm), 5 μm, flow rate 17 mL / min to obtain the title compound (peak 1, 1.23 mg, 100% ee; and peak 2, 1.16 mg, 100% ee).

[0850] Example 54a: Peak 1 (tentatively assigned stereochemistry)

[0851] LCMS (Method C): [M+H] + m / z 459.3, RT 1.02 min

[0852] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 50:50 n-hexane:ethanol + 0.1% isopropylamine): RT 6.7 min

[0853] 1 H NMR (400 MHz, CDCl 3 ) δ 7.12 (t, J = 7.7 Hz, 1H), 6.63 - 7.03 (m, 3H), 6.13 (s, 1H), 4.90 (dd, J = 7.8, 3.6 Hz, 1H), 4.57 - 4.79 (m, 1H), 4.34 - 4.46 (m, 1H), 4.25 - 4.32 (m, 1H), 4.22 - 4.29 (m, 1H), 4.15 - 4.21 (m, 1H), 4.13 - 4.18 (m, 1H), 4.06 - 4.13 (m, 1H), 3.89 - 4.02 (m, 1H), 3.79 - 3.86 (m, 1H), 3.69 - 3.77 (m, 2H), 3.35 (d, J = 11.7 Hz, 1H), 3.25 (td, J = 13.1, 3.0 Hz, 1 H), 2.53 (tt, J = 12.1, 3.5 Hz, 1H), 2.18 - 2.35 (m, 1H), 1.86 - 1.98 (m, 1H), 1.37 - 2.15 (m, 12H).

[0854] Example 54b: Peak 2 (Provisionally Assigned Stereochemistry)

[0855] LCMS (Method C): [M+H] + m / z 459.3, RT 1.02 minutes

[0856] Chiral Analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 50:50 n-hexane:ethanol + 0.1% isopropylamine): RT 8.6 minutes

[0857] 1 H NMR (400 MHz, CDCl 3 ) δ 7.12 (t, J = 7.7 Hz, 1H), 6.63 - 7.03 (m, 3H), 6.13 (s, 1H), 4.90 (dd, J = 7.8, 3.6 Hz, 1H), 4.57 - 4.79 (m, 1H), 4.34 - 4.46 (m, 1H), 4.25 - 4.32 (m, 1H), 4.22 - 4.29 (m, 1H), 4.15 - 4.21 (m, 1H), 4.13 - 4.18 (m, 1H), 4.06 - 4.13 (m, 1H), 3.89 - 4.02 (m, 1H), 3.79 - 3.86 (m, 1H), 3.69 - 3.77 (m, 2H), 3.35 (d, J = 11.7 Hz, 1H), 3.25 (td, J = 13.1, 3.0 Hz, 1 H), 2.53 (tt, J = 12.1, 3.5 Hz, 1H), 2.18 - 2.35 (m, 1H), 1.86 - 1.98 (m, 1H), 1.37 - 2.15 (m, 12H).

Chemical Structure

[0858] Intermediate 115

Chemical Structure

[0859] tert-Butyl 2-[(2-bromophenyl)methoxy]acetate

[0860] To a mixture of (2-bromophenyl)methanol (1.0 g, 5.35 mmol) and sodium hydride (60%, 134 mg, 5.61 mmol) in THF (27 mL) was added tert-butyl 2-bromoacetate (0.95 mL, 6.42 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc and washed with water. The combined organic extracts were dried (Na 2 SO 4 ) and evaporated in vacuo. The crude product was purified by column chromatography (0 - 10% EtOAc in cyclohexane) to afford the title compound (1.76 g) as a colorless oil. [M + H + Na] + m / z 323.1, 325.1

[0861] Intermediate 116

Chemical Structure

[0862] tert-Butyl-rel-(6S,7R)-7-({[4-(2-{[2-(tert-butoxy)-2-oxoethoxy]methyl}phenyl)cyclohex-3-en-1-yl]oxy}methyl)-2-oxo-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0863] A solution of Intermediate 109 (300 mg), cesium carbonate (432 mg, 1.33 mmol), Intermediate 115 (200.01 mg), and cataCXium (registered trademark) (19 mg, 0.050 mmol) in 1,4-dioxane (3 mL) was evacuated and filled with nitrogen three times. Next, Pd(OAc) 2(6 mg, 0.030 mmol) was added, and the mixture was heated to 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled, filtered through a Celite pad, and washed with DCM. The filtrate was concentrated in vacuo and then diluted with DCM (50 mL). The organic phase was washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 and filtered, and concentrated in vacuo. The product was purified by column chromatography (0 - 40% EtOAc / EtOH 9:1 in cyclohexane) to afford the title compound (217 mg) as a yellow oil. [M+H] + m / z 601.4

[0864] Intermediate 117

Chemical Structure

[0865] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(2-{[2-(tert-butoxy)-2-oxoethoxy]methyl}phenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0866] To a solution of Intermediate 116 (197 mg) in ethanol (22 mL) were added sodium carbonate (104 mg, 0.980 mmol) and palladium on carbon (10%, 69 mg, 0.070 mmol). The mixture was set under a hydrogen atmosphere (1 atm.) and stirred for 40 min. The mixture was filtered through a Celite pad, and the filtrate was concentrated in vacuo. The crude product was dissolved in EtOAc, and the solution was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo to afford the title compound (177 mg) as a white solid. [M+H] + m / z 603.4

[0867] Intermediate 118

Chemical Structure

[0868] 2-({2-[(1S,4S)-4-{[rel-(6S,7R)-2-oxo-4-oxa-1,8-diazaspiro[5.5]undecan-7-yl]methoxy}cyclohexyl]phenyl}methoxy)acetic acid

[0869] Intermediate 118 was prepared according to the same procedure as described for Intermediate 32, and the title compound (22 mg) was obtained as a white solid. [M+H] + m / z 447.3

[0870] Example 55

Chemical Structure

[0871] Rel-(1’s,3S,17’R,20’s)-9’,19’-dioxa-12’-azaspiro[morpholine-3,16’-tetracyclo[18.2.2.0 2,7 .0 12,17 tetracosane]-2’(7’),3’,5’-triene-5,11’-dione

[0872] Example 55 was prepared using Intermediate 118 according to the same procedure as described for Example 8, and the title compound (3 mg) was obtained as a white solid.

