Sulfonamide orexin receptor agonists and uses thereof

Abstract

This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, A, L1, L2, Y, and Z are defined herein. This invention also provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof, and methods of using compounds of formula (I) or pharmaceutically acceptable salts thereof, for example, for treating diseases or conditions that can be treated by administration of orexin agonists.

Description

Technical Field

[0001] This invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, A, L1, L2, Y, and Z are defined herein. This invention also provides 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, for treating diseases or conditions that can be treated by administration of orexin agonists. Prior Technology

[0002] Orexin is a neuropeptide produced sparsely by specific neurons located in and around the lateral hypothalamus. Orexin consists of two subtypes: orexin A and orexin B. Both orexin A (OX-A) and orexin B (OX-B) are endogenous ligands of the orexin receptor, primarily found in the brain. Two orexin receptors have been selected and characterized in mammals. They belong to the superfamily of G protein-coupled receptors: the orexin-1 receptor (OX or OX1R) is partially selective for OX-A, and the orexin-2 receptor (OX2 or OX2R) binds to both OX-A and OX-B with similar affinity. It is hypothesized that the physiological functions of orexin are expressed through one or both of the two orexin receptor subtypes, OX1 and OX2.

[0003] Orexin regulates sleep and wakefulness, making the orexin system a potential target for treating sleep disorders. The discovery that orexin stimulates food intake in rats suggests the physiological role of these peptides as mediators in the central feedback mechanism regulating eating behavior. Orexin has also been shown to play roles in arousal, mood, energy homeostasis, reward, learning, and memory.

[0004] Compounds that modulate orexin receptors and compositions and methods for treating diseases or conditions that can be treated by administration of orexin agonists. Summary of the Invention

[0005] This invention relates to compounds that act as agonists of orexin-2 receptors, pharmaceutical compositions thereof, and their use in treating diseases or conditions that can be treated by administration of orexin agonists.

[0006] In one state sample, this paper provides compounds of formula (I): Or its medically acceptable salts or N-oxides, in A is a heteroaryl group; L1 can be -O-, -CR 5R 6-, or a single key; L2 is -CR 5R 6; R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or -NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle; R2, R3, and R4 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, or halogen, or R2 and R3 together with the atoms they are attached to form a carbocyclic or heterocyclic ring, or R2 and R4 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, -O-cycloalkyl, -O-heterocyclic, or halogen, or R5 and R6 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, or heterocyclic groups, or R7 and R8 together with the atoms they are attached to form a heterocycle; Y is a cycloalkyl, heterocyclic, heteroaryl, or aryl group; and Z is either nonexistent or is a heteroaryl or aryl group, wherein if L1 is a single bond or CR5R6, then Z is a heteroaryl or aryl group; and the limiting condition is that the compound is not: .

[0007] In one state sample, this paper provides compounds of formula (I): Or a medically acceptable salt, in A is a heteroaryl group; L1 can be -O-, -CR 5R 6-, or a single key; L2 is -CR 5R 6; R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or -NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle; R2, R3, and R4 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, or halogen, or R2 and R3 together with the atoms they are attached to form a carbocyclic or heterocyclic ring, or R2 and R4 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, -O-cycloalkyl, -O-heterocyclic, or halogen, or R5 and R6 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, or heterocyclic groups, or R7 and R8 together with the atoms they are attached to form a heterocycle; Y is a cycloalkyl, heterocyclic, heteroaryl, or aryl group; and Z is either nonexistent or is a heteroaryl or aryl group, wherein if L1 is a single bond or CR5R6, then Z is a heteroaryl or aryl group; and the limiting condition is that the compound is not: .

[0008] In some embodiments, the present invention provides a compound of formula (IA): Or its medically acceptable salts, wherein o, A, L1, L2, R1, R2, R3, R4 and RB are defined herein.

[0009] In some embodiments, the present invention provides a compound of formula (IAI): Or its medically acceptable salts, wherein o, A, L1, L2, R1, R2, R3, R4 and RB are defined herein.

[0010] In some embodiments, the present invention provides a compound of formula (IB): Or its pharmaceutically acceptable salts, wherein o, q, A, L2, R1, R2, R3, R4, RA, and RB are defined herein.

[0011] In some embodiments, the present invention provides a pharmaceutical composition comprising one or more of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.

[0012] In some embodiments, the present invention provides a pharmaceutical composition comprising one or more of the compounds of the present invention or their pharmaceutically acceptable salts or N-oxides and a pharmaceutically acceptable carrier.

[0013] In some embodiments, the present invention provides a method for treating a disease or condition that can be treated by administration of an orexin agonist, comprising administering a therapeutically effective amount of one or more of the compounds of the present invention or a medically acceptable salt thereof. Implementation

[0014] Cross-reference to related applications

[0015] This application claims priority to U.S. Provisional Application No. 63 / 215,054, filed on June 25, 2021, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0016] Throughout this invention, numerous patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety for all purposes, to more fully describe the current state of the art as known to those skilled in the art up to the date of this invention. In the event of any inconsistency between the referenced patents, patent applications, and publications and this invention, this invention shall prevail. [, , ] [definition] []

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

[0018] When immediately preceding a numerical value, the term "about" means a range (e.g., the value plus or minus 10%). For example, unless the context of this invention otherwise indicates or is inconsistent with such an interpretation, "about 50" may mean 45 to 55, "about 25,000" may mean 22,500 to 27,500, etc. For example, in a list of values ​​such as "about 49, about 50, about 55, ...", "about 50" means a range extending to less than half the interval between the preceding and following values, such as greater than 49.5 to less than 50.5. Furthermore, the phrases "less than about" or "greater than about" should be understood according to the definition of the term "about" provided herein. Similarly, when preceding a series of numerical values ​​or a range of values ​​(e.g., "about 10, 20, 30" or "about 10-30"), the term "about" refers to all values ​​in the series or the endpoints of the range, respectively. [, , ]

[0019] As used herein, the term "administer / administering / administration" refers to administering a compound or a pharmaceutically acceptable salt thereof, or a composition or formulation containing the compound or a pharmaceutically acceptable salt thereof, to a patient. [, , ]

[0020] The term "medically acceptable salt" includes both acid and base addition salts. Medically acceptable salts include those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Base addition salts include, but are not limited to, ethylenediamine, N-methylglucosamine, lysine, arginine, ornithine, choline, N,N'-diphenylmethylethylenediamine, chloroprocaine, diethanolamine, procaine, N-phenylmethylphenylethylamine, diethylamine, piperidine, trimethylammonium hydroxide, tetramethylammonium hydroxide, triethylamine, diphenylmethylamine, ephenamine, dehydroabimethamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids (e.g., lysine and dicyclohexylamine arginine) and their analogues. Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts and their analogues. Examples of ammonium salts and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, and their analogues. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, and their analogues. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid via any of a variety of known methods.

[0021] As used in relation to patients in this article, the term "treatment" refers to the improvement of at least one symptom of a patient's condition. Treatment may be for the improvement or at least partial relief of the condition or related symptoms.

[0022] The terms "effective amount" and "therapeutic effective amount" are used interchangeably in this invention and refer to the amount of a compound or its salt (or a pharmaceutical composition containing the compound or its salt) that, when administered to a patient, achieves the intended result. "Effective amount" will vary depending on the active ingredient, the state to be treated, the disease or symptom and its severity, and the age, weight, physical condition, and response of the mammal to be treated.

[0023] The term "therapeuticly effective" applies to dosage or amount, referring to the amount of a compound or pharmaceutical preparation sufficient to produce the desired clinical benefit after administration to a patient in need.

[0024] As used interchangeably herein, the terms "carrier" or "medium" include carriers, excipients, adjuvants, and diluents, or combinations thereof, meaning materials, compositions, or media (such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials) that involve transporting or delivering 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 also include nanoparticles of both organic and inorganic properties.

[0025] When listing a range of values, it is desirable that the range encompasses all values ​​and subranges. For example, "C1-C6 alkyl" is intended to cover C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0026] "alkyl" or "alkyl group" means a fully saturated, straight-chain or branched hydrocarbon chain having one to twelve carbon atoms connected to the rest of the molecule by single bonds. Alkyl groups containing any number of carbon atoms from 1 to 12 are included. Alkyl groups containing up to 12 carbon atoms are C1-C12 alkyl groups, alkyl groups containing up to 10 carbon atoms are C1-C10 alkyl groups, alkyl groups containing up to 6 carbon atoms are C1-C6 alkyl groups, and alkyl groups containing up to 5 carbon atoms are C1-C5 alkyl groups. C1-C5 alkyl groups include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups include not only all the portions described above for C1-C5 alkyl groups, but also C6 alkyl groups. C1-C10 alkyl groups include not only all the portions described above for C1-C5 and C1-C6 alkyl groups, but also C7, C8, C9, and C10 alkyl groups. Similarly, C1-C12 alkyl groups include not only all the aforementioned portions, but also C11 and C12 alkyl groups. Non-limiting examples of C1-C12 alkyl groups include methyl, ethyl, n-propyl, isopropyl, dipropyl, n-butyl, isobutyl, dipropyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated in this specification, alkyl groups may be substituted as appropriate.

[0027] "Phenylalkyl" or "phenylalkyl chain" refers to a fully saturated, straight-chain or branched divalent hydrocarbon chain radical having one to twelve carbon atoms. Non-limiting examples of C1-C12 phenylalkyl groups include methylene, phenylethyl, phenylpropyl, phenyl-n-butyl, and similar groups. The phenylalkyl chain is attached to the remainder of the molecule and to a group (e.g., those described herein) via a single bond. The attachment points of the phenylalkyl chain to the remainder of the molecule and to the group can be achieved via one or any two carbons within the chain. Unless otherwise specifically stated in this specification, the phenylalkyl chain may be substituted as appropriate.

[0028] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched hydrocarbon chain having two to twelve carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is connected to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are C2-C12 alkenyl groups, alkenyl groups containing up to 10 carbon atoms are C2-C10 alkenyl groups, alkenyl groups containing up to 6 carbon atoms are C2-C6 alkenyl groups, and alkenyl groups containing up to 5 carbon atoms are C2-C5 alkenyl groups. C2-C5 alkenyl groups include C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl groups. C2-C6 alkenyl groups include not only all the portions described above for C2-C5 alkenyl groups but also C6 alkenyl groups. C2-C10 alkenyl groups include not only all the portions described above for C2-C5 and C2-C6 alkenyl groups, but also C7, C8, C9, and C10 alkenyl groups. Similarly, C2-C12 alkenyl groups include not only all the aforementioned portions, but also C11 and C12 alkenyl groups. C2-C Non-limiting examples of 12-alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl-1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-... -Nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless otherwise specified in this specification, the alkenyl group may be substituted as appropriate.

[0029] "Alkenyl" or "alkenyl chain" refers to an unsaturated straight-chain or branched divalent hydrocarbon chain group having one or more olefins and two to twelve carbon atoms. Non-limiting examples of C2-C12 alkenyl groups include alkenylvinyl, alkenylpropenyl, alkenyl-butenyl, and similar groups. The alkenyl chain is attached to the remainder of the molecule and to a group (e.g., those described herein) via a single bond. The attachment points of the alkenyl chain to the remainder of the molecule and to the group can be achieved via one or any two carbons within the chain. Unless otherwise specifically stated in this specification, the alkenyl chain may be substituted as appropriate.

[0030] "Alynyl" or "alkynyl group" refers to a straight-chain or branched hydrocarbon chain having two to twelve carbon atoms and one or more carbon-carbon linkages. Each alkynyl group is connected to the rest of the molecule by a single bond. Alynyl groups containing any number of carbon atoms from 2 to 12 are included. Alynyl groups containing up to 12 carbon atoms are C2-C12 alkynyl groups, alkynyl groups containing up to 10 carbon atoms are C2-C10 alkynyl groups, alkynyl groups containing up to 6 carbon atoms are C2-C6 alkynyl groups, and alkynyl groups containing up to 5 carbon atoms are C2-C5 alkynyl groups. C2-C5 alkynyl groups include C5 alkynyl, C4 alkynyl, C3 alkynyl, and C2 alkynyl groups. C2-C6 alkynyl groups include not only all the portions described above for C2-C5 alkynyl groups, but also C6 alkynyl groups. The C2-C10 ynyl group includes not only all the portions described above for the C2-C5 and C2-C6 ynyl groups, but also C7, C8, C9, and C10 ynyl groups. Similarly, the C2-C12 ynyl group includes not only all the aforementioned portions, but also C11 and C12 ynyl groups. Non-limiting examples of the C2-C12 ynyl group include ethynyl, propynyl, butynyl, pentyynyl, and similar groups. Unless otherwise specifically stated in this specification, the ynyl group may be substituted as appropriate.

[0031] "Phenynyl" or "Phenynyl chain" refers to an unsaturated straight-chain or branched divalent hydrocarbon chain group having one or more alkynes and two to twelve carbon atoms. Non-limiting examples of C2-C12 phenynyl groups include phenynylethynyl, phenynylpropynyl, phenynyl-n-butynyl, and similar groups. The phenynyl chain is connected to the rest of the molecule and to a group (e.g., those described herein) via single bonds. The connection points of the phenynyl chain to the rest of the molecule and to the group can be achieved via any two carbons in the chain having suitable valence states. Unless otherwise specifically stated in this specification, the phenynyl chain may be substituted as appropriate.

[0032] "Alkoxy" refers to a group of the formula -ORa, where Ra is an alkyl, alkenyl, or alkynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in this specification, alkoxy groups may be substituted as appropriate.

[0033] "Aryl" refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, which is connected to the rest of the molecule by a single bond. For the purposes of this invention, 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, aryl derived from: ethylene anthracene, ethylene naphthalene, ethylene phenanthrene, anthracene, azurite, benzene, arsenylene, arsenylene, α-dicyclopentadienylbenzene, α-dicyclopentadienylbenzene, indane, indene, naphthalene, phenanthrene, heptane, pyrene, and terphenyl. Unless otherwise specifically stated in this specification, "aryl" may be substituted as appropriate.

[0034] "Arylalkyl" or "arylalkyl" refers to a group of the formula -RbRc, wherein Rb is an alkyl group as defined above and Rc is one or more aryl groups as defined above, such as benzyl, diphenylmethyl and similar groups. Unless otherwise specified in this specification, arylalkyl groups may be substituted as appropriate.

[0035] "Carbocyclic ring" or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon and is connected to the rest of the molecule by a single bond. A carbocyclic ring may contain 3 to 20 carbon atoms. Carbocyclic rings include aryl, cycloalkyl, cycloalkenyl, and cycloynyl groups as defined herein. Unless otherwise specified in this specification, carbocyclic groups may be substituted as appropriate.

[0036] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon consisting only of carbon and hydrogen atoms. It may include fused, bridged, or spirocyclic ring systems, having three to twenty carbon atoms (e.g., three to ten carbon atoms), and is connected to the rest of the molecule by single bonds. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norfyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and similar groups. Unless otherwise specified in this specification, cycloalkyl groups may be substituted as appropriate.

[0037] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds. It may include fused or bridged ring systems, having three to twenty carbon atoms, preferably three to ten, and is connected to the rest of the molecule by single bonds. Monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclopentenyl, and similar groups. Polycyclic cycloalkenyl groups include, for example, bicyclic [2.2.1]hept-2-enyl and similar groups. Unless otherwise specifically stated in this specification, cycloalkenyl groups may be substituted as appropriate.

[0038] "Cycloynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting only of carbon and hydrogen atoms, having one or more carbon-carbon linkages. It may include fused or bridged ring systems, having three to twenty carbon atoms, preferably three to ten, and is connected to the rest of the molecule by single bonds. Monocyclic cycloynyl groups include, for example, cycloheptynyl, cyclooctyynyl, and similar groups. Unless otherwise specified in this specification, cycloynyl groups may be substituted as appropriate.

[0039] "Haloalkyl" means an alkyl group substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and similar groups. Unless otherwise specified in this specification, haloalkyl may be substituted as appropriate.

[0040] "Heterocyclic group" or "heterocycle" refers to a stable saturated, unsaturated, or aromatic 3- to 20-membered ring composed of two to nineteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and connected to the rest of the molecule by single bonds. Heterocyclic groups or heterocycles include heteroaryl, heterocyclic alkyl, heterocyclic alkenyl, and heterocyclic alkynyl groups. Unless otherwise specified in this specification, heterocyclic groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused, bridged, or spirocyclic ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclic group may be oxidized as appropriate; the nitrogen atom may be quaternarily ammonized as appropriate; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxacyclopentyl, thienyl[1,3]dithiayl, decahydroisoquinolinyl, imidazolinyl, imidazodinyl, isothiazolinyl, isothiazolinyl, succinyl, octahydroindolyl, octahydroisoindolyl, 2-side-oxypiperidyl, 2-side-oxypiperidinyl, 2-side-oxypyrrolidinyl, succinyl, piperidinyl, piperidinyl, 4-piperidinoneyl, pyrrolidinyl, pyrazolidinyl. The heterocyclic groups include pyridyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperanyl, thiopyrinyl, thiapyrinyl, 1-side-oxy-thiopyrinyl, and 1,1-diside-oxy-thiopyrinyl. Unless otherwise specified in this specification, the heterocyclic groups may be substituted as appropriate.

[0041] "Heteroaryl" refers to a 5- to 20-membered ring system comprising a hydrogen atom, one to nineteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, at least one aromatic ring (including compounds with an aromatic resonance structure (e.g., 2-pyridone)), and which is connected to the rest of the molecule by a single bond. For the purposes of this invention, heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl may be oxidized as appropriate; the nitrogen atom may be quaternized as appropriate. Examples include, but are not limited to, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzo[m-dioxanepentenyl, benzofuranyl, benzo[azolyl, benzothiazolyl, benzothiadiazolyl, benzo[] [b][1,4]dioxanyl, 1,4-benzodioxanyl, benzonaphthylfuranyl, benzoazolyl, benzo[m]dioxacyclopentenyl, benzo[m]dioxacyclohexenyl, benzopiperanyl, benzopiperanone, benzofuranyl, benzofuranone, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, linyl, dibenzofuranyl, dibenzothienyl, furanyl, furanone, isothiazolyl, imidazoyl, indazole, indole, indazole, isoindole, indolinyl, isoindolinyl, isoquinolinyl, indole alkyl, isozolyl, acetylated, acediazolyl, 2-side-oxy-nitropyridyl, acezolyl, ethylene oxide, 1-oxo-pyridyl, 1-oxo-pyrimidinyl, 1-oxo-pyridine, 1-oxo-pyridine, 1-oxo-pyridine, 1-phenyl-1H-pyrroleyl, phenanthryl, phenanthryl, phenanthryl, pyridinyl, purine, pyrroleyl, pyrazolyl, pyridyl, pyridine, pyridine, pyridine, pyrimidinyl, pyridine, pyridine, quinazolinyl, quinazolinyl, quinolinyl The compounds include pyridyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazolyl, and thiophenyl (i.e., thienyl). Unless otherwise specified in this specification, heteroaryl groups may be substituted as appropriate.

[0042] "Heterocyclic alkyl" refers to a group of the formula -RbRe, wherein Rb is an alkyl, alkenyl, or ynyl group as defined above and Re is a heterocyclic group as defined above. Unless otherwise specified in this specification, heterocyclic alkyl groups may be substituted as appropriate.

[0043] As used herein, the term "substituted" means any of the groups described herein (e.g., alkyl, alkenyl, alkoxy, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclic and / or heteroaryl) in which at least one hydrogen atom is substituted to a non-hydrogen atom such as (but not limited to) halogen atoms such as F, Cl, Br and I; hydroxyl, alkoxy and ester groups. The oxygen atom in the group; the sulfur atom in groups such as thioalkyl, thioalkyl, ternary, sulfonylurea, and ternidine; the nitrogen atom in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, amide, and enamine; the silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher valence bond (e.g., a double bond or a triple bond) to a heteroatom, such as oxygen in side oxygen, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile groups. For example, "substitution" includes the substitution of one or more hydrogen atoms in any of the above groups by -NR gR h, -NR gC(=O)R h, -NR gC(=O)NR gR h, -NR gC(=O)OR h, -NR gSO 2R h, -OC(=O)NR gR h, -OR g, -SR g, -SOR g, -SO 2R g, -OSO 2R g, -SO 2OR g, =NSO 2R g, and -SO 2NR gR h. "Substitution" also means that one or more hydrogen atoms in any of the above groups are substituted by -C(=O)R g, -C(=O)OR g, -C(=O)NR gR h, -CH 2SO 2R g, and -CH 2SO 2NR gR h. In the foregoing, Rg and Rh are the same or different and independently represent hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substituted" further means that one or more hydrogen atoms in any of the above groups are replaced by bonds to: amino, cyano, hydroxyl, imino, nitro, oxy, thionyl, haloalkyl, alkyl, alkenyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. In some embodiments, "substituted" further means that one or more hydrogen atoms in any alkyl, cycloalkyl, or heterocyclic alkyl group are replaced by an isotope (e.g., deuterium).Furthermore, each of the aforementioned substituents may also be substituted by one or more of the aforementioned substituents, depending on the circumstances.

[0044] As used in this article, the symbol " "(Hereinafter referred to as a "connection point bond") indicates a bond that serves as a connection point between two chemical entities, one of which is depicted as connected to a connection point bond and the other is not depicted as connected to a connection point bond. For example, " The term "XY" indicates that chemical entity "XY" is bonded to another chemical entity via a linker bond. Furthermore, specific linkers to undescribed chemical entities can be inferred. For example, the compound CH3-R3, where R3 is H or " "It is inferred that when R3 is "XY", the connection point key is the same key as the key that R3 is described as being used to bond to CH3. compound

[0045] This invention provides compounds that act as agonists of orexin type 2 receptors, pharmaceutical compositions thereof, and their use in treating various diseases and conditions.

[0046] In an embodiment, the present invention provides a compound of formula (I): Or its medically acceptable salts or N-oxides, in A is a heteroaryl group; L1 can be -O-, -CR 5R 6-, or a single key; L2 is -CR 5R 6; R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or -NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle; R2, R3, and R4 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, or halogen, or R2 and R3 together with the atoms they are attached to form a carbocyclic or heterocyclic ring, or R2 and R4 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, -O-cycloalkyl, -O-heterocyclic, or halogen, or R5 and R6 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, or heterocyclic groups, or R7 and R8 together with the atoms they are attached to form a heterocycle; Y is a cycloalkyl, heterocyclic, heteroaryl, or aryl group; and Z is either nonexistent or is a heteroaryl or aryl group, wherein if L1 is a single bond or CR5R6, then Z is a heteroaryl or aryl group; and the limiting condition is that the compound is not: .

[0047] In some embodiments, the present invention provides a compound of formula (I): Or a medically acceptable salt, in A is a heteroaryl group; L1 can be -O-, -CR 5R 6-, or a single key; L2 is -CR 5R 6; R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or -NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle; R2, R3, and R4 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, or halogen, or R2 and R3 together with the atoms they are attached to form a carbocyclic or heterocyclic ring, or R2 and R4 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, -O-cycloalkyl, -O-heterocyclic, or halogen, or R5 and R6 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, or heterocyclic groups, or R7 and R8 together with the atoms they are attached to form a heterocycle; Y is a cycloalkyl, heterocyclic, heteroaryl, or aryl group; and Z is either nonexistent or is a heteroaryl or aryl group, wherein if L1 is a single bond or CR5R6, then Z is a heteroaryl or aryl group; and the limiting condition is that the compound is not: .

[0048] In some embodiments, the present invention provides a compound of formula (IA): Or its medically acceptable salts, wherein o, A, L1, L2, R1, R2, R3, R4 and RB are defined herein.

[0049] In some embodiments, the present invention provides a compound of formula (IA): Or a medically acceptable salt thereof, wherein: A is a heteroaryl group; L1 can be -O-, -CR 5R 6-, or a single key; L2 is -CR 5R 6; R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or -NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle; R2, R3, and R4 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, or halogen, or R2 and R3 together with the atoms they are attached to form a carbocyclic or heterocyclic ring, or R2 and R4 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, -O-cycloalkyl, -O-heterocyclic, or halogen, or R5 and R6 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, or heterocyclic groups, or R7 and R8 together with the atoms they are attached to form a heterocycle; RB, in each occurrence, is independently selected from the following groups of components: hydroxyl, halogen, -NO 2, -CN, -NR 7R 8, -CO 2R 10, -OC(O)R 10, -COR 10, -C(O)NR 7R 8, -NR 7C(O)R 10, -OC(O)NR 7R 8, -NR 7C(O)OR 10, -S(O) wR 10 (where w is 0, 1, or 2), -OSO 2R 10, -SO 3R 10, -S(O) 2NR 7R 8, -NR 7S(O) 2R 10, -NR 7C(O)NR 7R 8, -C 1-6 alkyl-NR 7R 8, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl, C 1- 6-alkoxy, C2-6 alkenyl, and C2-6 alkynyl; R 10, in each occurrence, is independently chosen from the group consisting of: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heterocyclic, and heteroaryl; and o can be 0, 1, 2, 3, 4 or 5.

