Macrocyclic orexin receptor agonists and uses thereof

Abstract

Provided herein are compounds of Formula (I): or pharmaceutically acceptable salts thereof, wherein m, n, p, A1, A2, A3, A4, L, R1, R2, R3, R4, formulae (II), (III), V, X, Y, and Z are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for example in the treatment of a disease or condition treatable by administering an orexin agonist. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 347,708, filed on June 1, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Orexin is a neuropeptide that is produced exclusively by specific neurons sparsely located in the lateral hypothalamus and its surrounding areas. Orexin consists of two subtypes, orexin A and orexin B. Orexin A (OX-A) and orexin B (OX-B) are both endogenous ligands for orexin receptors, primarily found 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 OX-A and OX-B with similar affinity. It is believed that the physiological effects of orexin are expressed through one or both of the OX1 receptor and OX2 receptor, two subtypes of orexin receptors.

[0004] Orexins regulate sleep and wakefulness, making the orexin system a potential therapeutic target for treating sleep disorders. Orexins have been found to stimulate food intake in rats, suggesting a physiological role for these peptides as mediators of central feedback mechanisms regulating feeding behavior. Orexins have also been implicated in arousal, mood, energy homeostasis, reward, learning, and memory.

[0005] There is a need for compounds that modulate orexin receptors, as well as compositions and methods for treating diseases or conditions that can be treated by administering orexin agonists. Summary of the Invention

[0006] The present disclosure relates to compounds that are agonists of the orexin-2 receptor, as well as pharmaceutical compositions thereof and their use in treating diseases or conditions treatable by administering orexin agonists.

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

[0008]

[0009] or a pharmaceutically acceptable salt or stereoisomer thereof,

[0010] in:

[0011] L is a linker selected from the group consisting of aryl, heteroaryl, -carbocyclyl-O- and -heterocyclyl-O-, wherein -carbocyclyl-O- and -heterocyclyl-O- have the following orientations:

[0012]

[0013] A1 is -C(O)-, -S(O)2- or -C(H)(CF3)-;

[0014] A2 and A3 are each independently a bond, -O-, -CR5R6-, -NR7- or -S-; or A2 and A3 together with the optionally substituted carbon atom form a cyclopropyl ring having the following structure:

[0015]

[0016] A4 is a bond, -O-, -CR5R6-, -NR7-, -S-, -(CR5R6)2-, -CR5R6-O-, -CR5R6-S-, -CR5R6-N(R7)-, -O-CR5R6-, -S-CR5R6- or -N(R7)-CR5R6-, with the proviso that the ring including A2, A3 and A4 does not contain -OO-, -O-NR7- or -NR7-NR7-;

[0017] is phenyl, 5-membered or 6-membered heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted;

[0018] V and Z are each independently -O-, -CR8R9- or -NR 10 -;

[0019] X is -O-, -CR 11 R 12 -or-NR 13 -;

[0020] Y is a bond, -O-, -CR8R9- or -NR 10 -;

[0021] R1, R2, R3, R4, R5, R6, R8, R9, R 11 、R 12 and R 14 are each independently hydrogen, halogen, alkyl, cycloalkyl or heterocyclic; and / or R1 and R2 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R3 and R4 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R5 and R6 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R8 and R9 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R 11 and R 12 together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring;

[0022] R7, R 10 and R 13each independently represents 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, -S(O)2-alkyl, -S(O)2-cycloalkyl, or -S(O)2-heterocyclyl; and

[0023] m, n, p and r are each independently 0, 1 or 2.

[0024] In some embodiments, the present disclosure provides a compound of formula (IA):

[0025]

[0026] or a pharmaceutically acceptable salt thereof,

[0027] in:

[0028] A1 is -C(O)-, -S(O)2- or -C(H)(CF3)-;

[0029] A2 and A3 are each independently a bond, -O-, -CR5R6-, -NR7- or -S-; or A2 and A3 together with the optionally substituted carbon atom form a cyclopropyl ring having the following structure:

[0030]

[0031] A4 is a bond, -O-, -CR5R6-, -NR7-, -S-, -(CR5R6)2-, -CR5R6-O-, -CR5R6-S-, -CR5R6-N(R7)-, -O-CR5R6-, -S-CR5R6- or -N(R7)-CR5R6-, with the proviso that the ring including A2, A3 and A4 does not contain -OO-, -O-NR7- or -NR7-NR7-;

[0032] A5 and A6 are each independently -O- or -CH2-;

[0033] is phenyl, 5-membered or 6-membered heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted;

[0034] V and Z are each independently -O-, -CR8R9- or -NR 10 -;

[0035] X is -O-, -CR 11 R 12 -or-NR 13 -;

[0036] Y is a bond, -O-, -CR8R9- or -NR 10 -;

[0037] R1, R2, R3, R4, R5, R6, R8, R9, R 11 、R 12 and R 14 are each independently hydrogen, halogen, alkyl, cycloalkyl or heterocyclic; and / or R1 and R2 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R3 and R4 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R5 and R6 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R8 and R9 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R 11 and R 12 together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring;

[0038] R7, R 10 and R 13 each independently represents 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, -S(O)2-alkyl, -S(O)2-cycloalkyl, or -S(O)2-heterocyclyl; and

[0039] m, n, p and r are each independently 0, 1 or 2.

[0040] In some embodiments, the present disclosure provides a compound of formula (IB):

[0041]

[0042] or a pharmaceutically acceptable salt thereof,

[0043] in:

[0044] A1 is -C(O)-, -S(O)2- or -C(H)(CF3)-;

[0045] A2 and A3 are each independently a bond, -O-, -CR5R6-, -NR7- or -S-; or A2 and A3 together with the optionally substituted carbon atom form a cyclopropyl ring having the following structure:

[0046]

[0047] A4 is a bond, -O-, -CR5R6-, -NR7-, -S-, -(CR5R6)2-, -CR5R6-O-, -CR5R6-S-, -CR5R6-N(R7)-, -O-CR5R6-, -S-CR5R6- or -N(R7)-CR5R6-, with the proviso that the ring including A2, A3 and A4 does not contain -OO-, -O-NR7- or -NR7-NR7-;

[0048] Ar is an aryl or heteroaryl linker;

[0049] is phenyl, 5-membered or 6-membered heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted;

[0050] V and Z are each independently -O-, -CR8R9- or -NR 10 -;

[0051] X is -O-, -CR 11 R 12 -or-NR 13 -;

[0052] Y is a bond, -O-, -CR8R9- or -NR 10 -;

[0053] R1, R2, R3, R4, R5, R6, R8, R9, R 11 、R 12 and R 14 are each independently hydrogen, halogen, alkyl, cycloalkyl or heterocyclic; and / or R1 and R2 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R3 and R4 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R5 and R6 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R8 and R9 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R 11 and R 12 together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring;

[0054] R7, R 10 and R 13 each independently represents 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, -S(O)2-alkyl, -S(O)2-cycloalkyl, or -S(O)2-heterocyclyl; and

[0055] m, n, p and r are each independently 0, 1 or 2.

[0056] In some embodiments, the present disclosure provides a compound of formula (IC):

[0057]

[0058] or a pharmaceutically acceptable salt thereof, wherein m, n, p, A5, A6, R1, R2, V, X, Y and Z are as defined herein.

[0059] In some embodiments, the present disclosure provides a compound of formula (ID):

[0060]

[0061] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, A5, A6, R1, R2, R b 、 V, X, Y, and Z are defined herein.

[0062] In some embodiments, A1 is -C(O)- or -S(O)2-. In some embodiments, A1 is -C(O)-. In some embodiments, A1 is -S(O)2-.

[0063] In some embodiments, A2 is -O-, -NR7-, or -CR5R6-. In some embodiments, A2 is a bond, -O-, or -CR5R6-. In some embodiments, A2 is -CR5R6-. In some embodiments, A2 is -O-. In some embodiments, A2 is a bond.

[0064] In some embodiments, A3 is a bond, -O-, or -CR5R6-. In some embodiments, A3 is -O- or -CR5R6-. In some embodiments, A3 is -O-. In some embodiments, A3 is -CR5R6-. In some embodiments, A3 is a bond.

[0065] In some embodiments, A4 is -CR5R6-.

[0066] In some embodiments, R5 and R6 are each independently H, halogen, or alkyl. In some embodiments, R5 and R6 are each independently H or alkyl. In some embodiments, the alkyl is methyl or ethyl.

[0067] In some embodiments, R5 and R6 are H. In some embodiments, R5 and R6 are halogen. In some embodiments, R5 and R6 together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6In some embodiments, the heterocycle is a 3-membered or 6-membered heterocycle. In some embodiments, the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0068] In some embodiments, R 7 is H or alkyl.

[0069] In some embodiments, R1 and R2 are each independently H, halogen, or alkyl. In some embodiments, R1 and R2 are each independently H or alkyl. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, R1 and R2 are H. In some embodiments, R1 and R2 are H or halogen. In some embodiments, halogen is fluorine. In some embodiments, R1 and R2, together with the carbon atoms to which they are attached, form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6 In some embodiments, the heterocycle is a 3-membered or 6-membered heterocycle. In some embodiments, the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0070] In some embodiments, R3 and R4 are each independently H, halogen, or alkyl. In some embodiments, R3 and R4 are each independently H or alkyl. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, R3 and R4 are H. In some embodiments, R3 and R4 are halogen. In some embodiments, the halogen is fluorine. In some embodiments, R3 and R4 together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6 In some embodiments, the heterocycle is a 3-membered or 6-membered heterocycle. In some embodiments, the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0071] In some embodiments, is phenyl or a 5-membered or 6-membered heteroaryl.

[0072] In some embodiments, V is -O- or -CR8R9-. In some embodiments, V is -O- or -NR 10 -. In some embodiments, V is -O-. In some embodiments, V is -CR8R9-. In some embodiments, R8 and R9 are each independently H or alkyl. In some embodiments, R8 and R9 together with the carbon atom to which they are attached form C 3-6 In some embodiments, R 10 is H, alkyl, -(C=O)alkyl, or -S(O)2-alkyl. In some embodiments, R 10is H or alkyl. In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the alkyl is methyl.

[0073] In some embodiments, Y is a bond or -CR8R9-. In some embodiments, R8 and R9 are each independently H or alkyl. In some embodiments, R8 and R9 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl.

[0074] In some embodiments, Z is -NR 10 - or -CR8R9-. In some embodiments, Z is -NR 10 -. In some embodiments, Z is -CR8R9-. In some embodiments, R8 and R9 are each independently H or alkyl. In some embodiments, R8 and R9 together with the carbon atom to which they are attached form C 3-6 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.

[0075] In some embodiments, X is -CR 11 R 12 -. In some embodiments, R 11 and R 12 Each is independently H or alkyl. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, R 11 and R 12 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl.

[0076] In some embodiments, In some embodiments, the optionally substituted phenyl group is: where R a is halogen, alkyl, or alkoxy; and q is 0, 1, or 2. In some embodiments, is an optionally substituted 5-membered heteroaryl. In some embodiments, is an optionally substituted 6-membered heteroaryl. In some embodiments, the optionally substituted 6-membered heteroaryl is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, alkyl, alkoxy, or a combination thereof. In some embodiments, the optionally substituted 6-membered heteroaryl is:

[0077]

[0078]

[0079] where R a is halogen, alkyl, or alkoxy; and q is 0, 1, or 2. In some embodiments, R a In some embodiments, q is 0 or 1. In some embodiments, q is 0.

[0080] In some embodiments, m is 0 or 1. In some embodiments, m is 0.

[0081] In some embodiments, n is 0 or 1. In some embodiments, n is 1.

[0082] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0083] In some embodiments, L is a -carbocyclyl-O- or -heterocyclyl-O- linker having the structure: wherein A5 and A6 are each independently -O- or -CH2-. In some embodiments, A5 is -O-. In some embodiments, A5 is -CH2-. In some embodiments, A6 is -O-. In some embodiments, A6 is -CH2-.

[0084] In some embodiments, L is where R b is halogen, alkyl, or alkoxy; and r is 0, 1, or 2. In some embodiments, R b In some embodiments, the halogen is fluorine. In some embodiments, r is 1. In some embodiments, r is 0. In some embodiments, L is

[0085] In some embodiments, L is a 5-membered or 6-membered heteroaryl linker. In some embodiments, L is a 5-membered or 6-membered heteroaryl linker having 1 or 2 nitrogen atoms. In some embodiments, L is where R b is halogen, alkyl or alkoxy; and r is 0 or 1.

[0086] In some embodiments, the present disclosure provides a compound selected from the group consisting of:

[0087]

[0088]

[0089] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), (I-1), (I-2), (IA), (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID), (ID-1), (ID-2), (IE), (IF), Table 1 or Table 2) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Specific implementation plan

[0090] Throughout this disclosure, reference is made to various patents, patent applications, and publications. The entire disclosures of these patents, patent applications, and publications are incorporated herein by reference for all purposes to more fully describe the state of the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and the present disclosure, the present disclosure will control.

[0091] For convenience, certain terms used in the specification, examples and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.

[0092] When immediately preceding a numerical value, the term "about" means a range (e.g., plus or minus 10% of the value). For example, unless otherwise indicated by the context of the present disclosure or inconsistent with such an explanation, "about 50" may mean 45 to 55, and "about 25,000" may mean 22,500 to 27,500, etc. For example, in a numerical list such as "about 49, about 50, about 55, ... ", "about 50" means a range extending to less than half of the interval between the preceding and succeeding values, for example, greater than 49.5 to less than 50.5. In addition, the phrase "less than about" a value or "greater than about" a value should be understood according to the definition of the term "about" provided herein. Similarly, when preceding a series of numerical values ​​or value ranges (e.g., "about 10, 20, 30" or "about 10-30"), the term "about" refers to all values ​​in the series, or the endpoints of the range, respectively.

[0093] As used herein, the terms "administer," "administering," and "administration" refer to administering a compound or a pharmaceutically acceptable salt of the compound, or a composition or formulation comprising the compound or a pharmaceutically acceptable salt of the compound, to a patient.

[0094] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound that acts as a base with an inorganic or organic acid to form a salt, such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, and the like. Base addition salts include, but are not limited to, ethylenediamine, N-methyl-glucosamine, lysine, arginine, ornithine, choline, N,N'-diphenylmethylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, diphenylmethylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids (e.g., lysine and arginine), dicyclohexylamine, and the like. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium, and the like. Examples of ammonium salts and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting the compound with an appropriate inorganic or organic acid by any of a variety of known methods.

[0095] As used herein with respect to a patient, the term "treating" refers to ameliorating at least one symptom of a disorder in the patient. Treatment can be amelioration or at least partial alleviation of a disorder or symptoms associated with the disorder.

[0096] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound or a salt thereof (or a pharmaceutical composition containing the compound or salt) that is capable of achieving the desired result when administered to a patient. The "effective amount" may vary depending on the active ingredient, the condition, disorder or illness to be treated and its severity, as well as the age, weight, physical condition and responsiveness of the mammal to be treated.

[0097] The term "therapeutically effective" as applied to dosage or amount refers to that amount of a compound or pharmaceutical formulation sufficient to produce the desired clinical benefit following administration to a patient in need thereof.

[0098] The terms "carrier" or "vehicle," used interchangeably herein, encompass carriers, excipients, adjuvants, and diluents, or any combination thereof, and refer to materials, compositions, or vehicles that participate in carrying or transporting an agent from one organ or body part to another, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. In addition to adjuvants, excipients, and diluents known to those skilled in the art, carriers include nanoparticles of both organic and inorganic nature.

[0099] When a range of values ​​is listed, it is intended to encompass each value and sub-range within that range. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0100] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain having from one to twelve carbon atoms and attached to the rest of the molecule by a single bond. Alkyl groups containing any number of carbon atoms from 1 to 12 are included. Alkyl groups containing up to 12 carbon atoms are C1-C 12 Alkyl, containing up to 10 carbon atoms is C1-C 10 Alkyl groups, alkyl groups containing up to 6 carbon atoms are C1-C6 alkyl groups, and alkyl groups containing up to 5 carbon atoms are C1-C5 alkyl groups. C1-C5 alkyl groups include C5 alkyl groups, C4 alkyl groups, C3 alkyl groups, C2 alkyl groups, and C1 alkyl groups (i.e., methyl groups). C1-C6 alkyl groups include not only all of the parts described above for C1-C5 alkyl groups, but also C6 alkyl groups. C1-C 10 Alkyl groups include not only all the moieties described above for C1-C5 alkyl and C1-C6 alkyl groups, but also C7, C8, C9 and C 10 Similarly, C1-C 12 Alkyl groups include not only all of the aforementioned moieties, but also C 11 and C 12 Alkyl. C1-C 12The limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Unless otherwise specifically stated in this specification, alkyl may be optionally substituted.

[0101] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical having from one to twelve carbon atoms. 12 The non-limiting examples of alkylene groups include methylene, ethylene, propylene, n-butylene and similar groups. The alkylene chain is connected to the rest of the molecule via a single bond and is connected to a group (e.g., those groups described herein) via a single bond. The connection point of the alkylene chain to the rest of the molecule and the group can be formed via one carbon or any two carbons in the chain. Unless otherwise specifically stated in this specification, the alkylene chain may be optionally substituted.

[0102] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain having from two to twelve carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are C2-C 12 Alkenyl, alkenyl containing up to 10 carbon atoms is C2-C 10 Alkenyl, alkenyl containing up to 6 carbon atoms is C2-C6 alkenyl, and alkenyl containing up to 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl and C2 alkenyl. C2-C6 alkenyl includes not only all the parts described above for C2-C5 alkenyl, but also C6 alkenyl. C2-C 10 Alkenyl includes not only all the moieties described above for C2-C5 alkenyl and C2-C6 alkenyl, but also C7, C8, C9 and C 10 Similarly, C2-C 12 Alkenyl includes not only all of the aforementioned parts, but also C 11 and C 12 Alkenyl. C2-C 12Non-limiting examples of alkenyl groups 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- Alkyl, alkyl, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals, alkyl radicals,

[0103] "Alkenylene" or "alkenylene chain" refers to an unsaturated straight or branched divalent hydrocarbon chain radical having one or more olefins and two to twelve carbon atoms. 12 The limiting examples of alkenylene include vinylene, propenylene, n-butenylene and similar groups.Alkenylene chain is connected to the rest of the molecule via a single bond and is connected to a group (e.g., those groups described herein) via a single bond. The attachment point of the alkenylene chain to the rest of the molecule and the group can be formed via one carbon or any two carbons within the chain. Unless otherwise specifically stated in this specification, the alkenylene chain may be optionally substituted.

[0104] "Alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain having from two to twelve carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms are C2-C 12 Alkynyl, alkynyl containing up to 10 carbon atoms is C2-C 10Alkynyl, an alkynyl containing up to 6 carbon atoms is a C2-C6 alkynyl, and an alkynyl containing up to 5 carbon atoms is a C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl and C2 alkynyl. C2-C6 alkynyl includes not only all of the moieties described above for C2-C5 alkynyl, but also C6 alkynyl. C2-C 10 Alkynyl includes not only all the moieties described above for C2-C5 alkynyl and C2-C6 alkynyl, but also C7, C8, C9 and C 10 Similarly, C2-C 12 Alkynyl includes not only all of the aforementioned moieties, but also C 11 and C 12 Alkynyl. C2-C 12 Non-limiting examples of alkenyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted.

[0105] "Alkyne" or "alkynylene chain" refers to an unsaturated straight or branched divalent hydrocarbon chain radical having one or more alkynes and two to twelve carbon atoms. 12 Non-limiting examples of alkynylene groups include ethynylene, propynylene, n-butynylene, and similar groups. The alkynylene chain is connected to the rest of the molecule via a single bond and to a group (e.g., those described herein) via a single bond. The point of attachment of the alkynylene chain to the rest of the molecule and the group can be formed via any two carbons in the chain with suitable valence states. Unless otherwise specifically stated in this specification, the alkynylene chain may be optionally substituted.

[0106] "Alkoxy" refers to a group of the formula -OR a A group in which R a is an alkyl, alkenyl or alkynyl group as defined above containing from one to twelve carbon atoms. Unless specifically stated otherwise in the specification, an alkoxy group may be optionally substituted.

[0107] "Aryl" refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, and connected to the rest of the molecule by a single bond. For the purposes of this disclosure, an aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, In some embodiments, the aryl group may be substituted with any of the following: chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated in the specification, the aryl group may be optionally substituted.

[0108] "Aralkyl" or "arylalkyl" refers to a group of the formula -R b -R c A group in which R b is an alkylene group as defined above and R c is one or more aryl groups as defined above, such as benzyl, benzhydryl, and the like. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

[0109] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a ring structure in which the atoms forming the ring are each carbon and are connected to the rest of the molecule by a single bond. A carbocycle may contain from 3 to 20 carbon atoms in the ring. Carbocycles include aryl and cycloalkyl, cycloalkenyl, and cycloalkynyl groups as defined herein. Unless specifically stated otherwise in this specification, a carbocyclyl group may be optionally substituted.

[0110] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon consisting only of carbon atoms and hydrogen atoms, which may include fused, bridged or spirocyclic ring systems having three to twenty carbon atoms (e.g., three to ten carbon atoms) and connected to the remainder of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl and similar groups. Unless otherwise specifically stated in this specification, cycloalkyls may be optionally substituted.

[0111] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting only of carbon atoms and hydrogen atoms, having one or more carbon-carbon double bonds, which may include fused or bridged ring systems, having three to twenty carbon atoms, preferably three to ten carbon atoms, and being connected to the remainder of the molecule by a single bond. Monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and similar groups thereof. Polycyclic cycloalkenyls include, for example, bicyclo[2.2.1]hept-2-enyl, and similar groups thereof. Unless otherwise specifically indicated in this specification, cycloalkenyls may be optionally substituted.

[0112] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting only of carbon atoms and hydrogen atoms, having one or more carbon-carbon triple bonds, which may include fused or bridged ring systems, having three to twenty carbon atoms, preferably three to ten carbon atoms, and being connected to the remainder of the molecule by a single bond. Monocyclic cycloalkynyl includes, for example, cycloheptynyl, cyclooctynyl, and similar groups thereof. Unless otherwise specifically indicated in this specification, cycloalkynyl may be optionally substituted.

[0113] "Haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halo groups, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless otherwise specifically stated in this specification, a haloalkyl group may be optionally substituted.

[0114] "Heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a stable saturated or unsaturated 3- to 20-membered ring consisting of two to nineteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and attached to the rest of the molecule by a single bond. Heterocyclyl or heterocycle includes heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl. Unless otherwise specifically stated in the specification, a heterocyclyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, bridged, or spirocyclic ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolane, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, a heterocyclic group may be optionally substituted.

[0115] "Heteroaryl" refers to a 5- to 20-membered ring system comprising hydrogen atoms, one to nineteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, at least one aromatic ring, and attached to the rest of the molecule by a single bond. For the purposes of this disclosure, a heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples include, but are not limited to, aza yl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (b enzothienyl / benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindololinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine Unless otherwise specifically stated in the specification, the heteroaryl group may be optionally substituted.

[0116] "Heterocyclylalkyl" refers to a group of the formula -R b -R e A group in which R b is an alkylene, alkenylene or alkynylene group as defined above and R e is a heterocyclyl group as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.

[0117] As used herein, the term "substituted" means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and / or heteroaryl) in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxy, alkoxy, and ester groups; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl; and other heteroatoms in various other groups. "Substituted" also means that one or more hydrogen atoms in any of the above groups are replaced by a heteroatom through a high-valent bond (e.g., a double bond or a triple bond), such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. For example, "substituted" includes one or more hydrogen atoms in any of the above groups replaced by -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、-NR g SO2R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-SOR g 、-SO2R g 、-OSO2R g 、-SO2OR g , =NSO2R g and-SO2NR g R h "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h 、-CH2SO2R g 、-CH2SO2NR g R h In the foregoing, R g and R h"Substituted" further means that one or more hydrogen atoms of any one of the above groups are replaced by a bond connected to the following: amino, cyano, hydroxyl, imino, nitro, oxo, thioketone, halo, 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 of any one of the above groups are replaced by a bond connected to the following: amino, cyano, hydroxyl, imino, nitro, oxo, thioketone, halo, 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. In addition, each of the aforementioned substituents may also be optionally substituted by one or more of the above substituents.

[0118] As used herein, the symbol (hereinafter may be referred to as a "point of attachment bond") represents a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to a point of attachment bond and the other of which is not depicted as being attached to a point of attachment bond. For example, Indicates that the chemical entity "XY" is bonded to another chemical entity via a point of attachment. In addition, the specific point of attachment to chemical entities not depicted can be specified by inference. For example, the compound CH3-R 3 , where R 3 H or Infer that when R 3 When it is "XY", the connection point key is the same as the one drawn by R 3 The same bond used to bond to CH3.

[0119] Compound

[0120] The present disclosure provides macrocyclic compounds as orexin type 2 receptor agonists and pharmaceutical compositions thereof, as well as their uses in treating various diseases and conditions.

[0121] In one aspect, the present disclosure provides a compound of formula (I):

[0122]

[0123] or a pharmaceutically acceptable salt or stereoisomer thereof,

[0124] in:

[0125] L is a linker selected from the group consisting of aryl, heteroaryl, -carbocyclyl-O-, and -heterocyclyl-O-;

[0126] A1 is -C(O)-, -S(O)2- or -C(H)(CF3)-;

[0127] A2 and A3 are each independently a bond, -O-, -CR5R6-, -NR7- or -S-; or A2 and A3 together with the optionally substituted carbon atom form a cyclopropyl ring having the following structure:

[0128]

[0129] A4 is a bond, -O-, -CR5R6-, -NR7-, -S-, -(CR5R6)2-, -CR5R6-O-, -CR5R6-S-, -CR5R6-N(R7)-, -O-CR5R6-, -S-CR5R6- or -N(R7)-CR5R6-, with the proviso that the ring including A2, A3 and A4 does not contain -OO-, -O-NR7- or -NR7-NR7-;

[0130] is phenyl, 5-membered or 6-membered heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted;

[0131] V and Z are each independently -O-, -CR8R9- or -NR 10 -;

[0132] X is -O-, -CR 11 R 12 -or-NR 13 -;

[0133] Y is a bond, -O-, -CR8R9- or -NR 10 -;

[0134] R1, R2, R3, R4, R5, R6, R8, R9, R 11 、R 12 and R 14 are each independently hydrogen, halogen, alkyl, cycloalkyl or heterocyclic; and / or R1 and R2 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R3 and R4 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R5 and R6 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R8 and R9 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R 11 and R 12 together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring;

[0135] R7, R 10 and R 13each independently represents 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, -S(O)2-alkyl, -S(O)2-cycloalkyl, or -S(O)2-heterocyclyl; and

[0136] m, n, p and r are each independently 0, 1 or 2.

[0137] In another aspect, the present disclosure provides a compound of formula (I):

[0138]

[0139] or a pharmaceutically acceptable salt or stereoisomer thereof,

[0140] in:

[0141] L is a linker selected from the group consisting of aryl, heteroaryl, -carbocyclyl-O-, and -heterocyclyl-O-;

[0142] A1 is -C(O)- or -S(O)2-;

[0143] A2 and A3 are each independently a bond, -O-, -CR5R6-, -NR7- or -S-; or A2 and A3 together with the optionally substituted carbon atom form a cyclopropyl ring having the following structure:

[0144]

[0145] A4 is a bond, -O-, -CR5R6-, -NR7-, -S-, -(CR5R6)2-, -CR5R6-O-, -CR5R6-S-, -CR5R6-N(R7)-, -O-CR5R6-, -S-CR5R6- or -N(R7)-CR5R6-, with the proviso that the ring including A2, A3 and A4 does not contain -OO-, -O-NR7- or -NR7-NR7-;

[0146] is phenyl, 5-membered or 6-membered heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted;

[0147] V and Z are each independently -O-, -CR8R9- or -NR 10 -;

[0148] X is -O-, -CR 11 R 12 -or-NR 13 -;

[0149] Y is a bond, -O-, -CR8R9- or -NR 10 -;

[0150] R1, R2, R3, R4, R5, R6, R8, R9, R 11 、R 12 and R 14 are each independently hydrogen, halogen, alkyl, cycloalkyl or heterocyclic; and / or R1 and R2 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R3 and R4 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R5 and R6 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R8 and R9 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring; and / or R 11 and R 12 together with the atoms to which they are attached, form a carbocyclic or heterocyclic ring;

[0151] R7, R 10 and R 13 each independently represents 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, -S(O)2-alkyl, -S(O)2-cycloalkyl, or -S(O)2-heterocyclyl; and

[0152] m, n, p and r are each independently 0, 1 or 2.

[0153] In some embodiments, L is a linker selected from the group consisting of aryl, heteroaryl, -carbocyclyl-O-, and -heterocyclyl-O-, wherein -carbocyclyl-O- and -heterocyclyl-O- have the following orientations:

[0154]

[0155] In some embodiments, L is a linker selected from the group consisting of aryl, heteroaryl, -cycloalkyl-O-, and -heterocyclyl-O-, wherein -cycloalkyl-O- and -heterocyclyl-O- have the following orientations:

[0156]

[0157] In some embodiments, the present disclosure provides a compound of formula (I-1):

[0158]

[0159] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A1, A2, A3, A4, R1, R2, R3, R4, L, V, X, Y and Z are as defined herein.

[0160] In some embodiments, the present disclosure provides a compound of formula (I-2):

[0161]

[0162] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A1, A2, A3, A4, R1, R2, R3, R4, L, V, X, Y and Z are as defined herein.

[0163] In some embodiments, the present disclosure provides a compound of formula (IA):

[0164]

[0165] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A1, A2, A3, A4, A5, A6, R1, R2, R3, R4, V, X, Y and Z are as defined herein.

[0166] In some embodiments, the present disclosure provides a compound of formula (IA-1):

[0167]

[0168] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A1, A2, A3, A4, A5, A6, R1, R2, R3, R4, V, X, Y and Z are as defined herein.

[0169] In some embodiments, the present disclosure provides a compound of formula (IA-1-1):

[0170]

[0171] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, p, A1, A2, A s 、A4、R1、R2、 Y and Z are as defined herein.

[0172] In some embodiments, the present disclosure provides a compound of formula (IA-2):

[0173]

[0174] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A1, A2, A3, A4, A5, A6, R1, R2, R3, R4, V, X, Y and Z are as defined herein.

[0175] In some embodiments, the present disclosure provides a compound of formula (IA-2-1):

[0176]

[0177] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, p, A1, A2, A s 、A4、R1、R2、 Y and Z are as defined herein.

[0178] In some embodiments, the present disclosure provides a compound of formula (IA-3):

[0179]

[0180] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, p, A1, R1, R5, R6, Y and Z are as defined herein.

[0181] In some embodiments, the present disclosure provides a compound of formula (IA-4):

[0182]

[0183] or a pharmaceutically acceptable salt thereof, wherein m, p, A1, R1, R5, R6, Y and Z are as defined herein.

[0184] In some embodiments, the present disclosure provides a compound of formula (IA-5):

[0185]

[0186] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, p, A1, R1, R5, R6, Y and Z are as defined herein.

[0187] In some embodiments, the present disclosure provides a compound of formula (IB):

[0188]

[0189] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A1, A2, A3, A4, R1, R2, R3, R4, Ar, V, X, Y and Z are as defined herein.

[0190] In some embodiments, the present disclosure provides a compound of formula (IB-1):

[0191]

[0192] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A1, A2, A3, A4, R1, R2, R3, R4, Ar, V, X, Y and Z are as defined herein.

[0193] In some embodiments, the present disclosure provides a compound of formula (IB-2):

[0194]

[0195] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A1, A2, A3, A4, R1, R2, R3, R4, Ar, V, X, Y and Z are as defined herein.

