Substituted piperidino compounds and related therapeutic methods

Abstract

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

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 128,511, filed on 21 December 2020. The entire contents of the above application are incorporated herein by reference as forming part of this specification.

[0002] The present invention relates to substituted piperidino compounds, and more particularly to substituted piperidino compounds having agonist activity. [Background technology]

[0003] Orexin is a neuropeptide synthesized and released by a subpopulation of neurons within the lateral hypothalamus and its surrounding areas. Orexin consists of two subtypes: 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 subtypes of orexin receptors (type 1 and type 2) (Cell, Vol. 92, 573-585, 1998). Activation of orexin receptors is known to be important for various central nervous system functions, including maintaining wakefulness, energy homeostasis, reward processing, and motivation (Saper et al., TRENDS in Neuroscience 2001; Yamanaka et al., Neuron 2003; Sakurai, Nature Reviews Neuroscience 2014).

[0004] Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, sudden episodes of muscle paralysis (cataplexy), and disrupted sleep patterns (Mahoney et al., Nature Reviews Neuroscience, 2019). Narcolepsy is known to be caused by the degeneration of orexin neurons. Narcolepsy symptoms can be modeled in transgenic mice genetically modified to degenerate 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 suggested that the orexin 2 receptor plays a dominant role in maintaining wakefulness (Cell, Vol. 98, 437-451, 1999, Neuron, Vol. 38, 715-730, 2003). Therefore, orexin 2 receptor agonists may be a therapeutic agent for narcolepsy or other disorders that cause excessive daytime sleepiness, such as Parkinson's disease (CNS Drugs, Vol.27, 83-90, 2013; Brain, Vol.130, 2007, 1586-1595).

[0005] Compounds with agonist activity at the orexin 2 receptor are hypothesized to be useful as novel therapeutic agents for conditions such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, coma and other disorders of consciousness, narcolepsy syndrome, hypersomnia syndromes characterized by hypersomnia (e.g., Parkinson's disease, Guillain-Barré syndrome, or Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with osteopenia, 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; International Publication No. 2015 / 073707; Journal of the American College of Cardiology, Vol.66, 2015, pages) 2522-2533; International Publication No. 2015 / 048091; International Publication No. 2015 / 147240).

[0006] Several compounds possessing orexin 2 receptor agonist activity have been reported (U.S. Patent No. 8,258,163; International Publication No. 2015 / 088000; International Publication No. 2014 / 198880; Journal of Medicinal Chemistry, Vol. 58, pages 7931-7937; U.S. Patent Application Publication No. 20190040010; U.S. Patent Application Publication No. 20190031611; U.S. Patent Application Publication No. 20170226137). However, these compounds are not satisfactory in terms of, for example, activity, pharmacokinetics, permeability to the brain / central nervous system, or safety, and the development of improved compounds with orexin 2 receptor agonist activity is desired. [Overview of the Initiative]

[0007] The present invention aims to provide substituted piperidino compounds having orexin 2 receptor agonist activity.

[0008] Thus, in a first aspect, the present invention provides a compound represented by formula I-A or a pharmaceutically acceptable salt thereof: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein: In the formula: T is CR6 or N; U is CR5 or N; V is CR4 or N; W is CR3 or N; X is CR2 or N; [Chemical formula] provided that the ring contains no more than three nitrogen atoms; E is NR b , , d , 10 , d , <00DO009>, c , n R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl and C1-C3 alkylene-(4-10 member heterocyclyl), selected from the group consisting of, C1-C3 alkylene-NR a R<DDDDDD06>, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C H-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl or C1-C3 alkylene-(4-10 member heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; R a and R b are each independently H or unsubstituted C1-C3 alkyl; R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d )n -(5-10 member heteroaryl), where the aryl or heteroaryl is unsubstituted or 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 groups; R c and R d Each of these is independently H, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium atoms; n is either 0 or 1; Each of R2, R3, R4, R5, and R6, when present, is independently selected from the group consisting of H, halogens, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl groups, and C1-C3 alkyl groups substituted with one or more halogens or deuterium; R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H, a halogen, an unsubstituted C1-C3 alkyl, or a C1-C3 alkyl substituted with one or more halogens or deuterium; Alternatively, R8 and R 11 It forms either an unsubstituted C1-C3 alkylene or a C1-C3 alkylene substituted with one or more halogens; Alternatively, R9 and R 10 It forms either an unsubstituted C1-C3 alkylene or a C1-C3 alkylene substituted with one or more halogens; p is 0, 1, 2, 3, or 4. Each R 14 This provides compounds represented by formula IA, or pharmaceutically acceptable salts thereof, independently selected from the group consisting of deuterium, halogens, hydroxyl, and cyano.

[0009] In one embodiment, a compound of formula IA having the structure of formula I, or a pharmaceutically acceptable salt thereof: [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: 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; [ka] Under the condition that the ring contains three or fewer nitrogen atoms; E is NR a R b C1-C3 Alkylene-NR a R b Selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, and C1-C3 alkylene-(4-10 member heterocyclyl), C1-C3 alkylene-NR a R b C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclil, or C1-C3 alkylene-(4-10 member heterocyclil) may be unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl molecules; R a and R b Each of these is independently H or an unsubstituted C1-C3 alkyl group; R1 is (CR c R d ) n -(C6-C 10 (Aryl) or (CR) c R d ) n -(5-10 member heteroaryl), where the aryl or heteroaryl is unsubstituted or 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 groups; R c and R d Each of these is independently H, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium atoms; n is either 0 or 1; Each of R2, R3, R4, R5, and R6, when present, is independently selected from the group consisting of H, halogens, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl groups, and C1-C3 alkyl groups substituted with one or more halogens or deuterium; R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H, a halogen, an unsubstituted C1-C3 alkyl, or a C1-C3 alkyl substituted with one or more halogens or deuterium; Alternatively, R8 and R 11 It forms either an unsubstituted C1-C3 alkylene or a C1-C3 alkylene substituted with one or more halogens; Alternatively, R9 and R 10 It forms either an unsubstituted C1-C3 alkylene or a C1-C3 alkylene substituted with one or more halogens; p is 0, 1, 2, 3, or 4. Each R 14 This provides compounds represented by formula IA, or pharmaceutically acceptable salts thereof, independently selected from the group consisting of deuterium, halogens, hydroxyl, and cyano.

[0010] Pharmaceutical compositions comprising compounds of formula IA or formula I, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers are also provided herein.

[0011] In another embodiment, the Specified Provision provides a method for treating narcolepsy in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to the subject in need.

[0012] In another embodiment, the Specified Reference Indicators provide a method for treating cataplexy in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to a subject in need. [Modes for carrying out the invention]

[0013] For example, compounds useful for treating a given narcolepsy or cataplexy are provided herein, such as compounds of formula IA or formula I, or pharmaceutically acceptable salts thereof.

[0014] In non-limiting embodiments, these compounds can modulate the orexin 2 receptor. In certain embodiments, the compounds provided herein are considered to be orexin 2 agonists. Therefore, in one embodiment, the compounds provided herein are useful for treating narcolepsy in a given area by acting as agonists of the orexin 2 receptor.

[0015] definition The following is a list of definitions for various terms used to describe the present invention. These definitions apply to the terms used herein and throughout the claims, individually or as part of a larger group, unless otherwise limited in specific cases.

[0016] Unless otherwise defined, all technical and chemical terms used herein have the same meaning as commonly understood by those skilled in the art. Generally, the nomenclature and testing methods used herein in cell culture, molecular genetics, organic chemistry, and peptide chemistry are well known and commonly used in the art.

[0017] As used herein, articles such as "a" and "an" refer to one or more than one (i.e., at least one) of their grammatical objects. For example, "element" means one term or more than one element. Furthermore, the use of terms such as "including" and other forms such as "include," "includes," and "included" is not limited.

[0018] Where used herein, the term “about” is understood by those skilled in the art and varies to some extent depending on the context in which it is used. Where used herein when referring to measurable values ​​such as quantity or duration, the term “about” means that the given value and variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1%, are appropriate for carrying out the methods of this disclosure.

[0019] When used herein, "EC 50 The term "maximum effect" refers to the concentration of a compound required to achieve an effect that represents 50% of the compound's maximum impact.

[0020] As used herein, the term "agonist" refers to a compound that, upon contact with a target of interest (e.g., an orexin 2 receptor), increases the magnitude of activity or function of a certain target compared to the magnitude of activity or function observed in the absence of the agonist.

[0021] The terms “treat,” “treated,” “treating,” or “treatment” include the reduction or alleviation of at least one symptom associated with, or caused by, the condition, disorder, or disease being treated. In certain embodiments, treatment includes contacting an orexin 2 receptor with an effective amount of the compound of the present invention for a condition associated with narcolepsy or cataplexy.

[0022] As used herein, the terms “prevent” or “prevention” mean the absence of a disability or disease if one does not already exist, or the absence of further disability or disease if one already exists. The ability to prevent some or all of the symptoms associated with a disability or disease is also considered.

[0023] As used herein, the terms “patient,” “individual,” or “subject” refer to human or non-human mammals. Non-human mammals include livestock and pets, such as sheep, cattle, pigs, dogs, cats, and mice. Preferably, the patient, subject, or individual is human.

[0024] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” and “therapeutic effective dose” refer to a sufficient amount of a drug that is non-toxic but provides a desired biological effect. This effect may be a reduction or alleviation of signs, symptoms, or causes of a disease, or other desired changes in the biological system. An appropriate therapeutic dose for any given individual can be determined by those skilled in the art using routinely performed experiments.

[0025] As used herein, the term "pharmaceutically acceptable" means a substance, such as a carrier or diluent, that does not inhibit the biological activity or properties of a compound and is relatively non-toxic. This means that the substance can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components contained in the composition.

[0026] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound, the parent compound modified by converting an existing acidic or base moiety to 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; and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of a suitable salt or acid in water, an organic solvent, or a mixture of water and an organic solvent. Generally, ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred as non-aqueous media. The term “pharmaceutically acceptable salt” is not limited to monosalts or 1:1 salts. For example, “pharmaceutically acceptable salts” also include bis salts such as bis-hydrochloride. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference as constituting part of this specification.

[0027] As used herein, the terms “composition” or “pharmaceutical composition” refer to a mixture of at least one compound useful within the scope of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates the administration of the compound to a patient or subject. Multiple techniques for administering the compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0028] As used herein, “pharmaceutically acceptable carrier” means 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 is involved in transporting or delivering a compound useful within the present invention into or to a patient in such a way that it can perform its intended function. Typically, such a construct is transported or delivered from one organ or part of the body to another. Each carrier must be “acceptable” in the sense that it is compatible with other components of a formulation containing a compound useful within the scope of the present invention and is not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, and acetylcellulose; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; arginine; pyrogen-free water; physiological saline; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other non-toxic and suitable substances used in pharmaceutical formulations.

[0029] As used herein, “pharmaceutically acceptable carrier” includes any and all coatings, antimicrobial and antifungal agents, and absorption retarders, etc., that are compatible with the activity of compounds useful within the scope of the present invention and are physiologically acceptable to the patient. Supplementary active compounds may also be introduced into the composition. “pharmaceutically acceptable carrier” may further include pharmaceutically acceptable salts of compounds useful within the scope of the present invention. Other additional components that may be included in pharmaceutical compositions used in the practice of the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference as part of this specification.

