Macrocyclic orexin receptor agonists and uses thereof

Abstract

Provided herein are compounds of formula (I), (I), or a pharmaceutically acceptable salt thereof, wherein m, n, p, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Formulas (AA), (AA), 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 disorder treatable by administration of an orexin agonist. [Formula 1] TIFF2026506356000495.tif58165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 442,247, filed January 31, 2023, which is incorporated herein by reference in its entirety. [Background technology]

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

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

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

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

[0006] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, L is aryl, heteroaryl, -carbocyclyl-(CR7CR 7’ ) r -O-, and -heterocyclyl-(CR7CR 7’ ) r -O-, wherein -carbocyclyl-(CR7CR 7’ ) r -O- and -heterocyclyl-(CR7CR 7’ ) r -O- has the following orientation: [ka] and [ka] is phenyl, 5- or 6-membered heteroaryl, cycloalkyl, or heterocyclyl; V and Z are each independently -O-, -CR8R9-, or -NR 10 - and X is -O-, -CR 11 R 12 -, or -NR 13 - and Y is a bond, -O-, -CR8R9-, or -NR 10 - and R1 and R2 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R1 and R2 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring; R3 and R4 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R3 and R4 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring; R5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, aryl, heteroaryl, alkylene-heteroaryl, or alkylene-S(O)2-alkyl; R6 is H, alkyl, cycloalkyl, heterocyclyl, alkylene-cycloalkyl, alkylene-heterocyclyl, or -CN; R7 and R 7’ are each independently H, halogen, or alkyl; R8 and R9 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R8 and R9 together with the atoms to which they are attached form a carbocycle or heterocycle; R 11 and R 12 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R 11 and R 12 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, R 10 and R 13 are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, -(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; m, n, and p are each independently 0, 1, or 2; r is 0 or 1.

[0007] In some embodiments, the present disclosure provides a compound of formula (IA-1): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, [ka] is phenyl, 5- or 6-membered heteroaryl, cycloalkyl, or heterocyclyl; V and Z are each independently -O-, -CR8R9-, or -NR 10 - and X is -O-, -CR 11 R 12 -, or -NR 13 - and Y is a bond, -O-, -CR8R9-, or -NR 10 - and A5 and A6 are each independently -O- or -CH2-; R1, R2, R3, R4, R8, R9, R 11 , and R 12 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, and / or R1 and R2 together with the atoms to which they are attached form a carbocycle or heterocycle, and / or R3 and R4 together with the atoms to which they are attached form a carbocycle or heterocycle, and / or R8 and R9 together with the atoms to which they are attached form a carbocycle or heterocycle, and / or R 11 and R 12 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, R5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, aryl, heteroaryl, alkylene-heteroaryl, or alkylene-S(O)2-alkyl; R6 is H, alkyl, cycloalkyl, heterocyclyl, alkylene-cycloalkyl, alkylene-heterocyclyl, or -CN; R 10 and R 13 are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, -(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; m, n, and p are each independently 0, 1, or 2.

[0008] In some embodiments, the present disclosure provides a compound of formula (IB-1): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ar is an aryl or heteroaryl linker; [ka] is phenyl, 5- or 6-membered heteroaryl, cycloalkyl, or heterocyclyl; V and Z are each independently -O-, -CR8R9-, or -NR 10 - and X is -O-, -CR 11 R 12 -, or -NR 13 - and Y is a bond, -O-, -CR8R9-, or -NR 10 - and R1, R2, R3, R4, R8, R9, R 11 , and R 12 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, and / or R1 and R2 together with the atoms to which they are attached form a carbocycle or heterocycle, and / or R3 and R4 together with the atoms to which they are attached form a carbocycle or heterocycle, and / or R8 and R9 together with the atoms to which they are attached form a carbocycle or heterocycle, and / or R 11 and R 12 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, R5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, aryl, heteroaryl, alkylene-heteroaryl, or alkylene-S(O)2-alkyl; R6 is H, alkyl, cycloalkyl, heterocyclyl, alkylene-cycloalkyl, alkylene-heterocyclyl, or -CN; R 10 and R 13 are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, -(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; m, n, and p are each independently 0, 1, or 2.

[0009] 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, alkyl, 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 atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, a carbocyclic ring is a C 3-6 In some embodiments, the heterocycle is a cycloalkyl. In some embodiments, the heterocycle is a 3- or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0010] 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, alkyl, methyl, or ethyl. 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 atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, a carbocyclic ring is a C 3-6 In some embodiments, the heterocycle is a cycloalkyl. In some embodiments, the heterocycle is a 3- or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0011] In some embodiments, R5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heteroaryl, alkylene-heteroaryl, or alkylene-S(O)2-alkyl. In some embodiments, R5 is alkyl or haloalkyl. In some embodiments, R5 is C 1-5 Alkyl or C 1-5 In some embodiments, R is C 1-5 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-(C 3-6 cycloalkyl), 4- to 6-membered heterocyclyl, C 1-3 Alkylene-(4- to 6-membered heterocyclyl), 5- or 6-membered heteroaryl, C 1-3 alkylene-(5- or 6-membered heteroaryl), or C 1-3 Alkylene-S(O)2-C 1-3 In some embodiments, R5 is alkyl optionally substituted with one or more halogens. In some embodiments, R5 is alkyl optionally substituted with one or more fluorines. In some embodiments, R5 is alkyl, C 1-5 Alkyl, or C 1-5 In some embodiments, R is C 1-3 Alkylene-cycloalkyl, C 1-3 Alkylene-heterocyclyl, C 1-3 Alkylene-heteroaryl, or C 1-3 In some embodiments, R is alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-heteroaryl, or alkylene-S(O)-alkyl, where alkylene is methylene or ethylene. In some embodiments, R is alkylene-cycloalkyl, alkylene-heterocyclyl, alkylene-heteroaryl, or alkylene-S(O)-alkyl, where alkylene is methylene.

[0012] In some embodiments, V is -O- or -CR8R9-. In some embodiments, V is -O- or -NR 10 In some embodiments, V is -. 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)-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.

[0013] 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 Forms a cycloalkyl.

[0014] In some embodiments, Z is —NR 10 - or -CR8R9-. In some embodiments, Z is -NR 10 In some embodiments, R and R are each independently H or alkyl. In some embodiments, R and R, together with the carbon atom to which they are attached, are C 3-6 In some embodiments, R 10 is H, alkyl, —(C═O)alkyl, or —S(O)-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.

[0015] In some embodiments, X is -CR 11 R 12 In some embodiments, R 11 and R 12 are each independently H or alkyl. In some embodiments, alkyl, methyl, or ethyl. In some embodiments, R 11 and R 12 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl.

[0016] In some embodiments, [ka] is phenyl or 5- or 6-membered heteroaryl. In some embodiments, [ka] is phenyl. In some embodiments, [ka] teeth, [ka] where R a is halogen, alkyl, —CN, or alkoxy, and q is 0, 1, or 2. In some embodiments, [ka] is a 5- or 6-membered heteroaryl. In some embodiments, [ka] is a 5-membered heteroaryl. In some embodiments, [ka] is a 6-membered heteroaryl. In some embodiments, [ka] is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, [ka] is pyridinyl. In some embodiments, [ka] teeth, [ka] where R a is halogen, alkyl, —CN, or alkoxy, and q is 0, 1, or 2. In some embodiments, R a is a halogen, C 1-5 alkyl, or -CN. In some embodiments, [ka] teeth, [ka] where R a is halogen, alkyl, —CN, or alkoxy, and q is 0, 1, or 2. In some embodiments, R a is alkyl optionally substituted with one or more fluorides. In some embodiments, R a is alkoxy optionally substituted with one or more fluorides. In some embodiments, R a is F, CH, CHCH, CH(CH), CF, CHCF, -OCH, -OCHCH, -OCH(CH), -OCF, -OCHCF, or -CN. ais F, CH3, CH2CH3, CH(CH3)2, CF3, CHCF2, or -CN. In some embodiments, q is 0 or 1. In some embodiments, q is 0.

[0017] In some embodiments, m is 0 or 1. In some embodiments, m is 0.

[0018] In some embodiments, n is 0 or 1. In some embodiments, n is 1.

[0019] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0020] In some embodiments, r is 0. In some embodiments, r is 1.

[0021] In some embodiments, L is heteroaryl, -carbocyclyl-(CR7CR 7’ ) r -O-, or -heterocyclyl-(CR7CR 7’ ) r In some embodiments, L is -carbocyclyl-(CH) r -O- or -heterocyclyl-(CH2) r In some embodiments, L is the structure [ka] 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 [ka] Carbocyclyl-(CH2)r In some embodiments, L is an -O-linker, where r is 0 or 1, s is 1 or 2, and t is 1 or 2. In some embodiments, s is 1 and t is 1. In some embodiments, s is 2 and t is 2. In some embodiments, L is the structure [ka] Carbocyclyl-(CH2) r -O-linker, where r is 0 or 1.

[0022] In some embodiments, L is [ka] where R b is halogen, alkyl, or alkoxy, and u is 0, 1, or 2. In some embodiments, R b is a halogen. In some embodiments, the halogen is a fluoride. In some embodiments, R b is F, CH3, CH2CH3, CH(CH3)2, CF3, CHCF2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, or -OCHCF2. In some embodiments, u is 1. In some embodiments, u is 0. In some embodiments, L is [ka] is.

[0023] In some embodiments, L is a 5- or 6-membered heteroaryl linker. In some embodiments, L is a 5- or 6-membered heteroaryl linker having 1 or 2 nitrogen atoms. In some embodiments, L is [ka] where R bis halogen, alkyl, or alkoxy; and u is 0 or 1.

[0024] In some embodiments, the present disclosure provides a compound of formula (IC-1): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R1, R2, R3, R4, R5, R6, [ka] V, X, Y, and Z are as defined herein; s is 1 or 2; and t is 0, 1, or 2.

[0025] In some embodiments, s is 1. In some embodiments, s is 2.

[0026] In some embodiments, t is 1. In some embodiments, t is 2.

[0027] In some embodiments, s is 1 and t is 1. In some embodiments, s is 2 and t is 2.

[0028] In some embodiments, the present disclosure provides a compound of formula (ID-1): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, [ka] V, X, Y and Z are defined herein.

[0029] In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), or Formula (IC-4)) is [ka] [ka] [ka] [ka] [ka] is.

[0030] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (ID-4), Formula (II), or a compound of Tables 1-24) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. DETAILED DESCRIPTION OF THE INVENTION

[0031] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure for all purposes in order to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, the present disclosure shall control.

[0032] For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0033] The term "about" immediately preceding a numerical value denotes a range (e.g., ±10% of that value). For example, unless otherwise indicated in the context of this disclosure or inconsistent with such interpretation, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc. For example, in a list of numerical values, e.g., "about 49, about 50, about 55, ...," "about 50" means a range spanning less than half the interval(s) of the preceding and following values, e.g., a range greater than 49.5 and less than 50.5. Furthermore, expressions such as "about" "less than" a value or "about" "greater than" a value should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" before a series of numerical values ​​or ranges of values ​​(e.g., "about 10, 20, 30" or "about 10 to 30") refer to all values ​​in the series or to the endpoints of the range, respectively.

[0034] As used herein, the terms "administer," "administering," or "administration" refer to administering a compound or a pharmaceutically acceptable salt of the compound, or a composition or formulation comprising the compound or a pharmaceutically acceptable salt of the compound, to a patient.

[0035] The term "pharmaceutically acceptable salts" includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form salts, such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, and the like. Examples of base addition salts include, but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine dicyclohexylamine, and the like. Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, and the like. Examples of ammonium salts and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reacting the compound with the appropriate inorganic or organic acid by any of a number of known methods.

[0036] As used herein with respect to a patient, the term "treating" refers to improving at least one symptom of the patient's disorder. Treatment can be improving, or at least partially improving, the disorder or a symptom associated with the disorder.

[0037] 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 an intended result when administered to a patient. The "effective amount" may vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, and the age, weight, physical condition, and responsiveness of the mammal to be treated.

[0038] The term "therapeutically effective" as applied to a dose or amount refers to that quantity of a compound or pharmaceutical preparation sufficient to result in a desired clinical benefit following administration to a patient in need thereof.

[0039] The terms "carrier" or "vehicle," as used interchangeably herein, encompass carriers, excipients, adjuvants, and diluents, or any combination of the foregoing, and refer to substances, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating agents, that are involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another organ or part of the body. In addition to adjuvants, excipients, and diluents known to those skilled in the art, carriers include organic and inorganic nanoparticles.

[0040] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" means C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0041] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain having from 1 to 12 carbon atoms, attached to the rest of the molecule by a single bond. Alkyl groups containing any number of carbon atoms from 1 to 12 are included. Alkyl groups containing up to 12 carbon atoms include C1-C 12 Alkyl, containing up to 10 carbon atoms, is C1-C 10 An alkyl having up to 6 carbon atoms is a C1-C6 alkyl, and an alkyl having up to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties described above for C1-C5 alkyl, and also includes C6 alkyl. C1-C 10 Alkyl includes all of the above C1-C5 alkyl and C1-C6 alkyl moieties, as well as C7, C8, C9 and C 10 Also includes alkyl. Similarly, C1-C 12 Alkyl includes all of the above moieties, but C 11 and C 12 Includes alkyl. C1-C 12 Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0042] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical having from 1 to 12 carbon atoms. 12Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., one described herein) through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0043] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain having from 2 to 12 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 containing up to 10 carbon atoms is C2-C 10 An alkenyl group containing up to 6 carbon atoms is C2-C6 alkenyl, and an alkenyl containing up to 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all of the moieties described above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C 10 Alkenyl includes all of the moieties described above for C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9 and C 10 Also includes alkenyl. Similarly, C2-C 12 Alkenyl includes all of the above moieties, but C 11 and C 12 Includes alkenyl. C2-C 12Non-limiting examples of alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, and 3-nonenyl. , 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted.

[0044] "Alkenylene" or "alkenylene chain" refers to an unsaturated, linear or branched divalent hydrocarbon chain radical having one or more olefins and 2 to 12 carbon atoms. C2-C 12 Non-limiting examples of alkenylene include ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., those described herein) through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.

[0045] "Alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain having from 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms include C2-C 12 Alkynyl containing up to 10 carbon atoms is C2-C 10 An alkynyl group containing up to 6 carbon atoms is C2-C6 alkynyl, and an alkynyl containing up to 5 carbon atoms is C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl, and C2 alkynyl. C2-C6 alkynyl includes all of the moieties listed above for C2-C5 alkynyl, and also includes C6 alkynyl. C2-C 10 Alkynyl includes all of the moieties described above for C2-C5 alkynyl and C2-C6 alkynyl, as well as C7, C8, C9 and C 10 Also includes alkynyl. Similarly, C2-C 12 Alkynyl includes all of the above moieties, but also includes C 11 and C 12 Alkynyl is also included. C2-C 12 Non-limiting examples of alkenyls include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted.

[0046] "Alkynylene" or "alkynylene chain" refers to an unsaturated, linear or branched divalent hydrocarbon chain radical having one or more alkynes and 2 to 12 carbon atoms. C2-C 12Non-limiting examples of alkynylene include ethynylene, propynylene, n-butynylene, etc. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group (e.g., one described herein) through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain having appropriate valences. Unless stated otherwise specifically in the specification, the alkynylene chain can be optionally substituted.

[0047] "Alkoxy" means a group of the formula -OR a where R a is alkyl, alkenyl, or alkynyl as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0048] "Aryl" refers to a hydrocarbon ring system containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, and is attached to the rest of the molecule by a single bond. For purposes of this disclosure, aryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl includes, but is not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, "aryl" can be optionally substituted.

[0049] An "aralkyl" or "arylalkyl" is a group of the formula -R b -R c where R b is an alkylene group as defined above, and R cis one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl, etc. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

[0050] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a ring structure in which the atoms forming the ring are each carbon and are attached to the rest of the molecule by a single bond. Carbocyclic rings can contain from 3 to 20 carbon atoms in the ring. Carbocyclic rings can include aryl and cycloalkyl, cycloalkenyl, and cycloalkynyl, as defined herein. Unless otherwise specifically stated in the specification, carbocyclyl groups can be optionally substituted.

[0051] "Cycloalkyl" refers to a stable non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon, consisting solely of carbon and hydrogen atoms, which may include fused, bridged, or spirocyclic ring systems, having from 3 to 20 carbon atoms (e.g., from 3 to 10 carbon atoms), and attached to the rest of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cyclohexyl ring has the structure: [ka] where the stereochemistry is as provided in the compounds disclosed herein. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specifically stated in the specification, cycloalkyl groups can be optionally substituted.

[0052] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon, consisting solely of carbon and H atoms, containing one or more carbon-carbon double bonds, which may include fused or bridged ring systems, having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Examples of polycyclic cycloalkenyls include bicyclo[2.2.1]hept-2-enyl, and the like. Unless otherwise specifically stated in the specification, cycloalkenyl groups can be optionally substituted.

[0053] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon, consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds, which may include fused or bridged ring systems, having from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, and attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkynyl include cycloheptynyl, cyclooctynyl, and the like. Unless otherwise specifically stated in the specification, cycloalkynyl groups can be optionally substituted.

[0054] "Haloalkyl" refers to an alkyl, as defined above, substituted by one or more halo radicals, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0055] "Heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a stable, saturated or unsaturated, 3- to 20-membered ring consisting of 2 to 19 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, attached to the remainder of the molecule by single bonds. Heterocyclyl or heterocyclic rings include heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl. Unless otherwise specifically stated in the specification, a heterocyclyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused, bridged, or spirocyclic ring systems; the nitrogen, carbon, or sulfur atom of a heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially saturated or fully saturated. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, heterocyclyl groups may be optionally substituted.

[0056] "Heteroaryl" refers to a 5- to 20-membered ring system consisting of a hydrogen atom, 1 to 19 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring, attached to the remainder of the molecule by a single bond. For purposes of this disclosure, heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atom of a heteroaryl can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indophenyl, and indophenyl. These include, but are not limited to, dolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted.

[0057] "Heterocyclylalkyl" refers to a group of the formula -R b -R e where R b is an alkylene, alkenylene, or alkynylene group as defined above, and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.

[0058] The compounds disclosed herein, or their pharmaceutically acceptable salts, contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomers that can be defined in terms of absolute stereochemistry as (R)- or (S)- or by their relative stereochemistry (rel). Accordingly, as used herein, the term "Rel" or "rel" refers to a compound in which the relationship between the identified stereocenters is known. Unless otherwise indicated, the present disclosure is meant to encompass all such possible isomers, as well as their racemic and optically pure forms, whether or not the stereochemistry is specifically indicated herein. Optically active compounds can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, e.g., chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, e.g., chiral high-pressure liquid chromatography (HPLC). Thus, in some embodiments, the compounds of the present disclosure are stereopure, meaning that the compounds exist as single enantiomers and single diastereomers (if multiple stereocenters are present). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0059] "Stereoisomers" refer to compounds made up of the same atoms joined by the same bonds, but with different three-dimensional structures and are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and also includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0060] 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 has been replaced by a non-hydrogen atom, for example, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and a bond to another heteroatom of various other groups. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms have been replaced by a heteroatom, such as the oxygen of oxo, carbonyl, carboxyl, and ester groups; and a higher bond (e.g., a double or triple bond) to the nitrogen of groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any group in which one or more hydrogen atoms have been replaced by a heteroatom such as -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 refers to any of the above groups in which one or more hydrogen atoms have been replaced with a C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h It also means any of the above groups substituted with R g and R h are the same or different and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. Additionally, "substituted" refers to any of the above groups where one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. In addition, each of the aforementioned substituents may also be optionally substituted with one or more of the above substituents.

