Substituted amide macrocyclic compounds having orexin-2 receptor agonist activity

Abstract

The present invention provides compounds of formula (I) 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] Related applications This application claims the benefits of U.S. Provisional Application No. 63 / 179,616, filed on 26 April 2021. The entire contents of the said application are incorporated herein by reference.

[0002] Technical field The present invention relates to substituted macrocyclic compounds, particularly substituted macrocyclic compounds having agonist activity. [Background technology]

[0003] Background of the Invention Orexin is a neuropeptide synthesized and released by a subpopulation of neurons in the lateral hypothalamus and surrounding regions. It 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 that are 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 sustained 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 engineered to degenerate orexin neurons, and these symptoms can be reversed by intracardiac administration of orexin peptides (Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004). Studies in orexin-2 receptor knockout mice suggest that the orexin-2 receptor plays a preferential role in maintaining wakefulness (Cell, Vol. 98, 437-451, 1999, Neuron, Vol. 38, 715-730, 2003). Thus, orexin-2 receptor agonists may be therapeutic agents 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 exhibiting 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, disturbances of consciousness such as coma, narcolepsy syndrome, hypersomnolence syndromes characterized by excessive sleep (e.g., in Parkinson's disease, Guian-Barré syndrome, or Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, or sepsis. (Cell Metabolism, Vol. 9, 64-76, 2009;Neuroscience, Vol. 121, 855-863, 2003;Respiration, Vol. 71, 575-579, 2004;Peptides, Vol. 23, 1683-1688, 2002;WO 2015 / 073707;Journal of the American College of Cardiology, Vol. 66, 2015, pages 2522-2533;WO 2015 / 048091;WO 2015 / 147240).

[0006] Several compounds possessing orexin-2 receptor agonist activity have been reported (US Patent No. 8,258,163; WO 2015 / 088000; WO 2014 / 198880; Journal of Medicinal Chemistry, Vol. 58, pages 7931-7937; US 20190040010; US 20190031611; US ​​20170226137). However, these compounds are considered unsatisfactory 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 project]

[0007] Summary of the Invention The present invention intends to provide substituted macrocyclic compounds having orexin-2 receptor agonist activity.

[0008] Thus, in a first aspect, the present invention provides a compound of formula I-A:

Chemical formula

[0009] In one embodiment, formula I: [ka] Compounds of formula IA having the structure of the above, or pharmaceutically acceptable salts thereof, are provided herein, in which: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3; E is NR a R b , C(=O)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 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 Selected from the group consisting of aryls, 5-10 member heteroaryls, and C1-C3 alkylene-(5-10 member heteroaryls), where 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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C10 A C1-C3 alkylene (5-10 member heteroaryl) is either unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; T is either CR1R2 or O; W is either CR4R5 or O; U is CR6R7; X is CR8R9; V is either CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; Each R is independently selected from the group consisting of halogens, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with one or more halogens or deuterium; p is 0, 1, 2, 3, or 4; R a and R b Each of these is independently H or an unsubstituted C1-C3 alkyl; m is 1, 2, 3, or 4; And further: R1, R2, R4, and R5 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; Alternatively, R2 and R5, together with the carbon atoms to which they are bonded, form a single bond; R3 is selected from the group consisting of H, deuterium, halogens, hydroxyl, and cyano; Alternatively, R3 and R1, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; R6, R7, R8, R9 and R 11 Each of these is independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R 12 and R 13 is independently selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogens; R<00已翻译内容0050>[[ID=已翻译内容3]]、R 15 and R 16 is each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens; Each R[[ID=2已翻译内容0]] 17 [[ID=2已翻译内容1]]and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens.<00008已翻译内容4>

[0010] 第26行: Formula II-A:

Chemical formula

[0011] In one embodiment, Formula II: [ka] Compounds of formula II-A having the structure of the above, or pharmaceutically acceptable salts thereof, are provided herein, wherein: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2 or 3; E is NR a R b 、C(=O)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 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 member heteroaryl and C1-C3 alkylene-(5-10 member heteroaryl) selected from the group consisting of, where 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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-10 member heteroaryl or C1-C3 alkylene-(5-10 member heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl; T is CR1R2 or O; W is CR4R5 or O; U is CR6R7; X is CR8R9; V is CR3 or N; Y is NR 10 、O or absent; Z is (CR 12 R 13 ) m ; Each R is independently selected from the group consisting of halogens, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with one or more halogens or deuterium; p is 0, 1, 2, 3, or 4; R a and R b Each of these is independently H or an unsubstituted C1-C3 alkyl; If Y does not exist, then m is 2, 3, 4 or 5; or Y is NR 10 Or, if it is O, then m is 1, 2, 3 or 4; And further: R1, R2, R4, and R5 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; Alternatively, R2 and R5, together with the carbon atoms to which they are bonded, form a single bond; R3 is selected from the group consisting of H, deuterium, halogens, hydroxyl, and cyano; Alternatively, R3 and R1, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; R6, R7, R8, R9 and R 11 Each of these is independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 This is selected from the group consisting of H, unsubstituted C1-C3 alkyl groups, and C1-C3 alkyl groups substituted with one or more halogens; Each R 12 and R 13 These are independently selected from the group consisting of H, halogens, deuterium, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; each R 17 and R 18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens.

[0012] Also provided herein are pharmaceutical compositions comprising a compound of any of Formulas I-A, I, II-A or II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] In another aspect, provided herein is a method of treating narcolepsy in a subject, comprising administering to the subject a compound of Formulas I-A, I, II-A or II, or a pharmaceutically acceptable salt thereof, which is in need of treatment of narcolepsy.

[0014] In another aspect, provided herein is a method of treating cataplexy in a subject, comprising administering to the subject a compound of Formulas I-A, I, II-A or II, or a pharmaceutically acceptable salt thereof, which is in need of treatment of cataplexy.

Best Mode for Carrying Out the Invention

[0015] Detailed Description of the Invention Compounds useful for the treatment of narcolepsy or cataplexy in a subject, such as compounds of Formulas I-A, I, II-A or II, or pharmaceutically acceptable salts thereof, are provided herein.

[0016] In a non-limiting aspect, these compounds can modulate the orexin-2 receptor. In certain embodiments, the compounds provided herein are considered orexin-2 agonists. Thus, in one aspect, the compounds provided herein are useful for the treatment of narcolepsy in a subject by acting as an agonist of the orexin-2 receptor.

[0017] definition The definitions of various terms used to describe the present invention are listed below. These definitions apply to the terms used throughout this specification and the claims, unless otherwise specifically limited to those terms individually or as part of a larger group.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains. Generally, the nomenclature and laboratory procedures used herein in cell culture, molecular genetics, organic chemistry, and peptide chemistry are well known and commonly used in the art.

[0019] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” means one or more elements. Furthermore, the use of the term “including” as well as other forms such as “include,” “includes,” and “included” is not limited.

[0020] As used herein, the term “about” will be understood by those skilled in the art and will vary to some extent in the context in which it is used. As used herein, when referring to a measurable value, such as a quantity or a temporal duration, the term “about” means to include variations of ±20% or ±10%, e.g., ±5%, ±1%, and ±0.1%, from the specified value, such as being appropriate for performing the disclosed method.

[0021] When used in this specification, the term "EC" 50 " is the concentration of a compound required to achieve an effect that is 50% of the compound's maximum observed effect.

[0022] As used herein, the term "agonist" refers to a compound that, when in contact with a target of interest (e.g., an orexin-2 receptor), produces an increase in the magnitude of a particular activity or function of the target compared to the magnitude of the activity or function observed in the absence of the agonist.

[0023] The terms “treat,” “treated,” “treating,” or “treatment” include reduction or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In one embodiment, 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.

[0024] As used herein, the terms “prevent” or “prevention” mean the absence of the onset of a disability or disease if nothing happens, or the absence of further onset of a disability or disease if one has already occurred. The ability of something to prevent some or all of the symptoms associated with a disability or disease is also taken into consideration.

[0025] As used herein, the terms “patient,” “individual,” or “subject” refer to a human or a non-human mammal. Examples of non-human mammals include livestock and pets, such as sheep, cattle, pigs, dogs, cats, and mice. Preferably, the patient, subject, or individual is human.

[0026] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” and “therapeutic effective dose” refer to an amount of a drug that is non-toxic but sufficient to produce a desired biological effect. This effect may be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in the biological system. The appropriate therapeutic dose in any individual case can be determined by a person skilled in the art using conventional experiments.

[0027] As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not preclude the biological activity or properties of a compound and is relatively non-toxic; that is, the material can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of a composition containing it.

[0028] As used herein, the term “pharmaceutically acceptable salt” means a derivative of the disclosed compound, where the parent compound is modified by converting the present 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 with non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase “pharmaceutically acceptable salt” is not limited to mono or 1:1 salts. For example, “pharmaceutically acceptable salt” also includes 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 in its entirety.

[0029] As used herein, the terms “composition” or “pharmaceutical composition” mean a mixture of at least one compound useful in the present invention, having 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, but are not limited to, intravenous, oral, aerosol, parenteral, intraocular, pulmonary, and topical administration.

[0030] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, concentrator, solvent, or encapsulating agent, that is involved in transporting or delivering a compound useful in the present invention into or to a patient so 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 the formulation, such as the compound useful in the present invention, and is not harmful to the patient. Some examples of materials that can act as pharmaceutically acceptable carriers include: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffering agents, e.g., magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; heat-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate-buffered solutions; and other non-toxic, suitable substances used in pharmaceutical formulations.

[0031] As used herein, “pharmaceutically acceptable carrier” also includes the activity and compatibility of compounds useful in the present invention and any and all coatings, antimicrobial and antifungal agents, and absorption retarders that are physiologically acceptable to the patient. Auxiliary active compounds may also be incorporated into the composition. “pharmaceutically acceptable carrier” may further include pharmaceutically acceptable salts of compounds useful in the present invention. Other further components that may be included in pharmaceutical compositions used in the implementation 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.

[0032] As used herein, the term “alkyl” means a hydrocarbon having the indicated number of carbon atoms in a straight or branched chain, either by itself or as part of another substituent, unless otherwise stated (i.e., C 1-6 Alkyl (meaning alkyl having 1 to 6 carbon atoms) 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.

[0033] As used herein, the term “halo” or “halogen” means, alone or as part of another substituent, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine, unless otherwise stated.

[0034] As used herein, the term "alkylene" refers to a divalent aliphatic hydrocarbyl group having, for example, 1 to 4 carbon atoms, which may be either linear or branched. Examples of this term include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), etc.

[0035] 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 in the form of a bond to another group. Examples of alkenyl groups (e.g., C2-C8 alkenyls) include, but are not limited to, ethenyl, propenyl, propane-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0036] 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 in the form of bonding to another group. Examples of alkynyl groups (e.g., C2-C8-alkynyl) include, but are not limited to, ethynyl, propynyl, propa-1-in-2-yl, butynyl, 1-methyl-2-butyne-1-yl, heptenyl, octinyl, and others.

[0037] As used herein, the term "alkoxy" means 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.

[0038] As used herein, the term “cycloalkyl” means a non-aromatic carbocyclic system having one, two, or three rings that are partially or completely saturated and can be condensed. The term “condensation” means that a second ring exists (i.e., is bonded or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyls also include bicyclic structures that can be bridged in nature or are spirocyclic systems, where each individual ring within the bicyclic system is varied by 3 to 8 atoms. Examples of the term “cycloalkyl” but not limited to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl.

[0039] As used herein, the term “heterocyclyl” means a non-aromatic carbocyclic system having 1, 2, 3, or 3 rings, comprising 1, 2, or 4 heteroatoms independently selected from N, O, and S, where such rings may be condensed, condensation as defined above. Heterocyclyls also include bicyclic structures that may be bridged in nature or may be spirocyclic, where each individual ring within the bicyclic structure varies by 3 to 8 atoms and contains 0, 1, or 2 N, O, or S atoms. The term "heterocyclyl" includes, but is not specifically limited to, cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), such as epoxyzyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil (i.e., oxanil), pyranil, dioxanil, azilidinyl, azetidinil, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinil, piperazinyl, thiomorpholinil, 1,3-oxazinanyl, and 1,3-thiadinyl. For example, the term "heterocycline" can refer to 4-10 membered heterocyclines, 4-7 membered heterocyclines, 5-10 membered heterocyclines, 6-10 membered heterocyclines, 4-6 membered heterocyclines, 4 membered heterocyclines, 5 membered heterocyclines, 6 membered heterocyclines, 7 membered heterocyclines, 8 membered heterocyclines, 9 membered heterocyclines, or 10 membered heterocyclines.

[0040] As used herein, the term “aromatic” means a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and possessing aromatic properties, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0041] As used herein, the term “aryl” means an aromatic carbocyclic system comprising one, two, or three rings, where such rings may be condensed, condensation as defined above. When rings are condensed, one of the rings may be fully unsaturated, and the condensed ring(s) may be fully saturated, partially unsaturated, or fully unsaturated. Examples of the term “aryl” include, but are not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. For example, the term “aryl” is C6-C 10 Examples include aryl, C6-C8 aryl, or C6 aryl (i.e., phenyl).

[0042] As used herein, the term “heteroaryl” means an aromatic carbocyclic system comprising one, two, three, or four heteroatoms independently selected from N, O, and S, and having one, two, or three rings, where such rings may be condensed, condensation is defined above. Examples of the term “heteroaryl” include, but are not limited to, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl. For example, the term “heteroaryl” may include 5-10 membered heteroaryls, 5-8 membered heteroaryls, 5-6 membered heteroaryls, 6-10 membered heteroaryls, 6-8 membered heteroaryls, 5 membered heteroaryls, 6 membered heteroaryls, 7 membered heteroaryls, 8 membered heteroaryls, 9 membered heteroaryls, or 10 membered heteroaryls.

[0043] When an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety can be bonded to a moiety that is otherwise shown via different ring atoms (i.e., shown or described without indication of specific points of bonding), it is understood that all possible points, whether via carbon atoms or, for example, trivalent nitrogen atoms, are intended. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, and the term "thiophenyl" means 2- or 3-thiophenyl, and so on.

[0044] As used herein, the term “substituted” means that an atom or group of atoms has hydrogens that have been replaced as substituents attached to another group.