[0196] In some embodiments, the present disclosure provides a compound of formula (IC):

[0197]

[0198] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A5, A6, R1, R2, V, X, Y and Z are as defined herein.

[0199] In some embodiments, the present disclosure provides a compound of formula (IC-1):

[0200]

[0201] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A5, A6, R1, R2, Y and Z are as defined herein.

[0202] In some embodiments, the present disclosure provides a compound of formula (IC-2):

[0203]

[0204] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A5, A6, R1, R2, and Z are as defined herein.

[0205] In some embodiments, the present disclosure provides a compound of formula (IC-3):

[0206]

[0207] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, p, R1, R5, R6, Y and Z are as defined herein.

[0208] In some embodiments, the present disclosure provides a compound of formula (IC-4):

[0209]

[0210] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p, R1, R5, R6, Y and Z are as defined herein.

[0211] In some embodiments, the present disclosure provides a compound of formula (IC-5):

[0212]

[0213] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p, R5, R6, Y and Z are as defined herein.

[0214] In some embodiments, the present disclosure provides a compound of formula (IC-6):

[0215]

[0216] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, q, R a , R1, R2, R5, R6, X, Y and Z are as defined herein.

[0217] In some embodiments, the present disclosure provides a compound of formula (ID):

[0218]

[0219] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, r, R1, R2, Rb, V, X, Y, and Z are defined herein.

[0220] In some embodiments, the present disclosure provides a compound of formula (ID-1):

[0221]

[0222] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, r, R1, R2, R b 、 Y and Z are defined herein.

[0223] In some embodiments, the present disclosure provides a compound of formula (ID-2):

[0224]

[0225] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, r, R1, R2, R b 、 and Z are defined herein.

[0226] In some embodiments, the present disclosure provides a compound of formula (IE):

[0227]

[0228] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, A5, A6, R1, R2, V, X, Y and Z are as defined herein.

[0229] In some embodiments, the present disclosure provides a compound of formula (IF):

[0230]

[0231] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, r, R1, R2, R b 、 V, X, Y, and Z are defined herein.

[0232] In some embodiments, stereoisomers are diastereomers of a compound. In some embodiments, stereoisomers are enantiomers of a compound.

[0233] 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, carbocyclyl is C 3-6 In some embodiments, the carbocyclyl group is cyclohexyl. In some embodiments, the carbocyclyl group is wherein x is 1, 2, 3, or 4. In some embodiments, the heterocyclyl is a 4- to 6-membered heterocyclyl. In some embodiments, the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, L is a -carbocyclyl-O- or -heterocyclyl-O- linker having the following structure: wherein A5 and A6 are each independently -O- or -CH2-. In some embodiments, A5 is -O-. In some embodiments, A5 is -CH2-. In some embodiments, A6 is -O-. In some embodiments, A6 is -CH2-. In some embodiments, L has the structure In some embodiments, L has the structure wherein x is 1, 2, 3, or 4. In some embodiments, L has the structure In some embodiments, L has the structure

[0234] In some embodiments, A1 is -C(O)- or -S(O)2-. In some embodiments, A1 is -C(O)-. In some embodiments, A1 is -S(O)2-. In some embodiments, A1 is -C(H)(CF3)-.

[0235] In some embodiments, A2, A3 and A4 are each independently -O-, -CR5R6-, -NR7- or -S-, with the proviso that the ring including A2, A3 and A4 does not contain -OO-, -OS-, -SS-, -O-NR7-, -S-NR7- or -NR7-NR7-. In some embodiments, A2, A3 and A4 are each independently -CR5R6-, -NR7- or -S-, with the proviso that the ring including A2, A3 and A4 does not contain -OO-, -O-NR7- or -NR7-NR7-. In some embodiments, A2, A3 and A4 are each independently -O-, -CR5R6- or -NR7-, with the proviso that the ring including A2, A3 and A4 does not contain -OO-, -O-NR7- or -NR7-NR7-. In some embodiments, A2 and A3, together with the optionally substituted carbon atom, form a cyclopropyl ring having the following structure: In some embodiments, A2 and A3, together with the optionally substituted carbon atom, form a cyclopropyl ring having the following structure:

[0236] In some embodiments, A2 is -O-, -NR7-, or -CR5R6-. In some embodiments, A2 is a bond, -O-, or -CR5R6-. In some embodiments, A2 is -O-, or -CR5R6-. In some embodiments, A2 is -O-, or -NR7-. In some embodiments, A2 is -CR5R6-. In some embodiments, A2 is -O-. In some embodiments, A2 is a bond.

[0237] In some embodiments, A3 is -O-, -NR7-, or -CR5R6-. In some embodiments, A3 is a bond, -O-, or -CR5R6-. In some embodiments, A3 is -O-, or -CR5R6-. In some embodiments, A3 is -O-, or -NR7-. In some embodiments, A3 is -O-. In some embodiments, A3 is -CH2-. In some embodiments, A3 is a bond.

[0238] In some embodiments, A4 is a bond, -O-, -CR5R6-, -NR7-, -(CR5R6)2-, -CR5R6-O-, -CR5R6-N(R7)-, -O-CR5R6-, or -N(R7)-CR5R6-. In some embodiments, A4 is a bond, -O-, -CR5R6-, -(CR5R6) 2- In some embodiments, A4 is -O-, -NR7- or -CR5R6-. In some embodiments, A4 is -O- or -NR7-. In some embodiments, A4 is -O- or -CR5R6-. In some embodiments, A4 is -CR5R6-. In some embodiments, A4 is -O-.

[0239] In some embodiments, A2 is -O-, -NR7-, or -S-, and A3 and A4 are each -CR5R6-. In some embodiments, A2 is -O-, and A3 and A4 are each -CR5R6-. In some embodiments, A2 is -O-, A3 is -CR5R6-, and A4 is a bond. In some embodiments, A2 is -CR5R6-, A3 is -O-, and A4 is a bond. In some embodiments, A3 is -O-, -NR7-, or -S-, and A2 and A4 are each -CR5R6-. In some embodiments, A3 is -O-, and A2 and A4 are each -CR5R6-. In some embodiments, A4 is -O-, -NR7-, or -S-, and A2 and A3 are each -CR5R6-. In some embodiments, A4 is -O-, and A2 and A3 are each -CR5R6-.

[0240] In some embodiments, A1 is -C(O)-, -S(O)2-, or -C(H)(CF3)-; A2 is -O- or -CR5R6-; A3 is -O- or -CR5R6-; and A4 is a bond or -CH2-. In some embodiments, A1 is -C(O)- or -S(O)2-; A2 is -O- or -CR5R6-; A3 is -O- or -CR5R6-; and A4 is a bond or -CH2-. In some embodiments, A1 is -C(O)- or -S(O)2-; A2 is -O-; A3 is -CR5R6-; and A4 is a bond or -CH2-. In some embodiments, A1 is -C(O)- or -S(O)2-; A2 is -O-; A3 is -CR5R6-; and A4 is a bond or -CH2-.

[0241] In some embodiments, the ring comprising A2, A3 and A4 does not contain -OO-, -O-NR7- or -NR7-NR7-. In some embodiments, the ring comprising A2, A3 and A4 does not contain two adjacent heteroatoms.

[0242] In some embodiments, R1, R2, R3, R4, R5, R6, R8, R9, R 11 、R 12 and R 14 are each independently hydrogen, halogen, alkyl, or cycloalkyl. In some embodiments, R1, R2, R3, R4, R5, R6, R8, R9, R 11 、R 12 and R 14 Each is independently hydrogen, halogen or alkyl. In some embodiments, alkyl is C 1-5 In some embodiments, the alkyl group is methyl, ethyl or isopropyl. In some embodiments, the cycloalkyl group is C 3-6 In some embodiments, the cycloalkyl group is cyclopropyl.

[0243] In some embodiments, R1 and R2 are each independently H, halogen, or alkyl. In some embodiments, R1 and R2 are each independently H or alkyl. In some embodiments, R1 and R2 are alkyl. In some embodiments, alkyl is methyl or ethyl. In some embodiments, alkyl is methyl. In some embodiments, R1 is methyl and R2 is H. In some embodiments, R1 and R2 are H. In some embodiments, R1 and R2 are each independently H or halogen. In some embodiments, halogen is fluorine. In some embodiments, R1 and R2, together with the carbon atoms 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 cyclopropyl group. In some embodiments, the heterocycle is a 3-membered or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0244] In some embodiments, R3 and R4 are each independently H, halogen, or alkyl. In some embodiments, R3 and R4 are each independently H or alkyl. In some embodiments, R3 and R4 are alkyl. In some embodiments, alkyl is methyl or ethyl. In some embodiments, R3 and R4 are each independently H or halogen. In some embodiments, R3 and R4 are H. In some embodiments, R3 and R4 are halogen. In some embodiments, halogen is fluorine. In some embodiments, R3 and R4 together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6 In some embodiments, the carbocycle is a cyclopropyl group. In some embodiments, the heterocycle is a 3-membered or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0245] In some embodiments, R5 and R6 are each independently H, halogen, or alkyl. In some embodiments, R5 and R6 are each independently H or alkyl. In some embodiments, R5 and R6 are alkyl. In some embodiments, R5 and R6 are each independently H or halogen. In some embodiments, alkyl is haloalkyl. In some embodiments, haloalkyl is CF3. In some embodiments, alkyl is methyl or ethyl. In some embodiments, R5 and R6 are each independently H, F, or CF3. In some embodiments, R5 and R6 are H. In some embodiments, R5 and R6 are halogen. In some embodiments, halogen is fluorine. In some embodiments, R5 and R6, together with the carbon atoms to which they are attached, form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6 In some embodiments, the carbocycle is a cyclopropyl group. In some embodiments, the heterocycle is a 3-membered or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0246] In some embodiments, R7, R 10 and R 13 Each is 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, R7, R 10 、R 13 and R 14Each is independently 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, R7, R 10 、R 13 and R 14 Each is independently hydrogen, alkyl, -(C=O)alkyl, or -S(O)2-alkyl. In some embodiments, alkyl is C 1-5 In some embodiments, the alkyl group is methyl, ethyl, or isopropyl. In some embodiments, the cycloalkyl group is C 3-6 In some embodiments, the aryl group is a phenyl group. In some embodiments, the heterocyclyl group is a 5- or 6-membered heterocyclyl group having 1 or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heteroaryl group is a 5- or 6-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.

[0247] In some embodiments, R7 is H, alkyl, cycloalkyl, -(C=O)-O-alkyl, -S(O)2-alkyl. In some embodiments, R7 is H, alkyl, cycloalkyl, -(C=O)-O-alkyl, or -S(O)2-alkyl. In some embodiments, R7 is H, alkyl, -(C=O)-O-alkyl, or -S(O)2-alkyl. In some embodiments, R7 is H, alkyl, -(C=O)-O-alkyl, or -S(O)2-alkyl. In some embodiments, R7 is H, alkyl, or cycloalkyl. In some embodiments, R 7 In some embodiments, R 7 In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is methyl, ethyl, or isopropyl. In some embodiments, the alkyl group is methyl. In some embodiments, the cycloalkyl group is C 3-6 Cycloalkyl.

[0248] In some embodiments, V is -O- or -CR8R9-. In some embodiments, V is -O- or -NR 10 -. In some embodiments, V is -O-. In some embodiments, V is -CR8R9-. In some embodiments, R8 and R9 are each independently H or alkyl.

[0249] 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 -.

[0250] In some embodiments, Y is a bond, -CR8R9-, or -NR 10 -. In some embodiments, Y is a bond, -O- or -CR8R9-. In some embodiments, Y is a bond or -CR8R9-. In some embodiments, Y is a bond. In some embodiments, Y is -CR8R9-. In some embodiments, R8 and R9 together with the carbon atoms to which they are attached form C 3-6 In some embodiments, R8 and R9, taken together with the carbon atoms to which they are attached, form a cyclopropyl group.

[0251] In some embodiments, Z is -NR 10 - or -CR8R9-. In some embodiments, Z is NR 10 -. In some embodiments, R8 and R9 are each independently H or alkyl. In some embodiments, R8 and R9 together with the carbon atom to which they are attached form C 3-6 In some embodiments, R8 and R9 together with the carbon atom to which they are attached form a cyclopropyl group. 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.

[0252] In some embodiments, V-(X) p -YZ is -O-(CH2) p -CH2-CR8R9-, -O-(CH2) p CR8R9- or -O-(CH2) p -CR8R9-O-, wherein p is 0, 1 or 2. In some embodiments, V-(X) p -YZ is -O-(CH2) p -CH2-CR8R9- or -O-(CH2) p -CR8R9-, wherein p is 0, 1 or 2. In some embodiments, V-(X) p -YZ is -O-(CH2) p -CH2-CR8R9- or -O-(CH2) p -CR8R9-, wherein p is 0 or 1. In some embodiments, V-(X) p -YZ is -O-(CH2) p-CH2-CH2- or -O-(CH2) p -CH2-, wherein p is 0 or 1. In some embodiments, V-(X) p -YZ is -O-(CH2) p -CH2-O-, wherein p is 1. In some embodiments, V-(X) p -YZ is -O-CH2-CH2-CH2-CH2-, -O-CH2-CH2-CH2-, -O-CH2-CH2-, -O-CH2-, -O-CH(CH3)-, -O-CH2-CH2-CH2-O-, -O-CH2-CH2-O-. In some embodiments, V-(X) p -YZ is -O-CH2-CH2-O-. In some embodiments, V-(X) p -YZ is -O-CH2-O-. In some embodiments, V-(X) p -YZ is -O-CH2-. In some embodiments, V-(X) p -YZ is -O-CH2-CH2-.

[0253] In some embodiments, V-(X) p -YZ does not contain -OO- or -NN- bonds.

[0254] In some embodiments, R8 and R9 are each independently H, halogen or alkyl. In some embodiments, R8 and R9 are each independently H or alkyl. In some embodiments, R8 and R9 are alkyl. In some embodiments, alkyl is methyl or ethyl. In some embodiments, R8 and R9 are each independently H or halogen. In some embodiments, R8 and R9 are H. In some embodiments, R8 and R9 are halogen. In some embodiments, halogen is fluorine. In some embodiments, R8 and R9 together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6 In some embodiments, the carbocycle is a cyclopropyl group. In some embodiments, the heterocycle is a 3-membered or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0255] 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. 10is 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 In some embodiments, R 10 In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is methyl, ethyl, or isopropyl. In some embodiments, the alkyl group is methyl. In some embodiments, the cycloalkyl group is C 3-6 Cycloalkyl.

[0256] In some embodiments, R 11 and R 12 Each is independently H, halogen or alkyl. In some embodiments, R 11 and R 12 Each is independently H or alkyl. In some embodiments, R 11 and R 12 In some embodiments, the alkyl group is methyl or ethyl. 11 and R 12 are each independently H or halogen. In some embodiments, R 11 and R 12 is H. In some embodiments, R 11 and R 12 In some embodiments, halogen is fluorine. In some embodiments, R 11 and R 12 Together with the carbon atoms to which they are attached, they form a carbocyclic or heterocyclic ring. In some embodiments, the carbocyclic ring is C 3-6 In some embodiments, the carbocycle is a cyclopropyl group. In some embodiments, the heterocycle is a 3-membered or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0257] In some embodiments, is phenyl or a 5-membered or 6-membered heteroaryl, each of which is optionally substituted.

[0258] In some embodiments, In some embodiments, the optionally substituted phenyl group is: where R a is halogen, alkyl, or alkoxy; and q is 0, 1, or 2. In some embodiments, the optionally substituted phenyl is: where R a is halogen, alkyl, or alkoxy; and q is 0, 1, or 2. In some embodiments, the optionally substituted phenyl is: where R a is halogen, alkyl, or alkoxy; and q is 0, 1, or 2. In some embodiments, R a is halogen. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, for In some embodiments, for

[0259] In some embodiments, is an optionally substituted 5-membered heteroaryl. In some embodiments, is an optionally substituted 5-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, is an optionally substituted 6-membered heteroaryl. In some embodiments, is an optionally substituted 6-membered heteroaryl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S. In some embodiments, the optionally substituted 6-membered heteroaryl is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl. In some embodiments, the optionally substituted 6-membered heteroaryl is:

[0260] where R a is halogen, alkyl, or alkoxy; and q is 0, 1, or 2. In some embodiments, the optionally substituted 6-membered heteroaryl is:

[0261] where R a is halogen, alkyl, or alkoxy; and q is 0, 1, or 2. In some embodiments, R a In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, for In some embodiments, for

[0262] In some embodiments, for where R a is halogen, alkyl or alkoxy; and q is 0, 1 or 2.

[0263] In some embodiments, for

[0264] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0265] In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0.

[0266] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0267] In some embodiments, L is a -carbocyclyl-O- or -heterocyclyl-O- linker having the structure: wherein A5 and A6 are each independently -O- or -CH2-. In some embodiments, A5 is -O-. In some embodiments, A5 is -CH2-. In some embodiments, A6 is -O-. In some embodiments, A6 is -CH2-.

[0268] In some embodiments, L is an aryl linker having the structure: where R b is halogen, alkyl, or alkoxy; and r is 0, 1, or 2. In some embodiments, R b is halogen. In some embodiments, halogen is fluorine. In some embodiments, r is 1. In some embodiments, r is 0. In some embodiments, the aryl linker is

[0269] In some embodiments, L is a 5-membered or 6-membered heteroaryl linker. In some embodiments, L is a 5-membered or 6-membered heteroaryl linker having 1 or 2 nitrogen atoms. In some embodiments, linker L is a heteroaryl linker having the following structure: where R b is halogen, alkyl, or alkoxy; and r is 0 or 1. In some embodiments, r is 0. In some embodiments, r is 1.

[0270] In some embodiments, A1 is -C(O)- or -S(O)2-, A2 is -CR5R6-, A3 is -O-, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CR8R9-, Z is -O- or -CR8R9-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0271] In some embodiments, A1 is -C(O)- or -S(O)2-, A2 is -O-, A3 is -CR5R6-, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CR8R9-, Z is -O- or -CR8R9-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0272] In some embodiments, A1 is -C(O)-, A3 is -O-, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -O-, -CH2- or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0273] In some embodiments, A1 is -C(O)-, A2 and A4 are -CH2-, A3 is -O-, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -O-, -CH2-, -CH(Me)-, or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0274] In some embodiments, A1 is -C(O)-, A2 and A4 are -CH2-, A3 is -O-, L is -carbocyclyl-O- or -heterocyclyl-O-, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -O-, -CH2-, -CH(Me)-, or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0275] In some embodiments, A1 is -C(O)-, A2 and A4 are -CH2-, A3 is -O-, and L is wherein A5 and A6 are each independently -CH2- or -O-, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -O-, -CH2-, -CH(Me)- or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0276] In some embodiments, A1 is -C(O)-, A2 is -O-, A3 and A4 are -CH2-, and L is wherein A5 and A6 are each independently -CH2- or -O-, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -O-, -CH2-, -CH(Me)- or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0277] In some embodiments, A1 is -C(O)-, A2 and A4 are -CH2-, A3 is -O-, is an optionally substituted phenyl group or an optionally substituted heteroaryl group having 1 or 2 N atoms, and L is wherein A5 and A6 are each independently -CH2- or -O-, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -O-, -CH2-, -CH(Me)- or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0278] In some embodiments, A1 is -C(O)-, A2 is -O-, A3 and A4 are -CH2-, is an optionally substituted phenyl group or an optionally substituted heteroaryl group having 1 or 2 N atoms, and L is wherein A5 and A6 are each independently -CH2- or -O-, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -O-, -CH2-, -CH(Me)- or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0279] In some embodiments, A1 is -C(O)-, A2 and A4 are -CH2-, A3 is -O-, is an optionally substituted phenyl group or an optionally substituted heteroaryl group having 1 or 2 N atoms, and L is where R a is halogen, alkyl or alkoxy and q is 0 or 1, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -O-, -CH2-, -CH(Me)- or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0280] In some embodiments, A1 is -C(O)-, A2 and A4 are -CH2-, A3 is -O-, is an optionally substituted phenyl group, L is where R a is halogen, alkyl or alkoxy and q is 0 or 1, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -O-, -CH2-, -CH(Me)- or -N(alkyl)-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0281] In some embodiments, the compounds of the present disclosure have one of the following structures:

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300] or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the present disclosure provides a compound selected from the group consisting of:

[0302]

[0303]

[0304] In some embodiments, the compounds disclosed herein are racemic mixtures. In some embodiments, the compounds disclosed herein are enriched in one enantiomer. In some embodiments, the compounds disclosed herein are enriched in one enantiomer and are substantially free of the opposite enantiomer. In some embodiments, the compounds disclosed herein have an enantiomeric excess of about or more than about 55%, about or more than about 60%, about or more than about 65%, about or more than about 70%, about or more than about 75%, about or more than about 80%, about or more than about 85%, about or more than about 90%, about or more than about 91%, about or more than about 92%, about or more than about 93%, about or more than about 94%, about or more than about 95%, about or more than about 96%, about or more than about 97%, about or more than about 98%, about or more than about 98.5%, about or more than about 99%, about or more than about 99.5% or more (including all sub-ranges and values ​​therebetween). In some embodiments, the compounds of the present disclosure are provided as a mixture of diastereomers. In some embodiments, diastereomers of the compounds of the present disclosure are provided that are substantially free of other possible diastereomers. The present disclosure includes tautomers of any compound described herein.

[0305] In some embodiments, provided herein is one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0306] In some embodiments, provided herein is one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or an enantiomer thereof.

[0307] In some embodiments, provided herein is one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a diastereomer or mixture of diastereomers thereof.

[0308] In some embodiments, provided herein are one or more compounds selected from Table 1.

[0309] In some embodiments, provided herein are one or more pharmaceutically acceptable salts of a compound selected from Table 1.

[0310] Table 1. Compounds

[0311]

[0312]

[0313]

[0314] 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 activity.

[0315] Composition

[0316] The present disclosure provides pharmaceutical compositions for modulating orexin receptors (e.g., orexin type 2 receptors) in a subject. In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure (e.g., compounds of Formula (I), (I-1), (I-2), (IA), (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID), (ID-1), (ID-2), (IE), (IF), or a compound of Table 1 or Table 2) or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments of the present disclosure, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula (A)-7, (I-1), (I-2), (IA)-7, (IA-1), (IA-2), (IB)-7, (IB-1), (IB-2), (IC)-7, (IC-1), (IC-2), (IC-3), (ID)-7, (ID-1), (ID-2), (IE)-8, (IF)-9, or a compound of Table 1 or Table 2) or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, a pharmaceutical composition as described herein comprises one or more compounds selected from Table 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0319] In some embodiments, a pharmaceutical composition as described herein comprises one or more compounds selected from Table 2, or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (A)-7, (A-1), (A-2), (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID), (ID-1), (ID-2), (IE), (IF), or a compound of Table 1 or Table 2) or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients.

[0321] In some embodiments of the present disclosure, a pharmaceutical composition is provided, comprising one or more compounds of the present disclosure (e.g., compounds of Formula (A)-7, (A-1), (A-2), (IA), (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID), (ID-1), (ID-2), (IE), (IF), or a compound of 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 compositions or formulations for a variety of purposes. In some embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprises a pharmaceutically acceptable carrier. In some embodiments, pharmaceutically acceptable carriers include pharmaceutically acceptable excipients, binders, and / or diluents. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, saline solutions, alcohols, polyethylene glycols, gelatin, lactose, amylases, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0322] For the purposes of this disclosure, the compounds of the present disclosure can be formulated for administration in a variety of ways in formulations containing pharmaceutically acceptable carriers, adjuvants, and vehicles, including oral, parenteral, by inhalation spray, topical, or rectal. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, and intraarterial injections, as well as various infusion techniques. Intraarterial and intravenous injections as used herein include administration via a catheter.

[0323] In general, the compounds of the present disclosure are administered in a therapeutically effective amount. The amount of compound actually administered will generally be determined by a physician in view of the 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.

[0324] Treatment

[0325] The disclosed compounds can be used in a variety of methods. For example, in some embodiments, the compound is suitable for use in regulating a method for regulating an appetite hormone receptor (such as an orexin type 2 receptor). Therefore, in some embodiments, the disclosure provides the aforementioned 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), any one of the compounds of table 1 or table 2 or their pharmaceutically acceptable salts is used to regulate the activity of an appetite hormone receptor (such as an orexin type 2 receptor). For example, in some embodiments, regulating the activity of an orexin receptor (such as an orexin type 2 receptor) in mammalian cells. The activity of an orexin receptor (eg, orexin type 2 receptor) can be modulated in a subject in need thereof (eg, a mammalian subject, such as a human) and used to treat any of the conditions or diseases described.

[0326] In some embodiments, modulating orexin receptor (eg, orexin type 2 receptor) activity is binding. In some embodiments, modulating orexin receptor (eg, orexin type 2 receptor) activity is agonizing or stimulating the orexin receptor.

[0327] In some embodiments, the present disclosure provides a method of treating a disease or condition treatable by administering 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 (A), (IA), (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID), (ID-1), (ID-2), (IE), (IF), or a compound of Table 1 or Table 2).

[0328] In some embodiments, the present disclosure provides a method of treating a disease or condition treatable by administering 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 (A), (IA), (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID), (ID-1), (ID-2), (IE), (IF), or a compound of Table 1 or Table 2).

[0329] In some embodiments, the compounds of the present disclosure are used to treat, prevent, alleviate, manage, or reduce the risk of a variety of disorders associated with orexin receptors, including 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, repetitive hypersomnia, intrinsic hypersomnia, hypersomnia with daytime sleepiness, fragmented sleep, sleep apnea, hypersomnia associated with sleep apnea, nocturnal myoclonus, confusion (such as coma), interrupted REM sleep, jet lag, excessive daytime sleepiness, sleep disturbances in shift workers, dyssomnias, sleep disorders, sleep disturbances, hypersomnia associated with depression, mood disorders, drug abuse, Alzheimer's disease or cognitive impairment, Parkinson's disease, disease, Guillain-Barre syndrome, Kleine-Levin syndrome; and sleep disorders associated with aging, muscular dystrophy, and immune-mediated diseases; Alzheimer's sundowning; conditions related to circadian rhythms and mental and physical disorders associated with travel across time zones and rotating shift work schedules; fibromyalgia; heart failure; diseases associated with bone loss; sepsis; syndromes characterized by non-restorative sleep and muscle pain or sleep apnea associated with disturbed breathing during sleep; conditions resulting from impaired sleep quality; and other diseases associated with general orexin system dysfunction. In some embodiments, the compounds of the present disclosure are useful for treating, preventing, alleviating, controlling, or reducing the risk of narcolepsy, essential hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime sleepiness (e.g., Parkinson's disease, Guillain-Barre syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, confusion (such as coma, and the like), side effects and complications due to anesthesia, and the like, or anesthetic antagonists.

[0330] In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (I-1), (I-2), (IA), (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID), (ID-1), (ID-2), (IE), (IF), or a compound of Table 1 or Table 2), a pharmaceutically acceptable salt thereof, or a composition thereof, is used to treat a disease, condition, or symptom associated with excessive sleepiness in a subject in need thereof. In some embodiments, excessive sleepiness is caused by any of the following: poor quality or inadequate sleep at night; a misalignment between the body's circadian pacemaker and the environment (e.g., caused by the need to stay awake at night due to occupational conditions such as shift work or personal obligations such as caring for a sick, young, 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, possible narcolepsy), sleep apnea (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), idiopathic hypersomnia, idiopathic excessive sleepiness, and restless legs syndrome; a disorder, such as clinical depression or atypical depression; a tumor; head trauma; anemia; renal failure; hypothyroidism; central nervous system injury; drug abuse; hereditary vitamin deficiencies, such as biotin deficiency; and certain categories of prescription and over-the-counter medications.

[0331] In some embodiments, the compounds of the present disclosure (e.g., compounds of Formula (I) (I-1), (I-2), (IA) (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB) (IB-1), (IB-2), (IC) (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID) (ID-1), (ID-2), (IE) (IF), or a compound of Table 1 or Table 2), pharmaceutically acceptable salts thereof, 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 to treat any of the following: narcolepsy type 1, narcolepsy type 2, possible narcolepsy, idiopathic hypersomnia, idiopathic excessive hypersomnia, hypersomnia, excessive sleepiness, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure); or confusion (such as coma and the like); and narcolepsy syndrome with narcolepsy-like symptoms; excessive sleepiness or hypersomnia syndrome with daytime sleepiness (e.g., Parkinson's disease, Guillain-Barre syndrome, and Kleine-Levin syndrome); excessive daytime sleepiness in Parkinson's disease, Prader-Willi syndrome, Syndrome), depression (depression, atypical depression, major depressive disorder, refractory depression), ADHD, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea using continuous positive airway pressure) and other insomnia disorders; residual daytime excessive sleepiness in sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea using continuous positive airway pressure); and the like. Narcolepsy (e.g., narcolepsy type 1, narcolepsy type 2, possible narcolepsy) can be diagnosed by diagnostic criteria commonly used in the art, such as the third edition of the International Classification of Sleep Disorders (ICSD-3) and the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In some embodiments, excessive sleepiness is excessive daytime sleepiness or excessive sleepiness during work hours, or excessive sleepiness or reduced sleep amount caused by the need to stay awake at night due to occupations such as shift work or personal obligations such as caring for sick, young or elderly family members. In some embodiments, the subject suffers from 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 reduced sleepiness. In some embodiments, the present disclosure provides methods 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 (CPAP). In some embodiments, methods of increasing wakefulness in a subject in need thereof are provided. In some embodiments, the subject's orexin levels are not impaired or are partially impaired.

[0332] In some embodiments of the present disclosure, a method for treating a sleep disorder in a subject in need thereof (e.g., as disclosed herein) is provided, comprising administering to the subject a compound of the present disclosure (e.g., a compound of Formula (A)-7, 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), a compound of 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), (I-1), (I-2), (IA), (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID), (ID-1), (ID-2), (IE), (IF), or a compound of 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 a symptom of a sleep disorder.

[0333] In some embodiments of the present disclosure, a method for treating narcolepsy in a subject in need thereof is provided, comprising administering to a subject in need thereof a compound of the present disclosure (e.g., a compound of Formula (A)-7, 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), or a compound of Table 1 or Table 2) or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (A)-7, (I-1), (I-2), (IA)-7, (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID), (ID-1), (ID-2), (IE), (IF), or a compound of 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 a symptom of narcolepsy.

[0334] In some embodiments of the present disclosure, a method for treating idiopathic hypersomnia (IH) in a subject in need thereof is provided, comprising administering to a subject in need thereof a compound of the present disclosure (e.g., a compound of Formula (A)-7, 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), or a compound of Table 1 or Table 2) or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (I-1), (I-2), (IA), (IA-1), (IA-1-1), (IA-2), (IA-2-1), (IA-3), (IA-4), (IA-5), (IB), (IB-1), (IB-2), (IC), (IC-1), (IC-2), (IC-3), (IC-4), (IC-5), (IC-6), (ID), (ID-1), (ID-2), (IE), (IF), or a compound of 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 a symptom of IH.

[0335] Example

[0336] Having generally described the disclosure, the disclosure will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the disclosure and are not intended to limit the disclosure.

[0337] The compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.

[0338] The preparation of compounds may involve the protection and deprotection of various chemical groups. The demand for protection and deprotection and the selection of appropriate protecting groups can be easily determined by one skilled in the art. The chemical properties of protecting groups can be found in, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 44th edition, Wiley and Sons, 2006 and Jerry March, Advanced Organic Chemistry, 4th edition, John Wiley and Sons, publisher, New York, 1992, which are incorporated herein by reference in their entirety.