[0061] As used herein, [ka] The symbol (which may hereinafter be referred to as a "point bond") indicates a bond that is a point of attachment between two chemical entities, one of which is shown as being attached to the point bond and the other of which is not shown as being attached to the point bond. For example, [ka] indicates that a chemical entity "XY" is attached to another chemical entity via a point-of-attachment bond. Additionally, specific points of attachment for chemical entities not shown may be identified by inference. For example, R 3 is H or [ka] The compound CH3-R 3 is R 3 If "XY" is selected, the connection point is R 3 is inferred to be the same bond as when depicted as being attached to CH3.

[0062] compound The present disclosure provides macrocyclic compounds that are agonists of the orexin type 2 receptor, and pharmaceutical compositions thereof, and their use in the treatment of various diseases and disorders.

[0063] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, L is aryl, heteroaryl, -carbocyclyl-(CR7CR 7’ ) r -O-, and -heterocyclyl-(CR7CR 7’ ) r -O-, wherein -carbocyclyl-(CR7CR 7’) r -O- and -heterocyclyl-(CR7CR 7’ ) r -O- has the following orientation: [ka] and [ka] is phenyl, 5- or 6-membered heteroaryl, cycloalkyl, or heterocyclyl; V and Z are each independently -O-, -CR8R9-, or -NR 10 - and X is -O-, -CR 11 R 12 -, or -NR 13 - and Y is a bond, -O-, -CR8R9-, or -NR 10 - and R1 and R2 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R1 and R2 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring; R3 and R4 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R3 and R4 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring; R5 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, aryl, heteroaryl, alkylene-heteroaryl, or alkylene-S(O)2-alkyl; R6 is H, alkyl, cycloalkyl, heterocyclyl, alkylene-cycloalkyl, alkylene-heterocyclyl, or -CN; R7 and R 7’ are each independently H, halogen, or alkyl; R8 and R9 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R8 and R9 together with the atoms to which they are attached form a carbocycle or heterocycle; R 11 and R 12 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R 11 and R 12 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, R 10 and R 13 are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, -(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; m, n, and p are each independently 0, 1, or 2; r is 0 or 1.

[0064] In some embodiments, the linker L is an aryl, heteroaryl, -carbocyclyl-(CH) r -O-, or -heterocyclyl-(CH2) r -O-, where -carbocyclyl-(CH) r -O- and -heterocyclyl-(CH2) r -O- has the following orientation: [ka] and r is as defined herein.

[0065] In some embodiments, the linker L is aryl, heteroaryl, -cycloalkyl-O-, and -heterocyclyl-O-, where -cycloalkyl-O- and -heterocyclyl-O- are in the following orientations: [ka] It has.

[0066] In some embodiments, the present disclosure provides a compound of formula (I-1): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, L, [ka] V, X, Y and Z are as defined herein.

[0067] In some embodiments, the present disclosure provides a compound of formula (I-2): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, L, [ka] V, X, Y and Z are as defined herein.

[0068] In some embodiments, the present disclosure provides a compound of formula (IA): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, [ka] V, X, Y and Z are as defined herein.

[0069] In some embodiments, the present disclosure provides a compound of formula (IA-1): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, [ka] V, X, Y and Z are as defined herein.

[0070] In some embodiments, the present disclosure provides a compound of formula (IA-2): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, [ka] V, X, Y and Z are as defined herein.

[0071] In some embodiments, the present disclosure provides a compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, Ar, [ka] V, X, Y and Z are as defined herein.

[0072] In some embodiments, the present disclosure provides a compound of formula (IB-1): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, Ar, [ka] V, X, Y and Z are as defined herein.

[0073] In some embodiments, the present disclosure provides a compound of formula (IB-2): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, Ar, [ka] V, X, Y and Z are as defined herein.

[0074] In some embodiments, the present disclosure provides a compound of formula (IC-1): [ka]

[0075] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R1, R2, R3, R4, R5, R6, [ka] V, X, Y, and Z are as defined herein; s is 1 or 2; and t is 0, 1, or 2.

[0076] In some embodiments, s is 1. In some embodiments, s is 2.

[0077] In some embodiments, t is 1. In some embodiments, t is 2.

[0078] In some embodiments, s is 1 and t is 1. In some embodiments, s is 2 and t is 2. In some embodiments, s is 1 or 2 and t is 1. In some embodiments, s is 1 or 2 and t is 2. In some embodiments, s is 1 and t is 1 or 2. In some embodiments, s is 2 and t is 1 or 2.

[0079] In some embodiments, the present disclosure provides a compound of formula (IC-2): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, s, t, R1, R2, R3, R4, R5, R6, [ka] V, Y and Z are as defined herein.

[0080] In some embodiments, the present disclosure provides a compound of formula (IC-2a): [ka] or a pharmaceutically acceptable salt thereof, wherein p, r, R5, [ka] V, Y and Z are as defined herein.

[0081] In some embodiments, the present disclosure provides a compound of formula (IC-2b): [ka] or a pharmaceutically acceptable salt thereof, wherein p, r, R5, [ka] V, Y and Z are as defined herein.

[0082] In some embodiments, the present disclosure provides a compound of formula (IC-2c): [ka] or a pharmaceutically acceptable salt thereof, wherein m, p, R1, R2, R3, R4, R5, R6, [ka] V, X, Y and Z are defined herein.

[0083] In some embodiments, the present disclosure provides a compound of formula (IC-2d): [ka] or a pharmaceutically acceptable salt thereof, wherein m, p, R1, R2, R3, R4, R5, R6, [ka] V, X, Y and Z are defined herein.

[0084] In some embodiments, the present disclosure provides a compound of formula (IC-2e): [ka] or a pharmaceutically acceptable salt thereof, wherein q, R a and R5 are as defined herein.

[0085] In some embodiments, the present disclosure provides a compound of formula (IC-2f): [ka] or a pharmaceutically acceptable salt thereof, wherein q, R a and R5 are as defined herein.

[0086] In some embodiments, R ais H, halogen, or alkyl, and q is 1 or 2. In some embodiments, R a is H, F, or Me, and q is 0 or 1. In some embodiments, R a is F or Me and q is 1. In some embodiments, R a is F and q is 1.

[0087] In some embodiments, the present disclosure provides a compound of formula (IC-2g): [ka] or a pharmaceutically acceptable salt thereof, wherein R5 is as defined herein.

[0088] In some embodiments, the present disclosure provides a compound of formula (IC-2h): [ka] or a pharmaceutically acceptable salt thereof, wherein R5 is as defined herein.

[0089] In some embodiments, the present disclosure provides a compound of formula (IC-3): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, s, t, R1, R2, R3, R4, R5, R6, V, X, Y and Z are as defined herein.

[0090] In some embodiments, the present disclosure provides a compound of formula (IC-3a): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, q, r, s, t, R a , R1, R2, R3, R4, R5, R6, V, X, Y and Z are as defined herein.

[0091] In some embodiments, the present disclosure provides a compound of formula (IC-3b): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, q, r, s, t, R a , R1, R2, R3, R4, R5, R6, V, X, Y and Z are as defined herein.

[0092] In some embodiments, R a is H, halogen, or alkyl, and q is 1 or 2. In some embodiments, R a is H, F, or Me, and q is 0 or 1. In some embodiments, R a is F or Me and q is 1. In some embodiments, R a is F and q is 1.

[0093] In some embodiments, the present disclosure provides a compound of formula (IC-4): [ka]

[0094] or a pharmaceutically acceptable salt thereof, wherein m, n, p, q, r, s, t, R a , R1, R2, R3, R4, R5, R6, V, X, Y and Z are as defined herein.

[0095] In some embodiments, the present disclosure provides a compound of formula (ID-1): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R b , R1, R2, R3, R4, R5, R6, [ka] V, X, Y and Z are defined herein.

[0096] In some embodiments, the present disclosure provides a compound of formula (ID-2): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R b , R1, R2, R3, R4, R5, R6, [ka] V, Y and Z are defined herein.

[0097] In some embodiments, the present disclosure provides a compound of formula (ID-3): [ka] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R b , R1, R2, R3, R4, R5, R6, V, and Z are defined herein.

[0098] In some embodiments, the present disclosure provides a compound of formula (ID-4): [ka]

[0099] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R b , R1, R2, R3, R4, R5, R6, V, and Z are defined herein.

[0100] In some embodiments, the linker L is aryl, -carbocyclyl-(CH) r -O- and -heterocyclyl-(CH2) r -O-, where r is 0 or 1. In some embodiments, L is -carbocyclyl-(CH) r -O- or -heterocyclyl-(CH2) r-O-, where r is 0 or 1. In some embodiments, L is -carbocyclyl-(CH) r -O-, where r is 0 or 1. In some embodiments, L is -heterocyclyl-(CH) r -O-, where r is 0 or 1. In some embodiments, r is 0 and L is -carbocyclyl-O- or -heterocyclyl-O-. In some embodiments, carbocyclyl is C 3-6 In some embodiments, the carbocyclyl is cyclohexyl or cyclobutyl. In some embodiments, the carbocyclyl is cyclohexyl. In some embodiments, the carbocyclyl is cyclobutyl. In some embodiments, the carbocyclyl is [ka] 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 contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, L is a group having the structure [ka] 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 is a -carbocyclyl-O- or -heterocyclyl-O- linker having the structure [ka] In some embodiments, L has the structure [ka] In some embodiments, L has the structure [ka] wherein x is 1, 2, 3, or 4. In some embodiments, L has the structure [ka] In some embodiments, L has the structure [ka] In some embodiments, L has the structure [ka] Carbocyclyl-(CH2) r In some embodiments, L is an -O-linker, where r is 0 or 1, s is 1 or 2, and t is 1 or 2. In some embodiments, s is 1 and t is 1. In some embodiments, s is 2 and t is 2. In some embodiments, L is the structure [ka] Carbocyclyl-(CH2) r -O-linker, where r is 0 or 1. In some embodiments, L has the structure [ka] Carbocyclyl-(CH2) r -O-linker, where r is 0 or 1. In some embodiments, L has the structure [ka] Carbocyclyl-(CH2) r -O-linker, where r is 0 or 1. In some embodiments, L has the structure [ka] Carbocyclyl-(CH2) r -O-linker, where r is 0. In the above embodiment, * represents [ka] Represents the attachment point to

[0101] In some embodiments, L is the structure [ka] wherein A5 and A6 are each independently -O- or -CH2-; and * represents [ka] represents the point of attachment to. In some embodiments, A5 is -O-. In some embodiments, A5 is -CH2-. In some embodiments, A6 is -O-. In some embodiments, A6 is -CH2-.

[0102] In some embodiments, L is the structure [ka] wherein R b is halogen, alkyl, or alkoxy, and u is 0, 1, or 2. In some embodiments, R b In some embodiments, u is a halogen. In some embodiments, the halogen is a fluoride. In some embodiments, u is 1. In some embodiments, u is 0. In some embodiments, the aryl linker is [ka] is.

[0103] In some embodiments, L is a 5- or 6-membered heteroaryl linker. In some embodiments, L is a 5- or 6-membered heteroaryl linker having 1 or 2 nitrogen atoms. In some embodiments, the linker L has the structure [ka] wherein R b is halogen, alkyl, or alkoxy, and u is 0 or 1. In some embodiments, u is 0. In some embodiments, u is 1.

[0104] In some embodiments, R1, R2, R3, R4, R8, R9, R 11 , and R 12 are each independently H, halogen, alkyl, or cycloalkyl. In some embodiments, R, R, R, R, R, R 11 , and R 12 are each independently H, halogen, or alkyl. In some embodiments, alkyl is 1-5 In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the cycloalkyl is C 3-6 In some embodiments, the cycloalkyl is cyclopropyl.

[0105] 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, 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 fluoride. 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, a carbocyclic ring is a C 3-6 In some embodiments, the carbocycle is cycloalkyl. In some embodiments, the carbocycle is cyclopropyl. In some embodiments, the heterocycle is a 3- or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0106] In some embodiments, 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 each alkyl. In some embodiments, alkyl, 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 fluoride. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, a carbocyclic ring is a C 3-6 In some embodiments, the carbocycle is cycloalkyl. In some embodiments, the carbocycle is cyclopropyl. In some embodiments, the heterocycle is a 3- or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0107] In some embodiments, R5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, aryl, heteroaryl, alkylene-heteroaryl, or alkylene-S(O)2-alkyl. In some embodiments, R5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, aryl, heteroaryl, alkylene-heteroaryl, or alkylene-S(O)2-alkyl, each of which is selected from the group consisting of one or more halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, -OC 1-5 In some embodiments, R5 is optionally substituted with alkoxy and / or -CN. In some embodiments, R5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heteroaryl, or alkylene-heteroaryl. In some embodiments, R5 is optionally substituted with C 1-5 Alkyl, C 3-6 Cycloalkyl, (C 1-3 Alkylene)-C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, (C 1-3 alkylene)-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, or (C 1-3 In some embodiments, R5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or alkylene-heterocyclyl. In some embodiments, R5 is C 1-5 Alkyl, C 3-6 Cycloalkyl, (C 1-3 Alkylene)-C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, or (C 1-3In some embodiments, R5 is cycloalkyl, heterocyclyl, or heteroaryl. In some embodiments, R5 is cycloalkyl or heterocyclyl. In some embodiments, R5 is heteroaryl. In some embodiments, R5 is C optionally substituted with one or more halogens and / or hydroxy. 1-5 In some embodiments, R5 is C 1-5 Alkyl or -CH2-(C 3-6 cycloalkyl), each of which is optionally substituted with one or more F, CN, or CH. In some embodiments, R is C optionally substituted with one or more F, CN, or CH. 1-5 In some embodiments, R5 is C 1-5 In some embodiments, R5 is one or more halogens and / or C 1-3 C optionally substituted with haloalkyl 3-6 In some embodiments, R5 is cyclopropyl or cyclobutyl, each of which is selected from the group consisting of one or more halogens and / or C 1-3 In some embodiments, R5 is cyclopropyl or cyclobutyl, each of which is optionally substituted with one or more halogens and / or C 1-3 In some embodiments, R5 is oxetane, tetrahydrofuran, tetrahydropyran, morpholine, or thiomorpholine, each of which is optionally substituted with haloalkyl. In some embodiments, R5 is 4- to 6-membered heterocyclyl. In some embodiments, R5 is oxetane, tetrahydrofuran, tetrahydropyran, morpholine, or thiomorpholine, each of which is C 1-3 In some embodiments, R5 is optionally substituted with haloalkyl. [ka] In some embodiments, R5 is phenyl. In some embodiments, R5 is a 5- or 6-membered heteroaryl. In some embodiments, R5 is a 5- or 6-membered nitrogen-containing heteroaryl. In some embodiments, R5 is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, R5 is one or more halogens and / or C 1-5 In some embodiments, R5 is heteroaryl optionally substituted with alkyl. In some embodiments, R5 is heteroaryl optionally substituted with one or more of F, CH3, CH2CH3, CH(CH3)2, CF3, CHF2, and / or CH2CF3. In some embodiments, R5 is [ka] In some embodiments, alkylene is C 1-3 In some embodiments, R is alkylene. In some embodiments, alkylene is -CH-. In some embodiments, R is optionally substituted with one or more halogen, -OH, -O-alkyl, -CN, and / or alkyl. In some embodiments, R is optionally substituted with one or more F, -OH, -OCH, -OCHCH, -OCH(CH), -OCF, -OCHF, -OCHCF, -CN, CH, CHCH, CH(CH), CF, and / or CHF. In some embodiments, R is optionally substituted with one or more F, CH, CHCH, CH(CH), -CN, CF, and / or CHF.

[0108] In some embodiments, R5 is [ka] [ka] is.

[0109] In some embodiments, R5 is [ka] is.

[0110] In some embodiments, R5 is [ka] In some embodiments, R5 is [ka] is.

[0111] In some embodiments, R6 is H, alkyl, cycloalkyl, heterocyclyl, or -CN. In some embodiments, R6 is H or C 1-5 In some embodiments, R6 is alkyl. In some embodiments, R6 is H or methyl. In some embodiments, R6 is H. In some embodiments, R6 is methyl.

[0112] In some embodiments, R 10 and R 13 are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, -(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. 10 and R 13 are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -S(O)-alkyl, or -S(O)-cycloalkyl. 10 and R 13are each independently H, alkyl, cycloalkyl, -(C=O)alkyl, -(C=O)cycloalkyl, -(C=O)-O-alkyl, -(C=O)-O-cycloalkyl, -S(O)-alkyl, -S(O)-cycloalkyl, or -S(O)-heterocyclyl. 10 and R 13 are each independently H, alkyl, —(C═O)alkyl, or —S(O)-alkyl. In some embodiments, alkyl is 1-5 In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the cycloalkyl is C 3-6 In some embodiments, the aryl is phenyl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.

[0113] In some embodiments, V is -O- or -CR8R9-. In some embodiments, V is -O- or -NR 10 In some embodiments, V is -. In some embodiments, V is -O-. In some embodiments, V is -CR8R9-. In some embodiments, R8 and R9 are each independently H or alkyl.

[0114] 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 12In some embodiments, X is —CH 2 —.

[0115] In some embodiments, Y is a bond, -CR8R9-, or -NR 10 In some embodiments, Y is -. 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, Y is -CH2-.

[0116] In some embodiments, Z is —NR 10 - or -CR8R9-. In some embodiments, Z is -NR 10 In some embodiments, R and R are each independently H or alkyl. In some embodiments, R and R, together with the carbon atom to which they are attached, are C 3-6 In some embodiments, R 10 is H, alkyl, —(C═O)alkyl, or —S(O)-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.

[0117] In some embodiments, V-(X) p -YZ is -O-(CH2) p -CH2-CH2- or -O-(CH2) p -CH2-, where p is 0 or 1. In some embodiments, V-(X) p -YZ is -O-(CH2) p -CH2-O-, where p is 1. In some embodiments, V-(X) p -YZ is -O-CH-CH-O-. In some embodiments, V-(X) p-YZ is -O-CH-O-. In some embodiments, V-(X) p -YZ is -O-CH-. In some embodiments, V-(X) p -YZ is -O-CH2-CH2-.

[0118] In some embodiments, V-(X) p -YZ does not contain an -OO- or -NN- bond.

[0119] 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, R8 and R9 are alkyl, 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 fluoride. In some embodiments, R8 and R9 together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, a carbocyclic ring is a C 3-6 In some embodiments, the carbocycle is cycloalkyl. In some embodiments, the carbocycle is cyclopropyl. In some embodiments, the heterocycle is a 3- or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0120] In some embodiments, R 10 is H, alkyl, cycloalkyl, —(C═O)—O-alkyl, —S(O)-alkyl. In some embodiments, R 10 is H, alkyl, cycloalkyl, —(C═O)—O-alkyl, or —S(O)-alkyl. In some embodiments, R 10 is H, alkyl, —(C═O)—O-alkyl, or —S(O)-alkyl. In some embodiments, R10 is H, alkyl, or cycloalkyl. In some embodiments, R 10 is H or alkyl. In some embodiments, R 10 is alkyl. In some embodiments, alkyl is C 1-5 In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the alkyl is methyl. In some embodiments, the cycloalkyl is C 3-6 It is cycloalkyl.

[0121] In some embodiments, R 11 and R 12 are each independently H, halogen, or alkyl. In some embodiments, R 11 and R 12 are each independently H or alkyl. In some embodiments, R 11 and R 12 is alkyl. In some embodiments, it is alkyl, methyl, or ethyl. In some embodiments, R 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 is a halogen. In some embodiments, the halogen is a fluoride. In some embodiments, R 11 and R 12 taken together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring. In some embodiments, a carbocyclic ring is 3-6 In some embodiments, the carbocycle is cycloalkyl. In some embodiments, the carbocycle is cyclopropyl. In some embodiments, the heterocycle is a 3- or 6-membered heterocycle. In some embodiments, the heterocycle contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0122] In some embodiments, [ka] is phenyl or a 5- or 6-membered heteroaryl.