[0873] LCMS (Method C): [M+H] + m / z 429.5, RT 0.87 min

[0874] 1 H NMR (400 MHz, CDCl 3) δ 7.36 - 7.43 (m, 1H), 7.09 - 7.25 (m, 3H), 6.20 (br s, 1H), 5.51 (dd, J = 11.9, 3.7 Hz, 1H), 5.25 (d, J = 9.9 Hz, 1H), 4.72 (d, J = 12.7 Hz, 1H), 4.26 - 4.37 (m, 1H), 4.23 (d, J = 10.0 Hz, 1H), 4.07 - 4.19 (m, 2H), 3.95 - 4.05 (m, 2H), 3.89 (br dd, J = 11.8, 9.2 Hz, 1H), 3.68 - 3.75 (m, 1H), 3.65 (br dd, J = 9.0, 4.1 Hz, 1H), 3.32 - 3.41 (m, 1H), 3.11 - 3.26 (m, 1H), 2.60 - 2.78 (m, 1H), 1.34 - 2.26 (m, 12H).

[0875] Example 56 [Chemical formula]

[0876] Rel-(1’s,3S,16’R,19’s)-6-Fluoro-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2,7 .0 11,16 tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0877] Example 56 was prepared using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate according to the same procedure as described for Example 8, and the title compound (36 mg) was obtained as a white solid. This was subjected to achiral preparative purification using UPLC Waters with mass spectrometric detection (MS: SQD2). Column: CSH C18 (2.1×50 mm, 1.7 μm). Conditions: [A1: water + 0.1% HCOOH]; [B1: MeCN + 0.1% HCOOH]. Gradient: 3% B1 to 99.9% B1, 1.4 minutes (flow rate: 0.90 mL / min). Detection: UV / Vis detection range 210 nm to 350 nm MS (ES+ / ES-). Scanning in the range of 100 - 1000 AMU gave the title compound (10.7 mg).

[0878] LCMS (Method B): [M+H]+ m / z 433.3, RT 2.99 min

[0879] 1 H NMR (400 MHz, CDCl3) δ 7.16 (td, J = 7.9, 1.7 Hz, 1H), 7.09 (dd, J = 7.4, 1.6 Hz, 1H), 6.90 (td, J = 7.4, 1.0 Hz, 1H), 6.78 - 6.72 (m, 1H), 6.70 (s, 1H), 5.58 (d, J = 52.0 Hz, 1H), 5.42 (dd, J = 10.4, 4.0 Hz, 1H), 5.11 (d, J = 10.6 Hz, 1H), 4.33 (d, J = 10.6 Hz, 1H), 4.17 (d, J = 11.4 Hz, 1H), 3.91 - 3.83 (m, 2H), 3.79 - 3.67 (m, 2H), 3.62 - 3.46 (m, 2H), 2.70 - 2.50 (m, 2H), 2.32 - 2.17 (m, 1H), 2.13 - 2.01 (m, 1H), 1.94 - 1.74 (m, 3H), 1.55 - 1.31 (m, 6H).

[0880] Examples 56a and 56b [Chemistry]

[0881] Example 56a: (1’S,3S,16’R,19’S)-6-Fluoro-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 11 , 16 tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0882] Example 56b: (1’S,3R,16’S,19’S)-6-Fluoro-8’,18’-dioxa-11’-azaspiro[morpholine-3,15’-tetracyclo[17.2.2.0 2 , 7 .0 11 , 16 tricosane]-2’(7’),3’,5’-triene-5,10’-dione

[0883] Example 56 (36 mg, 0.083 mmol) was subjected to chiral preparative purification using Waters 600 and Chiralpak IC, 25×2.0 cm, 5 μm column, eluting with 55:45 heptane:ethanol + 0.1% isopropylamine to obtain the title compound (peak 1, 2.84 mg, 100% ee; peak 2, 3.4 mg, 97.7% ee).

[0884] Example 56a: Peak 1 (tentatively assigned stereochemistry)

[0885] LCMS (Method C): [M+H] + m / z 433.3, RT 0.99 min

[0886] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 55:45 n-hexane:ethanol + 0.1% isopropylamine: RT 6.3 min

[0887] 11H NMR (500 MHz, CDCl 3 ) δ 7.18 (td, J = 7.7, 1.7 Hz, 1H), 7.10 (dd, J = 7.4, 1.5 Hz, 1H), 6.91 (td, J = 7.4, 1.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.91 (br s, 1H), 5.61 (d, J = 52.0 Hz, 1H), 5.43 (dd, J = 10.1, 3.8 Hz, 1H), 5.12 (d, J = 10.6 Hz, 1H), 4.34 (d, J = 10.6 Hz, 1H), 4.18 (d, J = 11.7 Hz, 1H), 3.91 - 3.83 (m, 2H), 3.80 - 3.71 (m, 2H), 3.60 - 3.51 (m, 2H), 2.71 - 2.52 (m, 2H), 2.29 - 2.19 (m, 1H), 2.09 - 2.02 (m, 1H), 1.95 - 1.88 (m, 1H), 1.89 - 1.80 (m, 2H), 1.80 - 1.74 (m, 1H), 1.56 (s, 2H), 1.47 - 1.33 (m, 3H).

