Substituted piperidines and related methods of treatment

Abstract

The present invention provides compounds useful for treating narcolepsy and cataplexy in a subject in need thereof. Related pharmaceutical compositions and methods are also provided herein.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 128,511, filed December 21, 2020. The entire contents of the above application are incorporated herein by reference. Technical Field

[0003] This invention relates to substituted piperidine compounds, and more particularly to substituted piperidine compounds having agonist activity. Background Technology

[0004] Orexin is a neuropeptide synthesized and released by a subset of neurons in the lateral hypothalamus and surrounding regions. It consists of two isoforms: orexin A and orexin B. Both orexin A and orexin B bind to orexin receptors. Orexin receptors are G protein-coupled receptors preferentially expressed in the brain. There are two isoforms of orexin receptors (type 1 and type 2) (Cell, Vol. 92, 573-585, 1998). Activation of orexin receptors is well known to be crucial for various functions of the central nervous system, such as maintaining wakefulness, energy balance, reward processing, and motivation (Saper et al., TRENDS in Neuroscience 2001; Yamanaka et al., Neuron 2003; Sakurai, Nature Reviews Neuroscience 2014).

[0005] Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, sudden onset of muscle paralysis (cataplexy), and disrupted sleep patterns (Mahoney et al., Nature Reviews Neuroscience, 2019). It is well-known that narcolepsy is caused by the degeneration of orexin neurons. Symptoms of narcolepsy can be modeled in transgenic mice modified to have degenerated orexin neurons, and these symptoms can be reversed by intraventricular administration of orexin peptides (Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004). Studies in orexin-2 receptor knockout mice have shown that the orexin-2 receptor plays a preferential role in maintaining wakefulness (Cell, Vol. 98, 437-451, 1999; Neuron, Vol. 38, 715-730, 2003). Therefore, orexin-2 receptor agonists could be used to treat narcolepsy or other diseases characterized by excessive daytime sleepiness, such as Parkinson's disease (CNS Drugs, Vol. 27, 83-90, 2013; Brain, Vol. 130, 2007, 1586-1595).

[0006] Compounds with agonist activity on the orexin-2 receptor are considered potential new therapeutic agents for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbances of consciousness such as coma, narcolepsy syndrome, hypersomnia syndrome characterized by excessive sleep (such as Parkinson's disease, Guillain-Barré syndrome, or Klein-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, or sepsis. (Cell Metabolism, Vol. 9, 64-76, 2009; Neuroscience, Vol. 121, 855-863, 2003; Respiration, Vol. 71, 575-579, 2004; Peptides, Vol. 23, 1683-1688, 2002; WO 2015 / 073707; Journal of the American College of Cardiology, Vol. 66, 2015, 2522-2533; WO 2015 / 048091; WO 2015 / 147240).

[0007] Several compounds with orexin-2 receptor agonist activity have been reported (US Pat. No. 8, 258, 163; WO 2015 / 088000; WO 2014 / 198880; Journal of Medicinal Chemistry, Vol. 58, pages 7931-7937; US 20190040010; US 20190031611; US ​​20170226137). However, these compounds are considered unsatisfactory, for example, in terms of activity, pharmacokinetics, penetration into the brain / central nervous system, or safety. There is a need to develop modified compounds with orexin-2 receptor agonist activity. Summary of the Invention

[0008] The object of this invention is to provide substituted piperidine compounds having orexin-2 receptor agonist activity.

[0009] Therefore, in its initial aspect, the present invention provides compounds represented by formula IA or pharmaceutically acceptable salts thereof:

[0010]

[0011] Or its pharmaceutically acceptable salt;

[0012] in:

[0013] T is either CR6 or N;

[0014] U is either CR5 or N;

[0015] V is either CR4 or N;

[0016] W is either CR3 or N;

[0017] X is either CR2 or N;

[0018] The condition is The ring contains no more than 3 nitrogen atoms;

[0019] E is selected from NR a R b C1-C3 alkylene-NR a R b C1-C3 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic groups and C1-C3 alkylene-(4- to 10-membered heterocyclic groups), wherein C1-C3 alkylene-NR a R b The C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene (C3-C8 cycloalkyl), 4- to 10-membered heterocyclic or C1-C3 alkylene (4- to 10-membered heterocyclic) are not substituted or are substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0020] R a and R b Each is independently H or an unsubstituted C1-C3 alkyl group;

[0021] R1 is (CR) c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is unsubstituted or substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted by one or more halogens or deuterium.

[0022] R c and R dEach is independently H, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium;

[0023] n is 0 or 1;

[0024] Each of R2, R3, R4, R5 and R6, when present, is independently selected from H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0025] R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is independently H, a halogen, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium;

[0026] Or, R8 and R 11 Together they form unsubstituted C1-C3 alkylene groups or C1-C3 alkylene groups substituted with one or more halogens;

[0027] Or, R9 and R 10 Together they form unsubstituted C1-C3 alkylene groups or C1-C3 alkylene groups substituted with one or more halogens;

[0028] p is 0, 1, 2, 3 or 4;

[0029] Each R 14 It is independently selected from deuterium, halogen, hydroxyl and cyano groups.

[0030] In one embodiment, this document provides a compound of formula IA having the structure of formula I or a pharmaceutically acceptable salt thereof:

[0031]

[0032] Or its pharmaceutically acceptable salt;

[0033] in:

[0034] T is either CR6 or N;

[0035] U is either CR5 or N;

[0036] V is either CR4 or N;

[0037] W is either CR3 or N;

[0038] X is either CR2 or N;

[0039] The condition is The ring contains no more than 3 nitrogen atoms;

[0040] E is selected from NR a R b C1-C3 alkylene-NR a R b C1-C3 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic groups and C1-C3 alkylene-(4- to 10-membered heterocyclic groups), wherein C1-C3 alkylene-NR a R b The C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene (C3-C8 cycloalkyl), 4- to 10-membered heterocyclic or C1-C3 alkylene (4- to 10-membered heterocyclic) are not substituted or are substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0041] R a and R b Each is independently H or an unsubstituted C1-C3 alkyl group;

[0042] R1 is (CR) c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is unsubstituted or substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted by one or more halogens or deuterium.

[0043] R c and R d Each is independently H, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium;

[0044] n is 0 or 1;

[0045] Each of R2, R3, R4, R5 and R6, when present, is independently selected from H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0046] R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is independently H, a halogen, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium;

[0047] Or, R8 and R 11 Together they form unsubstituted C1-C3 alkylene groups or C1-C3 alkylene groups substituted with one or more halogens;

[0048] Or, R9 and R 10 Together they form unsubstituted C1-C3 alkylene groups or C1-C3 alkylene groups substituted with one or more halogens;

[0049] p is 0, 1, 2, 3 or 4;

[0050] Each R 14 It is independently selected from deuterium, halogen, hydroxyl and cyano groups.

[0051] This article also provides pharmaceutical compositions comprising compounds of formula IA or I or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.

[0052] On the other hand, this article provides methods for treating narcolepsy in subjects in need, including administering the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0053] On the other hand, this article provides methods for treating sudden collapse in subjects in need, including administering the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof. Detailed Implementation

[0054] The compounds described herein, such as compounds of formula IA or I, or pharmaceutically acceptable salts thereof, are useful for treating subjects with narcolepsy or cataplexy.

[0055] In a non-limiting aspect, these compounds can modulate orexin-2 receptors. In a particular embodiment, the compounds provided herein are considered orexin-2 agonists. Thus, in one aspect, the compounds provided herein, by acting as orexin-2 receptor agonists, contribute to the treatment of narcolepsy in subjects.

[0056] definition

[0057] The following lists the definitions of various terms used to describe the invention. These definitions apply to the terminology used in this specification and claims, unless otherwise limited individually or as part of a larger group in a particular case.

[0058] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In general, the terminology and laboratory procedures of cell culture, molecular genetics, organic chemistry, and peptide chemistry used herein are well-known and commonly used in the art.

[0059] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) grammatical objects of the article. For example, “element” refers to one or more elements. Furthermore, the use of the term “including” and other forms such as “include,” “contains,” and “included” is not restrictive.

[0060] As used herein, the term “about” will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. As referred to herein as a measurable value, such as quantity, duration of time, etc., the term “about” means a variation of ±20% or ±10%, including ±5%, ±1%, and ±0.1%, compared to a specified value, because such variation is appropriate for performing the disclosed method.

[0061] As used in this article, the term "EC" 50 "This refers to the concentration of the compound required to achieve 50% of its maximum observed effect."

[0062] As used in this article, the term "agonist" refers to a compound that, when contacted with a target of interest (e.g., orexin-2 receptor), results in an increase in the activity or function of the target compared to the magnitude of activity or function observed without the agonist.

[0063] The term "treatment" includes reducing or alleviating at least one symptom associated with or caused by the treated state, disorder, or disease. In some embodiments, treatment includes contacting an effective amount of the compound of the invention with an orexin-2 receptor to treat a condition associated with narcolepsy or cataplexy.

[0064] As used in this article, the terms “prevention” or “avoidance” mean that if a disorder or disease does not occur, it will not occur; and if a disorder or disease has already occurred, it will not develop further. Furthermore, the ability of an individual to prevent some or all of the symptoms associated with a disorder or disease is also considered.

[0065] As used herein, the terms "patient," "individual," or "subject" refer to human or non-human mammals. Non-human mammals include, for example, livestock and pets such as sheep, cattle, pigs, dogs, cats, and rodents. Preferably, the patient, individual, or subject is a human.

[0066] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” and “therapeutic effective dose” refer to a dose of medicine that is non-toxic but sufficient to provide the desired biological outcome. This outcome may be a reduction or alleviation of signs, symptoms, or causes of disease, or any other anticipated alteration of a biological system. In any individual case, the appropriate therapeutic dose can be determined by a person skilled in the art through routine laboratory testing.

[0067] As used herein, the term “pharmaceutically acceptable” means a substance, such as a carrier or diluent, that does not impair the biological activity or properties of a compound and is relatively non-toxic, i.e., can be administered to an individual without causing adverse biological effects or interacting in a harmful manner with any component of the composition containing it.

[0068] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base molecule into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; basic or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention comprise conventional, non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic molecules using conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or basic form of these compounds with the corresponding base or acid in water or an organic solvent, or a mixture of both; generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "pharmaceutically acceptable salt" also includes disalts, such as dihydrochlorides. A suitable list of salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference.

[0069] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful in the present invention with a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of the compound to a patient or subject. Various techniques for administering compounds exist in the art, including but not limited to intravenous injection, oral administration, aerosol, parenteral administration, ophthalmic administration, pulmonary administration, and topical administration.

[0070] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that participates in or delivers compounds useful in this invention to a patient so that it can perform its intended function. Typically, such a structure is carried or transported from one organ or part of the body to another. Each carrier must be "acceptable," meaning compatible with other components of the formulation, including compounds useful in this invention, and harmless to the patient. Examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; tragacanth gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations.

[0071] As used herein, "pharmaceuticalally acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delay agents that are physiologically acceptable to patients and adapted to the activity of the compounds useful in this invention. Supplemental active compounds may also be incorporated into the composition. "Pharmaceuticalally acceptable carrier" may also include pharmaceutically acceptable salts of the compounds useful in this invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of this invention are known in the art, for example, as described in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa), which is incorporated herein by reference.

[0072] As used herein, unless otherwise stated, the term "alkyl" on its own or as part of another substituent refers to a straight-chain or branched hydrocarbon having a specified number of carbon atoms (i.e., C64-C ... 1-6 Alkyl groups (meaning alkyl groups having 1 to 6 carbon atoms) include straight-chain and branched groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C1-C6 alkyl groups include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0073] As used herein, unless otherwise stated, the terms "halogen" or "halogenated" alone or as part of another substituent indicate a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine.

[0074] As used herein, the term "alkylene" refers to a straight-chain or branched divalent aliphatic hydrocarbon group, for example having 1 to 4 carbon atoms. This term includes, for example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), etc.

[0075] As used herein, the term "alkenyl" refers to a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon double bond. The double bond may or may not be a junction with another group. Alkenyl groups (e.g., C2-C8 alkenyl groups) include, but are not limited to, vinyl, propenyl, prop-2-enyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0076] As used herein, the term "alkynyl" refers to a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon triple bond. The triple bond may or may not be a connection point to another group. Alynyl groups (e.g., C2-C8 alkynyl groups) include, but are not limited to, ethynyl, propynyl, prop-2-alkynyl, butynyl, 1-methyl-2-butyn-1-yl, heptyynyl, octyynyl, etc.