[0123] In some embodiments, [ka] is phenyl. In some embodiments, [ka] teeth, [ka] where R a are each independently halogen, alkyl, —CN, or alkoxy, and q is 0, 1, or 2. In some embodiments, [ka] teeth, [ka] where R a are each independently halogen, alkyl, —CN, or alkoxy, and q is 0, 1, or 2. In some embodiments, R a each independently represents a C optionally substituted with a halogen or one or more fluorides; 1-5 In some embodiments, R a are each independently F, CH, CHCH, CH(CH), CF, CHCF, -OCH, -OCHCH, -OCH(CH), -OCF, -OCHCF, or -CN. a are each independently F, CH, CHCH, CF, CHF, -OCH, -OCF, or -OCHF. aare each independently F, CH, CHCH, CH(CH), CF, CHCF, or —CN. In some embodiments, R a are each independently F or CH. In some embodiments, each R a is F. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 2. In some embodiments, [ka] When is phenyl, the phenyl is [ka] In some embodiments, [ka] When is phenyl, the phenyl is [ka] is.

[0124] In some embodiments, [ka] is a 5-membered heteroaryl. In some embodiments, [ka] is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the 5-membered heteroaryl is [ka] In some embodiments, [ka] is a 6-membered heteroaryl. In some embodiments, [ka] is a 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, [ka] is a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, the 6-membered heteroaryl is [ka] where R a are each independently halogen, alkyl, —CN, or alkoxy, and q is 0, 1, or 2. In some embodiments, the 6-membered heteroaryl is [ka] where R a are each independently halogen, alkyl, —CN, or alkoxy, and q is 0, 1, or 2. In some embodiments, the 6-membered heteroaryl is [ka] and [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, R a are each independently halogen or alkyl. In some embodiments, R a are each independently a halogen or C 1-5 In some embodiments, R a are each independently F, CH, CHCH, CH(CH), CF, CHCF, -OCH, -OCHCH, -OCH(CH), -OCF, -OCHCF, or -CN. a are each independently F, CH, CHCH, CF, CHF, -OCH, -OCF, or -OCHF. a are each independently F, CH, CHCH, CH(CH), CF, CHCF, or —CN. In some embodiments, R a are each independently F or CH. In some embodiments, each R a is F. In some embodiments, each R a is CH3. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1.

[0125] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0126] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0127] In some embodiments, n is 0 or 1. In some embodiments, n is 1.

[0128] In some embodiments, the sum of m and n is 1 to 3. In some embodiments, the sum of m and n is 1 or 2. In some embodiments, m is 0 and n is 1 or 2. In some embodiments, m is 1 and n is 0, 1, or 2. In some embodiments, n is 0 and m is 1 or 2. In some embodiments, n is 1 and m is 0, 1, or 2. In some embodiments, m is 0 and n is 1, or n is 0 and m is 1, or m is 1 and n is 1. In some embodiments, m is 1 and n is 1. In some embodiments, m is 0 and n is 1. In some embodiments, n is 0 and m is 1.

[0129] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0130] In some embodiments, 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.

[0131] In some embodiments, 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.

[0132] In some embodiments, 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 -CH2- or -O-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0133] In some embodiments, 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 -CH2-, m is 0 or 1, n is 1, and p is 0 or 1.

[0134] In some embodiments, R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is -CH2-, V is -O-, Y is a bond, Z is -CH2-, m is 0 or 1, n is 1, and p is 0.

[0135] In some embodiments, 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.

[0136] In some embodiments, 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 -CH2- or -O-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0137] In some embodiments, L is [ka] 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.

[0138] In some embodiments, L is [ka] 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 -CH2- or -O-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0139] In some embodiments, [ka] is phenyl or heteroaryl having 1 or 2 N atoms, and L is [ka] 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.

[0140] In some embodiments, [ka] is phenyl or heteroaryl having 1 or 2 N atoms, and L is [ka] 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 -CH2- or -O-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0141] In some embodiments, [ka] is phenyl or heteroaryl having 1 or 2 N atoms, and L is [ka] wherein r is 0 or 1, s is 1, t is 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 -CH2- or -O-, m is 0 or 1, n is 0 or 1, and p is 0 or 1.

[0142] In some embodiments, [ka] teeth, [ka] where R a and q is as defined herein, and L is [ka] wherein R and R are each independently H or alkyl, R and R are H, X is -CH-, V is -O-, Y is a bond or -CH-, Z is -CH- or -O-, m is 0 or 1, n is 1, and p is 0. In some embodiments, m is 1.

[0143] In some embodiments, [ka] teeth, [ka] where R a and q is as defined herein, and L is [ka] wherein R and R are each independently H or alkyl, R and R are H, X is -CH-, V is -O-, Y is a bond or -CH-, Z is -CH- or -O-, m is 0 or 1, n is 1, and p is 0. In some embodiments, m is 1.

[0144] In some embodiments, [ka] teeth, [ka] where R a and q is as defined herein, and L is [ka] wherein R and R are each independently H or alkyl, R and R are H, X is -CH-, V is -O-, Y is a bond or -CH-, Z is -CH- or -O-, m is 0 or 1, n is 1, and p is 0. In some embodiments, m is 1.

[0145] In some embodiments, [ka] teeth, [ka] where R a and q is as defined herein, and L is [ka] wherein 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 -CH2-, m is 1, n is 1, and p is 0 or 1.

[0146] In some embodiments, [ka] teeth, [ka] where R a and q is as defined herein, and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, R5 is as defined herein, R6 is H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -CH2-, m is 0 or 1, n is 1, and p is 0 or 1.

[0147] In some embodiments, [ka] teeth, [ka] where R a and q is as defined herein, and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, R5 is as defined herein, R6 is H, X is -CH2-, V is -O-, Y is a bond, Z is -CH2-, m is 1, n is 1, and p is 0.

[0148] In some embodiments, [ka] teeth, [ka] and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, R5 is as defined herein, R6 is H, X is -CH2-, V is -O-, Y is a bond, Z is -CH2-, m is 1, n is 1, and p is 0.

[0149] In some embodiments, [ka] teeth, [ka] and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, R5 is as defined herein, R6 is H, X is -CH2-, V is -O-, Y is a bond, Z is -CH2-, m is 1, n is 1, and p is 0.

[0150] In some embodiments, [ka] teeth, [ka] and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, R5 is as defined herein, R6 is H, X is -CH2-, V is -O-, Y is a bond, Z is -CH2-, m is 1, n is 1, and p is 0.

[0151] In some embodiments, [ka] teeth, [ka] where R a and q is as defined herein, and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, and R5 is [ka] wherein R6 is H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -CH2-, m is 0 or 1, n is 1, and p is 0 or 1.

[0152] In some embodiments, [ka] teeth, [ka] where R a and q is as defined herein, and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, and R5 is [ka] wherein R6 is H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -CH2-, m is 0 or 1, n is 1, and p is 0 or 1.

[0153] In some embodiments, [ka] teeth, [ka] where R a and q is as defined herein, and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, and R5 is [ka] wherein R6 is H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -CH2-, m is 0 or 1, n is 1, and p is 0 or 1.

[0154] In some embodiments, [ka] teeth, [ka] where R a and q is as defined herein, and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, and R5 is [ka] wherein R6 is H, X is -CH2-, V is -O-, Y is a bond or -CH2-, Z is -CH2-, m is 0 or 1, n is 1, and p is 0 or 1.

[0155] In some embodiments, [ka] teeth, [ka] and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, and R5 is [ka] wherein R6 is H, X is -CH2-, V is -O-, Y is a bond, Z is -CH2-, m is 1, n is 1, and p is 0.

[0156] In some embodiments, [ka] teeth, [ka] and L is [ka] wherein R1 and R2 are each independently H or alkyl, R3 and R4 are H, and R5 is [ka] wherein R6 is H, X is -CH2-, V is -O-, Y is a bond, Z is -CH2-, m is 1, n is 1, and p is 0.

[0157] In some embodiments, [ka] is phenyl or heteroaryl having 1 or 2 N atoms, and L is [ka] where R b is halogen, alkyl, or alkoxy; u is 0, 1, or 2; R and R are each independently H or alkyl; R and R are H; X is -CH-; V is -O-; Y is a bond or -CH-; Z is -O-, -CH-, -CH(Me)-, or -N(alkyl)-; m is 0 or 1; n is 0 or 1; and p is 0 or 1.

[0158] In some embodiments, [ka] is phenyl or heteroaryl having 1 or 2 N atoms, and L is [ka] where R b is halogen, alkyl, or alkoxy; u is 0, 1, or 2; 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-; m is 0 or 1; n is 0 or 1; and p is 0 or 1.

[0159] In some embodiments, [ka] is phenyl and L is [ka] where R b is halogen, alkyl, or alkoxy; u is 0, 1, or 2; R and R are each independently H or alkyl; R and R are H; X is -CH-; V is -O-; Y is a bond or -CH-; Z is -O-, -CH-, -CH(Me)-, or -N(alkyl)-; m is 0 or 1; n is 0 or 1; and p is 0 or 1.

[0160] 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 other enantiomer. In some embodiments, the compounds disclosed herein have an enantiomeric excess of about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5% or more, or more, including all subranges and values ​​therebetween. In some embodiments, the compounds disclosed herein are provided as mixtures of diastereomers. In some embodiments, diastereomers of the compounds of the present disclosure are provided substantially free of other possible diastereomer(s). The present disclosure includes tautomers of any compound described herein.

[0161] In some embodiments, provided herein is one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0162] In some embodiments, provided herein are one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof.

[0163] In some embodiments, provided herein are one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a diastereomer thereof, or a mixture of diastereomers.

[0164] In some embodiments, provided herein is one or more compounds selected from Table 1.

[0165] In some embodiments, provided herein are one or more pharmaceutically acceptable salts of a compound selected from Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0166] In some embodiments, the present disclosure provides compounds, for example, compounds of formula (I) having the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the compounds of the disclosure are compounds provided in Tables 3-24. In some embodiments, the compounds of the disclosure have "A" activity (EC 50 <100 nM) or "B" activity (EC 50 In some embodiments, the compounds of the present disclosure are compounds provided in Tables 3-24 having "A" activity.

[0168] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R1, R2, R3, R4, R6, R a , m, n, and p are as defined herein; R 14 is C 1-5 is haloalkyl, s and t are each independently 1 or 2.

[0169] In some embodiments, R 14 is CF3 or CHF2.

[0170] In some embodiments, R a is F.

[0171] In some embodiments, R and R are each H, R is H or CH, and R 14 is CF3 or CHF2, and R a is F, m and n are each 1, p is 0 or 1, q is 0 or 1, and s and t are each 2. In some embodiments, R and R are each H, R is H, and R 14is CF3 or CHF2, and R a is F, m and n are each 1, p is 0, q is 0 or 1, and s and t are each 2.

[0172] In some embodiments, the compound of Formula (II) is a compound having a structure provided in Table 2, or a pharmaceutically acceptable salt thereof. [Table 2]

[0173] In some embodiments, compounds of the present disclosure, e.g., compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), or Formula (II), exclude compounds disclosed in WO2021 / 108628 and WO2022 / 232025.

[0174] composition The present disclosure provides pharmaceutical compositions for modulating an orexin receptor (e.g., an orexin type 2 receptor) in a subject. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24) or a pharmaceutically acceptable salt thereof.

[0175] 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., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24), or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the pharmaceutical composition comprises a compound selected from Table 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as described herein. In some embodiments, the pharmaceutical composition comprises a compound selected from Table 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as described herein. In some embodiments, the pharmaceutical composition comprises a compound selected from any one of Tables 1-24, or a pharmaceutically acceptable salt thereof, as described herein.

[0177] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0178] In some embodiments of the present disclosure, one or more compounds of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC- Pharmaceutical compositions are provided comprising one or more compounds of Formula (I), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound in Tables 1-24) 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 various purposes. In some embodiments, pharmaceutical compositions comprising one or more compounds disclosed herein or a pharmaceutically acceptable salt thereof further comprise a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable excipient, binder, and / or diluent. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, saline, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0179] For purposes of this disclosure, the compounds of the present disclosure can be formulated for administration by various means, including oral, parenteral, inhalation spray, topical, or rectal, in formulations containing pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular, and intraarterial injections using various infusion techniques. As used herein, intraarterial and intravenous injections include administration via a catheter.

[0180] Generally, the compounds of the present disclosure are administered in a therapeutically effective amount. The amount of compound actually administered will usually be determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0181] How to use The compounds of the present disclosure are used in a number of ways. For example, in some embodiments, the compounds are useful in methods for modulating orexin receptors, such as the orexin type 2 receptor.

[0023] Accordingly, in some embodiments, the present disclosure provides use of any one of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or the foregoing compounds in Tables 1-24, or a pharmaceutically acceptable salt thereof, for modulating orexin receptor (e.g., orexin type 2 receptor) activity. For example, in some embodiments, modulation of orexin receptor (e.g., orexin type 2 receptor) activity in a mammalian cell is for the treatment of any of the above-mentioned conditions or diseases in a subject (e.g., a mammalian subject, e.g., a human) in need thereof.

[0182] In some embodiments, modulation of orexin receptor (e.g., orexin type 2 receptor) activity is binding. In some embodiments, modulation of orexin receptor (e.g., orexin type 2 receptor) activity is agonizing or stimulating the orexin receptor.

[0183] In some embodiments, the present disclosure provides a method of treating a disease or disorder treatable by administration of an orexin agonist, comprising administering a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f ... 2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24) to a subject in need thereof.

[0184] In some embodiments, the present disclosure provides a method for treating a disease or disorder treatable by administration of an orexin agonist, comprising administering a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f ... , Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24) to a subject in need thereof.

[0185] In some embodiments, compounds of the disclosure are used to treat, prevent, ameliorate, control, or reduce the risk of various disorders associated with orexin receptors, including one or more of the following conditions or diseases: narcolepsy, narcoleptic syndrome with narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, endogenous hypersomnia, hypersomnia with excessive daytime sleepiness, sleep awakenings, sleep apnea, hypersomnia with sleep apnea, nocturnal myoclonus, disorders of consciousness, including, for example, coma, REM sleep interruptions, jet lag, excessive daytime sleepiness, shift work sleep disorder, dyssomnia, sleep disorder ... hypersomnia associated with Alzheimer's disease or cognitive impairment, Parkinson's disease, Guillain-Barré syndrome, Kleine-Lewin syndrome, and sleep disorders associated with aging, muscular dystrophy, and immune-mediated disorders; Alzheimer's nightfall symptoms; conditions associated with circadian rhythms and mental and physical disorders associated with time zone travel and shift work schedules; fibromyalgia; heart failure; diseases associated with bone loss; sepsis; syndromes characterized by nonrestorative sleep and muscle pain or sleep apnea with disordered breathing during sleep; conditions resulting from poor sleep quality; and other diseases associated with general orexin system dysfunction. In some embodiments, compounds of the present disclosure are useful for treating, preventing, ameliorating, controlling, or reducing the risk of side effects and complications resulting from various conditions, including narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy with narcoleptic symptoms, hypersomnia with excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness such as coma, anesthesia, or anesthetic antagonists.

[0186] In some embodiments, compounds of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-2i), Formula (IC-2j ... (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24), a pharmaceutically acceptable salt thereof, or a composition thereof, is used to treat a disease or disorder or condition associated with excessive sleepiness in a subject in need thereof. In some embodiments, the excessive sleepiness is caused by any one of the following: insufficient quality or quantity of nighttime sleep; environmental misalignment of the body's circadian pacemaker (e.g., caused by needing to be awake at night due to work, e.g., shift work, or personal obligations, e.g., illness, or caring for a minor or elderly family member), e.g., jet lag, shift work, and other circadian rhythm sleep disorders; another underlying sleep disorder, e.g., narcolepsy (e.g., narcolepsy type 1, narcolepsy type 2, probable narcolepsy), sleep apnea (e.g., obstructive sleep apnea, obstructive sleep apnea with the use of continuous positive airway pressure), idiopathic hypersomnia, idiopathic excessive sleepiness, and restless legs syndrome; disorders such as clinical depression or atypical depression; tumors; head trauma; anemia; renal failure; hypothyroidism; central nervous system injury; drug abuse; genetic vitamin deficiencies, e.g., biotin deficiency; and certain classes of prescription and over-the-counter medications.

[0187] In some embodiments, the compounds of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), A compound of Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound in Tables 1-24), a pharmaceutically acceptable salt thereof, or a composition thereof, is used to treat any one 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 one of the following: narcolepsy type 1, narcolepsy type 2, probable narcolepsy, idiopathic hypersomnia, idiopathic excessive sleepiness, hypersomnolence, hypersomnolence, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with the use of continuous positive airway pressure therapy); or disturbance of consciousness such as coma; and narcolepsy syndrome with narcolepsy-like symptoms; hypersomnolence or hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson's disease, Excessive daytime sleepiness in Parkinson's disease, Prader-Willi syndrome, depression (depression, atypical depression, major depressive disorder, treatment-resistant depression), ADHD, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), and other wake disorders; excessive residual daytime sleepiness in sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure); etc. Narcolepsy (e.g., narcolepsy type 1, narcolepsy type 2, probable narcolepsy) can be diagnosed according to diagnostic criteria commonly used in the field, such as the International Classification of Sleep Disorders, Third Edition (ICSD-3) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).In some embodiments, the excessive sleepiness is excessive daytime sleepiness or excessive sleepiness during work hours, or excessive sleepiness or reduced sleep caused by having to be awake at night due to work (e.g., shift work) or personal obligations (e.g., illness, caring for a minor or elderly family member). In some embodiments, the subject has a disease, disorder, or condition 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, the excessive sleepiness is caused by narcolepsy type 1, narcolepsy type 2, or idiopathic hypersomnia. In some embodiments, the excessive sleepiness is caused by obstructive sleep apnea despite the use of continuous positive airway pressure (CPAP). In some embodiments, methods are provided for increasing wakefulness in a subject in need thereof. In some embodiments, orexin levels in the subject are intact or partially intact.

[0188] In some embodiments of the present disclosure, there is provided a method for treating a sleep disorder (e.g., as disclosed herein) in a subject in need thereof, comprising administering to a subject a compound of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f ... The present invention provides a method for treating a subject's inflammatory bowel disease, comprising administering to the subject a compound of Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24), a pharmaceutically acceptable salt thereof, or a composition thereof. In some embodiments, a compound of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-3), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24), or a pharmaceutically acceptable salt thereof, is used to treat a subject with a sleep disorder, to treat a sleep disorder, or to treat a symptom of a sleep disorder.

[0189] In some embodiments of the present disclosure, there is provided a method for treating narcolepsy in a subject in need thereof, comprising administering to a subject a compound of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f ... and administering to a subject in need thereof a compound of Formula (IC-1), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), or a compound of Tables 1-24), or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-2i), Formula (IC-2j), Formula (IC-2j), Formula (IC-2j), Formula (IC-2k), Formula (IC-2k), Formula (IC-2kj ... -2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24), or a pharmaceutically acceptable salt thereof, is used to treat a subject with narcolepsy, to treat narcolepsy, or to treat the symptoms of narcolepsy.

[0190] In some embodiments of the present disclosure, there is provided a method for the treatment of idiopathic hypersomnia (IH) in a subject in need thereof, comprising administering to a subject a compound of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f ... and administering to a subject in need thereof a compound of Formula (IC-1), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24), or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the present disclosure (e.g., Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-2i), Formula (IC-2j ...

[0039] The compound of Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula (ID-4), Formula (II), or a compound of Tables 1-24), or a pharmaceutically acceptable salt thereof, is used to treat a subject with IH, to treat IH, or to treat the symptoms of IH. [Example]

[0191] Having now generally described the present disclosure, it will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the present disclosure and are not intended to limit the disclosure.