[0339] abbreviation

[0340] AcOH acetic acid

[0341] DCM dichloromethane

[0342] DIPEA N,N-Diisopropylethylamine

[0343] DMPU N,N'-dimethylpropyleneurea

[0344] DMSO dimethyl sulfoxide

[0345] EtOAc

[0346] IPA Isopropyl alcohol

[0347] LDA lithium diisopropylamide

[0348] NMO N-Methylmorpholine-N-oxide

[0349] TEA triethylamine

[0350] TFA trifluoroacetic acid

[0351] TFAA trifluoroacetic anhydride

[0352] THF Tetrahydrofuran

[0353] Universal synthesis

[0354] The disclosed compounds can be synthesized using the following methods. General reaction conditions are given, and the reaction products can be purified by generally known methods, including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol, and the like, or preparative reverse-phase high pressure liquid chromatography.

[0355] Analysis conditions:

[0356] Method A:

[0357] ·Column: Waters BEH TM C18, part number 186002352, 2.1 × 100 mm, 1.7 μm

[0358] Column temperature: 40°C

[0359] Mobile phase A: 2 mM ammonium bicarbonate, buffered to pH 10

[0360] Mobile phase B: acetonitrile

[0361] Injection volume: 1 μL

[0362] Gradient program: flow rate 0.6 mL / min

[0363]

[0364] UV 215nm, PDA spectrum 200-400nm, step: 1nm

[0365] MSD scan positive: 100-1000; scan positive and negative: 150-850; scan negative: 100-1000

[0366] Method B:

[0367] Column: Phenomenex, Kinetex-XB C18, part number 00D-4498-AN, 2.1 mm × 100 mm, 1.7 μm

[0368] Column temperature: 40°C

[0369] Mobile phase A: water containing 0.1% formic acid

[0370] Mobile phase B: acetonitrile containing 0.1% formic acid

[0371] Injection volume: 1 μL

[0372] Gradient program: flow rate 0.6 mL / min

[0373]

[0374] UV 215nm, PDA spectrum 200-400nm, step: 1nm

[0375] MSD scan positive: 100-1000; scan positive and negative: 150-850

[0376] Method C:

[0377] Column: Acquity UPLC CSH C18 (5.0 mm × 2.1 mm I.d. 1.7 μm) column

[0378] Column temperature: 40°C

[0379] Mobile phase A: water containing 0.1% formic acid

[0380] Mobile phase B: acetonitrile containing 0.1% formic acid

[0381] Gradient program: flow rate 1 mL / min

[0382]

[0383] Method D:

[0384] Column: Kinetex EVO C18 (1.7 μm, 2.1×50 mm)

[0385] Column temperature: 40°C

[0386] Mobile phase A: 10 mM ammonium bicarbonate solution adjusted to pH 10 with NH3

[0387] Mobile phase B: acetonitrile

[0388] Gradient program: flow rate 1 mL / min

[0389]

[0390] Synthetic spirocyclic core

[0391]

[0392] Intermediate 1

[0393]

[0394] 3-Ethyl 4-oxo-5-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1,3-dicarboxylate 1-tert-butyl ester

[0395] 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 freshly prepared LDA was added 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 via an addition funnel over 0.5 hours without the reaction temperature rising 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 min. The reaction mixture was stirred at -78 ° C for 1 h, warmed to room temperature, and stirred for 2 hours. The reactant was quenched with NH4Cl, diluted with water (100 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-25% EtOAc / heptane) to give the title compound (17.50 g) as a yellow oil. (M+Na) + m / z: 574.3.

[0396] Intermediate 2

[0397]

[0398] tert-Butyl 3-oxo-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0399] To DMSO (148 mL) containing intermediate 1 (17.70 g, 32.1 mmol) was added sodium chloride (3.50 g, 59.9 mmol) and water (15 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 give a crude material. The crude material was purified by column chromatography (0-40% EtOAc / heptane) to give the title compound (10.00 g) as a yellow oil. [M+Na] + m / z 502.3.

[0400] Intermediate 3

[0401]

[0402] tert-Butyl (3E / Z)-3-(hydroxyimino)-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0403] 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 to 90°C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 75 mL). The organic extracts were 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.

[0404] Intermediate 4

[0405]

[0406] tert-Butyl 3-nitro-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0407] 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 bicarbonate (8.50 g, 0.101 mol) in acetonitrile (36 mL) at 80°C for 1 h. The reaction mixture was cooled to room temperature, quenched with saturated Na2SO3 (50 mL) and stirred for 10 min, 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% EtOAc / heptane) to give the title compound (6.70 g) as a yellow gum. [M+H] + m / z=511.3.

[0408] Intermediate 5

[0409]

[0410] tert-Butyl-rel-(2R,3S)-3-(hydroxymethyl-3-nitro-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0411] Formaldehyde (in water) (37%, 8.8 mL, 0.118 mol) was added to THF (66 mL) containing intermediate 5 (6.70 g, 13.1 mmol) and triethylamine (2.2 mL, 15.8 mmol) at room temperature. The solution was heated to 70 ° C and maintained 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 / heptane) to give the title compound (5.80 g) as a yellow solid. [M+H] + m / z = 541.4

[0412] Intermediate 6

[0413]

[0414] Tert-butyl-rel-(2R,3S)-3-amino-3-(hydroxymethyl-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate

[0415] 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 NaHCO3 and extracted with DCM (3 × 75 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the title compound (5.49 g) as a yellow oil. [M+H] + m / z 511.4.

[0416] Intermediate 7

[0417]

[0418] 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

[0419] To a solution of intermediate 6 (3.00 g, 5.87 mmol) in THF (25 mL) was added dipotassium carbonate (2.43 g, 17.6 mmol) at 0 ° C., followed by water (25 mL). Chloroacetyl chloride (0.65 mL, 8.15 mmol) was added dropwise to this mixture at 0 ° C. The reaction was stirred for 1 h at 0 ° C. 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 ), 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-methylpropan-2-olate (2.63 g, 23.4 mmol) was added and the reaction was stirred for 1 h at 0 ° C. The reaction was quenched by adding water (20 mL). The mixture was poured onto a saturated NaHCO aqueous solution (30 ml). After extraction with DCM (3 x 50 mL), the combined organic extracts were washed with brine (20 mL), dried (MgSO 4 ), filtered and concentrated to give the title compound as a yellow solid (3.12 g) [M+H] + m / z 551.4.

[0420] Intermediate 8

[0421]

[0422] 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

[0423] Intermediate 7 (1.00 g, 1.62 mmol) was dissolved in ethanol (77 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%) (5.0%, 344 mg, 0.161 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 6 hours, then 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

[0424]

[0425] Intermediate 9

[0426]

[0427] 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

[0428] To 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 intermediate 8 (84%, 200 mg, 0.365 mmol) in THF (8.4 mL) 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, 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.

[0429] Intermediate 10

[0430]

[0431] 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

[0432] Intermediate 9 (64%, 160 mg, 0.183 mmol) and ammonium formate (114 mg, 1.84 mmol) were dissolved in IPA (2.6 mL), followed by the addition of palladium (2+) hydroxide (20%, 129 mg, 0.184 mmol) at room temperature under nitrogen. The reaction was stirred at 80°C for 5 hours, cooled to room temperature, filtered through celite, washed with IPA, and concentrated in vacuo to give the title compound (120 mg) as a yellow oil. [M+H] + m / z 561.4

[0433] Intermediate 11

[0434]

[0435] 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}propanoic acid

[0436] 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 hours. The mixture was diluted with water (5 mL) and neutralized to pH 7 with 1M aqueous HCl, then extracted with 10% MeOH / DCM (3×10 mL). The organic layer was dried over MgSO 4 and concentrated in vacuo to give the title compound (110 mg) as a colorless oil. [M+H] + m / z: 533.4

[0437] Intermediate 12

[0438]

[0439] 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

[0440] 4M hydrochloric acid in dioxane (0.20 mL, 0.805 mmol) was added to intermediate 11 (50 mg, 0.109 mmol) and the reaction was stirred at room temperature for 30 min. The aqueous phase was neutralized with a few drops of 1M aqueous K2CO3 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

[0441] Example 1

[0442]

[0443] 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

[0444] To a stirred solution of HATU (49 mg, 0.129 mmol) and DIPEA (45 μL, 0.255 mmol) in acetonitrile (40 mL) was added acetonitrile (3.6 mL) containing intermediate 12 (62%, 60 mg, 0.0860 mmol) using a syringe pump over 2 h. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give a crude material. The mixture was diluted in water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO ), filtered and concentrated to give a crude solid. The crude material was purified by basic reverse phase column chromatography (10-55% acetonitrile / water (0.1% ammonia)) to give the title compound (33 mg) as a white solid.

[0445] LCMS (Method A): [M+H] + m / z 415.3, RT 2.87 min

[0446] 1 H NMR (500MHz, CDCl3) δ7.20-7.11 (m, 2H), 7.09 (dd, J=7.5, 1.7Hz, 1H), 7.01 (d, J=7.8Hz, 1H), 6.93-6.86 (m, 1H ), 6.42 (s, 1H), 4.57-4.32 (m, 2H), 4.29 (d, J = 2.4Hz, 1H), 4.29-4.10 (m, 3H), 4.07-3.95 (m, 1H), 3.83 (s, 1H), 3.78 (d, J=11.6Hz, 1H), 3.65-3.53 (m, 2H), 3.30 (d, J=9.4Hz, 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).

[0447] Examples 1a and 1b

[0448]

[0449] 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

[0450] 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

[0451] Example 1 (33 mg) was subjected to chiral preparative purification using a 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 give the title compound (peak 1, 11.1 mg, 100% ee; and peak 2, 10.9 mg, 100% ee).

[0452] Example 1a: Peak 1 (stereochemistry arbitrarily assigned to pyrrolidine)

[0453] LCMS (Method C): [M+H] + m / z 415.3, RT 1.00 min.

[0454] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 30:70 hexane:(ethanol / methanol 1:1+0.1% isopropylamine)): RT 9.2 min

[0455] 1H NMR (500MHz, CDCl3) δ7.21-7.13 (m, 1H), 7.09 (dd, J=7.5, 1.6Hz, 1H), 7.01 (d, J=8.1Hz, 1H), 6.89 (td, J=7.4, 1.0Hz, 1H), 6.26 (s, 1H), 4.47-4.44 (m, 1 H), 4.45-4.42 (m, 1H), 4.29 (d, J = 2.2Hz, 1H), 4.25 (d, J = 16.9Hz, 1H), 4.26- 4.21(m, 1H), 4.18(d, J=16.9Hz, 1H), 4.01(td, J=10.0, 3.2Hz, 1H), 3.83(br s, 1H), 3.78 (d, J=11.7Hz, 1H), 3.59 (d, J=11.7Hz, 1H), 3.59-3.53 (m, 1H), 3. 30(d, J=9.5Hz, 1H), 3.12(ddd, J=14.2, 12.2, 4.2Hz, 1H), 2.50-2.40(m, 2H), 2.42-2.36 (m, 1H), 2.30 (qd, J=12.8, 3.7Hz, 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=12.2Hz, 1H), 1.43-1.30 (m, 2H).

[0456] Example 1b: Peak 2 (stereochemistry arbitrarily assigned to pyrrolidine)

[0457] LCMS (Method C): [M+H] + m / z 415.3, RT 1.00 min.

[0458] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 30:70 hexane:(ethanol / methanol 1:1+0.1% isopropylamine)): RT 15.9 min

[0459] 1H NMR (500MHz, CDCl3) δ7.21-7.13 (m, 1H), 7.09 (dd, J=7.5, 1.6Hz, 1H), 7.01 (d, J=8.1Hz, 1H), 6.89 (td, J=7.4, 1.0Hz, 1H), 6.26 (s, 1H), 4.47-4.44 (m, 1 H), 4.45-4.42 (m, 1H), 4.29 (d, J = 2.2Hz, 1H), 4.25 (d, J = 16.9Hz, 1H), 4.26- 4.21(m, 1H), 4.18(d, J=16.9Hz, 1H), 4.01(td, J=10.0, 3.2Hz, 1H), 3.83(br s, 1H), 3.78 (d, J=11.7Hz, 1H), 3.59 (d, J=11.7Hz, 1H), 3.59-3.53 (m, 1H), 3. 30(d, J=9.5Hz, 1H), 3.12(ddd, J=14.2, 12.2, 4.2Hz, 1H), 2.50-2.40(m, 2H), 2.42-2.36 (m, 1H), 2.30 (qd, J=12.8, 3.7Hz, 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=12.2Hz, 1H), 1.43-1.30 (m, 2H).

[0460]

[0461] Intermediate 13

[0462]

[0463] Tert-butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-[2-(4-ethoxy-4-oxobutyloxy)phenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0464] To a solution of intermediate 8 (200 mg, 0.434 mmol) and ethyl 4-bromobutyrate (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 to 50 ° C for 24 hours. The solid was removed by filtration, and 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 give the title compound (202 mg) as a colorless oil. [M+H] + m / z 575.4

[0465] Intermediate 14

[0466]

[0467] 4-{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

[0468] To a solution of intermediate 13 (64%, 202 mg, 0.225 mmol) in THF (6.4 mL) and water (1.8 mL) was added 2M aqueous lithium hydroxide solution (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) and neutralized with 1M aqueous HCl to pH 7, and the aqueous phase was extracted with 10% methanol / DCM (3×10 mL). The organic layer was dried (MgSO 4 ) and concentrated in vacuo to give the title compound (200 mg) as a colorless oil. [M+H] + m / z: 547.4

[0469] Intermediate 15

[0470]

[0471] 4-{2-[(1s,4s)-4-{[rel-(1R,5S)-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methoxy}cyclohexyl]phenoxy}butanoic acid

[0472] 4M hydrochloric acid (0.45 mL, 1.80 mmol) was added to intermediate 14 (50 mg, 0.109 mmol) at room temperature and the reaction was stirred for 30 min. 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

[0473] Example 2

[0474]

[0475] 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

[0476] 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 acetonitrile (2.6 mL) containing intermediate 15 (74%, 80 mg, 0.133 mmol) using a syringe pump over 2 h. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give the crude material. The mixture was diluted with water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO ), filtered, and concentrated to give a solid residue. The crude material was purified by basic reverse phase column chromatography (10-50% acetonitrile / water (0.1% ammonia)) to give the title compound (31 mg) as a white solid.

[0477] LCMS (Method A): [M+H] + m / z 429.3, RT 2.98 min

[0478] 1 H NMR (500MHz, CDCl3) δ7.77 (s, 1H), 7.19-7.12 (m, 1H), 7.08 (dd, J=7.4, 1.6Hz, 1H), 6.86 (d, J=8.6Hz, 1H), 6.83 (d, J=7.3Hz, 1H), 4.38 ( dd, J=10.7, 2.7Hz, 1H), 4.28 (d, J=17.1Hz, 1H), 4.23-4.18 (m, 1H), 4.13 (d, J=17.1Hz, 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, 2.9Hz, 1H), 3.58 (s, 1H), 3.57-3.50 (m, 1H), 3.49-3.45 (m, 1H), 3.39 (d, J=11.8Hz, 1 H), 2.56-2.48 (m, 3H), 2.40 (ddd, J=16.4, 9.6, 5.1Hz, 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).

[0479] Example 3

[0480]

[0481] rel-(1′s,3S,15′R,18′s)-8′,17′-dioxa-11′-azaspiro[morpholine-3,14′-tetracyclo[16.2.2.0 2 , 7 .011 , 15 ]docosane]-2′(7′),3′,5′-triene-5,10′-dione

[0482] Example 3 was prepared using intermediate 8 and according to the procedure described for Example 2 to give the title compound as an off-white solid (2.4 mg).

[0483] LCMS (Method A): [M+H] + m / z 401.2, RT 2.88 min

[0484] 1 H NMR (500MHz, CDCl3) δ7.23-7.16 (m, 1H), 7.10 (dd, J=7.5, 1.7Hz, 1H), 6.93 (td, J=7.4, 1.1Hz, 1H), 6.78 (dd, J=8.0, 0.9Hz, 1H), 6 .38 (s, 1H), 5.00 (d, J = 10.4Hz, 1H), 4.42-4.37 (m, 1H), 4.36 (dd, J = 10.2, 3.4Hz, 1H), 4.33-4.25 (m, 3H), 4.20 (d, J = 16.7Hz, 1H), 3.87 (s, 1H), 3.83 (d, J = 11.7Hz, 1H), 3.64 (d, J = 11.7Hz, 1H), 3.62-3.53 (m, 1H), 3.34 (d, J = 9.8Hz, 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).

[0485]

[0486] Intermediate 16

[0487]

[0488] Tert-butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-(2-{[4-ethoxy-4-oxobut-2-en-2-yl]oxy}phenyl)cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0489] 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 nitrogen and the solution was heated to 70 ° C. Ethyl butane-2-ynoate (0.047 mL, 0.401 mmol) was added to the reactant 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, dried over MgSO4 and concentrated in vacuo. The crude material was purified by column chromatography (0-100% EtOAc / heptane) to give the title compound (198 mg) as a yellow oil. [M+H] + m / z 573.4

[0490] Intermediate 17

[0491]

[0492] 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

[0493] Intermediate 16 (89%, 198 mg, 0.308 mmol) and ammonium formate (191 mg, 3.08 mmol) were dissolved in IPA (4.4 mL). Palladium (2+) hydroxide (20%, 216 mg, 0.308 mmol) was added at room temperature under nitrogen. The reaction was stirred at 80° C. for 5 hours, then filtered through celite, washed with isopropanol and concentrated in vacuo to give the title compound (168 mg) as a yellow oil [M+H]. + m / z 575.3

[0494] Intermediate 18

[0495]

[0496] 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

[0497] 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 hours. The reaction mixture was diluted with water (5 ml), washed with DCM (2 × 3 mL) and neutralized with 1M aqueous HCl solution to pH 7, and the aqueous layer was extracted with 10% MeOH / DCM (3 × 10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give the title compound (90 mg) as a colorless oil. [M+H] + m / z 547.4

[0498] Intermediate 19

[0499]

[0500] 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

[0501] 4M hydrochloric acid 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 min. The aqueous phase was washed with DCM (2×2 mL) and concentrated in vacuo to give the title compound (74 mg) as a yellow solid. [M+H] + m / z 447.3

[0502] Example 4

[0503]

[0504] 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

[0505] To a stirred solution of HATU (76 mg, 0.200 mmol) and DIPEA (69 μL, 0.395 mmol) in acetonitrile (33 mL) was added acetonitrile (2.9 mL) containing intermediate 19 (80%, 74 mg, 0.133 mmol) using a syringe pump over 2 hours. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give the crude material. The mixture was diluted in 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 (10-60% acetonitrile / water (0.1% ammonia)) to give the title compound (26 mg) as a white solid. [M+H] + m / z 429.3

[0506] LCMS (Method A): [M+H] + m / z 429.3, RT 2.98 min

[0507] 1 H NMR (400MHz, CDCl3) δ7.08-6.98(m, 2H), 6.88-6.76(m, 2H), 6.42(s, 1H), 4.69-4.53(m, 1H), 4.40 (dd, J=9.6, 3.3Hz, 1H), 4.20-4.06 (m, 3H), 3.74 (s, 1H), 3.73-3.64 (m, 1H), 3. 52(d, J=11.7Hz, 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).

[0508] Examples 4a, 4b, 4c and 4d

[0509]

[0510] 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

[0511] 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

[0512] 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

[0513] 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

[0514] Example 4 (24 mg) was subjected to chiral preparative purification using a Waters 600 with 50 / 50% v / v hexane / ethanol + 0.1% isopropylamine (Chiralpak AD-H (25×2.0 cm), 5 μm, flow rate 17 mL / min) to give the title compounds (peak 1, 1 mg; peak 2, 3.7 mg, 99% ee; peak 3, 3.2 mg; peak 4, 4.5 mg, 100% ee).

[0515] Example 4a: Peak 1 (stereochemistry arbitrarily assigned to pyrrolidine and methyl centers)

[0516] LCMS (Method C): [M+H] + m / z 429.3, RT 0.96, 0.99 min.

[0517] Chiral analysis (Chiralpak AD-H, 25 × 0.46 cm, 5 μm, 50:50 hexane: (ethanol + 0.1% isopropylamine): RT 9.0 min

[0518] 1H NMR (400MHz, CDCl3) δ7.21-7.14 (m, 1H), 7.09 (d, J=7.5Hz, 1H), 7.01 (d, J=8.1Hz, 1H), 6.91-6.85 (m, 1H), 6.22 (s, 1H), 5.09-4.97 (m, 1H), 4.35 (br d, J=9.4Hz, 1H), 4.32 (s, 1H), 4.29-4.12 (m, 2H), 4.03 (br t, J=10.0Hz, 1H), 3.83 (br s, 1H), 3.80-3.74 (m, 1H), 3.56 (d, J=11.6Hz, 1H), 3.55-3.46 (m, 1H), 3.37-3.31 (m, 1H), 3.24 (dd, J=13.6, 5.3H z, 1H), 2.57-2.41 (m, 2H), 2.34 (d, J=13.6Hz, 1H), 2.15-2.00 (m, 1H), 1.44 (d, J=6.4Hz, 3H), 2.25-1.15 (m, 8H).

[0519] Example 4b: Peak 2 (stereochemistry arbitrarily assigned with respect to the pyrrolidine and methyl centers)

[0520] LCMS (Method C): [M+H] + m / z 429.3, RT 0.97 min.

[0521] Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 50:50 hexane:(ethanol+0.1% isopropylamine): RT 18.4 min

[0522] 1H NMR (400MHz, CDCl3) δ7.16-7.05(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, 3.1Hz, 1H), 4.29-4.15 (m, 3H), 4.09 (td, J=9.8, 3.9Hz, 1H), 3.82 (br s, 1H), 3.75 (d, J = 11.6Hz, 1H), 3.61 (d, J = 11.6Hz, 1H), 3.58-3.48 (m, 1H), 3.28 (d, J =9.6Hz, 1H), 2.98 (dd, J = 14.5, 9.9Hz, 1H), 2.54-2.41 (m, 2H), 2.40-2.27 (m, 2H), 2.2 4-2.16 (m, 1H), 2.09 (td, J=8.3, 3.7Hz, 1H), 2.08-1.96 (m, 1H), 1.82 (brd, J=13.6Hz, 1H), 1.59-1.47 (m, 1H), 1.45 (d, J=5.9Hz, 3H), 1.50-1.39 (m, 2H), 1.42-1.23 (m, 1H).

[0523] Example 4c: Peak 3 (stereochemistry arbitrarily assigned with pyrrolidine and methyl centers)

[0524] LCMS (Method C): [M+H] + m / z 429.3, RT 0.96, 0.99 min.

[0525] Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 50:50 hexane:(ethanol+0.1% isopropylamine): RT 21.8 min

[0526] 1H NMR (400MHz, CDCl3) δ7.21-7.14 (m, 1H), 7.09 (d, J=7.5Hz, 1H), 7.01 (d, J=8.1Hz, 1H), 6.91-6.85 (m, 1H), 6.22 (s, 1H), 5.09-4.97 (m, 1H), 4.35 (br d, J=9.4Hz, 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=11.6Hz, 1H), 3.55-3.46 (m, 1H), 3.37-3.31 (m, 1H), 3.24 (dd, J=13.6, 5.3H z, 1H), 2.57-2.41 (m, 2H), 2.34 (d, J=13.6Hz, 1H), 2.15-2.00 (m, 1H), 1.44 (d, J=6.4Hz, 3H), 2.25-1.15 (m, 8H).

[0527] Example 4d: Peak 4 (stereochemistry arbitrarily assigned with respect to the pyrrolidine and methyl centers)

[0528] LCMS (Method C): [M+H] + m / z 429.3, RT 0.97 min.

[0529] Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 50:50 hexane:(ethanol+0.1% isopropylamine): RT 27.4 min

[0530] 1H NMR (400MHz, CDCl3) δ7.16-7.05(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, 3.1Hz, 1H), 4.29-4.15 (m, 3H), 4.09 (td, J=9.8, 3.9Hz, 1H), 3.82 (br s, 1H), 3.75 (d, J = 11.6Hz, 1H), 3.61 (d, J = 11.6Hz, 1H), 3.58-3.48 (m, 1H), 3.28 (d, J =9.6Hz, 1H), 2.98 (dd, J = 14.5, 9.9Hz, 1H), 2.54-2.41 (m, 2H), 2.40-2.27 (m, 2H), 2.2 4-2.16 (m, 1H), 2.09 (td, J=8.3, 3.7Hz, 1H), 2.08-1.96 (m, 1H), 1.82 (brd, J=13.6Hz, 1H), 1.59-1.47 (m, 1H), 1.45 (d, J=5.9Hz, 3H), 1.50-1.39 (m, 2H), 1.42-1.23 (m, 1H).

[0531]

[0532] Intermediate 20

[0533]

[0534] Tert-butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-[2-(3-methoxy-2-methylene-3-oxopropoxy)phenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0535] To 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 potassium carbonate (181 mg, 1.31 mmol) and the solution was stirred at room temperature overnight. The reactant was heated to 60 ° C and stirred at this temperature for 5 h. The reactant was cooled to room temperature, the solid was filtered out and 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 / heptane) to give the title compound (200 mg) as a colorless oil. [M+H] + m / z=559.4

[0536] Intermediate 21

[0537]

[0538] 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

[0539] Intermediate 20 (200 mg, 0.358 mmol) was dissolved in ethanol (15 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 38 mg, 0.0358 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 5 h, then filtered through celite, washed with EtOAc, and concentrated in vacuo to give the title compound (200 mg) as a colorless oil.

[0540] [M+H]+m / z=561.4

[0541] Intermediate 22

[0542]

[0543] 2-Methyl-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}propanoic acid

[0544] 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 solution (8.9 mL, 17.8 mmol) at room temperature. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (5 mL) and neutralized with HCl (1 M) to pH 7, and the aqueous phase was extracted with 10% MeOH / DCM (3×10 mL). The organic layer was dried (MgSO 4 ) and concentrated in vacuo to give the title compound (200 mg) as a colorless oil. [M+H] + m / z=547.4

[0545] Intermediate 23

[0546]

[0547] 2-Methyl-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

[0548] 4M hydrochloric acid 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 K2CO3 (1 M), washed with DCM (2 x 2 mL) and concentrated in vacuo to give the title compound (200 mg) as a beige solid. [M+H] + m / z=447.3

[0549] Example 5

[0550]

[0551] (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 ]Tricosane]-2′(7′),3′,5′-triene-5,11′-dione

[0552] To a stirred solution of HATU (255 mg, 0.671 mmol) and DIPEA (232 μL, 1.33 mmol) in acetonitrile (112 mL) was added acetonitrile (9.8 mL) containing intermediate 22 (200 mg, 0.448 mmol) using a syringe pump over 2 h. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give the crude material. The mixture was diluted in water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO ), filtered and concentrated to give a solid residue. The crude material was purified by basic reverse phase column chromatography (10-50% acetonitrile / water (0.1% ammonia)) to give the title compound (18 mg) as a white solid.

[0553] LCMS (Method A): [M+H] + m / z 429.3, RT 3.12 and 3.17 min

[0554] 1H NMR (500MHz, CDCl3) δ7.17-6.76 (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=11.5H z, 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, 7.1Hz, 3H).

[0555] Examples 5a, 5b and 5c

[0556]

[0557] 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

[0558] 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

[0559] Example 5c: (1's, 3R, 10'R, 16'S, 19's)-10'-methyl-8', 18'-dioxa-12'-azaspiro[morpholine-3, 15'-tetracyclo[17.2.2.0 2 , 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 .012 , 16 ]Tricosane]-2′(7′),3′,5′-triene-5,11′-dione

[0560] Example 5 (16 mg) was subjected to chiral preparative purification using a Waters 600 eluting with 55 / 45% v / v hexane / (ethanol + 0.1% isopropylamine) (Chiralpak IC (25×2.0 cm), 5 μm, flow rate 17 mL / min) to give the title compound (peak 1, 3.8 mg, 100% ee; peak 2, 3.45 mg, 100% ee; peak 3, 8 mg).

[0561] Example 5a Peak 1 (arbitrarily assigned stereochemistry); 1 H NMR (500MHz, CDCl3) δ7.17-7.10 (m, 1H), 7.03 (dd, J=7.3, 1.2Hz, 1H), 6.86-6.76 (m, 3H), 4.67 (dd, J=10.2, 7.8Hz, 1H), 4.47 (dd, J=9. 7, 2.0Hz, 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, 2.1Hz, 1H), 3.74 (d, J=11.9Hz, 1H), 3.68 (br s, 1H), 3.62 (dd, J=7.6, 2.8Hz, 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=7.3Hz, 3H).

[0562] LCMS (Method C): [M+H] + m / z 429.2, RT 0.98 min.

[0563] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 55:45 hexane:(ethanol+0.1% isopropylamine)): RT 6.3 min

[0564] Example 5b Peak 2 (stereochemistry arbitrarily assigned); 1H NMR (500MHz, CDCl3) δ7.17-7.10 (m, 1H), 7.03 (dd, J=7.3, 1.2Hz, 1H), 6.86-6.76 (m, 3H), 4.67 (dd, J=10.2, 7.8Hz, 1H), 4.47 (dd, J=9. 7, 2.0Hz, 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, 2.1Hz, 1H), 3.74 (d, J=11.9Hz, 1H), 3.68 (br s, 1H), 3.62 (dd, J=7.6, 2.8Hz, 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=7.3Hz, 3H).

[0565] LCMS (Method C): [M+H] + m / z 429.2, RT 0.98 min.

[0566] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 55:45 hexane:(ethanol+0.1% isopropylamine)): RT 8.8 min

[0567] Example 5c Peak 3 / Peak 4 (stereochemistry arbitrarily assigned); 1 H NMR (500MHz, CDCl3) δ7.18-7.13 (m, 1H), 7.10-7.05 (m, 1H), 6.97 (d, J=8.1Hz, 1H), 6.87 (t, J=7.3Hz, 1H), 6 .27 (s, 1H), 4.48 (dd, J=9.5, 2.8Hz, 1H), 4.29-4.22 (m, 2H), 4.21-4.13 (m, 2H), 4.04-3.92 (m, 2H), 3.88-3.8 1 (m, 1H), 3.77 (d, J = 11.7Hz, 1H), 3.59 (d, J = 11.7Hz, 1H), 3.57-3.51 (m, 1H), 3.30 (d, J = 9.5Hz, 1H), 3.23 (dd d, J=10.8, 6.9, 4.2Hz, 1H), 2.52-2.28 (m, 2H), 2.24-2.08 (m, 1H), 2.57-1.27 (m, 8H), 1.19 (d, J=7.0Hz, 3H).

[0568] LCMS (Method C): [M+H] + m / z 429.2, RT 0.99 min.