[0077] As used herein, the term "alkoxy" refers to the -O-alkyl group, wherein the alkyl group is as defined herein. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, etc.

[0078] As used herein, the term "cycloalkyl" refers to a partially or fully saturated non-aromatic carbocyclic system having one, two, or three rings, wherein these rings may be fused. The term "fused" means that a second ring exists (i.e., is connected or formed) by sharing (i.e., having) two adjacent atoms with the first ring. Cycloalkyl also includes cyclic structures, which may be bridged or spirocyclic, with each individual ring in the cyclic structure having 3 to 8 atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, and bicyclo[1.1.1]pentyl.

[0079] As used herein, the term "heterocyclic group" refers to a non-aromatic carbocyclic system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having 1, 2, or 3 rings, wherein these rings may be fused, where fusion is defined as above. Heterocyclic groups also include bicyclic structures, which may be bridged or spirocyclic, with each individual ring containing 3 to 8 atoms and 0, 1, or 2 N, O, or S atoms. The term "heterocyclic group" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and particularly includes, but is not limited to, epoxy groups, oxocyclic groups, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxalyl), pyranyl, dioxalyl, aziridinyl, aziridineyl, pyrrolylyl, 2,5-dihydro-1H-pyrrolyl, oxazolyl, thiazolyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, 1,3-oxazolyl, 1,3-thiazolyl, etc.

[0080] As used herein, the term “bridged bicyclic heterocyclic group” refers to a non-aromatic heterocyclic system in which two rings share two or more atoms. For example, a bridged bicyclic system can be a [3.2.1] bicyclic system such as azirbicyclic [3.2.1]octane, or a [3.1.1] bicyclic system such as azirbicyclic [3.1.1]heptane.

[0081] It should be understood that if an aryl, heteroaryl, cycloalkyl, or heterocyclic molecule can be bonded to a specified molecule by different cyclic atoms or otherwise connected (i.e., shown or described without indicating a specific connection point), then all possible points are expected, whether by a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" refers to 2-, 3-, or 4-pyridinyl, and the term "thiophene" refers to 2- or 3-thiophene, etc.

[0082] As used herein, the term "substituted" refers to an atom or group of atoms replacing hydrogen as a substituent attached to another group.

[0083] The compounds of the present invention

[0084] Therefore, in its initial aspect, the present invention provides compounds represented by formula IA or pharmaceutically acceptable salts thereof:

[0085]

[0086] Or its pharmaceutically acceptable salt;

[0087] in:

[0088] T is either CR6 or N;

[0089] U is either CR5 or N;

[0090] V is either CR4 or N;

[0091] W is either CR3 or N;

[0092] X is either CR2 or N;

[0093] The condition is The ring contains no more than 3 nitrogen atoms;

[0094] E is selected from NR a R b C1-C3 alkylene-NR a R b C1-C3 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic groups and C1-C3 alkylene-(4- to 10-membered heterocyclic groups), wherein C1-C3 alkylene-NR a R b The C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene (C3-C8 cycloalkyl), 4- to 10-membered heterocyclic or C1-C3 alkylene (4- to 10-membered heterocyclic) are not substituted or are substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0095] R a and R b Each is independently H or an unsubstituted C1-C3 alkyl group;

[0096] R1 is (CR) c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is unsubstituted or substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted by one or more halogens or deuterium.

[0097] R c and R d Each is independently H, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium;

[0098] n is 0 or 1;

[0099] Each of R2, R3, R4, R5 and R6, when present, is independently selected from H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0100] R7, R8, R9, R10 R 11 R 12 and R 13 Each of them is independently H, a halogen, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium;

[0101] Or, R8 and R 11 Together they form unsubstituted C1-C3 alkylene groups or C1-C3 alkylene groups substituted with one or more halogens;

[0102] Or, R9 and R 10 Together they form unsubstituted C1-C3 alkylene groups or C1-C3 alkylene groups substituted with one or more halogens;

[0103] p is 0, 1, 2, 3 or 4;

[0104] Each R 14 It is independently selected from deuterium, halogen, hydroxyl and cyano groups.

[0105] In one embodiment, this document provides a compound of formula IA having the structure of formula I or a pharmaceutically acceptable salt thereof:

[0106]

[0107] Or its pharmaceutically acceptable salt;

[0108] in:

[0109] T is either CR6 or N;

[0110] U is either CR5 or N;

[0111] V is either CR4 or N;

[0112] W is either CR3 or N;

[0113] X is either CR2 or N;

[0114] The condition is The ring contains no more than 3 nitrogen atoms;

[0115] E is selected from NR a R b C1-C3 alkylene-NR a R b C1-C3 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic groups and C1-C3 alkylene-(4- to 10-membered heterocyclic groups), wherein C1-C3 alkylene-NR a R bThe C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene (C3-C8 cycloalkyl), 4- to 10-membered heterocyclic or C1-C3 alkylene (4- to 10-membered heterocyclic) are not substituted or are substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl or C1-C3 alkoxy groups;

[0116] R a and R b Each is independently H or an unsubstituted C1-C3 alkyl group;

[0117] R1 is (CR) c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is unsubstituted or substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted by one or more halogens or deuterium.

[0118] R c and R d Each is independently H, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium;

[0119] n is 0 or 1;

[0120] Each of R2, R3, R4, R5 and R6, when present, is independently selected from H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with one or more halogens or deuterium.

[0121] R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is independently H, a halogen, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium;

[0122] Or, R8 and R 11 Together they constitute an unsubstituted C1-C3 alkylene group or a C1-C3 alkylene group substituted with one or more halogens;

[0123] Or, R9 and R 10 Together they constitute an unsubstituted C1-C3 alkylene group or a C1-C3 alkylene group substituted with one or more halogens;

[0124] p is 0, 1, 2, 3 or 4;

[0125] Each R 14 It is independently selected from deuterium, halogen, hydroxyl and cyano groups.

[0126] In the implementation of formula (I), Selected from

[0127] In another embodiment of formula (I), Selected from

[0128] In another embodiment of formula (I), Selected from

[0129] In another embodiment of formula (I), Selected from

[0130] In another embodiment of formula (I), Selected from

[0131] In another embodiment of formula (I), yes

[0132] In another embodiment of formula (I), yes

[0133] In another embodiment of formula (I), yes

[0134] In another embodiment of formula (I), yes

[0135] In another embodiment of formula (I), yes

[0136] In another embodiment of formula (I), yes

[0137] In another embodiment of formula (I), yes

[0138] In another embodiment of formula (I), yes

[0139] In another embodiment of formula (I), yes

[0140] In another embodiment of formula (I), yes

[0141] In another embodiment of formula (I), yes

[0142] In another embodiment of formula (I), yes

[0143] In another embodiment of formula (I), yes

[0144] In another embodiment of formula (I), yes

[0145] In another embodiment of formula (I), yes

[0146] In another embodiment of formula (I), yes

[0147] In another embodiment of formula (I), p is 0. In another embodiment of formula (I), p is 1. In another embodiment of formula (I), p is 2. In another embodiment of formula (I), p is 3. In another embodiment of formula (I), p is 4. In another embodiment of formula (I), p is 0, 1, or 2. In another embodiment of formula (I), p is 0 or 1.

[0148] In another embodiment of equation (I), p is 1, R 14 It is deuterium. In another embodiment of equation (I), p is 0, R 14 It is a halogen. In another embodiment of formula (I), p is 0, R 14 It is fluorine. In another embodiment of formula (I), p is 1, R 14 It is a hydroxyl group. In another embodiment of formula (I), p is 0, R 14 It is cyano. In another embodiment of formula (I), p is 2, and each R 14 It is a hydroxyl group. In another embodiment of formula (I), p is 2, and each R 14It is a halogen. In another embodiment of formula (I), p is 2, and each R 14 It's fluorine.

[0149] In another embodiment of equation (I), E is NR a R b In another embodiment of formula (I), E is a C1-C3 alkylene-NR a R b In another embodiment of formula (I), E is an unsubstituted C1-C3 alkyl, an unsubstituted C2-C4 alkenyl, or an unsubstituted C2-C4 alkynyl. In another embodiment of formula (I), E is a C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), E is a C1-C3 alkyl substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted C3-C8 cycloalkyl. In another embodiment of formula (I), E is a C3-C8 cycloalkyl substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of formula (I), E is a C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted 4- to 10-membered heterocyclic group. In another embodiment of formula (I), E is a 4- to 10-membered heterocyclic group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups. In another embodiment of formula (I), E is an unsubstituted C1-C3 alkylene-(4- to 10-membered heterocyclic group). In another embodiment of formula (I), E is a C1-C3 alkylene-(4- to 10-membered heterocyclic group) substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups.

[0150] In another embodiment of formula (I), E is a C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group or C1-C3 alkylene-(4- to 10-membered heterocyclic group), wherein the C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group or C1-C3 alkylene-(4- to 10-membered heterocyclic group) is not substituted or is substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl groups or C1-C3 alkoxy groups.

[0151] In another embodiment of formula (I), E is a C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group or C1-C3 alkylene-(4- to 10-membered heterocyclic group), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclic group or C1-C3 alkylene-(4- to 10-membered heterocyclic group) is not substituted or is substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl groups or C1-C3 alkoxy groups.

[0152] In another embodiment of formula (I), E is a C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) is not substituted or is substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups.

[0153] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted by one or more halogens or deuterium.

[0154] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is unsubstituted, and further, where n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 0.

[0155] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is unsubstituted, and further, where n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted by one or more halogens or deuterium, and further wherein n is 1.

[0156] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 Aryl), wherein the aryl group is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10Aryl), wherein the aryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted by one or more halogens or deuterium.

[0157] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 Aryl), wherein the aryl group is unsubstituted, and further, where n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 Aryl), wherein the aryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or substituted C1-C3 alkyl groups by one or more halogens or deuterium, and further wherein n is 0.

[0158] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 Aryl), wherein the aryl group is unsubstituted, and further, where n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 Aryl), wherein the aryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 1.

[0159] In another embodiment of equation (I), R1 is (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the heteroaryl group is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the heteroaryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted by one or more halogens or deuterium.

[0160] In another embodiment of equation (I), R1 is (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the heteroaryl group is unsubstituted, and further, wherein n is 0. In another embodiment of formula (I), R1 is (CRc R d ) n -(5 to 10-membered heteroaryl), wherein the heteroaryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted by one or more halogens or deuterium, and further wherein n is 0.

[0161] In another embodiment of equation (I), R1 is (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the heteroaryl group is unsubstituted, and further, wherein n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the heteroaryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted by one or more halogens or deuterium, and further wherein n is 1.

[0162] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(5 to 7-membered heteroaryl), wherein the phenyl or heteroaryl group is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(5 to 7-membered heteroaryl), wherein the phenyl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium.

[0163] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(5 to 7-membered heteroaryl), wherein the phenyl or heteroaryl group is unsubstituted, and further, wherein n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d )n -(5 to 7-membered heteroaryl), wherein the phenyl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 0.

[0164] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(5 to 7-membered heteroaryl), wherein the phenyl or heteroaryl group is unsubstituted, and further, wherein n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(5 to 7-membered heteroaryl), wherein the phenyl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 1.

[0165] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(6-membered heteroaryl), wherein the phenyl or heteroaryl group is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(6-membered heteroaryl), wherein the phenyl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium.

[0166] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(6-membered heteroaryl), wherein the phenyl or heteroaryl group is unsubstituted, and further, wherein n is 0. In another embodiment of formula (I), R1 is (CR c Rd ) n -(phenyl) or (CR) c R d ) n -(6-membered heteroaryl), wherein the phenyl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 0.

[0167] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(6-membered heteroaryl), wherein the phenyl or heteroaryl group is unsubstituted, and further, wherein n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(6-membered heteroaryl), wherein the phenyl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 1.

[0168] In another embodiment of formula (I), each of R2, R3, R4, R5 and R6, when present, is independently selected from H, halogen, hydroxyl, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with one or more halogens.

[0169] In another embodiment of formula (I), each of R2, R3, R4, R5 and R6, when present, is independently selected from H, halogen, hydroxyl and unsubstituted C1-C3 alkyl.

[0170] In another embodiment of formula (I), each of R2, R3, R4, R5 and R6, when present, is independently selected from H, halogens and unsubstituted C1-C3 alkyl groups.