[0192] The compounds of the present disclosure can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art.

[0193] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. Protecting group chemistry is described, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th Ed., Wiley & Sons, 2006, as well as in Jerry March, Advanced Organic Chemistry, 4 th edition, John Wiley & Sons, publisher, New York, 1992, which is incorporated herein by reference in its entirety.

[0194] Abbreviation ABNO 9-Azabicyclo[3.3.1]nonane N-oxyl radical AcOH acetic acid cHex cyclohexane CPME Cyclopentyl methyl ether DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIPEA N,N'-diisopropylethylamine DMA N,N'-dimethylacetamide DMPU N,N'-dimethylpropylene urea DMSO dimethyl sulfoxide EtOAc ethyl acetate IPA Isopropyl Alcohol HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate LDA Lithium diisopropylamide MTBE Methyl tert-butyl ether NMO N-methylmorpholine-N-oxide TBAI Tetrabutylammonium Iodide TEA Triethylamine TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran

[0195] general synthesis The compounds of the present disclosure can be synthesized using the following methods: General reaction conditions are given and the reaction products can be purified by commonly known methods, including silica gel chromatography or preparative reversed-phase high pressure liquid chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol, etc.

[0196] Analysis conditions: Method A: Column: Waters UPLC® BEH™ C18, part number 186002352, 2.1 x 100 mm, 1.7 μm Column temperature: 40℃ Mobile phase A: 2 mM ammonium bicarbonate, buffered to pH 10 Mobile phase B: Acetonitrile ·Injection volume: 1μL Gradient program: Flow rate 0.6 mL / min Time A% B% 0.00 95.00 5.00 5.30 0 100 5.80 0 100 5.82 95.00 5.00 7.00 95.00 5.00 UV 215nm, PDA spectrum 200~400nm, step: 1nm MSD Scan Positive: 100~1000; Scan Positive Negative: 150~850; Scan Negative: 100~1000 Method B: Column: Phenomenex, Kinetex-XB C18, part number 00D-4498-AN, 2.1 mm x 100 mm, 1.7 μm Column temperature: 40℃ Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile ·Injection volume: 1μL Gradient program: Flow rate 0.6 mL / min Time A% B% 0.00 95 5 5.30 0 100 5.80 0 100 5.82 95 5 7.00 95 5 UV 215nm, PDA spectrum 200~400nm, step: 1nm MSD Scan Positive: 100~1000; Scan Positive Negative: 150~850 Method C: Column: Acquity UPLC CSH C18 (5.0 mm x 2.1 mm, 1.7 μm) column Column temperature: 40℃ Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Gradient program: Flow rate 1 mL / min Time A% B% 0.00 97.00 3.00 1.50 0.10 99.90 1.90 0.10 99.90 2.00 97.0 3.00 Method D: Column: Kintex EVO C18 (1.7 μm, 2.1 × 50 mm) column Column temperature: 40℃ Mobile phase A: 10 mM ammonium bicarbonate aqueous solution, adjusted to pH 10 with NH3 Mobile phase B: Acetonitrile Gradient program: Flow rate 1 mL / min Time A% B% 0.00 97.00 3.00 1.50 0.10 99.90 1.90 0.10 99.90 2.00 97.0 3.00

[0197] IP-1 accumulation assay

[0198] Inositol-1 monophosphate (IP-1) accumulation was measured in human recombinant OX1 (hOX1) and OX2 (hOX2) receptors expressed in CHO cells (DiscoverX) using the IP-One HTRF® terbium cryptate-based assay (Cisbio) according to the manufacturer's instructions for cells tested in suspension.

[0199] hOX1-CHO and hOX2-CHO cells were seeded in white 384-well plates at a density of 20,000 cells / well in Hank's Balanced Salt Solution (HBSS) containing 20 mM HEPES pH 7.4, 50 mM LiCl, and 0.1% bovine serum albumin (BSA).

[0200] Compounds of the invention were tested in 11-point concentration-response curves (CRCs) using 200-fold serial dilutions in pure DMSO and added to cells by echoacoustic liquid handling (Labcyte) (final 0.5% DMSO in the assay). After a 60-minute incubation at 37°C, the detection reagents IP1-d2 tracer and anti-IP1-cryptate were diluted in lysis buffer according to the manufacturer's instructions and added to the cells.

[0201] After 60 min of incubation at room temperature, time-resolved fluorescence (HTRF) was measured at 615 nm and 665 nm with an Envision Multilabel reader (Perkin Elmer), and the HTRF ratio (A665 / A615 × 10 4 ) was calculated.

[0202] IP-1 accumulation responses were expressed as a percentage of the maximum OX-A response.

[0203] Curve fitting and EC 50 Estimation of EC was performed using a four-parameter logistic model using XLfit software. 50 Mean data are calculated from at least two independent experiments performed in duplicate.

[0204] EC 50 Category A corresponds to compounds that exhibit an EC50 of <100 nM, Category B corresponds to compounds that exhibit an EC50 of 100 nM to 1,000 nM, Category C corresponds to compounds that exhibit an EC50 of 1,000 nM to 10,000 nM, and Category D corresponds to compounds that exhibit an EC50 of more than 10,000 nM. [ka]

[0205] Synthesis of intermediate 1

[0206] 1-tert-butyl-4-ethyl-3-oxo-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]-oxy}methyl)-piperidine-1,4-dicarboxylate [ka]

[0207] In a flask, a 2.4 M solution of nBuLi in heptane (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 held at this temperature for 40 minutes. This freshly prepared LDA solution was transferred to an addition funnel and added to a stirred solution of 1-tert-butyl-4-ethyl-3-oxopiperidine-1,4-dicarboxylate (24.00 g, 86.7 mmol) and DMPU (42 mL, 0.345 mol) in anhydrous THF (60 mL) at −78° C. over 0.5 hours, ensuring that the reaction temperature did not rise above −70° C. The solution was held at this temperature for 20 minutes. An oil containing 1-benzyloxy-2-[4-(chloromethoxy)cyclohexyl]benzene (28.65 g, 86.6 mmol, prepared as described in WO2022233872A1) was dissolved in anhydrous THF (90 mL) and added to the reaction mixture over 20 minutes, ensuring that the reaction temperature did not rise above -70 °C. The reaction mixture was stirred at -78 °C for 1 hour, warmed to room temperature, and stirred for 2 hours. The reaction was quenched with saturated aqueous 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 column chromatography using a silica cartridge (0–50% EtOAc in heptane) to afford the title compound (15 g, 26.55 mmol, 30% yield) as a pale yellow oil. [M+Na] + m / z = 588.3

[0208] Synthesis of intermediate 2

[0209] tert-Butyl-3-oxo-2-({[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]-oxy}methyl)piperidine-1-carboxylate [ka]

[0210] To a solution of Intermediate 1 (15 g, 26.55 mmol) in DMSO (95 mL) 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, diluted with water (200 mL), and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with water (2 × 200 mL) and brine (200 mL), dried (MgSO), filtered, and concentrated in vacuo to give the crude material. The latter was purified by column chromatography using a silica cartridge (0–50% EtOAc in heptane) to give the title compound (7.03 g, 14.25 mmol, 54% yield) as an orange oil. [M+Na] + m / z = 516.3

[0211] Synthesis of intermediate 3

[0212] tert-Butyl-3-oxo-2-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]-oxy}methyl)piperidine-1-carboxylate [ka]

[0213] Intermediate 2 (17.4 g, 35.3 mmol) was dissolved in EtOH (300 mL) and the reaction vessel was evacuated and filled with N 2(g) 10 wt% Pd / C (3.57 g, 3.36 mmol) was added, the reaction vessel was evacuated, and H 2(g) was charged three times. The reaction was stirred for 18 hours, then filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated in vacuo to give the title compound (13.9 g, 34.46 mmol, 97% yield) as a yellow oil. [M+Na] + m / z = 426.3

[0214] Synthesis of intermediate 4

[0215] tert-Butyl-3-oxo-2-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)-piperidine-1-carboxylate [ka]

[0216] To a solution of Intermediate 3 (11.80 g, 29.2 mmol) and tert-butyl bromoacetate (5.0 mL, 33.6 mmol) in acetone (152 mL) was added potassium carbonate (12.18 g, 88.1 mmol), and the mixture was stirred at room temperature overnight. The solid was filtered off, and the filtrate was concentrated in vacuo to give the title compound (15.50 g, quantitative yield) as a colorless oil. [M+Na] + m / z = 540.3

[0217] Synthesis of intermediate 5

[0218] tert-Butyl-3-hydroxy-2-({[(1s,4s)-4-{2-[2-(tert-butoxy)-2-oxoethoxy]phenyl}cyclohexyl]oxy}methyl)piperidine-1-carboxylate [ka]

[0219] Sodium borohydride (1.07 g, 28.3 mmol) was added portionwise to a stirred solution of Intermediate 4 (15.50 g, 28.4 mmol) in anhydrous DCM (118 mL) and MeOH (118 mL) at 0° C., and the mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo. The residue was resuspended in water (300 mL) and extracted with DCM (3×200 mL). The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo to give the title compound (14.7 g, quantitative yield) as a white solid. [M+H] + m / z = 542.3

[0220] Synthesis of intermediate 6

[0221] 2-{2-[(1s,4s)-4-[(3-hydroxypiperidin-2-yl)methoxy]cyclohexyl]phenoxy}acetic acid hydrochloride [ka]

[0222] A 4 M solution of HCl in 1,4-dioxane (69 mL, 0.277 mol) was added to Intermediate 5 (14.70 g, 27.7 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound (11.5 g, quantitative yield) as a white solid. [M+H] + m / z = 362.3

[0223] Synthesis of intermediate 7

[0224] (1s,19s)-15-hydroxy-8,18-dioxa-11-azatetracyclo[17.2.2.0 2,7 .0 11,16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0225] To a stirred solution of HATU (15.00 g, 39.4 mmol) and DIPEA (23 mL, 0.132 mol) in MeCN (1240 mL) was added Intermediate 6 (10.50 g, 26.3 mmol) in anhydrous DMF (124 mL) over 2 h using a syringe pump. The resulting solution was stirred for 1 h and then concentrated in vacuo to give the crude material. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried (MgSO), filtered, and concentrated in vacuo to give the crude product. The crude material was purified by column chromatography using a silica cartridge (0-40% 3:1 EtOAc / EtOH in heptane) to give the title compound (5.9 g, 17.0 mmol, 65% yield) as a white solid. [M+H] +m / z = 346.28

[0226] Synthesis of intermediate 8

[0227] (1s,19s)-8,18-dioxa-11-azatetracyclo[17.2.2.0 2,7 .0 11,16 ]tricosa-2(7),3,5-triene-10,15-dione [ka]

[0228] To a solution of Intermediate 7 (5.90 g, 15.9 mmol) in anhydrous DCM (130.64 mL) at 0 °C was added Dess-Martin periodinane (8.76 g, 20.6 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM (200 mL) and then washed with saturated aqueous NaHCO (100 mL), 1 M aqueous NaSO (100 mL), and 1 M aqueous NaCO (100 mL). The organic phase was dried by passing through a hydrophobic filter and concentrated in vacuo to give the crude product. The crude material was purified by column chromatography using a silica cartridge (0-100% 3:1 EtOAc / EtOH in heptane) to give the title compound (4.1 g, 11.94 mmol, 75% yield) as a pale yellow solid. [M+H] + m / z = 344.2

[0229] Example 1

[0230] Rel-(1s,15S,16R,19s)-15-[(2,2,2-trifluoroethyl)amino]-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0231] Method A: A solution of 2,2,2-trifluoroethanamine (8.6 mg, 0.0865 mmol) and Intermediate 8 (25 mg, 0.0721 mmol) in anhydrous THF (1 mL) was heated to 70 °C for 16 h. The reaction mixture was cooled to room temperature, then sodium triacetoxyborohydride (31 mg, 0.144 mmol) was added, and the mixture was stirred for 2 h. The reaction was quenched with water (2 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography using a C cartridge (10–100% MeCN + 0.1% NH in HO + 0.1% NH) to give the title compound (1.8 mg, 0.004 mmol, 6% yield) as a white solid.

[0232] Method B: A solution of 2,2,2-trifluoroethanamine (125 mg, 1.26 mmol), Ti(OEt) (191 mg, 0.839 mmol), and Intermediate 8 (150 mg, 0.420 mmol) in anhydrous THF (5 mL) was heated to 70 °C for 16 h. The reaction mixture was cooled to room temperature, then sodium borohydride (254 mg, 6.71 mmol) was added, and the mixture was stirred for 3 h. The reaction was quenched with water (15 mL) and diluted with EtOAc (15 mL). The mixture was filtered through a pad of Celite and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography using a C18 cartridge (10-100% MeCN+0.1% NH3+0.1% NH3 in H2O) to afford the title compound (108 mg, 0.253 mmol, 60% yield) as a white solid.

[0233] The following examples were prepared according to the procedures described in Example 1 using the appropriate reagents.

[0234] Stereoisomers were separated by chiral purification using appropriate chiral column and solvent mixture combinations: Chiralpak columns (AD-H, IC, OJ-H); solvent mixtures of n-hexane / EtOH, n-hexane / (EtOH+0.1% iPrNH2), n-hexane / (EtOH / MeOH 1:1+0.1% iPrNH2). [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [ka]

[0235] Synthesis of intermediate 9

[0236] ({[4-(chloromethoxy)cyclohexyl]oxy}methyl)benzene [ka]

[0237] In a 10 L reactor, 4-benzyloxycyclohexanol (924 g, 4479 mmol) was dissolved in DCM (5 L) at 20° C., and then paraformaldehyde (135 g, 4479 mmol) was added in one portion. The suspension was stirred at 20° C. for 1 hour, and then chloro(trimethyl)silane (1137 mL, 8958 mmol) was added dropwise over 2 hours. The reaction mixture was stirred at 20° C. for 3 hours, then filtered to remove small particulates in the suspension, and the filtrate was evaporated in vacuo at 22° C. to give the title compound (1115 g, 4375 mmol, 97% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 1.06 - 2.07 (m, 8 H) 3.15 - 4.03 (m, 2 H) 4.33 - 4.52 (m, 2 H) 4.53 - 4.95 (m, 2 H) 7.18 - 7.45 (m, 5 H).

[0238] Synthesis of intermediate 10

[0239] 1-tert-butyl 4-ethyl 2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-oxopiperidine-1,4-dicarboxylate [ka]

[0240] A 10 L jacketed reactor was charged with anhydrous MeTHF (3935 mL) followed by sodium hydride (89.16 g, 2229 mmol). The suspension was cooled to −15° C., and then a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (465.2 g, 1714.7 mmol) in anhydrous MeTHF (1093 mL) was added dropwise over 2 hours, maintaining the internal temperature below −10° C. The mixture was stirred for 30 minutes, and then a 2.5 M solution of n-BuLi in hexane (891.6 mL, 2229 mmol) was added dropwise over 2 hours, maintaining the internal temperature below −10° C. The mixture was stirred for 30 minutes. A solution of Intermediate 9 (550 g, 1714 mmol) in dry MeTHF (1093 mL) was added dropwise over 1 h, maintaining the internal temperature below -10 °C. The mixture was then stirred at 0 °C for 16 h. A 10% aqueous solution of KHSO (3.3 L) was added, and the mixture was stirred for 30 min. The phases were separated, and the organic layer was washed with water (2 L) and 13% aqueous NaCl (2 L) and concentrated in vacuo. The product was purified using a silica gel pad (2000 g, 0-20% EtOAc in cHex) to give the title compound (530 g, 1082 mmol, 63% yield) as a yellow oil. [M+Na] + m / z = 512.7

[0241] Synthesis of intermediate 11

[0242] tert-Butyl 2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-oxopiperidine-1-carboxylate [ka]

[0243] A Vapourtec flow setup was equipped with a 25 mL high-temperature, high-pressure stainless steel reactor and a back-pressure regulator set (450 psi, idle pressure approximately 34 bar). A solution of intermediate 10 (530 g, 1083 mmol) in a mixture of acetone (3180 mL) and water (265 mL) was pumped into the reactor, set at a temperature of 205 °C with a residence time of 7 min (flow rate = 3.75 mL / min). The collected reaction mixture was concentrated in vacuo to remove most of the volatiles, and the residue was then dissolved in EtOAc (1 L). The resulting organic phase was washed sequentially with 5% aqueous KHSO (200 mL) and brine (50 mL), water (500 mL) and brine (50 mL), saturated aqueous KHCO (200 mL), and brine (100 mL), dried over Na SO and concentrated in vacuo to give the title compound (486 g, quantitative yield) as a brown oil. [M+Na] + m / z = 440.6

[0244] Synthesis of intermediate 12

[0245] tert-Butyl 2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-hydroxypiperidine-1-carboxylate [ka]

[0246] A 4 L round-bottom flask was charged with a solution of Intermediate 11 (257 g, 616 mmol) in MeOH (1.2 L). The mixture was cooled to 0° C. and sodium borohydride (9.5 g, 251 mmol) was added portionwise, after which the mixture was stirred and allowed to warm to room temperature over 2 hours. The mixture was cooled in an ice / water bath and quenched by the dropwise addition of water (500 mL), stirred for 10 minutes, and then allowed to warm to room temperature. The mixture was concentrated in vacuo to remove most of the MeOH. The aqueous residue was diluted with additional water (500 mL) and extracted with MTBE (800 + 300 mL). The combined organic phase was washed with water (600 mL) and brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil that was purified by column chromatography using a silica cartridge (cHex / EtOAc 0% to 50%) to give the title compound (110 g, 262 mmol, 56% yield) as a pale yellow oil. [M+Na] + m / z = 442.8

[0247] Synthesis of intermediate 13

[0248] tert-Butyl 2-({[4-(benzyloxy)cyclohexyl]oxy}methyl)-3-(ethoxymethoxy)piperidine-1-carboxylate [ka]

[0249] Under a nitrogen atmosphere, TBAI (9.8 g, 12.9 mmol) and DIPEA (136 mL, 781 mmol) were added to a solution of intermediate 12 (110 g, 265 mmol) in DCM (500 mL). A solution of ethoxychloromethane (99.7 g, 526 mmol) in DCM (100 mL) was added dropwise, and the resulting mixture was heated under reflux for 2 h. The reaction mixture was cooled to 10 °C, and then saturated aqueous NH4Cl (300 mL) was added, followed by 1 M aqueous NaOH (200 mL). The mixture was stirred for 10 min, and the layers were separated. The organic phase was washed successively with 10% (v / v) aqueous AcOH (600 mL), water (600 mL), and saturated aqueous KHCO3 (600 mL), dried over Na2SO4, and evaporated in vacuo to give the title compound (138 g, quantitative yield) as a yellow oil. [M-Boc+2H] + m / z = 378.6

[0250] Synthesis of intermediate 14

[0251] tert-Butyl 3-(ethoxymethoxy)-2-{[(4-hydroxycyclohexyl)oxy]methyl}piperidine-1-carboxylate [ka]

[0252] A round-bottom flask was charged with a solution of intermediate 13 (13 g, 27.22 mmol) and EtOH (70 mL). Pd / C 5 wt% wet matrix (1.26 g, 0.59 mmol) was added, and the reactor was then heated to H 2(g) (1 bar). The mixture was vigorously stirred at room temperature for 4 hours. The suspension was filtered through a Celite pad, and the filtrate was then concentrated in vacuo. The colorless residue was co-evaporated with n-heptane (3 x 40 mL) in vacuo to give the title compound (60.5 g, 156 mmol, 69% yield) as a colorless oil. [M-Boc+2H] + m / z = 288.6