[0030] As used herein, the term "alkyl," either by itself or as part of another substituent, means a linear or branched hydrocarbon having a specified number of carbon atoms unless otherwise specified (i.e., C1-C6 alkyl means an alkyl having 1 to 6 carbon atoms), and includes linear and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C1-C6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0031] As used herein, the terms "halo" or "halogen," either alone or as part of another substituent, mean a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, unless otherwise specified, preferably a fluorine atom, a chlorine atom, or a bromine atom, more preferably a fluorine atom or a chlorine atom.

[0032] As used herein, the term "alkylene" refers to a divalent aliphatic hydrocarbyl group having 1 to 4 carbon atoms, for example, in a straight chain or branched chain. Examples of this term include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), and isopropylene (-CH2CH(CH3)-).

[0033] 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 bond to another group. Examples of alkenyl groups (e.g., C2-C8 alkenyls) include, but are not limited to, ethenyl, propenyl, propa-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, and octenyl.

[0034] 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 bond site to another group. Examples of alkynyl groups (e.g., C2-C8 alkynyls) include, but are not limited to, ethynyl, propynyl, propa-1-in-2-yl, butynyl, 1-methyl-2-butyne-1-yl, heptynyl, and octynyl.

[0035] As used herein, the term "alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and t-butoxy.

[0036] As used herein, the term “cycloalkyl” means a non-aromatic carbocyclic system that is partially or completely saturated and has one, two, or three rings, which may be condensed. The term “condensed” means that a second ring exists (i.e., is bonded or formed) by having two adjacent atoms common to (i.e., shared with) the first ring. Cycloalkyl also includes dicyclic structures that can be essentially crosslinked or are spirocyclic, with each individual ring in the dicyclic structure varying in number from 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]heptanyl, and bicyclo[1.1.1]pentyl.

[0037] As used herein, the term “heterocyclyl” means a non-aromatic carbocyclic system containing one, two, three, or four heteroatoms independently selected from N, O, and S, and having one, two, or three rings. Such rings may be condensed, as defined above. Heterocyclyls also include bicyclic structures that are essentially bridging or spiroring, where each individual ring in the bicyclic structure varies from 3 to 8 atoms and contains 0, 1, or 2 N, O, or S atoms. The term "heterocyclyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), specifically including but not limited to epoxyzil, oxetanyl, tetrahydrofuranil, tetrahydropyranil (i.e., oxanil), pyranil, dioxanil, azilidinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, and 1,3-thiazinanyl.

[0038] As used herein, the term “bridged bicyclic heterocyclil” refers to a non-aromatic heterocyclic system in which two rings share three or more atoms. A bridged bicyclic system may be, for example, a [3.2.1] bicyclic system such as azabicyclo[3.2.1]octane or a [3.1.1] bicyclic system such as azabicyclo[3.1.1]heptane.

[0039] It should be understood that when an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety can be bonded to a designated moiety via different ring atoms, or otherwise attached (i.e., shown or described without indication of a specific bond point), all possible points are intended, whether or not they are via a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, and the term "thiophenyl" means 2-thiophenyl or 3-thiophenyl.

[0040] As used herein, the term "substitution" means that an atom or group of atoms has been substituted with hydrogen as a substituent bonded to another group.

[0041] Compound of the present invention Therefore, in the first embodiment, the present invention relates to a compound represented by formula IA or a pharmaceutically acceptable salt thereof: [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: 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; [ka] Under the condition that the ring contains three or fewer nitrogen atoms; E is NR a R b C1-C3 Alkylene-NR a R b Selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, and C1-C3 alkylene-(4-10 member heterocyclyl), C1-C3 alkylene-NR a R b C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclil, or C1-C3 alkylene-(4-10 member heterocyclil) may be unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl molecules; R a and R b Each of these is independently H or an unsubstituted C1-C3 alkyl group; R1 is (CR c R d ) n -(C6-C 10 (Aryl) or (CR) c R d ) n -(5-10 member heteroaryl), where the aryl or heteroaryl is unsubstituted or 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 groups; R c and R d Each of these is independently H, an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one or more halogens or deuterium atoms; n is either 0 or 1; Each of R2, R3, R4, R5, and R6, when present, is independently selected from the group consisting of H, halogens, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl groups, and C1-C3 alkyl groups substituted with one or more halogens or deuterium; R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H, a halogen, an unsubstituted C1-C3 alkyl, or a C1-C3 alkyl substituted with one or more halogens or deuterium; Alternatively, R8 and R 11 It forms either an unsubstituted C1-C3 alkylene or a C1-C3 alkylene substituted with one or more halogens; Alternatively, R9 and R 10 It forms either an unsubstituted C1-C3 alkylene or a C1-C3 alkylene substituted with one or more halogens; p is 0, 1, 2, 3, or 4. Each R 14 This provides compounds represented by formula IA, or pharmaceutically acceptable salts thereof, independently selected from the group consisting of deuterium, halogens, hydroxyl, and cyano.

[0042] In one embodiment, a compound of formula IA having the structure of formula I, or a pharmaceutically acceptable salt thereof: [ka] or a pharmaceutically acceptable salt thereof; During the ceremony: 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; [ka] Under the condition that the ring contains three or fewer nitrogen atoms; E is NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl and C1-C3 alkylene-(4-10 membered heterocyclyl) selected from the group consisting of, C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl or C1-C3 alkylene-(4-10 membered heterocyclyl) is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; R a and R b are each, independently, H or unsubstituted C1-C3 alkyl; R1 is (CR c R d )- (C6-C 10 aryl) or (CR c R d ) n - (5-10 membered heteroaryl), aryl or heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens or deuterium; R c and R d are each, independently, H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens or deuterium; n is 0 or 1; When each of R2, R3, R4, R5 and R6 is present, it is independently selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl and C1-C3 alkyl substituted with one or more halogens or deuterium; When each of R2, R3, R4, R5 and R6 is present, it is independently selected from the group consisting of 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 is H, halogen, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogens or deuteriums; alternatively, R8 and R 11 together form unsubstituted C1-C3 alkylene or C1-C3 alkylene substituted with one or more halogens; alternatively, R9 and R 10 together form unsubstituted C1-C3 alkylene or C1-C3 alkylene substituted with one or more halogens; p is 0, 1, 2, 3 or 4, each R 14 is independently selected from the group consisting of deuterium, halogen, hydroxyl and cyano, and a compound represented by formula I-A or a pharmaceutically acceptable salt thereof is provided herein.

[0043] In one embodiment of formula (I),

Chemical formula

Chemical formula

[0044] In another embodiment of formula (I),

Chemical formula

[0046] In another embodiment of formula (I), [ka] teeth, [ka] It is selected from the group consisting of the following.

[0047] In another embodiment of formula (I), [ka] teeth, [ka] It is selected from the group consisting of the following.

[0048] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0049] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0050] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0051] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0052] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0053] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0054] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0055] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0056] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0057] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0058] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0059] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0060] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0061] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0062] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0063] In another embodiment of formula (I), [ka] teeth [ka] That is the case.

[0064] 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.

[0065] In another embodiment of equation (I), p is 1, and R 14 is deuterium. In another embodiment of formula (I), p is 1 and R 14 is a halogen. In another embodiment of equation (I), p is 1 and R 14 is fluorine. In another embodiment of formula (I), p is 1 and R 14 is hydroxyl. In another embodiment of formula (I), p is 1 and R 14 is cyano. In another embodiment of formula (I), p is 2 and R 14 is hydroxyl. In another embodiment of formula (I), p is 2 and R 14 is a halogen. In another embodiment of equation (I), p is 2, and each R 14 It is fluorine.

[0066] In another embodiment of equation (I), E is NR a R b In another embodiment of formula (I), E is C1-C3 alkylene-NR a R bIn 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, a C2-C4 alkenyl, or a C2-C4 alkynyl substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. 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, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. 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, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. 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, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (I), E is an unsubstituted 4- to 10-membered heterocyclil. In another embodiment of formula (I), E is a 4- to 10-membered heterocyclil substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (I), E is an unsubstituted C1-C3 alkylene-(4- to 10-membered heterocyclil). In another embodiment of formula (I), E is a C1-C3 alkylene-(4-10 member heterocycline) substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0067] 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), 4-10 member heterocyclyl, or C1-C3 alkylene-(4-10 member heterocyclyl), where the C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, or C1-C3 alkylene-(4-10 member heterocyclyl) is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

[0068] In another embodiment of formula (I), E is a C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclil, or C1-C3 alkylene-(4-10 member heterocyclil), where the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclil, or C1-C3 alkylene-(4-10 member heterocyclil) is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0069] In another embodiment of formula (I), E is a C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl), where the C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0070] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 (Aryl) or (CR) c R d ) n-(5-10 member heteroaryl), where the aryl or heteroaryl 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 -(5-10 member heteroaryl), where the aryl or heteroaryl is substituted with one or more halogens, hydroxyl atoms, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium atoms.

[0071] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 (Aryl) or (CR) c R d ) n -(5-10 member heteroaryl), where the aryl or heteroaryl is unsubstituted, and furthermore, 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 -(5-10 member heteroaryl), where the aryl or heteroaryl is substituted with one or more halogens, hydroxyl atoms, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium atoms, and furthermore, n is 0.

[0072] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 (Aryl) or (CR) c R d ) n -(5-10 member heteroaryl), where the aryl or heteroaryl is unsubstituted, and furthermore, n is 1. In another embodiment of formula (I), R1 is (CR c Rd ) n -(C6-C 10 (Aryl) or (CR) c R d ) n -(5-10 member heteroaryl), where the aryl or heteroaryl is substituted with one or more halogens, hydroxyl atoms, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium atoms, and furthermore, n is 1.

[0073] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 (aryl) and the aryl is non-substitutable. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 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 groups.

[0074] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 aryl) is non-substitutable, and furthermore, n is 0. In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 The aryl group is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium groups, and furthermore, n is 0.

[0075] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10aryl) is non-substitutable, and furthermore, n is 1. In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10 The aryl group is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium groups, and furthermore, n is 1.

[0076] In another embodiment of equation (I), R1 is (CR c R d ) n -(5-10 member heteroaryl), and the heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(5-10 member heteroaryl), where the heteroaryl is substituted with one or more halogens, hydroxyl atoms, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium atoms.

[0077] In another embodiment of equation (I), R1 is (CR c R d ) n -(5-10 member heteroaryl), where the heteroaryl is unsubstituted, and furthermore, n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(5-10 member heteroaryl), where the heteroaryl 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 groups, and furthermore, n is 0.

[0078] In another embodiment of equation (I), R1 is (CR c R d ) n -(5-10 member heteroaryl), where the heteroaryl is unsubstituted, and furthermore, n is 1. In another embodiment of formula (I), R1 is (CR c Rd ) n -(5-10 member heteroaryl), where the heteroaryl 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 groups, and furthermore, n is 1.

[0079] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5-7 member heteroaryl), where phenyl or heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5-7 member heteroaryl), where the phenyl or heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0080] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5-7 member heteroaryl), where phenyl or heteroaryl is unsubstituted, and furthermore, n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5-7 member heteroaryl), where the phenyl or heteroaryl 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 groups, and furthermore, n is 0.