[0050] In some embodiments, the present invention provides a compound of formula (IAI): Or its medically acceptable salts, wherein o, A, L1, L2, R1, R2, R3, R4 and RB are defined herein.

[0051] In some embodiments, the present invention provides a compound of formula (IAI): Or a medically acceptable salt thereof, wherein: A is a heteroaryl group; L1 can be -O-, -CR 5R 6-, or a single key; L2 is -CR 5R 6; R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or -NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle; R2, R3, and R4 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, or halogen, or R2 and R3 together with the atoms they are attached to form a carbocyclic or heterocyclic ring, or R2 and R4 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, -O-cycloalkyl, -O-heterocyclic, or halogen, or R5 and R6 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, or heterocyclic groups, or R7 and R8 together with the atoms they are attached to form a heterocycle; RB, in each occurrence, is independently selected from the following groups of components: hydroxyl, halogen, -NO 2, -CN, -NR 7R 8, -CO 2R 10, -OC(O)R 10, -COR 10, -C(O)NR 7R 8, -NR 7C(O)R 10, -OC(O)NR 7R 8, -NR 7C(O)OR 10, -S(O) wR 10 (where w is 0, 1, or 2), -OSO 2R 10, -SO 3R 10, -S(O) 2NR 7R 8, -NR 7S(O) 2R 10, -NR 7C(O)NR 7R 8, -C 1-6 alkyl-NR 7R 8, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl, C 1- 6-alkoxy, C2-6 alkenyl, and C2-6 alkynyl; R 10, in each occurrence, is independently chosen from the group consisting of: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heterocyclic, and heteroaryl; and o can be 0, 1, 2, 3, 4 or 5.

[0052] In some embodiments, the present invention provides a compound of formula (IB): Or its medically acceptable salts, wherein o, q, A, L2, R1, R2, R3, R4, RA and RB are defined herein.

[0053] In some embodiments, the present invention provides a compound of formula (IB): Or a medically acceptable salt thereof, wherein: A is a heteroaryl group; L2 is -CR 5R 6; R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or -NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle; R2, R3, and R4 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, or halogen, or R2 and R3 together with the atoms they are attached to form a carbocyclic or heterocyclic ring, or R2 and R4 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, -O-cycloalkyl, -O-heterocyclic, or halogen, or R5 and R6 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, or heterocyclic groups, or R7 and R8 together with the atoms they are attached to form a heterocycle; RA and RB, in each occurrence, are independently selected from the following groups of components: hydroxyl, halogen, -NO 2, -CN, -NR 7R 8, -CO 2R 10, -OC(O)R 10, -COR 10, -C(O)NR 7R 8, -NR 7C(O)R 10, -OC(O)NR 7R 8, -NR 7C(O)OR 10, -S(O)wR 10 (where w is 0, 1, or 2), -OSO 2R 10, -SO 3R 10, -S(O) 2NR 7R 8, -NR 7S(O) 2R 10, -NR 7C(O)NR 7R 8, C 1-6 alkyl-NR 7R 8, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl, C 1- 6-alkoxy, C2-6 alkenyl, and C2-6 alkynyl; R 10 is independently selected from the following groups of components in each occurrence: hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heterocyclic, and heteroaryl; q is 0, 1, 2, 3, or 4; and o can be 0, 1, 2, 3, 4 or 5.

[0054] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), A is a heteroaryl group.

[0055] In some embodiments of compounds of formulas (I), (I), (I), (I), and (IB), A is a substituted or unsubstituted heteroaryl group containing at least one nitrogen atom. In some embodiments, A contains one nitrogen atom. In some embodiments, A contains two nitrogen atoms.

[0056] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), A is a substituted or unsubstituted monocyclic or bicyclic nitrogen-containing heteroaryl group.

[0057] In the embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is selected from the group consisting of:

[0058] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is selected from the group consisting of:

[0059] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is... In some embodiments, A is In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is... In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is... In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is... In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is... In the embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is... In the embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is... In the embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is... In the embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is... In the embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is... .

[0060] In the examples of compounds of formula (I), (IA), (IAI) and (IB), R11 is an alkyl group substituted with cyano, haloalkyl, cycloalkyl or heterocyclic groups as appropriate.

[0061] In the examples of compounds of formulas (I), (IA), (IAI), and (IB), R11 is an alkyl group that is cyano-substituted, as appropriate. In the examples, R11 is a haloalkyl group. In the examples, R11 is a C3-6 cycloalkyl group. In the examples, R11 is a heterocyclic group.

[0062] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R 11 is an alkyl, cycloalkyl or heterocyclic group.

[0063] In the examples of compounds of formulas (I), (IA), (IAI) and (IB), R 11 is an alkyl or haloalkyl group.

[0064] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), R11 is a substituted alkyl group. In some embodiments, R11 is an unsubstituted alkyl group. In some embodiments, R11 is an alkyl group substituted with one or more deuterium atoms, as appropriate.

[0065] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), R11 is methyl, -CH2CN, cyclopropyl, -CH2CF2H or -CF2H.

[0066] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), n is an integer from 0 to 6 (i.e., 0, 1, 2, 3, 4, 5, or 6). In some embodiments, n is an integer from 0 to 4 or 1 to 4. In some embodiments, n is an integer from 0 to 3 or 1 to 3. In embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0067] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is substituted with one or more R9 radicals, depending on the situation. In some embodiments, A is substituted with R9 radicals. In some embodiments, A is unsubstituted.

[0068] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), R9 is independently hydrogen, alkyl, halogen, cyano, alkoxy, cycloalkyl, heterocyclic, or heteroaryl. In some embodiments, R9 is an alkyl group substituted with one or more deuterium atoms, as appropriate.

[0069] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R9 is independently alkyl, halogen, cyano, alkoxy or heteroaryl in each occurrence.

[0070] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), R9 is independently -CH3, -OCH3, -CH2CH3, -CF3, -OCHF2, -Br, -Cl, -F, cyano, pyridyl or pyrazolyl in each occurrence.

[0071] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), R9 is independently hydrogen, alkyl, halogen, cyano or alkoxy in each occurrence.

[0072] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), R9 is independently alkyl, halogen, cyano, or alkoxy in each occurrence. In the embodiments, R9 is alkyl or halogen.

[0073] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), R9 is independently a C1-3 alkyl, C1-3 alkoxy, -Br, -Cl, -F, and cyano group, each time it appears. In some embodiments, the C1-3 alkyl and C1-3 alkoxy groups are substituted with one or more -F groups, depending on the situation.

[0074] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), R9 is independently -CH3, -OCH3, -CH2CH3, -CF3, -OCHF2, -Br, -Cl, -F or cyano in each occurrence.

[0075] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), n is 2 and R9 is independently a C1-3 alkyl or halogen. In some embodiments, R9 is an unsubstituted C1-3 alkyl. In some embodiments, R9 is methyl. In some embodiments, R9 is -Cl.

[0076] In the embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is selected from the group consisting of: Where n is an integer between 0 and 6; R 9 is hydrogen, alkyl, haloalkyl, haloalkoxy, halogen, cyano, alkoxy, cycloalkyl, heterocyclic, or heteroaryl; and R 11 is an alkyl group that is substituted with a cyano, haloalkyl, cycloalkyl, or heterocyclic group, as appropriate.

[0077] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), A is selected from the group consisting of: Where n is an integer between 0 and 6; R 9 is hydrogen, alkyl, halogen, cyano, alkoxy, cycloalkyl, heterocyclic, or heteroaryl; and R 11 is an alkyl, cycloalkyl, or heterocyclic group.

[0078] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), n is 1 and R9 is -CH3, -OCH3, -CH2CH3, -CF3, -OCHF2, -Br, -Cl, -F, or a cyano group. In some embodiments, n is 2 and R9 is independently a heteroaryl, -CH3, or a halogroup.

[0079] In some embodiments of compounds of formulas (I), (IA), and (IAI), L1 is -O-, -CR5R6-, or a monobonded bond. In some embodiments, L1 is -O-. In some embodiments, L1 is a monobonded bond. In some embodiments, L1 is -CR5R6-.

[0080] In the examples of compounds of formula (I), (IA), (IAI) and (IB), L2 is -CR5R6.

[0081] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or -NR7R8, or R1 and R2 together with the atoms to which they are attached form a heterocycle.

[0082] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), R1 is alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or -NR7R8.

[0083] In the examples of compounds of formula (I), (IA), (IAI) and (IB), R1 is an alkyl, haloalkyl, cycloalkyl, alkyl-alkoxy or -NR7R8.

[0084] In the examples of compounds of formula (I), (IA), (IAI) and (IB), R1 is methyl, -N(CH3)2, cyclopropyl, -CH2CF2H, -CH2CF3, -CH2CH2F or -CH2CH2OMe.

[0085] In the examples of compounds of formula (I), (IA), (IAI) and (IB), R1 is an alkyl, haloalkyl or -NR7R8.

[0086] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), R1 is an alkyl group or -NR7R8.

[0087] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), R1 is an alkyl group.

[0088] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), R1 is a methyl group.

[0089] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), R1 is -NR 7R 8.

[0090] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R2, R3, and R4 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, halogen, or R2 and R3 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, or R2 and R4 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring.

[0091] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R2, R3, and R4 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, or halogen.

[0092] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R2, R3, and R4 are independently alkyl or hydrogen.

[0093] In the examples of compounds of formulas (I), (IA), (IAI) and (IB), R2 and R3 are independently hydrogen or alkyl and R4 is hydrogen.

[0094] In the embodiments of compounds of formula (I), (IA), (IAI) and (IB), R2 and R3 are independently hydrogen or methyl and R4 is hydrogen.

[0095] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), at least one of R2, R3, and R4 is an alkyl group.

[0096] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), at least two of R2, R3, and R4 are alkyl groups.

[0097] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R2, R3, and R4 are hydrogen.

[0098] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, -O-cycloalkyl, -O-heterocyclic or halogen, or R5 and R6 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring.

[0099] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, -O-cycloalkyl, -O-heterocyclic or halogen.

[0100] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R5 and R6 are hydrogen.

[0101] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), R7 and R8 are independently hydrogen, alkyl, cycloalkyl, or heterocyclic groups, or R7 and R8 together with the atoms to which they are attached form a heterocycle;

[0102] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R7 and R8 are independently hydrogen, alkyl, cycloalkyl or heterocyclic groups.

[0103] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R7 and R8 are alkyl groups.

[0104] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R7 and R8 are -CH3.

[0105] In some embodiments of compounds of formula (I), Y is a cycloalkyl, heterocyclic, heteroaryl, or aryl group.

[0106] In some embodiments of the compound of formula (I), Y is cycloalkyl or aryl.

[0107] In some embodiments of compounds of formula (I), Y is a 3-7 member monocyclic cycloalkyl, a 5-8 member bicyclic cycloalkyl, a 4-7 member saturated heterocyclic group, a 5-8 member bicyclic heterocyclic group, a 5-6 member heteroaryl or phenyl. In the embodiments, the 5-10 member heteroaryl or phenyl is substituted with one or more halogens.

[0108] In some embodiments of compounds of formula (I), Y is a 3-7 member monocyclic cycloalkyl group.

[0109] In some embodiments of compounds of formula (I), Y is a 6-membered monocyclic cycloalkyl group.

[0110] In some embodiments of the compound of formula (I), Y is an unsubstituted cyclohexyl group.

[0111] In some embodiments of compounds of formula (I), Y is substituted with one or more RA substituents as defined herein. In some embodiments, Y is substituted with 1, 2, 3 or 4 RA substituents, depending on the situation.

[0112] In the examples of compounds of formula (I), Y is 2-oxaspiro[4.5]decane or cyclohexyl substituted with one or more alkyl or cycloalkyl groups, as appropriate.

[0113] In the examples of compounds of formula (I), Y is 2-oxaspiro[4.5]decane or cyclohexyl substituted with C1-3 alkyl or cyclopropyl groups, as appropriate.

[0114] In some embodiments of the compound of formula (I), Y is phenyl.

[0115] In some embodiments of the compound of formula (I), Y is substituted with one or more deuteriums, depending on the case.

[0116] In some embodiments of the compound of formula (I), Z is absent or is heteroaryl or aryl, wherein Z is heteroaryl or aryl if L1 is a single bond or CR5R6.

[0117] In some embodiments of compounds of formula (I), Z is a heteroaryl or aryl.

[0118] In some embodiments of the compound of formula (I), Z is a heteroaryl group.

[0119] In some embodiments of the compound of formula (I), Z is aryl.

[0120] In some embodiments of the compound of formula (I), Z is absent.

[0121] In some embodiments of compounds of formula (I), Z is 5-10 heteroaryl or phenyl.

[0122] In some embodiments of the compound of formula (I), Z is phenyl.

[0123] In some embodiments of compounds of formula (I), Z is an unsubstituted phenyl group. In some embodiments, Z is a phenyl group substituted with one or more fluorine derivatives. In some embodiments, Z is a phenyl group substituted with one or two halogen derivatives.

[0124] In the examples of compounds of formula (I), Z is substituted with one or more RB substituents as defined herein. In the examples, Z is substituted with 1, 2, 3, 4 or 5 RB substituents as defined herein.

[0125] In some embodiments of the compound of formula (I), Y and Z are phenyl.

[0126] In some embodiments of the compound of formula (I), Y is cyclohexyl and Z is phenyl.

[0127] In some embodiments of the compound of formula (I), Y and Z together are: .

[0128] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), RA and RB, in each occurrence, are independently selected from the group consisting of: hydroxyl, halogen, -NO₂, -CN, -NR₇R₈, -CO₂R₁₀, -OC(O)R₁₀, -COR₁₀, -C(O)NR₇R₈, -NR₇₇C(O)R₁₀, -OC(O)NR₇R₈, -NR₇₇C(O)OR₁₀, -S(O)₂R₁₀ (where w is 0, 1, or 2), -OSO₂R₁₀, -SO₃R₁₀, -S(O)₂NR₇R₈, -NR₇₇S(O)₂R₁₀, -NR₇₇C(O)NR₇R₈, C₁-6 alkyl-NR₇R₈, -C₁-6 alkyl-OC₁- 6-alkyl, -C1-6alkyl, C1-6alkoxy, C2-6alkenyl and C2-6 ynyl.

[0129] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), RB is a halogen.

[0130] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), RB is fluorine.

[0131] In some embodiments of compounds of formula (I), (IA), (IAI) and (IB), o and q are each independently 0, 1, 2, 3, 4 or 5.

[0132] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), o is 0 or 1. In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. In some embodiments, o is 5.

[0133] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), o is 1 and RB is fluorine.

[0134] In some embodiments of compounds of formulas (I), (IA), (IAI), and (IB), 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 3. In some embodiments, q is 4. In some embodiments, q is 5.

[0135] In some embodiments of compounds of formulas (I), (IA), (IAI) and (IB), R10 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heterocyclic and heteroaryl.

[0136] In all embodiments of the present invention, the compound is not: .

[0137] In some embodiments, the compounds described herein may also contain one or more isotopic substitutions. Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen isotopes such as 2H and 3H; carbon isotopes such as 11C, 13C, and 14C; nitrogen isotopes such as 13N and 15N; oxygen isotopes such as 18O; phosphorus isotopes such as 32P; sulfur isotopes such as 35S; fluorine isotopes such as 18F; iodine isotopes such as 123I and 125I; and chlorine isotopes such as 36Cl. The isotope-enriched compounds of the present invention may be prepared, for example, by means of conventional techniques known to those skilled in the art or by means of methods similar to those described in the processes and examples herein, using suitable isotope-enriching reagents and / or intermediates.

[0138] In some embodiments, the compounds disclosed herein are racemic mixtures. In some embodiments, the compounds disclosed herein are enriched with a mirror-image isomer. In some embodiments, the compounds disclosed herein are enriched to be substantially free of their opposite mirror-image isomers. In embodiments, (+)-mirror-image isomers of the compounds disclosed herein are provided herein. In embodiments, (-)-mirror-image isomers of the compounds disclosed herein are provided herein. In some embodiments, the compounds disclosed herein have an excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, about 99.5%, or higher (including all subranges and their inter-range values) of mirror-image isomers. In some embodiments, the compounds of the present invention are provided as mixtures of non-mirror-image isomers. In some embodiments, non-mirror-image isomers of the compounds of the present invention are provided, which substantially do not contain other possible non-mirror-image isomers. In embodiments, the present invention includes any tautomers of such compounds.

[0139] In some embodiments, this document provides compounds selected from one or more of the compounds in Table 1, or their pharmaceutically acceptable salts or stereoisomers.

[0140] In some embodiments, this document provides one or more compounds selected from Table 1, or their pharmaceutically acceptable salts or mirror isomers.

[0141] In some embodiments, this document provides one or more compounds selected from Table 1, or their pharmaceutically acceptable salts, or their non-mirror isomers, or mixtures thereof.

[0142] In the embodiments, the compounds of formula (I), (IA), (IAI), (IB), or Table 1 have an (R)-configuration at the carbon marked with an asterisk (*): .

[0143] In the embodiments, the compounds of formula (I), (IA), (IAI), (IB) or Table 1 have an (S)-configuration at the carbon marked with an asterisk (*): .

[0144] In the embodiments, the compounds of formula (I), (IA), (IAI), (IB), or Table 1 have an (R)-configuration at the carbons marked with an asterisk (*). In the embodiments, the compounds of formula (I), (IA), (IAI), (IB), or Table 1 have an (S)-configuration at the carbons marked with an asterisk (*). In the embodiments, the compounds of formula (I), (IA), (IAI), (IB), or Table 1 have an (R)-configuration at the carbons marked with a double asterisk (**). In the embodiments, the compounds of formula (I), (IA), (IAI), (IB), or Table 1 have an (S)-configuration at the carbons marked with a double asterisk (**): .

[0145] In some embodiments, this document provides one or more compounds selected from Table 1.

[0146] In some embodiments, this document provides one or more medically acceptable salts selected from the compounds in Table 1. Table 1. Compounds Composition

[0147] This invention provides pharmaceutical compositions for modulating orexin receptors (e.g., orexin type 2 receptors) in an individual. In some embodiments, the pharmaceutical composition comprises one or more compounds of the present invention (e.g., formula (I), (IA), (IAI), (IB), or compounds in Table 1) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises one or more compounds of the present invention (e.g., formula (I), (IA), (IAI), (IB), or compounds in Table 1) or a pharmaceutically acceptable salt thereof or an N-oxide thereof.

[0148] In some embodiments of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of one or more of the compounds of the present invention (e.g., formula (I), (IA), (IAI), (IB), or the compounds in Table 1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0149] In some embodiments, the pharmaceutical compositions described herein comprise one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0150] In some embodiments, the pharmaceutical compositions described herein comprise one or more compounds selected from Table 1 or their pharmaceutically acceptable salts.

[0151] In some embodiments of the present invention, a pharmaceutical composition is provided comprising one or more compounds of the present invention (e.g., formula (I), (IA), (IAI), (IB), or compounds in Table 1) or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients or adjuvants. Pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for various purposes. In some embodiments, a pharmaceutical composition comprising one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof further comprises a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier includes pharmaceutically acceptable excipients, binders, and / or diluents. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0152] For the purposes of this invention, the compounds of this invention can be formulated for administration by a variety of methods (including oral, non-enteral, inhalation spray, topical, or rectal) in the form of a formulation containing a pharmaceutically acceptable carrier, adjuvant, and mediator. As used herein, non-enteral injection includes subcutaneous, intravenous, intramuscular, and intra-arterial injection, as well as various infusion techniques. As used herein, intra-arterial and intravenous injection include administration via a catheter.

[0153] Generally, the compounds of this invention are administered in therapeutically effective amounts. The actual amount of compound administered will usually be determined by the physician based on relevant circumstances, including the condition to be treated; the chosen route of administration; the actual compound administered; the individual patient's age, weight, and response; and the severity of the patient's symptoms, or similar factors. Treatment

[0154] The compounds of this invention can be used in any number of methods. For example, in some embodiments, the compounds are suitable for methods of modulating orexin receptors (e.g., orexin type 2 receptors). Therefore, in some embodiments, the invention provides the use of any of the compounds of formulas (I), (IA), (IAI), (IB) or in Table 1, or their pharmaceutically acceptable salts, for modulating orexin receptor (e.g., orexin type 2 receptor) activity. For example, in some embodiments, the activity of orexin receptors (e.g., orexin type 2 receptors) in mammalian cells is modulated. The activity of orexin receptors (e.g., orexin type 2 receptors) can be modulated in individuals in need (e.g., mammalian individuals, such as humans) and used to treat any of the described conditions or diseases.

[0155] In some embodiments, the activity of orexin receptors (e.g., orexin type 2 receptors) is modulated. In some embodiments, the activity of orexin receptors (e.g., orexin type 2 receptors) is modulated to promote or stimulate orexin receptor activity.

[0156] In some embodiments, the present invention provides a method for treating a disease or condition that can be treated by administration of an orexin agonist, the method comprising administering a therapeutically effective amount of one or more of the compounds of the present invention (e.g., formula (I), (IA), (IAI), (IB) or compounds in Table 1) or a medically acceptable salt thereof.

[0157] In some embodiments, the compounds of the present invention are used to treat, prevent, alleviate, control, or reduce the risk of various conditions related to orexin receptors, including one or more of the following conditions or diseases: narcolepsy, narcolepsy syndrome with narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, somnolence, idiopathic somnolence, repetitive somnolence, endogenous somnolence, somnolence with daytime somnolence, interrupted sleep, sleep apnea, somnolence associated with sleep apnea, nocturnal myoclonus, disturbance of consciousness (such as coma), REM sleep disturbance, jet lag, excessive daytime sleepiness, sleep disturbance in shift workers, sleep disorder, sleep dysregulation, sleep disturbance, somnolence associated with depression, affective / mood disorder, drug abuse, Alzheimer's disease or cognitive impairment, Parkinson's disease, Guillain-Barré syndrome. Kleine-Levin syndrome and sleep disorders associated with aging, muscular dystrophy, and immune-mediated diseases; Alzheimer's sundowning; conditions related to circadian rhythms and mental and physical symptoms associated with cross-time zone travel and shift work; fibromyalgia; heart failure; diseases associated with bone loss; sepsis; sleep apnea syndrome manifested as non-restorative sleep and muscle pain or associated with breathing disturbances during sleep; conditions caused by poor sleep quality; and other diseases associated with systemic orexin system dysfunction. In some embodiments, the compounds of the present invention are suitable for treating, preventing, alleviating, controlling, or reducing the risk of a variety of conditions, including: narcolepsy, idiopathic hypersomnia, somnolence, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, narcolepsy syndrome with daytime sleepiness (e.g., Parkinson's disease, G. Bartholomew's syndrome, and Klein-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, disturbances of consciousness (such as coma and similar), and side effects and complications caused by anesthesia and similar or anesthetic antagonists.

[0158] In some embodiments, the compounds of the present invention (e.g., formula (I), (IA), (IAI), (IB), or the compounds in Table 1) or their medically acceptable salts are used to treat diseases, conditions, or symptoms associated with excessive sleepiness in individuals in need. In some embodiments, excessive sleepiness is caused by any of the following: inadequate quality or quantity of nighttime sleep; a mismatch between the body's circadian rhythm pacemaker and the environment (e.g., due to occupational (e.g., shift work) or personal obligations (e.g., caregiver of a sick, young, or elderly family member) requiring wakefulness at night), such as jet lag, shift work, and other circadian sleep disorders; another underlying sleep disorder, such as narcolepsy (e.g., narcolepsy type 1, narcolepsy type 2, possible narcolepsy), sleep apnea (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), idiopathic somnolence, idiopathic excessive sleepiness, and restless legs syndrome; medical conditions, such as clinical depression or atypical depression; tumors; head trauma; anemia; kidney failure; hypothyroidism; central nervous system injury; substance abuse; hereditary vitamin deficiencies, such as biotin deficiency; and specific categories of prescription and over-the-counter medications.