[0253] Synthesis of intermediate 15

[0254] tert-Butyl 3-(ethoxymethoxy)-2-{[(4-oxocyclohexyl)oxy]methyl}piperidine-1-carboxylate [ka]

[0255] To a solution of Intermediate 14 (9.7 g, 25 mmol) in MeCN (60 mL) was added Cu(MeCN)OTf (0.23 g, 0.62 mmol), 4,4'-dimethoxy-2,2'-bipyridine (0.135 g, 0.62 mmol), ABNO (0.018 g, 0.125 mmol), and N-methylimidazole (0.21 g, 2.50 mmol). The mixture was stirred while bubbling air through the solution. After 1 h, the mixture was concentrated in vacuo. The residue was dissolved in MTBE (60 mL) and washed with 4 wt% aqueous NHOH (40 mL), 5 wt% aqueous KHSO (40 mL), and brine (30 mL). The organic layer was dried over NaSO, filtered, and evaporated in vacuo. The product was purified by column chromatography using a silica cartridge (0% to 30% EtOAc in cHex) to give the title compound (7 g, 18.2 mmol, 72% yield) as a pale yellow oil. [M-Boc+2H] + m / z = 286.6

[0256] Synthesis of intermediate 16

[0257] tert-Butyl 3-(ethoxymethoxy)-2-({[4-(trifluoromethanesulfonyloxy)cyclohex-3-en-1-yl]oxy}methyl)piperidine-1-carboxylate [ka]

[0258] In a 250 mL round-bottom flask, Intermediate 15 (5.0 g, 12.97 mmol) was dissolved in THF (40 mL), followed by the addition of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (4.63 g, 12.97 mmol). The mixture was cooled to −20° C., and then a 1 M solution of lithium bis(trimethylsilyl)amide in THF (14.27 mL, 14.27 mmol) was added dropwise, maintaining the internal temperature below −15° C. The resulting suspension was stirred at this temperature for 30 minutes, then gradually warmed to room temperature and stirred at this temperature for 1 hour. The mixture was quenched with saturated aqueous NH4Cl (40 mL), stirred for 10 minutes, and then the layers were separated. The organic layer was concentrated in vacuo, redissolved in MTBE (50 mL), and the aqueous phase was extracted with MTBE (30 mL). The combined organic fractions were washed with saturated aqueous KHCO (60 mL) and brine (40 mL), dried over NaSO, filtered, and concentrated in vacuo to give the title compound (8.3 g, quantitative yield) as a yellow oil. [M-Boc+2H] + m / z = 418.6

[0259] Synthesis of intermediate 17

[0260] tert-Butyl 3-(ethoxymethoxy)-2-({[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]oxy}methyl)piperidine-1-carboxylate [ka]

[0261] In a round-bottom flask, intermediate 16 (15.42 g, 29.79 mmol), bis(pinacolato)diboron (8.32 g, 32.77 mmol), potassium acetate (8.77 g, 89.37 mmol), and Pd(dppf)Cl (1.09 g, 1.49 mmol) were suspended in anhydrous CPME (298 mL). The suspension was subjected to several vacuum / N 2(g) Degas the mixture by cycles and then add N 2(g)The mixture was degassed by bubbling for 10 minutes. The mixture was stirred at 105°C for 16 hours, then cooled to room temperature, and saturated aqueous NaHCO3 was added. The mixture was extracted three times with EtOAc. The combined organic layers were dried by filtration through a hydrophobic frit (phase separator) and concentrated in vacuo. The product was purified by column chromatography using a silica cartridge (0-20% EtOAc in cHex) to give the title compound (7.3 g, 14.73 mmol, 49% yield) as a yellow oil. [M+H] + m / z = 496.3

[0262] Synthesis of intermediate 18

[0263] tert-Butyl 2-[({4-[2-(benzyloxy)-6-fluorophenyl]cyclohex-3-en-1-yl}oxy)methyl]-3-(ethoxymethoxy)piperidine-1-carboxylate [ka]

[0264] Pd(PPh3)2Cl2 (1.27 g, 1.82 mmol) was added to a mixture of Intermediate 17 (15 g, 30.27 mmol), 1-benzyloxy-2-bromo-3-fluorobenzene (9.36 g, 33.3 mmol), and potassium carbonate (20.92 g, 151.37 mmol) in water (130 mL) and 1,2-dimethoxyethane (130 mL). The suspension was degassed by bubbling N2 (g) into the mixture for 10 min and then stirred at 80 °C overnight. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4) and evaporated in vacuo. The product was purified by column chromatography using a silica cartridge (0–20% EtOAc in cHex) to give the title compound (11.7 g, 20.54 mmol, 68% yield) as a yellow oil. [M+H] + m / z = 570.3

[0265] Synthesis of intermediate 19

[0266] tert-Butyl 3-(ethoxymethoxy)-2-({[(1s,4s)-4-(2-fluoro-6-hydroxyphenyl)cyclohexyl]-oxy}methyl)piperidine-1-carboxylate [ka]

[0267] A 10 wt% Pd / C wet matrix 50% (6.0 g, 2.82 mmol) was added to a solution of intermediate 18 (23.6 g, 49.21 mmol) in ethanol (250 mL). The mixture was heated at 77°C for 1 hour. 2(g) The mixture was placed under atmosphere (7 atm) and stirred at room temperature overnight. The mixture was filtered through Celite and concentrated in vacuo to give the title compound (21.5 g, 44.64 mmol, 91% yield) as a colorless gum. [M-Boc+2H] + m / z = 382.5

[0268] Synthesis of intermediate 20

[0269] tert-Butyl 3-(ethoxymethoxy)-2-({[(1s,4s)-4-{2-[2-(tert-butoxy)-2-oxoethoxy]-6-fluorophenyl}cyclohexyl]oxy}methyl)piperidine-1-carboxylate [ka]

[0270] To a mixture of Intermediate 19 (75.0 g, 155.73 mmol) and potassium carbonate (47.35 g, 342.61 mmol) in MeCN (400 mL) was added dropwise 2-bromoacetic acid tert-butyl ester (22.52 mL, 155.73 mmol). The mixture was stirred at room temperature for 5 minutes and then heated to 70 °C for 30 minutes. The reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and washed with saturated aqueous NH4Cl (200 mL) and N aqueous NaOH (100 mL). The aqueous phase was extracted with EtOAc (150 mL), and the combined organic fractions were washed with saturated aqueous NH4Cl (300 mL) and brine (150 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography using a silica cartridge (0-20% EtOAc in cHex) to give the title compound (57 g, 95.68 mmol, 61% yield) as a colorless oil. [M+Na] + m / z = 618.5

[0271] Synthesis of intermediate 21

[0272] 2-{3-Fluoro-2-[(1s,4s)-4-[(3-hydroxypiperidin-2-yl)methoxy]cyclohexyl]phenoxy}acetic acid hydrochloride [ka]

[0273] Intermediate 20 (6.66 g, 11.18 mmol) was dissolved in 1,4-dioxane (40 mL), a 4 M solution of HCl in 1,4-dioxane (39.13 mL, 156.54 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and then co-evaporated twice with toluene to give the title compound (5.2 g, quantitative yield) as a white solid. [M+H] + m / z = 382.2

[0274] Synthesis of intermediate 22

[0275] (1s,19s)-3-Fluoro-15-hydroxy-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0276] Under nitrogen, a solution of Intermediate 21 (8.0 g, 19.14 mmol) in DMA (125 mL) was added dropwise via peristaltic pump to a solution of HATU (10.92 g, 28.72 mmol) and DIPEA (16.67 mL, 95.72 mmol) in MeCN (4.786 L) over 22 h at room temperature. After a further 60 min, the reaction mixture was concentrated in vacuo. The crude mixture was dissolved in EtO and washed five times with water, then once with 1 M aqueous HCl and saturated aqueous NaHCO, and finally with brine. The organic phase was filtered through a hydrophobic frit (phase separator) and concentrated in vacuo to give the title compound (6 g, 16.51 mmol, 86% yield) as an orange solid. [M+H] + m / z = 364.2

[0277] Synthesis of intermediate 23

[0278] (1s,19s)-3-Fluoro-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-triene-10,15-dione [ka]

[0279] To a solution of intermediate 22 (2.0 g, 5.5 mmol) in DCM (50 mL) at 0 °C was added Dess-Martin periodinane (2.57 g, 6.05 mmol). The mixture was stirred at room temperature for 2 h. Water was added, and the mixture was stirred overnight. Then, the precipitate was removed by filtration through a Gooch filter, and the filtrate was diluted with DCM. The separated aqueous phase was extracted with DCM. The combined organic phases were evaporated in vacuo. The resulting oil was suspended in EtO and stirred for 1.5 h. The resulting solid was filtered off and washed with EtO to give the title compound (1.3 g, 3.60 mmol, 65% yield) as a white solid. [M+H] + m / z = 362.2

[0280] Final Compound [Reductive Amination Procedure]

[0281] Procedure A: A solution of the appropriate amine (0.970 mmol), Ti(OEt)4 (88.36 mg, 0.390 mmol), and macrocyclic ketone intermediate (0.190 mmol) in THF (4.9 mL) was stirred at 70 °C for 2 h. The mixture was cooled to 0 °C, and sodium borohydride (73.27 mg, 1.94 mmol) was added portionwise. The suspension was allowed to warm to room temperature and stirred for 16 h. After the mixture was cooled to 0 °C, saturated aqueous NaHCO3 was added and stirring was continued for 15 min. The mixture was extracted with EtOAc, and the organic layer was filtered through a hydrophobic frit (phase separator) and concentrated in vacuo.

[0282] Procedure B: A solution of the appropriate amine (0.500 mmol), macrocyclic ketone intermediate (0.170 mmol), and Ti(OEt) (0.07 mL, 0.330 mmol) in THF (4.912 mL) was heated to 70 °C overnight. Sodium cyanoborohydride (164.24 mg, 2.66 mmol) was then added, and the mixture was stirred at room temperature for 5 h. Water was added, and the mixture was extracted three times with DCM. The combined organic layers were dried (NaSO) and evaporated in vacuo.

[0283] Procedure C: The appropriate macrocyclic ketone intermediate (0.170 mmol) and the appropriate amine (0.170 mmol) were suspended in DCM (2 mL). Sodium triacetoxyborohydride (148 mg, 0.700 mmol) and Na2SO4 (50 mg, 0.350 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo.

[0284] Procedure D: The appropriate macrocyclic ketone intermediate (0.140 mmol) and the appropriate amine (0.280 mmol) were suspended together in THF (1.4 mL). Sodium triacetoxyborohydride (176 mg, 0.830 mmol) was then slowly added, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO, saturated aqueous NHCl, and brine. The organic layer was dried (NaSO) and evaporated in vacuo.

[0285] Procedure E: The appropriate macrocyclic ketone intermediate (0.190 mmol), the appropriate amine (0.390 mmol), and sodium triacetoxyborohydride (123 mg, 0.580 mmol) were dissolved in DCM (1.3 mL). The mixture was stirred at room temperature for 3 h. EtOAc was added, and the suspension was filtered to remove inorganic salts. The filtrate was washed with saturated aqueous NH4Cl, dried (Na2SO4), and evaporated in vacuo.

[0286] The products listed in the table below were obtained using the procedures described above and purified using the most suitable method during normal-phase or reverse-phase column chromatography or using SCX cartridges. The appropriate ketone intermediates were synthesized using a synthetic route similar to that described for intermediate 23. Stereoisomers were separated by chiral HPLC purification using appropriate chiral column and solvent mixture combinations: Chiralpak columns (AD-H, AS-H, IC, ID), Chiralcel columns (OD-H, OJ-H); solvent mixtures of n-hexane / EtOH, n-hexane / (EtOH + 0.1% iPrNH), n-hexane / (EtOH / MeOH 1:1 + 0.1% iPrNH), or chiral SFC purification using appropriate chiral column and solvent mixture combinations: Chiralpak columns (AD-H, ID), MeOH + 0.1% iPrNH, or EtOH + 0.1% iPrNH as modifiers. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 Table 4-19 Table 4-20 Table 4-21 Table 4-22 Table 4-23 Table 4-24 Table 4-25 Table 4-26 Table 4-27 Table 4-28 Table 4-29 Table 4-30 Table 4-31 Table 4-32 Table 4-33 Table 4-34 Table 4-35 Table 4-36 Table 4-37 Table 4-38 Table 4-39 Table 4-40 Table 4-41 Table 4-42 Table 4-43 Table 4-44 Table 4-45 Table 4-46 Table 4-47 Table 4-48 Table 4-49 Table 4-50 Table 4-51 Table 4-52 Table 4-53 Table 4-54 Table 4-55 Table 4-56 Table 4-57 Table 4-58 Table 4-59 Table 4-60 Table 4-61 Table 4-62 Table 4-63 Table 4-64 Table 4-65 Table 4-66 Table 4-67 Table 4-68 Table 4-69 Table 4-70 Table 4-71 Table 4-72 Table 4-73 Table 4-74 Table 4-75 Table 4-76 Table 4-77 Table 4-78 [Table 4-79] [Table 4-80] [Table 4-81] [Table 4-82] [Table 4-83] [Table 4-84] [Table 4-85] [Table 4-86] [Table 4-87] [Table 4-88]

[0287] Example 204

[0288] Rel-(1s,15S,16R,19s)-3-fluoro-15-[(6-oxo-1,6-dihydropyridin-2-yl)amino]-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0289] A solution of intermediate 23 (100 mg, 0.280 mmol), 6-amino-1H-pyridin-2-one (61 mg, 0.550 mmol), and Ti(EtO) (0.12 mL, 0.550 mmol) in THF (6 mL) was heated to 70 °C overnight. Sodium cyanoborohydride (171 mg, 2.77 mmol) was then added, and the mixture was stirred at room temperature for 5 h. Since no reduction of the imine intermediate was observed, the mixture was diluted with EtOAc, washed with saturated aqueous NaHCO, dried (NaSO), filtered, and concentrated in vacuo. The resulting solid (125 mg, 0.280 mmol) was dissolved in methanol (6 mL), and ammonium formate (348 mg, 5.51 mmol) and 10 wt% Pd / C (32 mg, 0.300 mmol) were added, and the mixture was stirred at 60 °C overnight. The suspension was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc, washed with water, dried (NaSO), filtered, and evaporated in vacuo. The product was purified by column chromatography using a C18 cartridge (0-40% MeCN+0.1% HCOOH+0.1% HCOOH in HO) followed by preparative HPLC to give the title compound (2.5 mg, 0.005 mmol, 2% yield) as a white solid. [Table 5]

[0290] Example 205

[0291] Rel-2-({[(1s,15S,16R,19s)-3,6-difluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}methyl)benzonitrile [ka]

[0292] (1s,19s)-3,6-Difluoro-8,18-dioxa-11-azatetracyclo[17.2.2.0] in THF (7 mL) 2 , 7 .0 11 , 16 To a solution of tricosa-2(7),3,5-triene-10,15-dione (synthesized via a route similar to that described for Intermediate 23) (150 mg, 0.400 mmol) and 2-cyanobenzylamine (105 mg, 0.790 mmol), Ti(EtO) (180 mg, 0.790 mmol) was added, and the resulting mixture was heated to 70 °C overnight. Saturated aqueous NaHCO was added, and the mixture was extracted with EtOAc. The organic layer was dried (NaSO), filtered, and evaporated in vacuo. The intermediate was purified by column chromatography using a C18 cartridge (0–30% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO). The resulting intermediate (63.0 mg, 0.130 mmol) was dissolved in methanol (6 mL). Ammonium formate (161 mg, 2.55 mmol) and 10 wt% Pd / C (15 mg, 0.140 mmol) were added, and the mixture was stirred at 70 °C overnight. The suspension was filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in EtOAc, washed with water, dried (Na SO ), filtered, and evaporated in vacuo. The product was purified by preparative HPLC to give the title compound (5.3 mg, 0.011 mmol, 8% yield) as a white solid. [Table 6]

[0293] Synthesis of intermediate 24

[0294] Rel-tert-butyl 3-fluoro-3-({[(1s,15S,16R,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}methyl)azetidine-1-carboxylate [ka]

[0295] A solution of tert-butyl 3-(aminomethyl)-3-fluoroazetidine-1-carboxylate (424 mg, 2.08 mmol), Intermediate 23 (150 mg, 0.415 mmol), and Ti(OEt) (189 mg, 0.830 mmol) in THF (8 mL) was stirred at 70 °C overnight. The mixture was cooled to room temperature, and sodium cyanoborohydride (411 mg, 6.64 mmol) was added. The mixture was then stirred for 5 h. Saturated aqueous NaHCO was added, and the mixture was extracted with EtOAc. The organic layer was dried (NaSO) and evaporated in vacuo. The product was purified by column chromatography using a silica cartridge (30-80% EtOAc in cHex) to give the title compound (242 mg, quantitative yield) as a white solid. [M+H] + m / z = 550.4

[0296] Example 206

[0297] Rel-(1s,15S,16R,19s)-3-fluoro-15-{[(3-fluoroazetidin-3-yl)methyl]amino}-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0298] To a solution of intermediate 24 (242 mg, 0.440 mmol) in 1,4-dioxane (2 mL) was added a 4 M solution of HCl in 1,4-dioxane (2.2 mL, 8.81 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo, and the residue was then dissolved in MeOH and loaded onto an SCX cartridge (2 g), which was then washed with MeOH and eluted with a 7 M solution of NH3 in MeOH. The basic fractions were evaporated in vacuo to give the title compound (158 mg, 0.351 mmol, 80% yield) as a white solid. [Table 7]

[0299] Example 207

[0300] Rel-(1s,15S,16R,19s)-3-fluoro-15-{[(3-fluoro-1-methylazetidin-3-yl)methyl]amino}-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0301] To a solution of Example 202 (50 mg, 0.110 mmol) in DCM (3 mL) was added formaldehyde (0.41 mL, 0.110 mmol) and triethylamine (0.05 mL, 0.330 mmol), followed by sodium triacetoxyborohydride (47 mg, 0.220 mmol). The mixture was stirred at room temperature overnight. Saturated aqueous NaHCO was added, and the mixture was extracted with DCM. The combined organic layers were dried (NaSO), filtered, and evaporated in vacuo. The product was purified by preparative HPLC to give the title compound (1.7 mg, 0.004 mmol, 3% yield) as a white solid.