[0081] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5-7 member heteroaryl), where phenyl or heteroaryl is unsubstituted, and furthermore, n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5-7 member heteroaryl), where the phenyl or heteroaryl 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 groups, and furthermore, n is 1.

[0082] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), where phenyl or heteroaryl 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), where the phenyl or heteroaryl 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 groups.

[0083] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n-(6-membered heteroaryl), where phenyl or heteroaryl is unsubstituted, and furthermore, n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), where the phenyl or heteroaryl 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 groups, and furthermore, n is 0.

[0084] In another embodiment of equation (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), where phenyl or heteroaryl is unsubstituted, and furthermore, 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), where the phenyl or heteroaryl 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 groups, and furthermore, n is 1.

[0085] In another embodiment of formula (I), each of R2, R3, R4, R5, and R6, if present, is independently selected from the group consisting of H, halogens, hydroxyls, cyanos, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with one or more halogens.

[0086] In another embodiment of formula (I), each of R2, R3, R4, R5, and R6, if present, is independently selected from the group consisting of H, halogens, hydroxyls, and unsubstituted C1-C3 alkyls.

[0087] In another embodiment of formula (I), each of R2, R3, R4, R5, and R6, if present, is independently selected from the group consisting of H, halogens, and unsubstituted C1-C3 alkyl groups.

[0088] In another embodiment of formula (I), each of R2, R3, R4, R5, and R6 is independently selected from H or halogens when present. In another embodiment of formula (I), each of R2, R3, R4, R5, and R6 is independently selected from H or fluorine when present. In another embodiment of formula (I), each of R2, R3, R4, R5, and R6 is independently selected from H or chlorine when present. In another embodiment of formula (I), each of R2, R3, R4, R5, and R6 is independently selected from H or unsubstituted C1 alkyl when present. In another embodiment of formula (I), each of R2, R3, R4, R5, and R6 is independently selected from H or hydroxyl when present. In another embodiment of formula (I), each of R2, R3, R4, R5, and R6 is H when present.

[0089] 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, an unsubstituted C1-C3 alkyl, or a C1-C3 alkyl substituted with one or more halogens or deuterium atoms.

[0090] In another embodiment of formula (I), R8 and R 11 These form either 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 These form either an unsubstituted C2 alkylene or a C2 alkylene substituted with one or more halogens. In another embodiment of formula (I), R8 and R 11 They together form an azabicyclo[3.2.1]octanyl-bridged bicyclic heterocycline.

[0091] In another embodiment of formula (I), R9 and R 10 These together form 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 These form either an unsubstituted C2 alkylene or a C2 alkylene substituted with one or more halogens. In another embodiment of formula (I), R9 and R 10 They together form an azabicyclo[3.2.1]octanyl-bridged bicyclic heterocycline.

[0092] 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-C3 alkyl. 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. 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. 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 an unsubstituted C1 alkyl. 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 halogen. In another embodiment of formula (I), R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H.

[0093] In another embodiment of equation (I), each of R2, R3, R4, R5 and R6 is H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H. In another embodiment of equation (I), each of R2, R3, R4, R5 and R6 is H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), each of R2, R3, R4, R5 and R6 is H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or halogen. In another embodiment of formula (I), each of R2, R3, R4, R5 and R6 is H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0094] In another embodiment of equation (I), R1 is (CR c R d ) n -(5-10 member heteroaryl), where R2, R3, R4, R5 and R6 are H when present, and 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 -(5-10 member heteroaryl), where R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13Each of them is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(5-10 member heteroaryl), where R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(5-10 member heteroaryl), where R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0095] In another embodiment of equation (I), R1 is (CR c R d ) n -(5-7 member heteroaryl), where R2, R3, R4, R5 and R6 are H when present, and 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 -(5-7 member heteroaryl), where R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(5-7 member heteroaryl), where R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(5-7 member heteroaryl), where R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0096] In another embodiment of equation (I), R1 is (CR c R d ) n -(6-membered heteroaryl), where R2, R3, R4, R5 and R6 are each H when present, and 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), where R2, R3, R4, R5 and R6 are each H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), where R2, R3, R4, R5 and R6 are each H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n-(6-membered heteroaryl), where R2, R3, R4, R5 and R6 are each H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0097] In another embodiment of equation (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, and R2, R3, R4, R5 and R6 are H when present, and 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, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0098] In another embodiment of equation (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, and R2, R3, R4, R5 and R6 are H when present, and 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, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0099] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6-C 10It is aryl, and each of R2, R3, R4, R5 and R6 is H when present, and 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 10 It is aryl, and each of R2, R3, R4, R5 and R6 is H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 It is aryl, and each of R2, R3, R4, R5 and R6 is H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 It is aryl, and each of R2, R3, R4, R5 and R6 is H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0100] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13Each of them is H. In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0101] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, and R2, R3, R4, R5 and R6 are H when present, and 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, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0102] In another embodiment of equation (I), R1 is (CR c R d ) n -(C6 aryl), n is 1, and R2, R3, R4, R5 and R6 are H when present, and 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, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n-(C6 aryl), n is 1, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 1, and R2, R3, R4, R5 and R6 are H when present, and R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0103] In another embodiment of equation (I), R1 is (CR c R d ) n -(6-membered heteroaryl), where 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), where 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. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), where n is 0, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), where n is 0, R7, R8, R9, R10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0104] In another embodiment of equation (I), R1 is (CR c R d ) n -(6-membered heteroaryl), where 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), where 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. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), where n is 1, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), where n is 1, R7, R8, R9, R 10 , R 11 , R 12 and R 13 Each of these is either H or fluorine.

[0105] 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 13Each 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. 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 these 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 these is either H or fluorine.

[0106] 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 12 and R 13 Each of them is H or an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 1, R7, R8, R9, R10 , R 11 , R 12 and R 13 Each of these is H or a halogen. In another embodiment of formula (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 these is either H or fluorine.

[0107] Each of the embodiments described herein with respect to the compound of formula I also applies to the compound of formula IA.

[0108] Table 1 shows certain embodiments of compounds of formula IA or formula I, or pharmaceutically acceptable salts thereof. Compounds of formula IA or formula I, or pharmaceutically acceptable salts thereof, and the compounds or pharmaceutically acceptable salts thereof shown in Table 1 may be referred to collectively or individually as “the compounds of the present invention” or “the compounds provided herein.” [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

[0109] The disclosed compounds have one or more stereocenters, each stereocenter may exist independently in either an R or S configuration. In one embodiment, the compounds described herein exist as optically active or racemic compounds. It should be understood that the compounds described herein encompass racemic compounds, optically active compounds, regioisomers, and stereoisomers or combinations thereof having the therapeutically useful properties described herein.

[0110] The preparation of optically active compounds can be carried out in any preferred manner, including, but not limited to, recrystallization techniques for racemic mixtures, synthesis of optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In one embodiment, a mixture of two or more isomers is used as the compounds of the disclosure described herein. In another embodiment, pure isomers are used as the compounds of the disclosure described herein. In yet another embodiment, the compounds described herein contain 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 separation of compounds and their isomers can be carried out by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0111] In one embodiment, the disclosed compound may exist as a tautomer. All tautomers are included within the range of compounds presented herein.

[0112] The compounds described herein also include isotope-labeled compounds in which one or more atoms have the same atomic number but are replaced by atoms with atomic masses or mass numbers different from those typically found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P and 35Examples include, but are not limited to, S. In one embodiment, isotope-labeled compounds are useful in studies of the tissue distribution of drugs or substrates. In another embodiment, substitution with a high-mass-number isotope such as deuterium provides greater metabolic stability (e.g., increased half-life in vivo or decreased required dose). In yet another embodiment, the compounds described herein are 2 It contains the H (i.e., deuterium) isotope.

[0113] In yet another embodiment, 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 1N is useful in positron emission tomography (PET) studies to investigate receptor occupancy in substrates. Isotope-labeled compounds are prepared by any suitable method or by a process that uses an appropriate isotope-labeling reagent instead of an unlabeled reagent used in other methods.

[0114] Certain compounds and other compounds described herein, which are encompassed by one or more of the formulas having different substituents, are used with the techniques and materials described herein, for example, in 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 Reactions, Volumes 1-40 (John Wiley and Sons, 1991); Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989); March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001); and Green and Wuts, Protective Groups in Organic Synthesis 3rd The compounds are synthesized as described in Ed., (Wiley 1999) (all of which are incorporated herein by reference as constituting part of this disclosure). The general methods for preparing the compounds described herein are modified by using appropriate reagents and conditions to introduce the various parts found in the formulas provided herein.

[0115] The compounds described herein are synthesized starting from compounds available from commercial sources using any preferred procedure, or prepared using the procedures described herein.

[0116] Treatment method The compounds of the present invention can be used in methods to treat a target disease or condition, the method comprising administering the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to the target. In one embodiment of the method described herein, the target is a human. In one aspect, the compounds provided herein are useful in treating a disease or condition by acting as an orexin 2 receptor agonist.

[0117] The compounds of the present invention may be used to treat a disease or condition selected from the group consisting of narcolepsy, cataplexy, or hypersomnia in a subject where such treatment is necessary.

[0118] In one embodiment, the compounds of the present invention may be used to treat narcolepsy in a given subject. In one embodiment, the compounds of the present invention may be used to treat cataplexy in a given subject. In one embodiment, the compounds of the present invention may be used to treat hypersomnia in a given subject.

[0119] Orexin 2 receptors are important in a wide range of biological functions. This suggests that orexin 2 receptors play a certain role in a diverse range of disease processes in humans and other species. The compounds of the present invention are useful in treating, preventing, or relieving one or more of the following symptoms or diseases among various neurological and psychiatric disorders associated with altered sleep / wake function. In other words, narcolepsy, narcolepsy with cataplexy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome characterized by hypersomnia (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Mobius 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 encephalopathy, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cell disease, exogenous obesity, hyperinsulinemia obesity, hyperplastic obesity, pituitary obesity, hyperplastic obesity) Obesity, hypothyroidism, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, diet-induced obesity, hypogonadism, systemic mast cell disease, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects and complications of anesthesia, sleep disorders, excessive daytime sleepiness, insomnia, sleeplessness, intermittent sleep, nocturnal myoclonus, REM sleep clusters, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep disorders (sleepSleep disorders, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, dusk in dementia, twilight syndrome, circadian rhythm disorders, fibromyalgia, conditions resulting from poor sleep quality, bulimia, obsessive-compulsive eating disorder, obesity-related disorders, hypertension, diabetes mellitus, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rate, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, coronary artery disease, polycystic ovary syndrome, craniopharyngioma, Prader-Willi syndrome, Fröhlich syndrome, growth hormone deficiency, normal mutant short stature Children with stature, Turner syndrome, acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, reduced birth rate, infertility, male gonadal dysfunction, sexual and reproductive dysfunction such as hirsutism in men and women, fetal defects associated with obesity in pregnant women, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux disease, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, risk of secondary outcomes of obesity such as reduced risk of left ventricular hypertrophy, migraine, headache, neuropathic Pain, Parkinson's disease, mental disorders, autoimmune encephalitis, cancer-related fatigue (such as excessive daytime sleepiness or fatigue associated with cancer and / or chemotherapy), cancer-related nausea and vomiting, corticobasal degeneration, Huntington's disease, neuromyelitis optica, nociception, progressive supranuclear palsy, schizophrenia, systemic lupus erythematosus, traumatic brain injury, facial flushing, night sweats, genital / urinary tract disorders, sexual dysfunction or fertility disorders, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder**Disorders**, separation anxiety disorder, social anxiety disorder, anxiety disorders, acute neurological disorders such as cardiac bypass surgery and post-transplant brain defects, acute psychiatric disorders, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, nerve damage due to hypoglycemia, Huntington's disease, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders related to muscle spasms, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, drug-induced parkinsonism, Gilles de la Tourette syndrome, chorea, myoclonus, tic symptoms, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD). These include disorders (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury (TBI).