[0159] In some embodiments, the compounds of the present invention (e.g., formulas (I), (IA), (IAI), (IB), or compounds in Table 1) or their medically acceptable salts are used to treat any of the following: shift work disorder; shift work sleep disorder; time lag syndrome. In some embodiments, the methods and uses described herein are used to treat any of the following: narcolepsy type 1, narcolepsy type 2, possible narcolepsy, idiopathic hypersomnia, idiopathic excessive hypersomnia, hypersomnia, excessive hypersomnia, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure); or disturbance of consciousness (e.g., coma and the like); and narcolepsy syndrome with narcolepsy-like symptoms; excessive hypersomnia or narcolepsy syndrome with daytime sleepiness (e.g., Parkinson's disease, G. Bartholomew's syndrome, and Klein-Levin syndrome); excessive daytime sleepiness in Parkinson's disease, Prader-Willi syndrome. 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 sleep disorders; residual excessive daytime sleepiness in sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure); and similar conditions. Narcolepsy (e.g., narcolepsy type 1, narcolepsy type 2, possible narcolepsy) can be diagnosed using diagnostic criteria commonly used in this 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, excessive sleepiness is excessive daytime sleepiness or excessive sleepiness during working hours, or excessive sleepiness or reduced sleep volume due to occupational (e.g., shift work) or personal obligations (e.g., caregiver of a sick, young, or elderly family member). In some embodiments, an individual suffers from a disease, condition, or symptom associated with excessive sleepiness. In some embodiments, the individual is a sleep-deprived individual, an excessively sleepy individual, an individual with disrupted regular sleep cycles, or an individual who needs to reduce sleepiness. In some embodiments, the present invention provides a method for reducing or treating excessive sleepiness. In some embodiments, excessive sleepiness is caused by narcolepsy type 1, narcolepsy type 2, or idiopathic sleepiness. In some embodiments, excessive sleepiness is caused by obstructive sleep apnea, even with the use of continuous positive airway pressure (CPAP). In some embodiments, a method is provided to increase the wakefulness of an individual in need. In some embodiments, the individual's orexin levels are not impaired or are partially impaired.

[0160] In some embodiments of the present invention, a method for treating sleep disorders in an individual in need (e.g., as disclosed herein) is provided, comprising administering to the individual in need a compound of the present invention (e.g., formula (I), (IA), (II), (IB), or a compound of Table 1) or a medically acceptable salt thereof. In some embodiments, an individual suffering from a sleep disorder, a sleep disorder, or symptoms of a sleep disorder is treated using a compound of the present invention (e.g., formula (I), (IA), (II), (IB), or a compound of Table 1) or a medically acceptable salt thereof.

[0161] In some embodiments of the present invention, a method for treating narcolepsy in an individual in need is provided, comprising administering to the individual in need a compound of the present invention (e.g., formula (I), (IA), (IAI), (IB), or Table 1) or a medically acceptable salt thereof. In some embodiments, an individual suffering from narcolepsy, narcolepsy, or symptoms of narcolepsy is treated using a compound of the present invention (e.g., formula (I), (IA), (IAI), (IB), or a compound of Table 1) or a medically acceptable salt thereof.

[0162] In some embodiments of the present invention, a method for treating idiopathic somnolence (IH) in an individual of need is provided, comprising administering to the individual of need a compound of the present invention (e.g., formula (I), (IA), (IAI), (IB), or a compound of Table 1) or a medically acceptable salt thereof. In some embodiments, the compound of the present invention (e.g., formula (I), (IA), (IAI), (IB), or a compound of Table 1) or a medically acceptable salt thereof is used to treat an individual suffering from IH, to treat IH, or to treat symptoms of IH. Example

[0163] The invention has now been generally described. The invention will be more readily understood by referring to the following examples, which are included only to illustrate certain aspects and embodiments of the invention and are not intended to limit the invention.

[0164] The compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in organic synthetic chemistry, or variations thereof as understood by those skilled in the art. [, , ]

[0165] The preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be easily determined by those skilled in the art. Chemical methods for protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th edition, Wiley & Sons, 2006, and Jerry March, Advanced Organic Chemistry, 4th edition, John Wiley & Sons, New York, 1992, which are incorporated herein by reference in their entirety. [, , ] IP-1 Accumulation Analysis

[0166] Using an analysis based on IP-1 HTRF® cavitation compounds (Cisbio), the accumulation of inositol-1 monophosphate (IP-1) in CHO cells (DiscoverX) representing human recombinant OX1 (hOX1) and OX2 (hOX2) receptors was measured in suspension test cells according to the manufacturer's instructions.

[0167] hOX1-CHO and hOX2-CHO cells were seeded at a density of 20,000 cells / well in white 384-well plates in Hank's Balanced Salt Solution (HBSS) containing 20 mM HEPES pH 7.4, 50 mM LiCl and 0.1% bovine serum albumin (BSA).

[0168] The compound of this invention was serially diluted 200-fold in pure DMSO and tested using an 11-point concentration-response curve (CRC). It was added to cells using an Echo acoustic liquid handling device (Labcyte) (the final concentration in DMSO was 0.5% in the analysis). After incubation at 37°C for 60 minutes, the detection reagent, IP1-d2 tracer, and anti-IP1-camber compound were diluted in lysis buffer and added to the cells according to the manufacturer's instructions.

[0169] After incubation at room temperature for 60 minutes, time-resolved fluorescence (HTRF) at 615 nm and 665 nm was measured using an Envision multi-label reader (Perkin Elmer), and the HTRF ratio (A665 / A615x104) was calculated.

[0170] IP-1 accumulation reaction is expressed as the percentage of maximum OX-A reaction.

[0171] Curve fitting and EC50 estimation were performed using XLfit software and a four-parameter logical model. The average EC50 data were calculated using at least two independently repeated experiments.

[0172] In the table, category A below corresponds to compounds exhibiting IC50 < 100 nM, category B is between 100 nM and 1,000 nM, category C is between 1,000 nM and 10,000 nM, and category D exceeds 10,000 nM. Example 1: N-[2-(2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide (1) []

[0173] [(] [2E] [)-] [3] [-{[(] [Shun] [)-] [4] [-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-] [2] [-] [Methyl acrylate] [(] [Intermediate substance] [1] [)] []

[0174] At 0 °C, cis-4-phenylcyclohexane-1-ol (2.04 g, 11.57 mmol) and DABCO (0.13 g, 1.16 mmol) were stirred in DCM (45 mL) while methyl 2-propynate (1.34 mL, 15.05 mmol) was added dropwise over 5 minutes. The solution was stirred at room temperature for 30 minutes. The solvent was removed under vacuum, and the residue was purified by column chromatography using a C18 filter (H₂O + 0.1% formic acid / MeCN + 0.1% formic acid, 80:20 to 0:100) to give the title compound (2.31 g, 8.87 mmol, 77% yield) as a grayish-white solid. [M+H] +m / z 261.2

[0175] [(] [2Z] [)-] [2] [-(] [2] [-] [Side group] [-] [1] [,] [2] [-] [Dihydropyridine] [-] [1] [-] [base] [)-] [3] [-{[(] [Shun] [)-] [4] [-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-] [2] [-] [Methyl acrylate] [(] [Intermediate substance] [2] [)] []

[0176] Over a 10-minute interval, a solution of tribromopyridinium (3.93 g, 12.3 mmol) in THF (10 ml) was added to a solution of methyl ester intermediate 1 (3.05 g, 11.72 mmol) in anhydrous THF (55 ml) at 0 °C. The reaction mixture was heated and stirred at room temperature for 30 minutes. 1H-pyridin-2-one (2.79 g, 29.29 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum, and the product was purified by column chromatography using a silica filter (0-100% EtOAc / cHex) to give the title compound (1.62 g, 4.58 mmol, 39% yield) as a colorless glassy solid. [M+H]+m / z 354.2

[0177] [1] [-(] [1] [-] [Hydroxy] [-] [3] [-{[(] [Shun] [)-] [4] [-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-] [2] [-] [base] [)-] [1] [,] [2] [-] [Dihydropyridine] [-] [2] [-] [ketone] [(] [Intermediate substance] [3] [)] [] []

[0178] NaBH₄ (814 mg, 21.5 mmol) was added to a solution of intermediate 2 (1.52 g, 4.3 mmol) in THF (50 mL) and MeOH (5 mL). The mixture was heated at 80 °C, and acetone was added at room temperature after 1 hour. The solvent was removed under vacuum, followed by the addition of H₂O and 1 M HCl aqueous solution. The mixture was extracted with EtOAc, and the combined organic layers were then evaporated under vacuum to give the title compound (1.56 g, quantitative yield) as a white foamy substance. [M+H]⁺m / z 328.2.

[0179] [1] [-(] [1] [-] [azido group] [-] [3] [-{[(] [Shun] [)-] [4] [-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-] [2] [-] [base] [)-] [1] [,] [2] [-] [Dihydropyridine] [-] [2] [-] [ketone] [(] [Intermediate substance] [4] [)] [] []

[0180] At 0 °C, TEA (0.5 mL, 3.62 mmol) and methanesulfonyl chloride (0.21 mL, 2.65 mmol) were added to a solution of intermediate 3 (823 mg, 2.41 mmol) in THF (15 mL). After 30 minutes, NaN 3 (29 mg, 0.440 mmol) was added at 0 °C. The mixture was heated to room temperature and stirred overnight. After 18 hours, the mixture was diluted with H 2O and extracted twice with EtOAc. The combined organic layers were evaporated under vacuum to give the title compound (877 mg, quantitative yield) as a pale pink oil. [M+H] +m / z 353.2

[0181] [1] [-(] [1] [-] [Amine] [-] [3] [-{[(] [Shun] [)-] [4] [-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-] [2] [-] [base] [)-] [1] [,] [2] [-] [Dihydropyridine] [-] [2] [-] [ketone] [(] [Intermediate substance] [5] [)] []

[0182] PPh3 (1.31 g, 4.98 mmol) and H2O (4 mL) were added to a stirred solution of intermediate 4 (0.88 g, 2.49 mmol) in THF (9 mL). The mixture was stirred at room temperature for 4 hours, then diluted with water and extracted twice with EtOAc. The combined organic layers were evaporated under vacuum. The product was purified using an SCX filter (loaded with MeOH, washed with MeOH, and recovered using MeOH containing 2 M NH3) to give a pink oil, which was further purified by column chromatography using a silica filter (0-5% methanol / DCM) to give the title compound (0.24 g, 0.74 mmol, 30% yield) as a pale yellow oil. [M+H]+m / z 327.5

[0183] [N] [-[] [2] [-(] [2] [-] [Side group] [-] [1] [,] [2] [-] [Dihydropyridine] [-] [1] [-] [base] [)-] [3] [-{[(] [Shun] [)-] [4] [-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Propyl] []] [Methylsulfonylurea] [(] [1] [)] [] [, , ]

[0184] At room temperature, TEA (12.81 μL, 0.090 mmol) was added to a stirred solution of intermediate 5 (15 mg, 0.050 mmol) in THF (0.6 mL), followed by the addition of methanesulfonyl chloride (4 μL, 0.060 mmol). The mixture was stirred at room temperature, and the solvent was removed under vacuum after 30 minutes. The product was purified by column chromatography using a C18 filter cartridge (H₂O + 0.1% formic acid / MeCN + 0.1% formic acid, 95:5 to 40:60) to give the title compound (12.8 mg, 0.032 mmol, 69% yield) as a white solid. Examples 1a-1e:

[0185] Down [surface] [2] Examples [1a] [-] [1e] Prepared using a suitable heterocyclic reagent following the procedure described in Example 1. The starting material was prepared as described in the Intermediates section (commercially available), or prepared using commercially available reagents using a known reaction familiar to this technique. The mirror-image isomers were separated by unidirectional purification using a suitable Chiralpak column (AD-H, IC, OJ-H) and a mixture of n-hexane / EtOH, n-hexane / (EtOH + 0.1% iPrNH2), or n-hexane / (EtOH / MeOH 1:1 + 0.1% iPrNH2), at ratios between 35:65 and 70:30. During unidirectional separation using one of the conditions reported above, isomer 1 was designated as the first unidirectional compound and isomer 2 as the second unidirectional compound. The products are reported in the table below: Table 2. Characterization and EC50 data for hOX2 - Compounds 1-1e: [Example] [structure] [name] [Observation Quality] [, 1 , ] [H NMR] [EC50 hOX2] [1] N-[2-(2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide (1) 405.2 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.68 (dd, J = 6.9, 1.8 Hz, 1H), 7.37 (ddd, J = 9.0, 6.8, 1.9 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.22 - 7.16 (m, 3H), 6.60 (d, J = 9.2 Hz, 1H), 6.26 (td, J = 6.8, 1.4 Hz, 1H), 5.21 - 5.01 (m, 2H), 3.90 (dd, J = 10.4, 5.4 Hz, 1H), 3.80 (dd, J = 10.3, 3.7 Hz, 1H), 3.78 - 3.73 (m, 1H), 3.71 - 3.63 (m, 2H), 2.90 (s, 3H), 2.63 - 2.45 (m, 1H), 2.09 - 1.93 (m, 2H), 1.75 -1.62 (m, 4H), 1.61 - 1.49 (m, 2H). [C] [1a] (R or S) N-[2-(2-sidekto-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide (1)-Isomer 1 405.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.70 - 7.64 (m, 1H), 7.36 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.29 (dd, J = 8.1, 6.9 Hz, 2H), 7.22 - 7.15 (m, 3H), 6.59 (dt, J = 9.0, 1.2 Hz, 1H), 6.25 (td, J = 6.8, 1.4 Hz, 1H), 5.18 (t, J = 6.2 Hz, 1H), 5.11 (dt, J = 8.8, 4.6 Hz, 1H), 3.89 (dd, J = 10.3, 5.4 Hz, 1H), 3.81 - 3.71 (m, 2H), 3.71 - 3.61 (m, 2H), 2.89 (s, 3H), 2.52 (p, J = 7.8 Hz, 1H), 2.05 - 1.95 (m, 2H), 1.71 - 1.61 (m, 4H), 1.56 (s, 2H). [C] [1b] (S or R) N-[2-(2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide (1)-Isomer 2 405.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.67 (dd, J = 6.8, 2.1 Hz, 1H), 7.36 (ddd, J = 9.0, 6.6, 2.0 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.22 - 7.15 (m, 3H), 6.59 (d, J = 9.1 Hz, 1H), 6.28 - 6.22 (m, 1H), 5.14 - 5.01 (m, 2H), 3.90 (dd, J = 10.4, 5.4 Hz, 1H), 3.84 - 3.71 (m, 2H), 3.71 - 3.61 (m, 2H), 2.89 (s, 3H), 2.53 (t, J = 7.7 Hz, 1H), 2.00 (d, J = 13.8 Hz, 2H), 1.71 - 1.61 (m, 4H), 1.54 (s, 2H). [D] [1c] N-[2-(3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 419.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.53 (d, J = 7.2 Hz, 1H), 7.28 (d, J = 13.4 Hz, 3H), 7.20 - 7.14 (m, 3H), 6.17 (t, J = 6.8 Hz, 1H), 5.11 (d, J = 4.9 Hz, 2H), 3.89 (dd, J = 10.3, 5.5 Hz, 1H), 3.84 - 3.61 (m, 4H), 2.88 (s, 3H), 2.51 (q, J = 9.2, 7.7 Hz, 1H), 2.15 (s, 3H), 2.03 - 1.96 (m, 2H), 1.74 - 1.60 (m, 4H). [B] [1d] (R or S) N-[2-(3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 419.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.56 - 7.51 (m, 1H), 7.29 (dd, J = 8.1, 6.9 Hz, 2H), 7.24 (ddd, J = 6.7, 2.0, 1.1 Hz, 1H), 7.21 - 7.14 (m, 3H), 6.17 (t, J = 6.8 Hz, 1H), 5.11 (dt, J = 9.2, 4.7 Hz, 1H), 3.89 (dd, J = 10.3, 5.4 Hz, 1H), 3.79 (dd, J = 10.3, 4.0 Hz, 1H), 3.76 - 3.60 (m, 3H), 2.88 (s, 3H), 2.58 - 2.46 (m, 1H), 2.15 (s, 3H), 1.99 (ddd, J = 11.9, 6.2, 3.0 Hz, 2H), 1.73 - 1.44 (m, 6H). NH is not visible. [D] [1e] (S or R) N-[(2R)-2-(3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 419.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.56 - 7.50 (m, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.25 - 7.21 (m, 1H), 7.22 - 7.14 (m, 3H), 6.17 (t, J = 6.8 Hz, 1H), 5.17 - 4.98 (m, 2H), 3.89 (dd, J = 10.3, 5.4 Hz, 1H), 3.79 (dd, J = 10.3, 4.0 Hz, 1H), 3.76 - 3.60 (m, 3H), 2.88 (s, 3H), 2.57 - 2.44 (m, 1H), 2.15 (s, 3H), 2.06 - 1.94 (m, 2H), 1.55 (s, 6H). [B] Example 1f: 1-{1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl-2-yl}-1,2-dihydropyridin-2-one (1f)

[0186] At room temperature, TEA (26 μL, 0.18 mmol) was added to a stirred solution of intermediate 5 (30 mg, 0.090 mmol) in THF (3.4 mL), followed by the addition of N,N-dimethylaminesulfonyl chloride (12 μL, 0.11 mmol). The mixture was stirred at 50 °C for 24 h. Additional N,N-dimethylaminesulfonyl chloride (12 μL, 0.11 mmol) was added, and the mixture was stirred at 50 °C for 20 h. The solvent was removed under vacuum. The product was purified by HPLC to give the title compound (4.5 mg, 0.010 mmol, 11% yield) as a white solid. Table 3. Characterization and EC50 data for hOX2 - Compound 1f: [Example] [structure] [name] [Observation Quality] [, 1 , ] [H NMR] [EC50 hOX2] [1f] 1-{1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl-2-yl}-1,2-dihydropyridin-2-one 434.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.66 (dd, J = 7.0, 2.0 Hz, 1H), 7.35 (ddd, J = 8.9, 6.5, 2.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 2H), 7.12 - 7.20 (m, 3H), 6.58 (dt, J = 9.0, 1.2 Hz, 1H), 6.23 (td, J = 6.8, 1.4 Hz, 1H), 5.09 (dt, J = 9.1, 4.6 Hz, 1H), 4.91 (t, J = 6.1 Hz, 1H), 3.89 (dd, J = 10.3, 5.3 Hz, 1H), 3.78 (dd, J = 10.3, 3.8 Hz, 1H), 3.51 - 3.70 (m, 3H), 2.74 (s, 6H), 2.53 (dd, J = 14.7, 7.1 Hz, 1H), 1.93 - 2.04 (m, 2H), 1.64 (dt, J = 7.8, 3.7 Hz, 6H). [C] Example 2: N-[2-(3-ethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide

[0187] [Shun] [-] [4] [-(] [C] [-] [2] [-] [ene] [-] [1] [-] [kcalcium oxide] [)] [Cyclohexyl] []] [benzene] [(] [Intermediate substance] [6] [)] []

[0188] NaH (0.89 g, 22.13 mmol) (60% w / w, dispersed in mineral oil) was added to a mixture of cis-4-phenylcyclohexane-1-ol (3.0 g, 17.02 mmol) in anhydrous THF (50 mL) at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 45 min, followed by the addition of allyl bromide (2.21 mL, 25.54 mmol). The mixture was stirred at 60 °C for 5 h, then poured onto ice and extracted with EtOAc (3 × 150 mL). The organic layer was dried over Na₂SO₄ and evaporated under vacuum. The product was purified by column chromatography using a silica filter (cHex / EtOAc, 100:0 to 70:30) to give the title compound (3.35 g, 15.49 mmol, 91% yield) as a pale yellow oil. [M-Allyl-H₂O] +m / z 159.0.

[0189] [[] [Shun] [-] [4] [-{[(] [2E] [)-] [3] [-] [Nitropropyl] [-] [2] [-] [ene] [-] [1] [-] [base] []] [Oxygen group] [}] [Cyclohexyl] []] [benzene] [(] [Intermediate substance] [7] [)] []

[0190] TEMPO (200 mg, 1.27 mmol) and tBuONO (0.76 mL, 6.36 mmol) were added to a suspension of intermediate 6 (688 mg, 3.18 mmol) in anhydrous 1,4-dimethyl ether (25 mL) at room temperature and in air. The mixture was stirred at 50 °C for 2.5 h, then diluted with EtOAc (100 mL) and washed with saturated aqueous solution of NH4Cl (2 × 40 mL). The organic layer was dried by a phase separator and concentrated under vacuum. The product was purified by column chromatography using a silica filter (0–15% EtOAc / cHex) followed by a C18 filter (H2O + 0.1% formic acid / MeCN + 0.1% formic acid, 100:0 to 0:100) to give the title compound (300 mg, 1.15 mmol, 36% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl 3) δ 7.39 - 7.28 (m, 4H), 7.25 - 7.17 (m, 3H), 4.27 (dd, J = 3.2, 2.0 Hz, 2H), 3.72 (t, J = 3.1 Hz, 1H), 2.56 (tt, J = 11.9, 3.7 Hz, 1H), 2.05 (dt, J = 14.7, 2.8 Hz, 2H), 1.89 - 1.76 (m, 2H), 1.72 - 1.55 (m, 4H) [。]

[0191] [3-] [Ethyl] [-] [1] [-(] [1] [-] [Nitro] [-] [3] [-{[(] [Shun] [)-] [4] [-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-] [2] [-] [base] [)-] [1] [,] [2] [-] [Dihydropyridine] [-] [2] [-] [ketone] [(] [Intermediate substance] [8] [)] []

[0192] 3-Ethyl-1H-pyridin-2-one (188 mg, 1.53 mmol) and intermediate 7 (200 mg, 0.77 mmol) were dissolved in THF (14 mL). The solution was stirred at 80 °C for 39 hours. The mixture was diluted with H₂O and extracted with EtOAc. The organic layer was evaporated under vacuum to give the title compound (357 mg, quantitative yield) as a yellow oil. [M+H] +m / z 385.2 [。]

[0193] [1-(1-] [Amine] [-] [3] [-{[(] [Shun] [)-] [4] [-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-] [2] [-] [base] [)-] [3] [-] [Ethyl] [-] [1] [,] [2] [-] [Dihydropyridine] [-] [2] [-] [ketone] [(] [Intermediate substance] [9] [)] []

[0194] To a solution of intermediate 8 (350 mg, 0.91 mmol) in EtOH (8 mL), AcOH (1.3 mL) and Zn powder (595 mg, 9.1 mmol) were added, and the mixture was stirred at room temperature for 45 minutes. The mixture was filtered through diatomaceous earth and washed with MeOH. The filtrate was concentrated under vacuum, and NaOH (2 M, in H₂O) was added. The mixture was extracted with EtOAc, and the organic layer was evaporated under vacuum to give a crude product, which was further purified by an SCX (packed with MeOH, washed in MeOH, and recovered with MeOH / NH₄⁴ 4 M). The solvent was removed under vacuum to give the title compound (202 mg, 0.57 mmol, 63% yield) as a yellow oil. [M+H]⁺m / z 356.6 [。]

[0195] [N] [-[] [2] [-(] [3] [-] [Ethyl] [-] [2] [-] [Side group] [-] [1] [,] [2] [-] [Dihydropyridine] [-] [1] [-] [base] [)-] [3] [-{[(] [Shun] [)-] [4] [-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Propyl] []] [Methylsulfonylurea] [(] [2] [)] [] []

[0196] Starting with intermediate 9 (50 mg, 0.14 mmol), Example 2 was prepared following the procedure described in Example 1, yielding the title compound (34 mg, 0.078 mmol, 55% yield) in a colorless, glassy solid state.

[0197] The following examples follow the same three-step procedure described in Synthetic Example 2, using the corresponding commercially available starting materials, which are prepared as described in the Intermediates section (commercially available), or prepared using commercially available reagents using conventional reactions well known in this art. Example 2aa is prepared following the three-step procedure used in Synthetic Example 2, except for step 1, in which 3-methylpyrazole is reacted with intermediate 7 in DCM at room temperature. Examples 2af, 2ag, 2ah, and 2ai are prepared using F-phenylcyclohexanol following the same procedure described for Synthetic Example 2.