[0045] Compound of the present invention Therefore, in the first phase, the present invention is defined by formula IA: [ka] We provide a compound represented by or a pharmaceutically acceptable salt thereof, in which: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3; E is NR a R b , C(=O)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 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 Selected from the group consisting of aryls, 5-10 member heteroaryls, and C1-C3 alkylene-(5-10 member heteroaryls), where 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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 A C1-C3 alkylene-(5-C3 heteroaryl) is either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls; T is either CR1R2 or O; W is either CR4R5 or O; U is CR6R7; X is CR8R9; V is either CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; Each R is independently selected from the group consisting of halogens, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with one or more halogens or deuterium; p is 0, 1, 2, 3, or 4; R a and R b Each of these is independently H or an unsubstituted C1-C3 alkyl; m is 1, 2, 3, or 4; And further: R1, R2, R4, and R5 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; Alternatively, R2 and R5, together with the carbon atoms to which they are bonded, form a single bond; R3 is selected from the group consisting of H, deuterium, halogens, hydroxyl, and cyano; Alternatively, R3 and R1, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; R6, R7, R8, R9 and R 11 Each of these is independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 This is selected from the group consisting of H, unsubstituted C1-C3 alkyl groups, and C1-C3 alkyl groups substituted with one or more halogens; Each R 12 and R 13 These are independently selected from the group consisting of H, halogens, deuterium, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 Each of these is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 The following are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens.

[0046] In one embodiment, formula I: [ka] Compounds of formula IA having the structure of the above, or pharmaceutically acceptable salts thereof, are provided herein, in which: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3; E is NR a R b , C(=O)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 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 Selected from the group consisting of aryls, 5-10 member heteroaryls, and C1-C3 alkylene-(5-10 member heteroaryls), where 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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 A C1-C3 alkylene-(5-C3 heteroaryl) is either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls; T is either CR1R2 or O; W is either CR4R5 or O; U is CR6R7; X is CR8R9; V is either CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; Each R is independently selected from the group consisting of halogens, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with one or more halogens or deuterium; p is 0, 1, 2, 3, or 4; R a and R b Each of these is independently H or an unsubstituted C1-C3 alkyl; m is 1, 2, 3, or 4; And further: R1, R2, R4, and R5 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; Alternatively, R2 and R5, together with the carbon atoms to which they are bonded, form a single bond; R3 is selected from the group consisting of H, deuterium, halogens, hydroxyl, and cyano; Alternatively, R3 and R1, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; R6, R7, R8, R9 and R 11 Each of these is independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 This is selected from the group consisting of H, unsubstituted C1-C3 alkyl groups, and C1-C3 alkyl groups substituted with one or more halogens; Each R 12 and R 13 These are independently selected from the group consisting of H, halogens, deuterium, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 Each of these is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 The following are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens.

[0047] In one embodiment of equation (I), n is 1. In another embodiment of equation (I), n is 2. In yet another embodiment of equation (I), n is 3.

[0048] In another embodiment of formula (I), ring A is phenyl. In another embodiment of formula (I), ring A is pyridinyl. In another embodiment of formula (I), ring A is pyridazinyl. In another embodiment of formula (I), ring A is pyrimidinyl. In another embodiment of formula (I), ring A is pyrazinyl. In another embodiment of formula (I), ring A is triazinyl.

[0049] In another embodiment of equation (I), Y is NR 10 In another embodiment of formula (I), Y is O. In another embodiment of formula (I), Y is absent. In another embodiment of formula (I), ring A is phenyl and Y is NR 10 In another embodiment of formula (I), ring A is phenyl and Y is O. In another embodiment of formula (I), ring A is phenyl and Y is absent. In another embodiment of formula (I), ring A is pyridinyl and Y is NR 10 In another embodiment of formula (I), ring A is pyridinyl and Y is O. In another embodiment of formula (I), ring A is pyridinyl and Y is absent. In another embodiment of formula (I), ring A is pyridazinyl and Y is NR 10 In another embodiment of formula (I), ring A is pyridazinyl and Y is O. In another embodiment of formula (I), ring A is pyridazinyl and Y is absent. In another embodiment of formula (I), ring A is pyrimidinyl and Y is NR 10 In another embodiment of formula (I), ring A is pyrimidinyl and Y is O. In another embodiment of formula (I), ring A is pyrimidinyl and Y is absent. In another embodiment of formula (I), ring A is pyrazinyl and Y is NR 10 In another embodiment of formula (I), ring A is pyrazinyl and Y is O. In another embodiment of formula (I), ring A is pyrazinyl and Y is absent. In another embodiment of formula (I), ring A is triazinyl and Y is NR 10 In another embodiment of equation (I), ring A is a triazinyl and Y is O. In another embodiment of equation (I), ring A is a triazinyl and Y is absent.

[0050] In another aspect of equation (I), T is CR1R2. In another aspect of equation (I), T is O. In another aspect of equation (I), W is CR4R5. In another aspect of equation (I), W is O. In another aspect of equation (I), T is CR1R2 and W is CR4R5. In another aspect of equation (I), T is O and W is CR4R5. In another aspect of equation (I), T is CR1R2 and W is O.

[0051] In another embodiment of equation (I), V is CR3. In another embodiment of equation (I), V is N.

[0052] In another embodiment of equation (I), T is CR1R2 and V is CR3. In another embodiment of equation (I), T is O and V is CR3. In another embodiment of equation (I), T is CR1R2 and V is N. In another embodiment of equation (I), T is O and V is N.

[0053] In another aspect of equation (I), W is CR4R5 and V is CR3. In another aspect of equation (I), W is O and V is CR3. In another aspect of equation (I), W is CR4R5 and V is N. In another aspect of equation (I), W is O and V is N.

[0054] In another embodiment of equation (I), T is CR1R2, W is CR4R5, and V is CR3. In another embodiment of equation (I), T is CR1R2, W is O, and V is CR3. In another embodiment of equation (I), T is CR1R2, W is CR4R5, and V is N. In another embodiment of equation (I), T is CR1R2, W is O, and V is N. In another embodiment of equation (I), T is O, W is CR4R5, and V is CR3.

[0055] In another embodiment of equation (I), E is NR a R b Therefore, in another form of equation (I), E is C(=O)NR a R bIn another embodiment of equation (I), E is C1-C3 alkylene-NR a R b In another embodiment of formula (I), E is an unsubstituted C1-C3 alkyl, an unsubstituted C2-C4 alkenyl, or an unsubstituted C2-C4 alkynyl. In another embodiment of formula (I), E is a C1-C3 alkyl, 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 heterocycline. In another embodiment of formula (I), E is a 4- to 10-membered heterocycline 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 heterocycline). In another embodiment of formula (I), E is a C1-C3 alkylene-(4-10 member heterocycline) substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (I), E is an unsubstituted C6-C 10 It is an aryl compound. In another embodiment of formula (I), E is a C6-C alkyl or C1-C3 alkoxyl compound substituted with one or more halogens, hydroxyls, C1-C3 alkyls or C1-C3 alkoxyls. 10It is an aryl compound. In another embodiment of formula (I), E is an unsubstituted C1-C3 alkylene-(C6-C 10 It is an aryl. In another embodiment of formula (I), E is a C1-C3 alkylene-(C6-C) which is substituted with one or more halogens, hydroxyls, C1-C3 alkyls or C1-C3 alkoxyls. 10 E is an aryl. In another embodiment of formula (I), E is an unsubstituted 5- to 10-membered heteroaryl. In another embodiment of formula (I), E is a 5- to 10-membered heteroaryl substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0056] In another embodiment of formula (I), E is an unsubstituted 4- to 7-membered heterocycline. In another embodiment of formula (I), E is a 4- to 7-membered heterocycline 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 6-membered heterocycline. In another embodiment of formula (I), E is a 4- to 6-membered heterocycline 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-membered heterocycline. In another embodiment of formula (I), E is a 4-membered heterocycline substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (I), E is an unsubstituted 5-membered heterocycline. In another embodiment of formula (I), E is a 5-membered heterocycline substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (I), E is an unsubstituted 6-membered heterocycline. In another embodiment of formula (I), E is a 6-membered heterocycline substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0057] In another embodiment of equation (I), E is NR a R b , C(=O)NR a R bC1-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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl) and here 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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 The aryl group is either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0058] In another embodiment of formula (I), E is C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 (aryl), where C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 The aryl group is either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0059] In another embodiment of formula (I), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 (aryl), where C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 The aryl group is either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0060] 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 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 either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0061] 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 either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0062] In another embodiment of formula (I), E is methyl, where methyl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of formula (I), E is methyl. In another embodiment of formula (I), E is trifluoromethyl. In another embodiment of formula (I), E is dioxanyl, where dioxanyl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of formula (I), E is tetrahydropyranyl, where tetrahydropyranyl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of formula (I), E is tetrahydrofuranyl, where tetrahydrofuranyl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of formula (I), E is azetidinyl, where azetidinyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (I), E is oxetanyl, where oxetanyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (I), E is morpholinyl, where morpholinyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0063] In another embodiment of equation (I), R 14 is H. In another form of equation (I), R 14 is an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R 15 and R 16 These are H, respectively. In another form of equation (I), R 15 R is an unsubstituted C1-C3 alkyl group, 16 is H. In another form of equation (I), R 16R is an unsubstituted C1-C3 alkyl group, 15 is H. In another form of equation (I), each R 17 and R 18 is H. In another form of equation (I), R 17 R is an unsubstituted C1-C3 alkyl group, 18 is H. In another form of equation (I), R 18 R is an unsubstituted C1-C3 alkyl group, 17 is H. In another form of equation (I), R 14 , R 15 , R 16 , R 17 and R 18 One of them is an unsubstituted C1-C3 alkyl group, and the others are each H.

[0064] In another embodiment of equation (I), m is 1. In another embodiment of equation (I), m is 2. In another embodiment of equation (I), m is 3. In another embodiment of equation (I), m is 4. In another embodiment of equation (I), m is 1, 2, or 3. In another embodiment of equation (I), m is 2, 3, or 4. In another embodiment of equation (I), m is 1 or 2. In another embodiment of equation (I), m is 3 or 4.

[0065] In another embodiment of equation (I), Y is O and m is 1. In another embodiment of equation (I), Y is O and m is 2. In another embodiment of equation (I), Y is O and m is 3. In another embodiment of equation (I), Y is O and m is 4. In another embodiment of equation (I), Y is O and m is 1, 2, or 3. In another embodiment of equation (I), Y is O and m is 2, 3, or 4. In another embodiment of equation (I), Y is O and m is 1 or 2. In another embodiment of equation (I), Y is O and m is 3 or 4.

[0066] In another aspect of equation (I), Y is nonexistent and m is 1. In another aspect of equation (I), Y is nonexistent and m is 2. In another aspect of equation (I), Y is nonexistent and m is 3. In another aspect of equation (I), Y is nonexistent and m is 4. In another aspect of equation (I), Y is nonexistent and m is 1, 2, or 3. In another aspect of equation (I), Y is nonexistent and m is 2, 3, or 4. In another aspect of equation (I), Y is nonexistent and m is 1 or 2. In another aspect of equation (I), Y is nonexistent and m is 3 or 4.

[0067] In another embodiment of equation (I), Y is NR 10 And m is 1. In another embodiment of equation (I), Y is NR 10 And m is 2. In another embodiment of equation (I), Y is NR 10 And m is 3. In another embodiment of equation (I), Y is NR 10 And m is 4. In another embodiment of equation (I), Y is NR 10 And m is 1, 2 or 3. In another embodiment of equation (I), Y is NR 10 And m is 2, 3 or 4. In another embodiment of equation (I), Y is NR 10 And m is 1 or 2. In another embodiment of equation (I), Y is NR 10 And m is either 3 or 4.

[0068] In another embodiment of formula (I), ring A is phenyl and n is 1. In another embodiment of formula (I), ring A is phenyl and n is 2. In another embodiment of formula (I), ring A is phenyl and n is 3. In another embodiment of formula (I), ring A is pyridinyl and n is 1. In another embodiment of formula (I), ring A is pyridinyl and n is 2. In another embodiment of formula (I), ring A is pyridinyl and n is 3. In another embodiment of formula (I), ring A is pyridazinyl and n is 1. In another embodiment of formula (I), ring A is pyridazinyl and n is 2. In another embodiment of formula (I), ring A is pyridazinyl and n is 3. In another embodiment of formula (I), ring A is pyrimidinyl and n is 1. In another embodiment of formula (I), ring A is pyrimidinyl and n is 2. In another embodiment of formula (I), ring A is pyrimidinyl and n is 3. In another embodiment of formula (I), ring A is pyrazinyl and n is 1. In another embodiment of formula (I), ring A is pyrazinyl and n is 2. In another embodiment of formula (I), ring A is pyrazinyl and n is 3. In another embodiment of formula (I), ring A is triazinyl and n is 1. In another embodiment of formula (I), ring A is triazinyl and n is 2. In another embodiment of formula (I), ring A is triazinyl and n is 3.

[0069] In another embodiment of formula (I), ring A is phenyl, n is 1, and Y is NR 10 In another embodiment of formula (I), ring A is phenyl, n is 2, and Y is NR 10 In another embodiment of formula (I), ring A is phenyl, n is 3, and Y is NR 10In another embodiment of formula (I), ring A is phenyl, n is 1, and Y is O. In another embodiment of formula (I), ring A is phenyl, n is 2, and Y is O. In another embodiment of formula (I), ring A is phenyl, n is 3, and Y is O. In another embodiment of formula (I), ring A is phenyl, n is 1, and Y is absent. In another embodiment of formula (I), ring A is phenyl, n is 2, and Y is absent. In another embodiment of formula (I), ring A is phenyl, n is 3, and Y is absent.

[0070] In another embodiment of formula (I), ring A is phenyl, n is 1, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is phenyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, n is 2, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, n is 3, and Y is NR 10In another embodiment of formula (I), ring A is phenyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, n is 3, Y is absent, and m is 3 or 4.

[0071] In another embodiment of formula (I), ring A is pyridinyl, n is 1, and Y is NR 10 In another embodiment of formula (I), ring A is pyridinyl, n is 2, and Y is NR 10 In another embodiment of formula (I), ring A is pyridinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyridinyl, n is 1, and Y is O. In another embodiment of formula (I), ring A is pyridinyl, n is 2, and Y is O. In another embodiment of formula (I), ring A is pyridinyl, n is 3, and Y is O. In another embodiment of formula (I), ring A is pyridinyl, n is 1, and Y is absent. In another embodiment of formula (I), ring A is pyridinyl, n is 2, and Y is absent. In another embodiment of formula (I), ring A is pyridinyl, n is 3, and Y is absent.

[0072] In another embodiment of formula (I), ring A is pyridinyl, n is 1, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (I), ring A is pyridinyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (I), ring A is pyridinyl, n is 3, and Y is NR 10In another embodiment of formula (I), ring A is pyridinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridinyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridinyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridinyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridinyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (I), ring A is pyridinyl, n is 2, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (I), ring A is pyridinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyridinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridinyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridinyl, n is 3, Y is absent, and m is 3 or 4.

