Substituted Pyrrolidinyl and Piperidinyl Compounds and Related Therapeutic Methods

Abstract

The present invention provides compounds useful for the treatment of 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 benefit of U.S. Provisional Patent Application No. 63 / 353,985, filed on June 21, 2022. The entire content of the above application is incorporated herein by reference.

[0002] The present invention relates to substituted pyrrolidinyl and piperidinyl compounds, particularly substituted pyrrolidinyl and piperidinyl compounds having agonist activity.

Background Art

[0003] 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. 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 (type 1 and type 2) of orexin receptors (Cell, Vol. 92, 573-585, 1998). Activation of orexin receptors is known to be important for various central nervous system functions such as maintenance of 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 that causes 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 engineered to degenerate orexin neurons, and those symptoms can be reversed by intracerebroventricular administration of orexin peptides (Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004). Studies of orexin-2 receptor knockout mice suggest that the orexin-2 receptor plays a preferential role in maintaining the awake state (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 presenting excessive daytime sleepiness, such as Parkinson's disease (CNS Drugs, Vol. 27, 83-90, 2013; Brain, Vol. 130, 2007, 1586-1595).

[0005] Compounds having agonist activity for orexin-2 receptor are considered to be useful as novel therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disorders of consciousness such as lethargy, narcolepsy syndrome, hypersomnia syndrome characterized by hypersomnia (for example, in Parkinson's disease, Guillain-Barré syndrome or Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, or sepsis, etc. (Cell Metabolism, Vol.9, 64-76, 2009; Neuroscience, Vol.121, 855-863, 2003; Respiration, Vol.71, 575-579, 2004; Peptides, Vol.23, 1683-1688, 2002; International Publication No. 2015 / 073707; Journal of the American College of Cardiology, Vol.66, 2015, pages 2522-2533; International Publication No. 2015 / 048091; International Publication No. 2015 / 147240).

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

Summary of the Invention

[0007] An object of the present invention is to provide piperidinyl and pyrrolidinyl compounds having orexin-2 receptor agonist activity.

[0008] Accordingly, in a first aspect, the present invention provides a compound represented by formula I-A or a pharmaceutically acceptable salt thereof,

Chemical formula

[0009] In one embodiment, a compound of formula I - A having the structure of formula I or a pharmaceutically acceptable salt thereof is provided herein,

Chemical Structure

[0010] Also provided herein is a pharmaceutical composition comprising a compound of formula I-A or I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] In another aspect, provided herein is a method of treating narcolepsy in a subject in need thereof, the method comprising administering to the subject a compound of formula I-A or I, or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, provided herein is a method of treating cataplexy in a subject in need of treatment of cataplexy, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

Best Mode for Carrying Out the Invention

[0013] Provided herein are compounds useful for treating narcolepsy or cataplexy in a subject, such as a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0014] 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 treating narcolepsy in a subject by acting as an agonist of the orexin 2 receptor.

[0015] Definitions The following are definitions of various terms used to describe the present invention. These definitions apply to the terms used throughout this specification and the claims, individually or as part of a larger group, unless otherwise specifically limited in a particular instance.

[0016] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are well known and commonly used in the art.

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

[0018] As used herein, the term "about" is understood by those skilled in the art and varies to some extent in the context in which it is used. When used herein in reference to a measurable value such as an amount, duration, etc., the term "about" means an inclusion of a variation of ±20% or ±10% including ±5%, ±1%, and ±0.1% from the specified value, such variations being suitable for carrying out the disclosed method.

[0019] As used herein, "EC 50 " refers to the concentration of a compound required to achieve an effect that is 50% of the maximum observed effect of the compound.

[0020] As used herein, the term "agonist" refers to a compound that, when contacted with a target of interest (e.g., orexin 2 receptor), causes an increase in the magnitude of a particular activity or function of the target as compared to the magnitude of the activity or function observed in the absence of the agonist.

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

[0022] As used herein, the terms "prevent" or "prevention" mean, when a disorder or disease has not occurred, the absence of the occurrence of the disorder or disease, or when a disorder or disease has already occurred, the absence of the occurrence of a further disorder or disease. The ability to prevent some or all of the symptoms associated with a disorder or disease is also contemplated.