[0198] Chiralpak columns (AD-H, IC, OJ-H) were used, and the mirror-image isomers were separated by piezoresistive purification using mixtures of n-hexane / EtOH, n-hexane / (EtOH + 0.1% iPrNH₂), or n-hexane / (EtOH / MeOH 1:1 + 0.1% iPrNH₂) at ratios between 35:65 and 70:30. During piezoresistive separation using one of the conditions reported above, isomer 1 was designated as the first piezoresistive compound and isomer 2 as the second piezoresistive compound. The products are reported in the table below: Table 4. Characterization and EC50 data for hOX2 - Compound 2-2aj: [Example] [structure] [name] [Observation Quality] [, 1 , ] [H NMR] [EC50 hOX2] [2] N-[2-(3-ethyl-2-sidekto-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 433.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.54 (dd, J = 7.0, 2.0 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.25 - 7.14 (m, 4H), 6.21 (t, J = 6.9 Hz, 1H), 5.20 - 5.14 (m, 1H), 5.14 - 5.06 (m, 1H), 3.90 (dd, J = 10.3, 5.5 Hz, 1H), 3.83 - 3.61 (m, 4H), 2.87 (s, 3H), 2.61 - 2.46 (m, 3H), 2.05 - 1.95 (m, 2H), 1.71 - 1.60 (m, 4H), 1.55 - 1.46 (m, 2H), 1.18 (t, J = 7.5 Hz, 3H). [C] [2a] (R or S) N-[2-(3-ethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 433.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.56 - 7.50 (m, 1H), 7.32 - 7.27 (m, 2H), 7.23 - 7.14 (m, 4H), 6.21 (t, J = 6.8 Hz, 1H), 5.10 (s, 2H), 3.90 (dd, J = 10.3, 5.5 Hz, 1H), 3.83 - 3.60 (m, 4H), 2.87 (s, 3H), 2.60 - 2.47 (m, 3H), 1.98 (s, 2H), 1.54 (s, 6H), 1.18 (t, J = 7.4 Hz, 3H). [D] [2b] (S or R) N-[2-(3-ethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 433.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.54 (dd, J = 6.9, 1.9 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.24 - 7.14 (m, 4H), 6.21 (t, J = 6.8 Hz, 1H), 5.11 (d, J = 6.3 Hz, 2H), 3.90 (dd, J = 10.3, 5.5 Hz, 1H), 3.84 - 3.59 (m, 4H), 2.87 (s, 3H), 2.65 - 2.40 (m, 3H), 2.12 - 1.93 (m, 2H), 1.73 - 1.45 (m, 6H), 1.18 (t, J = 7.5 Hz, 3H). [B] [2c] N-{2-[2-sidekto-3-(trifluoromethyl)-1,2-dihydropyridin-1-yl]-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl}methanesulfonamide 473.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.92 (dd, J = 7.0, 2.0 Hz, 1H), 7.78 (ddd, J = 7.0, 2.0, 0.90 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.23 - 7.14 (m, 3H), 6.32 (t, J = 7.0 Hz, 1H), 5.22 (t, J = 6.4 Hz, 1H), 5.15 (dt, J = 10.4, 4.4 Hz, 1H), 3.91 (dd, J = 10.6, 5.2 Hz, 1H), 3.82 - 3.73 (m, 2H), 3.69 - 3.60 (m, 2H), 2.92 (s, 3H), 2.52 (td, J = 10.2, 5.1 Hz, 1H), 2.05 - 1.91 (m, 2H), 1.74 - 1.41 (m, 6H). [C] [2d] N-[2-(4-methyl-2-sidekto-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 419.47 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.52 (d, J = 7.0 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.22 - 7.14 (m, 3H), 6.38 (s, 1H), 6.09 (dd, J = 7.1, 2.0 Hz, 1H), 5.14 (t, J = 6.2 Hz, 1H), 5.07 - 5.00 (m, 1H), 3.88 (dd, J = 10.3, 5.5 Hz, 1H), 3.74 (ddd, J = 13.1, 9.8, 5.3 Hz, 2H), 3.70 - 3.57 (m, 2H), 3.49 (s, 1H), 2.89 (s, 3H), 2.52 (p, J = 7.8 Hz, 1H), 2.18 (d, J = 1.0 Hz, 3H), 2.06 - 1.91 (m, 2H), 1.69 - 1.60 (m, 5H). [C] [2e] N-[2-(3-cyano-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 430.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.97 (dd, J = 6.9, 2.1 Hz, 1H), 7.83 (dd, J = 7.1, 2.0 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.22 - 7.13 (m, 3H), 6.35 (t, J = 7.0 Hz, 1H), 5.33 (t, J = 6.5 Hz, 1H), 5.12 (h, J = 4.7 Hz, 1H), 3.90 (dd, J = 10.6, 5.3 Hz, 1H), 3.86 - 3.73 (m, 2H), 3.66 (dt, J = 13.9, 5.2 Hz, 2H), 3.17 - 3.06 (m, 1H), 2.96 (s, 3H), 2.53 (td, J = 10.9, 4.2 Hz, 1H), 2.05 - 1.91 (m, 2H), 1.72 - 1.60 (m, 1H), 1.56 (d, J = 9.9 Hz, 3H), 1.41 (t, J = 7.3 Hz, 1H). [C] [2f] N-[2-(3-fluoro-2-epoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 423.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.51 (dt, J = 7.1, 1.6 Hz, 3H), 7.29 (t, J = 7.5 Hz, 2H), 7.21 - 7.10 (m, 4H), 6.17 (td, J = 7.3, 4.6 Hz, 1H), 5.22 (t, J = 6.4 Hz, 1H), 5.15 (q, J = 4.2 Hz, 1H), 3.90 (dd, J = 10.4, 5.3 Hz, 1H), 3.83 - 3.61 (m, 4H), 2.91 (s, 1H), 2.53 (p, J = 7.8 Hz, 1H), 1.98 (d, J = 8.8 Hz, 3H), 1.64 (qd, J = 9.4, 8.9, 4.1 Hz, 5H). [C] [2g] (R or S) N-[2-(3-fluoro-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 423.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.50 (dt, J = 7.1, 1.6 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.24 - 7.09 (m, 4H), 6.17 (td, J = 7.3, 4.6 Hz, 1H), 5.14 (td, J = 9.0, 5.2 Hz, 1H), 5.07 (s, 1H), 3.91 (dd, J = 10.4, 5.4 Hz, 1H), 3.83 - 3.61 (m, 4H), 2.92 (s, 3H), 2.53 (p, J = 7.8 Hz, 1H), 2.00 (ddd, J = 14.3, 6.4, 2.9 Hz, 2H), 1.70 - 1.55 (m, 6H). [C] [2h] (S or R) N-[2-(3-fluoro-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 423.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.50 (dt, J = 7.1, 1.6 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.23 - 7.09 (m, 4H), 6.17 (td, J = 7.2, 4.6 Hz, 1H), 5.15 (dd, J = 8.4, 3.7 Hz, 2H), 3.91 (dd, J = 10.4, 5.5 Hz, 1H), 3.79 (dd, J = 10.4, 3.7 Hz, 1H), 3.77 - 3.66 (m, 2H), 3.66 - 3.61 (m, 1H), 2.92 (s, 3H), 2.53 (p, J = 7.8 Hz, 1H), 1.99 (ddq, J = 13.9, 8.6, 2.7 Hz, 2H), 1.69 - 1.57 (m, 6H). [D] [2i] N-[2-(5-methyl-2-sidekto-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 419.5 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.42 (d, J = 2.4 Hz, 1H), 7.26 (s, 9H), 6.53 (d, J = 9.2 Hz, 1H), 5.17 (t, J = 6.1 Hz, 1H), 5.08 - 5.01 (m, 1H), 3.88 (dd, J = 10.3, 5.5 Hz, 1H), 3.83 - 3.59 (m, 4H), 2.89 (s, 3H), 2.53 (p, J = 8.0 Hz, 1H), 2.07 (d, J = 1.1 Hz, 3H), 1.56 (m, 5H). [B] [2j] (R or S) N-[2-(5-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 419.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.44 - 7.39 (m, 1H), 7.29 (ddd, J = 7.7, 6.4, 1.3 Hz, 2H), 7.24 - 7.14 (m, 4H), 6.53 (d, J = 9.2 Hz, 1H), 5.18 (s, 1H), 5.05 (dq, J = 9.2, 5.0 Hz, 1H), 3.88 (dd, J = 10.3, 5.5 Hz, 1H), 3.79 (dd, J = 10.3, 3.8 Hz, 1H), 3.77 - 3.61 (m, 3H), 2.89 (s, 3H), 2.53 (p, J = 7.8 Hz, 1H), 2.07 (d, J = 1.1 Hz, 3H), 2.01 (ddd, J = 14.1, 6.5, 3.0 Hz, 2H), 1.65 (q, J = 6.5, 5.6 Hz, 4H), 1.55 (s, 2H). [B] [2k] (S or R) N-[2-(5-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 419.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.43 - 7.40 (m, 1H), 7.29 (ddd, J = 7.6, 6.4, 1.2 Hz, 2H), 7.24 - 7.15 (m, 4H), 6.53 (d, J = 9.2 Hz, 1H), 5.18 (s, 1H), 5.05 (dq, J = 9.0, 5.0 Hz, 1H), 3.88 (dd, J = 10.3, 5.4 Hz, 1H), 3.79 (dd, J = 10.3, 3.9 Hz, 1H), 3.77 - 3.61 (m, 3H), 2.89 (s, 3H), 2.53 (p, J = 7.7 Hz, 1H), 2.07 (d, J = 1.1 Hz, 3H), 2.05 - 1.94 (m, 2H), 1.70 - 1.61 (m, 4H), 1.55 (s, 2H). [D] [2l] N-{2-[2-sidekto-5-(trifluoromethyl)-1,2-dihydropyridin-1-yl]-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl}methanesulfonamide 473.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 8.20 (s, 1H), 7.49 (dd, J = 9.6, 2.6 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.18 (t, J = 8.9 Hz, 3H), 6.65 (d, J = 9.6 Hz, 1H), 5.12 (s, 1H), 4.96 (t, J = 6.1 Hz, 1H), 3.94 (dd, J = 10.7, 5.0 Hz, 1H), 3.81 (dd, J = 10.7, 3.0 Hz, 1H), 3.74 - 3.64 (m, 3H), 2.92 (s, 3H), 2.51 (d, J = 15.2 Hz, 1H), 2.01 (t, J = 13.2 Hz, 2H), 1.71 - 1.59 (m, 6H). [D] [2m] N-[2-(3,4-dimethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 433.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.42 (d, J = 7.1 Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.24 - 7.15 (m, 3H), 6.11 (d, J = 7.1 Hz, 1H), 5.24 (t, J = 6.1 Hz, 1H), 5.13 - 5.03 (m, 1H), 3.90 (dd, J = 10.2, 5.5 Hz, 1H), 3.82 - 3.62 (m, 4H), 2.91 (s, 3H), 2.62 - 2.47 (m, 1H), 2.19 (s, 3H), 2.11 (s, 3H), 2.06 - 1.96 (m, 2H), 1.71 - 1.62 (m, 4H), 1.58 - 1.43 (m, 2H). [B] [2n] (R or S) N-[2-(3,4-dimethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 433.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.48 - 7.37 (m, 1H), 7.35 - 7.29 (m, 2H), 7.25 - 7.13 (m, 3H), 6.11 (d, J = 7.1 Hz, 1H), 5.22 - 5.12 (m, 1H), 5.11 - 4.99 (m, 1H), 3.91 (dd, J = 10.2, 5.5 Hz, 1H), 3.85 - 3.58 (m, 4H), 2.91 (s, 3H), 2.63 - 2.43 (m, 1H), 2.19 (s, 3H), 2.11 (s, 3H), 2.08 - 1.93 (m, 2H), 1.77 - 1.61 (m, 4H), 1.56 - 1.42 (m, 2H). [B] [2o] (S or R) N-[2-(3,4-dimethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 433.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.42 (d, J = 7.1 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.25 - 7.15 (m, 3H), 6.11 (d, J = 7.1 Hz, 1H), 5.28 - 5.13 (m, 1H), 5.11 - 5.00 (m, 1H), 3.91 (dd, J = 10.2, 5.5 Hz, 1H), 3.84 - 3.61 (m, 4H), 2.91 (s, 3H), 2.62 - 2.46 (m, 1H), 2.19 (s, 3H), 2.11 (s, 3H), 2.07 - 1.93 (m, 2H), 1.75 - 1.61 (m, 4H), 1.56 - 1.45 (m, 2H). [D] [2p] N-[2-(5-chloro-2-sidekto-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 439.1 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.85 (d, J = 2.8 Hz, 1H), 7.38 - 7.30 (m, 3H), 7.26 - 7.16 (m, 3H), 6.58 (d, J = 9.7 Hz, 1H), 5.16 - 4.96 (m, 2H), 3.97 - 3.77 (m, 2H), 3.76 - 3.61 (m, 3H), 2.94 (s, 3H), 2.65 - 2.49 (m, 1H), 2.04 (d, J = 13.6 Hz, 2H), 1.78 - 1.61 (m, 6H). [C] [2q] N-{2-[5-(difluoromethoxy)-2-sideoxy-1,2-dihydropyridin-1-yl]-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl}methanesulfonamide 471.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.79 (d, J = 3.05 Hz, 1H), 7.34 - 7.27 (m, 3H), 7.20 (d, J = 7.39 Hz, 3H), 6.57 (dd, J = 9.79, 0.56 Hz, 1H), 6.36 (t, J = 72.81 Hz, 1H), 5.22 (d, J = 5.65 Hz, 1H), 5.14 (dtd, J = 8.07, 5.11, 3.05 Hz, 1H), 3.89 (dd, J = 10.63, 4.89 Hz, 1H), 3.80 (dd, J = 10.64, 3.08 Hz, 1H), 3.75 - 3.62 (m, 3H), 2.90 (s, 3H), 2.60 - 2.48 (m, 1H), 2.08 - 1.96 (m, 2H), 1.68 (tdd, J = 8.54, 4.93, 2.76 Hz, 3H), 1.59 (dt, J = 13.65, 4.25 Hz, 3H). [C] [2r] N-[2-(5-cyano-2-epoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 430.5 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 8.27 (dd, J = 2.5, 0.6 Hz, 1H), 7.45 (dd, J = 9.5, 2.5 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.26 - 7.16 (m, 3H), 6.62 (dd, J = 9.5, 0.6 Hz, 1H), 5.16 - 5.04 (m, 1H), 4.88 (t, J = 6.4 Hz, 1H), 3.95 (dd, J = 10.7, 5.3 Hz, 1H), 3.81 (dd, J = 10.7, 3.2 Hz, 1H), 3.75 - 3.63 (m, 3H), 2.96 (s, 3H), 2.63 - 2.49 (m, 1H), 2.09 - 1.96 (m, 2H), 1.82 - 1.58 (m, 6H). [C] [2s] N-[2-(3,5-dimethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 433.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.30 (s, 3H), 7.24 - 7.16 (m, 3H), 7.14 - 7.11 (m, 1H), 5.21 (s, 1H), 5.12 - 5.03 (m, 1H), 3.92 - 3.85 (m, 1H), 3.83 - 3.77 (m, 1H), 3.77 - 3.66 (m, 2H), 3.66 - 3.63 (m, 1H), 2.90 (s, 3H), 2.59 - 2.48 (m, 1H), 2.14 (s, 3H), 2.09 - 2.05 (m, 3H), 2.05 - 1.97 (m, 2H), 1.72 - 1.62 (m, 4H), 1.57 - 1.49 (m, 2H). [A] [2t] [] (R or S) N-[2-(3,5-dimethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 433.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.30 (d, J = 7.5 Hz, 3H), 7.20 (d, J = 1.5 Hz, 3H), 7.15 - 7.11 (m, 1H), 5.17 (s, 1H), 5.12 - 5.03 (m, 1H), 3.93 - 3.78 (m, 2H), 3.78 - 3.68 (m, 2H), 3.67 - 3.64 (m, 1H), 2.91 (s, 3H), 2.59 - 2.50 (m, 1H), 2.15 (s, 3H), 2.07 (d, J = 0.9 Hz, 3H), 2.06 - 1.98 (m, 2H), 1.72 - 1.63 (m, 4H), 1.63 - 1.58 (m, 1H), 1.57 - 1.51 (m, 1H). [A] [2u] (S or R) N-[2-(3,5-dimethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 433.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.34 - 7.29 (m, 3H), 7.20 (d, J=1.54 Hz, 3H), 7.15 - 7.09 (m, 1H), 5.19 - 5.13 (m, 1H), 5.12 - 5.03 (m, 1H), 3.94 - 3.79 (m, 2H), 3.70 (s, 2H), 3.67 - 3.64 (m, 1H), 2.91 (s, 3H), 2.54 (s, 1H), 2.15 (s, 3H), 2.07 (d, J=0.88 Hz, 3H), 2.06 - 1.97 (m, 2H), 1.74 - 1.63 (m, 4H), 1.57 - 1.50 (m, 2H). [C] [2v] N-[2-(5-methoxy-2-sidekto-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 435.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.35 - 7.29 (m, 3H), 7.26 - 7.16 (m, 4H), 6.58 (dd, J = 9.8, 0.6 Hz, 1H), 5.24 (t, J = 6.0 Hz, 1H), 5.13 (dq, J = 8.7, 4.6 Hz, 1H), 3.93 (dd, J = 10.5, 5.2 Hz, 1H), 3.87 - 3.75 (m, 2H), 3.73 - 3.62 (m, 5H), 2.92 (s, 3H), 2.62 - 2.49 (m, 1H), 2.13 - 1.95 (m, 2H), 1.82 - 1.60 (m, 6H). [C] [2w] N-{2-[2-sidekto-4-(trifluoromethyl)-1,2-dihydropyridin-1-yl]-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl}methanesulfonamide 473.2 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.83 (d, J = 7.3 Hz, 1H), 7.28 - 7.33 (m, 2H), 7.18 - 7.24 (m, 1H), 7.16 (d, J = 7.1 Hz, 2H), 6.86 (s, 1H), 6.39 (dd, J = 7.3, 1.9 Hz, 1H), 5.05 - 5.16 (m, 1H), 5.01 (br t, J = 6.2 Hz, 1H), 3.92 (dd, J = 10.4, 5.4 Hz, 1H), 3.72 - 3.81 (m, 2H), 3.68 (dt, J = 13.9, 5.6 Hz, 2H), 2.89 - 2.98 (m, 3H), 2.47 - 2.60 (m, 1H), 1.94 - 2.04 (m, 2H), 1.45 - 1.74 (m, 6H). [D] [2x] N-[2-(5-bromo-3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 499.1 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.79 (dd, J = 2.7, 0.9 Hz, 1H), 7.35 - 7.29 (m, 3H), 7.27 - 7.18 (m, 3H), 5.11 (q, J = 8.0 Hz, 1H), 5.04 (t, J = 6.1 Hz, 1H), 3.97 - 3.77 (m, 2H), 3.75 - 3.63 (m, 3H), 2.94 (s, 3H), 2.55 (p, J = 7.8 Hz, 1H), 2.17 (t, J = 0.9 Hz, 3H), 2.11 - 1.98 (m, 2H), 1.78 - 1.59 (m, 6H) [B] [2y] N-[2-(4-cyano-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 430.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.83 (d, J = 7.1 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.27 - 7.11 (m, 3H), 6.96 - 6.92 (m, 1H), 6.36 (dd, J = 7.2, 1.9 Hz, 1H), 5.13 - 5.01 (m, 1H), 4.91 (t, J = 6.3 Hz, 1H), 3.93 (dd, J = 10.5, 5.4 Hz, 1H), 3.84 - 3.73 (m, 2H), 3.72 - 3.60 (m, 2H), 2.96 (s, 3H), 2.65 - 2.46 (m, 1H), 2.01 (t, J = 10.9 Hz, 2H), 1.78 - 1.59 (m, 6H). [D] [2z] N-(2-{1H-pyrrolo[2,3-b]pyridin-1-yl}-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl)methanesulfonamide 428.48 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 8.29 (dd, J = 4.73, 1.43 Hz, 1H), 7.95 (dd, J = 7.81, 1.43 Hz, 1H), 7.50 (d, J = 3.52 Hz, 1H), 7.28 - 7.36 (m, 2H), 7.23 - 7.14 (m, 3H), 7.10 (dd, J = 7.81, 4.73 Hz, 1H), 6.53 (d, J = 3.52 Hz, 1H), 5.77 (t, J = 5.72 Hz, 1H), 5.19 - 5.05 (m, 1H), 4.04 - 3.95 (m, 1H), 3.95 - 3.86 (m, 2H), 3.84 - 3.74 (m, 1H), 3.64 (br. s., 1H), 2.74 - 2.66 (m, 3H), 2.49 (d, J = 3.08 Hz, 1H), 2.05 - 1.91 (m, 2H), 1.77 - 1.58 (m, 3H), 1.56 - 1.42 (m, 3H). [C] [2aa] N-[2-(3-methyl-1H-pyrazol-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 392.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.44 (dd, J = 10.9, 2.0 Hz, 1H), 7.32 - 7.26 (m, 2H), 7.21 - 7.14 (m, 3H), 6.04 (dd, J = 5.5, 1.6 Hz, 1H), 5.26 (dt, J = 20.4, 6.3 Hz, 1H), 4.63 - 4.39 (m, 1H), 3.81 - 3.62 (m, 4H), 3.61 - 3.51 (m, 1H), 2.91 (d, J = 7.0 Hz, 3H), 2.54 - 2.41 (m, 1H), 2.32 (d, J = 46.9 Hz, 3H), 2.03 - 1.90 (m, 2H), 1.75 - 1.39 (m, 6H). [D] [2ab] (R or S) N-[2-(3-methyl-1H-pyrazol-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 392.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.45 (d, J = 2.3 Hz, 1H), 7.33 - 7.27 (m, 2H), 7.18 (td, J = 5.6, 3.0 Hz, 3H), 6.05 (d, J = 2.3 Hz, 1H), 5.24 (t, J = 6.2 Hz, 1H), 4.51 - 4.40 (m, 1H), 3.81 - 3.63 (m, 4H), 3.59 (t, J = 3.0 Hz, 1H), 2.90 (s, 3H), 2.49 (td, J = 13.6, 11.8, 4.3 Hz, 1H), 2.26 (s, 3H), 2.04 - 1.90 (m, 2H), 1.78 - 1.40 (m, 6H). [D] [2ac] (S or R) N-[2-(3-methyl-1H-pyrazol-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 392.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.45 (d, J = 2.2 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.22 - 7.15 (m, 3H), 6.04 (d, J = 2.2 Hz, 1H), 5.24 (t, J = 6.1 Hz, 1H), 4.45 (qd, J = 6.4, 4.1 Hz, 1H), 3.81 - 3.63 (m, 4H), 3.58 (q, J = 2.9 Hz, 1H), 2.90 (s, 3H), 2.49 (td, J = 12.3, 10.9, 4.2 Hz, 1H), 2.26 (s, 3H), 1.97 (ddt, J = 17.2, 14.0, 3.1 Hz, 2H), 1.78 - 1.39 (m, 6H). [D] [2ad] (R or S) N-[2-(5-methyl-1H-pyrazol-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 392.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.42 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.22 - 7.12 (m, 3H), 6.06 - 6.01 (m, 1H), 5.29 (t, J = 6.3 Hz, 1H), 4.62 - 4.52 (m, 1H), 3.82 - 3.68 (m, 3H), 3.62 (ddd, J = 13.2, 6.1, 4.0 Hz, 1H), 3.54 (d, J = 3.9 Hz, 1H), 2.92 (s, 3H), 2.47 (d, J = 11.8 Hz, 1H), 2.38 (s, 3H), 2.02 - 1.93 (m, 1H), 1.89 - 1.81 (m, 1H), 1.76 - 1.35 (m, 6H). [D] [2ae] (S or R) N-[2-(5-methyl-1H-pyrazol-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-Isomer 2 392.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.42 (d, J = 1.8 Hz, 1H), 7.29 (d, J = 7.5 Hz, 2H), 7.22 - 7.12 (m, 3H), 6.03 (d, J = 1.7 Hz, 1H), 5.29 (t, J = 6.4 Hz, 1H), 4.57 (q, J = 10.7, 9.0 Hz, 1H), 3.81 - 3.68 (m, 3H), 3.62 (ddd, J = 13.2, 6.1, 3.9 Hz, 1H), 3.54 (s, 1H), 2.92 (s, 3H), 2.52 - 2.41 (m, 1H), 2.38 (s, 3H), 1.97 (dt, J = 13.8, 3.1 Hz, 1H), 1.86 (d, J = 11.7 Hz, 1H), 1.74 - 1.36 (m, 6H). [D] [2af] (R or S) N-[2-(3,5-dimethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 451.3 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.26 - 7.21 (m, 2H), 7.14 (d, J = 1.1 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 6.91 - 6.86 (m, 1H), 6.84 (dt, J = 10.4, 2.0 Hz, 1H), 5.21 (br t, J = 6.0 Hz, 1H), 5.10 - 4.91 (m, 1H), 3.89 (dd, J = 10.2, 5.7 Hz, 1H), 3.78 (dd, J = 10.2, 4.0 Hz, 1H), 3.76 - 3.70 (m, 1H), 3.70 - 3.61 (m, 2H), 2.90 (s, 3H), 2.58 - 2.47 (m, 1H), 2.13 (s, 3H), 2.06 (d, J = 0.7 Hz, 3H), 2.04 - 1.95 (m, 2H), 1.67 - 1.48 (m, 6H). [A] [2ag] (S or R) N-[2-(3,5-dimethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 451.3 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.26 - 7.20 (m, 2H), 7.16 - 7.10 (m, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.91 - 6.86 (m, 1H), 6.83 (dt, J = 10.4, 2.1 Hz, 1H), 5.22 (br t, J = 6.0 Hz, 1H), 5.12 - 4.93 (m, 1H), 3.89 (dd, J = 10.2, 5.8 Hz, 1H), 3.78 (dd, J = 10.2, 4.1 Hz, 1H), 3.76 - 3.71 (m, 1H), 3.69 - 3.62 (m, 2H), 2.90 (s, 3H), 2.57 - 2.48 (m, 1H), 2.13 (s, 3H), 2.06 (d, J = 0.7 Hz, 3H), 2.04 - 1.94 (m, 2H), 1.67 - 1.48 (m, 6H). [C] [2ah] (R or S) N-[2-(5-chloro-3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]methanesulfonamide-Isomer 1 471.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.68 (d, J = 2.4 Hz, 1H), 7.26 - 7.19 (m, 2H), 6.98 (d, J = 7.7 Hz, 1H), 6.95 - 6.83 (m, 2H), 5.16 - 5.05 (m, 2H), 3.95 - 3.84 (m, 1H), 3.84 - 3.76 (m, 1H), 3.74 - 3.61 (m, 3H), 2.93 (s, 3H), 2.62 - 2.45 (m, 1H), 2.15 (s, 3H), 2.09 - 1.94 (m, 2H), 1.75 - 1.48 (m, 6H). [A] [2ai] (S or R) N-[2-(5-chloro-3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 471.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.68 (d, J = 2.4 Hz, 1H), 7.26 - 7.19 (m, 2H), 6.98 (d, J = 7.7 Hz, 1H), 6.95 - 6.83 (m, 2H), 5.16 - 5.05 (m, 2H), 3.95 - 3.84 (m, 1H), 3.84 - 3.76 (m, 1H), 3.74 - 3.61 (m, 3H), 2.93 (s, 3H), 2.62 - 2.45 (m, 1H), 2.15 (s, 3H), 2.09 - 1.94 (m, 2H), 1.75 - 1.48 (m, 6H). [C] [2aj] N-[2-(5-methyl-6-sideoxy-1,6-dihydropyrimidin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 420.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 8.31 (s, 1H), 7.83 (d, J = 0.9 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.24 - 7.16 (m, 3H), 5.04 (s, 1H), 4.94 - 4.85 (m, 1H), 3.96 (d, J = 5.9 Hz, 1H), 3.87 - 3.76 (m, 2H), 3.72 (s, 1H), 3.67 (br. s., 1H), 2.95 (s, 3H),2.58 - 2.48 (m, 1H), 2.09 (s, 3H), 2.01 (d, J = 13.4 Hz, 2H), 1.72 - 1.58 (m, 5H), 1.55 - 1.47 (m, 1H). [D] [2al] N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]cyclopropanesulfonamide 477.4 [M+H]+ 1H NMR (400 MHz, CDCl 3) δ 7.26 - 7.20 (m, 2H), 7.13 (s, 1H), 6.95 (d, J=7.7 Hz, 1H), 6.92 - 6.80 (m, 2H), 5.18 - 4.95 (m, 2H), 3.89 (dd, J=10.2, 5.6 Hz, 1H), 3.82 - 3.62 (m, 4H), 2.59 - 2.46 (m, 1H), 2.38 (tt, J=8.1, 4.8 Hz, 1H), 2.14 (s, 3H), 2.06 (s, 3H), 2.05 - 1.93 (m, 2H), 1.72 - 1.44 (m, 6H), 1.20 - 1.11 (m, 2H), 1.00 - 0.90 (m, 2H). [A] [2am] (R or S) N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]cyclopropanesulfonamide-isomer 1 477.4 [M+H]+ 1H NMR (500 MHz, CDCl 3) δ 7.27 - 7.21 (m, 2 H), 7.15 - 7.11 (m, 1 H), 6.95 (d, J=7.7 Hz, 1 H), 6.90 - 6.85 (m, 1 H), 6.82 - 6.85 (m, 1 H), 5.14 (br t, J=5.9 Hz, 1 H), 5.11 - 5.03 (m, 1 H), 3.89 (dd, J=10.2, 5.6 Hz, 1 H), 3.78 (dd, J=10.2, 4.3 Hz, 1 H), 3.77 - 3.65 (m, 2 H), 3.66 - 3.62 (m, 1 H), 2.59 - 2.47 (m, 1 H), 2.38 (tt, J=8.0, 4.8 Hz, 1 H), 2.13 (s, 3 H), 2.06 (s, 3 H), 2.04 - 1.96 (m, 2 H), 1.68 - 1.47 (m, 6 H), 1.20 - 1.10 (m, 2 H), 1.02 - 0.90 (m, 2 H). [A] [2an] (S or R) N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]cyclopropanesulfonamide-isomer 2 477.4 [M+H]+ 1H NMR (500 MHz, CDCl 3) δ 7.26 - 7.21 (m, 2 H), 7.15 - 7.11 (m, 1 H), 6.94 (d, J=7.7 Hz, 1 H), 6.90 - 6.85 (m, 1 H), 6.85 - 6.81 (m, 1 H), 5.18 (br t, J=5.9 Hz, 1 H), 5.13 - 5.03 (m, 1 H), 3.89 (dd, J=10.2, 5.6 Hz, 1 H), 3.78 (dd, J=10.1, 4.2 Hz, 1 H), 3.77 - 3.65 (m, 2 H), 3.65 - 3.63 (m, 1 H), 2.61 - 2.45 (m, 1 H), 2.38 (tt, J=8.0, 4.8 Hz, 1 H), 2.13 (s, 3 H), 2.05 (s, 3 H), 2.04 - 1.96 (m, 2 H), 1.67 - 1.47 (m, 6 H), 1.19 - 1.11 (m, 2 H), 1.02 - 0.92 (m, 2 H). [C] [2ao] N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]-2,2-difluoroethane-1-sulfonamide 501.3 [M+H]+ 1H NMR (400 MHz, CDCl 3) δ 7.32 - 7.26 (m, 1 H), 7.26 - 7.19 (m, 1 H), 7.15 (s, 1 H), 6.94 (d, J=7.7 Hz, 1 H), 6.91 - 6.79 (m, 2 H), 6.14 - 6.10 (m, 1 H), 6.14 (tt, J=55.0, 4.6 Hz, 1 H), 5.16 - 4.90 (m, 1 H), 3.89 (dd, J=10.3, 5.5 Hz, 1 H), 3.79 (dd, J=10.3, 3.9 Hz, 1 H), 3.76 - 3.62 (m, 3 H), 3.58 - 3.44 (m, 2 H), 2.59 - 2.44 (m, 1 H), 2.13 (s, 3 H), 2.06 (s, 3 H), 2.05 - 1.94 (m, 2 H), 1.86 - 1.45 (m, 6 H). [B] [2ap] N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]-2,2,2-trifluoroethane-1-sulfonamide 519.3 [M+H]+ 1H NMR (400 MHz, CDCl 3) δ 7.29 - 7.21 (m, 2 H), 7.15 (s, 1 H), 6.94 (d, J=7.7 Hz, 1 H), 6.91 - 6.80 (m, 2 H), 6.37 - 6.08 (m, 1 H), 5.18 - 4.79 (m, 1 H), 3.91 (dd, J=10.3, 5.7 Hz, 1 H), 3.85 - 3.67 (m, 5 H), 3.67 - 3.62 (m, 1 H), 2.52 (td, J=9.9, 5.3 Hz, 1 H), 2.13 (s, 3 H), 2.06 (s, 3 H), 2.05 - 1.94 (m, 2 H), 1.71 - 1.46 (m, 6 H). [B] [2aq] 1-{1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl}-3,5-dimethyl-1,2-dihydropyridin-2-one 480.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.26 - 7.19 (m, 2 H), 7.13 (br s, 1 H), 6.94 (d, J=7.7 Hz, 1 H), 6.91 - 6.79 (m, 2 H), 5.04 (br t, J=5.9 Hz, 2 H), 3.93 - 3.83 (m, 1 H), 3.77 (dd, J=10.1, 4.2 Hz, 1 H), 3.72 - 3.52 (m, 3 H), 2.75 (s, 6 H), 2.57 - 2.46 (m, 1 H), 2.13 (s, 3 H), 2.06 (s, 3 H), 2.04 - 1.93 (m, 2 H), 1.72 - 1.43 (m, 6 H). [A] [2ar] (R or S) 1-[1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl]-3,5-dimethyl-1,2-dihydropyridin-2-one-isomer 1 480.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.26 - 7.19 (m, 2 H), 7.13 (dd, J=2.2, 1.1 Hz, 1 H), 6.95 (d, J=7.7 Hz, 1 H), 6.91 - 6.80 (m, 2 H), 5.07 - 4.99 (m, 1 H), 5.01 - 4.93 (m, 1 H), 3.88 (dd, J=10.1, 5.5 Hz, 1 H), 3.77 (dd, J=10.1, 4.2 Hz, 1 H), 3.72 - 3.61 (m, 2 H), 3.61 - 3.51 (m, 1 H), 2.75 (s, 6 H), 2.57 - 2.44 (m, 1 H), 2.14 (s, 3 H), 2.06 (d, J=0.9 Hz, 3 H), 2.04 - 1.94 (m, 2 H), 1.68 - 1.44 (m, 6 H). [A] [2as] (S or R) 1-[1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl]-3,5-dimethyl-1,2-dihydropyridine-2-one-isomer 2 480.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.26 - 7.19 (m, 2 H), 7.13 (dd, J=2.2, 1.1 Hz, 1 H), 6.95 (d, J=7.7 Hz, 1 H), 6.91 - 6.80 (m, 2 H), 5.07 - 4.99 (m, 1 H), 5.01 - 4.93 (m, 1 H), 3.88 (dd, J=10.1, 5.5 Hz, 1 H), 3.77 (dd, J=10.1, 4.2 Hz, 1 H), 3.72 - 3.61 (m, 2 H), 3.61 - 3.51 (m, 1 H), 2.75 (s, 6 H), 2.57 - 2.44 (m, 1 H), 2.14 (s, 3 H), 2.06 (d, J=0.9 Hz, 3 H), 2.04 - 1.94 (m, 2 H), 1.68 - 1.44 (m, 6 H). [B] [2at] N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]-1-fluoromethanesulfonamide 469.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.30 - 7.20 (m, 2 H), 7.15 (s, 1 H), 6.94 (d, J=7.7 Hz, 1 H), 6.92 - 6.79 (m, 2 H), 6.11 (br t, J=5.2 Hz, 1 H), 5.23 - 4.94 (m, 3 H), 3.91 (dd, J=10.3, 5.7 Hz, 1 H), 3.85 - 3.69 (m, 3 H), 3.65 (br s, 1 H), 2.58 - 2.46 (m, 1 H), 2.13 (s, 3 H), 2.06 (s, 3 H), 2.04 - 1.95 (m, 2 H), 1.67 - 1.46 (m, 6 H). [A] [2au] (R or S) N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]-1-fluoromethanesulfonamide-isomer 1 469.3 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.27 - 7.20 (m, 2 H), 7.15 (s, 1 H), 6.94 (d, J=7.7 Hz, 1 H), 6.88 (td, J=8.4, 1.9 Hz, 1 H), 6.85 - 6.79 (m, 1 H), 6.12 - 6.00 (m, 1 H), 5.17 - 4.96 (m, 3 H), 3.92 (dd, J=10.3, 5.8 Hz, 1 H), 3.83 - 3.70 (m, 3 H), 3.65 (br s, 1 H), 2.58 - 2.47 (m, 1 H), 2.13 (s, 3 H), 2.06 (s, 3 H), 2.04 - 1.94 (m, 2 H), 1.67 - 1.44 (m, 6 H). [A] [2av] (S or R) N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]-1-fluoromethanesulfonamide-isomer 2 469.3 [M+H] + 1H NMR (400 MHz, CDCl3) δ 7.26 - 7.18 (m, 2H), 7.14 (dd, J = 2.5, 1.2 Hz, 1H), 6.93 (dt, J = 7.7, 1.4 Hz, 1H), 6.90 - 6.79 (m, 2H), 6.11 (s, 1H), 5.12 (d, J = 0.8 Hz, 1H), 5.07 - 4.97 (m, 2H), 3.91 (dd, J = 10.3, 5.8 Hz, 1H), 3.82 - 3.70 (m, 3H), 3.64 (q, J = 2.9 Hz, 1H), 2.51 (td, J = 10.3, 5.3 Hz, 1H), 2.12 (t, J = 0.8 Hz, 3H), 2.05 (d, J = 1.0 Hz, 3H), 2.04 - 1.94 (m, 2H), 1.66 - 1.45 (m, 6H). [B] [2ax] N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]-2-methoxyethane-1-sulfonamide 495.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.26 - 7.19 (m, 2 H), 7.12 (s, 1 H), 6.94 (d, J=7.7 Hz, 1 H), 6.91 - 6.78 (m, 2 H), 5.20 - 4.88 (m, 2 H), 3.88 (dd, J=10.1, 5.7 Hz, 1 H), 3.80 - 3.72 (m, 3 H), 3.72 - 3.56 (m, 3 H), 3.33 (d, J=0.7 Hz, 3 H), 3.25 (t, J=5.7 Hz, 2 H), 2.61 - 2.40 (m, 1 H), 2.13 (s, 3 H), 2.05 (s, 3 H), 1.99 (br t, J=14.1 Hz, 2 H), 1.68 - 1.44 (m, 6 H). [A] [2ay] N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]oxy}propyl]methanesulfonamide 454.4 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 8.18 (s, 2 H), 7.16 (s, 1 H), 7.11 (s, 1 H), 5.09 (br t, J=5.7 Hz, 1 H), 4.98 (br dd, J=7.5, 5.0 Hz, 1 H), 4.09 (ddd, J=9.8, 6.4, 3.1 Hz, 2 H), 3.98 - 3.81 (m, 2 H), 3.77 - 3.50 (m, 3 H), 3.48 - 3.34 (m, 2 H), 2.87 (s, 3 H), 2.12 (s, 3 H), 2.04 (s, 3 H), 1.93 - 1.81 (m, 2 H), 1.54 (br s, 2 H) [D] [2az] (R or S) N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]oxy}propyl]methanesulfonamide - isomer 1 454.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 8.19 (s, 2 H), 7.17 (s, 1 H), 7.11 (s, 1 H), 5.09 (br t, J=6.0 Hz, 1 H), 5.04 - 4.93 (m, 1 H), 4.18 - 4.04 (m, 2 H), 3.94 (dd, J=10.3, 5.5 Hz, 1 H), 3.86 (dd, J=10.2, 4.5 Hz, 1 H), 3.77 - 3.65 (m, 1 H), 3.68 - 3.62 (m, 1 H), 3.60 - 3.52 (m, 1 H), 3.48 - 3.35 (m, 2 H), 2.88 (s, 3 H), 2.13 (s, 3 H), 2.05 (s, 3 H), 1.96 - 1.80 (m, 2 H), 1.64 - 1.50 (m, 2 H). [C] [2ba] (S or R) N-[2-(3,5-dimethyl-2-oxy-1,2-dihydropyridin-1-yl)-3-{[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]oxy}propyl]methanesulfonamide-isomeric 2 454.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 8.19 (s, 2 H), 7.17 (s, 1 H), 7.11 (s, 1 H), 5.09 (br t, J=6.0 Hz, 1 H), 5.04 - 4.93 (m, 1 H), 4.18 - 4.04 (m, 2 H), 3.94 (dd, J=10.3, 5.5 Hz, 1 H), 3.86 (dd, J=10.2, 4.5 Hz, 1 H), 3.77 - 3.65 (m, 1 H), 3.68 - 3.62 (m, 1 H), 3.60 - 3.52 (m, 1 H), 3.48 - 3.35 (m, 2 H), 2.88 (s, 3 H), 2.13 (s, 3 H), 2.05 (s, 3 H), 1.96 - 1.80 (m, 2 H), 1.64 - 1.50 (m, 2 H). [D] [2bb] 1-{1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-propylcyclohexyl]oxy}propyl-2-yl}-3,5-dimethyl-1,2-dihydropyridin-2-one 428.5 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.30 (s, 1 H), 7.10 (s, 1 H), 5.15 - 5.04 (m, 1 H), 4.96 (br t, J=5.9 Hz, 1 H), 3.83 - 3.71 (m, 2 H), 3.65 - 3.54 (m, 2 H), 3.52 (br s, 1 H), 2.74 (s, 6 H), 2.13 (s, 3 H), 2.06 (s, 3 H), 1.88 - 1.76 (m, 2 H), 1.53 - 1.34 (m, 4 H), 1.34 - 1.22 (m, 3 H), 1.21 - 1.07 (m, 4 H), 0.89 (t, J=7.2 Hz, 3 H). [A] [2bc] 1-{1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-cyclopropylcyclohexyl]oxy}propyl-2-yl}-3,5-dimethyl-1,2-dihydropyridin-2-one 426.4 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.33 - 7.30 (m, 1H), 7.13 - 7.08 (m, 1H), 5.15 - 5.05 (m, 1H), 4.98 (br t, J=6.0 Hz, 1H), 3.85 - 3.73 (m, 2H), 3.64 - 3.52 (m, 2H), 3.52 - 3.47 (m, 1H), 2.74 (s, 6H), 2.14 (s, 3H), 2.07 (d, J=0.7 Hz, 3H), 1.90 - 1.76 (m, 2H), 1.62 - 1.49 (m, 2H), 1.42 - 1.33 (m, 4H), 0.59 - 0.46 (m, 2H), 0.43 - 0.34 (m, 2H), 0.04 (dd, J=4.3, 1.4 Hz, 2H). [B] [2bd] N-[2-(3,5-dimethyl-2-sideoxy-1,2-dihydropyridin-1-yl)-3-{2-oxaspiro[4,5]dec-8-yloxy}propyl]methanesulfonamide 413.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.24 - 7.17 (m, 1H), 7.11 (s, 1H), 5.17 (br t, J=5.9 Hz, 1H), 5.08 - 4.94 (m, 1H), 3.92 - 3.75 (m, 4H), 3.73 - 3.57 (m, 2H), 3.55 - 3.46 (m, 2H), 3.39 - 3.26 (m, 1H), 2.87 (s, 3H), 2.13 (s, 3H), 2.09 - 2.04 (m, 3H), 1.85 - 1.63 (m, 6H), 1.56 - 1.28 (m, 4H). [D] Example 2ak:N-[2-(2-sideoxy-1,2-dihydroquinolin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide []

[0199] [1-(1-] [Nitro] [-3-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-2-] [base] [)-1,2-] [Dihydroquinoline] [-2-] [ketone] [(] [Intermediate substance] [10)] []

[0200] At 0 °C, tBuOK (52 mg, 0.46 mmol) and 18-crown-6 (40 mg, 0.15 mmol) were added to a suspension of 2-hydroxyquinoline (111 mg, 0.77 mmol) in THF (2 mL). The reaction mixture was stirred at this temperature for 1 hour and then cooled to -50 °C. Intermediate 7 (100 mg, 0.38 mmol) was added to a solution of THF (2 mL) and the reaction mixture was stirred at -50 °C for 15 minutes. The solution was diluted with H₂O and extracted with EtOAc. The organic layer was evaporated under vacuum. The product was purified by column chromatography using a C18 filter cartridge (H₂O + 0.1% formic acid / MeCN + 0.1% formic acid, 95:5 to 0:100) to give the title compound (17 mg, 0.042 mmol, 11% yield). [M+H] +m / z 407.3 [。]

[0201] [1-(1-] [Amine] [-3-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-2-] [base] [)-1,2-] [Dihydroquinoline] [-2-] [ketone] [(] [Intermediate substance] [11)]

[0202] Starting with intermediate 10 (17 mg, 0.042 mmol), intermediate 11 was prepared following the procedure described for intermediate 9, yielding the title compound as a white solid (8 mg, 0.021 mmol, yield 64%). [M+H]+m / z 377.2.