[0073] In another embodiment of formula (I), ring A is pyridazinyl, n is 1, and Y is NR 10 In another embodiment of formula (I), ring A is pyridazinyl, n is 2, and Y is NR 10In another embodiment of formula (I), ring A is pyridazinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyridazinyl, n is 1, and Y is O. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, and Y is O. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, and Y is O. In another embodiment of formula (I), ring A is pyridazinyl, n is 1, and Y is absent. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, and Y is absent. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, and Y is absent.

[0074] In another embodiment of formula (I), ring A is pyridazinyl, n is 1, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyridazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyridazinyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, and Y is NR 10And m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyridazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyridazinyl, n is 3, Y is absent, and m is 3 or 4.

[0075] In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, and Y is NR 10 In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, and Y is NR 10 In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, and Y is O. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, and Y is O. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, and Y is O. In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, and Y is absent. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, and Y is absent. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, and Y is absent.

[0076] In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, and Y is NR10 And m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrimidinyl, n is 3, Y is absent, and m is 3 or 4.

[0077] In another embodiment of formula (I), ring A is pyrazinyl, n is 1, and Y is NR 10 In another embodiment of formula (I), ring A is pyrazinyl, n is 2, and Y is NR 10 In another embodiment of formula (I), ring A is pyrazinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyrazinyl, n is 1, and Y is O. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, and Y is O. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, and Y is O. In another embodiment of formula (I), ring A is pyrazinyl, n is 1, and Y is nonexistent. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, and Y is nonexistent. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, and Y is nonexistent.

[0078] In another embodiment of formula (I), ring A is pyrazinyl, n is 1, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (I), ring A is pyrazinyl, n is 1, and Y is NR10 And m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 1, Y is nonexistent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 2, Y is nonexistent, and m is 3 or 4. In another embodiment of formula (I), ring A is pyrazinyl, n is 3, Y is nonexistent, and m is 3 or 4.

[0079] In another embodiment of formula (I), ring A is a triazinyl, n is 1, and Y is NR 10 In another embodiment of formula (I), ring A is a triazinyl, n is 2, and Y is NR 10 In another embodiment of formula (I), ring A is a triazinyl, n is 3, and Y is NR 10 In another aspect of equation (I), ring A is a triazinyl, n is 1, and Y is O. In another aspect of equation (I), ring A is a triazinyl, n is 2, and Y is O. In another aspect of equation (I), ring A is a triazinyl, n is 3, and Y is O. In another aspect of equation (I), ring A is a triazinyl, n is 1, and Y is nonexistent. In another aspect of equation (I), ring A is a triazinyl, n is 2, and Y is nonexistent. In another aspect of equation (I), ring A is a triazinyl, n is 3, and Y is nonexistent.

[0080] In another embodiment of formula (I), ring A is a triazinyl, n is 1, and Y is NR10 And m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is a triazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl, n is 1, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl, n is 2, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl, n is 3, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (I), ring A is a triazinyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl, n is 2, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl, n is 3, and Y is NR 10 In another embodiment of formula (I), ring A is a triazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl, n is 1, Y is nonexistent, and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl, n is 2, Y is nonexistent, and m is 3 or 4. In another embodiment of formula (I), ring A is a triazinyl, n is 3, Y is nonexistent, and m is 3 or 4.

[0081] In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, and V is CR3. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, and V is CR3. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 1. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 2. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 3. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 1. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 2. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 3.

[0082] In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and Y is O. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and Y is O. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 1. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 2. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 3. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 1. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 2. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 3.

[0083] In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4.In another embodiment of formula (I), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4. In another embodiment of formula (I), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4.

[0084] In another embodiment of equation (I), p is 0 and R1, R2, R4 and R5 are each H. In another embodiment of equation (I), p is 0; R1, R2, R4 and R5 are each H; R3 is H. In another embodiment of equation (I), p is 0; R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 H and R are respectively. 12 and R 13 These are H.

[0085] In another embodiment of equation (I), p is 1 and R1, R2, R4 and R5 are each H. In another embodiment of equation (I), p is 1; R1, R2, R4 and R5 are each H; R3 is H. In another embodiment of equation (I), p is 1; R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R11 H and R are respectively. 12 and R 13 These are H.

[0086] In another embodiment of equation (I), p is 2, and R1, R2, R4 and R5 are each H. In another embodiment of equation (I), p is 2; R1, R2, R4 and R5 are each H; R3 is H. In another embodiment of equation (I), p is 2; R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 H and R are respectively. 12 and R 13 These are H.

[0087] In another embodiment of formula (I), p is 1, 2, 3, or 4, and R is fluorine. In another embodiment of formula (I), p is 1, 2, 3, or 4, and R is deuterium. In another embodiment of formula (I), p is 1, 2, 3, or 4, and each R is independently selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium. In another embodiment of formula (I), p is 1, 2, 3, or 4, and each R is independently selected from the group consisting of cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium. In another embodiment of formula (I), p is 1, and R is an unsubstituted C1-C3 alkyl. In another embodiment of formula (I), p is 1, and R is methyl. In another embodiment of formula (I), p is 1 or 2, and each R is methyl. In another embodiment of formula (I), p is 1 and R is a C1-C3 alkyl substituted with one or more halogens. In another embodiment of formula (I), p is 1 and R is CF3. In another embodiment of formula (I), p is 1 or 2 and each R is CF3.

[0088] In another embodiment of formula (I), one or more of R1, R2, R4, and R5 are fluorine. In another embodiment of formula (I), one or more of R1, R2, R4, and R5 are deuterium. In another embodiment of formula (I), R6, R7, R8, R9, and R 11 One or more of them are fluorine. In another embodiment of formula (I), R6, R7, R8, R9 and R 11 One or more of them are deuterium. In another form of equation (I), each R 12 and R 13 One or more of them are fluorine. In another form of formula (I), each R 12 and R 13 One or more of them are deuterium.

[0089] In another embodiment of equation (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H. In another embodiment of equation (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H and m is 1. In another embodiment of equation (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 Each of them is H. In another embodiment of equation (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 Each of them is H and m is 1. In another embodiment of equation (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R18 Each of them is H. In another embodiment of equation (I), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each of them is H, and m is 1.

[0090] Each of the embodiments described herein with respect to compounds of formula I also applies to compounds of formula IA.

[0091] Formula II-A: [ka] Compounds having the structure of the formula or pharmaceutically acceptable salts thereof are also provided herein, in which: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3; E is NR a R b , C(=O)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 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 Selected from the group consisting of aryls, 5-10 member heteroaryls, and C1-C3 alkylene-(5-10 member heteroaryls), where 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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 A C1-C3 alkylene (5-C3 heteroaryl) is either unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; T is either CR1R2 or O; W is either CR4R5 or O; U is CR6R7; X is CR8R9; V is either CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; Each R is independently selected from the group consisting of halogens, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with one or more halogens or deuterium; p is 0, 1, 2, 3, or 4; R a and R b Each of these is independently H or an unsubstituted C1-C3 alkyl; If Y does not exist, then m is 2, 3, 4 or 5; or Y is NR 10 Or, if it is O, then m is 1, 2, 3 or 4; And further: R1, R2, R4, and R5 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; Alternatively, R2 and R5, together with the carbon atoms to which they are bonded, form a single bond; R3 is selected from the group consisting of H, deuterium, halogens, hydroxyl, and cyano; Alternatively, R3 and R1, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; R6, R7, R8, R9 and R 11 Each of these is independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 This is selected from the group consisting of H, unsubstituted C1-C3 alkyl groups, and C1-C3 alkyl groups substituted with one or more halogens; Each R 12 and R 13 These are independently selected from the group consisting of H, halogens, deuterium, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 Each of these is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 The following are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens.

[0092] In one embodiment, Formula II: [ka] Compounds of formula II-A having the structure of the above, or pharmaceutically acceptable salts thereof, are provided herein, wherein: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3; E is NR a R b, C(=O)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 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 Selected from the group consisting of aryls, 5-10 member heteroaryls, and C1-C3 alkylene-(5-10 member heteroaryls), where 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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 A C1-C3 alkylene (5-C3 heteroaryl) is either unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; T is either CR1R2 or O; W is either CR4R5 or O; U is CR6R7; X is CR8R9; V is either CR3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; Each R is independently selected from the group consisting of halogens, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with one or more halogens or deuterium; p is 0, 1, 2, 3, or 4; R aand R b Each of these is independently H or an unsubstituted C1-C3 alkyl; If Y does not exist, then m is 2, 3, 4 or 5; or Y is NR 10 Or, if it is O, then m is 1, 2, 3 or 4; And further: R1, R2, R4, and R5 are each independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; Alternatively, R2 and R5, together with the carbon atoms to which they are bonded, form a single bond; R3 is selected from the group consisting of H, deuterium, halogens, hydroxyl, and cyano; Alternatively, R3 and R1, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a C3-C5 cycloalkyl group; R6, R7, R8, R9 and R 11 Each of these is independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 This is selected from the group consisting of H, unsubstituted C1-C3 alkyl groups, and C1-C3 alkyl groups substituted with one or more halogens; Each R 12 and R 13 These are independently selected from the group consisting of H, halogens, deuterium, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with hydroxyl or one or more halogens; R 14 , R 15 and R 16 Each of these is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each R 17 and R 18 The following are independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens.

[0093] In one aspect of equation (II), n is 1. In another aspect of equation (II), n is 2. In yet another aspect of equation (II), n is 3.

[0094] In another embodiment of formula (II), ring A is phenyl. In another embodiment of formula (II), ring A is pyridinyl. In another embodiment of formula (II), ring A is pyridazinyl. In another embodiment of formula (II), ring A is pyrimidinyl. In another embodiment of formula (II), ring A is pyrazinyl. In another embodiment of formula (II), ring A is triazinyl.

[0095] In another embodiment of equation (II), Y is NR 10 In another embodiment of formula (II), Y is O. In another embodiment of formula (II), Y is absent. In another embodiment of formula (II), ring A is phenyl and Y is NR 10 In another embodiment of formula (II), ring A is phenyl and Y is O. In another embodiment of formula (II), ring A is phenyl and Y is absent. In another embodiment of formula (II), ring A is pyridinyl and Y is NR 10 In another embodiment of formula (II), ring A is pyridinyl and Y is O. In another embodiment of formula (II), ring A is pyridinyl and Y is absent. In another embodiment of formula (II), ring A is pyridazinyl and Y is NR 10 In another embodiment of formula (II), ring A is pyridazinyl and Y is O. In another embodiment of formula (II), ring A is pyridazinyl and Y is absent. In another embodiment of formula (II), ring A is pyrimidinyl and Y is NR 10 In another embodiment of formula (II), ring A is pyrimidinyl and Y is O. In another embodiment of formula (II), ring A is pyrimidinyl and Y is absent. In another embodiment of formula (II), ring A is pyrazinyl and Y is NR 10In another embodiment of formula (II), ring A is pyrazinyl and Y is O. In another embodiment of formula (II), ring A is pyrazinyl and Y is absent. In another embodiment of formula (II), ring A is triazinyl and Y is NR 10 In another embodiment of equation (II), ring A is a triazinyl and Y is O. In another embodiment of equation (II), ring A is a triazinyl and Y is absent.

[0096] In another aspect of equation (II), T is CR1R2. In another aspect of equation (II), T is O. In another aspect of equation (II), W is CR4R5. In another aspect of equation (II), W is O. In another aspect of equation (II), T is CR1R2 and W is CR4R5. In another aspect of equation (II), T is O and W is CR4R5. In another aspect of equation (II), T is CR1R2 and W is O.

[0097] In another embodiment of equation (II), V is CR3. In another embodiment of equation (II), V is N.

[0098] In another embodiment of equation (II), T is CR1R2 and V is CR3. In another embodiment of equation (II), T is O and V is CR3. In another embodiment of equation (II), T is CR1R2 and V is N. In another embodiment of equation (II), T is O and V is N.

[0099] In another embodiment of equation (II), W is CR4R5 and V is CR3. In another embodiment of equation (II), W is O and V is CR3. In another embodiment of equation (II), W is CR4R5 and V is N. In another embodiment of equation (II), W is O and V is N.

[0100] In another embodiment of equation (II), T is CR1R2, W is CR4R5, and V is CR3. In another embodiment of equation (II), T is CR1R2, W is O, and V is CR3. In another embodiment of equation (II), T is CR1R2, W is CR4R5, and V is N. In another embodiment of equation (II), T is CR1R2, W is O, and V is N. In another embodiment of equation (II), T is O, W is CR4R5, and V is CR3.

[0101] In another embodiment of equation (II), E is NR a R b Therefore, in another form of equation (II), E is C(=O)NR a R b In another embodiment of equation (II), E is C1-C3 alkylene-NR a R bIn another embodiment of formula (II), E is an unsubstituted C1-C3 alkyl, an unsubstituted C2-C4 alkenyl, or an unsubstituted C2-C4 alkynyl. In another embodiment of formula (II), E is a C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (II), E is an unsubstituted C1-C3 alkyl. In another embodiment of formula (II), 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 (II), E is an unsubstituted C3-C8 cycloalkyl. In another embodiment of formula (II), 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 (II), E is an unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of formula (II), 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 (II), E is an unsubstituted 4- to 10-membered heterocycline. In another embodiment of formula (II), E is a 4- to 10-membered heterocycline substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (II), E is an unsubstituted C1-C3 alkylene-(4- to 10-membered heterocycline). In another embodiment of formula (II), E is a C1-C3 alkylene-(4-10 member heterocycline) substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (II), E is an unsubstituted C6-C 10 It is an aryl. In another embodiment of formula (II), E is a C6-C alkyl or C1-C3 alkoxyl substituted with one or more halogens, hydroxyls, C1-C3 alkyls or C1-C3 alkoxyls. 10 It is aryl. In another embodiment of formula (II), E is unsubstituted C1-C3 alkylene-(C6-C 10It is an aryl. In another embodiment of formula (II), E is a C1-C3 alkylene-(C6-C) which is substituted with one or more halogens, hydroxyls, C1-C3 alkyls or C1-C3 alkoxyls. 10 E is an aryl. In another embodiment of formula (II), E is an unsubstituted 5- to 10-membered heteroaryl. In another embodiment of formula (II), E is a 5- to 10-membered heteroaryl substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0102] In another embodiment of formula (II), E is an unsubstituted 4- to 7-membered heterocycline. In another embodiment of formula (II), E is a 4- to 7-membered heterocycline substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (II), E is an unsubstituted 4- to 6-membered heterocycline. In another embodiment of formula (II), E is a 4- to 6-membered heterocycline substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (II), E is an unsubstituted 4-membered heterocycline. In another embodiment of formula (II), E is a 4-membered heterocycline substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (II), E is an unsubstituted 5-membered heterocycline. In another embodiment of formula (II), E is a 5-membered heterocycline substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (II), E is an unsubstituted 6-membered heterocycline. In another embodiment of formula (II), E is a 6-membered heterocycline substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0103] In another embodiment of equation (II), E is NR a R b , C(=O)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 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl) and here 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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 The aryl group is either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0104] In another embodiment of formula (II), E is C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 (aryl), where C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 The aryl group is either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0105] In another embodiment of formula (II), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 (aryl), where C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 The aryl group is either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0106] In another embodiment of formula (II), 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 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 either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0107] In another embodiment of formula (II), 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 either unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0108] In another embodiment of formula (II), E is methyl, where methyl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of formula (II), E is methyl. In another embodiment of formula (II), E is trifluoromethyl. In another embodiment of formula (II), E is dioxanyl, where dioxanyl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of formula (II), E is tetrahydropyranyl, where tetrahydropyranyl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of formula (II), E is tetrahydrofuranyl, where tetrahydrofuranyl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of formula (II), E is azetidinyl, where azetidinyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (II), E is oxetanyl, where oxetanyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls. In another embodiment of formula (II), E is morpholinyl, where morpholinyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkyls, or C1-C3 alkoxyls.