[0171] In another embodiment of formula (I), each of R2, R3, R4, R5, and R6, when present, is independently selected from H or a halogen. In another embodiment of formula (I), each of R2, R3, R4, R5, and R6, when present, is independently selected from H or fluorine. In another embodiment of formula (I), each of R2, R3, R4, R5, and R6, when present, is independently selected from H or chlorine. In another embodiment of formula (I), each of R2, R3, R4, R5, and R6, when present, is independently selected from H or an unsubstituted C1 alkyl group. In another embodiment of formula (I), each of R2, R3, R4, R5, and R6, when present, is independently selected from H or a hydroxyl group. In another embodiment of formula (I), each of R2, R3, R4, R5, and R6, when present, is H.

[0172] In another embodiment of formula (I), R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is independently H, a halogen, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium.

[0173] In another embodiment of formula (I), R8 and R 11 Together they constitute an unsubstituted C1-C3 alkylene or a C1-C3 alkylene substituted with one or more halogens. In another embodiment of formula (I), R8 and R... 11 Together they constitute an unsubstituted C2 alkylene or a C2 alkylene substituted with one or more halogens. In another embodiment of formula (I), R8 and R 11 Together they form a nitrogen-based bicyclic [3.2.1]octane-bridged bicyclic heterocyclic ring.

[0174] In another embodiment of formula (I), R9 and R 10 Together they constitute an unsubstituted C1-C3 alkylene or a C1-C3 alkylene substituted with one or more halogens. In another embodiment of formula (I), R9 and R 10 Together they constitute an unsubstituted C2 alkylene or a C2 alkylene substituted with one or more halogens. In another embodiment of formula (I), R9 and R 10 Together they form a nitrogen-based bicyclic [3.2.1]octane-bridged bicyclic heterocyclic ring.

[0175] In another embodiment of formula (I), R7, R8, R9, R 10 R 11 R 12 and R 13Each of these is independently H, a halogen, or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R7, R8, R9, R 10 R 11 R 12 and R 13 Each of these is independently H, fluorine, or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R7, R8, R9, R 10 R 11 R 12 and R 13 Each of these is independently H, a halogen, or an unsubstituted C1 alkyl group. In another embodiment of formula (I), R7, R8, R9, R... 10 R 11 R 12 and R 13 Each of these is independently H or an unsubstituted C1 alkyl group. In another embodiment of formula (I), R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is independently H or a halogen. In another embodiment of formula (I), R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H.

[0176] In another embodiment of equation (I), each of R2, R3, R4, R5, and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of R2, R3, R4, R5, and R6, when present, is H; R7, R8, R9, and R6 are also H. 10 R 11 R 12 and R 13 Each of R2, R3, R4, R5, and R6, when present, is H, and R7, R8, R9, R6 is H. 10 R 11 R 12 and R 13 Each of R2, R3, R4, R5, and R6, when present, is H, and R7, R8, R9, R... 10R 11 R 12 and R 13 Each of them is H or fluorine.

[0177] In another embodiment of equation (I), R1 is (CR c R d ) n -(5 to 10 heteroaryl groups), each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n -(5 to 10 heteroaryl groups), each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(5 to 10 heteroaryl groups), each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(5 to 10 heteroaryl groups), each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0178] In another embodiment of equation (I), R1 is (CR c R d ) n -(5 to 7 heteroaryl groups), each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R13 Each of these is H. In another embodiment of formula (I), R1 is (CRcRd)n-(5 to 7-membered heteroaryl), each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(5 to 7 heteroaryl groups), each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(5 to 7 heteroaryl groups), each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0179] In another embodiment of equation (I), R1 is (CR c R d ) n -(6-membered heteroaryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n -(6-membered heteroaryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n-(6-membered heteroaryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d )-(6-membered heteroaryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0180] In another embodiment of equation (I), R1 is (CR c R d )-(6-membered heteroaryl), n is 0, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d )-(6-membered heteroaryl), n is 0, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d )-(6-membered heteroaryl), n is 0, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0181] In another embodiment of equation (I), R1 is (CR c R d )-(6-membered heteroaryl), n is 1, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of formula (I), R1 is (CRcRd)-(6-membered heteroaryl), n is 1, each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d )-(6-membered heteroaryl), n is 1, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0182] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 Aryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10Aryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 Aryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 Aryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0183] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), each of R2, R3, R4, R5, and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0184] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0185] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), n is 1, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), n is 1, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 1, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 1, each of R2, R3, R4, R5 and R6, when present, is H, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0186] In another embodiment of equation (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n-(6-membered heteroaryl), n is 0, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0187] In another embodiment of equation (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, R7, R8, R9, R 10R 11 R 12 and R 13 Each of them is H or fluorine.

[0188] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0189] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), n is 1, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), n is 1, R7, R8, R9, R 10 R 11 R 12and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group. In another embodiment of formula (I), (CR c R d ) n -(C6 aryl), n is 1, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or a halogen. In another embodiment of formula (I), (CR) c R d ) n -(C6 aryl), n is 1, R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

[0190] Each embodiment of the compound of formula I described herein also applies to the compound of formula IA.

[0191] Certain embodiments of compounds of formula IA or I, or pharmaceutically acceptable salts thereof, are shown in Table 1 below. Compounds of formula IA or I, or pharmaceutically acceptable salts thereof, and the compounds in Table 1, or pharmaceutically acceptable salts thereof, are sometimes collectively referred to herein as “compounds of the invention” or “compounds provided herein.”

[0192] Table 1

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209] The disclosed compounds have one or more stereocenters, each of which may exist independently in an R or S configuration. In one embodiment, the compounds described herein are present in an optically active or racemic form. It should be understood that the compounds described herein include racemic, optically active, positional isomers, and stereoisomers, or combinations thereof, which possess the therapeutically useful properties described herein.

[0210] The preparation of the optically active form can be achieved by any suitable means, including by recrystallization, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase, as described in non-limiting embodiments. In one embodiment, a mixture of two or more isomers is used as the disclosed compound described herein. In another embodiment, a pure isomer is used as the disclosed compound described herein. In yet another embodiment, the compound described herein contains one or more chiral centers. These compounds can be prepared by any means, including stereoselective synthesis, enantioselective synthesis, or separation of mixtures of enantiomers or diastereomers. The resolution of the compound and its isomers can be achieved by any means, including non-limiting embodiments, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0211] In one embodiment, the disclosed compound may exist as an isomer. All isomers are included within the scope of the compounds described herein.

[0212] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by atoms having the same atomic number, but whose atomic mass or mass number differs from that of atoms commonly found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to, those... 2 H, 3 H, 11 C 13 C 14 C 36 Cl、 18 F, 123 I, 125 I, 13N、 15 N、 15 O、 17 O、 18 O、 32 P and 35 S. In one embodiment, the isotope-labeled compound is useful in drug or substrate tissue distribution studies. In another embodiment, substitution with a heavy isotope (such as deuterium) can yield greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). In yet another embodiment, the compounds described herein include 2 H (i.e., deuterium) isotope.

[0213] In yet another implementation scheme, isotopes are emitted using positron emission, such as 11 C 18 F, 15 O and 13 Nitrogen substitution is helpful in examining substrate-acceptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds are prepared by any suitable method or by using an appropriate isotopically labeled reagent in place of the originally used unlabeled reagent.

[0214] The specific compounds described herein, as well as other compounds contained in one or more structural formulas with different substituents described herein, were synthesized using the techniques and materials described herein or cited below, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reaction, Volumes 1-40 (John Wiley and Sons, 1991); Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed. (Advanced Organic Chemistry, 4th Edition), (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4 thEd. (Advanced Organic Chemistry, 4th Edition), Vols. A and B (Plenum 2000, 2001) and Green and Wuts, Protective Groups in Organic Synthesis 3 rd Ed. (Protecting Groups in Organic Synthesis, 3rd Edition), (Wiley 1999) (all of which are incorporated herein by reference). General methods for preparing the compounds described herein are modified by using appropriate reagents and conditions to introduce the different parts found in the formulas provided herein.

[0215] The compounds described herein were synthesized using any suitable procedure, starting with compounds available from commercial sources, or prepared using the procedure described herein.

[0216] Treatment

[0217] Methods for treating a disease or condition with the compounds of the present invention include administering the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention to the subject. In one embodiment of the methods described herein, the subject is a human. In one aspect, the compounds provided herein are useful for treating a disease or condition by acting as agonists of the orexin-2 receptor.

[0218] The compounds of the present invention can be used to treat diseases or conditions selected from narcolepsy, cataplexy, or narcolepsy in subjects with such need.

[0219] In one embodiment, the compound of the present invention can be used to treat narcolepsy in a subject. In one embodiment, the compound of the present invention can be used to treat cataplexy in a subject. In one embodiment, the compound of the present invention can be used to treat narcolepsy in a subject.

[0220] Orexin-2 receptors play important roles in a variety of biological functions. This suggests that orexin-2 receptors play a role in various disease processes in humans and other species. The compounds of this invention can be used to treat, prevent, or improve the risk of one or more of the following symptoms or diseases associated with various neurological and psychiatric disorders related to altered sleep / wake function. That is, narcolepsy, narcolepsy with cataplexy, idiopathic narcolepsy, narcolepsy, sleep apnea syndrome, narcolepsy syndrome, and hypersomnia characterized by excessive sleepiness (such as in subjects with Klein-Levin syndrome, severe depression with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prad-Willi syndrome, Möbius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, multiple system atrophy, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen encephalitis, Wernicke's encephalitis, limbic encephalitis, or Hashimoto's encephalopathy). Combination syndromes, coma, loss of consciousness, obesity (such as malignant mast cell disease, exogenous obesity, hyperinsulinemia obesity, proliferative obesity, pituitary obesity, hypoplastic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, dietary obesity, hypogonadism obesity, systemic mastocytosis, simple obesity or central obesity), insulin resistance syndrome, Alzheimer's disease, altered consciousness such as coma, side effects and complications of anesthesia, sleep disorders, excessive daytime sleepiness, sleep problems, insomnia, intermittent sleep, nocturnal muscle twitching, REM sleep interruption, jet lag, time difference. Syndrome, sleep disorders in shift workers, sleep disturbances, night terrors, depression, major depressive disorder, somnambulism, enuresis, sleep disorders, Alzheimer's disease, dusk, sunset, diseases related to circadian rhythms, fibromyalgia, conditions caused by poor sleep quality, binge eating, obsessive-compulsive eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, gallstones, heart disease, abnormal heart rhythm, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease Cardiovascular disorders, polycystic ovary syndrome, craniopharyngioma, Prad-Willi syndrome, Florich syndrome, growth hormone deficiency, normal-mutant short stature, Turner syndrome, children with acute lymphoblastic leukemia, Syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, sexual and reproductive dysfunction such as female-to-male hirsutism, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity-hypopnea syndrome (Pickwick syndrome), respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia.Risks associated with lower back pain, gallbladder disease, gout, kidney cancer, secondary consequences of obesity such as reduced risk of left ventricular hypertrophy, migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, autoimmune encephalitis, cancer-related fatigue (e.g., excessive daytime sleepiness or fatigue associated with cancer and / or chemotherapy), cancer-related nausea and vomiting, corticobasal degeneration, Huntington's disease, neuromyelitis optica, nociceptive symptoms, progressive supranuclear palsy, schizophrenia, systemic lupus erythematosus, traumatic brain injury, facial flushing, night sweats, reproductive / urinary system disorders, disorders related to sexual function or fertility, dysphoric disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, amnesia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder (PTSD), separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders. Conditions include: brain dysfunction after coronary artery bypass surgery and transplantation; stroke; ischemic stroke; cerebral ischemia; spinal cord injury; head trauma; perinatal hypoxia; cardiac arrest; hypoglycemic nerve damage; Huntington's disease; amyotrophic lateral sclerosis (ALS); eye injury; retinopathy; cognitive impairment; muscle spasms; tremor; epilepsy; diseases related to muscle spasms; delirium; amnesia; age-related cognitive decline; schizoaffective disorder; delirious disorder; drug addiction; movement disorders; chronic fatigue syndrome; fatigue; drug-induced Parkinson's syndrome; Tourette syndrome; chorea; myoclonus; convulsions; restless limb syndrome; dystonia; movement disorders; attention deficit disorder (ADHD); behavioral disorders; urinary incontinence; withdrawal symptoms; trigeminal neuralgia; hearing loss; tinnitus; nerve damage; retinopathy; macular degeneration; vomiting; cerebral edema; pain; bone pain; arthralgia; toothache; sudden collapse; and traumatic brain injury (TBI).

[0221] In particular, the compounds of the present invention can be used as therapeutic or preventive drugs for the treatment of narcolepsy, idiopathic narcolepsy, narcolepsy, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome characterized by excessive sleepiness (such as Parkinson's disease, Guillain-Barré syndrome or Klein-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, disturbances of consciousness such as coma, side effects and complications caused by anesthesia, or anesthetic antagonists.