[0569] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 55:45 hexane:(ethanol+0.1% isopropylamine)): RT 13.3, 13.8 min

[0570]

[0571] Intermediate 24

[0572]

[0573] Tert-butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-(2-{[(2E)-4-ethoxy-1,1,1-trifluoro-4-oxobut-2-en-2-yl]oxy}phenyl)cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0574] 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-ynoate (36 μL, 0.253 mmol) at room temperature under nitrogen, and the solution was stirred at room temperature for 30 min. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2 × 5 mL). The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (140 mg) as a yellow oil. [M+H] + m / z 627.5

[0575] Intermediate 25

[0576]

[0577] 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}but-2-enoic acid

[0578] To a solution of intermediate 24 (82%, 140 mg, 0.183 mmol) in THF (5.2 mL) and water (1.5 mL) was added 2M aqueous lithium hydroxide solution (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 with HCl (1 M) to pH 7, and the aqueous phase was extracted with 10% MeOH / DCM (3×10 mL). The organic layer was dried (MgSO 4 ) and concentrated in vacuo to give the title compound (130 mg) as a white solid. [M+Na] + 621.2

[0579] Intermediate 26

[0580]

[0581] 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

[0582] Intermediate 25 (78%, 130 mg, 0.169 mmol) was dissolved in ethanol (32 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 90 mg, 0.0847 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred overnight and then filtered through celite, washed with EtOAc, and concentrated in vacuo to give a colorless oil (100 mg). [M+H] + m / z 601.35

[0583] Intermediate 27

[0584]

[0585] 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

[0586] 4M hydrochloric acid 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 was stirred for 30 min. The reaction mixture was concentrated in vacuo to give the title compound (97 mg) as a yellow solid. [M+H] + m / z 501.3

[0587] Example 6

[0588]

[0589] 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

[0590] To a stirred solution of HATU (82 mg, 0.216 mmol) and DIPEA (74 μL, 0.426 mmol) in acetonitrile (36 mL) was added acetonitrile (3.1 mL) containing intermediate 28 (72 mg, 0.144 mmol) using a syringe pump over 2 hours. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give the crude material. The mixture was diluted in water and extracted with DCM (3×5 mL). The combined organic extracts were dried (MgSO ), filtered and concentrated to give a solid residue. The crude material was purified by basic reverse phase column chromatography (10-65% acetonitrile / water (0.1% ammonia) to give a mixture of diastereomers (1: 1) (38 mg) as the title compound as a white solid.

[0591] LCMS (Method A): [M+H] + m / z 483.3, RT = 3.35 and 3.39 min

[0592] Isomer 1: 1H NMR (500 MHz, CDCl3) 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=15.7Hz, 1H), 2.41-2.30( m, 2H), 2.18 (d, J=14.6Hz, 1H), 2.11-2.03 (m, 2H), 1.99-1.77 (m, 3H), 1.62-1.25 (m, 4H).

[0593] Isomer 2: 1H NMR (500 MHz, CDCl3) 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=11.5Hz, 2H), 3.70 (d, J=11.8Hz, 1H), 3.29 (d, J=9.5Hz, 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).

[0594] Example 7

[0595]

[0596] 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 ]Tricosane-15′,3″-morpholine]-2′(7′),3′,5′-triene-5″,11′-dione

[0597] Example 7 was prepared using intermediate 8 and according to the procedure described for Example 2 to give the title compound as a white solid (28 mg).

[0598] LCMS (Method A): [M+H] + m / z 441.3, RT 3.14 min.

[0599] 1H NMR (500MHz, CDCl3) δ7.18-7.12 (m, 1H), 7.10 (dd, J=7.5, 1.5Hz, 1H), 6.97-6.89 (m, 2H), 6.36 (s, 1H), 4.45 (dd, J=9.8, 2.1Hz, 1H ), 4.38 (td, J=10.5, 2.6Hz, 1H), 4.33 (d, J=10.2Hz, 1H), 4.26-4.21 (m, 2H), 4.16 (d, J=16.7Hz, 1H), 3.81 (s, 1H), 3.72-3.64 (m, 2 H), 3.62 (d, J=10.2Hz, 1H), 3.55 (d, J=11.7Hz, 1H), 3.31 (d, J=9.6Hz, 1H), 2.54-2.40 (m, 2H), 2.34 (qd, J=13.1, 3.3Hz, 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).

[0600]

[0601] Intermediate 28

[0602]

[0603] 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

[0604] The chloro-2-fluoro-acetyl chloride (64 mg, 0.489 mmol) of 2- in DCM (4.7 mL) was added to a stirred solution of intermediate 6 (91%, 250 mg, 0.446 mmol) and N-ethyl-N-(propyl-2-yl)propan-2-amine (0.30 mL, 1.71 mmol) in DCM (4.7 mL) at 0 ° C. The mixture was quenched with water (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layer was passed through a phase separator and concentrated in vacuo to give crude material. The crude material was purified by column chromatography (0-60% EtOAc / heptane) to give the corresponding amide intermediate. The residue was dissolved in anhydrous THF (2.6 mL) and sodium hydride (60%, 91 mg, 2.28 mmol) was slowly added at 0 ° C. The mixture was stirred for 30 min at this temperature and then heated at 50 ° C for 2 h. The reaction mixture was quenched with water (5 ml) and extracted with DCM (2 x 5 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated to give the title compound as a colorless oil (225 mg). [M+H] + m / z 569.4

[0605] Intermediate 29

[0606]

[0607] 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

[0608] Intermediate 28 (99%, 400 mg, 0.696 mmol) was dissolved in ethanol (33 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%) (5.0%, 592 mg, 0.278 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 16 hours, then filtered through celite, washed with EtOAc, and concentrated in vacuo to give the title compound (300 mg) as a colorless oil. [M+H] + m / z 479.3

[0609] Intermediate 30

[0610]

[0611] Tert-butyl-rel-(1R,5S)-8-fluoro-7-oxo-1-({[(1s,4s)-4-(2-{[3-(tert-butoxy)-3-oxo-1-en-1-yl]oxy}phenyl)cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0612] 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 THF (2.6 mL) containing intermediate 29 (90%, 300 mg, 0.564 mmol) at 0 ° C under nitrogen and the solution was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2×5 mL). The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography (0-80% EtOAc / heptane) to give the title compound (215 mg) as a colorless oil. [M+H] + m / z 605.5

[0613] Intermediate 31

[0614]

[0615] Tert-butyl-rel-(1R,5S)-8-fluoro-7-oxo-1-({[(1s,4s)-4-{2-[3-(tert-butyloxy)-3-oxopropoxy]phenyl}cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0616] Intermediate 30 (91%, 215 mg, 0.324 mmol) was dissolved in ethanol (61 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 69 mg, 0.0647 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 5 hours, 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

[0617] Intermediate 32

[0618]

[0619] 3-{2-[(1s,4s)-4-{[rel-(1R,5S)-8-fluoro-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methoxy}cyclohexyl]phenoxy}propanoic acid

[0620] 4M hydrochloric acid 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 was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo to give the title compound (130 mg) as a white solid. [M+H] + m / z 451.3

[0621] Example 8

[0622]

[0623] 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

[0624] To a stirred solution of HATU (162 mg, 0.426 mmol) and DIPEA (147 μL, 0.843 mmol) in acetonitrile (72 mL) was added acetonitrile (6.2 mL) containing intermediate 32 (99%, 130 mg, 0.286 mmol) using a syringe pump over 2 h. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give the crude material. The mixture was diluted in water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO ), filtered and concentrated to give a solid residue. The crude material was purified by basic reverse phase column chromatography (10-65% acetonitrile / water (0.1% ammonia)) to give the title compound (57 mg) as a yellow solid.

[0625] LCMS (Method A): [M+H] + m / z 433.3, RT 3.14 and 3.22 min.

[0626] 1H NMR (500MHz, CDCl3) δ7.12-7.05 (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. 1Hz, 1H), 4.44-4.40 (m, 1H), 4.41-4.34 (m, 1H), 4.33 (dd, J=9.4, 2.9Hz, 1H), 4.19-4.10 (m, 1H), 3.96 (d, J=11.8Hz, 1H), 3.77-3.70 (m , 2H), 3.53-3.43 (m, 1H), 3.15 (d, J=9.5Hz, 1H), 3.01 (dd, J=11.3, 7.0Hz, 1H), 2.39-2.33 (m, 2H), 2.33-2.25 (m, 1H), 2.18 (td, J=12.7 , 3.7Hz, 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=14.1Hz, 3H).

[0627] Example 9

[0628]

[0629] 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′-trien-11′-one

[0630] To a stirred solution of HATU (481 mg, 1.27 mmol) and DIPEA (442 μL, 2.53 mmol) in acetonitrile (58 mL) was added DMF (5.8 mL) containing intermediate 37 (415 mg) using a syringe pump over 2 h. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give the crude material. The mixture was diluted in water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO ), filtered and concentrated to give a solid residue. The crude material was purified by basic reverse phase column chromatography (20-60% acetonitrile / water (0.1% ammonia)) to give the title compound (136 mg) as a yellow solid.

[0631] LCMS (Method A): [M+H] +m / z 401.4, RT 3.17 min

[0632] 1 H NMR (500MHz, CDCl3) δ7.21-7.09 (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=11.2Hz, 1H), 3.32 (d, J=9.4Hz, 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).

[0633]

[0634] Intermediate 38

[0635]

[0636] 1-tert-Butyl 3-ethyl 5-({[4-(benzyloxy)cyclohexyl]oxy}methyl).4-oxopyrrolidine-1,3-dicarboxylate

[0637] To a solution of 4-benzyloxycyclohexanol (23.50 g, 0.114 mol) in anhydrous DCM (134 mL) was added paraformaldehyde (3.40 g, 0.113 mol) followed by chloro(trimethyl)silane (20 mL, 0.155 mol). The reaction was stirred at room temperature for 2.5 h. The reaction was concentrated in vacuo at 30 ° C to give the chloro intermediate as a pale yellow oil. In a separate flask, 2.4 M butyllithium in THF (87 mL, 0.209 mol) was added to a stirred solution of N-(propyl-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, freshly prepared LDA was added 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) via an addition funnel at -78°C over 0.5 h. The reaction temperature did not rise 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 another funnel over 20 min. The reaction mixture was stirred at -78°C for 2 h. The reaction was quenched with saturated aqueous NH4Cl. The crude mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 300 mL). The combined organic extracts were dried over MgSO 4 , filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-20% EtOAc / heptane) and yielded the title compound (4.00 g) as a yellow oil. [M+Na] + :m / z 498.3

[0638] Intermediate 39

[0639]

[0640] tert-Butyl 2-({[4-(Benzyloxy)cyclohexyl]oxy}methyl)-3-oxopyrrolidine-1-carboxylate

[0641] To a stirred solution of intermediate 38 (13.50 g) in DMSO (131 mL) was added sodium chloride (3.10 g, 53.0 mmol) and water (13 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 extracts were washed with water (2 × 50 mL) and brine (50 mL), dried over sodium sulfate, filtered and evaporated to dryness to give a crude material. The crude material was purified by column chromatography (0-100% EtOAc / heptane) to give the title compound (13.5 g) as a yellow oil. [M+Na] + m / z 426.3

[0642] Intermediate 40

[0643]

[0644] tert-Butyl 2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(hydroxyimino)pyrrolidine-1-carboxylate

[0645] 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 to 90°C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 75 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give the title compound (8.6 g) as a yellow oil. [M+Na] + m / z 441.3

[0646] Intermediate 41

[0647]

[0648] tert-Butyl 2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-nitropyrrolidine-1-carboxylate

[0649] 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 h. The resulting solution was added dropwise to a mixture of intermediate 40 (8.60 g) and sodium bicarbonate (8.6 g, 0.103 mol) in acetonitrile (37 mL) at 80°C for 1 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous Na2SO3 (50 mL) and stirred for 10 min, 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 (0-70% EtOAc / heptane) to give the title compound (4.80 g) as a light yellow oil. [M+H] + m / z 435.3

[0650] Intermediate 42

[0651]

[0652] tert-Butyl-rel-(2R,3S)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(hydroxymethyl)-3-nitropyrrolidine-1-carboxylate

[0653] 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 and maintained 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 / heptane) to give the title compound (4.0 g) as a colorless oil. [M+H] + m / z 465.5

[0654] Intermediate 43

[0655]

[0656] tert-Butyl-rel-(2R,3S)-3-amino-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(hydroxymethyl)pyrrolidine-1-carboxylate

[0657] 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 aqueous NaHCO3 and extracted with DCM (3×75 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (3.63 g) as a colorless oil. [M+H] + m / z 435.3.

[0658] Intermediate 44

[0659]

[0660] Tert-butyl-rel-(1R,5S)-1-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0661] To a solution of intermediate 43 (3.63 g) in THF (36 mL) was added dipotassium carbonate (3.46 g, 25.0 mmol) at 0 ° C, followed by water (36 mL). Chloroacetyl chloride (0.93 mL, 11.7 mmol) was added dropwise to this mixture at 0 ° C. The reaction was stirred at 0 ° C for 1 h. The mixture was quenched with water and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO ), filtered and concentrated to give an oily residue. This intermediate was dissolved in DCM (75 mL) and IPA (117 mL), cooled to 0 ° C, and potassium 2-methylpropan-2-olate (3.75 g, 33.4 mmol) was added and the reaction was stirred at 0 ° C for 1 h. The reaction was quenched by adding water (20 mL). The mixture was poured onto a saturated NaHCO aqueous solution (30 ml). After extraction with DCM (3 x 50 mL), the combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered and concentrated to give the title compound as a yellow oil (3.72 g). [M+H]+ m / z 475.4.

[0662] Intermediate 45

[0663]

[0664] Tert-butyl-rel-(1R,5S)-1-{[(4-hydroxycyclohexyl)oxy]methyl}-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0665] Intermediate 44 (2.43 g) was dissolved in ethanol (95 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (5.0%, 1013 mg, 0.476 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction 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

[0666] Intermediate 46

[0667]

[0668] Tert-butyl-rel-(1R,5S)-7-oxo-1-{[(4-oxocyclohexyl)oxy]methyl}-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0669] To a solution of intermediate 45 (1.90 g) in DCM (10 mL) was added Dess-Martin periodinane (2.73 g, 6.43 mmol) portionwise at 0°C. The mixture was stirred at room temperature for 40 minutes, quenched by the addition of a saturated aqueous solution of Na2S2O3 (10 mL) and NaHCO3 (10 mL), and extracted with DCM (3 x 10 mL). The crude material was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (1 g) as a white solid. [M+H]+ m / z: 383.3

[0670] Intermediate 47

[0671]

[0672] 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

[0673] To a stirred solution of intermediate 46 (1.00 g) in ethanol (20 mL) was added 4-methylbenzenesulfonyl hydrazide (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 ), filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (1.1 g) as a white solid. [M+H] + m / z 551.4

[0674] Intermediate 48

[0675]

[0676] 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

[0677] A solution of intermediate 47 (600 mg), (1E, 4E) -1,5-diphenylpenta-1,4-diene-3-one-palladium (50 mg, 0.0545 mmol), dicyclohexyl [2 ', 4 ', 6 '-tri (propan-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-fluoro-benzene (368 mg, 1.31 mmol) in anhydrous 1,4-dioxane (10 mL) was heated to 110 ° C under a nitrogen atmosphere for 18 hours. The mixture was cooled to room temperature and filtered through celite, 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 / heptane) to give the title compound (452 ​​mg) as an off-white solid. [M+H] + m / z 567.4

[0678] Intermediate 49

[0679]

[0680] Tert-butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-(2-fluoro-6-hydroxyphenyl)-cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0681] Intermediate 48 (450 mg) was dissolved in ethanol (20 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 169 mg, 0.159 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 18 hours, 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 / z 479.3

[0682] Intermediate 50

[0683]

[0684] 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

[0685] To 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 THF (3 mL) containing intermediate 49 (330 mg) at 0°C under nitrogen and the solution was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give a crude material. The crude material was purified by column chromatography (0-100% EtOAc / heptane) to give the title compound (352 mg) as a colorless gum. [M+H] + m / z 605.4.

[0686] Intermediate 51

[0687]

[0688] Tert-butyl-rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-{2-[3-(tert-butyloxy)-3-oxopropoxy]-6-fluorophenyl}cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate

[0689] Intermediate 50 (350 mg) was dissolved in ethanol (15 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 123 mg, 0.12 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 5 hours, then filtered through celite, washed with EtOAc and the filtrate was concentrated under vacuum to give the title compound (303 mg) as a colorless gum. [M+H] + m / z 607.4

[0690] Intermediate 52

[0691]

[0692] Rel-(1R,5S)-7-oxo-1-({[(1s,4s)-4-[2-(2-carboxyethoxy)-6-fluorophenyl]cyclohexyl]oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]dec-2-ium chloride

[0693] 4M hydrochloric acid in dioxane (3.5 mL, 14.0 mmol) was added to Intermediate 51 (300 mg) at room temperature and the reaction was stirred for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (254 mg). [M+H] + m / z 451.3

[0694] Example 10

[0695]

[0696] 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

[0697] To a stirred solution of HATU (281 mg, 0.739 mmol) and DIPEA (430 μL, 2.46 mmol) in acetonitrile (85 mL) was added dropwise anhydrous DMF (6 mL) containing intermediate 52 (240 mg) at room temperature under nitrogen for 2 h. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give a crude material. The crude material was diluted in water and extracted with DCM (3 × 20 mL). The combined organic extracts were dried (MgSO ), filtered and concentrated to give a solid residue. The crude material was purified by basic reverse phase column chromatography (20-50% acetonitrile / water (0.1% ammonia)) to give the title compound (99 mg) as a white solid.

[0698] LCMS (Method B): [M+H] + m / z 433.3, RT 2.80 min

[0699] 1H NMR (500MHz, CDCl3) δ7.11-7.03 (m, 1H), 6.76 (d, J=8.3Hz, 1H), 6.71-6.65 (m, 1H), 6.29 (s, 1H), 4.44 (dd, J=9.6, 3 .1Hz, 1H), 4.42-4.37(m, 1H), 4.29-4.14(m, 4H), 3.95(td, J=9.9, 3.6Hz, 1H), 3.86-3.81(m, 1H), 3.77(d, J=11.7Hz , 1H), 3.60-3.53 (m, 2H), 3.28 (dd, J=9.5, 0.9Hz, 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, 3.1Hz, 1H), 1.64-1.60 (m, 1H), 1.46-1.33 (m, 2H), 1.32-1.23 (m, 1H).

[0700] Examples 10a and 10b

[0701]

[0702] 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

[0703] 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

[0704] Example 10 (95 mg, 0.220 mmol) was purified chirally using a Chiralcel OD-H, 20 x 250 mm, 5 μm column eluting with 85:15 heptane:ethanol to afford the title compounds (peak 1, 35 mg, 100% ee; and peak 2, 30 mg, 100% ee).

[0705] Example 10a: Peak 1 (stereochemistry tentatively assigned by pyrrolidine)

[0706] LCMS (Method B): [M+H] + m / z 433.3, RT 2.80 min

[0707] Chiral analysis (Chiralcel OD-H, 4.6 × 250 mm, 5 μm, 85:15 hexane:ethanol:RT 14.0 min

[0708] 1 H NMR (500MHz, CDCl3) δ7.10-7.04 (m, 1H), 6.76 (d, J=8.4Hz, 1H), 6.71-6.65 (m, 1H), 6.30 (s, 1H), 4.44 (dd, J=9.6, 3 .1Hz, 1H), 4.42-4.37(m, 1H), 4.30-4.15(m, 4H), 3.95(td, J=9.9, 3.6Hz, 1H), 3.85-3.81(m, 1H), 3.77(d, J=11.6Hz , 1H), 3.61-3.53 (m, 2H), 3.28 (dd, J=9.5, 0.9Hz, 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, 3.1Hz, 1H), 1.64-1.60 (m, 1H), 1.45-1.33 (m, 2H), 1.31-1.25 (m, 1H).

[0709] Example 10b: Peak 2 (stereochemistry tentatively assigned by pyrrolidine)

[0710] LCMS (Method B): [M+H] + m / z 433.3, RT 2.79 min

[0711] Chiral analysis (Chiralcel OD-H, 4.6 × 250 mm, 5 μm, 85:15 hexane:ethanol: RT 22.4 min)

[0712] 1H NMR (500MHz, CDCl3) δ7.11-7.03 (m, 1H), 6.76 (d, J = 8.3Hz, 1H), 6.72-6.64 (m, 1H), 6.32 (s, 1H), 4.44 (dd, J = 9.6, 3 .2Hz, 1H), 4.42-4.37(m, 1H), 4.28-4.15(m, 4H), 3.95(td, J=9.9, 3.6Hz, 1H), 3.84-3.81(m, 1H), 3.77(d, J=11.6Hz , 1H), 3.61-3.53 (m, 2H), 3.28 (dd, J=9.5, 0.9Hz, 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, 3.1Hz, 1H), 1.59-1.54 (m, 1H), 1.44-1.33 (m, 2H), 1.31-1.26 (m, 1H).

[0713]

[0714] Intermediate 53

[0715]

[0716] 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

[0717] A solution of intermediate 47 (561 mg), (1{E},4{E})-1,5-diphenylpenta-1,4-dien-3-one: palladium (47 mg, 0.0509 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]-phosphine (49 mg, 0.102 mmol), lithium tert-butoxide (0.23 mL, 2.55 mmol) and 2-benzyloxy-1-bromo-3,5-difluoro-benzene (274 mg, 0.917 mmol) in anhydrous 1,4-dioxane (6 mL) was heated to 110° C. under a nitrogen atmosphere for 4 hours. The mixture was cooled to room temperature and filtered through celite, washing 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 ) and concentrated in vacuo to afford the crude material. The crude material was purified by flash column chromatography (0-100% EtOAc / heptane) to afford the title compound (250 mg) as a yellow oil [M+H] + m / z: 585.3

[0718] Intermediate 54

[0719]

[0720] 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

[0721] Intermediate 53 (300 mg) was dissolved in ethanol (10 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 33 mg, 0.0313 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 6 hours, then filtered through celite, washed with EtOAc and the filtrate was concentrated in vacuo to give the title compound (278 mg) as an orange oil. [M+H] + m / z 495.3.

[0722] Intermediate 55

[0723]

[0724] 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

[0725] 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) at 0 ° C under nitrogen was added THF (2 mL) containing intermediate 54 (278 mg) and the solution was stirred at room temperature for 16 hours. Additional THF (2 mL) containing tert-butyl prop-2-ynoate (63 mg, 0.496 mmol) and 1,4-diazabicyclo [2.2.2] octane (18 mg, 0.164 mmol) was 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 phase was washed with brine, dried over MgSO4 and concentrated in vacuo to give crude material. The crude material was purified by flash column chromatography (0-100% EtOAc / heptane) to give the title compound as a yellow solid (206 mg) [M+H] + :m / z 621.3

[0726] Intermediate 56

[0727]

[0728] 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

[0729] Intermediate 55 (205 mg) was dissolved in ethanol (5 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 61 mg, 0.0576 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction 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

[0730] Intermediate 57

[0731]

[0732] 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]dec-2-ium chloride

[0733] 4M hydrochloric acid (2.7 mL, 11.0 mmol) was added to intermediate 56 (136 mg) at room temperature and the reaction 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

[0734] Intermediate 58

[0735]

[0736] 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

[0737] To a stirred solution of HATU (136 mg, 0.359 mmol) and DIPEA (168 μL, 0.960 mmol) in acetonitrile (60 mL) was added anhydrous DMF (5 mL) containing intermediate 57 (112 mg) using a syringe pump over 2 h. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give a crude material. The crude material was diluted in water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO ), filtered and concentrated to give a solid residue. The crude material was purified by basic reverse phase column chromatography (10-100% acetonitrile / water (0.1% ammonia)) to give the title compound (60 mg) [M+H] as a yellow solid. + m / z 449.5

[0738] Example 11

[0739]

[0740] 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

[0741] Intermediate 58 (60 mg) is dissolved in ethanol (2.75 mL) and vacuumed and backfilled 3 times with nitrogen. Palladium / carbon (10%, 5.5 mg, 5.17 μmol) is added and vacuumed and backfilled 3 times with hydrogen. The reactant is stirred for 16 hours, then filtered through diatomaceous earth, washed with EtOAc and the filtrate is concentrated in vacuo to give a crude material. The crude material is purified by basic reverse phase column chromatography (10-45% acetonitrile / water (0.1% ammonia)) to give the title compound (3 mg) as a white solid.

[0742] LCMS (Method A): [M+H] + m / z 451.3, RT 3.13 min

[0743] 1 H NMR (500MHz, DMSO) δ8.15 (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).

[0744] Examples 12a and 12b

[0745]

[0746] 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 , 15 ]docosane]-2′(7′),3′,5′-triene-5,10′-dione

[0747] 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

[0748] The above Examples 12a and 12b were prepared according to similar procedures described for Example 3. The crude material was purified by acidic reverse phase column chromatography (20-40% acetonitrile / water (0.1% formic acid)) to give the title compound Example 12a (11 mg) as an orange solid and Example 12b (16 mg) as a yellow solid.

[0749] Example 12a: LCMS (Method B): [M+H] + m / z 415.3, RT = 2.76 min

[0750] 1 H NMR (500MHz, CDCl3) δ7.47 (s, 1H), 7.17 (t, J=7.7Hz, 1H), 7.08 (d, J=7.3Hz, 1H), 6 .89(t, J=7.4Hz, 1H), 6.77(s, 1H), 4.98(d, J=8.4Hz, 1H), 4.44-4.11(m, 6H), 3.88( s, 1H), 3.71-3.62 (m, 2H), 3.23 (d, J=9.0Hz, 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).

[0751] Example 12b: LCMS (Method B): [M+H] + m / z 415.3, RT = 2.99 min

[0752] 1H NMR (500MHz, CDCl3) δ7.21-7.14 (m, 1H), 7.09 (d, J=7.4Hz, 1H), 6.91 (t, J=7.4Hz, 1H), 6.77 (d, J=8.0Hz, 1H), 6 .17 (s, 1H), 5.09 (d, J = 10.5Hz, 1H), 4.70 (dt, J = 13.5, 6.6Hz, 1H), 4.55 (s, 1H), 4.35-4.22 (m, 3H), 4.13 (d, J = 1 6.7Hz, 1H), 4.04 (d, J=11.5Hz, 1H), 3.84 (s, 1H), 3.61 (d, J=11.6Hz, 1H), 3.24 (d, J=9.8Hz, 1H), 2.64 (dd, J=12 .9, 9.9Hz, 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).

[0753] Example 13

[0754]

[0755] 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

[0756] Example 13 was prepared according to the similar procedure described for Example 1 using known starting material (2R)-1-tert-butyl 3-ethyl 2-methyl-4-oxopyrrolidine-1,3-dicarboxylate to give the title compound as an off-white solid (38 mg).

[0757] LCMS (Method A): [M+H] + m / z 429.3, RT 3.08 and 3.17 min

[0758] 1H NMR (500MHz, CDCl3) δ7.18-7.10(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).

[0759] Examples 13a and 13b

[0760]

[0761] 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

[0762] 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

[0763] Example 13 (35 mg) was subjected to chiral preparative purification using a 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 compounds (peak 1, 11.8 mg, 100% ee; and peak 2, 6.4 mg, 100% ee).

[0764] Example 13a: Peak 1 (stereochemistry arbitrarily assigned to pyrrolidine); 1H NMR (500MHz, CDCl3) δ7.19-7.12 (m, 1H), 7.06 (ddd, J=14.5, 7.4, 1.5Hz, 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), 3.96-3.3 4(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).

[0765] LCMS (Method C): [M+H] + m / z 429.3, RT 0.97 min.

[0766] Chiral analysis (Chiralpak OD-H, 25×0.46 cm, 5 μm, 70:30 hexane:(ethanol+0.1% isopropylamine)): RT 6.6 min

[0767] Example 13b: Peak 2 (stereochemistry arbitrarily assigned to pyrrolidine); 1 H NMR (500MHz, CDC13) δ7.19-7.12 (m, 1H), 7.10-7.04 (m, 1H), 6.95 (d, J=8.1Hz, 1H), 6.86 (t, J=7.3Hz, 1H), 6.03 (s, 1H), 4.56 (dd, J =9.6, 2.6Hz, 1H), 4.45 (d, J = 1.6Hz, 1H), 4.41-4.29 (m, 3H), 4.29-4.20 (m, 1H), 4.18-4.08 (m, 1H), 4.02 (d, J = 11.5Hz, 1H), 3.84 (br s, 1H), 3.60 (d, J=11.5Hz, 1H), 3.19 (d, J=9.5Hz, 1H), 3.09 (ddd, J=15.0, 11.4, 4.0Hz, 1H), 2.61 (dd, J=12.9, 9.7Hz, 1H), 2.52-2.34 (m, 3H), 2.22-2.04 (m, 2H), 1.85 (d, J=13.0Hz, 1H), 1.79 (br d, J=13.3Hz, 1H), 1.57-1.40 (m, 2H), 1.38-1.24 (m, 5H).

[0768] LCMS (Method C): [M+H] +m / z 429.2, RT 0.99 min.

[0769] Chiral analysis (Chiralpak OD-H, 25×0.46 cm, 5 μm, 70:30 hexane:(ethanol+0.1% isopropylamine)): RT 9.5 min

[0770] Example 14

[0771]

[0772] 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 ]Tetracosane]-2′(7′),3′,5′-triene-5,12′-dione

[0773] Example 14 was prepared using known starting material, (2R)-1-tert-butyl 3-ethyl 2-methyl-4-oxopyrrolidine-1,3-dicarboxylate and according to similar procedures described for Example 2 to give the title compound as a yellow solid (15 mg).

[0774] 1 H NMR (500MHz, CDCl3) δ7.18-7.12 (m, 1H), 7.07 (dd, J=7.4, 1.9Hz, 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).

[0775] LCMS (Method B): [M+H] + m / z 443.3, RT 3.05 min.

[0776]

[0777] Intermediate 59

[0778]

[0779] (3R)-3-Methyl-1-[({4-[(4-methylbenzenesulfonamido)imino]cyclohexyl}oxy)-methyl]-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester

[0780] Intermediate 59 was prepared according to a similar procedure as described for Intermediate 47 using known starting material, 1-tert-butyl 3-ethyl (2R)-2-methyl-4-oxopyrrolidine-1,3-dicarboxylate to give the title compound as a white solid (6.80 g). [M+H] + m / z 565.3.

[0781] Intermediate 60

[0782]

[0783] 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

[0784] A solution of Intermediate 59 (2.85 g), 2-benzyloxy-1-bromo-3-fluoro-benzene (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) was degassed for 10 minutes and then heated to 110° C. under nitrogen for 21 hours. The mixture was cooled to room temperature and filtered through celite, washing with ethyl acetate. The filtrate was concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give the title compound (2.32 g) as an orange oil. [M+Na] + m / z 603.3

[0785] Intermediate 61

[0786]

[0787] 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

[0788] Intermediate 60 (2.32 g) was dissolved in ethanol (78 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 850 mg, 0.799 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction 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 light yellow gum. [M+H] m / z 491.4.

[0789] Intermediate 62

[0790]

[0791] 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

[0792] 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 dipotassium carbonate (676 mg, 4.89 mmol) and the solution was heated to 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.

[0793] Intermediate 63

[0794]

[0795] (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]dec-2-ium chloride

[0796] 4M hydrochloric acid in dioxane (11 mL, 42.3 mmol) was added to intermediate 62 (1.28 g) at room temperature and the reaction was stirred for 2 hours. 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.

[0797] Intermediate 64

[0798]

[0799] (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

[0800] 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 DMF (10 mL) containing intermediate 63 (1.31 g) using a syringe pump over 2 h. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give a crude material. The crude material was diluted in 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 (10-50% acetonitrile / water (0.1% ammonia)) to give the title compound (350 mg) as a yellow oil. [M+H] + m / z 431.3.

[0801] Examples 15a and 15b

[0802]

[0803] 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

[0804] 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

[0805] Intermediate 64 (300mg) is dissolved in ethanol (24mL) and is vacuumed and backfilled 3 times with nitrogen.Add palladium / carbon (10%, 345mg, 0.324mmol) and be vacuumed and backfilled 3 times with hydrogen.The reactant is stirred 24 hours, then filtered through diatomite, washed with EtOAc and the filtrate is concentrated in vacuo to obtain a crude mixture.The crude material is purified by basic reverse phase column chromatography (15-50% acetonitrile / water (0.1% ammonia)) to obtain the title compound (peak 1,53mg) and the title compound (peak 2,30mg) as a white solid.