[0120] In particular, the compounds of the present invention are assumed to be useful as therapeutic or prophylactic agents, or anesthetic antagonists, for disorders of consciousness such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, and coma; narcolepsy syndrome, hypersomnia syndromes characterized by hypersomnia (e.g., Parkinson's disease, Guillain-Barré syndrome, or Kleine-Levin syndrome); Alzheimer's disease; obesity; insulin resistance syndrome; heart failure; diseases related to osteopenia; or sepsis; disorders of consciousness such as coma; and side effects and complications of anesthesia.

[0121] In one embodiment, the compound of the present invention has orexin 2 receptor agonist activity and is useful as a preventive or therapeutic agent for narcolepsy.

[0122] In another embodiment, the compounds of the present invention are useful as a preventive or therapeutic agent for type 1 narcolepsy. In another embodiment, the compounds of the present invention are useful as a preventive or therapeutic agent for type 2 narcolepsy. In another embodiment, the compounds of the present invention are useful as a preventive or therapeutic agent for narcolepsy and excessive daytime sleepiness. In another embodiment, the compounds of the present invention are useful as a preventive or therapeutic agent for narcolepsy, cataplexy, and excessive daytime sleepiness. In another embodiment, the compounds of the present invention are useful as a preventive or therapeutic agent for narcolepsy and cataplexy. In another embodiment, the compounds of the present invention are useful as a preventive or therapeutic agent for excessive daytime sleepiness. In another embodiment, the compounds of the present invention are useful as a preventive or therapeutic agent for idiopathic hypersomnia. In another embodiment, the compounds of the present invention are useful as a preventive or therapeutic agent for obstructive sleep apnea.

[0123] In another embodiment, the compounds of the present invention have orexin 2 receptor agonist activity and are useful as a preventive or therapeutic agent for hypersomnia in Parkinson's disease.

[0124] In another embodiment, the compound of the present invention has orexin 2 receptor agonist activity and is useful as a preventive or therapeutic agent for hypersomnia. In yet another embodiment, the compound of the present invention has orexin 2 receptor agonist activity and is useful as a preventive or therapeutic agent for excessive daytime sleepiness associated with Parkinson's disease.

[0125] In another embodiment, the compounds of the present invention have orexin 2 receptor agonist activity and are useful as prophylactic or therapeutic agents for excessive daytime sleepiness or fatigue associated with cancer and / or chemotherapy.

[0126] In another embodiment, the present invention provides a method for treating narcolepsy in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0127] In another embodiment, the present invention provides a method for treating type 1 narcolepsy in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0128] In another embodiment, the present invention provides a method for treating type 2 narcolepsy in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0129] In another embodiment, the present invention provides a method for treating narcolepsy and excessive daytime sleepiness in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to the subject in need.

[0130] In another embodiment, the present invention provides a method for treating narcolepsy, cataplexy, and excessive daytime sleepiness in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to the subject in need.

[0131] In another embodiment, the present invention provides a method for treating narcolepsy and cataplexy in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to the subject in need.

[0132] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to the subject in need.

[0133] In another embodiment, the present invention provides a method for treating idiopathic hypersomnia in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0134] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and idiopathic hypersomnia in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to the subject in need.

[0135] In another embodiment, the present invention provides a method for treating obstructive sleep apnea in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to the subject in need.

[0136] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and obstructive sleep apnea in a subject, comprising administering a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, to the subject in need.

[0137] In any of the methods described herein, the subject is administered a compound of formula IA. In any of the methods described herein, the subject is administered a compound of formula I.

[0138] Each of the embodiments described herein with respect to the use of compounds of formula I also applies to compounds of formula IA.

[0139] In any of the compositions or methods described herein, a compound of formula IA or formula I, or a pharmaceutically acceptable salt thereof, is present and / or administered in a therapeutically effective amount.

[0140] Dosage / Formulation In another embodiment, pharmaceutical compositions comprising at least one compound of the present invention together with a pharmaceutically acceptable carrier are provided herein.

[0141] The actual dose level of the active ingredient in the pharmaceutical composition of the present invention may be modified to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and administration method without causing toxicity to the patient.

[0142] In particular, the selected dose varies depending on various factors, including the activity of the specific compound used, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds or substances used in combination with the compound, age, sex, weight, condition, the general health status and medical history of the patient being treated, and similar factors well known in the medical field.

[0143] A physician skilled in the art (e.g., an internist or veterinarian) can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, an internist or veterinarian can start administering the pharmaceutical composition with a lower level of the compound than required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0144] In certain embodiments, it is particularly advantageous to formulate the compound in unit dosage forms to facilitate administration and ensure uniformity of dose. As used herein, unit dosage forms refer to physically distinct units suitable as unit doses for the patient being treated, each unit containing a predetermined amount of the disclosed compound calculated to produce the desired therapeutic effect with the necessary pharmaceutical vehicle. The unit dosage forms of the present invention are indicated by (a) the specific characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the inherent limitations of the technology for mixing / formulating such disclosed compound for the treatment of a patient's narcolepsy or cataplexy, and vary directly accordingly.

[0145] In one embodiment, the compound of the present invention is formulated using 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.

[0146] In some embodiments, the dose of the disclosed compound is about 1 mg to about 1,000 mg. In some embodiments, the dose of the disclosed compound used in the compositions described herein is less than about 1,000 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, the dosage is approximately 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 600 mg.

[0147] Any of the administration routes for the compositions of the present invention include oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical administration. Compounds for use in the present invention may be formulated for administration by any preferred route, such as oral or parenteral administration, including transdermal administration, transmucosal administration (e.g., sublingual, lingual, (trans) buccal, (trans) urethral, ​​vaginal (e.g., transvaginal and perivaginal), (trans) nasal and (trans) rectal), intravesical administration, intrapulmonary administration, intraduodenal administration, intragastric administration, intrathecal administration, subcutaneous administration, intramuscular administration, intradermal administration, intra-arterial administration, intravenous administration, intrabronchial administration, inhalation administration, and topical administration. In one embodiment, the preferred route of administration is oral.

[0148] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma preparations, medicinal candies, creams, pastes, ointments, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders and aerosolized preparations for inhalation, and compositions and preparations for intravesical administration. It should be understood that the preparations and compositions useful in the present invention are not limited to the specific preparations and compositions described herein.

[0149] For oral administration, tablets, sugar-coated tablets, liquids, drops, suppositories, or capsules, caplets, and gel caps are particularly preferred. Compositions intended for oral use may be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Examples of such excipients include inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques to improve appearance or to delay the release of the active ingredient. Formulations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0150] For parenteral administration, the disclosed compounds may be formulated for injection or infusion, such as intravenous, intramuscular, or subcutaneous injection or infusion, or for administration by bolus or continuous infusion. A suspension, solution, or emulsion of an oily or aqueous vehicle may be used, optionally containing other processing agents such as suspending agents, stabilizers, or dispersants as needed.

[0151] Those skilled in the art will recognize, or can verify, numerous equivalents of the specific procedures, embodiments, claims, and examples described herein by means of routine experiments. Such equivalents are considered to be within the scope of the present invention and are encompassed by the appended claims. For example, changes in reaction time, reaction size / volume, and experimental reagents, including but not limited to solvents, catalysts, pressure, atmospheric pressure conditions (e.g., nitrogen atmosphere) and reducing / oxidizing agents, by means of alternatives recognized in the art and by means of routine experiments, are within the scope of this application.

[0152] Where values ​​and ranges are provided herein, it should be understood that all values ​​and ranges encompassed by those values ​​and ranges are included within the scope of the present invention. In addition, upper or lower limits on all values ​​and ranges within those limits are also contemplated in this application.

[0153] The following examples further illustrate aspects of the present invention; however, they do not limit the teachings or disclosures of the present invention as set forth herein. [Examples]

[0154] The present invention will be further illustrated by the following examples, but should not be construed as further limitations. Unless otherwise specified, the implementation of the present invention will utilize the prior art of organic synthesis, cell biology, cell culture, molecular biology, transgenic biology, microbiology and immunology, within the scope of the skills possessed by those skilled in the art.

[0155] General procedure Example 1: Synthesis Procedure The synthetic procedures for preparing the compounds of the present invention are readily available to those skilled in the art. Unless otherwise specified, the starting materials were typically obtained from commercial sources.

[0156] The following abbreviations are used in the following composite examples: DCM = Dichloromethane MsCl = Methanesulfonyl Chloride MeOH = methanol THF = Tetrahydrofuran EtOH = Ethanol DIPEA = N,N-diisopropylethylamine ACN or MeCN = Acetonitrile NEt3 or TEA = Triethylamine PE = Petroleum Ether alkyl = ethyl acetate TFA = Trifluoroacetic Acid min = minutes hr=hour NaH = Sodium hydride DMSO = Dimethyl sulfoxide TMSCl = Trimethylsilyl Chloride Pd / C = Palladium Carbon Ms = Methanesulfonyl Bn = Benzyl Ph = Phenyl LiHMDS = Lithium bis(trimethylsilyl)amide Pd(OH)2 / C = Palladium Carbon Hydrogen DMAP = 4-(dimethylamino)pyridine KOAc = potassium acetate Pd(dppf)Cl2=[1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) Pd(PPh3)4 = Tetrakis(triphenylphosphine)palladium(0)

[0157] Scheme 1 [ka]

[0158] Scheme 2 [ka]

[0159] Scheme 3 [ka]

[0160] Scheme 4 [ka]

[0161] Example 1.1 [ka] To a stirred solution of 4-hydroxycyclohexane-1-one (2.00 g, 17.5 mmol, 1.00 equivalent) and benzoyl chloride (2.46 g, 17.522 mmol, 1.00 equivalent) in DCM (50.00 mL), triethylamine (2.66 g, 26.3 mmol, 1.50 equivalent) and DMAP (214.06 mg, 1.752 mmol, 0.10 equivalent) were added dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours. Benzoyl chloride (1.23 g, 8.761 mmol, 0.50 equivalent) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at room temperature for a further 3 hours. After the reaction was complete by TLC, the crude mixture was diluted with water. The aqueous layer was extracted with DCM (3 × 50 mL). The mixed organic layer was dried on anhydrous MgSO4. The residue was purified by silica gel chromatography and eluted with PE / siRNA (4:1) to obtain 4-oxocyclohexylbenzoate (3.37 g, yield 88.12%) as a solid.