[0222] In one embodiment, the compound of the present invention has orexin-2 receptor agonist activity and can be used as a preventive or therapeutic agent for narcolepsy.

[0223] In another embodiment, the compound of the present invention can be used as a preventive or therapeutic agent for type 1 narcolepsy. In another embodiment, the compound of the present invention can be used as a preventive or therapeutic agent for type 2 narcolepsy. In another embodiment, the compound of the present invention can be used as a preventive or therapeutic agent for narcolepsy and excessive daytime sleepiness. In another embodiment, the compound of the present invention can be used as a preventive or therapeutic agent for narcolepsy, cataplexy, and excessive daytime sleepiness. In another embodiment, the compound of the present invention can be used as a preventive or therapeutic agent for narcolepsy and cataplexy. In another embodiment, the compound of the present invention can be used as a preventive or therapeutic agent for excessive daytime sleepiness. In another embodiment, the compound of the present invention can be used as a preventive or therapeutic agent for idiopathic narcolepsy. In another embodiment, the compound of the present invention can be used as a preventive or therapeutic agent for obstructive sleep apnea.

[0224] In another embodiment, the compound of the present invention has orexin-2 receptor agonist activity and can be used as a preventive or therapeutic agent for narcolepsy in Parkinson's disease.

[0225] In another embodiment, the compound of the present invention has orexin-2 receptor agonist activity and can be used as a preventive or therapeutic agent for narcolepsy. In another embodiment, the compound of the present invention has orexin-2 receptor agonist activity and can be used as a preventive or therapeutic agent for excessive daytime sleepiness associated with Parkinson's disease.

[0226] In another embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and can be used as a preventive or therapeutic agent for excessive daytime sleepiness and fatigue associated with cancer and / or chemotherapy.

[0227] In another embodiment, the present invention provides a method for treating narcolepsy in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0228] In another embodiment, the present invention provides a method for treating type 1 narcolepsy in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0229] In another embodiment, the present invention provides a method for treating type 1 narcolepsy in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0230] In another embodiment, the present invention provides a method for treating narcolepsy and excessive daytime sleepiness in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0231] In another embodiment, the present invention provides a method for treating narcolepsy, cataplexy, and excessive daytime sleepiness in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0232] In another embodiment, the present invention provides a method for treating narcolepsy and cataplexy in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0233] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0234] In another embodiment, the present invention provides a method for treating idiopathic narcolepsy in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0235] In another embodiment, the present invention provides a method for treating idiopathic narcolepsy and excessive daytime sleepiness in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0236] In another embodiment, the present invention provides a method for treating obstructive sleep apnea in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0237] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and obstructive sleep apnea in a subject in need, comprising administering to the subject a compound of formula IA or I or a pharmaceutically acceptable salt thereof.

[0238] In any of the methods described herein, a compound of formula IA is administered to a subject. In any of the methods described herein, a compound of formula I is administered to a subject.

[0239] Each embodiment of the use of the compound of formula I described herein also applies to the compound of formula IA.

[0240] In any composition or method described herein, a compound of formula IA or I or a pharmaceutically acceptable salt thereof is present and / or administered in a therapeutically effective amount.

[0241] Usage / Dosage / Preparation

[0242] In another respect, this article provides a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable carrier.

[0243] The actual dose level of the active ingredient in the pharmaceutical composition of the present invention can be varied in order to obtain an effective amount of active ingredient to achieve the therapeutic response required for a particular patient, composition and route of administration without causing toxicity to the patient.

[0244] In particular, the selected dose level will depend on a variety of factors, including the activity of the specific compound used, the timing of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical community.

[0245] A physician with ordinary skills in the field, such as an internist or veterinarian, can easily determine and prescribe the required effective amount of the pharmaceutical composition. For example, a physician or veterinarian may start administering the pharmaceutical composition at a dose of the disclosed compound below the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0246] In certain embodiments, it is particularly advantageous to formulate the compound into dosage units to facilitate administration and ensure uniformity of dosage. The dosage unit form used herein refers to physically discontinuous units suitable as a unit dose for a patient to be treated; each unit contains a predetermined quantity of the disclosed compound, calculated to produce the desired therapeutic effect when used with a desired drug carrier. The dosage unit form of the present invention depends on (a) the unique properties of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations of the techniques for compounding / formulating such disclosed compounds for treating narcolepsy or cataplexy in patients.

[0247] In one embodiment, the compound of the present invention is formulated with one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition of the present invention comprises a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0248] In some embodiments, the dosage of the disclosed compound is from about 1 mg to about 1000 mg. In some embodiments, the dosage of the disclosed compound used in the compositions described herein is less than about 1000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 20 mg, or less than about 10 mg. For example, dosages are about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or about 600 mg.

[0249] Routes of administration for any composition of the present invention include oral, nasal, rectal, intravaginal, parenteral, oral, sublingual, or local administration. The compounds used in the present invention can be formulated for administration via any suitable route, such as oral or parenteral, including transdermal, transmucosal (e.g., sublingual, lingual, oral, urethral, ​​vaginal (e.g., vaginal and perivasal), nasal (internal), and transrectal), intravenous, intrapulmonary, intraduodenal, intragastric, intrathecal, intrasheathal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and local administration. In one embodiment, the preferred route of administration is oral.

[0250] Suitable compositions and dosage forms include, for example, tablets, capsules, pouches, pills, gel caps, lozenges, dispersants, suspensions, solutions, syrups, granules, microspheres, transdermal patches, gels, powders, microcapsules, emulsions, sugar lozenges, creams, pastes, plasters, lotions, ointments, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol formulations for inhalation, and compositions and dosage forms for intravenous injection. It should be understood that the formulations and compositions useful to this invention are not limited to the specific formulations and compositions described herein.

[0251] For oral applications, tablets, pills, liquids, drops, suppositories, or capsules, pouches, and gel caps are particularly suitable. Compositions for oral administration can be prepared according to any method known in the art, and such compositions may contain one or more pharmaceutical agents selected from inert, non-toxic pharmaceutical excipients suitable for tablet manufacturing. These excipients include, for example, inert diluents such as lactose; granulating and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or coated using known techniques to achieve an aesthetic effect or to delay the release of the active ingredient. Formulations for oral administration may also be in the form of hard capsules in which the active ingredient is mixed with an inert diluent.

[0252] For parenteral administration, the disclosed compounds can be formulated as injections or infusions, for example, intravenous, intramuscular, or subcutaneous injections or infusions, or administered in embolic doses or via continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous carriers may be used, and alternatively, other formulations such as suspensions, stabilizers, or dispersants may be included.

[0253] Those skilled in the art will recognize or be able to use conventional experiments to determine many equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this invention and are covered by the appended claims. For example, it should be understood that modifications to reaction conditions, including but not limited to reaction time, reaction size / volume, and experimental reagents such as solvents, catalysts, pressure, atmospheric conditions (e.g., nitrogen atmosphere), and reducing / oxidizing agents, as well as art-recognized alternatives and the use of experiments not exceeding conventional methods, are all within the scope of this application.

[0254] It should be understood that all numerical values ​​and ranges provided herein, and all numerical values ​​and ranges included herein, are included within the scope of this invention. Furthermore, all numerical values ​​falling within these ranges, as well as the upper or lower limits of the numerical ranges, are also considered in this application.

[0255] The following examples further illustrate various aspects of the invention. However, they are by no means intended to limit the teachings or disclosures of the invention as described herein.

[0256] Example

[0257] The following examples further illustrate the invention and should not be construed as further limitations. Unless otherwise stated, the practice of this invention will employ conventional techniques from organic synthesis, cell biology, cell culture, molecular biology, transgenic biology, microbiology, and immunology, techniques that are well-known in the art.

[0258] General Procedure

[0259] Example 1: Synthesis Procedure

[0260] The synthetic procedures for preparing the compounds of this invention are readily available to those skilled in the art. Unless otherwise stated, the starting materials are generally available from commercial sources.

[0261] The following abbreviations are used in the following synthetic examples:

[0262] DCM = dichloromethane

[0263] MsCl = Methylsulfonyl chloride

[0264] MeOH = methanol

[0265] THF = Tetrahydrofuran

[0266] EtOH = ethanol

[0267] DIPEA = N,N-Diisopropylethylamine

[0268] ACN or MeCN = Acetonitrile

[0269] NEt3 or TEA = Triethylamine

[0270] PE = Petroleum Ether

[0271] EtOAc = Ethyl acetate

[0272] TFA = Trifluoroacetic acid

[0273] min = minutes

[0274] hr = hours

[0275] NaH = Sodium hydride

[0276] DMSO = dimethyl sulfoxide

[0277] TMSCl = Trimethylchlorosilane

[0278] Pd / C = Palladium on carbon

[0279] Ms = Methanesulfonyl group

[0280] Bn = benzyl

[0281] Ph = phenyl

[0282] LiHMDS = Bis(trimethylsilyl)lithium amide

[0283] Pd(OH)2 / C = Palladium hydroxide

[0284] DMAP = 4-Dimethylaminopyridine

[0285] KOAc = Potassium acetate

[0286] Pd(dppf)Cl2=[1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride

[0287] Pd(PPh3)4 = tetra(triphenylphosphine)palladium(0) scheme 1

[0288]

[0289] Option 2

[0290]

[0291] Option 3

[0292]

[0293] Option 4

[0294]

[0295] Example 1.1

[0296]

[0297] At 0 °C, triethylamine (2.66 g, 26.3 mmol, 1.50 equivalent) and DMAP (214.06 mg, 1.752 mmol, 0.10 equivalent) were added dropwise to a stirred solution of 4-hydroxycyclohexane-1-one (2.00 g, 17.522 mmol, 1.00 equivalent) in DCM (50.00 mL). The resulting mixture was stirred at room temperature for two hours. Benzoyl chloride (1.23 g, 8.761 mmol, 0.50 equivalent) was then added dropwise to the mixture at room temperature. The resulting mixture was stirred at room temperature for another three hours. When TLC showed complete reaction, the crude mixture was diluted with water. The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous MgSO4. The residue was purified by silica gel chromatography and eluted with PE / EtOAc (4:1) to give 4-oxocyclohexylbenzoate (3.37 g, yield 88.12%) as a solid.

[0298] LCMS: m / z(ES+),[M+H]+=219.65.

[0299]

[0300] Under a nitrogen atmosphere at -60°C, Br2 (1.41 mL, 8.81 mmol, 1.20 equivalence) was added dropwise to a stirred solution of P(OPh)3 (7.82 g, 25.2 mmol, 1.10 equivalence) in DCM (70.00 mL). After 30 minutes, NEt3 (4.14 mL, 40.9 mmol, 1.30 equivalence) and 4-oxocyclohexylbenzoate (5.00 g, 22.9 mmol, 1.00 equivalence) were added to the mixture at -60°C. The resulting mixture was stirred at room temperature for 18 hours. The reaction was quenched at 0°C by adding saturated aqueous NaSO3 solution (20 mL), and the resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (20:1) to give 4-bromocyclohexane-3-en-1-ylbenzoate (5.8 g, 90.05%) as a racemic solid.

[0301] LCMS: m / z(ES+),[M+H]+=282.15.

[0302]

[0303] A solution of racemic 4-bromocyclohexyl-3-en-1-ylbenzoate (3.00 g, 10.7 mmol, 1.00 equivalent) and sodium methoxide (634.11 mg, 11.738 mmol, 1.10 equivalent) in MeOH (30 mL) was stirred overnight at room temperature. The desired product could be detected by TLC. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with DCM (4 x 50 mL). The combined organic layers were washed with water (3 x 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (4:1) to give 4-bromocyclohexyl-3-en-1-ol (1.7 g, 90% yield) as an oil.

[0304] 1 ¹H NMR (400 MHz, chloroform-d) δ 5.94 (d, ¹H), 4.08–3.95 (m, ¹H), 2.68–2.32 (m, ³H), 2.23–1.74 (m, ³H).

[0305]

[0306] A solution of 4-bromocyclohexyl-3-en-1-ol (6.50 g, 36.7 mmol, 1.00 equivalent) and paraformaldehyde (1.65 g, 55.1 mmol, 1.50 equivalent) in TMSCl (19.5 mL, 180 mmol, 4.16 equivalent) was stirred overnight at room temperature under nitrogen atmosphere. The desired product could be detected by TLC. The resulting mixture was filtered, and the filter cake was washed with tetrahydrofuran (3 x 10 mL). The filtrate was concentrated under reduced pressure, and the crude product was used directly in the next step without purification.