[0023] As used herein, the terms "patient", "individual" or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, domestic animals and pets such as sheep, cows, pigs, dogs, cats and mouse mammals. Preferably, the patient, subject or individual is human.

[0024] As used herein, the terms "effective amount", "pharmaceutically effective amount", and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to provide the desired biological result. The result can be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0025] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not inactivate the biological activity or properties of a compound and is relatively non-toxic, i.e., 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 the composition in which it is contained.

[0026] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present invention include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two, and 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-salts or 1:1 salts. For example, "pharmaceutically acceptable salts" include bis-salts such as bis-hydrochloride salts. Lists 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.

[0027] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of the compounds to a patient or subject. A plurality of techniques for administering compounds exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary and topical administration.

[0028] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention in or to a patient so as to perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a formulation containing a compound useful within the invention and not injurious to the patient. Some examples of substances which can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations.

[0029] As used herein, "pharmaceutically acceptable carrier" also includes any coating, antibacterial and antifungal agents, and absorption delaying agents, etc. that are compatible with the activity of the compounds useful within the present invention and are physiologically acceptable to the patient. Auxiliary active compounds can also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds useful within the present invention. Other additional ingredients that can be included in the pharmaceutical compositions used in the practice of the present invention are known in the art and are described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

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

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

[0032] As used herein, the term "alkylene" refers to a divalent aliphatic hydrocarbyl group having 1 to 4 carbon atoms, which can be either straight or branched, for example. This term includes, for example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), etc.

[0033] As used herein, the term "alkenyl" means a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon double bond. The double bond may or may not be a point of attachment to another group. Examples of alkenyl groups (e.g., C2-C8-alkenyl) include, but are not limited to, ethenyl, propenyl, prop-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0034] As used herein, the term "alkynyl" means a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon triple bond. The triple bond may or may not be a point of attachment to another group. Examples of alkynyl groups (e.g., C2-C8-alkynyl) include, but are not limited to, ethynyl, propynyl, prop-1-yn-2-yl, butynyl, 1-methyl-2-butyn-1-yl, heptynyl, octynyl, and the like.

[0035] As used herein, the term "alkoxy" refers to an -O-alkyl group where alkyl is as defined herein. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, and the like.

[0036] As used herein, the term "cycloalkyl" means a non-aromatic carbocyclic system that is partially or fully saturated and has 1, 2 or 3 rings, such rings may be fused. The term "fused" means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common (i.e., shared) with a first ring. Cycloalkyl also includes bicyclic structures that may be essentially bridged or spirocyclic, with each individual ring within the ring varying from 3 to 8 atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl.

[0037] As used herein, the term "heterocyclyl" means a non-aromatic carbocyclic system containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and having 1, 2 or 3 rings, such rings may be fused, and the fusion is defined above. Heterocyclyl also includes bicyclic structures which may be essentially bridged or spirocyclic and which vary from 3 to 8 atoms and have each individual ring within the bicyclic containing 0, 1, or 2 N, O, or S atoms. The term "heterocyclyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and specifically includes, but is not limited to, epoxyidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, etc. For example, the term "heterocyclyl" can include 4- to 10-membered heterocyclyl, 4- to 7-membered heterocyclyl, 5- to 10-membered heterocyclyl, 6- to 10-membered heterocyclyl, 4- to 6-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, or 10-membered heterocyclyl.

[0038] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromaticity, i.e., having (4n + 2) delocalized π (pi) electrons, where n is an integer.

[0039] As used herein, the term "aryl" means an aromatic carbocyclic system containing 1, 2 or 3 rings, such rings may be fused, and the fusion is defined above. When the rings are fused, one of the rings must be completely unsaturated, and the fused ring(s) may be completely saturated, partially unsaturated or completely unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. For example, the term "aryl" can include C6-C 10 aryl, C6-C8 aryl, or C6 aryl (i.e., phenyl).