number

[0162] [ka] To a stirred solution of P(OPh)3 (7.82 g, 25.2 mmol, 1.10 equivalents) in DCM (70.00 mL), Br2 (1.41 mL, 8.81 mmol, 1.20 equivalents) was added dropwise at -60°C under a nitrogen atmosphere. After 30 minutes, NEt3 (4.14 mL, 40.9 mmol, 1.30 equivalents) and 4-oxocyclohexyl benzoate (5.00 g, 22.9 mmol, 1.00 equivalent) were added to the mixture at -60°C. The resulting mixture was stirred at room temperature for 18 hours. The reaction was quenched by adding saturated aqueous NaSO3 solution (aqueous solution, 20 mL) at 0°C. The resulting mixture was extracted with DCM (3 × 50 mL). The mixed organic layer was washed with brine (2 × 50 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (20:1) to obtain 4-bromocyclohexa-3-en-1-ylbenzoate (5.8 g, 90.05%) as a racemic solid.

number

[0163] [ka] A solution of the racemic mixture 4-bromocyclohexa-3-en-1-ylbenzoate (3.00 g, 10.7 mmol, 1.00 equivalent) and sodium methoxide (634.11 mg, 11.738 mmol, 1.10 equivalents) in MeOH (30 mL) was stirred overnight at room temperature under a nitrogen atmosphere. 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 × 50 mL). The mixed organic layer was washed with water (3 × 30 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (4:1) to obtain 4-bromocyclohexa-3-en-1-ol (1.7 g, 90% yield) as oil.

number

[0164] [ka] A solution of 4-bromocyclohexa-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 equivalents) was stirred overnight at room temperature under a nitrogen atmosphere. The desired product could be detected by TLC. The resulting mixture was filtered, and the filter cake was washed with THF (3 × 10 mL). The filtrate was concentrated under reduced pressure, and the resulting crude product was used directly in the next step without further purification.

number

[0165] [ka] To a stirred mixture of 1-(pyridine-2-yl)piperidine-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), racemic methylbenzylamine (3.44 g, 28.4 mmol, 1.00 equivalent) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. Subsequently, the crude reaction product was filtered, and the filtrate cake was washed with toluene (2 × 20 mL). The filtrate was concentrated under reduced pressure. The obtained crude product was used directly in the next step without purification. The desired product could be detected by TLC.

number

[0166] [ka] To a stirred solution of diethylamine (2.45 g, 33.5 mmol, 1.20 equivalents) in tetrahydrofuran (30 mL), n-butyllithium (13.4 mL, 33.5 mmol, 1.20 equivalents) was added dropwise at -78°C under a nitrogen atmosphere. The resulting mixture was prepared as follows: The mixture was stirred at -78°C under a nitrogen atmosphere for 30 minutes. To the above mixture, imine (1S)-1-phenyl-N-[1-(pyridine-2-yl)piperidine-4-ylidene]ethanamine (7.80 g, 27.9 mmol, 1.00 equivalent) in THF (20 mL) was added dropwise over 15 minutes at -78°C. The resulting mixture was stirred for a further 1 hour. To the above mixture, 1-bromo-4-(chloromethoxy)cyclohexa-1-ene (7.56 g, 33.5 mmol, 1.20 equivalent) in THF (20 mL) was added dropwise over 15 minutes at -78°C. The resulting mixture was stirred for a further 1 hour. Subsequently, the reaction was quenched by adding sodium phosphate buffer (200 mL, 10% aqueous solution) and stirred for 1 hour.

[0167] The resulting mixture was extracted with DCM. The mixed organic layer was washed with brine and dried on anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (4:1) to obtain 3-[[(4-bromocyclohexa-3-en-1-yl)oxy]methyl]-1-(pyridine-2-yl)piperidine-4-one (3 g, yield 29%) as oil.

number

[0168] [ka] To a stirred methanol (40 mL) solution of 3-[[(4-bromocyclohexa-3-en-1-yl)oxy]methyl]-1-(pyridine-2-yl)piperidine-4-one (5.20 g, 14.2 mmol, 1.00 equivalent), ZnCl2 (2.85 mL, 1.99 mmol, 0.14 equivalent) was added dropwise at room temperature under a nitrogen atmosphere. 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 a further 1 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 a further 2 days at room temperature. The reaction was then quenched by adding water (20 mL) at room temperature. Next, the mixture was extracted with DCM (3 × 100 mL), and the mixed organic layer was washed with brine (2 × 50 mL) and anhydrous sodium 2SO4. -4 The mixture was dried above ground. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with DCM / MeOH (6:1) to obtain 3-[[(4-bromocyclohexa-3-en-1-yl)oxy]methyl]-1-(pyridine-2-yl)piperidine-4-amine (3.7 g, yield 71%) as oil.

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[0169] [ka] To a stirred solution of 3-[[(4-bromocyclohexa-3-en-1-yl)oxy]methyl]-1-(pyridine-2-yl)piperidine-4-amine (1.90 g, 5.187 mmol, 1.00 equivalent) and diisopropylethylamine (2.01 g, 15.6 mmol, 3.00 equivalent) in DCM (30 mL), methanesulfonyl chloride (0.89 g, 7.78 mmol, 1.50 equivalent) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The crude residue was purified by silica gel column chromatography and eluted with PE / siRNA (1:1) to obtain N-[3-([[((1R)-4-bromocyclohexa-3-en-1-yl]oxy]methyl]-1-(pyridine-2-yl)piperidine-4-yl]methanesulfonamide (1.3g, yield 65%) as oil. This product was then eluted under the following conditions (column: DAISEL DCpak® (Daicel Corporation, Osaka, Japan) P4VP, 20mm*250mm, 5um; mobile phase A: CO2, mobile phase B: ACN / MeOH=4:1 (0.1% 2M) The solution was purified by preparative HPLC (NH3-MeOH); flow rate: 50 mL / min; gradient 25% B; 254 nm) to obtain N-[3-([[(1R)-4-bromocyclohexa-3-en-1-yl]oxy]methyl)-1-(pyridine-2-yl)piperidine-4-yl]methanesulfonamide (375 mg, yield 18.8%) as oil.

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[0170] [ka] To a stirred dioxane solution of N-(3-[[(4-bromocyclohexa-3-en-1-yl)oxy]methyl]-1-(pyridine-2-yl)piperidine-4-yl)methanesulfonamide (1.00 g, 2.25 mmol, 1.00 equivalent) and bis(pinacolate)diborone (857.15 mg, 3.375 mmol, 1.50 equivalent), KOAc (0.66 g, 6.751 mmol, 3.00 equivalent) was added at room temperature under an air atmosphere. To the above mixture, Pd(dppf)Cl2 (0.16 g, 0.225 mmol, 0.10 equivalent) was added at room temperature. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 4 hours. The resulting crude product was extracted with ethyl acetate (3 × 50 mL). The mixed organic layer was washed with brine (20 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (1:1) to obtain N-[1-(pyridine-2-yl)-3-([[(1R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-yl]oxy]methyl)piperidine-4-yl]methanesulfonamide (1.0 g, 90% yield) as a solid.

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[0171] [ka] To a stirred solution of N-(3-[[(4-bromocyclohexa-3-en-1-yl)oxy]methyl]-1-(pyridine-2-yl)piperidine-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), Cs2CO3 (366.6 mg, 1.125 mmol, 2.50 equivalents) and Pd(PPh3)4 (52.0 mg, 0.045 mmol, 0.10 equivalents) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C under a nitrogen atmosphere. The resulting residue was purified by preparative TLC(siRNA) to obtain N-[1-(pyridine-2-yl)-3-([[4-(pyridine-2-yl)cyclohexa-3-en-1-yl]oxy]methyl)piperidine-4-yl]methanesulfonamide (170 mg, yield 85.4%) as oil.

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[0172] [ka] To a stirred MeOH (10 mL) solution of N-[1-(pyridine-2-yl)-3-([[4-(pyridine-2-yl)cyclohexa-3-en-1-yl]oxy]methyl)piperidine-4-yl]methanesulfonamide (150.0 mg, 0.339 mmol, 1.00 equivalent) at room temperature, Pd / C (72.1 mg, 0.0678 mmol, 2.00 equivalent) was added. The atmosphere was changed to hydrogen, and the resulting mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The resulting mixture was filtered, and the filtrate cake was washed with methanol (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: TFA / MeCN in water, 0% to 20% gradient for 30 minutes; detector: UV 254 nm. This resulted in the product N-[1-(pyridine-2-yl)-3-([[4-(pyridine-2-yl)cyclohexyl]oxy]methyl)piperidine-4-yl]methanesulfonamide (60 mg, 40% yield) being produced as an oil mixture of isomers.

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[0173] A mixture of these isomers (60 mg) was further purified by chiral preparative HPLC under the following conditions (column: CHIRALPAK® (Daicel Corporation, Osaka, Japan) IE, 2 cm * 25 cm, 5 μm; mobile phase A: hexane (using 0.2% diethylamine); mobile phase B: IPA; flow rate: 20 mL / min; isocratic 40% B for 25 minutes; detector: 220 / 254 nm) to obtain N-[(3R,4S)-1-(pyridine-2-yl)-3-([[(1s,4s)-4-(pyridine-2-yl)cyclohexyl]oxy]methyl)piperidine-4-yl]methanesulfonamide (15.8 mg, 26.33%) as a solid.

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[0174] Example 1.2 [ka] In a 20 mL sealed tube, N-(3-[[(4-bromocyclohexa-3-en-1-yl)oxy]methyl]-1-(pyridine-2-yl)piperidine-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 at room temperature. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The aqueous layer was extracted with ELISA (1 × 10 mL). The resulting mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: aqueous ACN solution, gradient 10% to 60% for 20 minutes; detector: UV 254 nm. This yielded N-[3-([[4-(3-fluorophenyl)cyclohexa-3-en-1-yl]oxy]methyl)-1-(pyridine-2-yl)piperidine-4-yl]methanesulfonamide (200 mg, yield 96.7%) as a solid.

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[0175] [ka] A mixture of N-[3-([[4-(3-fluorophenyl)cyclohexa-3-en-1-yl]oxy]methyl)-1-(pyridine-2-yl)piperidine-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 under a hydrogen atmosphere for 2 hours. The desired product could be detected by LC-MS. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN in water, 10% to 60% gradient for 20 minutes; detector: UV 254 nm. This resulted in N-[3-([[4-(3-fluorophenyl)cyclohexyl]oxy]methyl)-1-(pyridine-2-yl)piperidine-4-yl]methanesulfonamide (97 mg, yield 52%) being produced as a solid mixture of isomers.

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[0176] A mixture of these isomers (97 mg) was purified by preparative chiral HPLC under the following conditions: column, CHIRALPAK® IE, 2*25 cm, 5 μm; mobile phase A: hexane containing 0.2% diethylamine; mobile phase B: ethanol; flow rate: 20 mL / min; isocratic 35% B over 15.5 minutes; detector: 220 / 254 nm. This yielded N-[(3R,4S)-1-(pyridine-2-yl)-3-([[(1s,4s)-4-(3-fluorophenyl)cyclohexyl]oxy]methyl)piperidine-4-yl]methanesulfonamide (20.7 mg, 21.34%) as a solid.