[0307] 1 ¹H-NMR (400MHz, chloroform-d) δ 6.00–5.85 (m, 1H), 5.57 (s, 2H), 4.11 (d, 1H), 2.73–2.35 (m, 3H), 2.31–2.13 (m, 1H), 2.03–1.81 (m, 2H).

[0308]

[0309] Racemic methylbenzylamine (3.44 g, 28.4 mmol, 1.00 equivalent) was added dropwise to a stirred mixture of 1-(pyridin-2-yl)piperidin-4-one (5.00 g, 28.4 mmol, 1.00 equivalent) and MgSO4 (10.25 g, 85.12 mmol, 3.00 equivalent) in toluene (75 mL) under nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The crude reaction mixture was then filtered, and the filter cake was washed with toluene (2 x 20 mL). The filtrate was concentrated under reduced pressure. The resulting crude product was used directly in the next step without purification. The desired product could be detected by TLC.

[0310] 1 ¹H NMR (400 MHz, chloroform-d) δ 8.26–8.14 (m, 1H), 7.57–7.41 (m, 1H), 7.42–7.15 (m, 6H), 6.74–6.53 (m, 2H), 4.76 (q, 1H), 3.98–3.88 (m, 1H), 3.87–3.63 (m, 3H), 2.75–2.57 (m, 2H), 2.58–2.27 (m, 2H), 1.73 (s, 1H), 1.47 (dd, 3H).

[0311]

[0312] Under a nitrogen atmosphere and at -78°C, n-butyllithium (13.4 mL, 33.5 mmol, 1.20 equivalent) was added dropwise to a stirred solution of diethylamine (2.45 g, 33.5 mmol, 1.20 equivalent) in tetrahydrofuran (30 mL). The resulting mixture was stirred for 30 minutes under a nitrogen atmosphere and at -78°C. Then, over 15 minutes at -78°C, imine (1S)-1-phenyl-N-[1-(pyridin-2-yl)piperidin-4-yl]ethylamine (7.80 g, 27.9 mmol, 1.00 equivalent) in tetrahydrofuran (20 mL) was added dropwise. The resulting mixture was then stirred for another hour. At -78°C, 1-bromo-4-(chloromethoxy)cyclohexene (7.56 g, 33.5 mmol, 1.20 equivalents) was added dropwise to the above mixture in THF (20 mL) over 15 minutes. The resulting mixture was then stirred for 1 hour. The reaction was then quenched by adding sodium phosphate buffer (200 mL, 10% aqueous solution) and stirring for one hour.

[0313] The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (4:1), to give 3-[[(4-bromocyclohexane-3-en-1-yl)oxy]methyl]-1-(pyridin-2-yl)piperidin-4-one (3 g, 29% yield) as an oil.

[0314] LCMS: m / z(ES+),[M+H]+=366.27.

[0315]

[0316] Under a nitrogen atmosphere, ZnCl2 (2.85 mL, 1.99 mmol, 0.14 equivalent) was added dropwise to a stirred solution of 3-[[(4-bromocyclohexyl-3-en-1-yl)oxy]methyl]-1-(pyridin-2-yl)piperidin-4-one (5.20 g, 14.2 mmol, 1.00 equivalent) in 40 mL of methanol. The reaction mixture was irradiated with microwaves at room temperature for 30 minutes. HCOONH4 (13.46 g, 213.5 mmol, 15.00 equivalent) was added to the mixture at room temperature. The resulting mixture was stirred for another hour at room temperature. ZnCl2 (2.85 mL, 1.99 mmol, 0.14 equivalent) was added to the mixture at 0 °C. The resulting mixture was stirred for another two days at room temperature. The reaction was then quenched by adding 20 mL of water at room temperature. The mixture was then extracted with DCM (3 x 100 mL), and the combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel chromatography, eluting with DCM / MeOH (6:1) to give 3-[[(4-bromocyclohexyl-3-en-1-yl)oxy]methyl]-1-(pyridin-2-yl)piperidin-4-amine (3.7 g, 71% yield) as an oil.

[0317] LCMS: m / z(ES+),[M+H]+=367.30.

[0318]

[0319] Under a nitrogen atmosphere at room temperature, methanesulfonyl chloride (0.89 g, 7.78 mmol, 1.50 equivalent) was added dropwise to a stirred solution of 3-[[(4-bromocyclohexyl-3-en-1-yl)oxy]methyl]-1-(pyridin-2-yl)piperidin-4-yl]methanesulfonamide (1.3 g, 65% yield) in a DCM (30 mL) solution (1.90 g, 5.187 mmol, 1.00 equivalent) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. The crude residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give N-[3-([[(1R)-4-bromocyclohexyl-1-en-yl]oxy]methyl)-1-(pyridin-2-yl)piperidin-4-yl]methanesulfonamide (1.3 g, 65% yield) as an oil. The product was then purified by preparative thin-layer chromatography under the following conditions (column: DAICEL). (Daicel Corporation, Osaka, Japan) P4VP, 20mm*250mm, 5um; mobile phase A: CO2, mobile phase B: ACN / MeOH = 4:1 (0.1% 2M NH3-MeOH); flow rate: 50 mL / min; gradient: 25% B; 254 nm), yielded N-[3-([[(1R)-4-bromocyclohexyl-1-yl]oxy]methyl)-1-(pyridin-2-yl)piperidin-4-yl]methanesulfonamide (375 mg, yield 18.8%), as an oil.

[0320] LCMS: m / z(ES+),[M+H]+=445.39.

[0321] 1 H-NMR (400Mhz, chloroform-d) δ8.23–8.08(m,1H),7.50(dd,1H),6.80–6.54(m,2H),5.9 2(dt,1H),5.11(dd,1H),4.46–4.17(m,2H),3.79–3.61(m,3H),3.61–3.43(m,2H ),3.02(d,3H),2.93(t,1H),2.74(dt,1H),2.61–2.47(m,2H),2.47–2.32(m,1H) ,2.27(d,1H),2.16(dt,1H),2.04–1.91(m,1H),1.84(d,2H),1.68–1.54(m,1H).

[0322]

[0323] Under air and at room temperature, KOAc (0.66 g, 6.751 mmol, 3.00 equivalent) was added to a stirred solution of N-(3-[[(4-bromocyclohexyl-1-yl)oxy]methyl]-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (1.00 g, 2.25 mmol, 1.00 equivalent) and bis(pinacol)diboron (857.15 mg, 3.375 mmol, 1.50 equivalent) in dioxane. Pd(dppf)Cl2 (0.16 g, 0.225 mmol, 0.10 equivalent) was added to the mixture at room temperature. The resulting mixture was stirred at 100 °C for 4 hours under nitrogen atmosphere. The crude product was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1:1) to give N-[1-(pyridin-2-yl)-3-[[(1R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)cyclohex-3-en-1-yl]oxy]methyl)piperidin-4-yl]methanesulfonamide (1.0 g, 90% yield) as a solid.

[0324] LCMS (E07880-030): m / z (ES+), [M+H]+ = 492.45.

[0325]

[0326] Under a nitrogen atmosphere, at room temperature, Cs₂CO₃ (366.6 mg, 1.125 mmol, 2.50 equivalent) and Pd(PPh₃)₄ (52.0 mg, 0.045 mmol, 0.10 equivalent) were added to a stirred solution of N-(3-[[(4-bromocyclohexyl-1-yl)oxy]methyl]-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (200.0 mg, 0.450 mmol, 1.00 equivalent) and 2-bromopyridine (71.1 mg, 0.450 mmol, 1.00 equivalent) in 1,4-dioxane (5 mL) and water (1 mL). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The residue was purified by preparative thin-layer chromatography (EtOAc) to give N-[1-(pyridin-2-yl)-3-([[4-(pyridin-2-yl)cyclohex-3-en-1-yl]oxy]methyl)piperidin-4-yl]methanesulfonamide (170 mg, yield 85.4%), as an oil.

[0327] LCMS: m / z(ES+),[M+H]+=443.58.

[0328]

[0329] Pd / C (72.1 mg, 0.0678 mmol, 2.00 equivalent) was added to a 10 mL solution of N-[1-(pyridin-2-yl)-3-([[4-(pyridin-2-yl)cyclohexyl-3-en-1-yl]oxy]methyl)piperidin-4-yl]methanesulfonamide (150.0 mg, 0.339 mmol, 1.00 equivalent) in MeOH under stirring at room temperature. The atmosphere was changed to hydrogen, and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for two hours. The resulting mixture was filtered, and the filter cake was washed with methanol (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in TFA / water, 0% to 20% gradient, 30 min; detector, UV 254 nm. The product obtained, N-[1-(pyridin-2-yl)-3-([[4-(pyridin-2-yl)cyclohexyl]oxy]methyl)piperidin-4-yl]methanesulfonamide (60 mg, yield 40%), was an oily substance and a mixture of isomers.

[0330] LCMS: m / z(ES+),[M+H]+=445.59.

[0331] This mixture of isomers (60 mg) was further purified by chiral preparative high-performance liquid chromatography under the following conditions (column: (Daicel Corporation, Osaka, Japan) IE, 2cm*25cm, 5um; Mobile phase A: hexane (containing 0.2% diethylamine); Mobile phase B: IPA; Flow rate: 20mL / min; Isocratic 40% B, 25min; Detector: 220 / 254nm), yielded N-[(3R,4S)-1-(pyridin-2-yl)-3-[[(1s,4s)-4-(pyridin-2-yl)cyclohexyl]oxy]methyl)piperidin-4-yl]methanesulfonamide (15.8mg, 26.33%) as a solid.

[0332] LCMS (E07273-129): m / z (ES+), [M+H]+ = 445.59.

[0333] 1H-NMR (400Mhz, methanol-d4) δ8.43(d,1H),8.06(dd,1H),7.78(d,1H),7.52(d,1H), 7.35(dt,1H),7.25(d,1H),6.92–6.84(m,1H),6.63(d,1H),3.87(dq,2H),3.7 5(dd,1H),3.71–3.60(m,2H),3.59–3.52(m,2H),3.47(dd,1H),3.05(s,3H),2 .76(t,1H),2.29(dt,1H),2.09(d,2H),2.00–1.80(m,4H),1.75–1.52(m,4H).

[0334] Example 1.2

[0335]

[0336] At room temperature, N-(3-[[(4-bromocyclohexyl-1-yl)oxy]methyl]-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (200.00 mg, 0.450 mmol, 1.00 equivalent), Na₂CO₃ (143.10 mg, 1.350 mmol, 3.00 equivalent), 3-fluorophenylboronic acid (94.46 mg, 0.675 mmol, 1.50 equivalent), dioxane (4.00 mL), water (1.00 mL), and Pd(dppf)Cl₂ (19.76 mg, 0.027 mmol, 0.06 equivalent) were added to a 20 mL sealed tube. The resulting mixture was stirred at 80 °C for two hours under a nitrogen atmosphere. The aqueous layer was extracted with EtOAc (1 x 10 mL). The resulting mixture was concentrated under reduced pressure, and the crude product was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase: ACN water, gradient 10% to 60%, 20 min; detector, UV 254 nm. N-[3-([[4-(3-fluorophenyl)cyclohexyl-3-en-1-yl]oxy]methyl)-1-(pyridin-2-yl)piperidin-4-yl]methanesulfonamide (200 mg, yield 96.7%) was obtained as a solid.

[0337] LCMS:m / z(ES+),[M+H]+=460.

[0338]

[0339] A solution / mixture of N-[3-([[4-(3-fluorophenyl)cyclohexyl-3-en-1-yl]oxy]methyl)-1-(pyridin-2-yl)piperidin-4-yl]methanesulfonamide (187 mg, 0.407 mmol, 1.00 equivalent) and Pd / C (49.8 mg, 0.468 mmol, 1.15 equivalent) in ethyl acetate (15.0 mL) was stirred at room temperature for two hours under a hydrogen atmosphere. The target product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water; gradient 10% to 60%, 20 min; detector, UV 254 nm. N-[3-([[4-(3-fluorophenyl)cyclohexyl]oxy]methyl)-1-(pyridin-2-yl)piperidin-4-yl]methanesulfonamide (97 mg, yield 52%) was obtained as a solid and as a mixture of isomers.

[0340] LCMS:m / z(ES+),[M+H]+=462.

[0341] The mixture of isomers (97 mg) was purified by preparative chiral high-performance liquid chromatography under the following conditions: column, IE, 2*25cm, 5µm; Mobile phase A: hexane plus 0.2% diethylamine; Mobile phase B: ethanol; Flow rate, 20mL / min; Isocratic rate 35% B, 15.5min; Detector, 220 / 254nm. N-[(3R,4S)-1-(pyridin-2-yl)-3-([[(1s,4s)-4-(3-fluorophenyl)cyclohexyl]oxy]methyl)piperidin-4-yl]methanesulfonamide (20.7mg, 21.34%) was obtained as a solid.