[0888] Example 56b: Peak 2 (tentatively assigned stereochemistry)

[0889] LCMS (Method C): [M+H] + m / z 433.3, RT 0.99 min

[0890] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 55:45 n - hexane:ethanol + 0.1% isopropylamine: RT 7.5 min

[0891] 1 1H NMR (500 MHz, CDCl 3) δ 7.18 (td, J = 7.7, 1.7 Hz, 1H), 7.10 (dd, J = 7.4, 1.5 Hz, 1H), 6.91 (td, J = 7.4, 1.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.91 (br s, 1H), 5.61 (d, J = 52.0 Hz, 1H), 5.43 (dd, J = 10.1, 3.8 Hz, 1H), 5.12 (d, J = 10.6 Hz, 1H), 4.34 (d, J = 10.6 Hz, 1H), 4.18 (d, J = 11.7 Hz, 1H), 3.91 - 3.83 (m, 2H), 3.80 - 3.71 (m, 2H), 3.60 - 3.51 (m, 2H), 2.71 - 2.52 (m, 2H), 2.29 - 2.19 (m, 1H), 2.09 - 2.02 (m, 1H), 1.95 - 1.88 (m, 1H), 1.89 - 1.80 (m, 2H), 1.80 - 1.74 (m, 1H), 1.56 (s, 2H), 1.47 - 1.33 (m, 3H).

Chem.

[0892] Intermediate 119

Chem.

[0893] tert-Butyl 2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-nitropiperidine-1-carboxylate

[0894] Intermediate 119 was prepared using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate according to the same procedure as described for Intermediate 41, and the title compound (12.2 g) was obtained as a yellow oil. [M - Boc + H] + m / z 349.3

[0895] Intermediate 120

Chem.

[0896] tert-butyl-rel-(2R,3R)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-nitro-3-(prop-2-en-1-yl)piperidine-1-carboxylate

[0897] A solution of potassium hydroxide (1.17 g, 20.87 mmol) in 2-propanol (42 mL) and methanol (42 mL) was stirred for 1 hour. A solution of Intermediate 119 (8.51 g) in methanol (42 mL) was added. Next, the solution was degassed, and Pd(OAc) 2 (426 mg, 1.9 mmol) was added, followed by triphenylphosphine (746 mg, 2.85 mmol). The solution was heated to 45 °C for 5 minutes, and then allyl acetate (2.25 mL, 20.87 mmol) was added. The reaction mixture was heated under nitrogen at 55 °C for 16 hours and then cooled to room temperature. The mixture was concentrated in vacuo and redissolved in MTBE. The mixture was filtered through a pad of celite and washed with water. The organic extract was dried (Na 2 SO 4 ) and concentrated in vacuo. The crude product was purified by column chromatography (0 - 10% EtOAc in cyclohexane) to afford the title compound (5.8 g) as a colorless oil. [M+H] + m / z 489.4

[0898] Intermediate 121

Chem.

[0899] tert-butyl-rel-(2R,3R)-3-amino-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(prop-2-en-1-yl)piperidine-1-carboxylate

[0900] Intermediate 121 was prepared according to the same procedure as described for Intermediate 6, and the title compound (3.85 g) was obtained as a yellow oil. [M+H] + m / z 459.4

[0901] Intermediate 122

Chemical formula

[0902] tert-Butyl-rel-(2R,3R)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(prop-2-en-1-yl)-3-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate

[0903] To a solution of Intermediate 121 (300 mg) in DCM (6.5 mL) were added dropwise triethylamine (0.18 mL, 1.31 mmol) and trifluoroacetic anhydride (0.1 mL, 0.690 mmol) at 0 °C. The reaction mixture was stirred for 1 hour, then diluted with DCM and washed with water, saturated NaHCO 3 aqueous solution, and 1M Na 2 CO 3 until the pH reached 9. The organic layer was dried (Na 2 SO 4 ) and concentrated in vacuo to give the title compound (337 mg) as a yellow oil. [M+H] + m / z 555.5

[0904] Intermediate 123

Chemical formula

[0905] tert-Butyl-rel-(2R,3R)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(2-oxoethyl)-3-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate

[0906] Intermediate 122 (3.13 g) was dissolved in DCM (256 mL) in a 3-necked round-bottom flask, and the solution was stirred at -78 °C while ozone was bubbled through the entire solution. After 15 minutes, ozone was replaced with N 2 + and. After 10 minutes, triphenylphosphine (1.48 g, 5.64 mmol) in DCM (9 mL) was slowly added to the cold mixture. The mixture was slowly warmed to room temperature and concentrated in vacuo to afford a clear oil. The crude product was purified by column chromatography (0 - 30% EtOAc + 10% EtOH in cyclohexane) to give the title compound (2 g). [M - Boc + H]m / z 457.5

[0907] Intermediate 124

Chem.