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[0177] Example 1.3 [ka] 4-phenylcyclohexane-1-one (15.00 g, 86.087 mmol, 1.00 equivalent), THF (130.00 mL), and L-selectride (129.08 mL, 679.021 mmol, 7.02 equivalents) were added to a 500 mL three-necked round-bottom flask at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours. Subsequently, water (0.16 mL, 8.609 mmol, 0.10 equivalents) and EtOH (0.10 mL, 2.171 mmol, 0.02 equivalents) were added. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. NaOH (5.99 g, 149.791 mmol, 1.74 equivalents) and H2O2 (0.02 mL, 0.590 mmol, 0.01 equivalents) were added, and the resulting mixture was stirred under a nitrogen atmosphere at 0°C for 1 hour. The resulting mixture was washed with water (2 × 50 mL). The residue was purified by silica gel column chromatography and eluted with PE / SiO(9:1) to obtain 4-phenylcyclohexane-1-ol (11.4 g, 75.1%) as a solid.

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[0178] [ka] A solution of 4-phenylcyclohexane-1-ol (10.00 g, 56.735 mmol, 1.00 equivalent) in 4N HCl dioxane (160.00 mL, 640.00 mmol, 11.3 equivalents) was treated with paraformaldehyde (2.56 g, 28.367 mmol, 0.50 equivalents) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The resulting mixture was concentrated under reduced pressure. Without further purification, the resulting mixture was used directly in the next step.

[0179] [ka] To a stirred solution of [4-(chloromethoxy)cyclohexyl]benzene (12.6 g, 56.067 mmol, 1.00 equivalent) in THF (200.00 mL), LiHMDS (56.07 mL, 56.070 mmol, 1.00 equivalent) was added dropwise over 15 minutes at -78°C under a nitrogen atmosphere. The resulting mixture was stirred at -78°C under a nitrogen atmosphere for 1.5 hours. To the above mixture, [4-(chloromethoxy)cyclohexyl]benzene (12.6 g, 56.067 mmol, 1.00 equivalent) as a THF (50 mL) solution was added dropwise over 20 minutes at -78°C. The resulting mixture was stirred for a further 2 hours at -78°C. The reaction was quenched with saturated NH4Cl aqueous solution at 0°C. The resulting mixture was extracted with RINKAN (3 × 100 mL). The mixed organic layer was washed with brine (2 × 130 mL) and dried on anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water, gradient from 10% to 100% for 15 minutes; detector: UV 220 nm, to obtain 1-benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidine-4-one (6.1 g, 28.80%) as oil.

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[0180] [ka] To a stirred methanol (12.00 mL) solution of 1-benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidine-4-one (2.00 g, 5.298 mmol, 1.00 equivalent), ZnCl2 (1.06 mL, 1.060 mmol, 0.2 equivalents) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. HCOONH4 (4.00 g, 63.413 mmol, 11.97 equivalents) was added all at once at room temperature to the mixture. The resulting mixture was stirred at room temperature for a further 1 hour. Solid NaBH3CN (665.83 mg, 10.595 mmol, 2.0 equivalents) was added. The reaction was then stirred at ambient temperature for 3 hours, and the reaction was terminated by adding water. The quenched reaction was partitioned between 5 M NaOH and DCM. The aqueous layer was extracted with DCM, the mixed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

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[0181] [ka] To a stirred solution of 1-benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidine-4-amine (2.00 g, 5.283 mmol, 1.00 equivalent) in DCM (40.00 mL), DIPEA (1.02 g, 7.925 mmol, 1.50 equivalent) and methanesulfonyl chloride (726.16 mg, 6.340 mmol, 1.20 equivalent) were added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for a further 1 hour. 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 HPLC under the following conditions (column: XBridge® (Waters Technologies Corp., Milford, Massachusetts) Prep OBD C18 column, 30 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 52%B to 86%B over 8 min; 254 / 220 nm) to obtain (cis)-N-(1-benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidine-4-yl)methanesulfonamide (420 mg, 17.5%) as a solid.

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[0182] [ka] To a stirred solution of N-[(cis)-1-benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidine-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), 4N HCl (230.00 μL, 0.920 mmol, 1.0 equivalent) was added dropwise at room temperature under a hydrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

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[0183] [ka] To a stirred DMSO (20.00 mL) solution of N-[(cis)-3-([[(1s,4s)-4-phenylcyclohexyl]oxy]methyl)piperidine-4-yl]methanesulfonamide (350.00 mg, 0.955 mmol, 1.00 equivalent) and K2CO3 (395.93 mg, 2.865 mmol, 3.00 equivalent), 2-fluoropyridine (185.43 mg, 1.910 mmol, 2.00 equivalent) was added all at once at room temperature under a nitrogen atmosphere. The resulting mixture was stirred further at 120°C for 8 hours. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN in water, 60% to 100% gradient for 15 minutes; detector: UV 254 nm, to obtain N-[(cis)-1-(pyridine-2-yl)-3-([[(1s,4s)-4-phenylcyclohexyl]oxy]methyl)piperidine-4-yl]methanesulfonamide (280 mg, 66.10%) as a solid. The racemic mixture was separated by chiral preparative HPLC to obtain the enantiopure product (95.1 mg) as a solid.

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[0184] Example 1.4 [ka] To a stirred mixture of N-((3R,4S)-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidine-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), K2CO3 (47.13 mg, 0.341 mmol, 2.5 equivalent) was added at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with MeCN (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water; gradient: 0-0 for 10 minutes, 0%-100% for 15 minutes, 100%-100% for 15 minutes; detector: UV 254 nm. This yielded N-[(3R,4S)-1-(pyrimidine-2-yl)-3-([[(1s,4s)-4-phenylcyclohexyl]oxy]methyl)piperidine-4-yl]methanesulfonamide (53 mg, 85.64%) as a solid.

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[0185] Example 1.5 [ka] To a solution of N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-yl)methanesulfonamide (200 mg, 1.00 equivalent, 546 μmol) in acetophenone (393 mg, 6.00 equivalent, 3.27 mmol), titanium(IV) isopropoxide (620 mg, 662 μL, 2.18 mmol, 4.00 equivalent) was added. The reaction mixture was stirred at 25°C for 30 minutes. EtOH (2 mL) and sodium cyanoborohydride (343 mg, 5.46 mmol, 10.0 equivalent) were added to the reaction mixture. The reaction mixture was stirred at 25°C under a nitrogen atmosphere for 1 hour. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The mixed organic layer was washed with brine (3 × 50 mL), dried on anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography under the following conditions (C18 column; mobile phase A: 0.08% NH₄HCO₃ (aqueous solution), 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-((S)-1-phenylethyl)piperidine-4-yl)methanesulfonamide (180 mg, 382 μmol, 70.1%) as oil. The racemic mixture was separated by chiral preparative HPLC to obtain the enantiopurity product (88.3 mg, 0.188 mmol, overall yield 34.4%) as solid.

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[0186] Example 1.6 [ka] To a methanol (5 mL) solution of N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-yl)methanesulfonamide (100 mg, 273 μmol, 1.00 equivalent) and picoline aldehyde (117 mg, 1.09 mmol, 4.00 equivalent), 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 under a nitrogen atmosphere for 2 hours. The crude product was purified by reverse-phase 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-(pyridine-2-ylmethyl)piperidine-4-yl)methanesulfonamide (48.1 mg, 105 μmol, 38.5%) as a solid.

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[0187] Example 1.7 [ka] N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-yl)methanesulfonamide (33 mg, 90 μmol, 1.00 equivalent) and 5-chloro[1,2,4]triazolo[1,5-c]pyrimidine (17 mg, 0.11 mmol, 1.2 equivalents) were dissolved in DMSO (1.5 mL), to which K2CO3 (25 mg, 0.18 mmol, 2.0 equivalents) was added. The resulting mixture was stirred at 120 °C for 18 hours and then filtered. The filtrate was washed with DCM (3 × 2 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography under the following conditions (C18 column; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN, 65% to 75% gradient over 30 minutes; detector: UV 254 nm) to obtain N-((3R,4S)-1-([1,2,4]triazolo[1,5-c]pyrimidine-5-yl)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-yl)methanesulfonamide (22.3 mg, 46.0 μmol, 51%) as a solid.

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[0188] Example 1.8 [ka] To a suspension of NaH (53.0 mg, 60 wt%, 1.32 mmol, 1.00 equivalent) in THF (10 mL), 1-benzyl-3-((((1S,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-one (500 mg, 1.32 mmol, 1.00 equivalent) in THF (10 mL) was added at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. A solution of iodomethane (0.166 mL, 0.376 g, 2.65 mmol, 2.00 equivalent) in THF (10 mL) was added dropwise to the reaction under a nitrogen atmosphere at 0°C. The resulting mixture was stirred for a further 2 hours at 25°C. Subsequently, the reaction was quenched by adding saturated sodium chloride aqueous solution at 0°C. The resulting mixture was extracted with ethyl acetate (3 × 50 mL, ethyl acetate). The mixed organic layer was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (PE / ELISA=8 / 1) to obtain (S)-1-benzyl-3-methyl-3-((((1S,4R)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-one (124 mg, 0.317 mmol, yield 20%) as oil.

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[0189] [ka] (S)-1-benzyl-3-methyl-3-((((1S,4R)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-one (230 mg, 0.587 mmol, 1.00 equivalent) was mixed in a 10 mL methanol solution and zinc chloride (117 μL, 0.7 mol, 82.2 μmol, 0.14 equivalent) was added at 25°C. The resulting mixture was stirred at 25°C for 10 minutes. Ammonium formate (741 mg, 11.7 mmol, 20.0 equivalent) was added to the mixture at 25°C under a nitrogen atmosphere. The resulting mixture was stirred for a further 30 minutes at 25°C. NaCNBH3 (221 mg, 3.52 mmol, 6.00 equivalent) was added to the mixture at 25°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for a further 3 hours, cooled to 0°C, and quenched by adding saturated sodium chloride aqueous solution. The resulting mixture was extracted with dichloromethane (3 × 50 mL). The mixed organic layer was washed with brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to obtain (3R)-1-benzyl-3-methyl-3-((((1S,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-amine (220 mg, 560 μmol, yield 95.4%) as oil. The crude product was used directly in the next step without further purification.

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[0190] [ka] (3R)-1-benzyl-3-methyl-3-((((1S,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-amine (230 mg, 0.586 mmol, 1.00 equivalent) and diisopropylethylamine (0.306 mL, 227 mg, 1.76 mmol, 3.00 equivalent) were dissolved in DCM (20 mL) to which methanesulfonyl chloride (0.0685 mL, 101 mg, 0.879 mmol, 1.50 equivalent) was added. The resulting mixture was stirred at 25°C for 1 hour. The residue was purified by preparative TLC (PE / EtOAC=2 / 1) to obtain N-((3R)-1-benzyl-3-methyl-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-yl)methanesulfonamide (90 mg, 0.19 mmol, 33%) as oil.

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[0191] [ka] To a solution of N-((3R)-1-benzyl-3-methyl-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-yl)methanesulfonamide (140 mg, 297 μmol, 1.00 equivalent) in isopropanol (15 mL), palladium carbon hydride (1.25 g, 10 wt%, 892 μmol, 3.00 equivalent) was added under a nitrogen atmosphere. HCl (744 μL, 4 mol, 2.97 mmol, 10.0 equivalent) was added to the above mixture. The resulting mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon at room temperature for 12 hours, filtered through a Celite® pad, and concentrated under reduced pressure to obtain the crude product. This crude product was used directly in the next step without further purification.