[0203] [N-[2-(2-)] [Side group] [-1,2-] [Dihydroquinoline] [-1-] [base] [)-3-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Propyl] []] [Methylsulfonylurea] [(2ak)] []

[0204] Starting with intermediate 11 (7 mg, 0.020 mmol), Example 2ak was prepared following the procedure described for Example 1, yielding the title compound (1.4 mg, 0.003 mmol, 16% yield) as a white solid. Table 5. Characterization and EC50 data for hOX2 - Compound 2ak: [Example] [structure] [name] [Observation Quality] [, 1 , ] [H NMR] [EC50 hOX2] [2ak] N-[2-(2-sidekto-1,2-dihydroquinolin-1-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 455.2 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.82 - 7.75 (m, 1H), 7.70 (d, J = 9.5 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.34 - 7.28 (m, 1H), 7.27 - 7.09 (m, 3H), 6.88 (br d, J = 6.9 Hz, 2H), 6.61 (br d, J = 9.3 Hz, 1H), 5.24 - 5.05 (m, 2H), 4.10 (br d, J = 6.3 Hz, 2H), 4.08 - 3.98 (m, 1H), 3.91 - 3.79 (m, 1H), 3.68 - 3.59 (m, 1H), 2.91 (s, 3H), 2.47 - 2.32 (m, 1H), 2.08 - 1.20 (m, 8H). [D] Examples 3a-3d: N-[(2S,3S)-3-(3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-4-{[(cis)-4-phenylcyclohexyl]oxy}but-2-yl]methanesulfonamide (3a); N-[(2R,3R)-3-(3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-4-{[(cis)-4-phenylcyclohexyl]oxy}but-2-yl]methanesulfonamide (3b); [N-[(2R,3S)-3-(3-] [methyl] [-2-] [Side group] [-1,2-] [Dihydropyridine] [-1-] [base] [)-4-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Man] [-2-] [base] []] [Methylsulfonylurea] [(3c)] [;and] [] [N-[(2S,3R)-3-(3-] [methyl] [-2-] [Side group] [-1,2-] [Dihydropyridine] [-1-] [base] [)-4-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Man] [-2-] [base] []] [Methylsulfonylurea] [(3d)] []

[0205] [2-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] Acetaldehyde [(] [Intermediate substance] [12)] []

[0206] Add K₂O₅·2H₂O (276 mg, 0.75 mmol) to a mixture of intermediate 6 (3.24 g, 14.98 mmol) in THF (34 mL) and H₂O (68 mL). Stir the mixture at room temperature for 3 hours. Add NaIO₄ (9.61 g, 44.93 mmol) and stir the mixture at room temperature for 3 hours. Pour the mixture into H₂O and extract with EtOAc. Wash the organic layer with brine and concentrate under vacuum. Purify the product by column chromatography using a silica filter (cHex / EtOAc, 100:0 to 20:80) to give the title compound (2.36 g, 10.81 mmol, 72% yield) as a yellow-green oil. 1H NMR (400 MHz, CDCl 3) δ 9.81 (t, J = 1.1 Hz, 1H), 7.37 - 7.13 (m, 5H), 4.07 (d, J = 1.1 Hz, 2H), 3.71 (p, J = 3.0 Hz, 1H), 2.62 - 2.47 (m, 2H), 2.12 - 2.03 (m, 2H), 1.87 (qd, J = 13.0, 3.4 Hz, 2H), 1.72 - 1.55 (m, 3H) [。]

[0207] [[(] [Shun] [)-4-{[-3-] [Nitrobutanol] [-2-] [ene] [-1-] [base] []] [Oxygen group] [}] [Cyclohexyl] []] [benzene] [(] [Intermediate substance] [13)] []

[0208] At 0 °C, nitrobenzene (0.65 mL, 11.0 mmol) and tBuOK (41 mg, 0.37 mmol) were added to a solution of intermediate 12 (0.80 g, 3.66 mmol) in anhydrous THF (4 mL) and anhydrous tBuOH (4 mL). The mixture was stirred at room temperature for 2 hours, then diluted with Et₂O (25 mL) and washed with saturated aqueous solution of NH₄Cl (20 mL). The combined aqueous layers were extracted with Et₂O (25 mL). The combined organic layers were concentrated under vacuum to give a crude substance (1.17 g) as a colorless oil. The crude substance was dissolved in anhydrous DCM (20 mL) at 0 °C, methanesulfonyl chloride (0.30 mL, 3.92 mmol) was added and stirred for 5 minutes, TEA (1.09 mL, 7.84 mmol) was added at 0 °C and stirred for 15 minutes at room temperature. The mixture was extracted with saturated aqueous NH₄Cl solution and DCM (2 × 15 mL). The combined organic layers were concentrated under vacuum. The product was purified by column chromatography using a silica filter cartridge (0-10% EtOAc / cHex) to give the title compound (594 mg, 2.16 mmol, 55% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl 3) δ 7.37 - 7.29 (m, 2H), 7.28 - 7.17 (m, 4H), 4.26 (dd, J = 6.0, 1.2 Hz, 2H), 3.72 (t, J = 3.1 Hz, 1H), 2.58 (tt, J = 12.0, 3.7 Hz, 1H), 2.26 (q, J = 1.2 Hz, 3H), 2.12 - 2.02 (m, 2H), 1.85 (qd, J = 12.9, 3.4 Hz, 2H), 1.74 - 1.66 (m, 2H), 1.66 - 1.51 (m, 2H) [。]

[0209] [3-] [methyl] [-1-(3-)] [Nitro] [-1-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Man] [-2-] [base] [)-1,2-] [Dihydropyridine] [-2-] [ketone] [(] [Intermediate substance] [14)] []

[0210] 3-Methylpyridin-2(1H)-one (106 mg, 0.97 mmol) was suspended in THF (3 mL), and tBuOK (65 mg, 0.58 mmol) and 18-crown-6 (51 mg, 0.19 mmol) were added at 0 °C. The reaction mixture was stirred for 1 hour, cooled to -50 °C, and then THF (3 mL) containing intermediate 13 (150 mg, 0.48 mmol) was added, and the reaction mixture was stirred at -50 °C for 15 minutes. The solution was diluted with H₂O and extracted with EtOAc. The aqueous layer was evaporated under vacuum to give the crude product, which was purified by column chromatography using a silica filter (0-5% methanol / DCM) to give the title compound (165 mg, 0.43 mmol, 89% yield). [M+H] +m / z 385.2

[0211] [1-(3-)] [Amine] [-1-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Man] [-2-] [base] [)-3-] [methyl] [-1,2-] [Dihydropyridine] [-2-] [ketone] [(] [Intermediate substance] [15)] []

[0212] Starting with intermediate 14 (164 mg, 0.43 mmol), intermediate 15 was prepared following the procedure described for intermediate 9, yielding the title compound as a white solid (168 mg, quantitative yield). [M+H]+m / z 355.2

[0213] [N-[(2S,3S)-3-(3-] [methyl] [-2-] [Side group] [-1,2-] [Dihydropyridine] [-1-] [base] [)-4-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Man] [-2-] [base] []] [Methylsulfonylurea] [(3a)] [;] [] N-[(2R,3R)-3-(3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-4-{[(cis)-4-phenylcyclohexyl]oxy}but-2-yl]methanesulfonamide (3b); [N-[(2R,3S)-3-(3-] [methyl] [-2-] [Side group] [-1,2-] [Dihydropyridine] [-1-] [base] [)-4-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Man] [-2-] [base] []] [Methylsulfonylurea] [(3c)] [;and] [] [N-[(2S,3R)-3-(3-] [methyl] [-2-] [Side group] [-1,2-] [Dihydropyridine] [-1-] [base] [)-4-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Man] [-2-] [base] []] [Methylsulfonylurea] [(3d)] []

[0214] Starting with intermediate 15 (145 mg, 0.31 mmol), Examples 3a, 3b, 3c, and 3d were prepared following the procedure described for Example 1, followed by preparative HPLC (MDAP Waters, column: xBridge C18 (30 x 100 mm, 3 µm). Conditions: [A: 10 mM NH₄HCO₃ aqueous solution, adjusted to pH 10 with NH₃]; [B: MeCN]. Gradient: from 49.0% B to 51.0% B over 10 minutes (flow rate: 40.00 mL / min), yielding dissociative fractions A (15 mg) and B (15 mg). During the anteroposterior separation using one of the conditions reported above, isomer 1 was designated as the first dissociative compound and isomer 2 as the second dissociative compound.

[0215] The soluble fraction A was subjected to palmar separation (Chiralpak AD-H, 25 × 2.0 cm, 5 μm, 70 / 30 n-hexane: (ethanol / methanol 1:1 + 0.1% IPA, flow rate: 17 mL / min) to obtain Example 41 (5.8 mg, 0.013 mmol, yield 4%, 100% mirror-image isomer excess, room temperature 7.0 min) and Example 42 (6.2 mg, 0.014 mmol, yield 5%, 100% mirror-image isomer excess, room temperature 10.9 min).

[0216] The soluble fraction B was subjected to palmar separation (Chiralpak AD-H, 25 × 2.0 cm, 5 μm, 55 / 45 n-hexane: (ethanol / methanol 1:1 + 0.1% IPA, flow rate: 17 mL / min) to obtain Example 43 (4.6 mg, 0.011 mmol, 3% yield, 100% mirror-image isomer excess, room temperature 6.4 min) and Example 44 (4.6 mg, 0.011 mmol, 3% yield, 100% mirror-image isomer excess, room temperature 10.5 min) as white solids. Table 6. Characterization and EC50 data for hOX2 - Compounds 3a-3d: [Example] [structure] [name] [Observation Quality] [, 1 , ] [H NMR] [EC50 hOX2] [3a] (2R or 2S) and (3R or 3S)N-[3-(3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-4-{[(cis)-4-phenylcyclohexyl]oxy}but-2-yl]methanesulfonamide-isomer 1 433.2 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.75 (br d, J = 6.6 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.27 - 7.18 (m, 4H), 6.18 (t, J = 6.9 Hz, 1H), 5.57 (d, J = 9.6 Hz, 1H), 5.07 (br s, 1H), 4.15 - 4.04 (m, 2H), 3.85 (dd, J = 10.8, 2.5 Hz, 1H), 3.71 (t, J = 2.6 Hz, 1H), 2.75 (s, 3H), 2.63 - 2.54 (m, 1H), 2.17 (s, 3H), 2.13 - 2.02 (m, 2H), 1.82 - 1.59 (m, 6H), 1.37 (d, J = 6.7 Hz, 3H). [C] [3b] (2S or 2R) and (3S or 3R)N-[3-(3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-4-{[(cis)-4-phenylcyclohexyl]oxy}but-2-yl]methanesulfonamide-isomer 2 433.2 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.75 (br d, J =6.6 Hz, 1 H), 7.30 - 7.35 (m, 2 H), 7.18 - 7.27 (m, 4 H), 6.18 (t, J=6.9 Hz, 1 H), 5.57 (d, J=9.6 Hz, 1 H), 5.07 (br s, 1 H), 4.04 - 4.15 (m, 2 H), 3.85 (dd, J=10.8, 2.5 Hz, 1 H), 3.71 (t, J=2.6 Hz, 1 H), 2.75 (s, 3 H), 2.54 - 2.63 (m, 1 H), 2.17 (s, 3 H), 2.02 - 2.13 (m, 2 H), 1.59 - 1.82 (m, 6 H), 1.37 (d, J=6.7 Hz, 3 H). [C] [3c] (2S or 2R) and (3R or 3S)N-[3-(3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-4-{[(cis)-4-phenylcyclohexyl]oxy}but-2-yl]methanesulfonamide-isomer 3 433.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.77 (br s, 1 H), 7.29 - 7.35 (m, 3 H), 7.11 - 7.26 (m, 4 H), 6.21 (t, J=6.8 Hz, 1 H), 4.61 (s, 1 H), 4.05 - 4.20 (m, 1 H), 3.83 - 4.04 (m, 1 H), 3.77 (dd, J=10.5, 2.2 Hz, 1 H), 3.60 - 3.67 (m, 1 H), 2.58 - 2.83 (m, 3 H), 2.46 - 2.58 (m, 1 H), 2.16 (s, 3 H), 1.94 - 2.09 (m, 2 H), 1.48 - 1.76 (m, 6 H), 1.38 - 1.47 (m, 3 H). [D] [3d] (2R or 2S) and (3S or 3R)N-[3-(3-methyl-2-sideoxy-1,2-dihydropyridin-1-yl)-4-{[(cis)-4-phenylcyclohexyl]oxy}but-2-yl]methanesulfonamide-isomer 4 433.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.77 (br s, 1H), 7.35 - 7.29 (m, 3H), 7.26 - 7.11 (m, 4H), 6.21 (t, J = 6.8 Hz, 1H), 4.61 (s, 1H), 4.20 - 4.05 (m, 1H), 4.04 - 3.83 (m, 1H), 3.77 (dd, J = 10.5, 2.2 Hz, 1H), 3.67 - 3.60 (m, 1H), 2.83 - 2.58 (m, 3H), 2.58 - 2.46 (m, 1H), 2.16 (s, 3H), 2.09 - 1.94 (m, 2H), 1.76 - 1.48 (m, 6H), 1.47 - 1.38 (m, 3H). [C] Example 4: N-[2-(1-methyl-2-sideoxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide (4) []

[0217] [2] [-bromine-] [3] [‐] [{[(] [Shun] [)] [‐] [4] [‐phenylcyclohexyl] []] [Oxygen group] [}] [C-] [2] [-methyl acrylate] [(] [Intermediate substance] [16)] []

[0218] Anhydrous THF (2 x 10 mL) containing intermediate 1 (3.41 g, 13.1 mmol) was added to a solution of tribromopyridamole (4.40 g, 13.7 mmol) in anhydrous THF (30 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 0.5 h. The solution was cooled to 0 °C, and then TEA (3.6 mL, 26.2 mmol) was added. The reaction mixture was heated to room temperature for 0.5 h. The reaction mixture was quenched with H₂O (20 mL) and extracted with DCM (3 × 75 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under vacuum. The product was purified by column chromatography using a silica filter cartridge (0-10% EtOAc / heptane) to give the title compound (3.50 g, 10.32 mmol, 79% yield) as a grayish-white solid. [M+H] +m / z 339.2 and 341.2

[0219] [2] [‐] [(1)] [-methyl-] [2] [‐Oxygen‐] [1,2] [-Dihydropyridine-] [3] [-base] [)] [‐] [3] [‐] [{[(] [Shun] [)] [‐] [4] [‐phenylcyclohexyl] []] [Oxygen group] [}] [C-] [2] [-methyl methacrylate]( [Intermediate substance] [17)] []

[0220] Intermediate 16 (75 mg, 0.22 mmol) and (2-methoxy-3-pyridyl) were prepared using N2. A solution of boronic acid (51 mg, 0.33 mmol) in 2M Na₂CO₃ aqueous solution (0.33 mL, 0.66 mmol) and 1,4-dimethylamine (0.4 mL) was degassed for 5 min, followed by the addition of Pd₂(dba)₃ (51 mg, 0.055 mmol) and XPos (53 mg, 0.11 mmol). The reaction mixture was heated at 100 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The combined organic layers were concentrated under vacuum and purified by column chromatography using a silica filter cartridge (0-20% EtOAc / heptane) to give the title compound (70 mg, 0.19 mmol, 87% yield) as a deep red gel. [M+H]⁺m / z 368.3

[0221] [3] [‐] [(1)] [‐hydroxy‐] [3] [‐] [{[(] [Shun] [)] [‐] [4] [‐phenylcyclohexyl] []] [Oxygen group] [}] [C-] [2] [-base] [)] [‐] [1] [-methyl-] [1,2] [-Dihydropyridine-] [2] [-ketone] [(] [Intermediate substance] [18)] []

[0222] Starting with intermediate 17 (200 mg, 0.54 mmol), intermediate 18 was prepared following the procedure described for intermediate 3, yielding the title compound (232 mg, quantitative yield). [M+H]+m / z 342.4

[0223] [3] [‐] [(1)] [‐hydroxy‐] [3] [‐] [{[(] [Shun] [)] [‐] [4] [‐phenylcyclohexyl] []] [Oxygen group] [}] [C-] [2] [-base] [)] [‐] [1] [-methyl-] [1,2] [-Dihydropyridine-] [2] [-ketone] [(] [Intermediate substance] [19)] []

[0224] Starting with intermediate 18 (388 mg, 1.14 mmol), intermediate 19 was prepared following the procedure described for intermediate 4, yielding the title compound (410 mg, quantitative yield). [M+H]+m / z 367.4 []

[0225] [3] [‐] [(1)] [‐hydroxy‐] [3] [‐] [{[(] [Shun] [)] [‐] [4] [‐phenylcyclohexyl] []] [Oxygen group] [}] [C-] [2] [-base] [)] [‐] [1] [-methyl-] [1,2] [-Dihydropyridine-] [2] [-ketone] [(] [Intermediate substance] [20)]

[0226] Starting with intermediate 19 (410 mg, 1.12 mmol), intermediate 20 was prepared following the procedure described for intermediate 5 to give the title compound (94 mg, 0.28 mmol, 25% yield). [M+H]+m / z 341.4 []

[0227] [N-[2-(1-] [methyl] [-2-] [Side group] [-1,2-] [Dihydropyridine] [-3-] [base] [)-3-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Propyl] []] [Methylsulfonylurea] [(4)] []

[0228] Starting with intermediate 20 (71 mg, 0.21 mmol), Example 4 was prepared following the procedure described for Example 1, yielding the title compound (35 mg, 0.082 mmol, 40% yield) as a white solid.

[0229] The mirror-image isomers were separated by palmar purification using Chiralpak columns (AD-H, IC, OJ-H) and dissociation with mixtures of n-hexane / EtOH, n-hexane / (EtOH + 0.1% iPrNH₂), or n-hexane / (EtOH / MeOH 1:1 + 0.1% iPrNH₂) at ratios between 35:65 and 70:30. During palmar separation using one of the conditions reported above, isomer 1 was designated as the first dissociated compound and isomer 2 as the second dissociated compound. Table 7. Characterization and EC50 data for hOX2 - Compound 4-4b: [Example] [structure] [name] [Observation Quality] [, 1 , ] [H NMR] [EC50 hOX2] [4] N-[2-(1-methyl-2-sideoxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 419.6 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.39 (dd, J = 6.9, 1.9 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.22 - 7.15 (m, 3H), 6.20 (t, J = 6.8 Hz, 1H), 3.76 - 3.69 (m, 2H), 3.65 (q, J = 2.8 Hz, 1H), 3.56 (s, 3H), 3.56 - 3.43 (m, 3H), 2.94 (s, 3H), 2.52 (tt, J = 11.6, 3.7 Hz, 1H), 2.07 - 1.96 (m, 2H), 1.80 - 1.61 (m, 5H), 1.58 - 1.46 (m, 2H). [C] [4a] (R or S) N-[2-(1-methyl-2-sideoxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 419.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.38 (dd, J = 6.9, 2.0 Hz, 1H), 7.26 (s, 3H), 7.23 - 7.15 (m, 3H), 6.18 (t, J = 6.8 Hz, 1H), 5.48 (d, J = 6.0 Hz, 1H), 3.77 - 3.70 (m, 2H), 3.65 (t, J = 3.0 Hz, 1H), 3.61 - 3.43 (m, 6H), 2.94 (s, 3H), 2.52 (tt, J = 11.8, 3.8 Hz, 1H), 2.03 (dd, J = 13.9, 3.2 Hz, 2H), 1.77 - 1.60 (m, 4H), 1.54 (s, 2H). [C] [4b] (S or R) N-[2-(1-methyl-2-sideoxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 419.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.38 (dd, J = 7.0, 2.0 Hz, 1H), 7.32 - 7.23 (m, 3H), 7.23 - 7.14 (m, 3H), 6.18 (t, J = 6.8 Hz, 1H), 5.48 (d, J = 6.0 Hz, 1H), 3.79 - 3.68 (m, 2H), 3.64 (d, J = 3.1 Hz, 1H), 3.61 - 3.40 (m, 6H), 2.94 (s, 3H), 2.52 (tt, J = 11.8, 3.8 Hz, 1H), 2.03 (dd, J = 14.1, 3.2 Hz, 2H), 1.80 - 1.60 (m, 4H), 1.54 (s, 2H). [D] Example 5a: N-[2-(1,5-dimethyl-2-sideoxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide (5a) []

[0230] [1,5-] [Dimethyl] [-3-(1-)] [Nitro] [-3-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-2-] [base] [)-1,2-] [Dihydropyridine] [-2-] [ketone] [(] [Intermediate substance] [twenty one)] []

[0231] At -78 °C, a solution of 2.5 M nBuLi in THF (0.18 mL, 0.46 mmol) was added dropwise to a solution of 3-bromo-1,5-dimethylpyridin-2-one (93 mg, 0.46 mmol) in anhydrous THF (2 mL). The solution was stirred at -78 °C for 45 min. Intermediate 7 (100 mg, 0.38 mmol) was added dropwise to a solution of THF (2 mL), and the solution was stirred at -78 °C for 30 min. The reaction mixture was quenched by adding a saturated aqueous solution of NH4Cl at -78 °C and allowed to reach room temperature. The solution was diluted with EtOAc and washed with H2O. The organic layer was evaporated under vacuum, and the product was purified by column chromatography using a silica filter (0-100% EtOAc / cHex) to give the title compound (58 mg, 0.15 mmol, 39% yield) as a pale yellow oil. [M+H] +m / z 385.3.

[0232] [Intermediate substance] [21a] [, , ]

[0233] 3-[1-[[4-(3-fluorophenyl)cyclohexyloxy]methyl]-2-nitro-ethyl]-1,5-dimethyl-pyridin-2-one

[0234] Under a nitrogen atmosphere at room temperature, a solution of 1.3 M isopropyl magnesium chloride-lithium chloride complex in THF (0.55 mL, 0.72 mmol) was added to a solution of 3-bromo-1,5-dimethyl-1,2-dihydropyridin-2-one (145 mg, 0.72 mmol) in THF (2.1 mL). The mixture was stirred for 10 min, followed by the addition of CuI (150 mg, 0.79 mmol) and stirring of the reaction mixture for 1 h. After the starting material was exhausted, a solution of 1-fluoro-3-[4-[(E)-3-nitroallyloxy]cyclohexyl]benzene (200 mg, 0.72 mmol) in THF (0.7 mL) was added and the reaction mixture was stirred for 2 h at room temperature. The mixture was quenched at room temperature by the addition of a saturated aqueous solution of NH4Cl. The solution was diluted with EtOAc and washed with H2O. The organic layer was evaporated under vacuum to give the title compound (247 mg, 0.61 mmol, 86% yield) as a yellow oil. [M+H]+m / z 403.9

[0235] [Intermediate substance] [21b] []

[0236] 5-Methyl-3-(1-nitro-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl)-1,2-dihydropyridin-2-one

[0237] KI (406 mg, 2.45 mmol) was added to a solution of 2-methoxy-5-methyl-3-(1-nitro-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl)pyridine (283 mg, 0.41 mmol) (prepared from 3-bromo-2-methoxy-5-methylpyridine following the same procedure described for synthetic intermediate 21) in acetic acid (2 mL). The emulsion was stirred at 90 °C for 18 hours, and then the mixture was poured into a saturated aqueous solution of NaHCO3. EtOAc was added and the mixture was washed again with NaHCO3. The organic phase was dried (Na2SO4) and evaporated under vacuum. The product was purified by column chromatography using a 12 g silica filter cartridge (DCM / MeOH, 100:0 to 95:5) to give the title compound (163 mg, quantitative yield) as a reddish-brown oil. [M+H] +m / z 389.4

[0238] [Intermediate substance] [21c]

[0239] 2-[5-methyl-3-(1-nitro-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl)-2-sideoxy-1,2-dihydropyridin-1-yl]acetonitrile 2-Bromoacetonitrile (0.02 mL, 0.26 mmol) was added to a stirred suspension of intermediate 21b (50 mg, 0.13 mmol) and K₂CO₃ (0.04 g, 0.26 mmol) in DMF (1 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over a hydrophobic funnel and evaporated under vacuum to give the title compound (65 mg, quantitative yield) as a brown oil. [M+H] +m / z 428.3

[0240] Intermediate 21d

[0241] 2-[5-methyl-3-(1-nitro-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl)-2-sideoxy-1,2-dihydropyridin-1-yl]acetonitrile

[0242] Under a nitrogen atmosphere, a solution of 2.5 MnBuLi (0.34 mL, 0.86 mmol) in hexane was added to a solution of 5-methylpyrazolo[1,5-a]pyridine (104 mg, 0.79 mmol) at approximately -78 °C. The mixture was stirred for 30 min, followed by the addition of intermediate 7 (200 mg, 0.72 mmol) and stirring of the reaction mixture at -78 °C for 1 h. The mixture was quenched by adding a saturated aqueous solution of NH₄Cl and washed and extracted with EtOAc. The organic layer was dried over a hydrophobic funnel and evaporated under vacuum. The product was purified by column chromatography using a silica filter (cHex / EtOAc, 100:0 to 70:30) to give the title compound (231 mg, 0.56 mmol, 78% yield) as an orange oil. [M+H] +m / z 412.3

[0243] Intermediate 21e

[0244] [1-(difluoromethyl)-5-methyl-2-sideoxy-1,2-dihydropyridin-3-yl] acid

[0245] A mixture of KOAc (5.77 g, 58.82 mmol), [Pd(dppf)Cl₂] (1.2 g, 1.47 mmol), 3-bromo-1-(difluoromethyl)-5-methylpyridin-2-one (7.0 g, 29.41 mmol), and B₂Pin₂ (7.47 g, 29.41 mmol) in anhydrous CPME (100 mL) was degassed by three cycles of N₂-vacuum circulation. The mixture was then stirred at 90 °C for 16 hours. The reaction mixture was cooled and filtered through a diatomaceous earth mat. The solution was concentrated under vacuum and the product was purified by column chromatography using a C18 filter cartridge (H₂O + FA 0.1% / MeCN + FA 0.1%, 95:5 to 65:35) to give the title compound (3 g, 14.78 mmol, 50% yield) as a white solid. [M+H] +m / z 204.1

[0246] Intermediate 21f

[0247] [1-(difluoromethyl)-5-methyl-2-sideoxy-3-pyridyl] acid

[0248] Under a nitrogen atmosphere, toluene (2 mL) containing chlorinated bis(ethyl)rhodium dimer (7 mg, 0.02 mmol) and (racemic)-BINAP (23 mg, 0.04 mmol) was stirred at room temperature for 1 hour. A solution of intermediate 21e (109 mg, 0.54 mmol) and 1-fluoro-3-[4-[(E)-3-nitroallyloxy]cyclohexyl]benzene (50 mg, 0.18 mmol) in toluene (0.5 mL) was added, followed by the addition of a solution of 0.75 M potassium hydroxide in water (0.12 mL, 0.09 mmol). The reaction mixture was stirred at 100 °C for 1 hour. The mixture was filtered through a diatomaceous earth filter and washed with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, followed by vacuum evaporation. The product was purified by column chromatography using a silica filter cartridge (0-20% EtOAc / cHex) to give the title compound (20 mg, 0.05 mmol, 26% yield) as an orange oil. [M+H]+m / z 439.3

[0249] [3-(1-] [Amine] [-3-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [C] [-2-] [base] [)-1,5-] [Dimethyl] [-1,2-] [Dihydropyridine] [-2-] [ketone] [(] [Intermediate substance] [twenty two)] []

[0250] Starting with intermediate 21 (58 mg, 0.15 mmol), intermediate 22 was prepared following the procedure described for intermediate 9, yielding the title compound (39 mg, 0.11 mmol, 74% yield). [M+H]+m / z 355.2

[0251] [N-[2-(1,5-] [Dimethyl] [-2-] [Side group] [-1,2-] [Dihydropyridine] [-3-] [base] [)-3-{[(] [Shun] [)-4-] [Phenyloncyclohexyl] []] [Oxygen group] [}] [Propyl] []] [Methylsulfonylurea] [(5a)] []

[0252] Starting from intermediate 22 (39 mg, 0.11 mmol), the title compound (9 mg, 0.022 mmol, 19% yield) was prepared following the procedure described for Example 1.