[0908] tert-Butyl-rel-(2R,3R)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(2-hydroxyethyl)-3-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate

[0909] Sodium borohydride (136 mg, 3.59 mmol) was added to a mixture of Intermediate 123 (2.0 g) and methanol (17 mL) at 0 °C. The suspension was stirred at 0 °C for 1 hour, then the reaction was warmed to room temperature, the mixture was diluted with EtOAc, and washed with water (100 mL). The aqueous phase was extracted 3 times with EtOAc, the combined organic phases were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (2 g). [M - Boc + H] + m / z 459.3

[0910] Intermediate 125

Chem.

[0911] tert-butyl-rel-(2R,3R)-3-amino-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(2-hydroxyethyl)piperidine-1-carboxylate

[0912] To a solution of Intermediate 124 (2.01 g) in methanol (9 mL) and water (4.5 mL) was added potassium carbonate (2.49 g, 17.99 mmol). The mixture was stirred at 50 °C for 1 hour, then the mixture was diluted with EtOAc and washed with H 2 O (50 mL) and brine (50 mL), dried over Na 2 SO 4 and concentrated in vacuo to afford the title compound (1.51 g). [M+H] + m / z 463.4

[0913] Intermediate 126 [Chemical formula]

[0914] tert-butyl-rel-(6R,7R)-7-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0915] A solution of N,N-diisopropylethylamine (0.85 mL, 4.86 mmol) was added dropwise at 0 °C to a stirred solution of bis(trichloromethyl) carbonate (1.85 g, 6.24 mmol) and Intermediate 125 (1.5 g) in anhydrous DCM (58 mL), and the resulting mixture was stirred for 30 minutes. The reaction mixture was warmed to room temperature and purged with N 2 flow for 30 minutes (the exhaust gas was passed through a trap containing 2N aqueous NaOH solution to quench excess phosgene). Then, the reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4It was dried, filtered, and concentrated. The crude product was purified by column chromatography (0 - 35% EtOAc + 20% EtOH in cyclohexane) to obtain the title compound (1.34 g). [M+H] + m / z 489.4

[0916] Intermediate 127

Chem.

[0917] tert-Butyl-rel-(6R,7R)-7-{[(4-hydroxycyclohexyl)oxy]methyl}-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0918] Intermediate 127 was prepared in the same procedure as described for Intermediate 8 to obtain the title compound (859 mg) as a colorless oil. [M+H] + m / z 399.5

[0919] Intermediate 128

Chem.

[0920] tert-Butyl-rel-(6R,7R)-2-oxo-7-{[(4-oxocyclohexyl)oxy]methyl}-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0921] Intermediate 128 was prepared according to the same procedure as described for Intermediate 46 to obtain the title compound (1.22 g). [M+H] + m / z 397.5

[0922] Intermediate 129

Chem.

[0923] tert-butyl-rel-(6R,7R)-7-[({4-[(4-methylbenzenesulfonamido)imino]cyclohexyl}oxy)methyl]-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0924] Intermediate 129 was prepared according to the same procedure as described for Intermediate 47 to give the title compound (1.1 g). [M+H] + m / z 565.5

[0925] Intermediate 130

Chemical Structure

[0926] tert-butyl-rel-(6R,7R)-7-[({4-[2-(benzyloxy)phenyl]cyclohex-3-en-1-yl}oxy)methyl]-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0927] Intermediate 130 was prepared according to the same procedure as described for Intermediate 48 to give the title compound (50 mg). [M+H] + m / z 563.3

[0928] Intermediate 131

Chemical Structure

[0929] tert-butyl-rel-(6R,7R)-2-oxo-7-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0930] Intermediate 131 was prepared according to the same procedure as described for Intermediate 49 to give the title compound (45 mg). [M+H] + m / z 475.3

[0931] Intermediate 132

Chem.

[0932] tert-Butyl-rel-(6R,7R)-2-oxo-7-({[(1s,4s)-4-{2-[2-(tert-butoxy)-2-oxoethoxy]phenyl}cyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0933] Intermediate 132 was prepared according to the same procedure as described for Intermediate 67 to give the title compound (38 mg). [M+H] + m / z 589.3

[0934] Intermediate 133

Chem.

[0935] 2-{2-[(1s,4s)-4-{[rel-(6R,7R)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecan-7-yl]methoxy}cyclohexyl]phenoxy}acetic acid hydrochloride

[0936] Intermediate 133 was prepared according to the same procedure as described for Intermediate 57 to give the title compound (28 mg). [M+H]+ m / z 433.3

[0937] Example 57

Chem.

[0938] Rel-(1’s,4R,16’R,19’s)-8’,18’-dioxa-11’-azaspiro[1,3-oxazinane-4,15’-tetracyclo[17.2.2.0 2 , 7 .011 , 16 Tricosane]-2’(7’),3’,5’-triene-2,10’-dione

[0939] Example 57 was prepared using Intermediate 133 according to the same procedure as described for Example 1, and the title compound (2.2 mg) was obtained.

[0940] LCMS (Method C): [M+H] + m / z 415.2, RT 0.92 min

[0941] 1 H NMR (500 MHz, CDCl 3 ) δ 7.14 - 7.24 (m, 1H), 7.05 - 7.13 (m, 1H), 6.91 (br t, J = 7.4 Hz, 1H), 6.75 (br d, J = 8.0 Hz, 1H), 6.35 (br s, 1H), 5.09 (br d, J = 10.4 Hz, 2H), 4.62 (br t, J = 12.0 Hz, 1H), 4.34 - 4.41 (m, 1H), 4.31 (br d, J = 10.4 Hz, 1H), 3.93 (br t, J = 9.5 Hz, 1H), 3.75 (br s, 1H), 3.70 (br d, J = 12.8 Hz, 1H), 3.58 (br d, J = 4.8 Hz, 1H), 3.44 - 3.54 (m, 1H), 2.52 - 2.72 (m, 1H), 1.21 - 2.77 (m, 14H).