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[0192] [ka] N-((3R)-3-methyl-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-yl)methanesulfonamide (113 mg, 297 μmol, 1.00 equivalent) and K2CO3 (82.1 mg, 594 μmol, 2.00 equivalent) were dissolved in DMSO (4 mL), to which 2-fluoropyridine (86.5 mg, 891 μmol, 3.00 equivalent) was added. The resulting mixture was stirred at 120 °C for 24 hours.

[0193] The crude product was purified by preparative chiral HPLC under the following conditions: column: DZ-CHIRALPAK® IG-3, 4.6*50 mm 3 μm; mobile phase A: hexane containing 0.2% isopropanol; mobile phase B: EtOH:DCM = 1:1; isocratic 85:15; flow rate: 1 mL / min. This yielded N-((3R,4S)-3-methyl-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)-1-(pyridine-2-yl)piperidine-4-yl)methanesulfonamide (10 mg, 22 μmol, 33%) as a solid.

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[0194] Example 2: Human OX2R IP1 assay T-Rex CHO cells stably overexpressing the human orexin 2 receptor (OX2R) were induced overnight in a T225 flask with doxycycline 1 μg / mL. 24 hours after induction, the cells were detached with accutase and seeded at 30,000 cells / well in a 384-well proxy plate. The cells were then treated with different test compounds at 37°C for 1 hour in a 1x stimulating buffer (pH 7.4) containing 10 mM HEPES, 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 a detection mix consisting of diluted IP1-d2 and anti-IP1-cryptate in cell lysis buffer and 1x stimulating buffer. The plates were incubated at room temperature for 1 hour, and then read using an EnVision® multimode plate reader to measure inositol phosphate.

[0195] Cisbio IP1 is a cell-based functional assay that quantifies the accumulation of inositol phosphate (IP), a metabolite released as a result of orexin 2 receptor activation 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 bound to a d2 fluorophore (acceptor) to bind to an anti-IP1 monoclonal antibody labeled with a Eu cryptotate (donor). The measured HTRF-FRET-based signal is inversely proportional to the concentration of IP1 produced.

[0196] Table 2 Reported EC 50 The values ​​were obtained using the human OX2R IP1 assay described above. The data are average EC2. 50 The values ​​are ±SEM. The compound methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)-piperidine-1-carboxylate (sometimes referred to herein as reference compound A) is the reference compound disclosed in Example 5 of PCT publication number WO2017 / 135306. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

[0197] Example 3: MDCK-MDR1 permeability assay The bidirectional permeability of test compounds in MDCK-MDR1 cells (from the luminal side to the basement membrane side, and from the basement membrane side to the luminal side) was evaluated using MDCK-MDR1 cells seeded in Solvo PreadyPort® MDCK 96-well plates. Upon receiving the plates from ReadyCell (Barcelona, ​​Spain), they were processed according to the PreadyPort® user manual.

[0198] To assess permeability from the luminal side to the outer basement membrane (A→B), 80 μL of the test compound (3 μM), administered simultaneously with LY (Lucifer Yellow) (100 μM) in HBSS (Hank's Balanced Salt Solution) assay buffer, was added to the donor side (A), and 250 μL of HBSS buffer was added to the receiver side (B). To assess permeability from the outer basement membrane to the luminal side (B→A), 255 μL of the test compound (3 μM) in HBSS assay buffer was added to the donor side (B), and 75 μL of HBSS buffer containing LY (100 μM) was added to the receiver side (A).

[0199] The plate was placed in an incubator set to 37°C. After preheating for 10 minutes, a 5 μL aliquot was removed from the donor compartment and set aside as the administration solution. The MDCK-MDR1 incubation plate was returned to the incubator for incubation at 37°C for 2 hours. After 2 hours of incubation, a 25 μL aliquot and a 5 μL aliquot were removed from the receiver and donor sides, respectively. The 5 μL aliquots removed from the donor side (before and after the 2-hour incubation) were diluted with 20 μL of HBSS buffer. All samples were mixed with 150 μL of acetonitrile containing an internal standard (IS) and 200 μL of water, and analyzed by LC-MS / MS.

[0200] The following formula: P app = dQ / dt × 1 / A × C0, During the ceremony: dQ / dt: Amount of substance moved during incubation time (nmol / s) A: Insert area (0.14 cm² for PreadyPort(trademark) MDR1-96) 2 ) C0: Initial concentration (nmol / mL) of the product applied to the luminal side (A→B) or basement membrane side (B→A) compartment. Using the formula, apparent transparency (P app ) was calculated.

[0201] P app (From the outside of the basement membrane toward the lumen side) app The efflux ratio (ER) was measured by dividing by the distance (from the luminal side to the outer side of the basement membrane). This is a common measure of the involvement of active processes. An ER greater than 2 is considered positive for active transport.

[0202] The following formula: Recovery rate =

number

[0203] The data reported in Table 3 were obtained by the MDCK-MDR1 permeability assay described above. [Table 3-1] [Table 3-2]

[0204] Example 4: Hepatocyte Stability Assay In vitro metabolic stability was evaluated using cryopreserved hepatocytes from male Sprague's Dolly rats and hepatocytes from a pool of 50 humans of various sexes. 2 × 10 6 An incubation mixture was prepared by mixing 250 μL of preheated KHB (Krebs-Henseleit buffer) containing 10 cells / mL of hepatocytes with 250 μL of preheated KHB buffer containing 2 μM of the test compound in a 48-well plate. The final concentration of the test compound (0.1% DMSO) was 1 μM, and 1x 10 6 Hepatocytes were obtained at a concentration of 10 cells / mL. The reaction mixture was incubated at 37°C. Aliquots of 50 μL of the incubation mixture were taken at time points (0, 15, 30, 60, 120, and 240 minutes) and 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). The reaction was immediately terminated by placing the plate on ice. The samples were centrifuged and transferred to a 96-well plate for liquid chromatography with tandem mass spectrometry (LC-MS / MS) analysis, and the deficiency of the test compound was monitored.

[0205] The half-life was calculated by assuming the peak region ratio (analyte / IS) at zero minutes to be 100% and dividing the peak region ratio at the remaining time by the peak region ratio at zero minutes. The data was fitted to a linear decomposition model to determine the half-life. The slope of the line was determined from the log(ln) peak region plot against time. Then, the half-life (T) was calculated using the following formula. 1 / 2 ) and inherent clearance (CL int ) was calculated. Emission rate constant (k) = (-slope) Half-life (T 1 / 2 )min=0.693 / k Intrinsic clearance (CL) int (mL / min / 1 million cells) = (V × 0.693) / T 1 / 2 V = Incubation volume (mL) / Cell number

[0206] The formula shown below is used to determine the in vitro T in units of mL / min / kg. 1 / 2 The intrinsic clearance (CL) in vitro int,hep It was converted to ).

number

[0207] The following formula was adapted from a thoroughly stirred model:

number

[0208] The extraction ratio (ER) was calculated by dividing the hepatic blood flow by the hepatic clearance of the compound. The data reported in Table 5 were obtained using the human hepatocyte stability assay described above. [Table 5-1] [Table 5-2]

[0209] Example 5: Evaluation of arousal enhancement in Sprague-Dolly rats In adult male Sprague-Dolly rats, enhanced arousal was evaluated using electroencephalography (EEG) and electromyography (EMG). All rats (Charles River Laboratories, Raleigh, NC, USA) under isoflurane anesthesia received intraperitoneal implantation of a telemetry device (F50-EEE, Data Sciences International Inc., MN, USA). For EEG, stainless steel screws were implanted in the frontal and parietal cortices, with a reference screw placed in the cerebellum. Electrodes were also placed in the neck muscles for EMG. After surgery, the rats were given carprofen and allowed a 7-10 day recovery period. The rats were then acclimated to the laboratory for 7 days, maintaining a 12-hour light-dark cycle.

[0210] EEG and EMG data were recorded using the DSI telemetry system and Ponemah software (Data Sciences International Inc., MN, USA). Sleep-wake stages were scored in 10-second intervals, both manually and using the supervised machine learning software platform Somnivore. After processing, the recordings were visually inspected as needed.

[0211] All test compounds were dissolved in 5% DMSO and suspended in 95% physiological saline with 0.5% methylcellulose and 0.5% tween. In the crossover design, the compounds were administered at a dose volume of 3.33 mL / kg body weight during the inactive light period of Zeitgeber time 5 (ZT5). Unless otherwise specified, all compounds were administered orally. Records for each rat were started immediately after administration and continued for up to 6 hours after administration.

[0212] Two important endpoints are wakefulness time and cortical activation time. Wakefulness time is derived from an analysis of sleep-wake stages. Cortical activation time is based on the period during which frontal gamma neuronal oscillatory activity (30–100 Hz), a key function of the wakeful state, increases compared to pre-treatment baseline. Mean cortical activation time was calculated against vehicle treatment time of 6 hours post-administration. The results are shown in Table 6 below. [Table 6]

[0213] While the present invention is specifically illustrated and described with reference to preferred embodiments, it will be understood by those skilled in the art that various modifications of form and detail are possible, as long as they do not deviate from the scope of the invention as encompassed in the appended claims. Furthermore, the present invention includes the following preferred embodiments. (1) Formula I: [ka] A compound of or a pharmaceutically acceptable salt thereof, During the ceremony: T is CR 6 or N; U is CR 5 or N; V is CR 4 or N; W is CR 3 or N; X is CR 2 or N; [ka] Under the condition that the ring contains three or fewer nitrogen atoms; E is NR a R b 、C 1 -C 3 Alkilen-NR a R b 、C 1 -C 3 Alkyl, C 2 -C 4 Alkenil, C 2 -C 4 Alkinyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C) 3 -C 8 Cycloalkyl, 4-10 membered heterocyclyl and C 1 -C 3 Selected from the group consisting of alkylene-(4-10 member heterocyclil), C 1 -C 3 Alkilen-NR a R b 、C 1 -C 3 Alkyl, C 2 -C 4 Alkenil, C 2 -C 4 Alkinyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C) 3 -C 8 Cycloalkyl, 4-10 membered heterocycline or C 1 -C 3 The alkylene-(4-10 member heterocyclyl) is either unsubstituted or has one or more halogens, hydroxyls, or C atoms. 1 -C 3 Alkyl or C 1 -C 3 Substituted with alkoxyl; R a and R b Each of these independently determines whether H or unsubstituted C 1 -C 3 It is alkyl; R 1 However, (CR c R d ) n -(C 6 -C 10 (Aryl) or (CR) c R d ) n -(5-10 member heteroaryl), where the aryl or heteroaryl is unsubstituted or one or more halogens, hydroxyl, or unsubstituted C 1 -C 3 C substituted with alkyl or one or more halogens or deuterium 1 -C 3 It is substituted with alkyl; R c and R d Each of these independently represents H and unsubstituted C. 1 -C 3 C substituted with alkyl or one or more halogens or deuterium 1 -C 3 It is alkyl; n is either 0 or 1; R 2 、R 3 、R 4 、R 5 and R 6 When each of these is present, they are H, halogen, deuterium, hydroxyl, cyano, and unsubstituted C. 1 -C 3 C substituted with alkyl and one or more halogens or deuterium 1 -C 3 Independently selected from the group consisting of alkyl groups; R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 Each of these independently consists of H, halogen, and unsubstituted C. 1 -C 3 C substituted with alkyl or one or more halogens or deuterium 1 -C 3 It is alkyl; Alternatively, R 8 and R 11 However, non-substituted C 1 -C 3 C substituted with alkylene or one or more halogens 1 -C 3 They form alkylenes together; Alternatively, R 9 and R 10 However, non-substituted C 1 -C 3 C substituted with alkylene or one or more halogens 1 -C 3 They form alkylenes together; p is 0, 1, 2, 3 or 4, and Each R 14 However, independently selected from the group consisting of deuterium, halogen, hydroxyl, and cyano, The compound of formula I described above, or a pharmaceutically acceptable salt thereof. (2)