[0109] In another embodiment of equation (II), R 14 is H. In another form of equation (II), R 14 is an unsubstituted C1-C3 alkyl. In another embodiment of formula (II), R 15 and R 16 These are H, respectively. In another form of equation (II), R 15 R is an unsubstituted C1-C3 alkyl group, 16 is H. In another form of equation (II), R 16R is an unsubstituted C1-C3 alkyl group, 15 is H. In another form of equation (II), each R 17 and R 18 is H. In another form of equation (II), R 17 R is an unsubstituted C1-C3 alkyl group, 18 is H. In another form of equation (II), R 18 R is an unsubstituted C1-C3 alkyl group, 17 is H. In another form of equation (II), R 14 , R 15 , R 16 , R 17 and R 18 One of them is an unsubstituted C1-C3 alkyl group, and the others are each H.

[0110] In another embodiment of formula (II), m is 1. In another embodiment of formula (II), m is 2. In another embodiment of formula (II), m is 3. In another embodiment of formula (II), m is 4. In another embodiment of formula (II), m is 5. In another embodiment of formula (II), m is 1, 2, or 3. In another embodiment of formula (II), m is 2, 3, or 4. In another embodiment of formula (II), m is 1 or 2. In another embodiment of formula (II), m is 3 or 4.

[0111] In another embodiment of equation (II), Y is O and m is 1. In another embodiment of equation (II), Y is O and m is 2. In another embodiment of equation (II), Y is O and m is 3. In another embodiment of equation (II), Y is O and m is 4. In another embodiment of equation (II), Y is O and m is 1, 2, or 3. In another embodiment of equation (II), Y is O and m is 2, 3, or 4. In another embodiment of equation (II), Y is O and m is 1 or 2. In another embodiment of equation (II), Y is O and m is 3 or 4.

[0112] In another embodiment of equation (II), Y is nonexistent and m is 1. In another embodiment of equation (II), Y is nonexistent and m is 2. In another embodiment of equation (II), Y is nonexistent and m is 3. In another embodiment of equation (II), Y is nonexistent and m is 4. In another embodiment of equation (II), Y is nonexistent and m is 1, 2, or 3. In another embodiment of equation (II), Y is nonexistent and m is 2, 3, or 4. In another embodiment of equation (II), Y is nonexistent and m is 1 or 2. In another embodiment of equation (II), Y is nonexistent and m is 3 or 4.

[0113] In another embodiment of equation (II), Y is NR 10 And m is 1. In another embodiment of equation (II), Y is NR 10 And m is 2. In another embodiment of equation (II), Y is NR 10 And m is 3. In another embodiment of equation (II), Y is NR 10 And m is 4. In another embodiment of equation (II), Y is NR 10 And m is 1, 2 or 3. In another embodiment of equation (II), Y is NR 10 And m is 2, 3 or 4. In another embodiment of equation (II), Y is NR 10 And m is 1 or 2. In another embodiment of equation (II), Y is NR 10 And m is either 3 or 4.

[0114] In another embodiment of formula (II), ring A is phenyl and n is 1. In another embodiment of formula (II), ring A is phenyl and n is 2. In another embodiment of formula (II), ring A is phenyl and n is 3. In another embodiment of formula (II), ring A is pyridinyl and n is 1. In another embodiment of formula (II), ring A is pyridinyl and n is 2. In another embodiment of formula (II), ring A is pyridinyl and n is 3. In another embodiment of formula (II), ring A is pyridazinyl and n is 1. In another embodiment of formula (II), ring A is pyridazinyl and n is 2. In another embodiment of formula (II), ring A is pyridazinyl and n is 3. In another embodiment of formula (II), ring A is pyrimidinyl and n is 1. In another embodiment of formula (II), ring A is pyrimidinyl and n is 2. In another embodiment of formula (II), ring A is pyrimidinyl and n is 3. In another embodiment of formula (II), ring A is pyrazinyl and n is 1. In another embodiment of formula (II), ring A is pyrazinyl and n is 2. In another embodiment of formula (II), ring A is pyrazinyl and n is 3. In another embodiment of formula (II), ring A is triazinyl and n is 1. In another embodiment of formula (II), ring A is triazinyl and n is 2. In another embodiment of formula (II), ring A is triazinyl and n is 3.

[0115] In another embodiment of formula (II), ring A is phenyl, n is 1, and Y is NR 10 In another embodiment of formula (II), ring A is phenyl, n is 2, and Y is NR 10 In another embodiment of formula (II), ring A is phenyl, n is 3, and Y is NR 10In another embodiment of formula (II), ring A is phenyl, n is 1, and Y is O. In another embodiment of formula (II), ring A is phenyl, n is 2, and Y is O. In another embodiment of formula (II), ring A is phenyl, n is 3, and Y is O. In another embodiment of formula (II), ring A is phenyl, n is 1, and Y is absent. In another embodiment of formula (II), ring A is phenyl, n is 2, and Y is absent. In another embodiment of formula (II), ring A is phenyl, n is 3, and Y is absent.

[0116] In another embodiment of formula (II), ring A is phenyl, n is 1, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is phenyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, n is 2, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, n is 3, and Y is NR 10In another embodiment of formula (II), ring A is phenyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, n is 3, Y is absent, and m is 3 or 4.

[0117] In another embodiment of formula (II), ring A is pyridinyl, n is 1, and Y is NR 10 In another embodiment of formula (II), ring A is pyridinyl, n is 2, and Y is NR 10 In another embodiment of formula (II), ring A is pyridinyl, n is 3, and Y is NR 10 In another aspect of formula (II), ring A is pyridinyl, n is 1, and Y is O. In another aspect of formula (II), ring A is pyridinyl, n is 2, and Y is O. In another aspect of formula (II), ring A is pyridinyl, n is 3, and Y is O. In another aspect of formula (II), ring A is pyridinyl, n is 1, and Y is absent. In another aspect of formula (II), ring A is pyridinyl, n is 2, and Y is absent. In another aspect of formula (II), ring A is pyridinyl, n is 3, and Y is absent.

[0118] In another embodiment of formula (II), ring A is pyridinyl, n is 1, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is pyridinyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is pyridinyl, n is 3, and Y is NR10 In another embodiment of formula (II), ring A is pyridinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridinyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridinyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridinyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridinyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (II), ring A is pyridinyl, n is 2, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (II), ring A is pyridinyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is pyridinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridinyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridinyl, n is 3, Y is absent, and m is 3 or 4.

[0119] In another embodiment of formula (II), ring A is pyridazinyl, n is 1, and Y is NR 10 In another embodiment of formula (II), ring A is pyridazinyl, n is 2, and Y is NR10 In another embodiment of formula (II), ring A is pyridazinyl, n is 3, and Y is NR 10 In another aspect of formula (II), ring A is pyridazinyl, n is 1, and Y is O. In another aspect of formula (II), ring A is pyridazinyl, n is 2, and Y is O. In another aspect of formula (II), ring A is pyridazinyl, n is 3, and Y is O. In another aspect of formula (II), ring A is pyridazinyl, n is 1, and Y is absent. In another aspect of formula (II), ring A is pyridazinyl, n is 2, and Y is absent. In another aspect of formula (II), ring A is pyridazinyl, n is 3, and Y is absent.

[0120] In another embodiment of formula (II), ring A is pyridazinyl, n is 1, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is pyridazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyridazinyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, and Y is NR10 And m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is pyridazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyridazinyl, n is 3, Y is absent, and m is 3 or 4.

[0121] In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, and Y is NR 10 In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, and Y is NR 10 In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, and Y is NR 10 In another aspect of formula (II), ring A is pyrimidinyl, n is 1, and Y is O. In another aspect of formula (II), ring A is pyrimidinyl, n is 2, and Y is O. In another aspect of formula (II), ring A is pyrimidinyl, n is 3, and Y is O. In another aspect of formula (II), ring A is pyrimidinyl, n is 1, and Y is absent. In another aspect of formula (II), ring A is pyrimidinyl, n is 2, and Y is absent. In another aspect of formula (II), ring A is pyrimidinyl, n is 3, and Y is absent.

[0122] In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, and Y is NR 10And m is 1 or 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, Y is absent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrimidinyl, n is 3, Y is absent, and m is 3 or 4.

[0123] In another embodiment of formula (II), ring A is pyrazinyl, n is 1, and Y is NR 10 In another embodiment of formula (II), ring A is pyrazinyl, n is 2, and Y is NR 10 In another embodiment of formula (II), ring A is pyrazinyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is pyrazinyl, n is 1, and Y is O. In another embodiment of formula (II), ring A is pyrazinyl, n is 2, and Y is O. In another embodiment of formula (II), ring A is pyrazinyl, n is 3, and Y is O. In another embodiment of formula (II), ring A is pyrazinyl, n is 1, and Y is absent. In another embodiment of formula (II), ring A is pyrazinyl, n is 2, and Y is absent. In another embodiment of formula (II), ring A is pyrazinyl, n is 3, and Y is absent.

[0124] In another embodiment of formula (II), ring A is pyrazinyl, n is 1, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is pyrazinyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is pyrazinyl, n is 3, and Y is NR 10In another embodiment of formula (II), ring A is pyrazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrazinyl, n is 1, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrazinyl, n is 2, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrazinyl, n is 3, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (II), ring A is pyrazinyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (II), ring A is pyrazinyl, n is 2, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (II), ring A is pyrazinyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is pyrazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrazinyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrazinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is pyrazinyl, n is 3, Y is absent, and m is 3 or 4.

[0125] In another embodiment of formula (II), ring A is a triazinyl, n is 1, and Y is NR 10 In another embodiment of equation (II), ring A is a triazinyl, n is 2, and Y is NR 10In another embodiment of formula (II), ring A is a triazinyl, n is 3, and Y is NR 10 In another aspect of equation (II), ring A is a triazinyl, n is 1, and Y is O. In another aspect of equation (II), ring A is a triazinyl, n is 2, and Y is O. In another aspect of equation (II), ring A is a triazinyl, n is 3, and Y is O. In another aspect of equation (II), ring A is a triazinyl, n is 1, and Y is nonexistent. In another aspect of equation (II), ring A is a triazinyl, n is 2, and Y is nonexistent. In another aspect of equation (II), ring A is a triazinyl, n is 3, and Y is nonexistent.

[0126] In another embodiment of formula (II), ring A is a triazinyl, n is 1, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl, n is 2, and Y is NR 10 And m is 1 or 2. In another embodiment of formula (II), ring A is triazinyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is a triazinyl, n is 1, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl, n is 2, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl, n is 3, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl, n is 1, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl, n is 2, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl, n is 3, Y is nonexistent, and m is 1 or 2. In another embodiment of formula (II), ring A is a triazinyl, n is 1, and Y is NR 10 And m is 3 or 4. In another embodiment of formula (II), ring A is triazinyl, n is 2, and Y is NR 10And m is 3 or 4. In another embodiment of formula (II), ring A is triazinyl, n is 3, and Y is NR 10 In another embodiment of formula (II), ring A is a triazinyl, n is 1, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is a triazinyl, n is 2, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is a triazinyl, n is 3, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is a triazinyl, n is 1, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is a triazinyl, n is 2, Y is absent, and m is 3 or 4. In another embodiment of formula (II), ring A is a triazinyl, n is 3, Y is absent, and m is 3 or 4.

[0127] In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, and V is CR3. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, and V is CR3. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 1. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 2. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and n is 3. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 1. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 2. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and n is 3.

[0128] In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, and Y is O. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, and Y is O. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 1. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 2. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 3. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 1. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 2. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and n is 3.

[0129] In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 1 or 2. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4.In another embodiment of formula (II), ring A is phenyl, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 1, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 2, and m is 3 or 4. In another embodiment of formula (II), ring A is phenyl, p is 0, T is CR1R2, W is CR4R5, V is CR3, Y is O, n is 3, and m is 3 or 4. In another embodiment of equation (II), p is 0 and R1, R2, R4 and R5 are each H. In another embodiment of equation (II), p is 0; R1, R2, R4 and R5 are each H; R3 is H. In another embodiment of equation (II), p is 0; R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R. 11 R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 H and R are respectively. 12 and R 13 These are H.

[0130] In another embodiment of equation (II), p is 1 and R1, R2, R4 and R5 are each H. In another embodiment of equation (II), p is 1; R1, R2, R4 and R5 are each H; R3 is H. In another embodiment of equation (II), p is 1; R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 H and R are respectively.12 and R 13 These are H.

[0131] In another embodiment of equation (II), p is 2, and R1, R2, R4 and R5 are each H. In another embodiment of equation (II), p is 2; R1, R2, R4 and R5 are each H; R3 is H. In another embodiment of equation (II), p is 2; R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 R1, R2, R4 and R5 are each H; R3 is H; R6, R7, R8, R9 and R 11 H and R are respectively. 12 and R 13 These are H.

[0132] In another embodiment of formula (II), p is 1, 2, 3, or 4, and R is fluorine. In another embodiment of formula (II), p is 1, 2, 3, or 4, and R is deuterium. In another embodiment of formula (II), p is 1, 2, 3, or 4, and each R is independently selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium. In another embodiment of formula (II), p is 1, 2, 3, or 4, and each R is independently selected from the group consisting of cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogens or deuterium. In another embodiment of formula (II), p is 1, and R is an unsubstituted C1-C3 alkyl. In another embodiment of formula (II), p is 1, and R is methyl. In another embodiment of formula (II), p is 1 or 2, and each R is methyl. In another embodiment of formula (II), p is 1 and R is a C1-C3 alkyl substituted with one or more halogens. In another embodiment of formula (II), p is 1 and R is CF3. In another embodiment of formula (II), p is 1 or 2 and each R is CF3.