Chemical Structure

[0942] Intermediate 134

Chemical Structure

[0943] tert-Butyl-rel-(2R,3R)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(prop-2-en-1-yl)-3-(prop-2-enamide)piperidine-1-carboxylate

[0944] To a solution of Intermediate 121 (2.65 g) in MeTHF (53 mL) was added triethylamine (5.3 mL, 38.03 mmol) and a 1 M solution of 2-propenoyl chloride (4.62 mL, 4.62 mmol) in MeTHF at 0 °C. The solution was stirred at 0 °C for 1 hour. Further triethylamine (3.0 mL, 21.52 mmol) and 2-propenoyl chloride (1.0 mL, 1 mmol, 1 M solution in MeTHF) were added and the mixture was stirred at 0 °C for 1 hour. The reaction was quenched by adding saturated NaHCO 3 aqueous solution (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were dried (Na 2 SO 4 ), and concentrated in vacuo. The crude product was purified by column chromatography (0 - 30% EtOAc in cyclohexane) to afford the title compound (1.5 g) as a colorless oil. [M+H] + m / z 513.4

[0945] Intermediate 135 [Chemical Structure]

[0946] tert-Butyl-rel-(6R,7R)-7-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-2-oxo-1,8-diazaspiro[5.5]undec-3-ene-8-carboxylate

[0947] A solution of Intermediate 134 (1.62 g) in toluene (632 mL) was degassed by bubbling N 2 (g) through it for 15 minutes. The degassed solution was heated at 65 °C and Zhan Catalyst-1B (100 mg, 0.140 mmol) was added. The pale yellow solution was slowly bubbled with N 2It was stirred at the same temperature for 3 hours under reflux. The reaction mixture was concentrated in vacuo, and the crude product was purified by column chromatography (0 - 50% EtOAc in cyclohexane) to give the title compound (1.23 g) as a pale yellow oil. [M+H] + m / z 485.4

[0948] Intermediate 136

Chem.

[0949] tert-Butyl-rel-(6S,7R)-7-{[(4-Hydroxycyclohexyl)oxy]methyl}-2-oxo-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0950] Intermediate 136 was prepared according to the same procedure as described for Intermediate 8 to give the title compound (1.02 g) as an off-white solid. [M+H] + m / z 397.4

[0951] Intermediate 137

Chem.

[0952] tert-Butyl-rel-(6S,7R)-2-oxo-7-{[(4-oxocyclohexyl)oxy]methyl}-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0953] Intermediate 137 was prepared in the same procedure as described for Intermediate 46 to give the title compound (1.6 g) as a colorless oil. [M+H] + m / z 395.4

[0954] Intermediate 138

Chem.

[0955] tert-butyl-rel-(6S,7R)-7-[({4-[(4-methylbenzenesulfonamido)imino]cyclohexyl}oxy)methyl]-2-oxo-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0956] Intermediate 138 was prepared according to the same procedure as described for Intermediate 47, and the title compound (1.02 g) was obtained as a white solid. [M+H] + m / z 563.4

[0957] Intermediate 139

Chemical formula

[0958] tert-butyl-rel-(6S,7R)-7-[({4-[2-(benzyloxy)phenyl]cyclohex-3-en-1-yl}oxy)methyl]-2-oxo-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0959] Intermediate 139 was prepared according to the same procedure as described for Intermediate 48, and the title compound (345 mg) was obtained as a yellow oil. [M+H] + m / z 561.5

[0960] Intermediate 140

Chemical formula

[0961] tert-butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0962] Intermediate 140 was prepared according to the same procedure as described for Intermediate 8, and the title compound (140 mg) was obtained as a yellow oil. [M+H] +m / z 473.4

[0963] Intermediate 141

Chem.

[0964] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-{2-[2-(tert-butoxy)-2-oxoethoxy]phenyl}cyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0965] Intermediate 141 was prepared according to the same procedure as described for Intermediate 67, and the title compound (120 mg) was obtained as a yellow oil. [M+H] + m / z 587.5

[0966] Intermediate 142

Chem.

[0967] 2-{2-[(1s,4s)-4-{[rel-(6S,7R)-2-oxo-1,8-diazaspiro[5.5]undecan-7-yl]methoxy}cyclohexyl]phenoxy}acetic acid hydrochloride

[0968] Intermediate 142 was prepared according to the same procedure as described for Intermediate 68, and the title compound (120 mg) was obtained as a yellow oil. [M-HCl+H] + m / z 431.4

[0969] Example 58

Chem.

[0970] Rel-(1’s,2S,16’R,19’s)-8’,18’-dioxa-11’-azaspiro[piperidine-2,15’-tetracyclo-[17.2.2.02 , 7 .0 11 , 16 Tricosane]-2’(7’),3’,5’-triene-6,10’-dione

[0971] Example 58 was prepared using Intermediate 142 according to the same procedure as described for Example 1, and the title compound (35 mg) was obtained as a white solid.

[0972] LCMS (Method C): [M+H] + m / z 413.4, RT 0.95 min.