[0302] The examples reported in the following table were synthesized starting from the appropriate amine intermediate using a procedure similar to that described for Example 207. Stereoisomers were separated by chiral SFC purification using the appropriate chiral column and eluent modifier: Chiralcel column (OD-H); methanol + 0.1% isopropylamine. [Table 8-1] [Table 8-2]

[0303] Synthesis of intermediate 25

[0304] Rel-(1s,15S,16R,19s)-15-amino-3-fluoro-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2-(7),3,5-trien-10-one [ka]

[0305] Intermediate 23 (1200 mg, 3.09 mmol) was dissolved in DCM (10 mL) and NaSO (890 mg, 6.18 mmol) was added, followed by (4-methoxyphenyl)methanamine (0.86 mL, 6.18 mmol). Sodium triacetoxyborohydride (1309 mg, 6.18 mmol) was added portionwise over 1 h while the reaction mixture was stirred, followed by stirring at room temperature for 1 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCO and brine. The organic layer was dried (NaSO), filtered, and concentrated in vacuo. The residue was dissolved in EtOH (37.2 mL), and then ammonium formate (5842 mg, 92.64 mmol) was added to the reaction mixture, followed by 10% wet palladium on carbon (3286 mg, 1.54 mmol). The round-bottom flask was then subjected to three cycles of vacuum / N 2(g)The mixture was then subjected to HCl, and then heated at 80° C. for 2 hours. The mixture was filtered through a pad of Celite, and the filtrate was evaporated in vacuo. The product was purified by precipitation in MeCN to give the title compound (1000 mg, 2.76 mmol, 89% yield) as a white solid. [M+H] + m / z = 363.4

[0306] Examples 211 and 212

[0307] Example 211: 3-{[(1s,15R,16R,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}propanenitrile

[0308] Example 212: 3-{[(1s,15S,16R,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}propanenitrile [ka]

[0309] To a solution of intermediate 25 (250 mg, 0.690 mmol) in MeOH (3 mL) was added 2-propenenitrile (0.07 mL, 1.03 mmol), and the mixture was stirred at 70 °C overnight. The solvent was evaporated in vacuo. The product was purified by column chromatography using a silica cartridge (0-5% MeOH in DCM) followed by another column chromatography using a C18 cartridge (0-30% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to give a mixture of stereoisomers. The latter was subjected to chiral preparative SFC separation using a Chiralpak ID column (25 × 2.0 cm), 20% 5μ modifier (methanol + 0.1% isopropylamine), flow rate 45 ml / min, pressure 120 bar, temperature 40 °C to give the title compounds (Example 210, 12.8 mg, 100% ee; Example 211, 20.1 mg, 99.2% ee). [Table 9]

[0310] Examples 213, 214, 215, 216, 217, and 218

[0311] Example 213: Rel-4,4,4-trifluoro-3-{[(1s,15R,16R,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}butanenitrile

[0312] Example 214: Rel-4,4,4-trifluoro-3-{[(1s,15S,16S,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}butanenitrile

[0313] Example 215: 4,4,4-trifluoro-3-{[(1s,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}butanenitrile

[0314] Example 216: 4,4,4-trifluoro-3-{[(1s,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}butanenitrile

[0315] Example 217: 4,4,4-trifluoro-3-{[(1s,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}butanenitrile

[0316] Example 218: Rel-4,4,4-trifluoro-3-{[(1s,15S,16R,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}butanenitrile [ka]

[0317] (1s,19s)-3-fluoro-15-nitro-8,18-dioxa-11-azatetracyclo[17.2.2.0] in AcOH (5 mL) and EtOH (40 mL) at 0 °C 2 , 7 .0 11 , 16To a mixture of tricosa-2(7),3,5-trien-10-one (1.2 g, 3.06 mmol), Zn powder (2.0 g, 30.58 mmol) was added portionwise, and the mixture was stirred for 16 hours. The mixture was allowed to warm to room temperature. The reaction mixture was filtered through a Celite pad and rinsed with MeOH. The filtrate was concentrated, and then saturated aqueous NaHCO3 and DCM were added, resulting in the formation of an emulsion. This emulsion was filtered through a Celite pad, and the two phases of the filtrate were separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered, and concentrated. A portion of the residue (250 mg, 0.690 mmol) was dissolved in MeCN (5 mL), and 4,4,4-trifluorobut-2-enenitrile (0.1 mL, 1.03 mmol) was added, followed by DBU (0.1 mL, 0.690 mmol). The mixture was shaken at room temperature for 5 hours. Additional 4,4,4-trifluorobut-2-enenitrile (0.1 mL, 1.03 mmol) was added, and the reaction was shaken overnight at room temperature. The mixture was evaporated in vacuo, and the residue was dissolved in EtOAc and washed with saturated aqueous NH4Cl. The organic layer was separated, dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by column chromatography using a C18 cartridge (5-80% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to give a mixture of diastereoisomers. The latter was subjected to chiral preparative separation using a Whelk O1 column (25 x 2.0 cm), eluent: hexane / (ethanol + 0.1% isopropylamine) 80% / 20%, flow rate 17 ml / min. Using this chiral HPLC method, the mixture of stereoisomeric products was separated into six peaks.Fractions corresponding to the six peaks were collected separately to give Examples 209-214 (Example 209, 6 mg, 100% a / a%, Peak 1 retention time = 9.8 min; Example 210, 13.1 mg, 100% a / a%, Peak 2 retention time = 11.1 min; Example 211, 6.8 mg, 99.1% a / a%, Peak 3 retention time = 14.6 min; Example 212, 7.7 mg, 83.9% a / a%, Peak 4 retention time = 15.8 min; Example 213, 17 mg, 93.4% a / a%, Peak 5 retention time = 17.4 min; Example 214, 11.3 mg, 99.6% a / a%, Peak 6 retention time = 20.5 min). The NMR spectra of these six examples show that some were single stereoisomers, while others were mixtures of stereoisomers (NMR peak lists are provided in the table below for the single stereoisomers but not for the mixtures). [Table 10-1] [Table 10-2] [Table 10-3]

[0318] Synthesis of intermediate 26

[0319] (3-cyanooxetan-3-yl)methyl trifluoromethanesulfonate [ka]

[0320] 3-(Hydroxymethyl)oxetane-3-carbonitrile (120 mg, 1.06 mmol) was dissolved in DCM (9.0 mL), and then triethylamine (0.19 mL, 1.38 mmol) was added at 0° C., followed by trifluoromethanesulfonic anhydride (0.2 mL, 1.17 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with DCM and then washed with saturated aqueous NaHCO and brine. The organic layer was dried (NaSO), filtered, and concentrated in vacuo to give the title compound (250 mg, 1.02 mmol, 96% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 5.07 (d, J = 7.0 Hz, 2H), 4.91 (s, 2H), 4.59 (d, J = 7.0 Hz, 2H).

[0321] Example 219

[0322] Rel-3-3-({[(1s,15S,16R,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}methyl)oxetane-3-carbonitrile [ka]

[0323] Intermediate 25 (120 mg, 0.330 mmol) was dissolved in MeCN (1.6 mL), and potassium carbonate (92 mg, 0.660 mmol) was added, followed by Intermediate 26 (162 mg, 0.660 mmol). The reaction mixture was heated to 60 °C for 30 min and then concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO, saturated aqueous NHCl, and brine. The organic layer was dried (NaSO), filtered, and concentrated in vacuo. The product was purified by column chromatography using a silica cartridge (0-100% EtOAc in cHex) followed by a second column chromatography using a C cartridge (0-45% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to give the title compound (12.6 mg, 0.028 mmol, 8% yield) as a white powder.

[0324] The examples reported in the following table were synthesized using a procedure similar to that described for Example 219, starting from the appropriate amine alkyl trifluoromethanesulfonate. Stereoisomers were separated by chiral SFC purification using the appropriate chiral column and eluent modifier: Chiralcel column (OD-H); methanol + 0.1% isopropylamine. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4]

[0325] Example 227

[0326] Rel-3-(dimethylamino)-4-{[(1s,15S,16R,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 ,7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}cyclobut-3-ene-1,2-dione [ka]

[0327] To a solution of intermediate 25 (15 mg, 0.040 mmol) and DIPEA (0.01 mL, 0.060 mmol) in ethanol (0.8 mL) at 0 °C, 3,4-diethoxycyclobut-3-ene-1,2-dione (0.01 mL, 0.060 mmol) was added. The reaction mixture was stirred at this temperature for 1 h. Upon complete consumption of the starting material, the reaction mixture was warmed to room temperature and additional DIPEA (0.11 mL, 0.620 mmol) was added. N,N-Dimethylamine hydrochloride (51 mg, 0.620 mmol) was added to the reaction mixture and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and then washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine. The organic phase was dried over (Na2SO4), filtered, and then concentrated to dryness in vacuo. The product was purified by column chromatography using a silica cartridge (0-75% EtOAc in cHex) to give the title compound (19 mg, 0.039 mmol, 95% yield) as a white solid. [Table 12]

[0328] Synthesis of intermediate 27

[0329] Rel-(1s,15S,16R,19s)-15-amino-3,5-difluoro-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0330] Intermediate 27 was synthesized using a similar procedure as described for Intermediate 25 using the appropriate ketone starting material to give the title compound (0.6 g) as a white solid. [M+H] + m / z = 381.3

[0331] Example 228 Rel-3-{[(1s,15S,16R,19s)-3,5-difluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}pyridazine-4-carbonitrile [ka]

[0332] 3-Chloropyridazine-4-carbonitrile (16.5 mg, 0.120 mmol), CsF (12 mg, 0.080 mmol), and Intermediate 27 (30.0 mg, 0.080 mmol) were dissolved in DMSO (1.5 mL). The mixture was stirred at room temperature for 30 min, then diluted with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layers were evaporated in vacuo and purified by column chromatography using a C18 cartridge (5-60% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) followed by column chromatography using a silica cartridge (0-60% EtOAc in DCM). The residue was triturated to give the title compound (4 mg, 0.008 mmol, 10% yield) as a white solid.

[0333] The examples reported in the table below were synthesized using a procedure similar to that described for Example 228, starting from the appropriate amine intermediate and the appropriate heteroaryl halide. Different reaction temperatures were used for the synthesis of Example 229 (40°C), Examples 235 and 236 (80°C), Examples 232, 233, and 237 (60°C), Examples 231 and 234 (100°C), and Example 230 (120°C). In addition to the standard procedure, triethylamine (2 equivalents) was also added to the reaction mixture for Examples 235 and 236. For Example 235, MeCN was used as the reaction solvent. Stereoisomers were separated by chiral purification using a combination of appropriate chiral columns and solvent mixtures. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5]

[0334] Example 238

[0335] Rel-(1s,15S,16R,19s)-3,5-difluoro-15-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0336] Intermediate 27 (30 mg, 0.080 mmol) was dissolved in MeCN (0.5 mL), and then triethylamine (0.02 mL, 0.160 mmol) was added, followed by 2-bromo-5-methyl-1,3,4-oxadiazole (13 mg, 0.080 mmol). The reaction mixture was heated at 80 °C overnight. After 18 h, the reaction mixture was cooled, diluted with saturated aqueous NaHCO3, and extracted three times with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by column chromatography using a C18 cartridge (0–45% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to afford the title compound (30 mg, 0.065 mmol, 82% yield) as a white solid. [Table 14]

[0337] Synthesis of intermediate 28

[0338] Rel-(1s,15S,16R,19s)-15-amino-4-fluoro-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0339] Intermediate 28 was synthesized using a similar procedure as described for Intermediate 25 using the appropriate ketone starting material to give the title compound (0.7 g) as a white solid. [M+H] + m / z = 363.4

[0340] Example 239

[0341] Rel-2-{[(1s,15S,16R,19s)-4-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}-1,3-thiazole-5-carbonitrile [ka]

[0342] Intermediate 28 (30 mg, 0.080 mmol) and 2-bromo-5-cyanothiazole (15.6 mg, 0.080 mmol) were dissolved in DMSO (2 mL). The mixture was heated at 180 °C for 10 min, then cooled to room temperature, diluted with saturated aqueous NaHCO3, and extracted twice with EtOAc. The combined organic layers were evaporated in vacuo, and the product was purified by column chromatography using a C18 cartridge (5-70% MeCN + HCOOH + 0.1% HCOOH in HO) to give the title compound (3 mg, 0.006 mmol, 8% yield) as a white solid.

[0343] The examples reported in the following table were synthesized using a procedure similar to that described for Example 239, starting from the appropriate amine intermediate and the appropriate heteroaryl halide. Different reaction temperatures were used in the synthesis of Example 242 (60°C), Examples 244, 245, 250, and 254 (120°C), Examples 246 and 253 (80°C), and Example 249 (150°C). Stereoisomers were separated by chiral SFC purification using the appropriate chiral column and eluent modifier: Chiralpak column (AD-H); methanol + 0.1% isopropylamine. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] [Table 15-7] [Table 15-8]

[0344] Example 255

[0345] Rel-(1s,15S,16R,19s)-4-fluoro-15-{[(6-methoxypyridin-2-yl)methyl]amino}-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0346] A mixture of Intermediate 28 (22 mg, 0.060 mmol), 6-methoxy-2-pyridinecarboxaldehyde (0.01 mL, 0.060 mmol), and Ti(OEt) (0.03 mL, 0.120 mmol) in THF (0.6 mL) was shaken at 70 °C overnight. The mixture was cooled to room temperature, and then sodium cyanoborohydride (23 mg, 0.360 mmol) was added, and the mixture was shaken at room temperature for 4 h. The mixture was evaporated in vacuo, and the product was purified by column chromatography using a C18 cartridge (3-30% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to give the title compound (13.1 mg, 0.027 mmol, 45% yield) as a white solid.

[0347] The examples reported in the table below were synthesized using procedures similar to those described for Example 252, starting from the appropriate amine intermediate and the appropriate aldehyde or ketone. [Table 16-1] [Table 16-2]

[0348] Example 259

[0349] Rel-(1s,15S,16R,19s)-4-fluoro-15-{[1-(6-oxo-1,6-dihydropyridin-2-yl)ethyl]amino}-8,18-dioxa-11-azatetracyclo[17.2.2.0 2 , 7 .0 11 , 16 ]tricosa-2(7),3,5-trien-10-one [ka]

[0350] A mixture of Example 258 (20 mg, 0.040 mmol), sodium iodide (12 mg, 0.080 mmol), and chloro(trimethyl)silane (5 μL, 0.040 mmol) in MeCN (1 mL) was shaken at 85° C. for 1.5 h. The mixture was cooled to room temperature, the pH was adjusted to approximately 10 by adding 20% ​​(wt.) aqueous NH4OH, and the mixture was extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by column chromatography using a C18 cartridge (3-33% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to give the title compound (10.8 mg, 0.022 mmol, 56% yield) as a white solid. [Table 17] [ka]

[0351] Synthesis of intermediate 29

[0352] tert-Butyl-3-oxo-2-({[(1s,4s)-4-(2-{[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]oxy}phenyl)cyclohexyl]oxy}methyl)piperidine-1-carboxylate [ka]

[0353] To a solution of tert-butyl prop-2-ynoate (0.78 mL, 5.68 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.21 mL, 1.89 mmol) in anhydrous THF (20 mL) at 0°C under nitrogen, Intermediate 3 (2.10 g, 4.74 mmol) in anhydrous THF (20 mL) was added, and the solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine, dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography (0-100% EtOAc in heptane) to give the title compound (2.40 g) as a colorless oil. [M+Na] + m / z = 552.3

[0354] Synthesis of intermediate 30

[0355] tert-Butyl 3-oxo-2-({[(1s,4s)-4-{2-[3-(tert-butoxy)-3-oxopropoxy]phenyl}cyclohexyl]-oxy}methyl)piperidine-1-carboxylate [ka]

[0356] Intermediate 29 (2.40 g, 4.30 mmol) was dissolved in ethanol (75 mL), and the atmosphere over the reaction mixture was evacuated and filled with nitrogen three times. Palladium on carbon (10%, 687 mg, 0.646 mmol) was added, and the atmosphere over the reaction mixture was evacuated and filled with nitrogen, then filled with hydrogen three times. The reaction was stirred for 2 hours, then filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated in vacuo to give the title compound (2.40 g) as a grey oil. [M+Na] + m / z = 554.3

[0357] Synthesis of intermediate 31

[0358] tert-Butyl-3-hydroxy-2-({[(1s,4s)-4-{2-[3-(tert-butoxy)-3-oxopropoxy]phenyl}cyclohexyl]oxy}methyl)piperidine-1-carboxylate [ka]

[0359] Sodium borohydride (0.17 g, 4.51 mmol) was added portionwise to a stirred solution of Intermediate 30 (2.40 g, 4.51 mmol) in anhydrous DCM (20 mL) and methanol (20 mL) at 0° C., and the mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo. The residue was resuspended in water (30 mL) and extracted with DCM (3×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (2.50 g) as a colorless oil. [M+Na] + m / z = 556.3

[0360] Synthesis of intermediate 32

[0361] 3-{2-[(1s,4s)-4-[(3-hydroxypiperidin-2-yl)methoxy]cyclohexyl]phenoxy}propanoic acid hydrochloride [ka]

[0362] A 4M solution of HCl in 1,4-dioxane (12 mL, 46.8 mmol) was added to Intermediate 31 (2.50 g, 4.68 mmol) at room temperature, and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound (2.00 g) as a white foam. [M+H] + m / z = 378.3

[0363] Synthesis of intermediate 33

[0364] (1s,20s)-16-Hydroxy-8,19-dioxa-12-azatetracyclo[18.2.2.0 2,7 .0 12,17 ]Tetracosa-2(7),3,5-trien-11-one [ka]

[0365] To a stirred solution of HATU (2.48 g, 6.52 mmol) and DIPEA (3797 μL, 21.7 mmol) in acetonitrile (135 mL) was added Intermediate 32 (2.00 g, 4.35 mmol) in anhydrous DMF (9 mL) using a syringe pump over 2 h. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo to give the crude material. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated to give the crude product. The crude material was purified by column chromatography (0-100% 3:1 EtOAc / EtOH in heptane) to give the title compound (1.10 g) as a white solid. [M+H] + m / z = 360.3

[0366] Synthesis of intermediate 34

[0367] (1s,20s)-8,19-dioxa-12-azatetracyclo[18.2.2.0 2,7 .0 12,17 ]Tetracosa-2(7),3,5-triene-11,16-dione [ka]

[0368] To a solution of Intermediate 33 (1.10 g, 3.06 mmol) in anhydrous DCM (22 mL) at 0 °C was added Dess-Martin periodinane (1.69 g, 3.98 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (30 mL) and then washed with saturated aqueous NaHCO (30 mL), 1 M aqueous NaSO (30 mL), and 1 M aqueous NaCO (30 mL). The organic layer was dried by passing through a hydrophobic frit (phase separator) and concentrated to dryness to give the crude product. The crude product was purified by column chromatography (0-40% 3:1 EtOAc / EtOH in heptane) to give the title compound (807 mg) as a white solid. [M+H] + m / z = 358.2

[0369] Example 260

[0370] Rel-(1s,16S,17R,20s)-16-[(2,2,2-trifluoroethyl)amino]-8,19-dioxa-12-azatetracyclo[18.2.2.0 2 , 7 .0 12 , 17 ]Tetracosa-2(7),3,5-trien-11-one [ka]

[0371] A solution of 2,2,2-trifluoroethanamine (125 mg, 1.26 mmol), Ti(OEt) (191 mg, 0.839 mmol), and Intermediate 34 (150 mg, 0.420 mmol) in anhydrous THF (5 mL) was heated to 70 °C for 16 h. The reaction mixture was cooled to room temperature, then sodium borohydride (254 mg, 6.71 mmol) was added, and the mixture was stirred for 3 h. The reaction was quenched with water (15 mL) and diluted with EtOAc (15 mL). The mixture was filtered through a pad of Celite and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by basic reverse phase column chromatography (10-100% acetonitrile in water (0.1% ammonia)) to give the title compound (108 mg) as a white solid.

[0372] The examples reported in the following tables were synthesized using procedures similar to those described for Example 1 and Example 260, using the appropriate reagents.