[0806] Example 15a: Peak 1

[0807] LCMS (Method A): [M+H] + m / z 433.3, RT 2.99 min

[0808] 1 H NMR (500MHz, CDCl3) δ7.42 (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=9.4Hz, 1H), 2.87-2 .71 (m, 1H), 2.66-2.50 (m, 1H), 2.35 (dd, J=13.4, 8.3Hz, 1H), 2.24-2.12 (m, 2H), 2.07-2.0 1 (m, 1H), 1.99-1.94 (m, 1H), 1.68 (d, J=6.9Hz, 3H), 1.50-1.37 (m, 3H), 1.37-1.29 (m, 1H).

[0809] Example 15b: Peak 2

[0810] LCMS (Method A): [M+H] + m / z 433.3, RT 3.29 min

[0811] 1H NMR (500MHz, CDCl3) δ7.01-6.82 (m, 3H), 6.22 (s, 1H), 5.36 (dd, J=12.7, 3.7Hz, 1H), 4.87 (ddt, J=12.3, 7.7, 3.8Hz, 1H) , 4.53 (d, J = 2.4Hz, 1H), 4.32 (dd, J = 9.9, 2.8Hz, 1H), 4.26 (d, J = 16.7Hz, 1H), 4.22 (dd, J = 12.7, 2.3Hz, 1H), 4.14 (d, J = 16 .7Hz, 1H), 4.02 (d, J=11.6Hz, 1H), 3.84 (s, 1H), 3.62 (d, J=11.6Hz, 1H), 3.25 (dd, J=9.8, 1.1Hz, 1H), 2.66-2.39 (m, 3H), 2.15 (d, J=14.7Hz, 1H), 1.92-1.72 (m, 3H), 1.49 (d, J=12.3Hz, 3H), 1.43 (d, J=6.6Hz, 3H), 1.34 (td, J=14.2, 3.9Hz, 1H).

[0812] The following examples were prepared according to similar procedures described for Examples 15a and 15b using appropriate reagents followed by purification.

[0813]

[0814]

[0815]

[0816] Intermediate 65

[0817]

[0818] 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

[0819] Intermediate 65 was prepared according to a similar procedure as described for Intermediate 60 using Intermediate 59 and known starting material 1-(benzyloxy)-2-bromo-3-fluorobenzene to give the title compound as a yellow oil (2.75 g). [M+H] + m / z 581.6.

[0820] Intermediate 66

[0821]

[0822] 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

[0823] Intermediate 65 (330 mg) was dissolved in ethanol (11.095 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 242 mg, 0.227 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction 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.

[0824] Intermediate 67

[0825]

[0826] 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

[0827] 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 dipotassium carbonate (145 mg, 1.05 mmol) and the solution was heated to 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.

[0828] Intermediate 68

[0829]

[0830] (3R)-3-Methyl-7-oxo-1-({[(1s,4s)-4-[2-(carboxymethoxy)-6-fluorophenyl]cyclohexyl]-oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]dec-2-ium chloride

[0831] 4M hydrochloric acid in dioxane (1.6 mL, 6.59 mmol) was added to intermediate 67 (250 mg) at room temperature and the reaction 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

[0832] Examples 17a and 17b

[0833]

[0834] 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

[0835] 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

[0836] 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 DMF (2.4 mL) containing intermediate 68 (250 mg) using a syringe pump over 2 h. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give a crude material. The mixture was diluted in water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO ), filtered and concentrated to give a solid residue. The crude material was purified by basic reverse phase column chromatography (15-45% acetonitrile / water (0.1% ammonia)) to give the title compound (peak 1, 8.6 mg) as a white solid and the title compound (peak 2, 11.3 mg) as a white solid.

[0837] Example 17a: Peak 1

[0838] LCMS (Method A): [M+H] + m / z 433.3, RT 3.03min

[0839] 1H NMR (500MHz, CDCl3) δ7.47 (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).

[0840] Example 17b: Peak 2

[0841] LCMS (Method A): [M+H] + m / z 433.3, RT 3.23min

[0842] 1 H NMR (500MHz, CDCl3) δ7.17-7.02 (m, 1H), 6.71 (t, J=8.8Hz, 1H), 6.55 (d, J=8.1Hz, 1H), 6.28 (s, 1H), 5.06 ( d, J=10.3Hz, 1H), 4.73-4.60 (m, 1H), 4.55 (s, 1H), 4.39-4.21 (m, 3H), 4.13 (d, J=16.8Hz, 1H), 4.03 (d, J=1 1.5Hz, 1H), 3.91-3.74 (m, 1H), 3.60 (d, J=11.6Hz, 1H), 3.24 (d, J=9.8Hz, 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).

[0843] The following examples were prepared according to similar procedures as described for Examples 17a and 17b using appropriate reagents.

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851] Intermediate 69

[0852]

[0853] tert-Butyl (3R)-1-({[4-(2-{[(1E)-3-(tert-Butoxy)-3-oxo-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

[0854] 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 THF (11 mL) containing intermediate 61 (1.30 g) at 0°C under nitrogen and the solution was stirred at room temperature for 5 hours. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 × 25 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give a crude material. The crude material was purified by silica gel column chromatography (0-80% EtOAc / heptane) to give the title compound (1.48 g) as a yellow oil. [M+H] + m / z 617.5.

[0855] Intermediate 70

[0856]

[0857] 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

[0858] Intermediate 69 (1.48 g) was dissolved in ethanol (40 mL) and vacuumed and backfilled with nitrogen three times. Palladium on carbon (10%, 255 mg, 0.240 mmol) was added and vacuumed and backfilled with hydrogen three times. The reactant was stirred for 16 hours, then filtered through celite, washed with EtOAc and the filtrate was concentrated in vacuo to give a crude material. The crude material was purified by silica gel column chromatography (0-80% EtOAc / heptane) to give the title compound (1.2 g) as a colorless oil. [M+H] +m / z 621.5.

[0859] Intermediate 71

[0860]

[0861] (3R)-3-Methyl-7-oxo-1-({[(1s,4s)-4-[2-(2-carbonylethoxy)-3-fluorophenyl]cyclohexyl]-oxy}methyl)-9-oxa-2,6-diazaspiro[4.5]dec-2-ium chloride

[0862] 4M hydrochloric acid 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 give the title compound (1.0 g) as an orange solid. [M+H] + m / z 463.4.

[0863] Examples 24a and 24b

[0864]

[0865] 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

[0866] 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

[0867] To a stirred solution of HATU (908 mg, 2.39 mmol) and DIPEA (822 μL, 4.70 mmol) in acetonitrile (110 mL) was added DMF (11 mL) containing intermediate 71 (0.74 g) using a syringe pump over 2 h. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give a crude material. The crude material was diluted in water and extracted with DCM (3 × 5 mL). The combined organic extracts were dried (MgSO ), filtered and concentrated in vacuo to give a solid residue. The crude material was purified by basic reverse phase column chromatography (15-45% acetonitrile / water (0.1% ammonia)) to give the title compound (245 mg) as a yellow solid in the form of a mixture of diastereomers. The mixture of diastereomers (245 mg) was subjected to achiral preparative purification (X-Bridge (100×30 mm), 5 μm, flow rate 40 mL / min) eluting with 5-95% acetonitrile / water (0.2% ammonia) to give the title compound (peak 1, 43 mg) as a white solid and the title compound (peak 2, 26 mg) as a white solid.

[0868] Example 24a: Peak 1

[0869] LCMS (Method A): [M+H] + m / z 447.3, RT 3.15min

[0870] 1 H NMR (500MHz, CDCl3) δ7.46 (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=6.9Hz, 2H), 1.50-1.41 (m, 2H), 1.38 (d, J=6.3Hz, 1H), 1.34-1.28 (m, 1H).

[0871] Example 24b: Peak 2

[0872] LCMS (Method A): [M+H] + m / z 447.3, RT 3.27 min

[0873] 1H NMR (500MHz, CDCl3) δ6.97-6.88 (m, 2H), 6.88-6.83 (m, 1H), 6.14 (s, 1H), 4.63 (dd, J=9.7, 2.4Hz, 1H), 4.56 (ddd, J=8.8, 4.9, 2.5Hz, 1H), 4. 46 (dq, J=9.4, 6.6Hz, 1H), 4.39 (d, J=1.9Hz, 1H), 4.28-4.19 (m, 2H), 4.12 (d, J=16.7Hz, 1H), 4.06-3.98 (m, 1H), 3.79 (s, 1H), 3.62 (d, J=11. 6Hz, 1H), 3.21 (ddd, J=13.9, 11.0, 2.6Hz, 1H), 3.15 (dd, J=9.7, 1.5Hz, 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=12.9Hz, 1H), 1.82-1.76 (m, 1H), 1.54-1.45 (m, 2H), 1.40 (d, J=6.6Hz, 3H), 1.37 (d, J=2.4Hz, 1H), 1.35-1.27 (m, 1H).

[0874] The following examples were prepared according to similar procedures as described for Examples 24a and 24b using appropriate reagents.

[0875]

[0876]

[0877] Intermediate 72

[0878]

[0879] (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-5-methyl-3-oxopyrrolidine-1-carboxylic acid benzyl ester

[0880] To a mixture of (2R)-2-methyl-4-oxo-pyrrolidine-1-carboxylic acid benzyl ester (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 at reflux using a Dean-Stark apparatus for 3 h, then concentrated under reduced pressure. The residue was co-evaporated twice with anhydrous MeCN (2 x 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 the mixture was heated to reflux for 2 h. 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 , filtered and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel column chromatography (5-25% EtOAc / cyclohexane) to give the title compound (71 g) as an orange oil. [M+H] + m / z 420.3, 422.3

[0881] Intermediate 73

[0882]

[0883] Benzyl (3E,5R)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxyimino)-5-methylpyrrolidine-1-carboxylate

[0884] 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 hours. 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 , filtered and concentrated under reduced pressure to give the title compound (79 g) as a yellow oil. [M+H] + m / z 435.3, 437.3

[0885] Intermediate 74

[0886]

[0887] (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-5-methyl-3-nitropyrrolidine-1-carboxylic acid benzyl ester

[0888] A solution of trifluoroacetic anhydride (54.7 mL, 393.35 mmol) was added 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 bicarbonate (70.55 g, 829.9 mmol) in anhydrous acetonitrile (280 mL) at 80°C for 1 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous Na2SO3 solution (200 mL) and stirred for 10 min, then extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography (5-30% EtOAc / cyclohexane) to give the title compound (73.6 g) as a yellow oil. [M+H] + m / z 451.3,453.3.

[0889] Intermediate 75

[0890]

[0891] (5R)-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-5-methyl-3-nitropyrrolidine-1-carboxylic acid benzyl ester

[0892] Formaldehyde (37% in water, 73.0 mL, 980.4 mmol) was added to THF (280 mL) containing intermediate 74 (73.6 g) and triethylamine (25 mL, 179.37 mmol) at room temperature. The solution was heated to 70 ° C for 3 h. 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 aqueous NH4Cl solution (300 mL), water (200 mL) and brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (44 g) as a yellow oil. [M+H] + m / z 481.3.483.3

[0893] Intermediate 76

[0894]

[0895] (5R)-3-Amino-2-[(3-bromo-2-fluorophenyl)methyl]-3-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylic acid benzyl ester

[0896] 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. The mixture was then heated to 60 ° C and kept for 1 hour. The reaction mixture was cooled to room temperature and filtered through a celite pad and washed with methanol. The filtrate was diluted with toluene (100 mL) and concentrated under reduced pressure. The residue was distributed between EtOAc and a saturated K2CO3 aqueous solution. The obtained 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 Na2SO4, filtered and concentrated under reduced pressure to give the title compound (40 g) as a yellow oil. [M+H] + m / z 451.3, 453.3.

[0897] Intermediate 77

[0898]

[0899] (3R)-1-[(3-Bromo-2-fluorophenyl)methyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid benzyl ester

[0900] To a solution of intermediate 76 (9.2 g) in THF (45 mL) was added dipotassium carbonate (8.45 g, 61.15 mmol) at 0°C, followed by water (45 mL). Chloroacetyl chloride (2.27 mL, 28.54 mmol) was added dropwise at 0°C to this mixture. The reaction was stirred at 0°C for 1 h. The mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (40 mL), dried (Na2SO4), filtered and concentrated to give an oily residue. The intermediate was dissolved in DCM (45 mL) and IPA (45 mL) and cooled to 0°C. Potassium 2-methylpropan-2-ol (9.15 g, 81.54 mmol) was added and the reaction was stirred at 0°C for 30 minutes. The mixture was poured onto saturated aqueous NaHCO3 (100 ml) and then concentrated to remove DCM and IPA. The aqueous suspension was extracted with EtOAc (2 x 100 mL) and the combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to give the title compound as a colorless oil (9.6 g). [M+H] + m / z 491.3,493.3.

[0901] Intermediate 78

[0902]

[0903] (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-carboxylic acid benzyl ester

[0904] XPHOSPdG3 (258.4 mg, 0.310 mmol), intermediate 77 (1.5 g), 1 M potassium phosphate tribasic aqueous 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 and purged with nitrogen for 10 minutes. The reaction mixture was heated to 70 ° C for 18 hours. The mixture was allowed to cool to room temperature and then filtered through celite and washed with EtOAc. The mixture was washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc / DCM) to give the title compound (1.16 g) as a white solid. [M+H] + m / z 505.2.

[0905] Intermediate 79

[0906]

[0907] (3R)-1-({2′-[(3-ethoxy-3-oxo-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-carboxylic acid benzyl ester

[0908] 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) was added THF (2.5 mL) containing intermediate 78 (150 mg) 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, dried over Na2SO4, and concentrated in vacuo to give the title compound (160 mg) as a yellow solid. [M+H] + m / z 603.3

[0909] Intermediate 80

[0910]

[0911] 3-[(3′-{[(3R)-2-[(benzyloxy)carbonyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methyl}-2′-fluoro-[1,1′-biphenyl]-2-yl)oxy]prop-2-enoic acid

[0912] 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 solution (54.55 mg, 1.27 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (5 mL) and neutralized with 2M aqueous HCl to pH 4, then extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na 2 SO 4 and concentrated in vacuo to give the title product (152 mg) as an off-white solid. [M+H] + m / z: 575.2

[0913] Intermediate 81

[0914]

[0915] 3-[(2′-Fluoro-3′-{[(3R)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methyl}-[1,1′-biphenyl]-2-yl)oxy]propanoic acid

[0916] Intermediate 80 (128 mg) was dissolved in methanol (5 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (23.71 mg, 0.020 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 18 hours, then filtered through celite, washed with methanol, and concentrated in vacuo to give the title compound (91 mg) as a white solid. [M+H] + m / z 443.3 Example 26

[0917]

[0918] (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

[0919] To a stirred solution of HATU (53.6 mg, 0.140 mmol) and DIPEA (32.74 μL, 0.190 mmol) in MeCN (200 mL) was added a solution of intermediate 81 (77 mg) in DMA (8 mL) dropwise at 25° C. under nitrogen over a period of 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 the crude material, which was purified by reverse phase column chromatography (0-55% MeCN / water) to give a crude residue, which was further purified using silica gel column chromatography (0-5% methanol / DCM) to give the crude product. The crude product was purified by preparative HPLC: MDAP Waters with mass spectrometry detection (MS: ZQ2000). Column: CSHC18 (30×100 mm, 3-m). Conditions: [A1: water + 0.1% HCOOH]; [B1: MeCN]. Gradient: 34.0% B1 to 35.0% B1 in 10 min (flow rate: 40.00 mL / min). Detection: UV / Vis detection range 210 nm to 350 nm; MS (ES+ / ES-) scan range 100 to 1000 AMU. The title compound (1.8 mg) was obtained as a white foam.

[0920] LCMS (Method C): [M+H] + m / z 425.3, RT 0.84 min

[0921] 1 H NMR (400MHz, CDCl3) δ7.28-7.47(m, 3H), 7.10-7.24(m, 4H), 6.21(s, 1H), 4.72(d d, J=12.5, 3.1Hz, 1H), 4.26-4.35 (m, 1H), 4.12-4.23 (m, 2H), 3.81-4.02 (m, 1H), 3 .59-3.76(m, 2H), 3.49(d, J=11.6Hz, 1H), 2.79-3.05(m, 3H), 2.52-2.65(m, 1H), 2.07 (dt, J=13.0, 3.1Hz, 1H), 1.95 (dd, J=13.7, 8.7Hz, 1H), 1.72 (d, J=6.2Hz, 3H)

[0922]

[0923] Intermediate 82

[0924]

[0925] (3R)-1-({2′-[4-(tert-Butoxy)-4-oxobutoxy]-2-fluoro-[1,1′-biphenyl]-3-yl}methyl)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid benzyl ester

[0926] To a solution of intermediate 78 (150 mg), tert-butyl 4-hydroxy-butyrate (73.2 μL, 0.450 mmol) and triphenylphosphine (116.97 mg, 0.450 mmol) in THF (3.0 mL) was added diisopropyl azodicarboxylate (87.55 μL, 0.450 mmol) at 0°C under nitrogen. The batch was removed and the reaction mixture was heated to 70°C overnight. The crude mixture was then cooled, diluted with EtOAc and quenched with water. The aqueous phase was then back-extracted with EtOAc (× 2) and 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 / water) to give the title compound (143 mg) as a white solid. [M+H] + m / z 647.3

[0927] Intermediate 83

[0928]

[0929] 4-[(3′-{[(3R)-2-[(benzyloxy)carbonyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methyl}-2′-fluoro-[1,1′-biphenyl]-2-yl)oxy]butanoic acid

[0930] To a stirred solution of intermediate 82 (143 mg) in DCM (2.211 mL) was added trifluoroacetic acid (851.72 μL, 11.06 mmol) at 25 ° C. The mixture was stirred for 2 h, 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 give the title compound (150 mg) as a light yellow solid. [M+H] + m / z 591.2

[0931] Intermediate 84

[0932]

[0933] 4-[(2′-Fluoro-3′-{[(3R)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methyl}-[1,1′-biphenyl]-2-yl)oxy]butanoic acid

[0934] 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) at 25° C., followed by stirring the reaction mixture under 1 atm of molecular hydrogen (0.49 mg, 0.240 mmol) overnight. The reaction was filtered through cellulose paper under vacuum, washed with methanol, and the filtrate was concentrated under reduced pressure to give the title compound (113 mg) as a white solid. [M+H] + m / z 457.3

[0935] Example 27

[0936]

[0937] (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

[0938] To a stirred solution of HATU (127.43 mg, 0.340 mmol) and DIPEA (77.83 μL, 0.450 mmol) in MeCN (89.16 mL) was added dropwise a solution of intermediate 84 (102 mg) in DMA (8 mL) at 25° C. under nitrogen over a period of 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 ethyl acetate and then washed with water (×3). The aqueous phase was back-extracted with diethyl ether (×2), and the combined organic extracts were then 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 / water) to give the title compound (83.2 mg) as a white foam.

[0939] LCMS (Method C): [M+H] + m / z 439.3, RT 0.92 min

[0940] 1H NMR (500MHz, CDCl3) δ7.23-7.41 (m, 2H), 7.02-7.26 (m, 4H), 6.83-7.02 (m, 1H), 6.36-6.78 (m, 1H), 4.15-4.81 (m, 1H), 4.14-4 .38(m, 2H), 3.81-4.21(m, 1H), 3.66-4.16(m, 2H), 3.29-3.67(m, 2H), 2.74-3.11(m, 2H), 1.63-2.70(m, 6H), 1.37-1.61(m, 3H)

[0941]

[0942] Intermediate 85

[0943]

[0944] (3E)-4-(2-Bromophenyl)but-3-enoic acid

[0945] To a suspension of 2-carboxyethyl (triphenyl) phosphonium bromide (4.94 g, 11.89 mmol) in THF (30 ml) and DMSO (10 mL) was added sodium hydride (951 mg, 23.78 mmol) at room temperature. After 10 min, THF (1.26 mL) containing 2-bromobenzaldehyde (1.26 mL, 10.81 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then acidified to approximately pH 4 with a 1M HCl aqueous solution and extracted with EtOAc (20 mL). The organic phase was washed with alkaline water (NaOH) of approximately pH 8. The washing aqueous solution was then acidified to approximately pH 4 with a 1M HCl aqueous solution and extracted with EtOAc (20 mL). The combined organic matter was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude material. The crude material was purified by silica gel column chromatography (10% methanol / DCM) to give the title compound (1.45 g) as a yellow solid. [M+H] + m / z 241.0, 243.0

[0946] Intermediate 86

[0947]

[0948] (3E)-4-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]but-3-enoic acid

[0949] Potassium acetate (1.33 g, 13.58 mmol), [1,1-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride (199.4 mg, 0.270 mmol), Intermediate 85 (1.31 g) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dioxaborolane (2.07 g, 8.15 mmol) and CPME (23 mL) were degassed with N for 10 min. The mixture was heated to 100 ° C. with stirring for 18 hours. The reaction was cooled to room temperature, filtered through a pad of celite, washed with diethyl ether and concentrated under reduced pressure to give the title compound (3.1 g) as a yellow solid.

[0950] [M+H] + m / z 289.2

[0951] Intermediate 87

[0952]

[0953] (3E)-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]but-3-enoic acid methyl ester

[0954] To a mixture of intermediate 86 (3.0 g) and methanol (15 mL) was added trimethylsilyldiazomethane (about 10% in hexane, about 0.6 mol / L) (34.7 mL, 20.82 mmol) dropwise at 0 ° C under a nitrogen atmosphere. The reaction was stirred at this temperature for 1 hour. The reaction was allowed to warm to room temperature and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel column chromatography (0-10% EtOAc / cyclohexane) to give the title compound (1.35 g) as a yellow solid. [M+H] + m / z 303.3

[0955] Intermediate 88

[0956]

[0957] Methyl 4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butyrate

[0958] A mixture of intermediate 87 (1.3 g) was dissolved in methanol (30 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 475 mg, 0.450 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 1 hour, then filtered through celite, washed with methanol, and concentrated in vacuo to give the title compound (721 mg) as an off-white solid. [M+H] + m / z 305.2

[0959] Intermediate 89

[0960]

[0961] (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-carboxylic acid benzyl ester

[0962] XPHOS Pd G3 (137.8 mg, 0.160 mmol), intermediate 77 (400 mg), 0.6 M potassium phosphate tribasic aqueous solution (4.07 ml, 2.44 mmol), THF (10 mL) and intermediate 88 (619 mg) were added to a microwave vial and purged with nitrogen for 10 minutes. The reaction mixture was heated at 70 ° C for 1 hour. The mixture was allowed to cool to room temperature, then filtered through celite and washed with EtOAc. The mixture was washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude material. The crude material was purified by silica gel column chromatography (0-5% methanol / DCM) to give the title compound (444 mg) as an orange oil. [M+H] + m / z 589.3.

[0963] Intermediate 90

[0964]

[0965] 4-(3′-{[(3R)-2-[(benzyloxy)carbonyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methyl}-2′-fluoro-[1,1′-biphenyl]-2-yl)butanoic acid

[0966] 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 hours. The mixture was diluted with water (5 mL) and neutralized to pH 4 with 1M aqueous HCl, then extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (468 mg) as an orange oil. [M+H] + m / z: 575.4

[0967] Intermediate 91

[0968]

[0969] 4-(2′-Fluoro-3′-{[(3R)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methyl}-[1,1′-biphenyl]-2-yl)butanoic acid

[0970] Intermediate 90 (468 mg) was dissolved in methanol (10 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 39 mg, 0.040 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 18 hours, then filtered through celite, washed with methanol, and concentrated in vacuo to give the title compound (354 mg) as a yellow oil. [M+H] + m / z 441.3

[0971] Example 28

[0972]

[0973] (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

[0974] To a stirred solution of HATU (307 mg, 0.810 mmol) and DIPEA (187.46 μL, 1.08 mmol) in MeCN (650 mL) was added a solution of intermediate 91 (354 mg) in DMA (15 mL) dropwise via a syringe pump over a period of 2 h at 25 ° C under nitrogen. After an additional 30 min, the reaction mixture was concentrated under reduced pressure. The crude mixture was dissolved with diethyl ether and then washed with water:brine 1:1 (×3). The aqueous phase was back-extracted with diethyl ether (×2), and the combined organic phases were then 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 (0-5% methanol / DCM) to give the crude product. The crude product was purified by preparative HPLC: MDAP Waters with mass spectrometry detection (MS: ZQ2000). Column: CSH C18 (30×100 mm, 3-m). Conditions: [A1: water + 0.1% HCOOH]; [B1: MeCN]. Gradient: 34.0% B1 to 35.0% B1 in 10 min (flow rate: 40.00 mL / min). Detection: UV / Vis detection range 210 nm to 350 nm. MS (ES+ / ES-) scan range 100 to 1000 AMU. The title compound (23 mg) was obtained as a white solid.

[0975] LCMS (Method C): [M+H]+ m / z 423.2, RT 0.92 min

[0976] 1 H NMR (500MHz, CDCl3) δ7.24-7.40 (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=11.8Hz, 1H), 3.47 (d, J=11.8Hz, 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).

[0977]

[0978] Intermediate 92

[0979]

[0980] (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-carboxylic acid benzyl ester

[0981] At -20 ℃, in the mixture of intermediate 78 (300mg) and DCM (12mL), add triethylamine (100.0 μ L, 0.720mmol) and trifluoromethanesulfonic acid trifluoromethyl sulfonyl ester (100.03 μ L, 0.590mmol).The reaction was stirred for 1h at -20 ℃.Add other trifluoromethanesulfonic acid trifluoromethyl sulfonyl ester (17.0 μ L, 0.100mmol), then at room temperature, stir the mixture and spend the night.Add other triethylamine (16.57 μ L, 0.120mmol) and trifluoromethanesulfonic acid trifluoromethyl sulfonyl ester (20.01 μ L, 0.120mmol).Continue to stir 2h, then the mixture is diluted with EtOAc and washed with saturated NaHCO3 aqueous solution.The organic extract merged is dried by passing through a phase separator, and concentrated in vacuo to obtain crude material. The crude material was purified by silica gel column chromatography (0-50% EtOAc / DCM) to give the title compound (359 mg) as a colorless oil. [M+H] + m / z 637.4

[0982] Intermediate 93

[0983]

[0984] (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-carboxylic acid benzyl ester

[0985] Dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (40.21 mg, 0.080 mmol), dichlorobis(acetonitrile)palladium (7.35 mg, 0.030 mmol) and cesium carbonate (549.68 mg, 1.69 mmol) were placed in a microwave vial and sealed. The vial was purged with nitrogen for 10 min, followed by the addition of a solution of intermediate 92 (358 mg) in anhydrous MeCN (5.5 mL) (previously purged with a nitrogen stream for 15 min), followed by the addition of methyl pent-4-ynoate (126.11 mg, 1.12 mmol). The reaction mixture was purged for an additional 5 min, then heated to 80 ° C. for 2 hours. The mixture was cooled to room temperature and filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude material 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 / DCM) to give the title compound (274 mg) as a pale yellow foam. [M+H] + m / z 599.12

[0986] Intermediate 94

[0987]

[0988] 5-(3′-{[(3R)-2-[(benzyloxy)carbonyl]-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methyl}-2′-fluoro-[1,1′-biphenyl]-2-yl)pent-4-ynoic acid

[0989] To a stirred solution of intermediate 93 (274 mg) in THF (6 mL) and water (6 mL) was added solid lithium hydroxide hydrate (98.33 mg, 2.29 mmol) at 25 ° C. The reaction mixture was stirred for 20 min and then concentrated under reduced pressure to remove THF. The pH of the aqueous phase was adjusted to 2-3 with 0.1M HCl aqueous solution, and the aqueous phase was subsequently extracted with EtOAc (× 3). The combined organic phase was filtered through a phase separator, concentrated under reduced pressure and triturated with diethyl ether to give the title compound (264 mg) as a light yellow foam. [M+H] + m / z 505.3

[0990] Intermediate 95

[0991]

[0992] 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

[0993] To a stirred solution of intermediate 94 (264 mg) in ethanol (15.11 mL) was added Pd / C 10% wt. (48.06 mg, 0.050 mmol), and the reaction mixture was stirred at 25° C. under 1 atm of molecular hydrogen (0.91 mg, 0.450 mmol) for 24 h. The reaction mixture was filtered through cellulose paper under vacuum, washed with methanol, and the filtrate was concentrated under reduced pressure to give the title compound (197 mg) as an off-white solid. [M+H] + m / z 455.3

[0994] Example 29

[0995]

[0996] (14'R)-23'-Fluoro-14'-methyl-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

[0997] To a stirred solution of HATU (247.2 mg, 0.650 mmol) and DIPEA (151 μL, 0.870 mmol) in MeCN (179.58 mL) was added a solution of intermediate 95 (197 mg) in DMA (16 mL) dropwise via a syringe pump over a period of 2 h at 25 ° C under nitrogen. After an additional 30 min, the reaction mixture was concentrated under reduced pressure. The crude mixture was dissolved with diethyl ether and then washed with water (× 3). The aqueous phase was back-extracted with diethyl ether (× 2), and the combined organic extracts were then filtered through a phase separator and concentrated under reduced pressure to give the crude material. The crude material was purified by reverse phase column chromatography (0-40% MeCN / water) to give the title compound (120 mg) as a light yellow foam.

[0998] LCMS (Method C): [M+H] + m / z 437.3, RT 0.99 min

[0999] 1H NMR (500MHz, CDCl3) δ7.04-7.43(m, 7H), 6.25-6.65(m, 1H), 4.14-4.38(m, 2H), 4. 06-4.94 (m, 1H), 3.75-4.23 (m, 1H), 3.52-3.67 (m, 1H), 3.32-3.48 (m, 1H), 2.82-3 .12(m, 2H), 2.53-2.73(m, 1H), 2.19-2.33(m, 1H), 2.18-2.54(m, 1H), 1.76-1.94( m, 1H), 1.43-1.57 (m, 3H), 1.11-1.43 (m, 1H), 1.01-2.08 (m, 4H), 0.76-1.38 (m, 1H)

[1000]

[1001] Intermediate 96

[1002]

[1003] (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-carboxylic acid benzyl ester

[1004] Potassium phosphate (610.56 μL, 1.22 mmol), [1,1-bis(diphenylphosphino)ferrocene] palladium (II) dichloride (20 mg, 0.030 mmol), intermediate 77 (200 mg), THF (1.357 mL) and 2M 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 and backfilled with nitrogen three times, and then the tube was transferred to a preheated metal block at 70 ° C and stirred for 5h. The mixture was cooled and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel column chromatography (0-100% EtOAc / cyclohexane) to give the title compound (198 mg) as an orange oil. [M+H] + m / z 662.4

[1005] Intermediate 97

[1006]

[1007] tert-Butyl N-{2-[(2′-fluoro-3′-{[(3R)-3-methyl-7-oxo-9-oxa-2,6-diazaspiro[4.5]dec-1-yl]methyl}.[1,1′-biphenyl]-2-yl)oxy]ethyl}-N-methylcarbamate

[1008] To a solution of intermediate 96 (194 mg) in methanol (19.54 mL) was added palladium on carbon (10%, 106.42 mg, 0.100 mmol) and the reaction mixture was stirred under a molecular hydrogen atmosphere (5 atm pressure) for 4 h. The reaction was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (274 mg) as a yellow oil. [M+H] + m / z 528.2

[1009] Intermediate 98

[1010]

[1011] (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

[1012] Intermediate 97 (260.19 mg) was dissolved in 4M hydrochloric acid in dioxane (3.21 mL, 12.82 mmol). The reaction mixture was stirred at 25°C for 2 hours and then concentrated in vacuo to give the title compound (244 mg) as a white solid. [M+H] + m / z 428.2

[1013] Example 30

[1014]

[1015] (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

[1016] 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 give the crude reaction material. The crude material was purified by preparative HPLC: UPLC Waters with mass spectrometry detection (MS: SQD2). Column: CSH C18 (2.1×50 mm, 1.7-m). Conditions: [A1: water + 0.1% HCOOH]; [B1: MeCN + 0.1% HCOOH]. Gradient: 3% B1 to 99.9% B1 in 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.