[0342] LCMS:m / z(ES+),[M+H]+=462.

[0343] 1 H-NMR(400MHz,MeOD)δ1.56(m,1H),1.61(m,3H),1.77(m,1H),1.88(m,3H) ,2.06(m,2H),2.30(dt,1H),2.58(m,1H),3.05(s,3H),3.46(dt,1H),3.56 (m,2H),3.64(m,2H),3.76(m,1H),3.86(m,2H),6.64(ddd,1H),6.88(m,2H ),6.97(dt,1H),7.05(dt,1H),7.27(m,1H),7.52(ddd,1H),8.07(ddd,1H).

[0344] Example 1.3

[0345]

[0346] At room temperature, 15.00 g (86.087 mmol, 1.00 equivalent) of 4-phenylcyclohexane-1-one, 130.00 mL of THF, and 129.08 mL (679.021 mmol, 7.02 equivalent) of tri-sec-butylborohydride were added to a 500 mL three-necked round-bottom flask. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. Then, 0.16 mL (8.609 mmol, 0.10 equivalent) of water and 0.10 mL (2.171 mmol, 0.02 equivalent) of EtOH were added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Then, 5.99 g (149.791 mmol, 1.74 equivalent) of NaOH and 0.02 mL (0.590 mmol, 0.01 equivalent) of H₂O₂ were added, and the resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1 hour. The resulting mixture was washed with water (2 x 50 mL). The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (9:1) to give 4-phenylcyclohexane-1-ol (11.4 g, 75.1%) as a solid.

[0347] 1 ¹H-NMR (400 MHz, chloroform-d) δ 7.41–7.15 (m, 5H), 4.16 (p, J = 3.0 Hz, 1H), 2.57 (tt, J = 12.0, 3.2 Hz, 1H), 2.04–1.84 (m, 4H), 1.71 (tdd, J = 14.5, 5.3, 2.4 Hz, 4H), 1.46 (d, J = 3.0 Hz, 1H).

[0348]

[0349] A solution of 4-phenylcyclohexane-1-ol (10.00 g, 56.735 mmol, 1.00 equivalent) in 4N dioxane hydrochloride (160.00 mL, 640.00 mmol, 11.3 equivalent) was treated with paraformaldehyde (2.56 g, 28.367 mmol, 0.50 equivalent) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification.

[0350]

[0351] Under a nitrogen atmosphere, at -78°C, LiHMDS (56.07 mL, 56.070 mmol, 1.00 equivalent) was added dropwise over 15 minutes to a stirred solution of [4-(chloromethoxy)cyclohexyl]benzene (12.6 g, 56.067 mmol, 1.00 equivalent) in tetrahydrofuran (200.00 mL). The resulting mixture was stirred at -78°C for 1.5 hours under a nitrogen atmosphere. At -78°C, a solution of [4-(chloromethoxy)cyclohexyl]benzene (12.6 g, 56.067 mmol, 1.00 equivalent) in tetrahydrofuran (50 mL) was added dropwise over 20 minutes. The resulting mixture was stirred at -78°C for another 2 hours. The reaction was quenched with a saturated aqueous NH4Cl solution at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 130 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 10% to 100%, 15 min; detector, UV 220 nm, yielding 1-benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidin-4-one (6.1 g, 28.80%) as an oil.

[0352] LCMS: m / z(ES+),[M+H]+=378.30.

[0353] 1 ¹H-NMR (400 MHz, chloroform-d) δ 7.42–7.29 (m, 7H), 7.21 (dtd, J = 7.0, 3.5, 1.7 Hz, 3H), 3.80 (dd, J = 9.6, 4.7 Hz, 1H), 3.77–3.61 (m, 2H), 3.59 (p, J = 3.1 Hz, 1H), 3.49 (dd, J = 9.6, 8.3 Hz, 1H), 3.33 (ddd, J = 11.4, 5.7, 2). 4Hz,1H),3.04(ddd,J=11.7,5.7,2.8Hz,1H),2.91(tt,J=9.7,5.3Hz,1H),2.68–2.35(m,5H),2.00(dt ,J=13.9,3.2Hz,2H),1.73(tdd,J=15.1,12.4,3.4Hz,2H),1.61(d,J=13.4Hz,2H),1.57–1.43(m,2H).

[0354]

[0355] Under a nitrogen atmosphere at room temperature, ZnCl2 (1.06 mL, 1.060 mmol, 0.2 equivalence) was added dropwise to a stirred solution of 1-benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidin-4-one (2.00 g, 5.298 mmol, 1.00 equivalence) in 12.00 mL of methanol (12.00 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. HCOONH4 (4.00 g, 63.413 mmol, 11.97 equivalence) was added in portions to the mixture at room temperature. The resulting mixture was stirred at room temperature for another 1 h. Solid NaBH3CN (665.83 mg, 10.595 mmol, 2.0 equivalence) was added. The reaction was then stirred at ambient temperature for 3 h and terminated by the addition of water. The reaction was quenched by partitioning between 5 M NaOH and DCM. The aqueous layer was extracted with DCM, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product can be used directly in the next step without further purification.

[0356] LCMS: m / z(ES+),[M+H]+=379.35.

[0357]

[0358] Under a nitrogen atmosphere and at 0 °C, DIPEA (1.02 g, 7.925 mmol, 1.50 equivalent) and methanesulfonyl chloride (726.16 mg, 6.340 mmol, 1.20 equivalent) were added to a stirred solution of 1-benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidin-4-amine (2.00 g, 5.283 mmol, 1.00 equivalent) in DCM (40.00 mL). The resulting mixture was stirred for another 1 hour at room temperature. The reaction was quenched with methanol at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (2.0 g) was purified by preparative high-performance liquid chromatography under the following conditions (column: (Waters Technologies Corp., Milford, Massachusetts) Prep OBD C18 column, 30×150mm 5um; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 52B to 86B 8min; 254 / 220nm), yielded (cis)-N-(1-benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidin-4-yl)methanesulfonamide (420mg, 17.5%) as a solid.

[0359] LCMS: m / z(ES+),[M+H]+=457.35.

[0360] 1H-NMR: (400Mhz, chloroform-d) δ7.37–7.17(m,13H),3.70–3.61(m,2H),3.52(d,J=11.8Hz,2H),3.42(d,J=13.5Hz,1H),2.98 (s,3H),2.75(s,1H),2.56(tt,J=10.8,4.3Hz,2H),2.31(d,J=26.5Hz,3H),2.13–1.90(m,4H),1.73(d,J=9.9Hz,4H).

[0361]

[0362] Under a hydrogen atmosphere, 4N HCl (230.00 μL, 0.920 mmol, 1.00 equivalent) was added dropwise to a stirred solution of N-[(cis)-1-benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidin-4-yl]methanesulfonamide (420.00 mg, 0.920 mmol, 1.00 equivalent) and Pd(OH)₂ / C (258.39 mg, 0.368 mmol, 0.4 equivalent) in isopropanol (30.00 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0363] LCMS: m / z(ES+),[M+H]+=367.20.

[0364]

[0365] Under a nitrogen atmosphere at room temperature, 2-fluoropyridine (185.43 mg, 1.910 mmol, 2.00 equivalent) was added in portions to a stirred solution of N-[(cis)-3-([[(1s,4s)-4-phenylcyclohexyl]oxy]methyl)piperidin-4-yl]methanesulfonamide (350.00 mg, 0.955 mmol, 1.00 equivalent) and K2CO3 (350.00 mg, 0.955 mmol, 1.00 equivalent) in DMSO (20.00 mL). The resulting mixture was then stirred at 120 °C for 8 hours. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water, gradient 60% to 100%, 15 min; detector, UV 254 nm, yielding N-[(cis)-1-(pyridin-2-yl)-3-([[(1s,4s)-4-phenylcyclohexyl]oxy]methyl)piperidin-4-yl]methanesulfonamide (280 mg, 66.10%) as a solid. The racemic mixture was separated by chiral pre-HPLC to give an enantiomeric pure product (95.1 mg) as a solid.

[0366] LCMS: m / z(ES+),[M+H]+=444.20.

[0367] 1 H-NMR (400 Mhz, methanol-d4) δ8.07 (ddd, J=5.0, 2.0, 0.8 Hz, 1H), 7.52 (ddd, J=8.8, 7.1, 2.0 Hz,1H),7.29–7.20(m,5H),7.18–7.12(m,1H),6.88(d,J=8.7 Hz,1H),6.64(ddd,J=7.2,5.0,0.8 Hz,1H),3.92–3.82(m,2H),3.76(dd,J=13.3,6.8 Hz,1H),3.66(dd,J=9.4,5.8 Hz,1H),3.63–3.60(m,1H),3.59–3.52(m,2H),3.46(dt,J=13.2,5.8 Hz,1H),3.05(s,3H),2.55(tt,J=12.3,3.4 Hz,1H),2.30(ddt,J=9.7,6.9,3.6Hz,1H),2.11–2.02(m,2H),1.93–1.78(m,4H),1.65–1.54(m,4H).

[0368] Example 1.4

[0369]

[0370] Under air atmosphere and at room temperature, K₂CO₃ (47.13 mg, 0.341 mmol, 2.5 equivalents) was added to a stirred mixture of N-((3R,4S)-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidin-4-yl)methanesulfonamide (50.00 mg, 0.136 mmol, 1.00 equivalent) and 2-fluoropyrimidine (20.07 mg, 0.205 mmol, 1.50 equivalent) in DMSO (10 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with MeCN (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution, gradient from 0 to 0 over 10 min, gradient from 0 to 100% over 15 min, gradient from 100% to 100% over 15 min; detector, UV 254 nm. N-[(3R,4S)-1-(pyrimidin-2-yl)-3-([[(1s,4s)-4-phenylcyclohexyl]oxy]methyl)piperidin-4-yl]methanesulfonamide (53 mg, 85.64%) was obtained as a solid.

[0371] LCMS:m / z(ES+),[M+H]+=445.

[0372] 1 H-NMR (400 Mhz, methanol-d4) δ8.30(d,J=4.8 Hz,2H),7.31–7.22(m,4H),7.20–7.12(m,1H),6.56(t,J=4.8 Hz,1H),4.06(td,J=14.7,13.8,6.4 Hz,2H),3.92–3.84(m,2H),3.87(s,2H),3.83–3.73(m,1H),3.64(dd,J=9.6,6.1 Hz,2H),3.54(dd,J=9.4,7.3Hz,1H),3.05(s,3H),2.60–2.50(m,1H),2.25(s,2H),1.71–1.49(m,6H),1.31(s,1H).

[0373] Example 1.5

[0374]

[0375] To a solution of N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (200 mg, 1.00 equivalence, 546 mmol) in acetophenone (393 mg, 6.00 equivalence, 3.27 mmol), titanium isopropoxide (IV) (620 mg, 662 μL, 2.18 mmol, 4.00 equivalence) was added. The reaction mixture was stirred at 25 °C for 30 min. EtOH (2 mL) and sodium cyanoborohydride (343 mg, 5.46 mmol, 10.0 equivalence) were added to the above reaction mixture. The reaction mixture was stirred at 25 °C for one hour under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse flash chromatography under the following conditions (C18 column; mobile phase A: 0.08% NH4HCO3 (aq), mobile phase B: ACN, gradient from 1% to 100% over 30 minutes; detector, UV 254 nm) to obtain N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)-1-(((S)-1-phenylethyl)-4-piperidinyl)methanesulfonamide (180 mg, 382 mmol, 70.1%) as an oil. The racemic mixture was then separated by chiral preparative high-performance liquid chromatography to obtain an enantiomeric pure product (88.3 mg, 0.188 mmol, overall yield 34.4%) as a solid. LCMS: m / z (ES+), [M+H]+ = 471.25.

[0376] 1 H-NMR (400Mhz, methanol-d4) δ7.37–7.27(m,4H),7.26(d,2H),7.25–7.18(m,2H),7.22–7.11(m,2H),3.64(d,2H),3.56–3.41( m,1H),2.98(s,3H),2.53(ddd,1H),2.16(d,1H),1.99(d,2H),1.85(q,2H),1.81–1.64(m,2H),1.57(s,5H),1.40(d,3H).