[0373] The enantiomers were separated by chiral purification using appropriate chiral column and solvent mixture combinations: Chiralpak columns (AD-H, IC, OJ-H, AS-H); solvent mixtures of n-hexane / EtOH, n-hexane / (EtOH+0.1% iPrNH2), n-hexane / (EtOH / MeOH 1:1+0.1% iPrNH2). [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [ka]

[0374] Synthesis of intermediate 35

[0375] 1-tert-butyl 3-methyl(2R)-2-methyl-4-oxo-5-({[(1s,4s)-4-[2-(benzyloxy)phenyl]-cyclohexyl]oxy}methyl)pyrrolidine-1,3-dicarboxylate [ka]

[0376] In a flask, a 2.5 M solution of nBuLi in heptane (55.9 mL, 0.140 mol) was added to a stirred solution of N-(propan-2-yl)propan-2-amine (19.7 mL, 0.140 mol) in anhydrous THF (50 mL) at −5° C. The reaction was maintained at this temperature for 30 minutes. This freshly prepared LDA solution was transferred to an addition funnel and added to a stirred solution of 1-tert-butyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (16.3 g, 63.5 mmol) and DMPU (30.6 g, 0.254 mol) in anhydrous THF (115 mL) at −78° C. over 0.5 hours, ensuring that the reaction temperature did not rise above −65° C. The solution was held at this temperature for 1 hour. A solution of 1-benzyloxy-2-[4-(chloromethoxy)cyclohexyl]benzene (22.9 g, 69.2 mmol, prepared as described in WO2022233872A1) in anhydrous THF (41 mL) was added to the reaction mixture over 30 minutes. The reaction mixture was stirred at -78 °C for 1 hour, warmed to room temperature, and stirred for 2 hours. The reaction was quenched with saturated aqueous NH4Cl, diluted with water (100 mL), and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (0-25% EtOAc in heptane) to give the title compound (17.50 g) as a yellow oil. (M+Na) + m / z = 574.3

[0377] Synthesis of intermediate 36

[0378] tert-Butyl-(5R)-5-methyl-3-oxo-2-({[(CIS)-4-[2-(benzyloxy)phenyl]-cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate [ka]

[0379] A Vapourtec flow setup was equipped with a 10 mL high-temperature, high-pressure stainless steel reactor and a backpressure regulator set to a total pressure of 250 psi (20 bar). A solution of intermediate 35 (31.2 g, 56.56 mmol) in a mixture of acetone (206 mL) and water (36 mL) (final substrate concentration 0.25 M) was pumped into the reactor at 155 °C with a residence time of 5 min (flow rate = 2 mL / min, pressure approximately 20 bar). The collected fractions were concentrated in vacuo. The crude mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by acidic reverse-phase column chromatography (5-85% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to give the title compound (13.3 g) as a colorless oil. [M+H] + m / z = 494.4

[0380] Synthesis of intermediate 37

[0381] tert-Butyl-(5R)-5-methyl-3-oxo-2-({[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate [ka]

[0382] To a solution of intermediate 36 (13.0 g, 26.34 mmol) in ethanol (180 mL) was added palladium on carbon 10% (4.2 g, 3.95 mmol). The mixture was placed under a hydrogen atmosphere (1 atm) and stirred at room temperature for 6 hours. The reaction mixture was filtered through a Celite pad and concentrated in vacuo to give the title compound (10.6 g) as a colorless oil. [M+H] + m / z = 404.3

[0383] Synthesis of intermediate 38

[0384] tert-Butyl-(5R)-5-methyl-3-oxo-2-({[(1s,4s)-4-{2-[2-(tert-butoxy)-2-oxoethoxy]phenyl}cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate [ka]

[0385] To a solution of Intermediate 37 (10.35 g, 25.65 mmol) and potassium carbonate (8.86 g, 64.12 mmol) in MeCN (320 mL) was added 2-bromoacetic acid tert-butyl ester (3.96 mL, 27.45 mmol) and the solution was heated to 55° C. for 3 h. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was suspended in water and extracted with DCM. The combined organic layers were concentrated in vacuo to give the title compound (13.5 g) as a colorless oil. [M+H] + m / z = 518.4

[0386] Synthesis of intermediate 39

[0387] tert-Butyl (5R)-3-hydroxy-5-methyl-2-({[(1s,4s)-4-{2-[2-(tert-butoxy)-2-oxoethoxy]phenyl}cyclohexyl]oxy}methyl)pyrrolidine-1-carboxylate [ka]

[0388] Sodium borohydride (0.99 g, 26.08 mmol) was added portionwise to a stirred solution of Intermediate 38 (13.5 g, 26.08 mmol) in DCM (125 mL) and MeOH (125 mL) at 0° C., and the mixture was stirred for 5 h. The reaction mixture was concentrated in vacuo. The residue was suspended in water and extracted with DCM. The organic phase was washed with saturated aqueous NaSO and brine. The organic phase was dried over MgSO, filtered, and concentrated in vacuo to give the title compound (12.9 g) as a colorless oil. [M+H] + m / z = 520.4

[0389] Synthesis of intermediate 40

[0390] 2-{2-[(1s,4s)-4-{[(5R)-3-hydroxy-5-methylpyrrolidin-2-yl]methoxy}cyclohexyl]-phenoxy}acetic acid hydrochloride [ka]

[0391] To a stirred solution of intermediate 39 (12.9 g, 24.82 mmol) in 1,4-dioxane (100 mL) was added dropwise a 4N solution of hydrogen chloride in 1,4-dioxane (51.53 mL, 206.14 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo to give the title compound (14 g) as a white solid. [M+H] + m / z = 364.3

[0392] Synthesis of intermediate 41

[0393] (1s,12R,18s)-14-hydroxy-12-methyl-8,17-dioxa-11-azatetracyclo[16.2.2.0 2 , 7 .0 11 , 15 ]docosa-2(7),3,5-trien-10-one [ka]

[0394] Three 4 L round-bottom flasks were each charged with HATU (5.7 g, 15 mmol), DIPEA (7.0 mL, 40 mmol), and MeCN (3.5 L). A solution of Intermediate 40 (4 g, 10 mmol) in DMA (100 mL) was added dropwise to each flask over 6 hours at room temperature using a syringe pump. Upon complete addition, the reaction mixture was stirred for 60 minutes and then concentrated in vacuo. The crude mixtures were combined, then dissolved in diethyl ether, washed with water (200 mL) and brine, filtered through a hydrophobic frit (phase separator), and concentrated in vacuo to give the title compound (8 g) as an orange solid. [M+H] + m / z = 346.3

[0395] Synthesis of intermediate 42

[0396] (1s,12R,15S,18s)-12-methyl-8,17-dioxa-11-azatetracyclo[16.2.2.0 2 , 7 .0 11 , 15 ]docosa-2(7),3,5-triene-10,14-dione [ka]

[0397] To a solution of intermediate 41 (7.9 g, 20.81 mmol) in DCM (198 mL) at 0 °C was added Dess-Martin periodinane (11.48 g, 27.06 mmol). The mixture was stirred at room temperature for 4 h. The mixture was diluted with DCM and 0.2 mL of HO and filtered. The filtrate was washed with saturated aqueous NaHCO, 1 M aqueous NaSO, and 1 M aqueous NaCO. The organic layer was dried by passing through a hydrophobic frit (phase separator) and concentrated in vacuo. The product was purified by acidic reverse-phase column chromatography (9-95% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to give the title compound (1.95 g) as a light brown solid. [M+H] + m / z = 344.3

[0398] Example 269

[0399] (1s,12R,14S,15R,18s)-12-methyl-14-[(2,2,2-trifluoroethyl)amino]-8,17-dioxa-11-azatetracyclo[16.2.2.0 2,7 .0 11,15 ]docosa-2(7),3,5-trien-10-one [ka]

[0400] A solution of 2,2,2-trifluoroethanamine (70 μL, 0.87 mmol), Ti(OEt) (0.12 mL, 0.58 mmol), and Intermediate 42 (100 mg, 0.29 mmol) in anhydrous THF (7 mL) was heated to 70 °C for 16 h. The reaction mixture was cooled to room temperature, and then sodium cyanoborohydride (288 mg, 4.66 mmol) was added, and the reaction mixture was stirred for 12 h. Water was added, and the resulting mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo, and the resulting residue was loaded onto an SCX cartridge, washed with MeOH, and then eluted with a 2 M solution of NH in MeOH. The basic fractions were concentrated in vacuo. The product was purified by column chromatography (0–10% EtOAc in cHex) to give the title compound (23 mg, 0.054 mmol, 18% yield) as a pale orange solid.

[0401] The examples reported in the following table were synthesized using procedures similar to those described for Examples 1, 260 and 269 using the appropriate reagents.

[0402] The enantiomers were separated by chiral purification using appropriate chiral column and solvent mixture combinations: Chiralpak columns (AD-H, IC, OJ-H, AS-H); solvent mixtures of n-hexane / EtOH, n-hexane / (EtOH+0.1% iPrNH2), n-hexane / (EtOH / MeOH 1:1+0.1% iPrNH2). [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4]

[0403] Synthesis of intermediate 43

[0404] (1s,19s)-3-Fluoro-15-hydroxy-8,18-dioxa-12-azatetracyclo[17.2.2.0 2 , 7 .0 12 , 16 ]tricosa-2(7),3,5-trien-11-one [ka]

[0405] Intermediate 43 was synthesized using the appropriate starting materials and a similar synthetic route as described for Intermediate 33 to give the title compound (3.5 g) as a light brown solid. [M+H] + m / z = 364.6

[0406] Synthesis of intermediate 44

[0407] (1s,19s)-3-Fluoro-8,18-dioxa-12-azatetracyclo[17.2.2.0 2 , 7 .0 12 , 16 ]tricosa-2(7),3,5-triene-11,15-dione [ka]

[0408] To a solution of intermediate 43 (3.4 g, 9.36 mmol) in MeCN (94 mL) was added tetrakis(acetonitrile)copper(I) trifluoromethanesulfonate (176 mg, 0.470 mmol), ABNO (13 mg, 0.090 mmol), 4-4'-dimethoxy-2,2'-bipyridine (101 mg, 0.470 mmol), and then N-methylimidazole (0.07 mL, 0.940 mmol). The reaction mixture was stirred at room temperature for 30 minutes while bubbling air through the solution. The precipitate was filtered off and washed with cold MeCN and cHex. The solid was set aside, and the filtrate was concentrated in vacuo and then suspended in cold MeCN. The filtration was repeated once more, retaining the resulting solid. The filtrate was concentrated again, and the process was repeated using less MeCN. The collected solids were combined to give the title compound (3.2 g, 8.854 mmol, 95% yield) as a white solid. [M+H] + m / z = 362.5

[0409] Example 278

[0410] Rel-1-({[(1s,15S,16R,19s)-3-fluoro-11-oxo-8,18-dioxa-12-azatetracyclo[17.2.2.0 2 , 7 .0 12 , 16 ]tricosa-2(7),3,5-trien-15-yl]amino}methyl)cyclopropane-1-carbonitrile [ka]

[0411] Intermediate 44 (50 mg, 0.140 mmol) and 1-(aminomethyl)cyclopropanecarbonitrile hydrochloride (37 mg, 0.280 mmol) were suspended in THF (1.4 mL). Sodium triacetoxyborohydride (176 mg, 0.830 mmol) was added slowly, and the reaction mixture was stirred at room temperature for 3 hours. Additional 1-(aminomethyl)cyclopropanecarbonitrile hydrochloride (18 mg, 0.140 mmol) and sodium triacetoxyborohydride (59 mg, 0.280 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour and then diluted with EtOAc. The suspension was washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by column chromatography using a C18 cartridge (0-40% MeCN+0.1% HCOOH+0.1% HCOOH in H2O) to give the title compound (51 mg, 0.116 mmol, 83% yield) as a white solid. [Table 20]

[0412] Synthesis of intermediate 45

[0413] tert-Butyl 2-[({4-[6-(benzyloxy)pyridin-2-yl]cyclohex-3-en-1-yl}oxy)methyl]-3-(ethoxymethoxy)piperidine-1-carboxylate [ka]

[0414] A mixture of intermediate 17 (500 mg, 1.01 mmol), 2-benzyloxy-6-bromo-pyridine (293 mg, 1.11 mmol) and potassium carbonate (697 mg, 5.05 mmol) in 1,2-dimethoxyethane (9.6 mL) and water (9.6 mL) was added to the mixture. 2(g) The mixture was degassed by bubbling N for 10 min, and then Pd(PPh) (117 mg, 0.100 mmol) was added.2(g) The mixture was degassed by bubbling HCl for 10 min and stirred at 80 °C for 1 h. After the mixture was cooled to room temperature, the suspension was diluted with EtOAc and washed with water and brine. The organic phase was filtered through a hydrophobic frit (phase separator) and concentrated in vacuo. The residue was purified by column chromatography using a silica cartridge (0-15% EtOAc in cHex) to give the title compound (519 mg, 0.939 mmol, 93% yield) as a colorless oil. [M+H] + m / z = 553.3

[0415] Synthesis of intermediate 46

[0416] tert-Butyl 3-(ethoxymethoxy)-2-({[(1s,4s)-4-(6-hydroxypyridin-2-yl)cyclohexyl]oxy}methyl)piperidine-1-carboxylate [ka]

[0417] To a solution of Intermediate 45 (519 mg, 0.940 mmol) in EtOH (30 mL) was added ammonium formate (1.18 g, 18.78 mmol) and 10 wt% Pd / C (100 mg, 0.090 mmol), and the mixture was stirred at 80 °C overnight. The mixture was then cooled to room temperature, filtered through a Celite cartridge, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and saturated aqueous NaHCO3. The organic phase was filtered through a hydrophobic frit (phase separator) and concentrated in vacuo to give the title compound (406 mg, 0.874 mmol, 93% yield) as a white solid. [M+H] + m / z = 465.3

[0418] Synthesis of intermediate 47

[0419] tert-Butyl 3-(ethoxymethoxy)-2-({[(1s,4s)-4-{6-[4-(tert-butoxy)-4-oxobutoxy]pyridin-2-yl}cyclohexyl]oxy}methyl)piperidine-1-carboxylate [ka]

[0420] Intermediate 46 (406 mg, 0.870 mmol), silver carbonate (482 mg, 1.75 mmol) and tert-butyl-4-bromobutyrate (585 mg, 2.62 mmol) in toluene (1.7 mL) were added to the mixture with N 2(g) The mixture was degassed by bubbling water through the mixture and then stirred at 120 °C for 16 h. The suspension was cooled to room temperature, diluted with DCM, and filtered through a pad of Celite. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography using a C18 cartridge (3-90% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to give the title compound (363 mg, 0.598 mmol, 68% yield) as a colorless solid. [M+H] + m / z = 608.0

[0421] Synthesis of intermediate 48

[0422] 4-({6-[(1s,4s)-4-[(3-hydroxypiperidin-2-yl)methoxy]cyclohexyl]pyridin-2-yl}oxy)butanoic acid hydrochloride [ka]

[0423] Intermediate 48 was synthesized using a similar procedure as described for Intermediate 6 to give the title compound (0.301 g) as a white solid. [M+H] + m / z = 393.6

[0424] Synthesis of intermediate 49

[0425] (1s,20s)-16-Hydroxy-7,19-dioxa-12,25-diazatetracyclo[18.2.2.1 2 , 6 .0 12 , 17 ]Pentacosa-2(25),3,5-trien-11-one [ka]

[0426] Intermediate 49 was synthesized using a similar procedure as described for Intermediate 7 to give the title compound (0.114 g) as a white solid. [M+H] + m / z = 375.3

[0427] Synthesis of intermediate 50

[0428] (1s,20s)-7,19-dioxa-12,25-diazatetracyclo[18.2.2.1 2 , 6 .0 12 , 17 ]Pentacosa-2(25),3,5-triene-11,16-dione [ka]

[0429] Intermediate 50 was synthesized using a similar procedure as described for Intermediate 8 to give the title compound (0.093 g) as a white solid. [M+H] + m / z = 373.6

[0430] Example 279

[0431] Rel-(1s,16S,17R,20s)-16-{[(2R)-1,1,1-trifluoropropan-2-yl]amino}-7,19-dioxa-12,25-diazatetracyclo[18.2.2.1 2 , 6 .0 12 , 17]Pentacosa-2(25),3,5-trien-11-one [ka]

[0432] Example 279 was synthesized using a similar procedure as described for Example 269 to afford the title compound (40 mg, 0.085 mmol, 35% yield) as a white solid.

[0433] The enantiomers were separated by chiral SFC purification using a Chiralcel OD-H column and 10% (ethanol + 0.1% isopropylamine) as the modifier. [Table 21-1] [Table 21-2]

[0434] Synthesis of intermediate 51

[0435] tert-Butyl 2-({[4-(1-ethoxy-1-oxopropan-2-ylidene)cyclohexyl]oxy}methyl)-3-(ethoxymethoxy)piperidine-1-carboxylate [ka]

[0436] A suspension of sodium hydride (60% in mineral oil, 451 mg, 11.28 mmol) in THF (65 mL) was cooled to 0 °C. A solution of 2-diethoxyphosphorylpropanoic acid ethyl ester (2.42 mL, 11.28 mmol) was slowly added, and the mixture was stirred at room temperature for 30 minutes. A solution of Intermediate 15 (2.9 g, 7.52 mmol) in THF (10 mL) was added, and the reaction mixture was stirred at room temperature overnight. The mixture was quenched by the addition of saturated aqueous NaHCO3. EtOAc was added, and the mixture was washed with water. The organic phase was dried (Na2SO4) and evaporated in vacuo. The product was purified by column chromatography using a silica cartridge (0-30 EtOAc in cHex) to give the title compound (3.06 g, 6.52 mmol, 87% yield) as a colorless oil. [M+Na] + m / z = 492.5

[0437] Synthesis of intermediate 52

[0438] tert-Butyl 2-({[4-(1-ethoxy-1-oxopropan-2-yl)cyclohexyl]oxy}methyl)-3-(ethoxymethoxy)piperidine-1-carboxylate [ka]

[0439] To a mixture of Intermediate 51 (2.9 g, 6.18 mmol) in ethanol (62 mL) was added 10 wt% Pd / C (1.31 g, 1.24 mmol) and ammonium formate (0.31 mL, 6.18 mmol). The suspension was stirred at room temperature for 12 hours. The mixture was filtered through a pad of Celite and concentrated in vacuo to give the title compound (2.9 g, 6.149 mmol, 99% yield) as a colorless oil. [M+Na] + m / z = 494.5

[0440] Synthesis of intermediate 53

[0441] tert-Butyl 3-(ethoxymethoxy)-2-({[4-(1-hydroxypropan-2-yl)cyclohexyl]oxy}methyl)piperidine-1-carboxylate [ka]

[0442] N 2(g) To a solution of Intermediate 52 (1.84 g, 3.90 mmol) in anhydrous THF (19.5 mL) under atmospheric pressure, sodium borohydride (738 mg, 19.52 mmol) was added portionwise. The reaction mixture was stirred at reflux overnight. Additional sodium borohydride (290 mg, 7.80 mmol) was added, and the reaction mixture was stirred at reflux overnight. The mixture was cooled to room temperature, and saturated aqueous NH4Cl was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography using a C18 cartridge (0-100% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to give the title compound (0.955 mg, 2.23 mmol, 57% yield) as a white solid. [M+Na] + m / z = 452.6

[0443] Synthesis of intermediate 54

[0444] tert-Butyl 2-{[(4-{1-[2-(tert-butoxy)-2-oxoethoxy]propan-2-yl}cyclohexyl)oxy]methyl}-3-(ethoxymethoxy)piperidine-1-carboxylate [ka]

[0445] Intermediate 54 was synthesized using a similar procedure as described for Intermediate 20 to give the title compound (1.33 g) as a white solid. [M+Na] + m / z = 566.2

[0446] Synthesis of intermediate 55

[0447] 2-[({4-[1-(carboxymethoxy)propan-2-yl]cyclohexyl}oxy)methyl]-3-hydroxypiperidin-1-ium chloride [ka]

[0448] Intermediate 55 was synthesized using a similar procedure as described for Intermediate 21 to give the title compound (1.47 g) as a white solid. [M+H + ] + m / z = 330.3

[0449] Synthesis of intermediate 56

[0450] 5-Hydroxy-14-methyl-2,12-dioxa-9-azatricyclo[13.2.2.0 4 , 9 ]Nonadecan-10-one [ka]

[0451] Intermediate 56 was synthesized using a similar procedure as described for Intermediate 22 to give the title compound (0.153 g) as a white solid. [M+H] + m / z = 312.2

[0452] Synthesis of intermediate 57

[0453] 14-Methyl-2,12-dioxa-9-azatricyclo[13.2.2.0 4 , 9 ]nonadecane-5,10-dione [ka]