[0133] In another embodiment of formula (II), one or more of R1, R2, R4, and R5 are fluorine. In another embodiment of formula (II), one or more of R1, R2, R4, and R5 are deuterium. In another embodiment of formula (II), R6, R7, R8, R9, and R 11 One or more of them are fluorine. In another embodiment of formula (II), R6, R7, R8, R9 and R 11 One or more of them are deuterium. In another form of equation (II), each R 12 and R 13 One or more of them are fluorine. In another embodiment of formula (II), each R 12 and R 13 One or more of them are deuterium.

[0134] In another embodiment of equation (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H. In another embodiment of equation (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 is H and m is 2. In another embodiment of equation (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 Each of them is H. In another embodiment of equation (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 14 , R 15 , R 16 , R 17 and R 18 Each of them is H and m is 2. In another embodiment of equation (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17and R 18 Each of them is H. In another embodiment of equation (II), Y is O, T is CR1R2, V is CR3, W is CR4R5, and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 Each of them is H, and m is 2.

[0135] Each of the embodiments described herein with respect to the compound of formula II also applies to the compound of formula II-A.

[0136] According to formulas IA, I, II-A, or II as used herein, when ring A is pyridinyl, the position of the pyridinyl N atom is determined as follows: [ka] .

[0137] Furthermore, according to formulas IA, I, II-A, or II as used herein, if ring A is pyridazinyl, the position of the pyridazinyl N atom is determined as follows: [ka] .

[0138] Furthermore, according to formulas IA, I, II-A, or II as used herein, if ring A is a pyrimidinyl, the position of the pyrimidinyl N atom is determined as follows: [ka] .

[0139] Furthermore, according to formulas IA, I, II-A, or II as used herein, if ring A is pyrazinyl, the position of the pyrazinyl N atom is determined as follows: [ka] .

[0140] Furthermore, according to formulas IA, I, II-A, or II as used herein, if ring A is a triazinyl atom, the position of the triazinyl N atom is determined as follows: [ka] All other variables in formulas IA, I, II-A, or II are as defined above.

[0141] Specific embodiments of the compounds of formulas IA, I, II-A, II or their pharmaceutically acceptable salts are shown below in Table 1. The compounds of formulas IA, I, II-A, II or their pharmaceutically acceptable salts and the compounds of Table 1 or their pharmaceutically acceptable salts are often referred to herein, 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 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23

[0142] The disclosed compounds have one or more stereocenters, each stereocenter independently existing in either the R or S conformation. In one embodiment, the compounds described herein are optically active or exist in racemic form. It is understood that the compounds described herein encompass racemic, optically active, positional and stereoisomeric forms, or combinations thereof having the therapeutically useful properties described herein.

[0143] Preparation of optically active forms can be achieved in any suitable manner, including, but not limited to, separation of racemic forms by recrystallization techniques, synthesis from optically active initiating 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 compound of the disclosure described herein. In another embodiment, pure isomers are used as the compound of the disclosure described herein. In another embodiment, the compound of the disclosure described herein contains one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantiomeroselective synthesis, or separation of mixtures of enantiomers or diastereomers. Separation of compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractionation crystallization, distillation, and chromatography.

[0144] In one embodiment, the disclosed compounds may exist as tautomers. All tautomers fall within the range of compounds presented herein.

[0145] The compounds described herein include isotope-labeled compounds, in which one or more atoms are replaced by atoms having the same atomic number but with atomic masses or mass numbers different from those commonly 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, 123I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P and 35 Examples include, but are not limited to, S. In one embodiment, isotope-labeled compounds are useful in tissue distribution studies of drugs or substrates. In another embodiment, substitution with heavier isomers such as deuterium provides greater metabolic stability (e.g., increased in vivo half-life or reduced administration requirements). In another embodiment, the compounds described herein are, 2 It contains the H (i.e., deuterium) isotope.

[0146] 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 test substrate receptor occupancy. Isotope-labeled compounds are prepared by any suitable method, or by a process that uses a suitable isotope-labeled reagent instead of the otherwise used unlabeled reagent.

[0147] Certain compounds described herein and other compounds encompassing one or more of the formulas described herein, having different substituents, can be synthesized using the techniques and materials described herein, for example: 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 4 th The compounds are synthesized as described in 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 Ed., (Wiley 1999) (all of which are incorporated by reference for the purposes of this disclosure). The general methods for preparing the compounds described herein are modified using appropriate reagents and conditions to introduce the various parts found in the formulas provided herein.

[0148] The compounds described herein are synthesized using any suitable procedure, starting with compounds available from commercial sources or prepared using the procedures described herein.

[0149] Treatment method The compounds of the present invention may be used in a method for treating a disease or condition in a subject, the method comprising the step of administering to the subject a compound of the present invention or a pharmaceutical composition containing a compound of the present invention. In one embodiment of the method described herein, the subject 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.

[0150] 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 subjects who require treatment for a disease or condition selected from the group consisting of narcolepsy, cataplexy, or hypersomnia.

[0151] In one embodiment, the compounds of the present invention may be used to treat narcolepsy in a subject. In one embodiment, the compounds of the present invention may be used to treat cataplexy in a subject. In one embodiment, the compounds of the present invention may be used to treat hypersomnia in a subject.

[0152] Orexin-2 receptors are important in a wide range of biological functions. This suggests that orexin-2 receptors play a role in various disease processes in humans and other species. The compounds of the present invention are useful for treating, preventing, or improving the risk of one or more of the following symptoms or diseases of various neurological and psychiatric disorders related to changes in sleep / wake function. In other words, narcolepsy, narcolepsy with cataplexy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnolence syndrome characterized by excessive sleep (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Möbius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, multiple system atrophy, acute disseminated encephalomyelitis, Guian-Barré syndrome, Rasmussen encephalitis, Wernicke encephalitis, limbic encephalitis, or Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinic obesity, hyperplastic obesity, pituitary (hypo Hyseal obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infant obesity, upper body obesity, diet-induced obesity, hypogonadism, systemic mastocytosis, simple obesity or central obesity, insulin resistance syndrome, Alzheimer's disease, disturbances of consciousness such as coma, side effects and complications of anesthesia, sleep disturbances, excessive daytime sleepiness, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep disorders, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight Dusk, sunset phenomenon, diseases related to circadian rhythms, fibromyalgia, conditions resulting from poor sleep quality, overeating, obsessive-compulsive eating disorder, obesity-related diseases, hypertension, diabetes, increased 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, cardiovascular disorders, polycystic ovary disease, craniopharingioma, Prader-Willi syndrome, Froelich syndrome, growth hormone deficiency, normal mutant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, X syndrome, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, female and male hirsutism, sexual and reproductive dysfunction, fetal defects associated with obesity in pregnant women, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity-induced hypovitaminosis Pickwick's syndrome, respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, renal cancer, risk of secondary consequences of obesity, such as a reduced risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, autoimmune encephalitis, cancer-related fatigue (e.g., excessive daytime sleepiness or fatigue associated with cancer and / or chemotherapy), cancer-related nausea and vomiting, corticobasal degeneration, Huntington's disease, neuromyelitis optica, nociception, progressive supranuclear palsy, Psychiatry, systemic lupus erythematosus, traumatic brain injury, facial flushing, night sweats, reproductive / urinary tract disorders, disorders related to sexual function or fertility, 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 (PTSD), separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant brain defects, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, low Blood glucose nerve damage, Huntington's disease, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, muscle spasm-related disorders, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, motor disorders, chronic fatigue syndrome, fatigue, drug-induced tremor-paralysis syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless limb syndrome, dystonia, motor disorders, attention deficit hyperactivity disorder (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).

[0153] In particular, the compounds of the present invention are useful as therapeutic or prophylactic agents for side effects and complications of anesthesia, such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndromes characterized by hypersomnia (e.g., in Parkinson's disease, Guian-Barré syndrome, or Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, and disturbances of consciousness such as coma, or for use as anesthetic antagonists.

[0154] In one embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as prophylactic or therapeutic agents for narcolepsy.

[0155] 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.

[0156] In another embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as prophylactic or therapeutic agents for hypersomnia in Parkinson's disease.

[0157] 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 sleepiness. 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 associated with Parkinson's disease.

[0158] 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.

[0159] In another embodiment, the present invention provides a method for treating narcolepsy in a subject requiring treatment for narcolepsy, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0160] In another embodiment, the present invention provides a method for treating narcolepsy type 1 in a subject requiring treatment for narcolepsy type 1, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0161] In another embodiment, the present invention provides a method for treating narcolepsy type 2 in a subject requiring treatment for narcolepsy type 2, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0162] In another embodiment, the present invention provides a method for treating narcolepsy and excessive daytime sleepiness in a subject requiring treatment for narcolepsy and excessive daytime sleepiness, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0163] In another embodiment, the present invention provides a method for treating narcolepsy, cataplexy, and excessive daytime sleepiness in a subject requiring treatment for narcolepsy, cataplexy, and excessive daytime sleepiness, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0164] In another embodiment, the present invention provides a method for treating narcolepsy and cataplexy in a subject requiring treatment for narcolepsy and cataplexy, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0165] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness in a subject requiring treatment of excessive daytime sleepiness, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0166] In another embodiment, the present invention provides a method for treating idiopathic hypersomnia in a subject requiring treatment for idiopathic hypersomnia, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0167] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and idiopathic hypersomnia in a subject requiring treatment for such excessive daytime sleepiness and idiopathic hypersomnia, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0168] In another embodiment, the present invention provides a method for treating obstructive sleep apnea in a subject requiring treatment for obstructive sleep apnea, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0169] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and obstructive sleep apnea in a subject requiring treatment for such excessive daytime sleepiness and obstructive sleep apnea, comprising the step of administering a compound of formula IA, I, II-A, or II or a pharmaceutically acceptable salt thereof to the subject.

[0170] In any of the methods described herein, the subject is administered the compound of formula I. In any of the methods described herein, the subject is administered the compound of formula II.

[0171] Each of the embodiments described herein with respect to the use of the compound of formula I also applies to the compound of formula IA. Each of the embodiments described herein with respect to the use of the compound of formula II also applies to the compound of formula II-A.

[0172] In any of the compositions or methods described herein, a compound of formula IA, I, II-A, II or a pharmaceutically acceptable salt thereof is present and / or administered in a therapeutically effective amount.

[0173] Dosage / Formulation In another context, pharmaceutical compositions comprising at least one compound of the present invention together with a pharmaceutically acceptable carrier are provided herein.

[0174] The actual dose level of the active ingredient in the pharmaceutical composition of the present invention can be modified to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response for a particular patient, composition, and dosage form without being toxic to the patient.

[0175] In particular, the selected dose level depends on various factors such as the activity of the specific compound used, the time of administration, the rate of elimination of the compound, the duration of treatment, other drugs, compounds, or materials used in combination with the compound, the age, sex, weight, condition, general health status, and previous medical history of the patient being treated, as well as similar factors known in the field of medicine.

[0176] A medical doctor with ordinary art in the art, such as a physician or veterinarian, can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian may start administering the pharmaceutical composition at a lower level than required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0177] In certain embodiments, it is particularly advantageous to formulate compounds in unit dosage forms for ease of administration and dose uniformity. As used herein, a unit dosage form means a physically separate unit adapted as a unit dose for a patient being treated; each unit contains a predetermined amount of the disclosed compound calculated to produce the desired therapeutic effect in relation to the required pharmaceutical vehicle. The unit dosage forms of the present invention are defined and directly depend upon (a) the distinctive characteristics of the disclosed compound and the specific therapeutic effect to be achieved, and (b) limitations specific to the field of compounding / formulating such disclosed compound for the treatment of narcolepsy or cataplexy in a patient.

[0178] In one embodiment, the compounds of the present invention are 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.

[0179] In some embodiments, the dose of the disclosed compound is approximately 1 mg to approximately 1,000 mg. In some embodiments, the dose of the disclosed compound used in the compositions described herein is less than approximately 1,000 mg, or less than approximately 800 mg, or less than approximately 600 mg, or less than approximately 500 mg, or less than approximately 300 mg, or less than approximately 200 mg, or less than approximately 100 mg, or less than approximately 50 mg, or less than approximately 20 mg, or less than approximately 10 mg. For example, the dose 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 approximately 600 mg.

[0180] Routes of administration for any of the compositions of the present invention include oral, nasal, rectal, vaginal, parenteral, intrabuccal, sublingual, or topical administration. Compounds for use in the present invention can be formulated for administration by any suitable route, such as oral or parenteral, transdermal, transmucosal (e.g. sublingual, tongue, (trans)buccal, (trans)urethral, ​​vagina (e.g. transvaginal and perivaginal), nasal (intra) and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrashelter, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral.

[0181] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, lozenges, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma, lozenges, creams, pastes, ointments, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions useful in the present invention are not limited to the specific formulations and compositions described herein.

[0182] For oral administration, tablets, sugar-coated pills, liquids, drops, suppositories or capsules, caplets, and gel caps are particularly suitable. 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 pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents, e.g., lactose; granulating and disintegrating agents, e.g., corn starch; binders, e.g., starch; and lubricants, e.g., magnesium stearate. Tablets may not be coated or may be coated by known techniques for scientific precision or to delay the release of the active ingredient. Formulations for oral use may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert diluent.

[0183] 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 in bolus or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles may be used, optionally containing other formulation agents such as suspensions, stabilizers, or dispersants.

[0184] Those skilled in the art will understand or verify that using common experiments, and many equivalents to the specific procedures, embodiments, claims, and examples described herein, does not exceed those described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the claims appended herein. For example, modifications using common experiments with reaction conditions including, but not limited to, reaction time, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressure, atmospheric conditions, such as nitrogen atmosphere, and reducing / oxidizing agents, which are recognized in the art, should be understood to be within the scope of the present application.

[0185] Whenever values ​​and ranges are provided herein, it is understood that all values ​​and ranges encompassed within those values ​​and ranges are intended to be included within the scope of the present invention. Furthermore, upper or lower limits on all values ​​and ranges included within those ranges are also contemplated in this application.

[0186] The following embodiments further illustrate aspects of the present invention. However, they are not in any way limiting to the teachings or disclosures of the present invention described herein. [Examples]

[0187] Examples The present invention is further illustrated by the following embodiments, which should not be construed as further limitations. Unless otherwise indicated, the implementation of the present invention utilizes the prior art of organic synthesis, cell biology, cell culture, molecular biology, transgenic biology, microbiology, and immunology that is in the art of the present invention.