[0377] Example 1.6

[0378]

[0379] To a solution of N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (100 mg, 273 mmol, 1.00 equivalent) and pyridinecarboxaldehyde (117 mg, 1.09 mmol, 4.00 equivalent) in methanol (5 mL), diisopropylethylamine (106 mg, 143 μL, 819 μmol, 3.00 equivalent) and sodium triacetoxyborohydride (578 mg, 2.73 mmol, 10.0 equivalent) were added. The reaction mixture was stirred at 25 °C for 2 hours under a nitrogen atmosphere. The crude product was purified by reverse flash chromatography under the following conditions (C18 column; mobile phase A: water, mobile phase B: ACN, 1% to 100% gradient over 30 minutes; detector, UV 254 nm) to obtain N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)-1-(pyridin-2-ylmethyl)piperidin-4-yl)methanesulfonamide (48.1 mg, 105 μmol, 38.5%) as a solid.

[0380] LCMS: m / z(ES+),[M+H]+=458.40.

[0381] 1 H-NMR(400Mhz, methanol-d4)δ8.46(dt,2H),7.79(td,2H),7.56(d,2H),7.32–7.21 (m,6H),7.21–7.10(m,6H),3.74–3.61(m,8H),3.64–3.53(m,4H),3.00(s,6H) ,2.70(s,2H),2.56(s,3H),2.55(d,1H),2.51(dt,4H),2.23(q,2H),2.06–2. 01(m,1H),2.00(s,3H),1.99–1.94(m,1H),1.92–1.63(m,9H),1.57(ddt,9H).

[0382] Example 1.7

[0383]

[0384] K₂CO₃ (25 mg, 0.18 mmol, 2.0 equivalent) was added to a solution of N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (33 mg, 90 mmol, 1.00 equivalent) and 5-chloro[1,2,4]triazol[1,5-c]pyrimidine (17 mg, 0.11 mmol, 1.2 equivalent) in DMSO (1.5 mL). The resulting mixture was stirred at 120 °C for 18 hours and then filtered. The filter cake was washed with DCM (3 x 2 mL) and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography under the following conditions (C18 column; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, gradient 65% to 75% over 30 minutes; detector, UV 254nm) to obtain N-((3R,4S)-1-([1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (22.3 mg, 46.0 μmol, 51%) as a solid.

[0385] LCMS:m / z(ES+),[M+H]+=485.

[0386] 1 H-NMR (400Mhz, methanol-d4) δ8.31(s,1H),7.97(d,J=6.1Hz,1H),7.26(dd,J=8.3,7.0Hz,2H),7.20–7.12(m,3H),7.09(d,J=6.1Hz,1H ),4.45–4.28(m,2H),4.17(dd,J=13.5,3.4Hz,1H),4.06(dd,J=13.5Hz,1H),3.89(m,1H),3.68(dd,J=9.6,5.6Hz,1H),3.57(dd, J=9.6,8.0Hz,1H),3.52–3.46(m,1H),3.06(s,4H),2.54–2.43(m,1H),2.43–2.37(m,1H),2.16–1.91(m,2H),1.85(d,J=13.1Hz, 1H),1.75(td,J=12.8,3.9Hz,1H),1.71(td,J=12.7Hz,1H),1.65(td,J=13.8,3.1Hz,1H),1.59–1.51(m,2H),1.49–1.41(m,2H).

[0387] Example 1.8

[0388]

[0389] At 0 °C, 1-benzyl-3-((((1S,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-one (500 mg, 1.32 mmol, 1.00 equivalent) was added to a suspension of NaH (53.0 mg, 60 wt%, 1.32 mmol, 1.00 equivalent) in THF (10 mL). The resulting mixture was stirred at 0 °C for 30 min. Under a nitrogen atmosphere, a solution of methyl iodide (0.166 mL, 0.376 g, 2.65 mmol, 2.00 equivalent) in THF (10 mL) was added dropwise to the reactants at 0 °C. The resulting mixture was stirred at 25 °C for another 2 h. The reaction was then quenched by adding a saturated aqueous solution of ammonium chloride at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 50 mL EtOAc). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (PE / EtOAc = 8 / 1) to give (S)-1-benzyl-3-methyl-3-((((1S,4R)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-one (124 mg, 0.317 mmol, yield 20%) as an oil.

[0390] LCMS:m / z(ES+),[M+H]+=312.

[0391] 1 ¹H-NMR (400 MHz, chloroform-d) δ 7.45–7.31 (m, 7H), 7.25–7.19 (m, 3H), 3.75–3.54 (m, 5H), 2.89–2.78 (m, 2H), 2.72–2.42 (m, 5H), 2.01 (dd, 2H), 1.84–1.71 (m, 2H), 1.67–1.59 (m, 2H), 1.51 (dd, 2H), 1.23 (s, 3H).

[0392]

[0393] At 25°C, zinc chloride (117 μL, 0.7 mol, 82.2 μmol, 0.14 equivalence) was added to a stirred solution of (S)-1-benzyl-3-methyl-3-((((1S,4R)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-one (230 mg, 0.587 mmol, 1.00 equivalence) in 10 mL of methanol. The resulting mixture was stirred at 25°C for 10 min. Under a nitrogen atmosphere, ammonium formate (741 mg, 11.7 mmol, 20.0 equivalence) was added to the mixture at 25°C. The resulting mixture was stirred at 25°C for another 30 min. Under a nitrogen atmosphere, NaCNBH3 (221 mg, 3.52 mmol, 6.00 equivalence) was added to the mixture at 25°C. The reaction was stirred at 25°C for another three hours, then cooled to 0°C and quenched by adding a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give (3R)-1-benzyl-3-methyl-3-((((1S,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-amine (220 mg, 560 μmol, 95.4% yield) as an oil. The crude product was used directly in the next step without further purification.

[0394] LCMS:m / z(ES+),[M+H]+=393.

[0395]

[0396] To a solution of (3R)-1-benzyl-3-methyl-3-((((1S,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-amine (230 mg, 0.586 mmol, 1.00 equivalent) and diisopropylethylamine (0.306 mL, 227 mg, 1.76 mmol, 3.00 equivalent) in DCM (20 mL), methanesulfonyl chloride (0.0685 mL, 101 mg, 0.879 mmol, 1.50 equivalent) was added. The resulting mixture was stirred at 25 °C for one hour. The residue was purified by preparative thin-layer chromatography (PE / EtOAC = 2 / 1) to give N-((3R)-1-benzyl-3-methyl-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (90 mg, 0.19 mmol, 33%) as an oil.

[0397] LCMS:m / z(ES+),[M+H]+=471.

[0398] 1H-NMR(400MHz,DMSO-d6)δ7.31–7.16(m,10H),6.84(d,1H),3.87(s,1H),3.66–3.51(m,2H),3.49–3.38(m,3H),3.23(s,1H),3.1 8(s,1H),3.07–2.99(m,1H),2.93(s,3H),2.80(d,2H),2.55(d,1H),2.00(d,2H),1.87–1.38(m,12H),1.25(dd,6H),0.98(s,3H).

[0399]

[0400] Under a nitrogen atmosphere, palladium hydroxide (1.25 g, 10 wt%, 892 μmol, 3.00 equivalent) was added to a solution of N-((3R)-1-benzyl-3-methyl-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (140 mg, 297 μmol, 1.00 equivalent) in isopropanol (15 mL). Hydrochloric acid (744 μL, 4 mol, 2.97 mmol, 10.0 equivalent) was then added to the mixture. The resulting mixture was hydrogenated for 12 hours at room temperature using a hydrogen balloon under a hydrogen atmosphere. The sample was filtered through a pad and concentrated under reduced pressure to obtain a crude product. This crude product was used directly in the next step without further purification.

[0401] LCMS:m / z(ES+),[M+H]+=381.

[0402]

[0403] 2-Fluoropyridine (86.5 mg, 891 μmol, 3.00 equivalent) was added to a solution of N-((3R)-3-methyl-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (113 mg, 297 μmol, 1.00 equivalent) and K2CO3 (82.1 mg, 594 μmol, 2.00 equivalent) in DMSO (4 mL). The resulting mixture was stirred at 120 °C for 24 hours.

[0404] The crude product was purified by preparative chiral high-performance liquid chromatography under the following conditions: column, IG-3, 4.6*50mm³ / um; mobile phase A, hexane plus 0.2% isopropanol; mobile phase B, EtOH:DCM = 1:1; isocratic ratio 85:15; flow rate, 1 mL / min. N-((3R,4S)-3-methyl-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (10 mg, 22 μmol, 33%) was obtained as a solid.

[0405] LCMS:m / z(ES+),[M+H]+=458.

[0406] 1 H-NMR (400Mhz, methanol-d4) δ8.04(dd,1H),7.50(dd,1H),7.33–7.23(m,2H),7.23–7.11 (m,3H),6.89(d,1H),6.62(dd,1H),4.43–4.29(m,1H),4.20(dd,1H),3.57(d,1H),3 .51–3.36(m,3H),3.09–2.89(m,4H),2.74(d,1H),2.54(dd,1H),2.08–1.98(m,3H), 1.98–1.83(m,1H),1.77(d,2H),1.66–1.47(m,2H),1.42–1.29(m,1H),1.24(s,3H).

[0407] Example 2: Human OX2R IP1 Detection

[0408] T-Rex CHO cells stably overexpressing human oxoxetine-2 receptor (OX2R) were induced overnight in T225 flasks with 1 μg / mL doxycycline. Twenty-four hours after induction, cells were cleaved with acoutec and plated onto 384-well surrogate plates at a rate of 30,000 cells / well. Cells were then treated for 1 hour at 37°C with different test compounds in 1X stimulation buffer (pH 7.4) containing 10 mM hydroxyethylpiperazine ethanethioate, 1 mM CaCl2, 0.5 mM MgCl2, 4.2 mM KCl, 146 mM NaCl, 5.5 mM glucose, and 50 mM LiCl. After incubation, the reaction was terminated by adding an assay mixture consisting of IP1-d2 and anti-IP1 cavitation compounds diluted in lysis buffer and 1X stimulation buffer. The plates were incubated at room temperature for 1 hour, and then… Inositol phosphate levels were measured using a multi-mode tablet reader.

[0409] Cisbio IP1 is a cell-based functional assay that quantifies the accumulation of inositol monophosphate (IP), a metabolite released upon activation of the orexin 2 receptor via the phospholipase C-Gq signaling pathway. This is a competitive immunoassay in which IP1 produced by cells upon receptor activation competes with IP1 analogs coupled to the d2 fluorophore (receptor) for binding to an anti-IP1 monoclonal antibody labeled with an Eu cavitation compound (donor). The measured HTRF-FRET-based signal is inversely proportional to the concentration of IP1 produced.

[0410] EC reported in Table 2 50 The values ​​were obtained based on the human OX2R IP1 trials described above. The data represent average EC50 values. 50 Values ​​± SEM. The compound (2R,3S)-3-((methanesulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)-piperidine-1-carboxylic acid methyl ester (sometimes referred to herein as reference compound A) is a reference compound disclosed in Example 5 of PCT International Publication No. WO2017 / 135306.

[0411] Table 2

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423] ***EC 50 <100nM

[0424] **EC 50 100-1000nM

[0425] *EC 50>1000nM

[0426] Example 3: MDCK-MDR1 Permeability Test

[0427] Use seeding in Solvo PreadyPort TM MDCK-MDR1 cells in MDCK 96-well plates were used to assess the bidirectional permeability of the test compounds in MDCK-MDR1 cells (apex-to-base and base-to-apex directions). Plates were received from ReadyCell (Barcelona, ​​Spain) and processed according to ReadyPort. TM The user manual will be used for processing.

[0428] For apex-to-base (A→B) permeability, 80 μL of HBSS (Hank's Balanced Salt Solution) assay buffer co-administered with the test compound (3 μM) and LY (Lucifax) (100 μM) was added to the donor side (A), while 250 μL of HBSS buffer was added to the recipient side (B). For base-to-apex (B→A) permeability, 255 μL of the test compound (3 μL) in HBSS assay buffer was added to the donor side (B), while 75 μL of HBSS buffer containing LY (100 μL) was added to the recipient side (A).

[0429] Place the plate in an incubator at 37°C. After preheating for 10 minutes, take a 5 μL aliquot from the donor compartment as the dosing solution. Return the MDCK-MDR1 incubation plate to the incubator and incubate at 37°C for 2 hours. After 2 hours of incubation, take 25 μL and 5 μL aliquots from the recipient and donor compartments, respectively. Dilute the 5 μL aliquots from the donor compartment (before and after 2 hours of incubation) with 20 μL of HBSS buffer. Mix all samples with 150 μL of acetonitrile containing internal standard (IS) and 200 μL of water, and analyze by LC-MS / MS.

[0430] Apparent penetration rate (P) app The following formula is used to calculate:

[0431] P app =dQ / dt x 1 / A x C0

[0432] in:

[0433] dQ / dt: The amount of substance transferred during the incubation time (nmol / s).