[0973] 1 H NMR (500 MHz, CDCl 3 ) δ 7.17 (td, J = 7.7, 1.7 Hz, 1H), 7.10 (dd, J = 7.4, 1.5 Hz, 1H), 6.90 (td, J = 7.4, 1.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.25 (br s, 1H), 5.13 (dd, J = 10.9, 3.6 Hz, 1H), 5.10 (d, J = 10.6 Hz, 1H), 4.31 (d, J = 10.6 Hz, 1H), 3.90 (dd, J = 10.8, 8.6 Hz, 1H), 3.71 (br s, 1H), 3.74 - 3.66 (m, 1H), 3.53 (dd, J = 8.4, 4.0 Hz, 1H), 3.52 - 3.43 (m, 1H), 2.71 - 2.61 (m, 1H), 2.62 - 2.53 (m, 1H), 2.53 - 2.44 (m, 1H), 2.37 - 2.28 (m, 2H), 2.29 - 2.21 (m, 1H), 2.20 - 2.13 (m, 1H), 2.12 - 2.05 (m, 1H), 1.94 - 1.85 (m, 2H), 1.83 - 1.69 (m, 4H), 1.54 - 1.47 (m, 1H), 1.46 - 1.31 (m, 4H).

[0974] Examples 58a and 58b

Chem.

[0975] Example 58a: (1’s,2S,16’R,19’s)-8’,18’-dioxa-11’-azaspiro[piperidine-2,15’-tetracyclo-[17.2.2.0 2 , 7 .0 11 , 16 tricosane]-2’(7’),3’,5’-triene-6,10’-dione

[0976] Example 58b: (1’s,2R,16’S,19’s)-8’,18’-dioxa-11’-azaspiro[piperidine-2,15’-tetracyclo-[17.2.2.0 2 , 7 .0 11 , 16 tricosane]-2’(7’),3’,5’-triene-6,10’-dione

[0977] Example 58 (33 mg, 0.080 mmol) was subjected to chiral preparative purification using Waters 600 and Chiralpak AD-H, 25×2.0 cm, 5 μm column, eluting with 65:35 heptane:(ethanol / methanol 1 / 1 + 0.1 isopropylamine) to obtain the title compound (peak 1, 9.52 mg; 100% ee; peak 2, 9.96 mg, 100% ee).

[0978] Example 58a: Peak 1 (tentatively assigned stereochemistry)

[0979] LCMS (method C): [M+H] + m / z 413.3, RT 0.95 min

[0980] Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 65:35 n-hexane:(ethanol / methanol 1 / 1 + 0.1 isopropylamine): RT 6.4 min

[0981] 1 H NMR (500 MHz, CDCl 3 ) δ 7.17 (td, J = 7.7, 1.7 Hz, 1H), 7.10 (dd, J = 7.4, 1.5 Hz, 1H), 6.90 (td, J = 7.4, 1.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.25 (br s, 1H), 5.13 (dd, J = 10.9, 3.6 Hz, 1H), 5.10 (d, J = 10.6 Hz, 1H), 4.31 (d, J = 10.6 Hz, 1H), 3.90 (dd, J = 10.8, 8.6 Hz, 1H), 3.71 (br s, 1H), 3.74 - 3.66 (m, 1H), 3.53 (dd, J = 8.4, 4.0 Hz, 1H), 3.52 - 3.43 (m, 1H), 2.71 - 2.61 (m, 1H), 2.62 - 2.53 (m, 1H), 2.53 - 2.44 (m, 1H), 2.37 - 2.28 (m, 2H), 2.29 - 2.21 (m, 1H), 2.20 - 2.13 (m, 1H), 2.12 - 2.05 (m, 1H), 1.94 - 1.85 (m, 2H), 1.83 - 1.69 (m, 4H), 1.54 - 1.47 (m, 1H), 1.46 - 1.31 (m, 4H).

[0982] Example 58b: Peak 2 (Provisionally Assigned Stereochemistry)

[0983] LCMS (Method C): [M+H] + m / z 413.3, RT 0.94 min

[0984] Chiral Analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 65:35 n-hexane:(ethanol / methanol 1 / 1 + 0.1 isopropylamine): RT 9.7 min

[0985] 1 H NMR (500 MHz, CDCl3 ) δ 7.17 (td, J = 7.7, 1.7 Hz, 1H), 7.10 (dd, J = 7.4, 1.5 Hz, 1H), 6.90 (td, J = 7.4, 1.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.25 (br s, 1H), 5.13 (dd, J = 10.9, 3.6 Hz, 1H), 5.10 (d, J = 10.6 Hz, 1H), 4.31 (d, J = 10.6 Hz, 1H), 3.90 (dd, J = 10.8, 8.6 Hz, 1H), 3.71 (br s, 1H), 3.74 - 3.66 (m, 1H), 3.53 (dd, J = 8.4, 4.0 Hz, 1H), 3.52 - 3.43 (m, 1H), 2.71 - 2.61 (m, 1H), 2.62 - 2.53 (m, 1H), 2.53 - 2.44 (m, 1H), 2.37 - 2.28 (m, 2H), 2.29 - 2.21 (m, 1H), 2.20 - 2.13 (m, 1H), 2.12 - 2.05 (m, 1H), 1.94 - 1.85 (m, 2H), 1.83 - 1.69 (m, 4H), 1.54 - 1.47 (m, 1H), 1.46 - 1.31 (m, 4H). [Chemical formula]

[0986] Intermediate 143 [Chemical formula]

[0987] tert-Butyl-rel-(2R,3R)-2-({[4-(Benzyloxy)cyclohexyl]oxy}methyl)-3-ethenesulfonamido-3-(prop-2-en-1-yl)piperidine-1-carboxylate