[0188] 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 indicated, the starting materials were generally obtained from commercial suppliers. Synthetic procedures for other macrocyclic compounds can be found, for example, in U.S. application number 17 / 104,993 and PCT application number PCT / US20 / 62320, both filed on November 25, 2020, and both are expressly incorporated herein by reference.

[0189] The following abbreviations may be used in the following composite examples: Acetic acid (ACOH) DCM = Dichloromethane MsCl = Methanesulfonyl Chloride MeOH = methanol THF = Tetrahydrofuran EtOH = Ethanol PtO2 = Platinum Dioxide HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate DIPEA or DIEA = N,N-diisopropylethylamine t Butyl tert-butyl MeCN = Acetonitrile PE = Petroleum Ether alkyl = ethyl acetate DMF = Dimethylformamide TFA = Trifluoroacetic Acid LiOH = Lithium hydroxide min = minutes hr=hour NaH = Sodium hydride Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(O) DMSO = Dimethyl sulfoxide i-PrOH = Isopropanol Pd / C = Palladium on carbon XantPhos=4,5-bis(diphenylphosphin)-9,9-dimethylxanthene Boc=tert-butyloxycarbonyl Ms = Methanesulfonyl Bn = Benzyl Et = ethyl Cbz = Carboxybenzyl PMB = Para-methoxybenzyl DBU = 1,8-diazabicyclo[5.4.0]undeca-7-ene NBS = N-bromosuccinimide Pd(dppf)Cl2=[1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) DMAP = 4-(dimethylamino)pyridine NCS = N-chlorosuccinimide DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone LDA = Lithium diisopropylamide HOBt = 1-hydroxybenzotriazole EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

[0190] Scheme 1 [ka]

[0191] Example 1.1 [ka] 210 g, 0.75 mol, 1.0 equivalent of 4-[2-(benzyloxy)phenyl]cyclohexane-1-one in 2.1 L of tetrahydrofuran was added to a 5 L four-neck round-bottom flask purged and maintained under nitrogen-inert air. L-selectlide (1 mol / L in THF) (1123 mL, 1.5 equivalents) was added dropwise while stirring at 0°C. The resulting solution was stirred at room temperature for 4 hours. The reaction was then quenched by adding water / ice. The resulting solution was extracted with ethyl acetate, and the organic phase was washed with brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain 137 g (64%) of (1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexane-1-ol as a solid. 1 H NMR (400MHz, CDCl3): δ 7.45 - 7.26 (6H, m), 7.16 (1H, dd), 6.98- 6.90 (2H, m), 5.09 (2H, s), 4.13 (1H, s), 3.12- 3.02 (1H, m), 1.93 - 1.82 (4H, m), 1.73 - 1.41 (4H, m).

[0192] [ka] In a 2 L four-necked round-bottom flask purged and maintained with nitrogen-inert air, NaH (60% wt, 26.9 g, 2.0 equivalents) in tetrahydrofuran (200 mL) was added. To this, a solution of (1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexane-1-ol (95.0 g, 336 mmol, 1.0 equivalent) in THF (200 mL) was added dropwise while stirring at 50-55°C. After stirring for 2 hours, a solution of 3-bromo-2-(bromomethyl)pyridine (143.5 g, 571 mmol, 1.70 equivalents) in THF (550 mL) was added dropwise at 50-55°C. The resulting solution was stirred at 50-55°C for 14 hours. The reaction mixture was cooled. Water was then added to quench the reaction. The resulting solution was extracted with ethyl acetate, and the organic layers were dried together over anhydrous sodium sulfate. The solid was removed by filtration. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain 94.0 g (62%) of 3-bromo-2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridine as a solid. 1 H NMR (400MHz, CDCl3): δ 8.57 (1H, d), 7.90 (1H, dd), 7.48 - 7.26 (6H, m), 7.18 - 7.14 (2H, m), 6.98 - 6.91 (2H, m), 5.12 (2H, s), 4.77 (2H, s), 3.86 (1H, s), 3.17 - 3.10 (1H, m), 2.20 - 2.15 (2H, m), 1.98 - 1.88 (2H, m), 1.69 - 1.57 (4H, m).

[0193] [ka] In a 2 L four-necked round-bottom flask purged and maintained with nitrogen-inert air, Xantphos (10.7 g, 18.0 mmol, 0.10 equivalents), Cs2CO3 (84 g, 258 mmol, 1.4 equivalents), 3-bromo-2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridine (84 g, 185 mmol, 1.0 equivalent), Pd2(dba)3 (8.5 g, 9.0 mmol, 0.05 equivalents), and tert-butylcarbamate (26 g, 222 mmol, 1.2 equivalents) were added in 1,4-dioxane (840 mL). The resulting solution was stirred at 100°C for 5 hours. The solid was removed by filtration. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain 74 g (82%) of tert-butyl N-[2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridine-3-yl]carbamate as a solid.

[0194] [ka] In a 2 L three-necked round-bottom flask, 74 g (151 mmol, 1.0 equivalent) of tert-butyl N-[2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridine-3-yl]carbamate and 7.4 g (10% wt) of Pd / C were added in 740 mL of ethyl alcohol, and hydrogen gas was then added to the resulting mixture and allowed to bubble. The resulting solution was stirred at room temperature for 14 hours. The solid was removed by filtration. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain 51.4 g (85%) of tert-butyl N-[2-([[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy]methyl)pyridine-3-yl]carbamate as a solid. LCMS (ESI): m / z [M+H] + = 399.1; 1H NMR (300MHz, CDCl3): δ 8.65(1H, s), 8.47 (1H, d), 8.19(1H, q), 7.26 - 7.21 (1H, m), 7.09 - 7.03 (1H, m), 6.92 - 6.86 (1H, m), 6.75(1H, q), 5.77 (1H, s), 4.84 (1H, s), 3.80 (1H, s), 2.94 - 2.93 (1H, m), 2.15 - 2.06 (2H, m), 1.88 - 1.47 (7H, m), 1.45 (9H, s), 1.26 (1H, d).

[0195] [ka] In a 250 mL round-bottom flask purged and maintained with nitrogen-inert air, tert-butyl N-[2-([[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy]methyl)pyridine-3-yl]carbamate (8.0 g, 20.1 mmol, 1.0 equivalent), K2CO3 (14.0 g, 100.4 mmol, 5.0 equivalent), acetone (120 mL), and ethyl bromoacetate (5.03 g, 30.1 mmol, 1.5 equivalent) were added. The resulting solution was stirred at 50°C for 24 hours. The solid was removed by filtration. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain ethyl 2-[2-[(1s,4s)-4-([3-[(tert-butoxycarbonyl)amino]pyridine-2-yl]methoxy)cyclohexyl]phenoxy]acetate (8.7g, 89.4%) as oil. LCMS (ESI): m / z [M+H] + = 485.

[0196] [ka] To a stirred mixture of ethyl 2-[2-[(1s,4s)-4-([3-[(tert-butoxycarbonyl)amino]pyridine-2-yl]methoxy)cyclohexyl]phenoxy]acetate (7.89 g, 16.3 mmol, 1.0 equivalent) in MeOH (142 mL) and AcOH (15.8 mL), PtO2 (1.85 g, 8.14 mmol, 0.50 equivalent) was added at room temperature under a hydrogen atmosphere. The resulting mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filtered cake was concentrated under reduced pressure. The reaction was quenched at 0°C with sat. NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3 x 500 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a cis-racemic and trans-racemic mixture (7 g, 88.7%) as a solid. The crude product was purified by Prep-TLC to obtain a cis-racemic and trans-racemic mixture (1.7 g) of ethyl 2-(2-((1S,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidine-2-yl)methoxy)cyclohexyl)phenoxy)acetate (4.1 g). LCMS (ESI): m / z [M+H] + = 491.

[0197] [ka] In a 500 mL round-bottom flask purged and maintained with nitrogen air, a cis-racemic mixture of ethyl 2-(2-((1S,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidine-2-yl)methoxy)cyclohexyl)phenoxy)acetate (4.1 g, 8.4 mmol, 1.0 equivalent), MeOH (30 mL), THF (60 mL), H2O (30 mL), and lithium hydroxide (83 mg, 3.5 mmol, 5.0 equivalents) were added. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated, and the residue was purified by reverse-phase chromatography to obtain 2-(2-((1S,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidine-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid (2.35 g, 60.8%) as a solid. LCMS (ESI): m / z [M+H] + = 463.

[0198] [ka] In a 2000 mL round-bottom flask, 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonylamino)piperidine-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid (100 mg, 0.216 mmol, 1.0 equivalent), MeCN (36 mL), DMF (9 mL), HATU (124 mg, 0.326 mmol, 1.5 equivalents), and DIPEA (56 mg, 0.436 mmol, 2.0 equivalents) were added under nitrogen atmosphere. The resulting solution was stirred at room temperature for 3 hours. The resulting mixture was concentrated. Crude product: tert-butyl((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 - The yl carbamate was purified by column chromatography to obtain the product. LCMS (ESI): m / z [M+H] + = 445.

[0199] [ka] In a 500 mL round-bottom flask purged and maintained with nitrogen-inert air, add the crude tert-butyl mixture ((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 - 120 mL of dichloromethane and 40 mL of TFA were added to a mixture containing 2 g, 4.50 mmol, 1.0 equivalent of -yl carbamate. The resulting solution was stirred at 25°C for 1 hour. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC and (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -Amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctafan-6-one (800 mg, 51.6%) was obtained as a solid. LCMS (ESI): m / z [M+H] + = 345.

[0200] [ka] (2) of DCM (5 mL) 1 S,2 4 S,5 2 R,5 3 S)-5 3To a solution of (S)-oxetane-2-carboxylic acid (62 mg, 0.61 mmol, 3.0 equivalents) and (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol, 1.5 equivalents), HOBt (47 mg, 0.30 mmol, 1.5 equivalents), and DIEA (79 mg, 0.61 mmol, 3.0 equivalents) were added. The resulting mixture was stirred at 25°C for 1 hour. The crude product was purified by reverse flash chromatography to obtain (S)-N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)oxetane-2-carboxamide (75 mg, 0.18 mmol, 86%) was obtained as a solid. LCMS (ESI): m / z [M+H] + = 429. 1 H NMR (400MHz, methanol-d4) δ 7.20 - 7.13 (m, 1H), 7.08 (dd, 1H), 6.91 - 6.83 (m, 2H), 5.34 (d, 1H), 5.29 - 5.23 (m, 1H), 5.08 (dd, 1H), 4.80 - 4.71 (m, 1H), 4.71 - 4.60 (m, 1H), 4.25 - 4.16 (m, 1H), 4.12 (d, 1H), 4.04 - 3.95 (m, 1H), 3.86 (d, 1H), 3.69 (s, 1H), 3.61 - 3.49 (m, 1H), 3.10 - 2.97 (m, 1H), 2.82 - 2.69 (m, 1H), 2.68 - 2.52 (m, 2H), 2.36 - 2.24 (m, 1H), 2.18 (d, 1H), 1.99 - 1.68 (m, 5H), 1.52 - 1.33 (m, 3H), 1.28 (d, 1H).

[0201] Example 1.2 [ka] (2) of DCM (5 mL) 1 S,2 4 S,5 2 R,5 3 S)-5 3 To a solution of (S)-tetrahydro-2H-pyran-2-carboxylic acid (91 mg, 0.70 mmol, 3.0 equivalents) containing -amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctafan-6-one (80 mg, 0.23 mmol, 1.0 equivalent) and (S)-tetrahydro-2H-pyran-2-carboxylic acid (91 mg, 0.70 mmol, 3.0 equivalents), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67 mg, 0.35 mmol, 1.5 equivalents), HOBt (53 mg, 0.35 mmol, 1.5 equivalents), and DIEA (90 mg, 0.70 mmol, 3.0 equivalents) were added. The resulting mixture was stirred at 25°C for 1 hour. The crude product was purified by reverse flash chromatography to obtain (S)-N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -I)tetrahydro-2H-pyran-2-carboxamide (64.4 mg, 61%) was obtained as a solid. LCMS (ESI): m / z [M+H] + = 457. 1H NMR (400MHz, methanol-d4) δ 7.20 - 7.13 (m, 1H), 7.08 (dd, 1H), 6.92 - 6.83 (m, 2H), 5.32 (d, 1H), 5.28 - 5.20 (m, 1H), 4.73 - 4.43 (m, 1H), 4.18 - 4.05 (m, 3H), 3.98 (dd, 1H), 3.87 - 3.76 (m, 2H), 3.70 (d, 1H), 3.58 - 3.47 (m, 2H), 2.83 - 2.68 (m, 1H), 2.64 - 2.51 (m, 1H), 2.36 - 2.11 (m, 2H), 2.07 - 1.99 (m, 1H), 1.98 - 1.76 (m, 5H), 1.71 - 1.53 (m, 4H), 1.52 - 1.37 (m, 4H), 1.33 - 1.23 (m, 1H).

[0202] Example 1.3 [ka] (2) of DCM (10 mL) 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctafan-6-one (200 mg, 0.58 mmol, 1.0 equivalent) and (S)-tetrahydro-2H-furan-2-carboxylic acid (101 mg, 0.87 mmol, 1.5 equivalents) were mixed with HATU (397 mg, 1.05 mmol, 1.5 equivalents) and N-diisopropylethylamine (113 mg, 0.87 mmol, 1.5 equivalents). The resulting mixture was stirred at 25°C for 1 hour. The crude product was purified by reverse flash chromatography to obtain (S)-N-((2 1 S,2 4 S,5 2 R,5 3S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -Tetrahydrofuran-2-carboxamide (64.4 mg, 61%) was obtained as a solid. LCMS (ESI): m / z [M+H] + = 443. 1 H NMR (400MHz, chloroform-d) δ 7.18 (t, J = 7.4 Hz, 1H), 7.12 - 7.09 (m, 1H), 6.91 - 6.88 (m, 1H), 6.80 - 6.72 (m, 2H), 5.24 - 5.11 (m, 2H), 4.41 - 4.23 (m, 3H), 4.00 - 3.83 (m, 2H), 3.83 (t, J = 9.1 Hz, 1H), 3.73 - 3.70 (m, 2H), 3.60 - 3.51 (m, 1H), 3.42 (dd, J = 8.6, 4.0 Hz, 1H), 2.76 - 2.54 (m, 2H), 2.41 - 2.20 (m, 2H), 2.12 - 2.09 (m, 2H), 1.99 - 1.82 (m, 5H), 1.76 - 1.64 (m, 2H), 1.53 - 1.45 (m, 1H), 1.46 - 1.32 (m, 3H), 1.28 (s, 1H).