[0434] A: Inserted area (PreadyPort) TM MDR1-96 is 0.14cm 2 )

[0435] C0: The initial concentration (nmol / mL) of the product applied in the top (A→B) or base (B→A) region.

[0436] Outflow rate (ER) is measured by P app (From base to apex) divided by P app Measured (from apex to base). It is a general measure of participation in active processes. Er > 2 is considered active dynamic transport.

[0437] Use the following formula to measure the recovery rate:

[0438]

[0439] in:

[0440] V R Volume of the receptor chamber (mL)

[0441] V D Volume of the donor chamber (mL)

[0442] C N Concentration (μM) of the drug solution collected after 10 minutes of incubation.

[0443] C R final Receptor concentration at the end of incubation (μM)

[0444] C D final Donor concentration (μM) at the end of incubation

[0445] The data reported in Table 3 are based on the aforementioned MDCK-MDR1 permeability test.

[0446] Table 3

[0447]

[0448]

[0449] Example 4: Hepatocyte stability test

[0450] In vitro metabolic stability was assessed using frozen hepatocytes (BioIVT, Baltimore, MD) from male Sprague Dawley rats and 50 mixed-sex humans. In 48-well plates, cells containing 2 × 10⁻⁶ cells were used. 6 The incubation mixture was prepared by mixing 250 μL of pre-warmed KHB (Krebs-Henseleit buffer) with 250 μL of pre-warmed KHB buffer containing 2 μM of the test compound. The final concentration was 1 μM of the test compound (0.1% DMSO) and 1 × 10⁻⁶ cells / mL hepatocytes.6 Hepatocytes / mL. The reaction mixture was incubated at 37°C. At time points (0, 15, 30, 60, 120, and 240 minutes), 50 μL of the incubation mixture was transferred to a 96-well plate containing 300 μL of ice-cold acetonitrile (containing 30 ng / mL labetalol and 10 ng / mL naltrexone-d3 as internal standards) and immediately placed on ice to terminate the reaction. The sample was centrifuged, and the supernatant was transferred to a 96-well plate for analysis by liquid chromatography-tandem mass spectrometry (LC-MS / MS) to monitor the consumption of the test compounds.

[0451] Assuming the peak area ratio (analyte / IS) at the zero-minute time point is 100%, the remaining percentage is calculated by dividing the remaining peak area ratio at other time points by the peak area ratio at the zero-minute time point. The data is fitted to a first-order decay model to determine the half-life. The slope of the line is determined from the logarithmic (ln) peak area versus time graph. Subsequently, the half-life (T) is calculated using the following formula. 1 / 2 ) and intrinsic clearance rate (CL) int ):

[0452] Elimination rate constant (k) = (-slope)

[0453] Half-life (T) 1 / 2 min=0.693 / k

[0454] Inherent clearance rate (CL) int (mL / min / million cells) = (V×0.693) / T 1 / 2

[0455] V = Incubation volume (mL) / Number of cells

[0456] In vitro T 1 / 2 Converted to in vitro intrinsic clearance rate (CL) int,hep The unit is mL / min / kg, and the formula is as follows:

[0457]

[0458] In vitro intrinsic clearance rate (CL) int,hep ) and liver clearance rate (CL) ,hep The proportion is calculated using the following formula, which is adapted from a well-mixed model.

[0459]

[0460] Where Q is the hepatic blood flow and fu is the unbound portion (assumed to be uniform here). All parameters used in the calculation are shown below (Table 4).

[0461] Table 4. Physiological parameters used in in vitro to in vivo scaling.

[0462]

[0463] Davies B. and Morris T. (1993) Physiological parameters in laboratory animals and humans. Pharma Res. 10(7):1093-1095.

[0464] Extraction ratio (ER) is calculated by dividing the hepatic clearance of the compound by the hepatic blood flow. The data reported in Table 5 were obtained based on the aforementioned human hepatocyte stability assays.

[0465] Table 5

[0466]

[0467]

[0468]

[0469] Example 5: Evaluation of the arousal effect in Sprague-Dawley rats

[0470] Arousal was assessed in adult male Sprague-Dawley rats using electroencephalography (EEG) and electromyography (EMG). All rats (Charles River Laboratories, Raleigh, NC, USA) underwent intraperitoneal implantation of a telemetry device (F50-EEE, Data Sciences International Inc., MN, USA) under isoflurane anesthesia. For EEG, stainless steel screws were implanted in the frontal and parietal cortices, and a reference screw was placed in the cerebellum. Additionally, an electrode was placed in the neck muscles for EMG. Rats were given carboprofen post-surgery and underwent a 7- to 10-day recovery period. Rats were acclimatized to the laboratory for 7 days and maintained a 12-hour light-dark cycle.

[0471] Electroencephalogram (EEG) and electromyogram (EMG) data were recorded using a DSI telemetry system and Ponemah software (Data Sciences International Inc., MN, USA). Sleep-wake cycles were scored manually and by Somnivore (a supervised machine learning software platform) in 10-second intervals. Visual inspection of the recordings was performed as needed for post-processing.

[0472] All test compounds were dissolved in 5% DMSO and suspended in 95% saline containing 0.5% methylcellulose and 0.5% Tween. In a crossover design, rats were administered the compound at time factor 5 (ZT5) during an inactive light phase at a dose of 3.33 ml / kg body weight. Unless otherwise stated, all compounds were administered orally. Recording for each rat began immediately after administration and continued for up to 6 hours post-administration.

[0473] Two key endpoints included wakefulness and cortical activation time. Wakefulness was determined by sleep-wake phase analysis. Cortical activation time was based on the duration of frontal lobe gamma oscillations (30–100 Hz), a key characteristic of wakefulness, which was elevated relative to baseline before treatment. Mean cortical activation time was calculated 6 hours post-administration relative to mediator treatment. Results are shown in Table 6 below.

[0474] Table 6

[0475]

[0476] PO (oral); SC (subcutaneous); mpk (mg / kg)

[0477] While the invention has been specifically shown and described with regard to its preferred embodiments, those skilled in the art will understand that various changes in form and detail may be made therein without departing from the scope of the invention as defined in the appended claims.

Claims

1. A compound of formula IA or a pharmaceutically acceptable salt thereof: (I-A) in: T is either CR6 or N; U is either CR5 or N; V is either CR4 or N; W is either CR3 or N; X is either CR2 or N; The condition is The ring contains no more than three nitrogen atoms; E is selected from C1-C3 alkyl, wherein the C1-C3 alkyl is not substituted or is substituted by one or more halogens, hydroxyl groups, C1-C3 alkyl groups or C1-C3 alkoxy groups; R1 is (CR) c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is unsubstituted or substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted by one or more halogens or deuterium; R c and R d Each is independently H, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium; n is 0 or 1; Each of R2, R3, R4, R5 and R6, when present, is independently selected from H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with one or more halogens or deuterium. R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is independently H, a halogen, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium; Or, R8 and R 11 Together they form unsubstituted C1-C3 alkylene groups or C1-C3 alkylene groups substituted with one or more halogens; Or, R9 and R 10 Together they form unsubstituted C1-C3 alkylene groups or C1-C3 alkylene groups substituted with one or more halogens; p is 0, 1, 2, 3 or 4; Each R 14 It is independently selected from deuterium, halogen, hydroxyl and cyano groups.

2. The compound according to claim 1, wherein the compound of formula IA or a pharmaceutically acceptable salt thereof is the compound of formula I or a pharmaceutically acceptable salt thereof: (I)。 3. The compound according to claim 1 or 2, wherein... Selected from , , and .

4. The compound according to claim 1 or 2, wherein... Selected from , , , , and .

5. The compound according to claim 1 or 2, wherein... Selected from , , , , and .

6. The compound according to claim 1 or 2, wherein yes .

7. The compound according to claim 1 or 2, wherein p is 0.

8. The compound according to claim 1 or 2, wherein p is 1 or 2.

9. The compound according to claim 1 or 2, wherein E is an unsubstituted C1-C3 alkyl group.

10. The compound according to claim 1 or 2, wherein E is a C1-C3 alkyl group substituted with one or more halogens, hydroxyl groups, C1-C3 alkyl groups, or C1-C3 alkoxy groups.

11. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10 heteroaryl groups), wherein the aryl or heteroaryl group is unsubstituted.

12. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted by one or more halogens or deuterium.

13. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10 heteroaryl), wherein the aryl or heteroaryl group is unsubstituted, and further wherein n is 0.

14. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 0.

15. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10 heteroaryl), wherein the aryl or heteroaryl group is unsubstituted, and further wherein n is 1.

16. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the aryl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 1.

17. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 (aryl), where the aryl group is unsubstituted.

18. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl), wherein the aryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted by one or more halogens or deuterium.

19. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 (aryl), where the aryl group is unsubstituted, and further where n is 0.

20. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl), wherein the aryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 0.

21. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(5 to 10 heteroaryl groups), where the heteroaryl groups are unsubstituted.

22. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the heteroaryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted by one or more halogens or deuterium.

23. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(5 to 10 heteroaryl groups), wherein the heteroaryl group is unsubstituted, and further wherein n is 0.

24. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(5 to 10-membered heteroaryl), wherein the heteroaryl group is substituted by one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted by one or more halogens or deuterium, and further wherein n is 0.

25. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(5 to 7-membered heteroaryl), wherein the phenyl or heteroaryl group is unsubstituted.

26. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(5 to 7-membered heteroaryl), wherein the phenyl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium.

27. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(5 to 7-membered heteroaryl), wherein the phenyl or heteroaryl group is unsubstituted, and further wherein n is 0.

28. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(5 to 7-membered heteroaryl), wherein the phenyl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 0.

29. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(6-membered heteroaryl), wherein the phenyl or heteroaryl group is unsubstituted.

30. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(6-membered heteroaryl), wherein the phenyl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium.

31. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(6-membered heteroaryl), wherein the phenyl or heteroaryl group is unsubstituted, and further wherein n is 0.

32. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(phenyl) or (CR) c R d ) n -(6-membered heteroaryl), wherein the phenyl or heteroaryl group is substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups or C1-C3 alkyl groups substituted with one or more halogens or deuterium, and further wherein n is 0.

33. The compound according to claim 1 or 2, wherein each of R2, R3, R4, R5 and R6, when present, is independently selected from H, halogen, hydroxyl and unsubstituted C1-C3 alkyl.

34. The compound according to claim 1 or 2, wherein R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is independently H, a halogen, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium.

35. The compound according to claim 1 or 2, wherein R8 and R 11 Together they constitute unsubstituted C1-C3 alkylene groups or C1-C3 alkylene groups substituted with one or more halogens.

36. The compound according to claim 1 or 2, wherein R9 and R 10 Together they form unsubstituted C1-C3 alkylene groups or C1-C3 alkylene groups substituted with one or more halogens.

37. The compound according to claim 1 or 2, wherein each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H.

38. The compound according to claim 1 or 2, wherein each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group.

39. The compound according to claim 1 or 2, wherein each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

40. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(5 to 10 heteroaryl groups), each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H.

41. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(5 to 10 heteroaryl groups), each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group.

42. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(5 to 10 heteroaryl groups), each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

43. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(5 to 7 heteroaryl), each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H.

44. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(5 to 7 heteroaryl), each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group.

45. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(5 to 7 heteroaryl), each of R2, R3, R4, R5 and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

46. ​​The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl), each of R2, R3, R4, R5, and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H.

47. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl), each of R2, R3, R4, R5, and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group.

48. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl), each of R2, R3, R4, R5, and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

49. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6 aryl), each of R2, R3, R4, R5, and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H.

50. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6 aryl), each of R2, R3, R4, R5, and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl group.

51. The compound according to claim 1 or 2, wherein R1 is (CR c R d ) n -(C6 aryl), each of R2, R3, R4, R5, and R6, when present, is H, and R7, R8, R9, R 10 R 11 R 12 and R 13 Each of them is H or fluorine.

52. A compound or a pharmaceutically acceptable salt thereof, selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

53. The compound according to claim 2, wherein the compound is Or its pharmaceutically acceptable salt.

54. The compound according to claim 2, wherein the compound is Or its pharmaceutically acceptable salt.

55. The compound according to claim 2, wherein the compound is Or its pharmaceutically acceptable salt.

56. The compound according to claim 2, wherein the compound is Or its pharmaceutically acceptable salt.

57. A pharmaceutical composition comprising a compound of any one of claims 1-56 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

58. Use of the compound of any one of claims 1-56 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 57, in the preparation of a medicament for treating narcolepsy.

59. Use of the compound of any one of claims 1-56 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 57, in the preparation of a medicament for treating sudden collapse.

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