[1017] LCMS (Method C): [M+H] + m / z 454.2, RT 0.89 min

[1018] 1 H NMR (400MHz, CDCl3) δ7.39-7.28 (m, 2H), 7.25-7.17 (m, 1H), 7.16-7.08 (m, 2H), 7.08-7.02 (m, 1H), 6.89 (d, J=8.2Hz, 1H), 6.46 (br s, 1H), 4.48-4.39 (m, 1H), 4.33 (d, J=16.9Hz, 1H), 4.24 (d, J=16.8Hz, 1H), 4.21-4.15 (m, 1H), 4.05-3.97 (m, 1H), 3.91 (br d, J=11.5Hz, 1H), 3.74(br d, J=11.5Hz, 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=13.0Hz, 1H), 2.23 (dd, J=13.5, 8.0Hz, 1H), 1.77 (dd, J=13.6, 3.9Hz, 1H), 1.49 (br d, J=6.7Hz, 3H)

[1019] Example 31

[1020]

[1021] (15′R)-24′-fluoro-12′,15′-dimethyl-8′-oxa-12′,14′-diazaspiro[morpholine-3,17′-tetracyclo[18.3.1.0 2，7 .014，18 ]Tetracosane]-1′(24′),2′(7′),3′,5′,20′,22′-hexaene-5,13′-dione

[1022] Example 31 was prepared according to a similar procedure described for 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 to give the title compound as a pink solid (13.1 mg).

[1023] LCMS (Method C): [M+H + m / z 468.2, RT 0.97 min

[1024] 1 H NMR (400MHz, CDCl3) δ7.35 (t, J=8.0Hz, 1H), 7.23 (d, J=6.2Hz, 2H), 7.09 (dt, J=24.9 , 7.3Hz, 3H), 6.92 (d, J = 8.1Hz, 1H), 6.20 (d, J = 20.1Hz, 1H), 4.69 (d, J = 10.2Hz, 1H), 4 .36-4.15(m, 2H), 4.06-3.68(m, 6H), 3.57(d, J=11.6Hz, 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, 5.3Hz, 1H), 1.55 (bs, 3H).

[1025] Example 32

[1026]

[1027] 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

[1028] Example 32 was prepared according to a similar procedure described for Example 3 using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate to give the title compound as a white solid (28 mg).

[1029] LCMS (Method A): [M+H] +m / z 415.3, RT 2.93min

[1030] 1 H NMR (500MHz, CDCl3) δ7.16 (td, J=7.8, 1.6Hz, 1H), 7.11-7.06 (m, 1H), 6.89 (t, J=7.4Hz, 1H), 6.74 (d, J=8.0Hz, 1H ), 6.20 (s, 1H), 5.36 (dd, J=10.1, 3.9Hz, 1H), 5.10 (d, J=10.6Hz, 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=11.7Hz, 1H), 2.60 (dtd, J=28.3, 12.4, 5.5Hz, 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).

[1031] Examples 32a and 32b

[1032]

[1033] 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

[1034] 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

[1035] Example 32 (25 mg) was subjected to chiral preparative purification using a Waters 600 (Chiralpak IC (25×2.0 cm), 5 μm, flow rate 17 mL / min) eluting with 60 / 40% v / v hexane / (ethanol + 0.1% isopropylamine) to provide the title compound (peak 1, 12.3 mg, 96.6% ee; and peak 2, 5.6 mg, 99% ee).

[1036] Example 32a: Peak 1 (stereochemistry tentatively assigned)

[1037] LCMS (Method C): [M+H] + m / z 415.2, RT 0.92 min.

[1038] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 60:40 hexane:(ethanol+0.1% isopropylamine): RT 9.9 min

[1039] 1 H NMR (500MHz, CDCl3) δ7.17 (td, J=7.7, 1.6Hz, 1H), 7.10 (dd, J=7.4, 1.5Hz, 1H), 6.93-6.88 (m, 1H), 6.75 (d, J=7.8Hz, 1H ), 5.96 (s, 1H), 5.37 (dd, J = 10.0, 3.8Hz, 1H), 5.11 (d, J = 10.6Hz, 1H), 4.33 (d, J = 10.6Hz, 1H), 4.31 (d, J = 16.7Hz, 1H), 4 .15 (d, J=11.5Hz, 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, 4.1Hz, 1H), 3.58-3.5 0 (m, 1H), 3.42 (d, J=11.8Hz, 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=13.3Hz, 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).

[1040] Example 32b: Peak 2 (stereochemistry tentatively assigned)

[1041] LCMS (Method C): [M+H]+ m / z 415.2, RT 0.92 min.

[1042] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 60:40 hexane:(ethanol+0.1% isopropylamine): RT 14.1 min

[1043] 1 H NMR (500MHz, CDCl3) δ7.17 (td, J=7.7, 1.6Hz, 1H), 7.10 (dd, J=7.4, 1.5Hz, 1H), 6.93-6.88 (m, 1H), 6.75 (d, J=7.8Hz, 1H ), 5.96 (s, 1H), 5.37 (dd, J = 10.0, 3.8Hz, 1H), 5.11 (d, J = 10.6Hz, 1H), 4.33 (d, J = 10.6Hz, 1H), 4.31 (d, J = 16.7Hz, 1H), 4 .15 (d, J=11.5Hz, 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, 4.1Hz, 1H), 3.58-3.5 0 (m, 1H), 3.42 (d, J=11.8Hz, 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=13.3Hz, 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).

[1044] Example 33

[1045]

[1046] 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

[1047] Example 33 was prepared according to a similar procedure described for Example 1 using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate to give the title compound as a white solid (48 mg).

[1048] LCMS (Method A): [M+H] + m / z 429.3, RT 2.99 min

[1049] 1 H NMR (500MHz, CDCl3) δ8.16 (s, 1H), 7.05 (t, J=7.1Hz, 1H), 6.94 (d, J=7.2Hz, 1H), 6.77-6.67 (m, 2H), 4.70 (dd, J=13.8, 4.2Hz, 1H), 4 .64 (t, J=8.8Hz, 2H), 4.23 (d, J=17.0Hz, 1H), 4.07 (d, J=11.9Hz, 1H), 4.02 (d, J=16.9Hz, 1H), 3.97-3.91 (m, 1H), 3.81 (t, J=9.8Hz, 1 H), 3.75-3.68 (m, 1H), 3.57 (s, 1H), 3.43 (t, J=12.2Hz, 1H), 3.16 (d, J=12.0Hz, 1H), 2.70-2.57 (m, 1H), 2.58-2.49 (m, 1H), 2.44-2.3 1 (m, 2H), 2.19 (d, J=15.5Hz, 1H), 1.84 (s, 1H), 1.73 (d, J=13.8Hz, 1H), 1.66 (d, J=4.6Hz, 2H), 1.44-1.34 (m, 2H), 1.33-1.19 (m, 4H).

[1050] Examples 33a and 33b

[1051]

[1052] 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

[1053] 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

[1054] Example 33 (44 mg) was purified by chiral preparative chromatography using a Waters 600 (Chiralpak OD-H (25×2.0 cm), 5 μm, flow rate 17 mL / min) with 75 / 25% v / v n-hexane / (ethanol + 0.1% isopropylamine) to give the title compounds (peak 1, 10.3 mg, 100% ee; and peak 2, 10.4 mg, 100% ee).

[1055] Example 33a: Peak 1 (stereochemistry tentatively assigned)

[1056] LCMS (Method C): [M+H] + m / z 429.4, RT 0.91 min.

[1057] Chiral analysis (Chiralpak OD-H, 25 × 0.46 cm, 5 μm, 75:25 hexane: (ethanol + 0.1% isopropylamine): RT 7.4 min

[1058] 1H NMR (500MHz, CDCl3) δ7.13 (td, J=7.7, 1.6Hz, 1H), 7.03 (br dd, J=7.4, 1.5Hz, 1H), 7.02 (br s, 1H), 6.81 (d, J=7.7Hz, 1H), 6.81-6.77 (m, 1H), 4.80 (br dd, J=14.1, 4.7Hz, 1H), 4.77-4.69 (m, 2H), 4.33 (d, J=17.0Hz, 1H), 4.16 (d, J=11.9Hz, 1H), 4.12(d, J=17.0Hz, 1H), 4.02(dt, J=7.7, 2.7Hz, 1H), 3.88(br t, J=9.7Hz, 1H), 3.77 (dd, J=9.3, 2.6Hz, 1H), 3.66 (br s, 1H), 3.56-3.46 (m, 1H), 3.26 (d, J=11.9Hz, 1H), 2.78-2.68 (m, 1H), 2.6 3(qd, J=12.6, 3.8Hz, 1H), 2.54-2.45(m, 1H), 2.46-2.36(m, 1H), 2.28(br dd, J=15.5, 1.2Hz, 1H), 1.92(br d, J=13.3Hz, 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).

[1059] Example 33b: Peak 2 (stereochemistry tentatively assigned)

[1060] LCMS (Method C): [M+H] + m / z 429.5, RT 0.91 min.

[1061] Chiral analysis (Chiralpak OD-H, 25 × 0.46 cm, 5 μm, 75:25 hexane: (ethanol + 0.1% isopropylamine): RT 10.7 min

[1062] 1H NMR (500MHz, CDCl3) δ7.13 (td, J=7.7, 1.6Hz, 1H), 7.03 (br dd, J=7.4, 1.5Hz, 1H), 7.02 (br s, 1H), 6.81 (d, J=7.7Hz, 1H), 6.81-6.77 (m, 1H), 4.80 (br dd, J=14.1, 4.7Hz, 1H), 4.77-4.69 (m, 2H), 4.33 (d, J=17.0Hz, 1H), 4.16 (d, J=11.9Hz, 1H), 4.12(d, J=17.0Hz, 1H), 4.02(dt, J=7.7, 2.7Hz, 1H), 3.88(br t, J=9.7Hz, 1H), 3.77 (dd, J=9.3, 2.6Hz, 1H), 3.66 (br s, 1H), 3.56-3.46 (m, 1H), 3.26 (d, J=11.9Hz, 1H), 2.78-2.68 (m, 1H), 2.6 3(qd, J=12.6, 3.8Hz, 1H), 2.54-2.45(m, 1H), 2.46-2.36(m, 1H), 2.28(br dd, J=15.5, 1.2Hz, 1H), 1.92(br d, J=13.3Hz, 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).

[1063] Example 34

[1064]

[1065] 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] Pentacosane]-2′(7′),3′,5′-triene-5,12′-dione

[1066] Example 34 was prepared according to a similar procedure described for Example 2 using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate to give the title compound as a white solid (36 mg).

[1067] LCMS (Method A): [M+H] + m / z 443.3, RT 3.11 min.

[1068] 1H NMR (500MHz, CDCl3) δ7.17-7.11 (m, 1H), 7.05 (dd, J=7.4, 1.6Hz, 1H), 6.87 (d, J=8.1Hz, 1H), 6.82 (t, J=7.3Hz, 1H), 6.01 (s, 1H), 4.73-4.65 (m, 1H), 4.65-4.59 (m, 1H), 4.32 (d, J = 17.0Hz, 1H), 4.24-4.18 (m, 2H), 4.10 (d, J = 17.0Hz, 1H), 4.02 (t d, J=8.8, 3.4Hz, 1H), 3.87-3.80 (m, 1H), 3.70-3.55 (m, 3H), 3.25 (d, J=11.9Hz, 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=14.3Hz, 1H), 1.78-1.65 (m, 2H), 1.64-1.57 (m, 1H), 1.52-1.37 (m, 5H).

[1069] Example 35

[1070]

[1071] 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

[1072] Example 35 was prepared according to a similar procedure described for Example 3 using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate to give the title compound as a pale yellow solid (20 mg).

[1073] LCMS (Method A): [M+H] + m / z 429.5, RT 2.81 min

[1074] 1H NMR (400MHz, CDCl3) δ7.18-7.13(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, 3.8Hz, 1H), 5.26 (q, J=6.0Hz, 1H), 4.28 (d, J=16.9Hz, 1H), 4.15 (d, J=11.7Hz, 1H), 4.08 (d, J=16.9Hz, 1H), 3.8 8(dd, J=11.5, 8.5Hz, 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=6.0Hz, 3H), 1.43-1.32 (m, 3H).

[1075] Examples 35a and 35b

[1076]

[1077] 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

[1078] 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

[1079] Example 35 (15.4 mg) was subjected to chiral preparative purification using a 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, flow rate 17 mL / min) to give the title compounds (peak 1, 3.32 mg, 100% ee; and peak 2, 4.06 mg, 100% ee).

[1080] Example 35a: Peak 1 (stereochemistry tentatively assigned)

[1081] LCMS (Method C): [M+H] + m / z 429.3, RT 0.95 min.

[1082] Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 65:35 hexane:(ethanol / methanol 1:1+0.1% isopropylamine)): RT 4.3 min

[1083] 1 HNMR (500MHz, CDCl3) δ7.16 (td, J=7.7, 1.7Hz, 1H), 7.10 (dd, J=7.4, 1.6Hz, 1H), 6.87 (td, J=7.4, 1.0Hz, 1H), 6.80 (d, J=8.1Hz, 1H), 5.98 (br s, 1H), 5.51 (dd, J=11.3, 3.6Hz, 1H), 5.26 (q, J=6.0Hz, 1H), 4.30 (d, J=16.9Hz, 1H), 4.14 (d, J= 11.7Hz, 1H), 4.11 (d, J=17.0Hz, 1H), 3.86 (dd, J=11.4, 8.4Hz, 1H), 3.71-3.75 (m, 1H), 3.68 (br dd, J=14.1, 3.7Hz, 1H), 3.47 (dd, J=8.3, 3.9Hz, 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).

[1084] Example 35b: Peak 2 (stereochemistry tentatively assigned)

[1085] LCMS (Method C): [M+H] +m / z 429.3, RT 0.95 min.

[1086] Chiral analysis (Chiralpak AD-H, 25×0.46 cm, 5 μm, 65:35 hexane:(ethanol / methanol 1:1+0.1% isopropylamine)): RT 7.3 min

[1087] 1 H NMR (500MHz, CDCl3) δ7.16 (td, J=7.7, 1.7Hz, 1H), 7.10 (dd, J=7.4, 1.6Hz, 1H), 6.87 (td, J=7.4, 1.0Hz, 1H), 6.80 (d, J=8.1Hz, 1H), 5.98 (br s, 1H), 5.51 (dd, J=11.3, 3.6Hz, 1H), 5.26 (q, J=6.0Hz, 1H), 4.30 (d, J=16.9Hz, 1H), 4.14 (d, J= 11.7Hz, 1H), 4.11 (d, J=17.0Hz, 1H), 3.86 (dd, J=11.4, 8.4Hz, 1H), 3.71-3.75 (m, 1H), 3.68 (br dd, J=14.1, 3.7Hz, 1H), 3.47 (dd, J=8.3, 3.9Hz, 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).

[1088] Example 36

[1089]

[1090] Rel-(1's,3S,16'R,19's)-9',9'-dimethyl-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

[1091] Example 36 was prepared according to a similar procedure described for Example 3 using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate to give the title compound as a white solid (1 mg).

[1092] LCMS (Method B): [M+H]+ m / z 443.3, RT 3.21 min

[1093] 1 H NMR (400MHz, CDCl3) δ7.16-7.06 (m, 2H), 7.03 (dd, J=8.2, 1.3Hz, 1H), 6.92 (td, J=7.4, 1.3Hz, 1H), 6.0 9 (s, 1H), 5.49 (dd, J = 10.8, 4.0Hz, 1H), 4.52 (d, J = 14.5Hz, 1H), 4.28 (d, J = 16.9Hz, 1H), 4.16-4.05 (m, 2H), 3.84 (dd, J=10.8, 8.3Hz, 1H), 3.74 (s, 1H), 3.54 (dd, J=8.3, 4.0Hz, 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).

[1094] Example 37

[1095]

[1096] 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 ]Tetracosane-16′,3″-morpholine]-2′(7′),3′,5′-triene-5′′,11′-dione

[1097] Example 37 was prepared according to a similar procedure described for Example 7 using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate to give the title compound as a white solid (9.4 mg).

[1098] LCMS (Method A): [M+H] + m / z 455.32, RT 3.01 min

[1099] 1H NMR (400MHz, CDCl3) δ7.76 (s, 1H), 7.19-7.05 (m, 2H), 6.99-6.83 (m, 2H), 5.40 (dd, J=10.1, 3.9Hz, 1H), 4.54 (dd, J=14.2, 3.4Hz, 1H) , 4.27 (d, J = 17.0Hz, 1H), 4.17 (d, J = 10.0Hz, 1H), 4.08 (d, J = 17.0Hz, 1H), 3.96-3.87 (m, 2H), 3.83 (d, J = 10.1Hz, 1H), 3.76-3.70 (m, 1H) ), 3.62 (dd, J=8.8, 4.0Hz, 1H), 3.45-3.34 (m, 1H), 3.31 (d, J=11.7Hz, 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).

[1100] Examples 37a and 37b

[1101]

[1102] 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 ]Tetracosane-16′,3″-morpholine]-2′(7′),3′,5′-triene-5″,11′-dione

[1103] 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 ]Tetracosane-16′,3″-morpholine]-2′(7′),3′,5′-triene-5″,11′-dione

[1104] Example 37 (6.1 mg) was subjected to chiral preparative purification using a Waters 600 (Whelk 01(R,R) (25×2.0 cm), 5 μm, flow rate 17 mL / min) with 70 / 30% v / v n-hexane / (ethanol / methanol 1:1 + 0.1% isopropylamine) to afford the title compounds (peak 1, 1.4 mg, 100% ee; and peak 2, 2.6 mg, 98.7% ee).

[1105] Example 37a: Peak 1 (stereochemistry tentatively assigned)

[1106] LCMS (Method C): [M+H] + m / z 455.3, RT 0.92 min.

[1107] Chiral analysis (Whelk O1 (R, R), 25 × 0.46 cm, 5 μm, 70:30 hexane: (ethanol / methanol 1:1 + 0.1% isopropylamine)): RT 13.2 min

[1108] 1 H NMR (500MHz, CDCl3) δ7.15 (td, J=7.8, 1.8Hz, 1H), 7.10 (dd, J=7.8, 1.8Hz, 1H), 6.90-6.97 (m, 2H), 5.78 (s, 1H), 5.31 (dd, J=8.9, 4.0Hz, 1H), 4.57 (br dd, J=14.3, 3.8Hz, 1H), 4.27 (d, J=16.7Hz, 1H), 4.21 (d, J=10.2Hz, 1H), 4.10 (d, J=17.0 Hz, 1H), 3.89 (d, J=11.8Hz, 1H), 3.83 (t, J=8.8Hz, 1H), 3.77 (d, J=10.2Hz, 1H), 3.72 (br s, 1H), 3.68-3.72 (m, 1H), 3.44 (td, J=13.6, 3.0Hz, 1H), 3.34 (d, J=11.8Hz, 1H), 2.42-2.54 (m, 1H), 1.21-2.41 (m, 12H), 0.76-1.32 (m, 4H).

[1109] Example 37b: Peak 2 (stereochemistry tentatively assigned)

[1110] LCMS (Method C): [M+H] + m / z 455.3, RT 0.92 min.

[1111] Chiral analysis (Whelk O1 (R, R), 25 × 0.46 cm, 5 μm, 70:30 hexane: (ethanol / methanol 1:1 + 0.1% isopropylamine)): RT 15.3 min

[1112] 1 H NMR (500MHz, CDCl3) δ7.15 (td, J=7.8, 1.8Hz, 1H), 7.10 (dd, J=7.8, 1.8Hz, 1H), 6.90-6.97 (m, 2H), 5.78 (s, 1H), 5.31 (dd, J=8.9, 4.0Hz, 1H), 4.57 (br dd, J=14.3, 3.8Hz, 1H), 4.27 (d, J=16.7Hz, 1H), 4.21 (d, J=10.2Hz, 1H), 4.10 (d, J=17.0 Hz, 1H), 3.89 (d, J=11.8Hz, 1H), 3.83 (t, J=8.8Hz, 1H), 3.77 (d, J=10.2Hz, 1H), 3.72 (br s, 1H), 3.68-3.72 (m, 1H), 3.44 (td, J=13.6, 3.0Hz, 1H), 3.34 (d, J=11.8Hz, 1H), 2.42-2.54 (m, 1H), 1.21-2.41 (m, 12H), 0.76-1.32 (m, 4H).

[1113] Examples 38a and 38b

[1114]

[1115] 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

[1116] 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 , 16 ]Tricosane]-2′(7′),3′,5′-triene-5,10′-dione

[1117] Examples 38a and 38b were prepared according to a procedure similar to that described for Examples 17a and 17b using commercially available starting material, 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate. The racemic mixture (8.6 mg) was subjected to chiral preparative purification using a Waters 600 eluting with 45 / 55% v / v n-hexane / ethanol + 0.1% isopropylamine (Chiralcel OJ-C (25×2.0 cm), 5 μm, flow rate 17 mL / min) to afford the title compounds (Peak 1, 1.5 mg, 100% ee; and Peak 2, 1.72 mg, 100% ee).

[1118] Example 38a: Peak 1 (stereochemistry tentatively assigned)

[1119] LCMS (Method C): [M+H] + m / z 433.3, RT 0.94 min.

[1120] Chiral analysis (Chiralcel OJ-H, 25×0.46 cm, 5 μm, 45:55 hexane:ethanol + 0.1% isopropylamine): RT 5.9 min

[1121] 1 H NMR (500MHz, CDCl3) δ6.80-7.01 (m, 3H), 5.99 (br s, 1H), 5.32-5.50 (m, 2H), 4.35 (dd, J=12.5, 1.4Hz, 1H), 4.31 (d, J=17.0Hz, 1H ), 4.13-4.17(m, 1H), 4.11(d, J=17.0Hz, 1H), 3.92-4.00(m, 1H), 3.84(dd, J=1 0.0, 8.5Hz, 1H), 3.74-3.79 (m, 1H), 3.55-3.60 (m, 1H), 3.47-3.55 (m, 1H), 3.4 0 (d, J=11.7Hz, 1H), 2.63-2.73 (m, 1H), 2.53-2.64 (m, 1H), 1.20-2.16 (m, 11H).

[1122] Example 38b: Peak 2 (stereochemistry tentatively assigned)

[1123] LCMS (Method C): [M+H] + m / z 433.3, RT 0.94 min.

[1124] Chiral analysis (Chiralcel OJ-H, 25×0.46 cm, 5 μm, 45:55 hexane:ethanol + 0.1% isopropylamine): RT 10.0 min

[1125] 1 H NMR (500MHz, CDCl3) δ6.80-7.01 (m, 3H), 5.99 (br s, 1H), 5.32-5.50 (m, 2H), 4.35 (dd, J=12.5, 1.4Hz, 1H), 4.31 (d, J=17.0Hz, 1H ), 4.13-4.17(m, 1H), 4.11(d, J=17.0Hz, 1H), 3.92-4.00(m, 1H), 3.84(dd, J=1 0.0, 8.5Hz, 1H), 3.74-3.79 (m, 1H), 3.55-3.60 (m, 1H), 3.47-3.55 (m, 1H), 3.4 0 (d, J=11.7Hz, 1H), 2.63-2.73 (m, 1H), 2.53-2.64 (m, 1H), 1.20-2.16 (m, 11H).

[1126] The following examples were prepared according to similar procedures as described for Examples 38a and 38b using appropriate reagents.

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136]

[1137] Intermediate 99

[1138]

[1139] 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

[1140] Intermediate 99 was prepared according to a similar procedure described for Examples 17a and 17b using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate to give the title compound as a yellow oil (1.80 g). M+H] + m / z 493.4.

[1141] Intermediate 100

[1142]

[1143] 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

[1144] 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 THF (8.4 mL) containing intermediate 99 (1.00 g) at 0 ° C under nitrogen and the solution was stirred at room temperature for 5 hours. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2×25 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give a crude material. The crude material was purified by flash column chromatography (0-100% EtOAc / heptane) to give the title compound (1.00 g) as a yellow oil. [M+H] + m / z 619.5

[1145] Intermediates 101

[1146]

[1147] 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

[1148] Intermediate 100 (1.00 g) was dissolved in ethanol (27 mL) and vacuumed and backfilled 3 times with nitrogen. Palladium on carbon (10%, 516 mg, 0.485 mmol) was added and vacuumed and backfilled 3 times with hydrogen. The reactant was stirred for 16 hours, then filtered through celite, washed with EtOAc and the filtrate was concentrated in vacuo to give a crude material. The crude material was purified by flash column chromatography (0-100% EtOAc / heptane) to give the title compound (800 g) as a yellow oil. [M+H] + m / z 621.5.

[1149] Intermediate 102

[1150]

[1151] Rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-[2-(2-carboxyethoxy)-3-fluorophenyl]cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-ium chloride

[1152] 4M hydrochloric acid in dioxane (3.2 mL, 12.8 mmol) was added to Intermediate 101 (800 mg) at room temperature and the reaction was stirred for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (650 mg) as an orange solid. [M+H] + m / z 465.4

[1153] Example 48

[1154]

[1155] 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 , 17 ]Tetracosane]-2′,4′,6′-triene-5,11′-dione

[1156] To a stirred solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 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 anhydrous DMF (4.2367 mL) containing intermediate 102 (550 mg) over 2 h using a syringe pump. The resulting solution was stirred for one hour. The reaction mixture was concentrated in vacuo to give the crude material. The crude material was diluted in 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 / water (0.1% ammonia)) to give the title compound (75 mg) as a white solid. [M+H] + m / z 447.4

[1157] Examples 48a and 48b

[1158]

[1159] 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 ]Tetracosane]-2′(7′),3′,5′-triene-5,11′-dione

[1160] 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 , 17 ]Tetracosane]-2′(7′),3′,5′-triene-5,11′-dione

[1161] Example 48 (75 mg) was subjected to chiral preparative purification using a Waters 600 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 give the title compounds (peak 1, 29 mg, 100% ee; and peak 2, 31 mg, 96.7% ee).

[1162] Example 48a: Peak 1 (stereochemistry tentatively assigned)

[1163] LCMS (Method C): [M+H] + m / z 447.4, RT 0.93 min.

[1164] Chiral analysis (Chiralpak IC, 25 × 0.46 cm, 5 μm, 40:60 hexane:ethanol + 0.1% isopropylamine): RT 7.4 minutes

[1165] 1 H NMR (600MHz, CDCl3) δ6.98-6.71 (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, 9.4Hz, 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).

[1166] Example 48b: Peak 2 (stereochemistry tentatively assigned)

[1167] LCMS (Method C): [M+H] + m / z 447.4, RT 0.93 min.

[1168] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 40:60 hexane:ethanol + 0.1% isopropylamine): RT 8.6 min

[1169] 1 H NMR (600MHz, CDCl3) δ6.98-6.71 (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, 9.4Hz, 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).

[1170] The following examples were prepared according to similar procedures as described for Examples 48a and 48b using appropriate reagents.

[1171]

[1172]

[1173]

[1174]

[1175] Intermediate 103

[1176]

[1177] 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

[1178] Intermediate 103 was prepared according to a similar procedure described for Example 3 using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate to give the title compound as a white solid (1.6 g). [M+H] + m / z 475.3

[1179] Intermediate 104

[1180]

[1181] 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

[1182] Trifluoromethylsulfonyl trifluoromethanesulfonate (0.38mL, 2.02mmol) in DCM (2ml) was added dropwise to a stirred solution of intermediate 103 (800mg) and pyridine (0.41mL, 5.06mmol) in DCM (20mL) at 0°C. The mixture was stirred at 0°C for 4hr. The reaction mixture was diluted with DCM (20mL) and water (20mL), the organic layer was separated and the aqueous layer was extracted with DCM (2×20ml). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give the crude material. The crude material was purified by column chromatography (0-100% EtOAc / heptane) to give the title compound (742mg) as a yellow solid. [M+H] + m / z 607.1

[1183] Intermediate 105

[1184]

[1185] Tert-butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(2-vinylphenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1186] Intermediate 104 (740 mg), potassium vinyl (trifluoro) borate (1-) (245 mg, 1.83 mmol) and dicesium carbonate (795 mg, 2.44 mmol) were stirred in 1,4-dioxane (18 mL) and water (3 mL) and degassed with N2. Bis(triphenylphosphine)palladium(II) dichloride (43 mg, 0.0610 mmol) was added to the reaction solution, which was then further degassed with N2, sealed, and heated to 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 (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give the crude material. The crude material was purified by column chromatography (0-100% EtOAc / heptane) to give the title compound (606 mg) as a light yellow gum. [M+H] + m / z 485.4

[1187] Intermediate 106

[1188]

[1189] Rel-(6S,7R)-7-({[(1s,4s)-4-(2-vinylphenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecan-2-one hydrochloride

[1190] 4M hydrochloric acid 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 hours. The solvent was removed in vacuo to give the title compound (504 mg) as a white solid. [M+H] + m / z 385.3

[1191] Intermediate 107

[1192]

[1193] Vinyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(2-vinylphenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1194] To a stirred solution of intermediate 106 (200 mg) triethylamine (331 μL, 2.38 mmol) in anhydrous DCM (5 mL) was added dropwise anhydrous DCM (1 mL) containing vinyl chloroformate (52 μL, 0.570 mmol) at 0°C and the mixture was stirred for 2 h. The reaction mixture was diluted with DCM, followed by addition of water (15 mL) and separation of the organic layer. The aqueous layer was extracted with DCM (2 × 20 mL) and the organic eluents were combined, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by column chromatography (0-100% EtOAc / heptane) to give the title compound (198 mg) as a colorless gum. [M+H] + m / z 455.3

[1195] Intermediate 108

[1196]

[1197] 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 ]Tetracosane]-2′,4′,6′,8′-tetraene-5,11′-dione

[1198] A solution of intermediate 107 (150 mg) in anhydrous DCE (60 mL) was degassed with N2 for 15 min. [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene](dichloro)[2-(prop-2-yloxy)benzylidene]ruthenium (62 mg, 0.0990 mmol) was then added and the reaction mixture was heated at 65 ° C for 16 hr. An additional 0.3 equivalents of [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene](dichloro)[2-(prop-2-yloxy)benzylidene]ruthenium was added and the reaction mixture was heated at 65 ° C for another 16 hr. The solvent was removed under reduced pressure. The resulting residue was diluted with DCM, followed by the addition of water (15 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (2×20 ml) and the organic fractions were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (0-100% EtOAc / heptane, then 0-20% methanol / DCM) to give the crude product, which was further purified by basic reverse phase column chromatography (10-100% MeCN / water (0.1% ammonia)) to give the title compound (19 mg) as a brown solid. [M+H] + m / z 427.4

[1199] Example 52

[1200]

[1201] 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

[1202] Intermediate 108 (19 mg) was dissolved in ethanol (4 mL) and vacuumed and backfilled 3 times with nitrogen. Palladium on carbon (10%, 9.5 mg, 8.91 μmol) was added and vacuumed and backfilled 3 times with hydrogen. The reaction 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 running methanol / water (+0.2% ammonium hydroxide) 5% to 95% to give the title compound (1.2 mg) as a white solid.