[0203] Example 1.4 [ka] (2) of DCM (5 mL) 1 S,2 4 S,5 2 R,5 3 S)-5 3-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctafan-6-one (80 mg, 0.23 mmol, 1.0 equivalent) and oxetane-3-carboxylic acid (71 mg, 0.70 mmol, 3.0 equivalents) were mixed with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67 mg, 0.35 mmol, 1.5 equivalents), HOBt (53 mg, 0.35 mmol, 1.5 equivalents), and DIEA (90 mg, 0.70 mmol, 3.0 equivalents). The resulting mixture was stirred at 25°C for 1 hour. The crude product was purified by reverse flash chromatography to obtain (N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)oxetane-3-carboxamide (58 mg, 58%) was obtained as a solid. LCMS (ESI): m / z [M+H] + = 429. 1 H NMR (400MHz, methanol-d4) δ 7.16 - 7.13 (m, 1H), 7.08 (dd, 1H), 6.92 - 6.82 (m, 2H), 5.37 - 5.24 (m, 2H), 4.89 - 4.59 (m, 5H), 4.13 (dd, 1H), 4.05 - 3.91 (m, 1H), 3.86 (ddd, 2H), 3.69 (s, 1H), 3.60 - 3.48 (m, 1H), 2.82 - 2.66 (m, 1H), 2.59 -2.55 (m, 1H), 2.29 - 2.26 (m, 1H), 2.16 (d, 1H), 1.91 (d, 1H), 1.81 (s, 3H), 1.82 - 1.65 (m, 2H), 1.52 - 1.33 (m, 2H), 1.33 - 1.24 (m, 1H).

[0204] Example 1.5 [ka] To a stirred mixture of benzyl 2-hydroxyacetate (21.9 g, 5.0 equivalents, 131.6 mmol) in DMF (100 mL), NaH (60%, 5.26 g, 5.0 equivalents, 131.6 mmol) was added in installments at 0°C. The resulting mixture was stirred at 0°C for 30 minutes under nitrogen atmosphere. 3-bromo-2-fluoro-4-methylpyridine (5.00 g, 1.0 equivalent, 26.314 mmol) was added to the above mixture at room temperature, and the resulting mixture was stirred for a further 2 hours at 80°C. The reaction was quenched by adding sat. NH4Cl (aq.) (500 mL) at 0°C. The resulting mixture was extracted with ELISA (3 x 200 mL). The combined organic layers were washed with water (3 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to obtain benzyl 2-((3-bromo-4-methylpyridine-2-yl)oxy)acetate (7.3 g, 83.0%) as oil. LCMS (ESI): m / z [M+H]+ = 337.

[0205] [ka] To a solution of benzyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-yl)oxy)methyl)piperidine-1-carboxylate (5.00 g, 1.0 equivalent, 3.51 mmol) and benzyl 2-((3-bromo-4-methylpyridine-2-yl)oxy)acetate (1.41 g, 1.2 equivalents, 4.21 mmol), Na2CO3 (1.12 g, 3.0 equivalents, 10.5 mmol) and Pd(dppf)Cl2 (385 mg, 0.15 equivalents, 0.53 mmol) were added. The reaction mixture was stirred under nitrogen atmosphere at 80°C for 2 hours. The crude product was purified by reverse flash chromatography to obtain benzyl(2R,3S)-2-(((4-(2-(2-(benzyloxy)-2-oxoethoxy)-4-methylpyridine-3-yl)cyclohexa-3-en-1-yl)oxy)methyl)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (2.0 g, 80.0%) as oil.

[0206] [ka] To a solution of benzyl(2R,3S)-2-(((4-(2-(2-(benzyloxy)-2-oxoethoxy)-4-methylpyridine-3-yl)cyclohexa-3-en-1-yl)oxy)methyl)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (2.00 g, 1.0 equivalent, 2.86 mmol) in i-PrOH (30 mL), Pd / C (152 mg, 0.5 equivalent, 1.43 mmol) was added under nitrogen atmosphere. The resulting mixture was hydrogenated for 15 hours at room temperature under hydrogen atmosphere using a hydrogen balloon. The mixture was filtered through a Celite® (Imerys Minerals California Inc., San Jose, CA) pad and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse flash chromatography to obtain 2-((3-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidine-2-yl)methoxy)cyclohexa-1-en-1-yl)-4-methylpyridine-2-yl)oxy)acetic acid (950 mg, 69.9%) as a solid. LCMS (ESI): m / z [M+H]+ = 477.

[0207] [ka] 2-((3-(4-(((2R,3S)-3-((tert-butoxycarbonyl)amino)piperidine-2-yl)methoxy)cyclohexa-1-en-1-yl)-4-methylpyridine-2-yl)oxy)acetic acid (900 mg, 1.0 equivalent, 1.89 mmol) and DIEA (734 mg, 3.0 equivalent, 5.68 mmol) were stirred in MeCN (400 mL) and HATU (1.08 g, 1.5 equivalent, 2.84 mmol) at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography to obtain tert-butyl((5 2 R,5 3 S,E)-1 4-Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-2 1 -EN-5 3 - yl carbamate (650 mg, 75.1%) was obtained as a solid. LC-MS (ESI): m / z [M+H]+ = 469.

[0208] [ka] tert-butyl((5) in MeOH (200 mL) and acetic acid (20.0 mL) 2 R,5 3 S,E)-1 4 -Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-2 1 -EN-5 3 To a solution of 1.2 g, 1.0 equivalent, 2.6 mmol of 1-yl carbamate, Pd / C (0.56 g, 10% Wt, 0.2 equivalent, 0.52 mmol) was added. The reaction mixture was stirred under hydrogen atmosphere for 5 days. The crude product was purified by reverse flash chromatography to obtain tert-butyl((2 1 S,2 4 S,5 2 R,5 3 S)-1 4 -Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 - yl carbamate (500 mg, 41.0%) was obtained as a solid. LC-MS (ESI): m / z [M+H]+ = 461.

[0209] [ka] DCM (15 mL) contains tert-butyl ((2 1 S,2 4 S,5 2 R,5 3 S)-1 4-Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 To a solution of (-yl)carbamate (400 mg, 1.0 equivalent, 0.87 mmol), TFA (3 mL) was added. The reaction mixture was stirred under nitrogen atmosphere at 25°C for 1 hour. The filtrate was concentrated under reduced pressure, and then aqueous Na2CO3 solution was added. The resulting mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography, and (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -Amino-1 4 Methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctafan-6-one (230 mg, 73.5%) was obtained as a solid. LC-MS (ESI): m / z [M+H]+ = 360.

[0210] [ka] (2) of DCM (1.5 mL) 1 S,2 4 S,5 2 R,5 3 S)-5 3 -Amino-1 4To a solution of -methyl-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctafan-6-one (50 mg, 1.0 equivalent, 0.14 mmol) and (S)-tetrahydrofuran-2-carboxylic acid (19 mg, 1.2 equivalents, 0.17 mmol), DIEA (36 mg, 2.0 equivalents, 0.28 mmol), HOBt (32 mg, 1.5 equivalents, 0.21 mmol), and EDC (40 mg, 1.5 equivalents, 0.21 mmol) were added. The resulting mixture was stirred at 25°C for 1.5 hours. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with H2O and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC, and (S)-N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 4 -Methyl-6-oxo-3,8-dioxa-1(3,2)-pyridina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 3 -I-tetrahydrofuran-2-carboxamide (69 mg, 63%) was obtained as a solid. LCMS (ESI): m / z [M+H]+ = 458; 1H NMR (400MHz, methanol-d4) δ 7.81 (dd, J = 5.2, 4.1 Hz, 1H), 6.81 - 6.79 (m, 1H), 5.39 - 5.23 (m, 2H), 4.79 - 4.75 (m, 1H), 4.40 - 4.23 (m, 2H), 4.19 -4.08 (m, 1H), 4.06 - 3.97 (m, 2H), 3.94 - 3.75 (m, 2H), 3.71 (s, 1H), 3.60 - 3.45 (m, 1H), 3.30 - 3.27 (m, 1H), 3.18 - 2.92 (m, 1H), 2.66 - 2.62 (m, 1H), 2.32 (s, 2H), 2.24 - 2.20 (m, 1H), 2.14 - 1.97 (m, 2H), 1.97 - 1.81 (m, 5H), 1.74 - 1.58 (m, 1H), 1.58 - 1.25 (m, 4H), 1.24 - 1.14 (m, 1H).

[0211] Example 1.6 [ka] (2 mL) of DMF 1 S,2 4 S,5 2 R,5 3 S)-5 3 -Amino-1 6 (S)-tetrahydrofuran-2-carboxylic acid (21 mg, 1.2 equivalents, 0.18 mmol) and HATU (88 mg, 1.5 equivalents, 0.23 mmol) were added to a solution of -methyl-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctafan-6-one (55 mg, 1.0 equivalent, 0.15 mmol) and DIEA (30 mg, 1.5 equivalents, 0.23 mmol). After stirring for 2 hours at 25°C under nitrogen atmosphere, the resulting mixture was purified by reverse flash chromatography to obtain (S)-N-((2 1 S,2 4 S,5 2 R,5 3 S)-1 6-Methyl-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -Tetrahydrofuran-2-carboxamide (50 mg, 0.11 mmol, 71%) was obtained as a solid. LC-MS (ESI): m / z [M+H]+ = 457; 1 H NMR (400MHz, chloroform-d) δ 7.06 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.28-5.16 (m, 1H), 5.1 - 5.071 (m, 1H), 4.41-4.22 (m, 3H), 4.01-3.90 (m, 2H), 3.89-3.80 (m, 1H), 3.72 - 3.69 (m, 2H), 3.59-3.47 (m, 1H), 3.39 - 3.35 (m, 1H), 3.00-2.89 (m, 1H), 2.77-2.60 (m, 1H), 2.37-2.20 (m, 5H), 2.18-2.05 (m, 2H), 2.02-1.82 (m, 6H), 1.73-1.66 (m, 1H), 1.49-1.36 (m, 3H), 1.29 - 1.26 (m, 1H).

[0212] 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 1 μg / mL doxycycline. 24 hours after induction, the cells were lifted with accutase and cultured in 384-well proxy plates at 30,000 cells / well. The cells were then treated for 1 hour at 37°C with different test compounds in 1X stimulation buffer 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, pH 7.4. After incubation, the reaction was terminated by adding a detection mixture, which consisted of anti-IP1-cryptate diluted in IP1-d2 and lysis buffer, as well as 1X stimulation buffer. The plates were incubated at room temperature for 1 hour, and then read with an EnVision® multimode plate reader to measure phosphate inositol levels.

[0213] Cisbio IP1 is a functional cell assay that quantifies the accumulation of inositol monophosphate (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 an IP1 analog linked to a d2 fluorophore (acceptor) for binding to an anti-IP1 monoclonal antibody labeled with Eucryptate (donor). The measured HTRF-FRET-based signal is inversely proportional to the concentration of IP1 produced.

[0214] EC reported in Table 2 50 The values ​​were obtained according to the human OX2R IP1 assay described above. The data represents the mean EC2. 50 The value is ±SEM. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0215] Example 3: Evaluation of arousal enhancement in Sprague-Dawley rats We will evaluate the enhancement of arousal using electroencephalography (EEG) and electromyography (EMG) in adult male Sprague-Dawley rats. Under isoflurane anesthesia, all rats (Charles River Laboratories, Raleigh, NC, USA) will have a telemetry device (F50-EEE, Data Sciences International Inc., MN, USA) implanted intraperitoneally. For EEG, stainless steel screws will be implanted in the frontal and parietal cortices, and a reference screw will be placed in the cerebellum. For EMG, electrodes will be placed in the neck muscles. Postoperatively, rats will be given carprofen and allowed to recover for 7-10 days. Rats will be acclimated to the laboratory for 7 days, maintained in a 12-hour light-dark cycle.

[0216] EEG and EMG data are recorded using a DSI telemetry system and Ponemah software (Data Sciences International Inc., MN, USA). Sleep-wake stages are scored at 10-second intervals (epochs) both manually and using the Somnivore machine learning software platform. After processing, the recordings are visually inspected if necessary.

[0217] All test compounds are dissolved in 5% DMSO and suspended in 95% saline containing 0.5% methylcellulose and 0.5% tween. In the cross-design, rats are administered a dose volume of 3.33 ml / kg body weight during the inactive light period at a Zeitgeber time of 5 (ZT5). Unless otherwise indicated, all compounds are administered orally. Records for each rat are started immediately after administration and continued for 6 hours post-administration.

[0218] Two key endpoints include wakefulness time and cortical activation time. Wakefulness time is derived from sleep-wake stage analysis. Cortical activation time is based on the duration of elevation of frontal gamma-oscillating activity (30–100 Hz), a key feature of wakefulness, compared to pre-treatment baseline. Mean cortical activation time is computer-calculated for vehicle treatment 6 hours after the administration period.