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Claims

1. Formula I-A: 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof, During the ceremony: T is CR ６ or N; U is CR ５ or N; V is CR ４ or N; W is CR ３ or N; X is CR ２ or N; Here, 【Chemistry 2】 The ring contains three or fewer nitrogen atoms; E is either unsubstituted or a C1-C3 alkyl substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; R ａ and R ｂ are each independently H or unsubstituted C １ -C ３ alkyl; R １ However, (CR ｃ R ｄ ) ｎ - (C ６ -C １０ (Aryl) or (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), where the aryl or heteroaryl is unsubstituted, or one or more halogens, hydroxyl, or unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ Substituted with alkyl; R ｃ and R ｄ Each of these independently consists of H and unsubstituted C. １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ It is alkyl; n is 0 or 1; R ２ , R ３ , R ４ , R ５ and R ６ When each of these is present, H, halogen, deuterium, hydroxyl, cyano, and unsubstituted C are present. １ -C ３ C substituted with alkyl and one or more halogens or deuterium １ -C ３ Independently selected from the group consisting of alkyls; R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of these independently consists of H, halogen, and unsubstituted C. １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ It is alkyl; Alternatively, R ８ and R １１ However, non-substituted C １ -C ３ C substituted with alkylene or one or more halogens １ -C ３ They form alkylenes together; Alternatively, R ９ and R １０ However, non-substituted C １ -C ３ C substituted with alkylene or one or more halogens １ -C ３ They form alkylenes together; p is 0, 1, 2, 3 or 4, and Each R １４ However, independently selected from the group consisting of deuterium, halogen, hydroxyl, and cyano, The compound of formula I-A above, or a pharmaceutically acceptable salt thereof.

2. The compound of formula I-A or a pharmaceutically acceptable salt thereof is formula I: 【Transformation 3】 The compound or pharmaceutically acceptable salt thereof according to claim 1, which is a compound or a pharmaceutically acceptable salt thereof. 【Request Item 3】 【Chemistry 4】 but, 【Transformation 5】 Selected from the group consisting of; 【Transformation 6】 Selected from the group consisting of; 【Transformation 7】 Selected from the group consisting of; or 【Transformation 8】 The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein p is 0.

5. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein p is 1 or 2.

6. R １ but: (i) (CR ｃ R ｄ ) ｎ - (C ６ -C １０ (Aryl) or (CR ｃ R ｄ ) ｎ - (5- to 10-membered heteroaryl), where the aryl or heteroaryl is unsubstituted; (ii) (CR ｃ R ｄ ) ｎ - (C ６ -C １０ (Aryl) or (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), where the aryl or heteroaryl is one or more halogens, hydroxyls, or unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ Substituted with alkyl; (iii) (CR ｃ R ｄ ) ｎ -(C ６ -C １０ aryl) or (CR ｃ R ｄ ) ｎ -(5- to 10-membered heteroaryl), wherein the aryl or heteroaryl is unsubstituted and further n is 0; (iv) (CR ｃ R ｄ ) ｎ -(C ６ -C １０ aryl) or (CR ｃ R ｄ ) ｎ -(5- to 10-membered heteroaryl), where aryl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C １ -C ３ alkyl, or C １ -C ３ alkyl substituted with one or more halogen or deuterium, and further n is 0; (v) (CR ｃ R ｄ ) ｎ - (C ６ -C １０ (Aryl) or (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), where the aryl or heteroaryl is unsubstituted, and furthermore, n is 1; (vi) (CR ｃ R ｄ ) ｎ - (C ６ -C １０ (Aryl) or (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), where the aryl or heteroaryl is one or more halogens, hydroxyls, or unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ It is substituted with alkyl, and furthermore, n is 1; (vii) (CR ｃ R ｄ ) ｎ - (C ６ -C １０ aryl) and; aryl is non-substitutable, (viiii) (CR ｃ R ｄ ) ｎ - (C ６ -C １０ It is an aryl group, and the aryl group is one or more halogens, hydroxyls, or unsubstituted C atoms. １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ Substituted with alkyl; (ix) (CR ｃ R ｄ ) ｎ - (C ６ -C １０ The aryl is non-substitutable, and n is 0; (x) (CR ｃ R ｄ ) ｎ - (C ６ -C １０ It is an aryl group, and the aryl group is one or more halogens, hydroxyls, or unsubstituted C atoms. １ -C ３ Alkyl, or C substituted with one or more halogens or deuterium １ -C ３ It is substituted with alkyl, and furthermore, n is 0; (xi) (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), where the heteroaryl is unsubstituted; (xi) (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), where the heteroaryl is one or more halogens, hydroxyls, or unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ Substituted with alkyl; (xiii) (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), the heteroaryl is unsubstituted, and n is 0; or (xiv) (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), where the heteroaryl is one or more halogens, hydroxyls, or unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl-substituted and n is 0.

7. R １ but: (i) (CR ｃ R ｄ ) ｎ - (phenyl) or (CR ｃ R ｄ ) ｎ - (5- to 7-membered heteroaryl), where the phenyl or heteroaryl is unsubstituted; (ii) (CR ｃ R ｄ ) ｎ - (phenyl) or (CR ｃ R ｄ ) ｎ - (5-7 member heteroaryl), where phenyl or heteroaryl is one or more halogens, hydroxyl, or unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ Substituted with alkyl; (iii) (CR ｃ R ｄ ) ｎ - (phenyl) or (CR ｃ R ｄ ) ｎ - (5- to 7-membered heteroaryl), where the phenyl or heteroaryl is unsubstituted, and furthermore, n is 0; (iv) (CR ｃ R ｄ ) ｎ - (phenyl) or (CR ｃ R ｄ ) ｎ - (5-7 member heteroaryl), where phenyl or heteroaryl is one or more halogens, hydroxyl, or unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ It is substituted with alkyl, and furthermore, n is 0; (v) (CR ｃ R ｄ ) ｎ - (phenyl) or (CR ｃ R ｄ ) ｎ - (6-membered heteroaryl), where the phenyl or heteroaryl is unsubstituted; (vi) (CR ｃ R ｄ ) ｎ - (phenyl) or (CR ｃ R ｄ ) ｎ - (6-membered heteroaryl), where phenyl or heteroaryl is one or more halogens, hydroxyl, or unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ Substituted with alkyl; (vii) (CR ｃ R ｄ ) ｎ - (phenyl) or (CR ｃ R ｄ ) ｎ - (6-membered heteroaryl), where the phenyl or heteroaryl is unsubstituted, and furthermore, n is 0; or (viiii) (CR ｃ R ｄ ) ｎ - (phenyl) or (CR ｃ R ｄ ) ｎ - (6-membered heteroaryl), where phenyl or heteroaryl is one or more halogens, hydroxyl, or unsubstituted C １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl-substituted and n is 0.

8. R ２ , R ３ , R ４ , R ５ and R ６ When each of these is present, H, halogen, hydroxyl, and unsubstituted C are present. １ -C ３ A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of alkyls.

9. (i) R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of these independently consists of H, halogen, and unsubstituted C. １ -C ３ C substituted with alkyl or one or more halogens or deuterium １ -C ３ It is alkyl; (ii) R ８ and R １１ However, non-substituted C １ -C ３ C substituted with alkylene or one or more halogens １ -C ３ They form alkylenes together; or (iii) R ９ and R １０ However, non-substituted C １ -C ３ C substituted with alkylene or one or more halogens １ -C ３ A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which together forms an alkylene.

10. (i) R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of them is H; (ii) R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of these is either H or unsubstituted C １ -C ３ It is alkyl; or (iii) R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein each of is H or fluorine.

11. (i)R １ However, (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of them is H; (ii) R １ However, (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of these is either H or unsubstituted C １ -C ３ It is alkyl; (iii) R １ However, (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of them is either H or fluorine; (iv)R １ However, (CR ｃ R ｄ ) ｎ - (5-7 member heteroaryl), R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of them is H; (v) R １ However, (CR ｃ R ｄ ) ｎ - (5-7 member heteroaryl), R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of these is either H or unsubstituted C １ -C ３ It is alkyl; or (vi)R １ However, (CR ｃ R ｄ ) ｎ - (5-7 member heteroaryl), R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each of is H or fluorine.

12. (i) R １ However, (CR ｃ R ｄ ) ｎ - (C ６ -C １０ aryl) and R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of them is H; (ii) R １ However, (CR ｃ R ｄ ) ｎ - (C ６ -C １０ aryl) and R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of these is either H or unsubstituted C １ -C ３ It is alkyl; (iii) R １ However, (CR ｃ R ｄ ) ｎ - (C ６ -C １０ aryl) and R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of them is either H or fluorine; (iv)R １ However, (CR ｃ R ｄ ) ｎ - (C ６ aryl) and R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of them is H; (v) R １ However, (CR ｃ R ｄ ) ｎ - (C ６ aryl) and R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ Each of these is either H or unsubstituted C １ -C ３ It is alkyl; or (vi)R １ However, (CR ｃ R ｄ ) ｎ - (C ６ aryl) and R ２ , R ３ , R ４ , R ５ and R ６ Each of them is H when it exists, and R ７ , R ８ , R ９ , R １０ , R １１ , R １２ and R １３ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each of is H or fluorine. 【Request Item 13】 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】 【Chemistry 9-5】 【Chemistry 9-6】 【Chemistry 9-7】 【Chemistry 9-8】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

14. The aforementioned compound or a pharmaceutically acceptable salt thereof: 【Chemistry 10】 The compound or pharmaceutically acceptable salt thereof according to claim 2.

15. The aforementioned compound or a pharmaceutically acceptable salt thereof: 【Chemistry 11】 The compound or pharmaceutically acceptable salt thereof according to claim 2.

16. The aforementioned compound or a pharmaceutically acceptable salt thereof: 【Chemistry 12】 The compound or pharmaceutically acceptable salt thereof according to claim 2.

17. The aforementioned compound or a pharmaceutically acceptable salt thereof: 【Chemistry 13】 The compound or pharmaceutically acceptable salt thereof according to claim 2.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for the manufacture of a medicine for narcolepsy.

20. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for the manufacture of a pharmacopoeia for cataplexy.

21. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in a method for treating narcolepsy in a subject requiring treatment.

22. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in a method of treating cataplexy in a subject requiring treatment.

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