[1203] LCMS (Method B): [M+H] + m / z 429.4, RT 3.19 min

[1204] 1H NMR (500MHz, CDCl3) δ7.23-7.08 (m, 4H), 6.24 (s, 1H), 4.66 (dd, J=13.7, 4.8Hz, 1H), 4. 40 (dd, J=7.3, 3.3Hz, 1H), 4.28 (dd, J=27.5, 16.8Hz, 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).

[1205]

[1206] Intermediate 109

[1207]

[1208] 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

[1209] Intermediate 109 was prepared according to a similar procedure as described for Intermediate 47 using known starting material tert-butyl 2-oxo-7-{[(4-oxocyclohexyl)oxy]methyl}-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate to give the title compound as a white solid (22.6 g). [M+H] + m / z 565.3.

[1210] Intermediate 110

[1211]

[1212] 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

[1213] Intermediate 110 was prepared according to a similar procedure described for Intermediate 60 using commercially available starting material 1-iodo-3-(phenoxymethyl)benzene and Intermediate 110 to give the title compound as a yellow solid (1.15 g). [M+H] + m / z 563.4

[1214] Intermediate 111

[1215]

[1216] 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

[1217] Intermediate 111 was prepared according to a similar procedure as described for Intermediate 8 to give the title compound (952 mg). [M+H] + m / z 475.4

[1218] Intermediate 112

[1219]

[1220] Rel-(6S,7R)-7-({[(1s,4s)-4-(3-hydroxyphenyl)cyclohexyl]oxy}methyl)-4-oxa-1,8-diazaspiro[5.5]undecan-2-one hydrochloride

[1221] Intermediate 112 was prepared according to a similar procedure as described for Intermediate 12 to give the title compound (134 mg). [M+H] + m / z 375.2

[1222] Intermediate 113

[1223]

[1224] 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

[1225] 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 chloroformate (0.07 mL, 0.720 mmol). After 30 min, the reaction was concentrated in vacuo at room temperature to afford the title compound (275 mg). [M+H] + m / z 587.3

[1226] Intermediate 114

[1227]

[1228] 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

[1229] 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 min, the reaction mixture was acidified with 2M aqueous HCl at room temperature, followed by addition of water and extraction of the crude material with EtOAc. The combined organic fractions were washed with brine, dried over Na2SO4, and evaporated in vacuo to give the title compound (170 mg). [M+H] + m / z 481.3

[1230] Example 53

[1231]

[1232] 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 Pentacosane]-2′(25′),3′,5′-triene-5,11′-dione

[1233] 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 first reverse phase column chromatography (0-100% acetonitrile + 0.1% formic acid / H2O + 0.1% formic acid) followed by second column chromatography (30-60% EtOAc + 20% EtOH / cyclohexane) to give the title compound (17.5 mg).

[1234] LCMS (Method C): [M+H] + m / z 445.3, RT 0.99 min

[1235] 1H NMR (500MHz, CDCl3) δ7.11 (br t, J=7.8Hz, 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=12.8Hz, 1H), 4.64 (br dd, J=14.1, 10.0Hz, 1H), 4.32 (br d, J=17.0Hz, 1H), 4.27 (br d, J=14.4Hz, 1H), 4.07-4.21 (m, 4H), 3.85 (br t, J=9.7Hz, 1H), 3.74(br s, 1H), 3.65(br dd, J=8.9, 3.1Hz, 1H), 3.35 (br d, J=11.8Hz, 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).

[1236] Examples 53a and 53b

[1237]

[1238] 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 ]pentacosane]-2′(25′),3′,5′-triene-5,11′-dione;

[1239] 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 Pentacosane]-2′(25′),3′,5′-triene-5,11′-dione

[1240] Example 53 (15.4 mg) was subjected to chiral preparative purification using a Waters 600 with 50 / 50% v / v hexane / ethanol + 0.1% isopropylamine (Chiralpak AS-H (25×2.0 cm), 5 μm, flow rate 17 mL / min) to afford the title compound (peak 1, 4.18 mg, 100% ee; and peak 2, 4.61 mg, 100% ee).

[1241] Example 53a: Peak 1 (stereochemistry tentatively assigned)

[1242] LCMS (Method C): [M+H] + m / z 445.3, RT 0.99 min.

[1243] Chiral analysis (Chiralpak AS-H, 25×0.46 cm, 5 μm, 50:50 hexane:ethanol + 0.1% isopropylamine): RT 6.2 min

[1244] 1 H NMR (400MHz, CDCl3) δ7.11 (br t, J=7.8Hz, 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=12.8Hz, 1H), 4.64 (br dd, J=14.1, 10.0Hz, 1H), 4.32 (br d, J=17.0Hz, 1H), 4.27 (br d, J=14.4Hz, 1H), 4.07-4.21 (m, 4H), 3.85 (br t, J=9.7Hz, 1H), 3.74(br s, 1H), 3.65(br dd, J=8.9, 3.1Hz, 1H), 3.35 (br d, J=11.8Hz, 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).

[1245] Example 53b: Peak 2 (stereochemistry tentatively assigned)

[1246] LCMS (Method C): [M+H] + m / z 445.3, RT 0.99 min.

[1247] Chiral analysis (Chiralpak AS-H, 25×0.46 cm, 5 μm, 50:50 hexane:ethanol + 0.1% isopropylamine): RT 10.2 min

[1248] 1H NMR (400MHz, CDCl3) δ7.11 (br t, J=7.8Hz, 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=12.8Hz, 1H), 4.64 (br dd, J=14.1, 10.0Hz, 1H), 4.32 (br d, J=17.0Hz, 1H), 4.27 (br d, J=14.4Hz, 1H), 4.07-4.21 (m, 4H), 3.85 (br t, J=9.7Hz, 1H), 3.74(br s, 1H), 3.65(br dd, J=8.9, 3.1Hz, 1H), 3.35 (br d, J=11.8Hz, 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).

[1249] Example 54

[1250]

[1251] 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

[1252] Example 54 was prepared according to a similar procedure described for Example 53 using intermediate 113 to give the title compound (10.9 mg).

[1253] LCMS (Method C): [M+H] + m / z 459.3, RT 1.01 min

[1254] 1H NMR (400MHz, CDCl3) δ7.12 (t, J=7.7Hz, 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=11.7Hz, 1H), 3.30-3.16 (m, 1H), 2.60-2.47 (m, 1H), 2.23 (td, J=14.1, 7.8Hz, 1H), 1.96-1.89 (m, 1H), 2.14-1.38 (m, 12H).

[1255] Examples 54a and 54b

[1256]

[1257] 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

[1258] 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

[1259] Example 54 (9.3 mg) was subjected to chiral preparative purification using a Waters 600 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 give the title compounds (peak 1, 1.23 mg, 100% ee; and peak 2, 1.16 mg, 100% ee).

[1260] Example 54a: Peak 1 (stereochemistry tentatively assigned)

[1261] LCMS (Method C): [M+H] + m / z 459.3, RT 1.02 min.

[1262] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 50:50 hexane:ethanol + 0.1% isopropylamine): RT 6.7 minutes

[1263] 1 H NMR (400MHz, CDCl3) δ7.12 (t, J=7.7Hz, 1H), 6.63-7.03 (m, 3H), 6.13 (s, 1H), 4.90 (dd, J=7.8, 3.6Hz, 1H), 4.5 7-4.79(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=11.7Hz, 1H), 3.25 (td , J=13.1, 3.0Hz, 1H), 2.53 (tt, J=12.1, 3.5Hz, 1H), 2.18-2.35 (m, 1H), 1.86-1.98 (m, 1H), 1.37-2.15 (m, 12H).

[1264] Example 54b: Peak 2 (stereochemistry tentatively assigned)

[1265] LCMS (Method C): [M+H] + m / z 459.3, RT 1.02 min.

[1266] Chiral analysis (Chiralpak IC, 25×0.46 cm, 5 μm, 50:50 hexane:ethanol + 0.1% isopropylamine): RT 8.6 min

[1267] 1H NMR (400MHz, CDCl3) δ7.12 (t, J=7.7Hz, 1H), 6.63-7.03 (m, 3H), 6.13 (s, 1H), 4.90 (dd, J=7.8, 3.6Hz, 1H), 4.5 7-4.79(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=11.7Hz, 1H), 3.25 (td , J=13.1, 3.0Hz, 1H), 2.53 (tt, J=12.1, 3.5Hz, 1H), 2.18-2.35 (m, 1H), 1.86-1.98 (m, 1H), 1.37-2.15 (m, 12H).

[1268]

[1269] Intermediate 115

[1270]

[1271] tert-Butyl 2-[(2-bromophenyl)methoxy]acetate

[1272] 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 (Na2SO4) and evaporated in vacuo. The crude product was purified by column chromatography (0-10% EtOAc / cyclohexane) to give the title compound (1.76 g) as a colorless oil. [M+H+Na] + m / z 323.1, 325.1

[1273] Intermediate 116

[1274]

[1275] 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

[1276] Intermediate 109 (300 mg), cesium carbonate (432 mg, 1.33 mmol), Intermediate 115 (200.01 mg) and A solution of (19 mg, 0.050 mmol) in 1,4-dioxane (3 mL) was evacuated and backfilled with nitrogen three times. Pd(OAc)2 (6 mg, 0.030 mmol) was then added and the mixture was heated to 100 ° C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled and filtered through a celite pad, 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 Na2SO4, filtered and concentrated in vacuo. The product was purified by column chromatography (0-40% EtOAc / EtOH 9: 1 in cyclohexane) to give the title compound (217 mg) as a yellow oil. [M+H] + m / z 601.4

[1277] Intermediate 117

[1278]

[1279] 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

[1280] To a solution of intermediate 116 (197 mg) in ethanol (22 mL) was added sodium carbonate (104 mg, 0.980 mmol) and palladium on carbon (10%, 69 mg, 0.070 mmol). The mixture was placed under a hydrogen atmosphere (1 atm) and stirred for 40 min. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude material was dissolved with EtOAc and the solution was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (177 mg) as a white solid. [M+H] + m / z 603.4

[1281] Intermediate 118

[1282]

[1283] 2-({2-[(1s,4s)-4-{[rel-(6S,7R)-2-oxo-4-oxa-1,8-diazaspiro[5.5]undec-7-yl]methoxy}cyclohexyl]phenyl}methoxy)acetic acid

[1284] Intermediate 118 was prepared according to a similar procedure as described for Intermediate 32 to give the title compound as a white solid (22 mg). [M+H] + m / z 447.3

[1285] Example 55

[1286]

[1287] 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

[1288] Example 55 was prepared according to a similar procedure described for Example 8 using intermediate 118 to give the title compound as a white solid (3 mg).

[1289] LCMS (Method C): [M+H] + m / z 429.5, RT 0.87 min

[1290] 1 H NMR (400MHz, CDCl3) δ7.36-7.43(m, 1H), 7.09-7.25(m, 3H), 6.20(br s, 1H), 5.51 (dd, J=11.9, 3.7Hz, 1H), 5.25 (d, J=9.9Hz, 1H), 4.72 (d, J=12.7Hz, 1H), 4. 26-4.37(m, 1H), 4.23(d, J=10.0Hz, 1H), 4.07-4.19(m, 2H), 3.95-4.05(m, 2H), 3.89(br dd, J=11.8, 9.2Hz, 1H), 3.68-3.75(m, 1H), 3.65(br dd, J=9.0, 4.1Hz, 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).

[1291] Example 56

[1292]

[1293] 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 .011，16 ]Tricosane]-2′(7′),3′,5′-triene-5,10′-dione

[1294] Example 56 was prepared according to a procedure similar to that described for Example 8 using commercially available starting material, 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate, to give the title compound (36 mg) as a white solid. Achiral preparative purification was performed using UPLC Waters with mass spectrometry detection (MS: SQD2). Column: CSHC18 (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 over 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 to give the title compound (10.7 mg).

[1295] LCMS (Method B): [M+H]+ m / z 433.3, RT 2.99

[1296] 1 H NMR (400MHz, CDCl3) δ7.16 (td, J=7.9, 1.7Hz, 1H), 7.09 (dd, J=7.4, 1.6Hz, 1H), 6.90 (td, J=7.4, 1.0Hz, 1 H), 6.78-6.72 (m, 1H), 6.70 (s, 1H), 5.58 (d, J=52.0Hz, 1H), 5.42 (dd, J=10.4, 4.0Hz, 1H), 5.11 (d, J=10.6 Hz, 1H), 4.33 (d, J=10.6Hz, 1H), 4.17 (d, J=11.4Hz, 1H), 3.91-3.83 (m, 2H), 3.79-3.67 (m, 2H), 3.62-3.4 6(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).

[1297] Examples 56a and 56b

[1298]

[1299] 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

[1300] 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

[1301] Example 56 (36 mg, 0.083 mmol) was subjected to chiral preparative purification using a Waters 600 and a Chiralpak IC, 25×2.0 cm, 5 μm column, eluting with 55:45 heptane:ethanol + 0.1% isopropylamine to provide the title compound (Peak 1, 2.84 mg, 100% ee; and Peak 2, 3.4 mg, 97.7% ee).

[1302] Example 56a: Peak 1 (stereochemistry tentatively assigned)

[1303] LCMS (Method C): [M+H] + m / z 433.3, RT 0.99 min

[1304] Chiral analysis (Chiralpak IC, 25 × 0.46 cm, 5 μm, 55:45 hexane: ethanol + 0.1% isopropylamine: RT 6.3 min)

[1305] 1H NMR (500MHz, CDCl3) δ7.18 (td, J=7.7, 1.7Hz, 1H), 7.10 (dd, J=7.4, 1.5Hz, 1H), 6.91 (td, J=7.4, 1.0Hz, 1H), 6.76 (d, J=8.0Hz, 1H), 5.91 (br s, 1H), 5.61 (d, J = 52.0Hz, 1H), 5.43 (dd, J = 10.1, 3.8Hz, 1H), 5.12 (d, J = 10.6Hz, 1H) , 4.34 (d, J = 10.6Hz, 1H), 4.18 (d, J = 11.7Hz, 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).

[1306] Example 56b: Peak 2 (stereochemistry tentatively assigned)

[1307] LCMS (Method C): [M+H] + m / z 433.3, RT 0.99 min

[1308] Chiral analysis (Chiralpak IC, 25 × 0.46 cm, 5 μm, 55:45 hexane: ethanol + 0.1% isopropylamine: RT 7.5 min

[1309] 1H NMR (500MHz, CDCl3) δ7.18 (td, J=7.7, 1.7Hz, 1H), 7.10 (dd, J=7.4, 1.5Hz, 1H), 6.91 (td, J=7.4, 1.0Hz, 1H), 6.76 (d, J=8.0Hz, 1H), 5.91 (br s, 1H), 5.61 (d, J = 52.0Hz, 1H), 5.43 (dd, J = 10.1, 3.8Hz, 1H), 5.12 (d, J = 10.6Hz, 1H) , 4.34 (d, J = 10.6Hz, 1H), 4.18 (d, J = 11.7Hz, 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).

[1310]

[1311] Intermediate 119

[1312]

[1313] tert-Butyl 2-({[4-(Benzyloxy)cyclohexyl]oxy}methyl)-3-nitropiperidine-1-carboxylate

[1314] Intermediate 119 was prepared according to a similar procedure as described for Intermediate 41 using commercially available starting material 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate to give the title compound as a yellow oil (12.2 g). [M-Boc+H] + m / z 349.3

[1315] Intermediate 120

[1316]

[1317] tert-Butyl-rel-(2R,3R)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-nitro-3-(prop-2-en-1-yl)piperidine-1-carboxylate

[1318] A solution of potassium hydroxide (1.17 g, 20.87 mmol) in 2-propanol (42 mL) and methanol (42 mL) was stirred for 1 h. A solution of intermediate 119 (8.51 g) in methanol (42 mL) was added. The solution was then 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, followed by the addition of propylene acetate (2.25 mL, 20.87 mmol). The reaction mixture was heated at 55 ° C under nitrogen for 16 h, then cooled to room temperature. The mixture was concentrated in vacuo and redissolved in MTBE. The mixture was filtered through a celite pad and washed with water. The organic extract was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (0-10% EtOAc / cyclohexane) to give the title compound (5.8 g) as a colorless oil. [M+H] + m / z 489.4

[1319] Intermediate 121

[1320]

[1321] tert-Butyl-rel-(2R,3R)-3-amino-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(prop-2-en-1-yl)piperidine-1-carboxylate

[1322] Intermediate 121 was prepared according to a similar procedure as described for Intermediate 6 to give the title compound as a yellow oil (3.85 g). [M+H] + m / z 459.4

[1323] Intermediate 122

[1324]

[1325] 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

[1326] To a solution of intermediate 121 (300 mg) in DCM (6.5 mL) was added triethylamine (0.18 mL, 1.31 mmol) and trifluoroacetic anhydride (0.1 mL, 0.690 mmol) dropwise at 0°C. The reaction mixture was stirred for 1 h before being diluted with DCM and washed with water, saturated aqueous NaHCO3, and 1 M aqueous Na2CO3 until pH = 9. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound (337 mg) as a yellow oil. [M+H]+ m / z 555.5

[1327] Intermediate 123

[1328]

[1329] tert-Butyl-rel-(2R,3R)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(2-oxoethyl)-3-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate

[1330] In a 3-neck round-bottom flask, intermediate 122 (3.13 g) was dissolved in DCM (256 mL) and the solution was stirred at -78 ° C while bubbling ozone through the solution. After 15 min, ozone was replaced with N2. After 10 min, DCM (9 mL) containing triphenylphosphine (1.48 g, 5.64 mmol) was slowly added to the cold mixture. The mixture was slowly warmed to room temperature and concentrated in vacuo to give a clear oil. The crude product was purified by column chromatography (0-30% EtOAc + EtOH 10% / cyclohexane) to give the title compound (2 g). [M-Boc + H] + m / z 457.5

[1331] Intermediate 124

[1332]

[1333] tert-Butyl-rel-(2R,3R)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(2-hydroxyethyl)-3-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate

[1334] To a mixture of intermediate 123 (2.0 g) and methanol (17 mL) was added sodium borohydride (136 mg, 3.59 mmol) at 0°C. The suspension was stirred at 0°C for 1 h, then the reaction was allowed to warm to room temperature and the mixture was diluted with EtOAc and washed with water (100 mL). The aqueous phase was extracted three times with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (2 g). [M-Boc+H] + m / z 459.3

[1335] Intermediate 125

[1336]

[1337] tert-Butyl-rel-(2R,3R)-3-amino-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(2-hydroxyethyl)piperidine-1-carboxylate

[1338] 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 h, then the mixture was diluted with EtOAc and washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (1.51 g). [M+H] + m / z 463.4

[1339] Intermediate 126

[1340]

[1341] Tert-butyl-rel-(6R,7R)-7-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1342] A solution of N, N-diisopropylethylamine (0.85 mL, 4.86 mmol) was added dropwise 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) at 0 ° C and the resulting mixture was stirred for 30 min. The reaction mixture was allowed to warm to room temperature and purged with a stream of N2 for 30 min until pH = 9 (the exhaust gas was passed through a trap containing a 2N NaOH aqueous solution to quench all excess phosgene). The reaction mixture was then diluted with water (30 mL) and extracted with DCM (3 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-35% EtOAc + 20% EtOH / cyclohexane) to give the title compound (1.34 g). [M+H] + m / z 489.4

[1343] Intermediate 127

[1344]

[1345] Tert-butyl-rel-(6R,7R)-7-{[(4-hydroxycyclohexyl)oxy]methyl}-2-oxo-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1346] Intermediate 127 was prepared according to a similar procedure as described for Intermediate 8 to give the title compound as a colorless oil (859 mg). [M+H] + m / z 399.5

[1347] Intermediate 128

[1348]

[1349] Tert-butyl-rel-(6R,7R)-2-oxo-7-{[(4-oxocyclohexyl)oxy]methyl}-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1350] Intermediate 128 was prepared according to a similar procedure as described for Intermediate 46 to give the title compound (1.22 g). [M+H] + m / z 397.5

[1351] Intermediate 129

[1352]

[1353] 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

[1354] Intermediate 129 was prepared according to a similar procedure as described for Intermediate 47 to give the title compound (1.1 g). [M+H] + m / z 565.5

[1355] Intermediate 130

[1356]

[1357] tert-Butyl-re1-(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

[1358] Intermediate 130 was prepared according to a similar procedure as described for Intermediate 48 to give the title compound (50 mg). [M+H] + m / z 563.3

[1359] Intermediate 131

[1360]

[1361] 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

[1362] Intermediate 131 was prepared according to a similar procedure as described for Intermediate 49 to give the title compound (45 mg). [M+H] + m / z 475.3

[1363] Intermediate 132

[1364]

[1365] tert-Butyl-rel-(6R,7R)-2-oxo-7-({[(1s,4s)-4-{2-[2-(tert-butyloxy)-2-oxoethoxy]phenyl}cyclohexyl]oxy}methyl)-3-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1366] Intermediate 132 was prepared according to a similar procedure as described for Intermediate 67 to give the title compound (38 mg). [M+H] + m / z 589.3

[1367] Intermediate 133

[1368]

[1369] 2-{2-[(1s,4s)-4-{[rel-(6R,7R)-2-oxo-3-oxa-1,8-diazaspiro[5.5]undec-7-yl]methoxy}cyclohexyl]phenoxy}acetic acid hydrochloride

[1370] Intermediate 133 was prepared according to a similar procedure as described for Intermediate 57 to give the title compound (28 mg). [M+H]+m / z 433.3

[1371] Example 57

[1372]

[1373] Rel-(1′s,4R,16′R,19′s)-8′,18′-dioxa-11′-azaspiro[1,3-oxazine-4,15′-tetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]Tricosane]-2′(7′),3′,5′-triene-2,10′-dione

[1374] Example 57 was prepared according to a similar procedure described for Example 1 using intermediate 133 to give the title compound (2.2 mg).

[1375] LCMS (Method C): [M+H] +m / z 415.2, RT 0.92 min

[1376] 1 H NMR (500MHz, CDCl3) δ7.14-7.24 (m, 1H), 7.05-7.13 (m, 1H), 6.91 (br t, J=7.4Hz, 1H), 6.75 (br d, J=8.0Hz, 1H), 6.35 (br s, 1H), 5.09 (br d, J=10.4Hz, 2H), 4.62 (br t, J=12.0Hz, 1H), 4.34-4.41 (m, 1H), 4.31 (br d, J=10.4Hz, 1H), 3.93 (br t, J=9.5Hz, 1H), 3.75 (br s, 1H), 3.70 (br d, J=12.8Hz, 1H), 3.58(br d, J=4.8Hz, 1H), 3.44-3.54(m, 1H), 2.52-2.72(m, 1H), 1.21-2.77(m, 14H).

[1377]

[1378] Intermediate 134

[1379]

[1380] tert-Butyl-rel-(2R,3R)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(prop-2-en-1-yl)-3-(prop-2-enamido)piperidine-1-carboxylate

[1381] To a stirred 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-acryloyl chloride (4.62 mL, 4.62 mmol) in MeTHF at 0 ° C. The solution was stirred at 0 ° C for 1 h. Additional triethylamine (3.0 mL, 21.52 mmol) and 2-acryloyl chloride (1.0 mL, 1 mmol, 1 M solution in MeTHF) were added and the mixture was stirred at 0 ° C for 1 h. The reactants were quenched by adding saturated NaHCO3 aqueous solution (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (0-30% EtOAc / cyclohexane) to give the title compound (1.5 g) as a colorless thick oil. [M+H] + m / z 513.4

[1382] Intermediate 135

[1383]

[1384] Tert-butyl-rel-(6R,7R)-7-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-2-oxo-1,8-diazaspiro[5.5]undec-3-ene-8-carboxylate

[1385] A solution of intermediate 134 (1.62 g) in toluene (632 mL) was degassed by bubbling with N2(g) 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 stirred under a slow N2 flow for 3 h at the same temperature. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (0-50% EtOAc / cyclohexane) to give the title compound (1.23 g) as a pale yellow oil. [M+H] + m / z 485.4

[1386] Intermediate 136

[1387]

[1388] Tert-butyl-rel-(6S,7R)-7-{[(4-hydroxycyclohexyl)oxy]methyl}-2-oxo-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1389] Intermediate 136 was prepared according to a similar procedure as described for Intermediate 8 to give the title compound as an off-white solid (1.02 g). [M+H] + m / z 397.4

[1390] Intermediate 137

[1391]

[1392] Tert-butyl-rel-(6S,7R)-2-oxo-7-{[(4-oxocyclohexyl)oxy]methyl}-1,8-diazaspiro[5.5]-undecane-8-carboxylate

[1393] Intermediate 137 was prepared according to a similar procedure as described for Intermediate 46 to give the title compound as a colorless oil (1.6 g). [M+H] + m / z 395.4

[1394] Intermediate 138

[1395]

[1396] Tert-butyl-rel-(6S,7R)-7-[({4-[(4-methylbenzenesulfonamido)imino]cyclohexyl}oxy)methyl]-2-oxo-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1397] Intermediate 138 was prepared according to a similar procedure as described for Intermediate 47 to give the title compound as a white solid (1.02 g). [M+H] + m / z 563.4

[1398] Intermediate 139

[1399]

[1400] 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

[1401] Intermediate 139 was prepared according to a similar procedure as described for Intermediate 48 to give the title compound as a yellow oil (345 mg). [M+H] + m / z 561.5

[1402] Intermediate 140

[1403]

[1404] Tert-butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1405] Intermediate 140 was prepared according to a similar procedure as described for Intermediate 8 to give the title compound as a yellow oil (140 mg). [M+H] + m / z 473.4

[1406] Intermediate 141

[1407]

[1408] tert-Butyl-rel-(6S,7R)-2-oxo-7-({[(1s,4s)-4-{2-[2-(tert-butyloxy)-2-oxoethoxy]phenyl}cyclohexyl]oxy}methyl)-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1409] Intermediate 141 was prepared according to a similar procedure as described for Intermediate 67 to give the title compound as a yellow oil (120 mg). [M+H]+ m / z 587.5

[1410] Intermediate 142

[1411]

[1412] 2-{2-[(1s,4s)-4-{[rel-(6S,7R)-2-oxo-1,8-diazaspiro[5.5]undec-7-yl]methoxy}cyclohexyl]phenoxy}acetic acid hydrochloride

[1413] Intermediate 142 was prepared according to a similar procedure as described for Intermediate 68 to give the title compound as a yellow oil (120 mg). [M-HCl+H] + m / z 431.4

[1414] Example 58

[1415]

[1416] Rel-(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

[1417] Example 58 was prepared according to a similar procedure described for Example 1 using intermediate 142 to give the title compound as a white solid (35 mg).

[1418] LCMS (Method C): [M+H] + m / z 413.4, RT 0.95 min

[1419] 1H NMR (500MHz, CDCl3) δ7.17 (td, J=7.7, 1.7Hz, 1H), 7.10 (dd, J=7.4, 1.5Hz, 1H), 6.90 (td, J=7.4, 1.0Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.25 (br s, 1H), 5.13 (dd, J=10.9, 3.6Hz, 1H), 5.10 (d, J=10.6Hz, 1H), 4.31 (d, J=10.6Hz, 1H), 3.90 (dd, J=10.8, 8.6Hz, 1H), 3.71 (br s, 1H), 3.74-3.66 (m, 1H), 3.53 (dd, J=8.4, 4.0Hz, 1H), 3.52-3.43 (m, 1 H), 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).

[1420] Examples 58a and 58b

[1421]

[1422] 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

[1423] 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

[1424] Example 58 (33 mg, 0.080 mmol) was subjected to chiral preparative purification using a Waters 600 and a Chiralpak AD-H, 25×2.0 cm, 5 μm column, eluting with 65:35 heptane:(ethanol / methanol 1 / 1 + 0.1 isopropylamine) to give the title compound (Peak 1, 9.52 mg, 100% ee; and Peak 2, 9.96 mg, 100% ee).

[1425] Example 58a: Peak 1 (stereochemistry tentatively assigned)

[1426] LCMS (Method C): [M+H] + m / z 413.3, RT 0.95min

[1427] Chiral analysis (Chiralpak AD-H, 25 × 0.46 cm, 5 μm, 65:35 hexane: (ethanol / methanol 1 / 1 + 0.1 isopropylamine): RT 6.4 min

[1428] 1 H NMR (500MHz, CDCl3) δ7.17 (td, J=7.7, 1.7Hz, 1H), 7.10 (dd, J=7.4, 1.5Hz, 1H), 6.90 (td, J=7.4, 1.0Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.25 (br s, 1H), 5.13 (dd, J=10.9, 3.6Hz, 1H), 5.10 (d, J=10.6Hz, 1H), 4.31 (d, J=10.6Hz, 1H), 3.90 (dd, J=10.8, 8.6Hz, 1H), 3.71 (br s, 1H), 3.74-3.66 (m, 1H), 3.53 (dd, J=8.4, 4.0Hz, 1H), 3.52-3.43 (m, 1 H), 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).

[1429] Example 58b: Peak 2 (stereochemistry tentatively assigned)

[1430] LCMS (Method C): [M+H] + m / z 413.3, RT 0.94 min

[1431] Chiral analysis (Chiralpak AD-H, 25 × 0.46 cm, 5 μm, 65:35 hexane: (ethanol / methanol 1 / 1 + 0.1 isopropylamine): RT 9.7 min

[1432] 1 H NMR (500MHz, CDCl3) δ7.17 (td, J=7.7, 1.7Hz, 1H), 7.10 (dd, J=7.4, 1.5Hz, 1H), 6.90 (td, J=7.4, 1.0Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.25 (br s, 1H), 5.13 (dd, J=10.9, 3.6Hz, 1H), 5.10 (d, J=10.6Hz, 1H), 4.31 (d, J=10.6Hz, 1H), 3.90 (dd, J=10.8, 8.6Hz, 1H), 3.71 (br s, 1H), 3.74-3.66 (m, 1H), 3.53 (dd, J=8.4, 4.0Hz, 1H), 3.52-3.43 (m, 1 H), 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).