[0988] A solution of intermediate 121 (3.65 g) and triethylamine (3.33 mL, 23.88 mmol) in dry DCM (79 mL) was treated with 2-chloroethanesulfonyl chloride (1.67 mL, 15.92 mmol) at 0 °C and the mixture was stirred for 30 minutes. The reaction mixture was cooled to room temperature, quenched with saturated NH 4 Cl aqueous solution, diluted with water and extracted with DCM. The combined organic extracts were washed with brine and concentrated in vacuo. The crude product was purified by column chromatography (0 - 100% EtOAc in cyclohexane) to afford the title compound (3.28 g) as a colorless gum. [M+H] + m / z 549.4

[0989] Intermediate 144

Chemical formula

[0990] tert-Butyl-rel-(6R,7R)-7-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-2,2-dioxo-2λ 6 -thia-1,8-diazaspiro[5.5]undec-3-ene-8-carboxylate

[0991] Intermediate 144 was prepared according to the same procedure as described for intermediate 135 to afford the title compound (2.81 g) as a pale yellow oil. [M+H] + m / z 521.4

[0992] Intermediate 145

Chemical formula

[0993] tert-Butyl-rel-(6R,7R)-7-{[(4-hydroxycyclohexyl)oxy]methyl}-2,2-dioxo-2λ 6 -thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0994] Intermediate 145 was prepared in the same procedure as described for Intermediate 8, and the title compound (2.1 g) was obtained as a colorless oil. [M+H] + m / z 433.3

[0995] Intermediate 146

Chem.

[0996] tert-Butyl-rel-(6R,7R)-2,2-dioxo-7-{[(4-oxocyclohexyl)oxy]methyl}-2λ 6 -thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[0997] Intermediate 146 was prepared in the same procedure as described for Intermediate 46, and the title compound (2.8 g) was obtained as a colorless oil. [M+H] + m / z 431.4

[0998] Intermediate 147

Chem.

[0999] tert-Butyl-rel-(6R,7R)-7-[({4-[(4-methylbenzenesulfonamido)imino]cyclohexyl}oxy)methyl]-2,2-dioxo-2λ 6 -thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1000] Intermediate 147 was prepared according to the same procedure as described for Intermediate 47, and the title compound (1.87 g) was obtained as a white solid. [M+H] + m / z 599.4

[1001] Intermediate 148

Chem.

[1002] tert-butyl-rel-(6R,7R)-7-[({4-[2-(benzyloxy)phenyl]cyclohex-3-en-1-yl}oxy)methyl]-2,2-dioxo-2λ 6 -thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1003] Intermediate 148 was prepared according to the same procedure as described for Intermediate 47, and the title compound (1.16 g) was obtained as a yellow oil. [M+H] + m / z 597.5

[1004] Intermediate 149

Chemical Structure

[1005] tert-butyl-rel-(6R,7R)-2,2-dioxo-7-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)-2λ 6 -thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1006] Intermediate 149 was prepared according to the same procedure as described for Intermediate 8, and the title compound (880 mg) was obtained as a white solid. [M+H] + m / z 509.4

[1007] Intermediate 150

Chemical Structure

[1008] tert-butyl-rel-(6R,7R)-2,2-dioxo-7-({[(1s,4s)-4-{2-[2-(tert-butoxy)-2-oxoethoxy]-phenyl}cyclohexyl]oxy}methyl)-2λ 6 -thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1009] The intermediate 150 was prepared according to the same procedure as described for intermediate 67, and the title compound (312 mg) was obtained as a white solid. [M+H] + m / z 623.4

[1010] Intermediate 151

Chemical formula

[1011] 2-{2-[(1s,4s)-4-{[rel-(6R,7R)-2,2-dioxo-2λ 6 -thia-1,8-diazaspiro[5.5]undecan-7-yl]methoxy}cyclohexyl]phenoxy}acetic acid

[1012] The intermediate 151 was prepared according to the same procedure as described for intermediate 68, and the title compound (265 mg) was obtained as a white solid. [M+H] + m / z 467.3

[1013] Example 59

Chemical formula

[1014] Rel-(1s,15R,16R,19s)-8,18-dioxa-11-azaspiro[tetracyclo[17.2.2.0 2 , 7 .0 11 , 16 tricosane-15,3’-[1λ 6 ,2]thiadinane]-2(7),3,5-triene-1’,1’,10-trione

[1015] Example 59 was prepared using intermediate 151 according to the same procedure as described for Example 1, and the title compound (50 mg) was obtained as a white solid.

[1016] LCMS (Method C): [M+H] +m / z 449.3, RT 1.06 min

[1017] 1 H NMR (500 MHz, CDCl 3 ) δ 7.17 (td, J = 7.7, 1.6 Hz, 1H), 7.10 (dd, J = 7.3, 1.5 Hz, 1H), 6.90 (td, J = 7.4, 0.8 Hz, 1H), 6.71 - 6.78 (m, 1H), 5.38 (br dd, J = 9.6, 4.1 Hz, 1H), 5.08 (d, J = 10.7 Hz, 1H), 4.31 (d, J = 10.7 Hz, 1H), 4.15 (br s, 1H), 3.88 - 3.95 (m, 1H), 3.80 - 3.88 (m, 1H), 3.75 (br s, 1H), 3.66 - 3.73 (m, 1H), 3.51 - 3....