[0253] [2] [‐] [(1] [-Methanesulfonamido-] [3] [‐] [{[(] [cis] [)] [‐] [4] [-Phenylcyclohexyl] []] [Oxy] [}] [Prop-] [2] [-yl] [)] [‐] [4,6] [-Dimethylpyridin-] [1] [-ium-] [1] [-olate] [(5j)]

[0254] To a mixture of Example 5i (15 mg, 0.04 mmol) in DCM (1 mL) was added 3-chlorobenzenecarboperoxoic acid (13.32 mg, 0.05 mmol) and the mixture was stirred at room temperature for 3 hours. Solid K2CO3 was added and the mixture was stirred at room temperature for 10 minutes. The mixture was diluted with DCM and washed with H2O. The organic layer was evaporated in vacuo and the product was purified by column chromatography using (0 - 5% methanol / DCM) to give the title compound as a white solid (8 mg, 0.02 mmol, 53% yield).

[0255] The following examples follow the procedure described for Example 5a using appropriate heterocyclic reagents. The starting materials are prepared as described in the Intermediates section (commercially available), or can be prepared using commercially available reagents via familiar reactions well known in this technique. Examples 5c and 5d follow the same three-step procedure described for Synthetic Example 5a, using F-phenylcyclohexanol instead of phenylcyclohexanol. Example 5e is prepared using intermediate 21c as the starting material, following the same procedure described for Synthetic Example 5a. Example 5g is prepared using intermediate 21d as the starting material, following the same procedure described for Synthetic Example 5a. Examples 5m-5w are prepared using the same three-step procedure described for Synthetic Example 5a, except for the first step, which follows the procedure used for intermediate 21a, reacting an appropriate nitroolefin derivative with an appropriate heterocyclic reagent. Example 5x-5ac was prepared following the same three-step procedure described for synthetic example 5a, except for the first step, which followed the procedure for intermediate 21f, reacting a suitable nitroolefin derivative with intermediate 21e. The F-analyte was prepared following the same procedure described for synthetic example 5a, using F-phenylcyclohexanol instead of phenylcyclohexanol. The sulfonamide analog was obtained by reacting an amine with a suitable sulfonyl chloride, following the procedure for synthetic example 5a. The mirror isomers were separated by lateral purification using Chiralpak columns (AD-H, IC, OJ-H) and dissolution with mixtures of n-hexane / EtOH, n-hexane / (EtOH + 0.1% iPrNH₂), and n-hexane / (EtOH / MeOH 1:1 + 0.1% iPrNH₂) at ratios between 35:65 and 70:30. During the anteroposterior separation using one of the conditions reported above, isomer 1 was designated as the first dissolution compound and isomer 2 as the second dissolution compound. The products are reported in the table below. [] Table 8. Characterization and EC50 data for hOX2 - Compounds 5a-5d: [Example] [structure] [name] [Observation Quality] [, 1 , ] [H NMR] [EC50 hOX2] [5a] N-[2-(1,5-dimethyl-2-sideoxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 433.3 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.32 - 7.28 (m, 2H), 7.24 (d, J = 2.5 Hz, 1H), 7.23 - 7.16 (m, 3H), 7.04 (dd, J = 2.3, 1.0 Hz, 1H), 5.60 (br t, J = 5.4 Hz, 1H), 3.78 - 3.69 (m, 2H), 3.66 (t, J = 2.7 Hz, 1H), 3.57 (td, J = 6.1, 4.8 Hz, 1H), 3.53 (s, 3H), 3.52 - 3.46 (m, 1H), 3.42 (s, 1H), 2.95 (s, 3H), 2.61 - 2.43 (m, 1H), 2.09 (d, J = 1.0 Hz, 3H), 2.07 - 1.99 (m, 2H), 1.79 - 1.69 (m, 2H), 1.68 - 1.61 (m, 2H), 1.59 - 1.49 (m, 2H). [C] [5b] N-[2-(4-methoxy-1-methyl-2-tekoxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 449.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.33 - 7.28 (m, 2H), 7.28 - 7.25 (m, 1H), 7.25 - 7.21 (m, 2H), 7.21 - 7.15 (m, 1H), 6.08 (d, J=7.6 Hz, 1H), 5.80 - 5.65 (m, 1H), 4.08 - 4.01 (m, 1H), 3.86 (s, 3H), 3.82 - 3.74 (m, 1H), 3.72 - 3.63 (m, 2H), 3.62 - 3.54 (m, 2H), 3.50 (s, 3H), 2.94 (s, 3H), 2.52 (tt, J=11.8, 3.4 Hz, 1H), 2.10 - 1.98 (m, 2H), 1.86 - 1.61 (m, 4H), 1.55 - 1.45 (m, 2H). [C] [5c] (R or S) N-[2-(1,5-dimethyl-2-sideoxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]methanesulfonamide-isomer 1 451.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.26 - 7.20 (m, 2H), 7.07 - 7.03 (m, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.91 - 6.82 (m, 2H), 5.57 (br t, J = 5.2 Hz, 1H), 3.78 - 3.70 (m, 2H), 3.65 (br s, 1H), 3.61 - 3.47 (m, 5H), 3.46 - 3.39 (m, 1H), 2.95 (s, 3H), 2.59 - 2.46 (m, 1H), 2.12 - 1.97 (m, 5H), 1.75 - 1.59 (m, 4H), 1.56 - 1.46 (m, 2H). [A] [5d] (S or R) N-[2-(1,5-dimethyl-2-sideoxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 451.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.26 - 7.18 (m, 2H), 7.08 - 7.02 (m, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.92 - 6.83 (m, 2H), 5.57 (br t, J = 5.3 Hz, 1H), 3.77 - 3.70 (m, 2H), 3.66 (br d, J = 2.6 Hz, 1H), 3.53 (s, 3H), 3.60 - 3.47 (m, 2H), 3.43 (q, J = 6.1 Hz, 1H), 2.95 (s, 3H), 2.59 - 2.47 (m, 1H), 2.09 (s, 3H), 2.04 (br d, J = 12.7 Hz, 2H), 1.77 - 1.59 (m, 4H), 1.59 - 1.47 (m, 2H). [B] [5e] N-{2-[1-(cyanomethyl)-5-methyl-2-oxy-1,2-dihydropyridin-3-yl]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl}methanesulfonamide 476.4 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.33 (d, J=2.4 Hz, 1 H), 7.26 - 7.20 (m, 1 H), 7.10 (d, J=1.1 Hz, 1 H), 6.98 (d, J=7.7 Hz, 1 H), 6.92- 6.80 (m, 2 H), 5.29 - 5.21 (m, 1 H), 4.96 - 4.66 (m, 2 H), 3.73 (d, J=5.9 Hz, 2 H), 3.69 - 3.63 (m, 1 H), 3.61 - 3.47 (m, 2 H), 3.47 - 3.37 (m, 1 H), 2.96 (s, 3 H), 2.60 - 2.47 (m, 1 H), 2.12 (d, J=0.9 Hz, 3 H), 2.09 - 1.96 (m, 2 H), 1.73 - 1.60 (m, 4 H), 1.60 - 1.39 (m, 2 H). [B] [5f] N-(3-{[(cis)-4-phenylcyclohexyl]oxy}-2-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}propyl)methanesulfonamide 447.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 8.84 (s, 1 H), 8.09 (d, J=6.8 Hz, 1 H), 7.30 (d, J=6.8 Hz, 1 H), 7.26 - 7.19 (m, 1 H), 6.95 (d, J=7.7 Hz, 1 H), 6.92 - 6.83 (m, 2 H), 6.79 (br d, J=10.7 Hz, 1 H), 5.49 - 5.31 (m, 1 H), 4.06 - 3.90 (m, 2 H), 3.88 - 3.80 (m, 3 H), 3.67 (br s, 1 H), 2.94 (s, 3 H), 2.58 - 2.41 (m, 1 H), 2.07 - 1.94 (m, 2 H), 1.66 - 1.40 (m, 6 H). [B] [5g] Dimethyl[(2-{5-methylpyrazolo[1,5-a]pyridin-7-yl}-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl)aminesulfonyl]amine 489.4 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.91 (d, J=2.2 Hz, 1 H), 7.30 - 7.26 (m, 1 H), 7.24 (d, J=6.4 Hz, 1 H), 6.96 (d, J=7.5 Hz, 1 H), 6.92 - 6.81 (m, 2 H), 6.64 (d, J=1.3 Hz, 1 H), 6.43 (d, J=2.2 Hz, 1 H), 5.36 (br t, J=5.7 Hz, 1 H), 4.15 (quin, J=5.9 Hz, 1 H), 4.02 - 3.90 (m, 2 H), 3.80 - 3.72 (m, 1 H), 3.71 - 3.61 (m, 2 H), 2.68 (s, 6 H), 2.51 (tt, J=10.1, 5.1 Hz, 1 H), 2.38 (s, 3 H), 2.08 - 1.96 (m, 2 H), 1.67 - 1.58 (m, 4 H), 1.56 - 1.45 (m, 2 H). [B] [5h] Dimethyl({[2-(1-methyl-1H-1,2,3-benzotriazol-4-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]aminesulfonyl})amine 490.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.52 - 7.47 (m, 1 H), 7.47 - 7.44 (m, 1 H), 7.33 (dd, J=6.6, 1.0 Hz, 1 H), 7.23 (td, J=7.9, 6.3 Hz, 1 H), 6.94 (d, J=7.7 Hz, 1 H), 6.87 (td, J=8.4, 1.9 Hz, 1 H), 6.77 (dt, J=10.4, 1.8 Hz, 1 H), 5.12 (br t, J=5.8 Hz, 1 H), 4.31 (s, 3 H), 4.09 - 4.02 (m, 1 H), 4.00 - 3.92 (m, 1 H), 3.94 - 3.89 (m, 1 H), 3.89 - 3.72 (m, 2 H), 3.67 (br s, 1 H), 2.76 (s, 6 H), 2.54 - 2.41 (m, 1 H), 2.07 - 1.97 (m, 2 H), 1.66 - 1.40 (m, 6H). [C] [5i] N-[2-(4,6-dimethylpyridin-2-yl)-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl]methanesulfonamide 417.3 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.32 - 7.28 (m, 2 H), 7.22 - 7.14 (m, 3 H), 6.90 (s, 1 H), 6.88 (s, 1 H), 6.09 (br dd, J=6.0, 4.9 Hz, 1 H), 3.79 - 3.73 (m, 1 H), 3.72 - 3.68 (m, 1 H), 3.68 - 3.61 (m, 2 H), 3.61 - 3.55 (m, 1 H), 3.26 (dq, J=7.9, 5.6 Hz, 1 H), 2.92 (s, 3 H), 2.54 - 2.48 (m, 1 H), 2.47 (s, 3 H), 2.30 (s, 3 H), 2.08 - 1.95 (m, 2 H), 1.80 - 1.43 (m, 6 H). [C] [5j] 2-(1-Methylsulfonamide-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl-2-yl)-4,6-dimethylpyridin-1-on-1-alkoxide 433.2 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.32 - 7.28 (m, 2 H), 7.23 (d, J=2.1 Hz, 1 H), 7.21 - 7.17 (m, 3 H), 7.05 (d, J=2.1 Hz, 1 H), 6.38 (br t, J=4.9 Hz, 1 H), 4.20 - 4.12 (m, 1 H), 3.83 (d, J=5.5 Hz, 2 H), 3.73 - 3.65 (m, 2 H), 3.62 - 3.54 (m, 1 H), 2.90 (s, 3 H), 2.52 (s, 3 H), 2.59 - 2.50 (m, 1 H), 2.32 (s, 3 H), 2.11 - 2.00 (m, 2 H), 1.80 - 1.63 (m, 4 H), 1.62 - 1.50 (m, 2 H). [A] [5k] (R or S) 2-[1-methanesulfonamide-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl-2-yl]-4,6-dimethylpyridine-1-onium-1-alkoxide-isomer 1 433.2 [M+H] + 1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 8.1, 7.0 Hz, 2H), 7.25 - 7.15 (m, 4H), 7.05 (s, 1H), 6.36 (d, J = 5.3 Hz, 1H), 4.21 - 4.10 (m, 1H), 3.84 (d, J = 5.4 Hz, 2H), 3.74 - 3.65 (m, 2H), 3.64 - 3.54 (m, 1H), 2.90 (s, 3H), 2.61 - 2.53 (m, 1H), 2.52 (s, 3H), 2.33 (s, 3H), 2.11 - 1.99 (m, 2H), 1.80 - 1.60 (m, 6H). [A] [5l] (S or R) 2-[1-methanesulfonamide-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl-2-yl]-4,6-dimethylpyridine-1-onium-1-alkoxide-isomer 2 433.2 [M+H] + 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 2H), 7.21 (t, J = 7.4 Hz, 4H), 7.05 (s, 1H), 6.36 (s, 1H), 4.21 - 4.12 (m, 1H), 3.84 (d, J = 5.4 Hz, 2H), 3.69 (q, J = 6.2 Hz, 2H), 3.58 (ddd, J = 12.7, 7.7, 5.7 Hz, 1H), 2.90 (s, 3H), 2.56 (d, J = 11.2 Hz, 1H), 2.52 (s, 3H), 2.33 (s, 3H), 2.04 (d, J = 8.9 Hz, 2H), 1.82 - 1.58 (m, 6H). [C] [5m] N-[2-(1,5-dimethyl-2-oxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]-1-fluoromethanesulfonamide 469.3 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 7.73 (br t, J=5.4 Hz, 1 H), 7.41 (d, J=1.1 Hz, 1 H), 7.30 (td, J=7.8, 6.4 Hz, 1 H), 7.23 (d, J=2.5 Hz, 1 H), 7.02 - 6.94 (m, 2 H), 6.90 (dt, J=10.6, 1.9 Hz, 1 H), 5.35 (dd, J=46.4, 10.1 Hz, 1 H), 5.31 (dd, J=46.2, 10.3 Hz, 1 H), 3.61 (dd, J=9.2, 5.8 Hz, 1 H), 3.54 (br s, 1 H), 3.52 (dd, J=9.3, 5.6 Hz, 1 H), 3.42 - 3.36 (m, 4 H), 3.30 - 3.26 (m, 1 H), 3.25 - 3.19 (m, 1 H), 2.57 - 2.51 (m, 1 H), 2.00 (s, 3 H), 1.95 - 1.82 (m, 2 H), 1.62 - 1.38 (m, 6 H). [A] [5n] (R or S) N-[2-(1,5-dimethyl-2-oxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]-1-fluoromethanesulfonamide-Isomer 1 469.3 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 7.73 (br t, J=5.4 Hz, 1 H), 7.41 (d, J=1.1 Hz, 1 H), 7.30 (td, J=7.8, 6.4 Hz, 1 H), 7.23 (d, J=2.5 Hz, 1 H), 7.02 - 6.94 (m, 2 H), 6.90 (dt, J=10.6, 1.9 Hz, 1 H), 5.35 (dd, J=46.4, 10.1 Hz, 1 H), 5.31 (dd, J=46.2, 10.3 Hz, 1 H), 3.61 (dd, J=9.2, 5.8 Hz, 1 H), 3.54 (br s, 1 H), 3.52 (dd, J=9.3, 5.6 Hz, 1 H), 3.42 - 3.36 (m, 4 H), 3.30 - 3.26 (m, 1 H), 3.25 - 3.19 (m, 1 H), 2.57 - 2.51 (m, 1 H), 2.00 (s, 3 H), 1.95 - 1.82 (m, 2 H), 1.62 - 1.38 (m, 6 H). [A] [5o] (S or R) N-[2-(1,5-dimethyl-2-oxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]-1-fluoromethanesulfonamide-isomeric 2 469.3 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 7.73 (br t, J=5.4 Hz, 1 H), 7.41 (d, J=1.1 Hz, 1 H), 7.30 (td, J=7.8, 6.4 Hz, 1 H), 7.23 (d, J=2.5 Hz, 1 H), 7.02 - 6.94 (m, 2 H), 6.90 (dt, J=10.6, 1.9 Hz, 1 H), 5.35 (dd, J=46.4, 10.1 Hz, 1 H), 5.31 (dd, J=46.2, 10.3 Hz, 1 H), 3.61 (dd, J=9.2, 5.8 Hz, 1 H), 3.54 (br s, 1 H), 3.52 (dd, J=9.3, 5.6 Hz, 1 H), 3.42 - 3.36 (m, 4 H), 3.30 - 3.26 (m, 1 H), 3.25 - 3.19 (m, 1 H), 2.57 - 2.51 (m, 1 H), 2.00 (s, 3 H), 1.95 - 1.82 (m, 2 H), 1.62 - 1.38 (m, 6 H). [B] [5p] N-[2-(1,5-dimethyl-2-oxy-1,2-dihydropyridin-3-yl)-3-{[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]oxy}propyl]methanesulfonamide 454.4 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 8.18 (s, 2 H), 7.17 (d, J=2.2 Hz, 1 H), 7.04 (s, 1 H), 5.42 (br t, J=5.4 Hz, 1 H), 4.28 - 4.08 (m, 2 H), 3.85 - 3.73 (m, 2 H), 3.53 (s, 3 H), 3.63 - 3.31 (m, 6 H), 2.93 (s, 3 H), 2.08 (s, 3 H), 1.97 - 1.85 (m, 2 H), 1.74 - 1.44 (m, 2 H). [D] [5q] 3-{1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl}-1,5-dimethyl-1,2-dihydropyridin-2-one 480.3 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 7.40 (d, J=1.1 Hz, 1 H), 7.34 - 7.27 (m, 1 H), 7.21 (d, J=2.3 Hz, 1 H), 7.11 (t, J=5.8 Hz, 1 H), 7.02 - 6.94 (m, 2 H), 6.93 - 6.87 (m, 1 H), 3.58 (dd, J=9.1, 5.4 Hz, 1 H), 3.54 (br s, 1 H), 3.48 (dd, J=9.1, 5.6 Hz, 1 H), 3.38 (s, 3 H), 3.31 - 3.28 (m, 1 H), 3.27 - 3.16 (m, 2 H), 2.62 (s, 6 H), 2.57 - 2.52 (m, 1 H), 2.00 (s, 3 H), 1.95 - 1.82 (m, 2 H), 1.62 - 1.37 (m, 6 H). [A] [5r] (R or S) 3-[1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl]-1,5-dimethyl-1,2-dihydropyridin-2-one-isomer 1 480.3 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 7.40 (d, J=1.1 Hz, 1 H), 7.35 - 7.27 (m, 1 H), 7.21 (d, J=2.3 Hz, 1 H), 7.11 (t, J=5.6 Hz, 1 H), 7.03 - 6.94 (m, 2 H), 6.94 - 6.85 (m, 1 H), 3.61 - 3.56 (m, 1 H), 3.54 (br s, 1 H), 3.48 (dd, J=9.1, 5.6 Hz, 1 H), 3.38 (s, 3 H), 3.35 - 3.29 (m, 1 H), 3.27 - 3.14 (m, 2H), 2.62 (s, 6 H), 2.57 - 2.51 (m, 1 H), 2.00 (s, 3 H), 1.95 - 1.81 (m, 2 H), 1.64 - 1.34 (m, 6 H). [A] [5s] (S or R) 3-[1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl]-1,5-dimethyl-1,2-dihydropyridine-2-one-isomer 2 480.3 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 7.40 (d, J=1.1 Hz, 1 H), 7.35 - 7.27 (m, 1 H), 7.21 (d, J=2.3 Hz, 1 H), 7.11 (t, J=5.6 Hz, 1 H), 7.03 - 6.94 (m, 2 H), 6.94 - 6.85 (m, 1 H), 3.61 - 3.56 (m, 1 H), 3.54 (br s, 1 H), 3.48 (dd, J=9.1, 5.6 Hz, 1 H), 3.38 (s, 3 H), 3.35 - 3.29 (m, 1 H), 3.27 - 3.14 (m, 2H), 2.62 (s, 6 H), 2.57 - 2.51 (m, 1 H), 2.00 (s, 3 H), 1.95 - 1.81 (m, 2 H), 1.64 - 1.34 (m, 6 H). [A] [5t] N-[2-(1,5-dimethyl-2-oxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-(3,5-difluorophenyl)cyclohexyl]oxy}propyl]-1-fluoromethanesulfonamide 487.3 [M+H] + 1H NMR (400 MHz, DMSO-d6 ) δ 7.72 (br t, J=5.6 Hz, 1 H), 7.39 (d, J=0.9 Hz, 1 H), 7.23 (d, J=2.2 Hz, 1 H), 7.00 (tt, J=9.4, 2.2 Hz, 1 H), 6.82 (dd, J=8.9, 1.9 Hz, 2 H), 5.44 - 5.18 (m, 2 H), 3.61 (dd, J=9.2, 5.7 Hz, 1 H), 3.57 - 3.48 (m, 2 H), 3.45 - 3.34 (m, 4 H), 3.30 - 3.16 (m, 2 H), 2.63 - 2.53 (m, 1 H), 2.00 (s, 3 H), 1.95 - 1.79 (m, 2 H), 1.63 - 1.31 (m, 6 H). [A] [5u] 3-{1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-(3,5-difluorophenyl)cyclohexyl]oxy}propyl-2-yl}-1,5-dimethyl-1,2-dihydropyridin-2-one 498.3 [M+H] + 1H NMR (400 MHz, DMSO-d6 ) δ 7.38 (d, J=1.1 Hz, 1 H), 7.21 (d, J=2.4 Hz, 1 H), 7.11 (br t, J=5.5 Hz, 1 H), 7.00 (tt, J=9.4, 2.2 Hz, 1 H), 6.82 (dd, J=9.0, 2.0 Hz, 2 H), 3.61 - 3.55 (m, 1 H), 3.53 (br s, 1 H), 3.48 (dd, J=9.0, 5.5 Hz, 1 H), 3.38 (s, 3 H), 3.31 - 3.12 (m, 3 H), 2.62 (s, 6 H), 2.59 - 2.52 (m, 1 H), 2.00 (s, 3 H), 1.95 - 1.78 (m, 2 H), 1.60 - 1.35 (m, 6 H). [A] [5v] N-[2-(1-cyclopropyl-5-methyl-2-oxy-1,2-dihydropyridin-3-yl)-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]methanesulfonamide 477.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.24 (br d, J=6.6 Hz, 1 H), 7.21 (d, J=1.8 Hz, 1 H), 7.05 (s, 1 H), 6.97 (d, J=7.7 Hz, 1 H), 6.93 - 6.80 (m, 2 H), 5.54 (br t, J=5.2 Hz, 1 H), 3.79 - 3.69 (m, 2 H), 3.65 (br s, 1 H), 3.61 - 3.46 (m, 2 H), 3.46 - 3.37 (m, 1 H), 3.34 - 3.23 (m, 1 H), 2.95 (s, 3 H), 2.59 - 2.47 (m, 1 H), 2.08 (s, 3 H), 2.03 (br d, J=12.7 Hz, 2 H), 1.74 - 1.45 (m, 6 H), 1.17 - 1.08 (m, 2 H), 0.89 - 0.80 (m, 2 H). [A] [5w] N-{2-[1-(2,2-difluoroethyl)-5-methyl-2-oxy-1,2-dihydropyridin-3-yl]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl}methanesulfonamide 501.3 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.31 (d, J=2.3 Hz, 1 H), 7.27 - 7.21 (m, 1 H), 7.06 - 6.94 (m, 2 H), 6.92 - 6.81 (m, 2 H), 6.11 (tt, J=56.1, 4.4 Hz, 1 H), 5.43 (br t, J=5.6 Hz, 1 H), 4.22 (tdd, J=13.4, 13.4, 4.4, 1.2 Hz, 2 H), 3.73 (d, J=5.8 Hz, 2 H), 3.68 - 3.63 (m, 1 H), 3.59 - 3.53 (m, 1 H), 3.53 - 3.46 (m, 1 H), 3.45 - 3.37 (m, 1 H), 2.95 (s, 3 H), 2.54 (tt, J=10.3, 5.2 Hz, 1 H), 2.10 (d, J=1.0 Hz, 3 H), 2.08 - 1.97 (m, 2 H), 1.84 - 1.45 (m, 6H). [A] [5x] N-{2-[1-(difluoromethyl)-5-methyl-2-oxy-1,2-dihydropyridin-3-yl]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl}methanesulfonamide 487.3 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 7.68 (t, J=60.4 Hz, 1 H), 7.32 (d, J=2.3 Hz, 1 H), 7.27 - 7.22 (m, 1 H), 7.20 (s, 1 H), 6.98 (d, J=7.7 Hz, 1 H), 6.93 - 6.79 (m, 2 H), 5.17 (br t, J=5.8 Hz, 1 H), 3.72 (d, J=5.8 Hz, 2 H), 3.69 - 3.63 (m, 1 H), 3.61 - 3.47 (m, 2 H), 3.40 (quin, J=6.0 Hz, 1 H), 2.95 (s, 3 H), 2.60 - 2.46 (m, 1 H), 2.12 (d, J=1.0 Hz, 3 H), 2.03 (ddt, J=14.1, 5.7, 2.6, 2.6 Hz, 2 H), 1.79 - 1.62 (m, 4 H), 1.61 - 1.46 (m, 2 H). [A] [5y] (R or S) N-[2-[1-(difluoromethyl)-5-methyl-2-oxy-1,2-dihydropyridin-3-yl]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]methanesulfonamide-Isomer 1 487.3 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 8.02 - 7.71 (m, 1 H), 7.49 (s, 1 H), 7.37 (d, J=2.3 Hz, 1 H), 7.30 (td, J=7.9, 6.4 Hz, 1 H), 7.05 - 6.93 (m, 3 H), 6.90 (dt, J=10.5, 2.1 Hz, 1 H), 3.63 - 3.57 (m, 1 H), 3.47 - 3.57 (m, 2 H), 3.36 - 3.30 (m, 1 H), 3.29 - 3.19 (m, 2 H), 2.87 (s, 3 H), 2.57 - 2.51 (m, 1 H), 2.05 (d, J=1.1 Hz, 3 H), 1.96 - 1.80 (m, 2 H), 1.60 - 1.38 (m, 6 H) [A] [5z] (S or R) N-[2-[1-(difluoromethyl)-5-methyl-2-oxy-1,2-dihydropyridin-3-yl]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl]methanesulfonamide-isomer 2 487.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.91 - 7.45 (m, 1 H), 7.32 (d, J=2.2 Hz, 1 H), 7.27 - 7.21 (m, 1 H), 7.20 (s, 1 H), 6.98 (d, J=7.7 Hz, 1 H), 6.91 - 6.83 (m, 2 H), 5.20 (br t, J=5.7 Hz, 1 H), 3.72 (d, J=5.5 Hz, 2 H), 3.68 - 3.62 (m, 1 H), 3.61 - 3.46 (m, 2 H), 3.45 - 3.36 (m, 1 H), 2.95 (s, 3 H), 2.63 - 2.44 (m, 1 H), 2.12 (s, 3 H), 2.03 (br dd, J=16.2, 2.6 Hz, 2 H), 1.78 - 1.43 (m, 6 H). [C] [5aa] 1-(difluoromethyl)-3-{1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl}-5-methyl-1,2-dihydropyridin-2-one 516.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.69 (t, J=60.5 Hz, 1 H), 7.33 (d, J=2.3 Hz, 1 H), 7.26 - 7.20 (m, 1 H), 7.19 (s, 1 H), 6.98 (d, J=7.8 Hz, 1 H), 6.93 - 6.83 (m, 2 H), 5.14 - 5.01 (m, 1 H), 3.79 - 3.61 (m, 3 H), 3.58 - 3.35 (m, 3 H), 2.78 (s, 6 H), 2.59 - 2.47 (m, 1 H), 2.12 (s, 3 H), 2.08 - 1.94 (m, 2 H), 1.80 - 1.46 (m, 6 H). [A] [5ab] (R or S) 1-(difluoromethyl)-3-[1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl]-5-methyl-1,2-dihydropyridin-2-one-isomer 1 516.3 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.68 (t, J=60.5 Hz, 1 H), 7.33 (d, J=2.2 Hz, 1 H), 7.26 - 7.21 (m, 1 H), 7.19 (s, 1 H), 6.98 (d, J=7.7 Hz, 1 H), 6.92 - 6.84 (m, 2 H), 5.07 (br t, J=5.3 Hz, 1 H), 3.75 - 3.62 (m, 3 H), 3.57 - 3.47 (m, 1 H), 3.46 - 3.37 (m, 2 H), 2.79 (s, 6 H), 2.59 - 2.48 (m, 1 H), 2.12 (s, 3 H), 2.08 - 1.96 (m, 2 H), 1.78 - 1.62 (m, 4 H), 1.57 - 1.46 (m, 2 H). [A] [5ac] (S or R) 1-(difluoromethyl)-3-[1-[(dimethylaminesulfonyl)amino]-3-{[(cis)-4-(3-fluorophenyl)cyclohexyl]oxy}propyl-2-yl]-5-methyl- 1,2-Dihydropyridine-2-one-isomer 2 516.3 [M+H] + 1H NMR (400 MHz, CDCl3) δ 7.68 (t, J = 60.5 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.97 (dt, J = 7.7, 1.4 Hz, 1H), 6.90 - 6.83 (m, 2H), 5.04 (d, J = 6.1 Hz, 1H), 3.74 - 3.67 (m, 2H), 3.66 - 3.61 (m, 1H), 3.55 - 3.46 (m, 1H), 3.45 - 3.36 (m, 2H), 2.78 (s, 6H), 2.53 (tt, J = 10.4, 5.5 Hz, 1H), 2.11 (d, J = 1.2 Hz, 3H), 2.08 - 1.96 (m, 2H), 1.66 (dddd, J = 11.1, 8.7, 6.6, 3.0 Hz, 4H), 1.56 (s, 2H). [B] Example 6a: N-(2-{5-methyl-6-sideoxy-1,6-dihydro-[3,3'-bipyridinyl]-1-yl}-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl)methanesulfonamide (6a)