[0219] While the present invention is particularly shown and described in relation to its preferred embodiments, it will be understood by those skilled in the art that various modifications in form and detail can be made in the present invention without departing from the scope of the invention as encompassed in the appended claims. The following are examples of aspects of the present invention. Item 1 Formula I: [ka] (In the formula: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3; E is NR a R b , C(=O)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, C 1 -C 3 Alkilen-(4-10 member heterocyclyl), C 6 -C 10 Ariel, C 1 -C 3 Alkylene-(C) 6 -C 10 Aryl, 5-10 member heteroaryl and C 1 -C 3 Selected from the group consisting of alkylene-(5-10 member heteroaryl), where 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, C 1 -C 3 Alkilen-(4-10 member heterocyclyl), C 6 -C 10 Ariel, C 1 -C 3 Alkylene-(C) 6 -C 10 Aryl, 5-10 member heteroaryl or C 1 -C 3 Alkylene-(5-10 member heteroaryl) is either unsubstituted or has one or more halogens, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 Substituted with alkoxyl; T is CR 1 R 2 or O; W is CR 4 R 5 or O; U is CR 6 R 7 and; X is CR 8 R 9 and; V is CR 3 or N; Y is NR 10 , O or non-existent; Z is (CR 12 R 13 ) m and; Each R can independently be a halogen, deuterium, hydroxyl, cyano, or unsubstituted C. 1 -C 3 C substituted with alkyl and one or more halogens or deuterium 1 -C 3 Selected from the group consisting of alkyl groups; p is 0, 1, 2, 3, or 4; R a and R b Each of these is independently H or unsubstituted C 1 -C 3 It is alkyl; m is 1, 2, 3, or 4; And further: R 1 、R 2 、R 4 and R 5 Each of these is independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; Alternatively, R 2 and R 5 They, together with the carbon atoms to which they bond, form a single bond; R 3 It is selected from the group consisting of H, deuterium, halogens, hydroxyl, and cyano; Alternatively, R 3 and R 1 Together with the carbon atoms to which they bond, C 3 -C 5 Forms a cycloalkyl group; Alternatively, R 3 and R 4 Together with the carbon atoms to which they bond, C 3 -C 5 Forms a cycloalkyl group; R 6 、R 7 、R 8 、R 9 and R 11 Each of these is independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 10 H, unsubstituted C 1 -C 3 C substituted with alkyl and one or more halogens 1 -C 3 Selected from the group consisting of alkyl groups; Each R 12 and R 13 These are independently H, halogen, deuterium, and unsubstituted C. 1 -C 3 C substituted with alkyl and hydroxyl or one or more halogens 1 -C 3 Selected from the group consisting of alkyl groups; R 14 、R 15 and R 16 These are H and unsubstituted C, respectively, independently. 1 -C 3 C substituted with alkyl or one or more halogens 1 -C 3 Selected from the group consisting of alkyl groups; Each R 17 and R 18 These are H and unsubstituted C, independently. 1 -C 3 C substituted with alkyl or one or more halogens 1 -C 3 (Selected from the group consisting of alkyl groups) Compounds of or pharmaceutically acceptable salts thereof. Section 2 The compound described in item 1, wherein n is 1. Section 3 The compound described in item 1, wherein n is 2. Section 4 A compound described in any of items 1 to 3, wherein ring A is phenyl. Section 5 A compound described in any of items 1 to 3, wherein ring A is pyridinyl. Section 6 A compound described in any of items 1 to 5, wherein Y is O. Section 7 A compound described in any of items 1 to 5, in which Y is absent. Section 8 A compound described in any of items 1 to 3, wherein ring A is phenyl and Y is O. Section 9 A compound described in any of items 1 to 3, wherein ring A is pyridinyl and Y is oxygen. Section 10 A compound described in any of items 1 to 3, wherein ring A is phenyl and Y is absent. Section 11 A compound described in any of items 1 to 3, wherein ring A is pyridinyl and Y is absent. Section 12 T is CR 1 R 2 The compound described in any of the preceding paragraphs. Section 13 A compound as described in any of the preceding items, wherein T is O. Section 14 W is CR 4 R 5 The compound described in any of the preceding paragraphs. Section 15 A compound as described in any of the preceding items, wherein W is O. Section 16 V is CR 3 The compound described in any of the preceding paragraphs. Section 17 E is C(=O)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, C 1 -C 3 Alkilen-(4-10 member heterocyclyl), C 6 -C 10 Ariel, C 1 -C 3 Alkylene-(C) 6 -C 10 Aryl, 5-10 member heteroaryl and C 1 -C 3 Selected from the group consisting of alkylene-(5-10 member heteroaryl), 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, C 1 -C 3 Alkilen-(4-10 member heterocyclyl), C 6 -C 10 Ariel, C 1 -C 3 Alkylene-(C) 6 -C 10 Aryl, 5-10 member heteroaryl or C 1 -C 3 Alkylene-(5-10 member heteroaryl) is either unsubstituted or has one or more halogens, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 A compound as described in any of the preceding paragraphs, substituted with an alkoxyl. Section 18 E is 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, C 1 -C 3 Alkilen-(4-10 member heterocyclyl), C 6 -C 10 Ariel, C 1 -C 3 Alkylene-(C) 6 -C 10 Aryl, 5-10 member heteroaryl and C 1 -C 3 Selected from the group consisting of alkylene-(5-10 member heteroaryl), 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, C 1 -C 3 Alkilen-(4-10 member heterocyclyl), C 6 -C 10 Ariel, C 1 -C 3 Alkylene-(C) 6 -C 10 Aryl, 5-10 member heteroaryl or C 1 -C 3 Alkylene-(5-10 member heteroaryl) is either unsubstituted or has one or more halogens, hydroxyl, C1 -C 3 Alkyl or C 1 -C 3 A compound substituted with an alkoxyl, as described in any of sections 1 to 16. Section 19 E is C 1 -C 3 Alkyl, C 2 -C 4 Alkenil, C 2 -C 4 Alkinyl, C 3 -C 8 Cycloalkyl and C 1 -C 3 Alkylene-(C) 3 -C 8 Selected from the group consisting of cycloalkyls, C 1 -C 3 Alkyl, C 2 -C 4 Alkenil, C 2 -C 4 Alkinyl, C 3 -C 8 Cycloalkyl or C 1 -C 3 Alkylene-(C) 3 -C 8 The cycloalkyl group is either unsubstituted or contains one or more halogens, hydroxyl groups, and C groups. 1 -C 3 Alkyl or C 1 -C 3 A compound substituted with an alkoxyl, as described in any of sections 1 to 16. Section 20 E is a 4-10 member heterocycline, C 1 -C 3 Alkilen-(4-10 member heterocyclyl), C 6 -C 10 Ariel, C 1 -C 3 Alkylene-(C) 6 -C 10 Aryl, 5-10 member heteroaryl and C 1 -C 3 Selected from the group consisting of alkylene-(5-10 member heteroaryl), 4-10 member heterocyclil, C 1 -C 3 Alkilen-(4-10 member heterocyclyl), C 6 -C 10 Ariel, C 1 -C 3 Alkylene-(C) 6 -C 10 Aryl, 5-10 member heteroaryl or C 1 -C 3 Alkylene-(5-10 member heteroaryl) is either unsubstituted or has one or more halogens, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 A compound substituted with an alkoxyl, as described in any of sections 1 to 16. Section 21 E is a 4-7 member heterocycline and C 1 -C3 Selected from the group consisting of alkylene-(4-7 membered heterocyclil), 4-7 membered heterocyclil or C 1 -C 3 Alkylene-(4-7 member heterocyclyl) is either unsubstituted or has one or more halogens, hydroxyl groups, or C 1 -C 3 Alkyl or C 1 -C 3 A compound substituted with an alkoxyl, as described in any of sections 1 to 16. Section 22 T is CR 1 R 2 And W is CR 4 R 5 And V is CR 3 The compound described in any of items 1 to 11. Section 23 The compound according to either of the preceding items, wherein m is 1 or 2. Section 24 A compound described in any of items 1 to 22, wherein m is 1. Section 25 Ring A is phenyl, and T is CR 1 R 2 And W is CR 4 R 5 And V is CR 3 The compound described in any of items 1 to 3. Section 26 The compound described in item 25, in which Y is absent. Section 27 The compound described in item 25, wherein Y is O. Section 28 A compound according to any one of items 25 to 27, wherein m is 1 or 2. Section 29 A compound described in any of items 25-27, wherein m is 1. Section 30 Ring A is pyridinyl, and T is CR 1 R 2 And W is CR 4 R 5 And V is CR 3 The compound described in any of items 1 to 3. Item 31 The compound described in item 30, in which Y is absent. Section 32 The compound described in item 30, wherein Y is O. Item 33 A compound according to any of items 30 to 32, wherein m is 1 or 2. Section 34 A compound described in any of items 30 to 32, wherein m is 1. Item 35

change

change

change

change

change

change

change

change

change

change

change

change

change

change

Claims

1. Equation (IA): 【Chemistry 1】 (In the formula: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3; E is NR a R b 、 C(=O)NR a R b 、 C 1 -C 3 -alkylene-NR a R b 、 C 1 -C 3 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 3 -C 8 -cycloalkyl, C 1 -C 3 -alkylene-(C 3 -C 8 -cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 -alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 -aryl, C 1 -C 3 -alkylene-(C 6 -C 10 -aryl), 5- to 10-membered heteroaryl and C 1 -C 3 -alkylene-(5- to 10-membered heteroaryl) selected from the group consisting of, where C 1 -C 3 -alkylene-NR a R b 、 C 1 -C 3 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 3 -C 8 -cycloalkyl, C 1 -C 3 -alkylene-(C 3 -C 8 -cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 -alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 -aryl, C 1 -C 3 Alkylene-(C) 6 -C 10 Aryl, 5-10 member heteroaryl or C 1 -C 3 Alkylene-(5-10 member heteroaryl) is either unsubstituted or has one or more halogens, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 Substituted with alkoxyl; T is CR 1 R is 2; W is CR 4 R is 5; U is CR 6 R 7 And; X is CR 8 R 9 And; V is CR 3; Y is O; Z is (CR 12 R 13 ) m And; Each R can independently be a halogen, deuterium, hydroxyl, cyano, or unsubstituted C. 1 -C 3 C substituted with alkyl and one or more halogens or deuterium 1 -C 3 Selected from the group consisting of alkyl groups; p is 0, 1, 2, 3, or 4; R a and R b Each of these is independently H or unsubstituted C 1 -C 3 It is alkyl; m is 1; R 1 , R 2 , R 4 and R 5 Each is independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 3 is selected from the group consisting of H, deuterium, halogens, hydroxyl, and cyano; R 6 , R 7 , R 8 , R 9 and R 11 Each is independently selected from the group consisting of H, hydroxyl, halogen, and deuterium; R 12 and R 13 is H; R 14 、R 15 and R 16 are each independently selected from the group consisting of H, unsubstituted C 1 -C 3 -alkyl or C 1 -C 3 -alkyl substituted with one or more halogens; Each R 17 and R 18 are independently selected from the group consisting of H, unsubstituted C 1 -C 3 -alkyl or C 1 -C 3 -alkyl substituted with one or more halogens) Compounds of or pharmaceutically acceptable salts thereof.

2. A compound of formula (IA) or a pharmaceutically acceptable salt thereof is of formula (I): 【Chemistry 1A】 The compound according to claim 1, which is a compound or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein n is 1 or 2.

4. The compound according to claim 1 or 2, wherein ring A is phenyl or pyridinyl.

5. The compound according to claim 1 or 2, wherein ring A is phenyl.

6. The compound according to claim 1 or 2, wherein ring A is pyridinyl.

7. E is selected from the group consisting of C(=O)NR a R b, C1-C3 alkyl-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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5-10 member heteroaryl and C1-C3 alkylene-(5-10 member heteroaryl), where C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2 The compound according to claim 1 or 2, wherein the -C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5-10 membered heteroaryl, or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 【Request Item 8】 【Chemistry 2-1】 【Chemistry 2-2】 [Chemistry 2-3] [Chemistry 2-4] 【Chemistry 2-5】 【Chemistry 2-6】 【Chemistry 2-7】 A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

9. Formula (II-A): 【Transformation 3】 (In the formula: Ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3; E is selected from the group consisting of NR a R b, C(=O)NR a R b, C1-C3 alkyl-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkyl-(C3-C8 cycloalkyl), 4-10 member heterocyclyl, C1-C3 alkyl-(4-10 member heterocyclyl), C6-C10 aryl, C1-C3 alkyl-(C6-C10 aryl), 5-10 member heteroaryl and C1-C3 alkyl-(5-10 member heteroaryl), where C1-C3 alkyl-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C 2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl) are either unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl; T is CR 1 R 2; W is CR 4 R 5; U is CR 6 R 7; X is CR 8 R 9; V is CR 3; Y is O; Z is (CR 12 R 13) m; Each R is independently selected from the group consisting of halogens, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with one or more halogens or deuterium; p is 0, 1, 2, 3, or 4; Ra and Rb are independently H or unsubstituted C1-C3 alkyl groups; m is either 1 or 2; And furthermore: R1, R2, R4, and R5 are each independently selected from the group consisting of H, hydroxyl, halogens, and deuterium; R3 is selected from the group consisting of H, deuterium, halogens, hydroxyl, and cyano; R6, R7, R8, R9, and R11 are each independently selected from the group consisting of H, hydroxyl, halogens, and deuterium; R12 and R13 are H; R14, R15, and R16 are each independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens; Each of R17 and R18 is independently selected from the group consisting of H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens. Compounds of or pharmaceutically acceptable salts thereof.

10. A compound of formula (II-A) or a pharmaceutically acceptable salt thereof, wherein formula (II): 【Chemistry 3A】 The compound according to claim 9, which is a compound or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 9 or 10, wherein n is 1 or 2.

12. The compound according to claim 9 or 10, wherein ring A is phenyl or pyridinyl.

13. The compound according to claim 9 or 10, wherein m is 2.

14. The compound according to claim 9 or 10, wherein ring A is phenyl.

15. The compound according to claim 14, wherein m is 2.

16. The compound according to claim 9 or 10, wherein ring A is pyridinyl.

17. The compound according to claim 16, wherein m is 2.

18. E is selected from the group consisting of C(=O)NR a R b, C1-C3 alkyl-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, C1-C3 alkylene-(4-10 member heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5-10 member heteroaryl and C1-C3 alkylene-(5-10 member heteroaryl), where C1-C3 alkylene-NR a R b, C1-C3 alkyl, C2-C4 alkenyl, C The compound according to claim 9 or 10, wherein a 2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5-10 membered heteroaryl, or C1-C3 alkylene-(5-10 membered heteroaryl) is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl. 【Request Item 19】 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] [Chemistry 4-6] A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

20. A pharmaceutical composition comprising the compound according to claim 1 or 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

21. Use of the compound according to claim 1 or 9 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for narcolepsy.

22. Use of the composition according to claim 20 in the manufacture of a pharmacopoeia for narcolepsy.

23. Use of the compound according to claim 1 or 9 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for cataplexy.

24. Use of the composition according to claim 20 in the manufacture of a pharmaceutical for cataplexy.

25. The composition according to claim 20, for use in a method of treating narcolepsy in a subject requiring treatment for narcolepsy.

26. The composition according to claim 20, for use in a method of treating cataplexy in a subject requiring treatment for cataplexy.

27. ​​A pharmaceutical composition comprising the compound according to claim 2 or 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

28. Use of the compound according to claim 2 or 10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for narcolepsy.

29. Use of the composition according to claim 27 in the manufacture of a pharmacopoeia for narcolepsy.

30. Use of the compound according to claim 2 or 10 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for cataplexy.

31. Use of the composition according to claim 27 in the manufacture of a pharmaceutical for cataplexy.

32. The composition according to claim 27, for use in a method of treating narcolepsy in a subject requiring treatment for narcolepsy.

33. The composition according to claim 27 for use in a method of treating cataplexy in a subject requiring treatment for cataplexy.

34. A pharmaceutical composition comprising the compound according to claim 8 or 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

35. Use of the compound according to claim 8 or 19 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for narcolepsy.

36. Use of the composition according to claim 34 in the manufacture of a pharmacopoeia for narcolepsy.

37. Use of the compound according to claim 8 or 19 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for cataplexy.

38. Use of the composition according to claim 34 in the manufacture of a pharmaceutical for cataplexy.

39. The composition according to claim 34, for use in a method of treating narcolepsy in a subject requiring treatment for narcolepsy.

40. The composition according to claim 34, for use in a method of treating cataplexy in a subject requiring treatment for cataplexy.

Images