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt or stereoisomer thereof. (In the formula, L is a linker selected from the group consisting of optionally substituted aryl, heteroaryl, -carbocykrill-O-, and -heterocyclyl-O-, where -carbocykrill-O- and -heterocyclyl-O- have the following orientations: 【Chemistry 2】 Having; A １ is -C(O)-, -S(O) ２ -, or -C(H)(CF ３ ) - and; A ２ and A ３ each independently represents a bond, -O-, -CR ５ R ６ -, -NR ７ -, or -S-; or A ２ and A ３ together with an optionally substituted carbon atom, has the following structure: 【Transformation 3】 Forming a cyclopropyl ring having; A ４ The bond is -O-, -CR ５ R ６ -, -NR ７ -, -S-, -(CR ５ R ６ ) ２ -, -CR ５ R ６ -O-, -CR ５ R ６ -S-, -CR ５ R ６ -N(R) ７ )-,-O-CR ５ R ６ -, -S-CR ５ R ６ -, or -N(R ７ )-CR ５ R ６ - and, however, A ２ A ３ , and A ４ The rings containing -O-O-, -O-NR ７ - or - NR ７ -NR ７ - shall not contain; 【Chemistry 4】 is a phenyl, a five- or six-membered heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted; V and Z are independently -O- and -CR ８ R ９ -, or -NR １０ - and; X is -O-, -CR １１ R １２ -, or -NR １３ - and; Y is a bond, -O-, -CR ８ R ９ -, or -NR １０ - and; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ８ , R ９ , R １１ , R １２ and R １４ Each of these is independently hydrogen, halogen, alkyl, cycloalkyl, or heterocyclyl; and / or R １ and R ２ They, together with the atoms to which they are bonded, form optionally substituted carbocyclic or heterocyclic rings; and / or R ３ and R ４ They, together with the atoms to which they are bonded, form optionally substituted carbocyclic or heterocyclic rings; and / or R ５ and R ６ They, together with the atoms to which they are bonded, form optionally substituted carbocyclic or heterocyclic rings; and / or R ８ and R ９ They, together with the atoms to which they are bonded, form optionally substituted carbocyclic or heterocyclic rings; and / or R １１ and R １２ These, together with the atoms bonded to them, form optionally substituted carbon rings or heterocycles; R ７ , R １０ , and R １３ These are, independently, hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)heterocyclyl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -(C=O)-O-heterocyclyl, -(C=O)-O-heteroaryl, and -S(O). ２ -alkyl, -S(O) ２ -Cycloalkyl, or -S(O) ２ - It is a heterocycline; (m, n, p, and r are each independently 0, 1, or 2.)

2. A １ However, -C(O)- or -S(O) ２ - The compound according to claim 1.

3. A ２ However, -O- or -CR ５ R ６ - The compound according to claim 1.

4. A ３ However, -O- or -CR ５ R ６ - The compound according to claim 1.

5. A ４ However, binding or -CR ５ R ６ - The compound according to claim 1.

6. R ５ and R ６ The compound according to claim 1, wherein each is independently H, halogen, or C1-5 alkyl.

7. R ５ and R ６ The compound according to claim 1, wherein these atoms, together with the carbon atoms to which they are bonded, form a C3-6 carbon ring or a 3-membered or 6-membered heterocycle.

8. R ７ The compound according to claim 1, wherein the compound is H or C1-5 alkyl.

9. R １ and R ２ The compound according to claim 1, wherein R and R are each independently H, halogen, or C1-5 alkyl.

10. R ３ and R ４ The compound according to claim 1, wherein each is independently H or C 1-5 alkyl.

11. The compound according to claim 1, wherein V is -O-.

12. Y is combined or -CR ８ R ９ - The compound according to claim 1.

13. Z is -O- or -CR ８ R ９ - and is the compound according to claim 1.

14. R ８ and R ９ The compound according to claim 1, wherein each is independently H or C 1-5 alkyl.

15. R ８ and R ９ However, together with the carbon atoms to which they are bonded, C ３－６ The compound according to claim 1, which forms a cycloalkyl group.

16. R １０ The compound according to claim 1, wherein the compound is H or C1-5 alkyl.

17. X is -CR １１ R １２ - The compound according to claim 1.

18. R １１ and R １２ The compound according to claim 1, wherein each is independently H or C 1-5 alkyl.

19. The aforementioned 【Transformation 5】 but, 【Transformation 6】 And R ａ The compound according to claim 1, wherein is a halogen, a C1-5 alkyl, or a C1-5 alkoxy; and q is 0, 1, or 2.

20. The aforementioned 【Transformation 7】 but, The compound according to claim 1, wherein each of the compounds is selected from the group consisting of phenyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, and each is optionally substituted.

21. The compound according to claim 19, wherein q is 0 or 1.

22. The compound according to claim 1, wherein m is 0 or 1.

23. The compound according to claim 1, wherein n is 0 or 1.

24. The compound according to claim 1, wherein p is 0 or 1.

25. L is structure 【Transformation 8】 A -carbocyryl-O- or -heterocyclyl-O-linker having, in formula A ５ and A ６ These are, independently, -O- or -CH ２ - The compound according to claim 1.

26. A ５ The compound according to claim 25, wherein A6 is each -O-.

27. L, 【Chemistry 9】 And R ｂ The compound according to claim 1, wherein is a halogen, a C1-5 alkyl, or a C1-5 alkoxy; and r is 0, 1, or 2.

28. The compound according to claim 1, wherein: 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 [Chemistry 10-4] [Transformation 10-5] 【Chemistry 10-6】 The compound selected from the group consisting of ,

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

30. A pharmaceutical composition according to claim 29, for use in treating a disease or disorder by modulating one or more orexin receptors.

31. A pharmaceutical composition according to claim 29, for use in treating, preventing, improving, controlling or reducing the risk of a disease or disorder associated with one or more orexin receptors.

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