[0454] Intermediate 57 was synthesized using a similar procedure as described for Intermediate 23 to give the title compound (0.174 g) as a white solid. [M+H] + m / z = 310.2

[0455] Example 282

[0456] Rel-1-({[(4R,5S)-14-methyl-10-oxo-2,12-dioxa-9-azatricyclo[13.2.2.0 4 , 9 ]nonadecan-5-yl]amino}methyl)cyclopropane-1-carbonitrile [ka]

[0457] A mixture of Intermediate 57 (50 mg, 0.160 mmol), (1-cyanocyclopropyl)methylammonium chloride (43 mg, 0.320 mmol), and DIPEA (56 μL, 0.320 mmol) in THF (1.8 mL) was shaken at room temperature for 15 minutes, and then AcOH (0.5 μL, 0.010 mmol) was added, and the mixture was shaken at room temperature for 8 hours. In a separate vessel, additional (1-cyanocyclopropyl)methylammonium chloride (28 mg, 0.210 mmol) and DIPEA (56 μL, 0.320 mmol) were shaken at room temperature for 15 minutes, and then this mixture was added to the main reaction mixture, followed by AcOH (0.5 μL, 0.010 mmol). The reaction mixture was shaken at 50° C. overnight and then cooled to room temperature. Sodium cyanoborohydride (60 mg, 0.970 mmol) was added, and the reaction mixture was shaken at room temperature for 7 h. The mixture was diluted with EtOAc (100 mL) and washed three times with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by column chromatography using a C18 cartridge (5-100% MeCN + 0.1% HCOOH + 0.1% HCOOH in HO) to give the title compound (29.5 mg, 0.076 mmol, 47% yield) as a white solid. [Table 22]

[0458] Synthesis of intermediate 58

[0459] 3-[(benzyloxy)methyl]-1-[2-(benzyloxy)phenyl]cyclobutan-1-ol [ka]

[0460] To a solution of 1-bromo-2-phenylmethoxybenzene (14.47 mL, 76.01 mmol) in THF (200 mL) cooled to -78 °C, a 2.5 M solution of nBuLi in hexane (33.44 mL, 83.61 mmol) was slowly added, and the mixture was stirred for 2 h. A solution of 3-(benzyloxymethyl)cyclobutanone (15.77 mL, 91.21 mmol) in THF (20 mL) was slowly added. The mixture was allowed to warm slowly to room temperature and stirred overnight. Saturated aqueous NH4Cl (4 mL) was added, and the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and brine, and the organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (34.3 g, quantitative yield) as an orange oil. [M+Na] + m / z = 397.2

[0461] Synthesis of intermediate 59

[0462] 2-[3-(hydroxymethyl)cyclobutyl]phenol [ka]

[0463] Intermediate 59 was synthesized using a similar procedure as described for Intermediate 3 to give the title compound (37.5 g) as a white solid. [MH] - m / z = 177.1

[0464] Synthesis of intermediate 60

[0465] 3-[2-(benzyloxy)phenyl]cyclobutan-1-ol [ka]

[0466] To a mixture of Intermediate 59 (27.09 g, 152.02 mmol) in MeCN (280 mL) and DMF (35 mL) was added potassium carbonate (63 g, 456.06 mmol) in portions, followed by the slow addition of bromomethylbenzene (20.43 mL, 167.22 mmol). The mixture was stirred at 50 °C overnight. Additional bromomethylbenzene (4.64 mL, 38.01 mmol) was added, and the mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with DCM, and filtered. The filtrate was concentrated in vacuo, and the product was purified by flash chromatography using a silica cartridge (0–25% EtOAc / EtOH 3:1 in cHex) to afford the title compound (27.68 g, 103.15 mmol, 68% yield) as a yellow oil. [M+H] + m / z = 269.1

[0467] Synthesis of intermediate 61

[0468] (1s,19s)-8,18-dioxa-11-azatetracyclo[17.1.1.0 2 , 7 .0 11 , 16 ]henicosa-2(7),3,5-triene-10,15-dione [ka]

[0469] Intermediate 61 was synthesized starting from Intermediate 60 using a similar route as described for Intermediate 8 to give the title compound (0.235 g) as a white solid. [M+H] + m / z = 330.2

[0470] Examples 283, 284, 285, and 286

[0471] Example 283: (1s,15S,16S,19s)-15-{[(2R)-1,1,1-trifluoropropan-2-yl]amino}-8,18-dioxa-11-azatetracyclo[17.1.1.0 2 , 7 .0 11 , 16 ]heneicosa-2(7),3,5-trien-10-one

[0472] Example 284: (1s,15S,16R,19s)-15-{[(2R)-1,1,1-trifluoropropan-2-yl]amino}-8,18-dioxa-11-azatetracyclo[17.1.1.0 2 , 7 .0 11 , 16 ]heneicosa-2(7),3,5-trien-10-one

[0473] Example 285: (1s,15R,16S,19s)-15-{[(2R)-1,1,1-trifluoropropan-2-yl]amino}-8,18-dioxa-11-azatetracyclo[17.1.1.0 2 , 7 .0 11 , 16 ]heneicosa-2(7),3,5-trien-10-one

[0474] Example 286: (1s,15R,16R,19s)-15-{[(2R)-1,1,1-trifluoropropan-2-yl]amino}-8,18-dioxa-11-azatetracyclo[17.1.1.0 2 , 7 .0 11 , 16 ]heneicosa-2(7),3,5-trien-10-one [ka]

[0475] To a solution of Intermediate 61 (60 mg, 0.180 mmol) and (R)-1,1,1-trifluoro-2-propylamine (0.07 mL, 0.730 mmol) in THF (2 mL) was added Ti(OEt) (0.08 mL, 0.360 mmol), and the mixture was stirred at 60 °C for 20 h. The mixture was cooled to room temperature, and sodium cyanoborohydride (180 mg, 2.91 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between EtOAc and saturated aqueous NaHCO, and the organic phase was dried (NaSO), filtered, and concentrated in vacuo. The product was purified by column chromatography using a silica cartridge (0-40% EtOAc in cHex) to give a mixture of different diastereoisomers, which was subjected to chiral preparative SFC separation using a Chiralpak AD-H column (25 x 2.0 cm) with 10% 5μ modifier (ethanol + 0.1% isopropylamine), at a flow rate of 45 ml / min, a pressure of 120 bar, and a temperature of 40 °C to give the title compounds (Example 280, 6 mg, 86.1% ee; Example 281, 12 mg, 98.5% ee; Example 282, 16 mg, 100% ee; Example 283, 4 mg, 71.8% ee). [Table 23-1] [Table 23-2]

[0476] Example 287

[0477] Rel-(1s,16S,17R,20s)-16-[(pyrimidin-2-yl)amino]-8,19-dioxa-12-azatetracyclo[18.2.2.0 2 , 7 .0 12 , 17 ]Tetracosa-2(7),3,5-trien-11-one [ka]

[0478] 2-Chloropyrimidine (42 mg, 0.368 mmol) was added to a stirred solution of the appropriate macrocyclic amine intermediate (synthesized using a procedure similar to that described for the synthesis of Intermediate 25 starting from Intermediate 34) (120 mg, 0.335 mmol) and triethylamine (0.093 mL, 0.670 mmol) in anhydrous DMF (1.5 mL) at room temperature, and the mixture was heated to 150° C. for 1 h under microwave irradiation. The reaction was then heated to 150° C. for 1 h twice more. The reaction was quenched with water (10 mL) and diluted with EtOAc (10 mL). The organic phase was separated, and the aqueous phase was extracted with additional EtOAc (2×10 mL). The combined organic phases were dried over MgSO and concentrated in vacuo. The crude material was subjected to chiral preparative purification using an X-Bridge, 100 × 19 mm, 5 μm column eluted with 5–95% MeCN in HO (0.2% ammonia) to afford the title compound (17 mg, 0.0372 mmol, 11% yield) as a colorless solid. [Table 24]

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt or stereoisomer thereof (In the formula, L is heteroaryl, -carbocyclyl-(CR ７ CR ７’ ) ｒ -O-, and -heterocyclyl-(CR ７ CR ７’ ) ｒ -O-, wherein -carbocyclyl-(CR ７ CR ７’ ) ｒ -O- and -heterocyclyl-(CR ７ CR ７’ ) ｒ -O- has the following orientation: 【Chemistry 2】 and 【Transformation 3】 is phenyl, 5- or 6-membered heteroaryl, cycloalkyl, or heterocyclyl; V and Z are each independently —O— or —CR ８ R ９ - or -NR １０ - and X is —O—, —CR １１ R １２ - or -NR １３ - and Y is a bond, —O—, or —CR ８ R ９ - or -NR １０ - and R １ and R ２ are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R １ and R ２ together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, R ３ and R ４ are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R ３ and R ４ together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, R ５ is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, aryl, heteroaryl, alkylene-heteroaryl, or alkylene-SO ２ - alkyl, R ６ is H, alkyl, cycloalkyl, heterocyclyl, alkylene-cycloalkyl, alkylene-heterocyclyl, or —CN; R ７ and R ７’ are each independently H, halogen, or alkyl; R ８ and R ９ are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R ８ and R ９ together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, R １１ and R １２ are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl, or R １１ and R １２ together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, R １０ and R １３ are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, -(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, m, n, and p are each independently 0, 1, or 2; and r is 0 or 1.

2. R ５ The compound of claim 1 , wherein is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heteroaryl, or alkylene-heteroaryl.

3. R ５ The compound of claim 1 or 2, wherein is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or alkylene-heterocyclyl.

4. R ５ The compound of claim 1 or 2, wherein is heteroaryl or alkylene-heteroaryl.

5. R ５ The compound according to any one of claims 1 to 3, wherein is alkyl.

6. R ５ But C １－５ Alkyl, C １－５ Haloalkyl, C ３－６ Cycloalkyl, C ３－６ halocycloalkyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, C １－３ Alkylene-C ３－６ Cycloalkyl, C １－３ alkylene-(4- to 6-membered heterocyclyl), or C １－３ The compound of any one of claims 1 to 5, which is alkylene-(5- or 6-membered heteroaryl).

7. R ５ The compound according to any one of claims 1 to 6, wherein is cyclopropyl or cyclobutyl.

8. R ５ is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.

9. R ５ but one or more F, CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , -CN, CF ３ , and / or CHF ２ 9. The compound of any one of claims 1 to 8, optionally substituted with:

10. R ５ but, 【Chemistry 4】 3. The compound of claim 1 or 2, wherein

11. R ５ but, 【Transformation 5】 3. The compound of claim 1 or 2, wherein

12. R ６ The compound of any one of claims 1 to 11, wherein is H or -CN.

13. R ６ The compound according to any one of claims 1 to 11, wherein is H.

14. R １ and R ２ The compound of any one of claims 1 to 12, wherein each is independently H, halogen, or alkyl.

15. R １ and R ２ The compound of any one of claims 1 to 12, wherein each is independently H or halogen.

16. R １ and R ２ The compound according to any one of claims 1 to 12, wherein is H.

17. R １ and R ２ and together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring.

18. R １ and R ２ together with the carbon atoms to which they are attached, C ３－６ The compound according to any one of claims 1 to 12, which forms a cycloalkyl.

19. R １ and R ２ The compound of any one of claims 1 to 12, wherein together with the carbon atoms to which they are attached, form a 3- or 6-membered heterocyclic ring.

20. R １ and R ２ together with the carbon atoms to which they are attached form a heterocycle containing one or two heteroatoms selected from the group consisting of N, O, and S.

21. R ３ and R ４ The compound of any one of claims 1 to 20, wherein each is independently H, halogen, or alkyl.

22. R ３ and R ４ are each independently H or C １－５ The compound of any one of claims 1 to 21, which is alkyl.

23. R ３ and R ４ The compound of any one of claims 1 to 22, wherein each is independently methyl or ethyl.

24. R ３ and R ４ The compound of any one of claims 1 to 22, wherein is H.

25. R ３ and R ４ The compound according to any one of claims 1 to 21, wherein is halogen.

26. R ３ and R ４ The compound according to any one of claims 1 to 21, wherein is fluorine.

27. R ３ and R ４ and together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring.

28. R ３ and R ４ together with the carbon atoms to which they are attached, C ３－６ A compound according to any one of claims 1 to 21, which forms a cycloalkyl.

29. R ３ and R ４ The compound of any one of claims 1 to 21, wherein together with the carbon atoms to which they are attached, form a 3- or 6-membered heterocyclic ring.

30. R ３ and R ４ together with the carbon atoms to which they are attached form a heterocycle containing one or two heteroatoms selected from the group consisting of N, O, and S.

31. V is —O— or —CR ８ R ９ The compound according to any one of claims 1 to 30, wherein

32. V is —O— or —NR １０ The compound according to any one of claims 1 to 30, wherein

33. The compound of any one of claims 1 to 30, wherein V is -O-.

34. Y is a bond or -CR ８ R ９ The compound according to any one of claims 1 to 33, wherein

35. The compound of any one of claims 1 to 34, wherein Y is a bond.

36. Z is -NR １０ -or-CR ８ R ９ The compound according to any one of claims 1 to 35, wherein

37. Z is -CR ８ R ９ The compound according to any one of claims 1 to 35, wherein

38. R ８ and R ９ are each independently H or C １－５ The compound of any one of claims 1 to 37, which is alkyl.

39. R ８ and R ９ together with the carbon atoms to which they are attached, C ３－６ A compound according to any one of claims 1 to 37, which forms a cycloalkyl.

40. R １０ is H or C １－５ The compound of any one of claims 1 to 39, which is alkyl.

41. R １０ The compound of any one of claims 1 to 39, wherein is methyl, ethyl, or isopropyl.

42. X is -CR １１ R １２ The compound according to any one of claims 1 to 41, wherein

43. R １１ and R １２ are each independently H or C １－５ The compound of any one of claims 1 to 42, which is alkyl.

44. R １１ and R １２ is each independently methyl or ethyl.

45. R １１ and R １２ together with the carbon atoms to which they are attached, C ３－６ A compound according to any one of claims 1 to 42 which forms a cycloalkyl. 【Request Item 46】 【Transformation 6】 but, 【Transformation 7】 wherein R ａ is a halogen, C １－５ Alkyl, or C １－５ 46. ​​The compound of any one of claims 1 to 45, wherein alkoxy is alkoxy and q is 0, 1, or 2. 【Request Item 47】 【Transformation 8】 but, 【Chemistry 9】 wherein R ａ is a halogen, C １－５ Alkyl, or C １－５ 47. The compound of any one of claims 1 to 46, wherein q is 0, 1, or 2. 【Request Item 48】 【Chemistry 10】 but, 【Chemistry 11】 The compound according to any one of claims 1 to 47, 【Request Item 49】 【Chemistry 12】 but, 【Chemistry 13】 wherein R ａ is a halogen, C １－５ Alkyl, or C １－５ 47. The compound of any one of claims 1 to 46, wherein q is 0, 1, or 2. 【Request Item 50】 【Chemistry 14】 but, 【Chemistry 15】 wherein R ａ is a halogen, C １－５ Alkyl, or C １－５ 50. The compound of any one of claims 1 to 46 and 49, wherein q is 0, 1, or 2. 【Request Item 51】 【Chemistry 16】 but, 【Chemistry 17】 The compound according to any one of claims 1 to 46,

52. 50. The compound of any one of claims 46, 47, and 49, wherein q is 0 or 1.

53. 53. The compound of any one of claims 46, 47, 49, and 52, wherein q is 0.

54. 54. The compound of any one of claims 1 to 53, wherein m is 0 or 1.

55. 55. The compound of any one of claims 1 to 54, wherein m is 1.

56. 56. The compound of any one of claims 1 to 55, wherein n is 0 or 1.

57. 57. The compound of any one of claims 1 to 56, wherein n is 1.

58. 58. The compound of any one of claims 1 to 57, wherein p is 0 or 1.

59. The compound of any one of claims 1 to 58, wherein p is 0.

60. 59. The compound of any one of claims 1 to 58, wherein p is 1.

61. L is -carbocyclyl-(CH ２ ) ｒ -O- or -heterocyclyl-(CH ２ ) ｒ The compound of any one of claims 1 to 60, wherein -O-.

62. L is -carbocyclyl-(CH ２ ) ｒ The compound of any one of claims 1 to 60, wherein -O-.

63. L, [Chemistry 18] 63. The compound according to any one of claims 1 to 62, wherein

64. L, 【Chemistry 19】 63. The compound according to any one of claims 1 to 62, wherein

65. 65. The compound of any one of claims 1 to 64, wherein r is 0.

66. 65. The compound of any one of claims 1 to 64, wherein r is 1.

67. When r is 0, L is the structure 【Chemistry 20】 a -carbocyclyl-O- or -heterocyclyl-O- linker having the formula ５ and A ６ are each independently —O— or —CH ２ - and * is 【Chemistry 21】 62. The compound of any one of claims 1 to 61, wherein:

68. A ５ The compound of claim 67, wherein is -O-.

69. A ５ But -CH ２ The compound of claim 67, wherein

70. A ６ The compound of any one of claims 67 to 69, wherein is -O-.

71. A ６ But -CH ２ The compound according to any one of claims 67 to 69, wherein

72. L, 【Chemistry 22】 wherein R ｂ 62. The compound of any one of claims 1 to 61, wherein is halogen, alkyl, or alkoxy; and u is 0, 1, or 2.

73. R ｂ 73. The compound of claim 72, wherein is a halogen.

74. R ｂ 74. The compound of claim 73, wherein is fluoride.

75. 75. The compound of any one of claims 72 to 74, wherein u is 1.

76. 75. The compound of any one of claims 72 to 74, wherein u is 0.

77. L, 【Chemistry 23】 76. The compound according to any one of claims 1 to 75,

78. 62. The compound of any one of claims 1 to 61, wherein L is a 5- or 6-membered heteroaryl linker having 1 to 2 nitrogen atoms.

79. L, 【Chemistry 24】 wherein R ｂ 80. The compound of any one of claims 1 to 61 and 78, wherein is halogen, alkyl, or alkoxy; and u is 0 or 1.

80. The following structure: 【Chemistry 25】 72. The compound of any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof, having the formula: (In the formula, r is 0 or 1; s is 1 or 2; t is 1 or 2).

81. 81. The compound of claim 80, wherein r is 0.

82. 82. The compound of claim 80 or 81, wherein s is 2.

83. 83. The compound of any one of claims 80 to 82, wherein t is 2.

84. The following structure: 【Chemistry 26】 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, having the formula: (In the formula, R ａ is a halogen, C １－５ Alkyl, or C １－５ alkoxy, and q is 0, 1, or 2).

85. Each R ａ 85. The compound of any one of claims 46, 47, 49, and 84, wherein is independently F or Me.

86. Each R ａ 86. The compound of any one of claims 46, 47, 49, 84, and 85, wherein is F.

87. 87. The compound of any one of claims 46, 47, 49, and 84-86, wherein q is 1 or 2.

88. The compound is 【Chemistry 27-1】 【Chemistry 27-2】 【Chemistry 27-3】 【Chemistry 27-4】 【Chemistry 27-5】 【Chemistry 27-6】 【Chemistry 27-7】 [Chemistry 27-8] 【Chemistry 27-9】 【Chemistry 27-10】 2. The compound of claim 1, wherein:

89. 89. A pharmaceutical composition comprising a compound according to any one of claims 1 to 88 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

90. 90. A method for treating a disease or disorder treatable by administration of an orexin agonist, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 88 or a pharmaceutical composition of claim 89.

91. 90. A method of treating a disease or disorder by modulating one or more orexin receptors, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 88 or a pharmaceutical composition of claim 89.

92. 90. A method for treating, preventing, ameliorating, controlling, or reducing the risk of a disease or disorder associated with one or more orexin receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 88 or a pharmaceutical composition of claim 89.

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