[1433]

[1434] Intermediate 143

[1435]

[1436] tert-Butyl-rel-(2R,3R)-2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-ethanesulfonamido-3-(prop-2-en-1-yl)piperidine-1-carboxylate

[1437] To a stirred solution of intermediate 121 (3.65 g) and triethylamine (3.33 mL, 23.88 mmol) in anhydrous DCM (79 mL) was added 2-chloroethanesulfonyl chloride (1.67 mL, 15.92 mmol) at 0 ° C and the mixture was stirred for 30 min. The reaction mixture was cooled to room temperature, quenched with saturated NH4Cl 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 / cyclohexane) to give the title compound (3.28 g) as a colorless gum. [M+H] + m / z 549.4

[1438] Intermediate 144

[1439]

[1440] 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

[1441] Intermediate 144 was prepared according to a similar procedure as described for Intermediate 135 to give the title compound as a pale yellow oil (2.81 g). [M+H] + m / z 521.4

[1442] Intermediate 145

[1443]

[1444] Tert-butyl-rel-(6R,7R)-7-{[(4-hydroxycyclohexyl)oxy]methyl}-2,2-dioxo-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1445] Intermediate 145 was prepared according to a similar procedure as described for Intermediate 8 to give the title compound as a colorless oil (2.1 g). [M+H] + m / z 433.3

[1446] Intermediate 146

[1447]

[1448] Tert-butyl-rel-(6R,7R)-2,2-dioxo-7-{[(4-oxocyclohexyl)oxy]methyl}-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1449] Intermediate 146 was prepared according to a similar procedure as described for Intermediate 46 to give the title compound as a colorless oil (2.8 g). [M+H] + m / z 431.4

[1450] Intermediate 147

[1451]

[1452] Tert-butyl-rel-(6R,7R)-7-[({4-[(4-methylbenzenesulfonylamino)imino]cyclohexyl}oxy)methyl]-2,2-dioxo-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1453] Intermediate 147 was prepared according to a similar procedure as described for Intermediate 47 to give the title compound as a white solid (1.87 g). [M+H] + m / z 599.4

[1454] Intermediate 148

[1455]

[1456] 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

[1457] Intermediate 148 was prepared according to a similar procedure as described for Intermediate 47 to give the title compound as a yellow oil (1.16 g). [M+H] + m / z 597.5

[1458] Intermediate 149

[1459]

[1460] 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

[1461] Intermediate 149 was prepared according to a similar procedure as described for Intermediate 8 to give the title compound as a white solid (880 mg). [M+H] + m / z 509.4

[1462] Intermediate 150

[1463]

[1464] tert-Butyl-rel-(6R,7R)-2,2-dioxo-7-({[(1s,4s)-4-{2-[2-(tert-butyloxy)-2-oxoethoxy]-phenyl}cyclohexyl]oxy}methyl)-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1465] Intermediate 150 was prepared according to a similar procedure as described for Intermediate 67 to give the title compound as a colorless oil (312 mg). [M+H] + m / z 623.4

[1466] Intermediate 151

[1467]

[1468] 2-{2-[(1s,4s)-4-{[rel-(6R,7R)-2,2-dioxo-2λ 6 -thia-1,8-diazaspiro[5.5]undec-7-yl]methoxy}cyclohexyl]phenoxy}acetic acid

[1469] Intermediate 151 was prepared according to a similar procedure as described for Intermediate 68 to give the title compound as a white solid (265 mg). [M+H] + m / z 467.3

[1470] Example 59

[1471]

[1472] 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]thiazinane]-2(7),3,5-triene-1′,1′,10-trione

[1473] Example 59 was prepared according to a similar procedure described for Example 1 using Intermediate 151 to give the title compound as a white solid (50 mg).

[1474] LCMS (Method C): [M+H] +m / z 449.3, RT 1.06 min

[1475] 1 H NMR (500MHz, CDCl3) δ7.17 (td, J=7.7, 1.6Hz, 1H), 7.10 (dd, J=7.3, 1.5Hz, 1H), 6.90 (td, J=7.4, 0.8Hz, 1H), 6.71-6.78 (m, 1H), 5.38 (br dd, J=9.6, 4.1Hz, 1H), 5.08 (d, J=10.7Hz, 1H), 4.31 (d, J=10.7Hz, 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), 3.51-3.62 (m, 1H), 3.18-3.25 (m, 1H), 2.96 (ddd, J=13.1, 11.3, 3.6Hz, 1H), 2.61-2.73(m, 2H), 2.51-2.62(m, 1H), 2.18-2.33(m, 3H), 2.05(br d, J=14.0Hz, 1H), 1.86-1.98 (m, 2H), 1.21-1.83 (m, 8H).

[1476] Examples 59a and 59b

[1477]

[1478] Example 59a: (1s, 15R, 16R, 19s)-8, 18-dioxa-11-azaspiro [tetracyclo [17.2.2.0 2 , 7 .0 11 , 16 ]-tricosane-15,3′-[1λ6,2]thiazinane]-2(7),3,5-triene-1′,1′,10-trione

[1479] Example 59b: (1s, 15S, 16S, 19s)-8,18-dioxa-11-azaspiro[tetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]-tricosane-15,3′-[1λ 6 ,2]thiazinane]-2(7),3,5-triene-1′,1′,10-trione

[1480] Example 59 (48 mg, 0.107 mmol) was subjected to chiral preparative purification using a Waters 600 and a Chiralcel OD-H, 25×2.0 cm, 5 μm column, eluting with 70:30 heptane:ethanol + 0.1 isopropylamine to provide the title compound (Peak 1, 20.8 mg, 97.4% ee; and Peak 2, 19.3 mg, 100% ee).

[1481] Example 59a: Peak 1 (stereochemistry tentatively assigned)

[1482] LCMS (Method C): [M+H] + m / z 449.2, RT 1.06 min

[1483] Chiral analysis (Chiralcel OD-H, 25 × 0.46 cm, 5 μm, 70:30 hexane: ethanol + 0.1 isopropylamine: RT 11.9 min

[1484] 1 H NMR (500MHz, CDCl3) δ7.17 (td, J=7.7, 1.6Hz, 1H), 7.10 (dd, J=7.3, 1.5Hz, 1H), 6.90 (td, J=7.4, 0.8Hz, 1H), 6.71-6.78 (m, 1H), 5.38 (br dd, J=9.6, 4.1Hz, 1H), 5.08 (d, J=10.7Hz, 1H), 4.31 (d, J=10.7Hz, 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), 3.51-3.62 (m, 1H), 3.18-3.25 (m, 1H), 2.96 (ddd, J=13.1, 11.3, 3.6Hz, 1H), 2.61-2.73(m, 2H), 2.51-2.62(m, 1H), 2.18-2.33(m, 3H), 2.05(br d, J=14.0Hz, 1H), 1.86-1.98 (m, 2H), 1.21-1.83 (m, 8H).

[1485] Example 59b: Peak 2 (stereochemistry tentatively assigned)

[1486] LCMS (Method C): [M+H] + m / z 449.2, RT 1.06 min

[1487] Chiral analysis (Chiralcel OD-H, 25 × 0.46 cm, 5 μm, 70:30 hexane: ethanol + 0.1 isopropylamine: RT 15.5 min)

[1488] 1 H NMR (500MHz, CDCl3) δ7.17 (td, J=7.7, 1.6Hz, 1H), 7.10 (dd, J=7.3, 1.5Hz, 1H), 6.90 (td, J=7.4, 0.8Hz, 1H), 6.71-6.78 (m, 1H), 5.38 (br dd, J=9.6, 4.1Hz, 1H), 5.08 (d, J=10.7Hz, 1H), 4.31 (d, J=10.7Hz, 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), 3.51-3.62 (m, 1H), 3.18-3.25 (m, 1H), 2.96 (ddd, J=13.1, 11.3, 3.6Hz, 1H), 2.61-2.73(m, 2H), 2.51-2.62(m, 1H), 2.18-2.33(m, 3H), 2.05(br d, J=14.0Hz, 1H), 1.86-1.98 (m, 2H), 1.21-1.83 (m, 8H).

[1489]

[1490] Intermediate 152

[1491]

[1492] tert-Butyl-rel-(6R,7R)-2,2-dioxo-7-({[(1s,4s)-4-(2-{[(1E)-3-(tert-butyloxy)-3-oxoprop-1-en-1-yl]oxy}phenyl)cyclohexyl]oxy}methyl)-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1493] Intermediate 154 was prepared from Intermediate 149 according to a similar procedure as described for Intermediate 30 to give the title compound as a pale yellow oil (150 mg). [M+H] + m / z 635.4 Intermediate 153

[1494]

[1495] tert-Butyl-rel-(6R,7R)-2,2-dioxo-7-({[(1s,4s)-4-{2-[3-(tert-butyloxy)-3-oxopropoxy]phenyl}cyclohexyl]oxy}methyl)-2λ 6 -Thia-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1496] Intermediate 153 was prepared according to a similar procedure as described for Intermediate 8 to give the title compound as a colorless oil (125 mg). [M+H] + m / z 637.4

[1497] Intermediate 154

[1498]

[1499] 3-{2-[(1s,4s)-4-{[rel-(6R,7R)-2,2-dioxo-2λ 6 -thia-1,8-diazaspiro[5.5]undec-7-yl]methoxy}cyclohexyl]phenoxy}propionic acid hydrochloride

[1500] Intermediate 154 was prepared according to a similar procedure as described for Intermediate 68 to give the title compound as a pale yellow solid (125 mg). [M+H] + m / z 481.3

[1501] Example 60

[1502]

[1503] Rel-(1s,16R,17R,20s)-8,19-dioxa-12-azaspiro[tetracyclo[18.2.2.0 2 , 7 .0 12 , 17 ]Tetracosane-16,3′-[1λ 6 ,2]thiazinane]-2(7),3,5-triene-1′,1′,11-trione

[1504] Example 60 was prepared according to a similar procedure described for Example 1 using intermediate 156 to give the title compound as a white solid (44 mg).

[1505] LCMS (Method C): [M+H] + m / z 463.3, RT 1.07 min

[1506] 1H NMR (500MHz, CDCl3) δ7.12 (td, J=7.8, 1.4Hz, 1H), 7.07-7.00 (m, 1H), 6.88-6.79 (m, 1H), 6.84-6.7 6(m, 1H), 5.60-4.84(m, 1H), 4.80-4.23(m, 1H), 4.07-4.01(m, 1H), 4.46-3.97(m, 1H), 4.16-3.94(m , 1H), 4.82-3.78(m, 1H), 3.94-3.73(m, 1H), 3.69-3.59(m, 1H), 3.27-3.18(m, 1H), 3.00-2.84(m, 1H ), 3.41-2.71(m, 1H), 3.61-2.39(m, 1H), 2.49-2.39(m, 1H), 3.18-2.15(m, 1H), 2.71-1.19(m, 16H).

[1507] Example 61

[1508]

[1509] Rel-(3S,18'S)-24'-fluoro-8'-oxa-13'-azaspiro[morpholine-3,17'-tetracyclo[18.3.1.0 2， 7 .0 13，18 ]Tetracosane]-1′(24′),2′(7′),3′,5′,20′,22′-hexaene-5,12′-dione

[1510] Example 61 was prepared according to a similar procedure described for Example 27 using commercially available starting material tert-butyl 3-oxopiperidine-1-carboxylate to give the title compound as a white solid (9.9 mg).

[1511] LCMS (Method B): [M+H] + m / z 439.3, RT 2.63 min

[1512] 1 H NMR (400MHz, CDCl3) δ7.42-6.56 (m, 8H), 5.26-4.36 (m, 1H), 4.34-3.52 (m, 4H), 3.47-2.48 (m, 4H), 2.48-1.78 (m, 3H), 1.79-1.07 (m, 7H).

[1513] Example 62

[1514]

[1515] Rel-(3S,18'S)-24'-fluoro-13'-azaspiro[morpholine-3,17'-tetracyclo[18.3.1.0 2，7 .0 13，18 ]Tetracosane]-1′(24′),2′(7′),3′,5′,20′,22′-hexaene-5,12′-dione

[1516] Example 62 was prepared according to a similar procedure described for Example 29 using commercially available starting material tert-butyl 3-oxopiperidine-1-carboxylate to give the title compound as a white solid (14.9 mg).

[1517] LCMS (Method B): [M+H] + m / z 437.0, RT 3.00 min

[1518] 1 H NMR (400MHz, CDCl3) δ7.42-6.56 (m, 8H), 5.26-4.36 (m, 1H), 4.34-3.52 (m, 4H), 3.47-2.48 (m, 4H), 2.48-1.78 (m, 3H), 1.79-1.07 (m, 7H).

[1519] Example 63

[1520]

[1521] Rel-(3S,18'S)-24'-fluoro-11'-methyl-8'-oxa-11',13'-diazaspiro[morpholine-3,17'-tetracyclo[18.3.1.0 2，7 .0 13，18 ]Tetracosane]-1′(24′),2′(7′),3′,5′,20′,22′-hexaene-5,12′-dione

[1522] Example 63 was prepared according to a similar procedure described for Example 30 using commercially available starting material tert-butyl 3-oxopiperidine-1-carboxylate to give the title compound as a white solid (1 mg).

[1523] LCMS (Method B): [M+H] + m / z 454.3, RT 2.73 min

[1524] 1H NMR (500MHz, CDCl3) δ7.43-7.31(m, 1H), 7.27-6.83(m, 6H), 6.13-5.91(m, 1H), 4.77-4.50( m, 1H), 4.39-4.26 (m, 1H), 4.24-4.06 (m, 2H), 3.96-3.86 (m, 1H), 3.53-3.44 (m, 1H), 3.42-3. 30 (m, 1H), 3.26-3.16 (m, 1H), 3.04-2.89 (m, 1H), 2.87-2.71 (m, 1H), 2.70-2.59 (m, 1H), 2.5 8-2.43 (m, 1H), 1.96-1.78 (m, 2H), 1.51-1.42 (m, 1H), 1.34-1.22 (m, 3H), 0.93-0.80 (m, 2H).

[1525] Example 64

[1526]

[1527] Rel-(3S,19'S)-25'-fluoro-12'-methyl-8'-oxa-12',14'-diazaspiro[morpholine-3,18'-tetracyclo[19.3.1.0 2，7 .0 14，19 Pentacosane]-1′(25′),2′(7′),3′,5′,21′,23′-hexaene-5,13′-dione

[1528] Example 64 was prepared according to a similar procedure described for Example 31 using commercially available starting material tert-butyl 3-oxopiperidine-1-carboxylate to give the title compound as a white solid (37.2 mg).

[1529] LCMS (Method A): [M+H] + m / z 486.3, RT 3.01 min

[1530] 1H NMR (500MHz, CDCl3) δ7.36 (td, J=7.9, 1.6Hz, 1H), 7.26-7.20 (m, 2H), 7.14-7.06 (m, 2H), 7.06- 7.00 (m, 1H), 6.96 (dd, J=8.0, 4.8Hz, 1H), 6.31-6.13 (m, 1H), 4.72 (dd, J=12.8, 3.1Hz, 1H), 4.39 -4.32(m, 2H), 4.16(d, J=16.9Hz, 1H), 4.06-3.95(m, 1H), 3.66-3.57(m, 1H), 3.54-3.42(m, 3H) , 3.42-3.32 (m, 1H), 2.98-2.88 (m, 2H), 2.67 (d, J=13.3Hz, 1H), 2.56 (s, 3H), 1.97-1.39 (m, 6H).

[1531]

[1532] Intermediate 155

[1533]

[1534] Tert-butyl-rel-(6S,7S)-7-({2-fluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl}methyl)-2-oxo.4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1535] Intermediate 155 was prepared according to a similar procedure described for Intermediate 78 using commercially available starting material tert-butyl 3-oxopiperidine-1-carboxylate to give the title compound as a white solid (108 mg). [M+H] + m / z 471.3

[1536] Intermediate 156

[1537]

[1538] Tert-butyl-rel-(6S,7S)-7-{[2′-(2-ethoxy-2-oxoethoxy)-2-fluoro-[1,1′-biphenyl]-3-yl]methyl}-2-oxo-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1539] To a solution of intermediate 155 (300 mg) and ethyl bromoacetate (0.095 mL, 0.861 mmol) in acetone (3.0259 mL) was added dipotassium carbonate (239 mg, 1.73 mmol) and the solution was heated to 50 ° C overnight. The solid was filtered off and the filtrate was concentrated in vacuo, then the residue was suspended in water (5 mL) and extracted with DCM (3×5 mL). The combined organic phases were concentrated in vacuo to give the title compound (332 mg) as a light brown solid. [M+H] + m / z 557.3

[1540] Intermediate 157

[1541]

[1542] Tert-butyl-rel-(6S,7S)-7-{[2-fluoro-2′-(2-hydroxyethoxy)-[1,1′-biphenyl]-3-yl]methyl}-2-oxo-4-oxa-1,8-diazaspiro[5.5]undecane-8-carboxylate

[1543] 2M lithium borohydride in THF (0.27 mL, 0.531 mmol) was added dropwise to a stirred solution of intermediate 156 (332 mg) in anhydrous THF (5 mL) at 0 ° C. and the mixture was stirred at room temperature for 20 h. Additional 2M lithium borohydride (0.27 mL, 0.531 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated in vacuo to give the title compound (284 mg) as a colorless solid. [M+H] + m / z 515.2

[1544] Intermediate 158

[1545]

[1546] Rel-(6S,7S)-7-{[2-fluoro-2′-(2-hydroxyethoxy)-[1,1′-biphenyl]-3-yl]methyl}-4-oxa-1,8-diazaspiro[5.5]undecan-2-one hydrochloride

[1547] Dioxane (6.0 mL, 24.0 mmol) containing 4 M hydrochloric acid was added to intermediate 157 (284 mg) at room temperature, and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo. The residue was resuspended with water (10 mL) and DCM (10 mL). The organic phase was discarded and the aqueous phase was washed with additional DCM (10 mL). The pH of the aqueous phase was adjusted to approximately pH 10 with 2 M NaOH. The aqueous phase was extracted with DCM (3 × 10 mL). These combined organic extracts were passed through a hydrophobic glass frit and concentrated in vacuo to give the title compound (233 mg) as a colorless solid. [M+H] + m / z 415.3

[1548] Example 65

[1549]

[1550] Rel-(3S,18'S)-24'-fluoro-8',11'-dioxa-13'-azaspiro[morpholine-3,17'-tetracyclo[18.3.1.0 2 , 7 .0 13 , 18 ]Tetracosane]-1′(24′),2′(7′),3′,5′,20′,22′-hexaene-5,12′-dione

[1551] To a solution of intermediate 158 (233 mg) and DIPEA (0.83 mL, 4.78 mmol) in anhydrous acetonitrile (27.049 mL) was added bis(trichloromethyl) carbonate (47 mg, 0.158 mmol) in anhydrous acetonitrile (8.791 mL) over 2 hours. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was then heated to 80°C for 18 hours. The reaction mixture was cooled to room temperature and then concentrated in vacuo to obtain the crude material. The crude material was purified by acidic preparative HPLC. Early acidic elution method: Waters Sunfire C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature). Injection volume 1500 μL, flow rate 40 mL / min. 10% B (A = 0.1% formic acid / water; B = 0.1% formic acid / acetonitrile) for 1.90 minutes, followed by a gradient of 10-95% B over 14.1 minutes and a hold of 1.9 minutes. The mixture was stirred for 2 hours at 4 ℃ for 30 minutes.Then a second gradient of 95-10% B was applied for 0.3 min and held for an additional 0.9 min. UV spectra were recorded at 215 nm using a Gilson detector. The appropriate fractions were collected, combined and concentrated to give the desired product in approximately 70% purity. The crude material was re-purified by reverse phase column chromatography (10-100% MeCN (0.1% formic acid) / water (0.1% formic acid) to give the title compound (8.9 mg) as a colorless solid.

[1552] LCMS (Method A): [M+H] + m / z 441.2, RT 2.71 and 2.90 min

[1553] 1 H NMR (500MHz, CDCl3) δ7.35 (q, J=8.5Hz, 1H), 7.24 (s, 1H), 7.15 (q, J=7.2Hz, 3H), 7.04 (q, J=7 .2Hz, 1H), 6.84 (d, J=8.2Hz, 1H), 6.63 (s, 1H), 5.25-5.16 (m, 1H), 4.77 (d, J=11.9Hz, 1H), 4. 37-4.27 (m, 1H), 4.16-4.08 (m, 3H), 4.06-3.98 (m, 2H), 3.80 (d, J=12.3Hz, 1H), 3.40 (d, J=11 .8Hz, 1H), 3.36-3.22(m, 2H), 2.65(d, J=13.1Hz, 1H), 1.83-1.62(m, 3H), 1.60-1.48(m, 1H).

[1554]

[1555] Intermediate 159

[1556]

[1557] 3-Oxo-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]-cyclohexyl]oxy}methyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester

[1558] In a flask, 2.4 M butyllithium in THF (79 mL, 0.191 mol) was added to a stirred solution of N-(propan-2-yl)propan-2-amine (26 mL, 0.188 mol) in anhydrous THF (90 mL) at -78°C. The reaction was maintained at this temperature for 40 minutes. In a second flask, freshly prepared LDA was added to a stirred solution of 1-tert-butyl-4-ethyl-3-oxopiperidine-1,4-dicarboxylate (24.00 g, 86.7 mmol) and 1,3-dimethylhexahydropyrimidin-2-one (42 mL, 0.345 mol) in anhydrous THF (60 mL) at -78°C via an addition funnel over 0.5 hours without the reaction temperature rising above -70°C. The solution was maintained at this temperature for 20 minutes. An oil containing 1-benzyloxy-2-[4-(chloromethoxy)cyclohexyl]benzene (28.65 g, 86.6 mmol) in anhydrous THF (90 mL) was added to the reaction mixture over 20 min, and the reaction temperature did not rise above -70 ° C. The reaction mixture was stirred at -78 ° C for 1 h, warmed to room temperature, and stirred for 2 hours. The reactants were quenched with NH4Cl. The crude mixture was diluted with water (100 mL) and extracted with EtOAc (3×300 mL). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-50% EtOAc / heptane) to give the title compound (15 g) as a light yellow oil. [M+Na] + m / z 588.3

[1559] Intermediate 160

[1560]

[1561] tert-Butyl 3-oxo-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy}methyl)piperidine-1-carboxylate

[1562] To DMSO (95 mL) containing intermediate 159 (15.00 g) was added sodium chloride (2.26 g, 38.6 mmol) and water (9.5 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 (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with water (2 × 200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and concentrated to dryness to give the crude material. The crude material was purified by silica gel column chromatography (0-50% EtOAc / heptane) to give the title compound (7.03 g) as an orange oil. [M+Na] + m / z 516.3

[1563] Intermediate 161

[1564]

[1565] tert-Butyl 3-oxo-2-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)piperidine-1-carboxylate

[1566] Intermediate 160 (17.4 g) was dissolved in ethanol (300 mL) and evacuated and backfilled with nitrogen three times. Palladium on carbon (10%, 3.57 g, 3.36 mmol) was added and evacuated and backfilled with hydrogen three times. The reaction was stirred for 18 hours, then filtered through celite, washed with ethyl acetate, and the filtrate was concentrated in vacuo to give the title compound (13.9 g) as a yellow oil. [M+Na] + m / z 426.3

[1567] Intermediate 162

[1568]

[1569] tert-Butyl 3-oxo-2-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)piperidine-1-carboxylate

[1570] To a solution of Intermediate 161 (11.80 g) and tert-butyl bromoacetate (5.0 mL, 33.6 mmol) in acetone (152 mL) was added dipotassium carbonate (12.18 g, 88.1 mmol) and the solution was stirr...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof, in: L is a linker selected from the group consisting of optionally substituted aryl, heteroaryl, -carbocyclyl-O-, and -heterocyclyl-O-, wherein -carbocyclyl-O- and -heterocyclyl-O- have the following orientations: A1 is -C(O)-, -S(O)2- or -C(H)(CF3)-; A2 and A3 are each independently a bond, -O-, -CR5R6-, -NR7- or -S-; or A2 and A3 together with the optionally substituted carbon atom form a cyclopropyl ring having the following structure: A4 is a bond, -O-, -CR5R6-, -NR7-, -S-, -(CR5R6)2-, -CR5R6-O-, -CR5R6-S-, -CR5R6-N(R7)-, -O-CR5R6-, -S-CR5R6- or -N(R7)-CR5R6-, with the proviso that the ring including A2, A3 and A4 does not contain -OO-, -O-NR7- or -NR7-NR7-; is phenyl, 5-membered or 6-membered heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted; V and Z are each independently -O-, -CR8R9- or -NR 10 -; X is -O-, -CR 11 R 12 -or-NR 13 -; Y is a bond, -O-, -CR8R9- or -NR 10 -; R1, R2, R3, R4, R5, R6, R8, R9, R 11 , R 12 and R 14 and / or R1 and R2 together with the atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; and / or R3 and R4 together with the atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; and / or R5 and R6 together with the atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; and / or R8 and R9 together with the atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; and / or R 11 and R 12 together with the atoms to which they are attached, form an optionally substituted carbocyclic or heterocyclic ring; R7, R 10 and R 13 each is 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, -S(O)2-alkyl, -S(O)2-cycloalkyl or -S(O)2-heterocyclyl; and m, n, p and r are each independently 0, 1 or 2.

2. The compound as claimed in claim 1, wherein A1 is -C(O)- or -S(O)2-.

3. The compound according to claim 1 or 2, wherein A2 is -O- or -CR5R6-.

4. The compound according to any one of claims 1 to 3, wherein A2 is -CR5R6-.

5. The compound according to any one of claims 1 to 4, wherein A3 is -O- or -CR5R6-.

6. The compound according to any one of claims 1 to 5, wherein A3 is -O-.

7. The compound according to any one of claims 1 to 6, wherein A4 is a bond or -CR5R6-.

8. A compound as claimed in any one of claims 1 to 7, wherein R5 and R6 are each independently H, halogen or alkyl.

9. The compound of any one of claims 1 to 8, wherein R5 and R6 are each independently H or alkyl.

10. The compound of claim 8 or 9, wherein the alkyl group is methyl, ethyl or CF3.

11. The compound of any one of claims 1 to 9, wherein R5 and R6 are H.

12. A compound as claimed in any one of claims 1 to 8, wherein R5 and R6 are halogen.

13. A compound as described in any one of claims 1 to 8, wherein R5 and R6 together with the carbon atom to which they are attached form a carbocyclic ring or a heterocyclic ring.

14. The compound according to any one of claims 1 to 13, wherein the carbocyclic ring is C 3-6 Cycloalkyl.

15. The compound according to any one of claims 1 to 14, wherein the heterocycle is a 3-membered or 6-membered heterocycle.

16. The compound of claim 13 or 15, wherein the heterocyclic ring comprises 1 or 2 heteroatoms selected from the group consisting of N, O and S.

17. A compound as claimed in any one of claims 1 to 16, wherein R7 is H or alkyl.

18. A compound as claimed in any one of claims 1 to 17, wherein R1 and R2 are each independently H, halogen or alkyl.

19. A compound as claimed in any one of claims 1 to 18, wherein R1 is alkyl and R2 is H.

20. The compound of claim 18 or 19, wherein the alkyl group is methyl or ethyl.

21. A compound as claimed in any one of claims 1 to 18, wherein R1 and R2 are H.

22. A compound as claimed in any one of claims 1 to 18, wherein R1 and R2 are H or halogen.

23. The compound of claim 18 or 22, wherein the halogen is fluorine.

24. A compound as described in any one of claims 1 to 18, wherein R1 and R2 together with the carbon atoms to which they are attached form a carbocyclic ring or a heterocyclic ring.

25. The compound of claim 24, wherein the carbocyclic ring is C 3-6 Cycloalkyl.

26. The compound of claim 24 or 25, wherein the heterocycle is a 3-membered or 6-membered heterocycle.

27. The compound of claim 24 or 26, wherein the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O and S.

28. A compound as described in any one of claims 1 to 27, wherein R3 and R4 are each independently H, halogen or alkyl.

29. A compound as described in any one of claims 1 to 28, wherein R3 and R4 are each independently H or alkyl.

30. The compound of claim 28 or 29, wherein the alkyl group is methyl or ethyl.

31. A compound as described in any one of claims 1 to 29, wherein R3 and R4 are H.

32. A compound as described in any one of claims 1 to 28, wherein R3 and R4 are halogen.

33. The compound of claim 32, wherein the halogen is fluorine.

34. A compound as described in any one of claims 1 to 28, wherein R3 and R4 together with the carbon atom to which they are attached form a carbocycle or a heterocycle.

35. The compound of claim 34, wherein the carbocyclic ring is C 3-6 Cycloalkyl.

36. The compound of claim 34 or 35, wherein the heterocycle is a 3-membered or 6-membered heterocycle.

37. The compound of claim 34 or 36, wherein the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O and S.

38. A compound as described in any one of claims 1 to 37, wherein V is -O- or -CR8R9-.

39. A compound as described in any one of claims 1 to 38, wherein V is -O- or -NR 10 -.

40. The compound of any one of claims 1 to 39, wherein V is -O-.

41. A compound as described in any one of claims 1 to 38, wherein V is -CR8R9-.

42. A compound as described in any one of claims 1 to 41, wherein Y is a bond or -CR8R9-.

43. A compound as described in any one of claims 1 to 42, wherein Z is -O- or -CR8R9-.

44. A compound as described in any one of claims 1 to 41, wherein Z is -CR8R9-.

45. A compound as described in any one of claims 1 to 44, wherein R8 and R9 are each independently H or alkyl.

46. ​​as described in any one of claims 1 to 44 compound, wherein R8 and R9 form C together with the carbon atom to which it is connected 3-6 Cycloalkyl.

47. A compound as described in any one of claims 1 to 46, wherein R 10 is H or alkyl.

48. The compound of claim 45 or 47, wherein the alkyl group is methyl, ethyl or isopropyl.

49. A compound as described in any one of claims 1 to 48, wherein X is -CR 11 R 12 -.

50. A compound as described in any one of claims 1 to 49, wherein R 11 and R 12 Each is independently H or alkyl.

51. The compound of claim 50, wherein the alkyl group is methyl or ethyl.

52. A compound as described in any one of claims 1 to 49, wherein R 11 and R 12 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl.

53. A compound as described in any one of claims 1 to 52, wherein is an optionally substituted phenyl group.

54. A compound as described in any one of claims 1 to 53, wherein the optionally substituted phenyl is: Where R a is halogen, alkyl or alkoxy; and q is 0, 1 or 2.

55. A compound as described in any one of claims 1 to 52, wherein is an optionally substituted 5-membered heteroaryl group.

56. A compound as described in any one of claims 1 to 52, wherein is an optionally substituted 6-membered heteroaryl group.

57. The compound of claim 56, wherein the optionally substituted 6-membered heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

58. The compound of claim 56 or 57, wherein the optionally substituted 6-membered heteroaryl is: Where R a is halogen, alkyl or alkoxy; and q is 0, 1 or 2.

59. A compound as described in any one of claims 54 to 58, wherein q is 0 or 1.

60. The compound of any one of claims 54 to 58, wherein q is 0.

61. The compound of any one of claims 1 to 60, wherein m is 0 or 1.

62. The compound of any one of claims 1 to 60, wherein m is 0.

63. The compound of any one of claims 1 to 62, wherein n is 0 or 1.

64. The compound of any one of claims 1 to 62, wherein n is 1.

65. The compound of any one of claims 1 to 64, wherein p is 0 or 1.

66. The compound of any one of claims 1 to 64, wherein p is 0.

67. A compound as described in any one of claims 1 to 64, wherein p is 1.

68. A compound as described in any one of claims 1 to 67, wherein L is a compound having the structure The invention further comprises a -carbocyclyl-O- or -heterocyclyl-O- linker, wherein A5 and A6 are each independently -O- or -CH2-.

69. The compound of claim 68, wherein A5 is -O-.

70. The compound of claim 68, wherein A5 is -CH2-.

71. A compound as described in any one of claims 68 to 70, wherein A6 is -O-.

72. A compound as described in any one of claims 68 to 70, wherein A6 is -CH2-.

73. A compound as described in any one of claims 1 to 67, wherein L is Where R b is halogen, alkyl or alkoxy; and r is 0, 1 or 2.

74. The compound of claim 73, wherein R b It is a halogen.

75. The compound of claim 74, wherein the halogen is fluorine.

76. A compound as described in any one of claims 73 to 75, wherein r is 1.

77. A compound as described in any one of claims 73 to 75, wherein r is 0.

78. A compound as described in any one of claims 1 to 67, wherein L is 79. The compound of any one of claims 1 to 67, wherein L is a 5- or 6-membered heteroaryl linker with 1 to 2 nitrogen atoms.

80. A compound as described in any one of claims 1 to 67 and 79, wherein L is Where R b is halogen, alkyl or alkoxy; and r is 0 or 1.

81. A compound as described in any one of claims 1 to 72 having the following structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

82. A compound as described in any one of claims 1 to 67 and 73 to 80 having the following structure: or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ar is an aryl or heteroaryl linker.

83. The compound of claim 1, wherein the compound is selected from the group consisting of:

84. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 83 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

85. A method of treating a disease or condition treatable by administration of an orexin agonist, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 83.

86. A method of treating a disease or condition by modulating one or more orexin receptors, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 83.

87. A method of treating, preventing, alleviating, controlling or reducing the risk of a disease or condition associated with one or more orexin receptors, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 83.

Images