[0256] DMF (2 mL) was added to a mixture of Example 2X (40 mg, 0.080 mmol), Cs₂CO₃ (105 mg, 0.32 mmol), Pd(PPh₃)₄ (28 mg, 0.020 mmol), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (66 mg, 0.32 mmol). The suspension was degassed by bubbling with N₂ for 10 minutes, followed by stirring at 120 °C for 16 hours. The mixture was diluted with EtOAc and washed with H₂O and brine. The organic layer was evaporated under vacuum. The product was purified by column chromatography using a C18 filter cartridge (H₂O + 0.1% formic acid / MeCN + 0.1% formic acid, 95:5 to 40:60), followed by preparative HPLC purification (MDAP Waters combined with mass spectrometry detection MS: ZQ2000, column: xBridge C18 (30×100 mm, 3 µm), conditions: [A2: 10 mM NH₄HCO₃ aqueous solution adjusted to pH 10 with NH₃]; [B2: MeCN], gradient: from 43.0% B₂ to 45.0% B₂ in 10 min, flow rate: 40.00 mL / min), yielding the title compound as a white solid (12 mg, 0.024 mmol, yield 30%). Table 9. Characterization and EC50 data for hOX2 - Compound 6a: [Example] [structure] [name] [Observation Quality] [, 1 , ] [H NMR] [EC50 hOX2] [6a] N-(2-{5-methyl-6-sideoxy-1,6-dihydro-[3,3'-bipyridinyl]-1-yl}-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl)methanesulfonamide 496.2 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 8.72 (dd, J = 2.3, 0.7 Hz, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.53 (dd, J = 2.5, 1.2 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.24 - 7.19 (m, 2H), 7.18 - 7.13 (m, 1H), 7.08 - 7.01 (m, 2H), 5.23 - 5.12 (m, 2H), 3.97 (dd, J = 10.4, 5.5 Hz, 1H), 3.90 - 3.79 (m, 2H), 3.72 (dt, J = 13.7, 5.5 Hz, 1H), 3.67 (br s, 1H), 2.93 (s, 3H), 2.55 - 2.45 (m, 1H), 2.24 (s, 3H), 2.08 - 1.94 (m, 2H), 1.69 - 1.50 (m, 6H). [C] Example 7a: N-{2-[3-methyl-2-sideoxy-5-(1H-pyrazol-1-yl)-1,2-dihydropyridin-1-yl]-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl}methanesulfonamide (7a)

[0257] DMSO (2 mL) was added to a mixture of Example 2X (40 mg, 0.080 mmol), pyrazole (22 mg, 0.32 mmol), Cu₂O (1 mg, 0.010 mmol), and Cs₂CO₃ (105 mg, 0.32 mmol). The suspension was degassed by bubbling with N₂ for 10 minutes, followed by stirring at 120 °C for 16 hours. The mixture was diluted with EtOAc and washed with H₂O and brine. The organic layer was evaporated under vacuum. The product was purified by column chromatography using a silica filter cartridge (cHex / EtOAc, 40:60 to 100:0), followed by preparative HPLC (MDAP Waters combined with mass spectrometry detection MS: ZQ2000, column: xBridge C18 (30×100 mm, 3 µm), conditions: [A2: 10 mM NH4HCO3 aqueous solution adjusted to pH 10 with NH3]; [B2: MeCN], gradient: from 45.0% B2 to 446.0% B2 in 10 min, flow rate: 40.00 mL / min), yielding the title compound as a white solid (12 mg, 0.024 mmol, yield 30%). Table 10. Characterization and EC50 data for hOX2 - Compound 7a [Example] [structure] [name] [Observation Quality] [, 1 , ] [H NMR] [EC50 hOX2] [7a] N-{2-[3-methyl-2-sideoxy-5-(1H-pyrazol-1-yl)-1,2-dihydropyridin-1-yl]-3-{[(cis)-4-phenylcyclohexyl]oxy}propyl}methanesulfonamide 485.2 [M+H] + 1H NMR (500 MHz, CDCl 3) δ 8.06 (d, J = 2.6 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.27 - 7.22 (m, 2H), 7.21 - 7.15 (m, 1H), 7.14 - 7.07 (m, 2H), 6.40 (t, J = 2.1 Hz, 1H), 5.25 - 5.19 (m, 1H), 5.16 (t, J = 6.2 Hz, 1H), 3.98 - 3.91 (m, 1H), 3.90 - 3.85 (m, 1H), 3.82 - 3.70 (m, 2H), 3.67 (t, J = 2.7 Hz, 1H), 2.93 (s, 3H), 2.56 - 2.47 (m, 1H), 2.24 (s, 3H), 2.08 - 1.97 (m, 2H), 1.72 - 1.50 (m, 6H). [B] Example 8a: N-(3-{[1,1'-biphenyl]-3-yl}-2-(2-sideoxy-1,2-dihydropyridin-1-yl)propyl)methanesulfonamide (8a)

[0258] [2-(2-)] [Side group] [-1,2-] [Dihydropyridine] [-1-] [base] [)] [Ethyl acetate] [(] [Intermediate substance] [twenty three)]

[0259] 2-Pyridone (3.42 g, 35.93 mmol) was added to a suspension of NaH (0.93 g, 38.92 mmol) in anhydrous DMF (40 mL). The mixture was stirred for 10 min, and then added to a solution of ethyl 2-bromoacetate (5.0 g, 29.94 mmol) in anhydrous DMF (35 mL). The reaction mixture was stirred at room temperature for 72 h, then diluted with DCM and washed with saturated aqueous solution of NaHCO3 and brine. The organic layer was dried using a phase separator and evaporated under vacuum. The product was purified by column chromatography using a silica filter cartridge (0-100% EtOAc / cHex) to give the title compound (5.56 g, quantitative yield) as a pale yellow oil. [M+H] +m / z 182.0

[0260] [3-{[1,1'-] [Biphenyl] []-3-] [base] [}-2-(2-] [Side group] [-1,2-] [Dihydropyridine] [-1-] [base] [)] [Propionic acid] [Ethyl acetate] [(] [Intermediate substance] [twenty four)]

[0261] At -78°C, a solution of 1 M LiHMDS in hexane (24.84 mL, 24.84 mmol) was added to a solution of intermediate 23 (3.0 g, 16.56 mmol) in THF (83 mL). After 15 minutes, 3-(bromomethyl)-1,1'-biphenyl (5.32 g, 21.52 mmol) was added and the mixture was stirred at -78°C for 90 minutes. A saturated solution of NH4Cl (30 mL) was added and the reaction mixture was heated to room temperature. The mixture was acidified with 1 M HCl and extracted with EtOAc (3 × 250 mL). The organic layer was dried using a phase separator and evaporated under vacuum. The product was purified by column chromatography using a silica filter (0-50% EtOAc / cHex) to give the title compound (5.2 g, 14.97 mmol, 90% yield) as a pale yellow oil. [M+H] +m / z 348.2 []

[0262] [1-(1-{[1,1'-] [Biphenyl] []-3-] [base] [}-3-] [Hydroxypropyl] [-2-] [base] [)-1,2-] [Dihydropyridine] [-2-] [ketone] [(] [Intermediate substance] [25)]

[0263] At -40°C, a solution of intermediate 24 (2.0 g, 5.76 mmol) in THF (41 mL) was added to a solution of intermediate 24 in THF (4.32 mL, 8.64 mmol). The mixture was stirred at -40°C for 1 h and then at room temperature for 24 h. The reaction mixture was quenched with water (50 mL) and 1 M NaOH aqueous solution (25 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were then dried (Na₂SO₄) and evaporated under vacuum to give the title product (2 g, quantitative yield) as a pale yellow oil. [M+H] +m / z 306.2

[0264] [1-(1-] [azido group] [-3-{[1,1'-] [Biphenyl] []-3-] [base] [}] [C] [-2-] [base] [)-1,2-] [Dihydropyridine] [-2-] [ketone] [(] [Intermediate substance] [26)]

[0265] At 0 °C, TEA (68 μL, 0.49 mmol) and MsCl (27 μL, 0.34 mmol) were added to a solution of intermediate 25 (100 mg, 0.33 mmol) in THF (3 mL). After 30 minutes, NaN3 (64 mg, 0.98 mmol) and DMF (0.1 mL) were added at 0 °C. The mixture was stirred at 60 °C for 1 hour. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were evaporated under vacuum and the product was purified by column chromatography using a silica filter (0-30% EtOAc / cHex) to give the title compound (46 mg, 0.14 mmol, 42% yield) as a colorless oil. [M+H] +m / z 331.2

[0266] [1-(1-] [Amine] [-3-{[1,1'-] [Biphenyl] []-3-] [base] [}] [C] [-2-] [base] [)-1,2-] [Dihydropyridine] [-2-] [ketone] [(] [Intermediate substance] [27)]

[0267] Intermediate 27 (46 mg, 0.14 mmol) was added to a solution of PPh 3 (73 mg, 0.28 mmol) in THF (0.5 mL) and H₂O (0.25 mL). The mixture was stirred at room temperature for 16 hours. H₂O (10 mL) was added and the product was extracted with Et₂O (3 × 50 mL). The organic layer was dried (Na₂SO₄) and evaporated under vacuum. The product was loaded into an SCX filter cartridge as a MeOH solution, washed with MeOH, and dissociated with MeOH containing NH₃ solution to give the title compound (18 mg, 0.059 mmol, 42% yield) as a colorless oil. [M+H]⁺m / z 305.3

[0268] [N-(3-{[1,1'-] [Biphenyl] []-3-] [base] [}-2-(2-] [Side group] [-1,2-] [Dihydropyridine] [-1-] [base] [)] [Propyl] [)] [Methylsulfonylurea] [(8a)]

[0269] Starting with intermediate 27 (18 mg, 0.059 mmol), Example 8a was prepared following the procedure described for Example 1 to obtain the title compound (5 mg, 0.013 mmol, 22% yield) in a colorless oil. [] Table 11. Characterization and EC50 data for hOX2 - Compound 8a: [Example] [structure] [name] [Observation Quality] [, 1 , ] [H NMR] [EC50 hOX2] [8a] N-(3-{[1,1'-biphenyl]-3-yl}-2-(2-sidekto-1,2-dihydropyridin-1-yl)propyl)methanesulfonamide 383.2 [M+H] + 1H NMR (400 MHz, CDCl 3) δ 7.56 - 7.49 (m, 2H), 7.48 - 7.29 (m, 7H), 7.13 (d, J = 7.5 Hz, 1H), 7.06 (br d, J = 6.6 Hz, 1H), 6.57 (d, J = 8.3 Hz, 1H), 6.12 (td, J = 6.7, 1.1 Hz, 1H), 5.01 - 4.82 (m, 2H), 3.91 - 3.79 (m, 1H), 3.65 - 3.55 (m, 1H), 3.36 (dd, J = 14.0, 8.8 Hz, 1H), 3.17 (dd, J = 13.9, 6.5 Hz (1H), 2.89 (s, 3H). [D] Example 1. A compound of formula (I): Or a medically acceptable salt, in A is a heteroaryl group; L1 can be -O-, -CR 5R 6-, or a single key; L2 is -CR 5R 6; R1 is an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or -NR7R8, or R1 and R2 together with the atoms they are attached to form a heterocycle; R2, R3, and R4 are independently hydrogen, alkyl, cycloalkyl, heterocyclic, or halogen, or R2 and R3 together with the atoms they are attached to form a carbocyclic or heterocyclic ring, or R2 and R4 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclic, alkoxy, -O-cycloalkyl, -O-heterocyclic, or halogen, or R5 and R6 together with the atoms they are attached to form a carbocyclic or heterocyclic ring; R7 and R8 are independently hydrogen, alkyl, cycloalkyl, or heterocyclic groups, or R7 and R8 together with the atoms they are attached to form a heterocycle; Y is a cycloalkyl, heterocyclic, heteroaryl, or aryl group; and Z is either nonexistent or is a heteroaryl or aryl group, wherein if L1 is a single bond or CR5R6, then Z is a heteroaryl or aryl group; and the limiting condition is that the compound is not: . 2. The compound of Example 1, wherein L1 is -O-. 3. The compound of Example 1, wherein L1 is a single bond. 4. The compound of any of Examples 1 to 3, wherein R1 is an alkyl group. 5. The compound of Example 4, wherein R1 is methyl. 6. The compound of any of Examples 1 to 3, wherein R1 is -NR 7R 8. 7. The compound of Example 6, wherein R7 and R8 are alkyl groups. 8. The compound of any of Examples 1 to 7, wherein R2, R3, and R4 are hydrogen. 9. In any of the compounds in Examples 1 to 8, Y is a 3-7 member monocyclic cycloalkyl group, a 5-8 member bicyclic cycloalkyl group, a 4-7 member saturated heterocyclic group, a 5-8 member bicyclic heterocyclic group, a 5-6 member heteroaryl group, or a phenyl group. 10. In any of the compounds in Examples 1 to 9, Z is 5-10 heteroaryl or phenyl. 11. The compound of any of Examples 1 to 8, wherein Y and Z are phenyl. 12. The compound of any of Examples 1 to 8, wherein Y is cyclohexyl and Z is phenyl. 13. The compound of Example 11, wherein Y and Z together are: . 14. The compound of any of Examples 1 to 13, wherein A is a substituted or unsubstituted monocyclic or bicyclic nitrogen-containing heteroaryl group. 15. The compound of Example 14, wherein A is selected from the group consisting of: Where n is an integer between 0 and 6; R 9 is hydrogen, alkyl, halogen, cyano, alkoxy, cycloalkyl, heterocyclic, or heteroaryl; and R 11 is an alkyl, cycloalkyl, or heterocyclic group. 16. The compounds of Example 1, wherein the compounds of formula (I) are selected from the group of compounds in Table 1. 17. A pharmaceutical composition comprising a compound as described in any one of Examples 1 to 16 and a pharmaceutically acceptable excipient. 18. A method for treating a disease or condition that can be treated by administering an orexin agonist, the method comprising administering a therapeutically effective amount of a compound as in any of Examples 1 to 16 or a composition as in Example 17. 19. A method for treating sleep disorders in an individual in need, comprising administering to the individual a therapeutically effective amount of a compound as in any one of Examples 1 to 16 or a composition as in Example 17. 20. A method of treating narcolepsy in an individual in need, comprising administering to the individual an effective amount of a compound as described in any one of Examples 1 to 16 or a composition as described in Example 17. 21. A method for treating drowsiness in an individual in need, comprising administering to the individual an effective amount of a compound as in any one of Examples 1 to 16 or a composition as in Example 17. 22. A method for reducing or treating excessive sleepiness in an individual in need, comprising administering to the individual an effective amount of a compound as in any of Examples 1 to 16 or a composition as in Example 17.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is a monocyclic or bicyclic nitrogen-containing heteroaryl group, which, as appropriate, is substituted with a sero-oxygen group, an alkyl group, a haloalkyl group, an alkoxy group, a cycloalkyl group, a CN group, a halogen group, a haloalkoxy group, a cyanomethyl group, or a nitrogen-containing heteroaryl group; L1 is -O-; L2 is -CR5R6; R1 is an alkyl group, a haloalkyl group, a cycloalkyl group, an alkyl-alkoxy group, or -NR7R8; R2, R3, and R4 are independently hydrogen, an alkyl group, or a halogen group; R5 and R6 are each independently hydrogen, an alkyl group, or a halogen group; R7 and R8 are independently hydrogen, an alkyl group, or a cycloalkyl group, or R7 and R8 together with the atoms to which they are attached form a heterocycle; Y is a cycloalkyl, heterocyclic, heteroaryl, or phenyl compound, each of which may be substituted with an alkyl or cycloalkyl group as appropriate; and Z is absent or is a nitrogen-containing heteroaryl or aryl group, wherein each of the nitrogen-containing heteroaryl and aryl groups may be substituted with a halogen as appropriate, and wherein if L1 is a single bond, then Z is a nitrogen-containing heteroaryl or aryl group; the limiting condition is that the compound is not: .

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is an alkyl, haloalkyl, cycloalkyl, or -NR7R8.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R1 is an alkyl, haloalkyl or -NR7R8.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are alkyl groups.

5. The compound of claim 1 or its pharmaceutically acceptable salt, wherein R2, R3 and R4 are hydrogen.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is a 3- to 7-membered monocyclic cycloalkyl, a 5- to 8-membered bicyclic cycloalkyl, a 4- to 7-membered saturated heterocyclic group, a 5- to 8-membered bicyclic heterocyclic group, a 5- to 6-membered heteroaryl or phenyl group.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is 5 to 10 nitrogen-containing heteroaryl or phenyl.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein Z is a phenyl group substituted with one or two halogens.

9. A compound or a pharmaceutically acceptable salt thereof, as specified in any of claims 1 to 8, wherein: (i) Y and Z are phenyl; or (ii) Y is cyclohexyl and Z is phenyl.

10. A compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein A is a monocyclic nitrogen-containing heteroaryl group.

11. A compound or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 8, wherein A is selected from the group consisting of: , , or where n is an integer from 0 to 6; R9 is hydrogen, alkyl, haloalkyl, haloalkoxy, halogen, cyano, alkoxy, cycloalkyl, heterocyclic or heteroaryl; and R11 is an alkyl group substituted with cyano, haloalkyl, cycloalkyl or heterocyclic as appropriate.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein n is 1.

13. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein n is 2.

14. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein A is...

15. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein A is...

16. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R9 is an alkyl or halogen.

17. A compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R11 is an alkyl or haloalkyl group.

18. The compound of claim 1, wherein the compound of formula (I) is selected from the group consisting of: and its pharmaceutically acceptable salts.

19. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , and a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

21. Use of a compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof or a composition of claim 20 in the preparation of a medicament for use in activating or stimulating orexin receptors.

22. Use of a compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof or a composition of claim 20 in the preparation of a medicament for the treatment of sleep disorders in an individual in need.

23. Use of any compound of claims 1 to 19 or a pharmaceutically acceptable salt thereof or a composition of claim 20 in the preparation of a medicament for the treatment of: (i) narcolepsy; or (ii) somnolence; or (iii) excessive somnolence.

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