[0040] As used herein, the term "heteroaryl" means an aromatic carbocyclic system having 1, 2 or 3 rings and containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, such rings may be fused, and the fusion is defined above. The term "heteroaryl" includes, but is not limited to, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. For example, the term "heteroaryl" can include 5- to 10-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 6-membered heteroaryl, 6- to 10-membered heteroaryl, 6- to 8-membered heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl.

[0041] When an aryl, heteroaryl, cycloalkyl or heterocyclyl moiety can be attached or otherwise bonded to the moiety designated via a different ring atom (i.e., shown or described without indication of a specific point of attachment), it should be understood that all possible points via either a carbon atom or, for example, a trivalent nitrogen atom are intended. For example, the term "pyridinyl" means 2-, 3- or 4-pyridinyl, the term "thiophenyl" means 2- or 3-thiophenyl, and the like.

[0042] As used herein, the term "substituted" means that an atom or group of atoms has replaced hydrogen as a substituent attached to another group.

[0043] The compounds of the present invention Accordingly, in a first aspect, the present invention provides a compound represented by formula I-A or a pharmaceutically acceptable salt thereof,

Chemical formula

[0044] In one embodiment, a compound of formula I-A having the structure of formula I or a pharmaceutically acceptable salt thereof is provided herein.

Chemical Formula

[0045] In one embodiment of formula (I), ring A is a phenyl ring, and the ring is unsubstituted or substituted with 1-3 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0046] In another embodiment of formula (I), ring A is a phenyl ring, and the ring is unsubstituted or substituted with 1-2 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0047] In another embodiment of formula (I), ring A is a phenyl ring, and the ring is substituted with 1-2 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0048] In another embodiment of formula (I), ring A is a phenyl ring, and the ring is substituted with 1-2 substituents each independently selected from C1-C3 alkyl or halogen.

[0049] In another embodiment of formula (I), ring A is a phenyl ring, and the ring is substituted with 1-2 substituents each independently selected from halogen.

[0050] In another embodiment of formula (I), ring A is a phenyl ring, and the rings are each independently substituted with 1 to 2 substituents selected from F or Cl.

[0051] In another embodiment of formula (I), ring A is a phenyl ring, and the rings are substituted with 1 to 2 F substituents.

[0052] In another embodiment of formula (I), ring A is 3-fluorophenyl.

[0053] In another embodiment of formula (I), ring A is a pyridinyl ring, and the rings are unsubstituted or each independently substituted with 1 to 3 substituents selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0054] In another embodiment of formula (I), ring A is a pyridinyl ring, and the rings are unsubstituted or each independently substituted with 1 to 2 substituents selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0055] In another embodiment of formula (I), ring A is a pyridinyl ring, and the rings are each independently substituted with 1 to 2 substituents selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0056] In another embodiment of formula (I), ring A is a pyridinyl ring, and the rings are each independently substituted with 1 to 2 substituents selected from C1-C3 alkyl or halogen.

[0057] In another embodiment of formula (I), ring A is a pyridinyl ring, and the rings are each independently substituted with 1 to 2 substituents selected from halogen.

[0058] In another embodiment of formula (I), ring A is a pyridinyl ring, and the rings are each independently substituted with 1 to 2 substituents selected from C1-C3 alkyl.

[0059] In another embodiment of formula (I), ring A is a pyridinyl ring, and the rings are monosubstituted with C3-C5 cycloalkyl.

[0060] In another embodiment of formula (I), ring A is a pyridazinyl ring, and the rings are unsubstituted or are each independently substituted with 1 to 3 substituents selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0061] In another embodiment of formula (I), ring A is a pyridazinyl ring, and the rings are unsubstituted or are each independently substituted with 1 to 2 substituents selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0062] In another embodiment of formula (I), ring A is a pyridazinyl ring, and the rings are each independently substituted with 1 to 2 substituents selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0063] In another embodiment of formula (I), ring A is a pyridazinyl ring, and the rings are each independently substituted with 1 to 2 substituents selected from C1-C3 alkyl or halogen.

[0064] In another embodiment of formula (I), ring A is a pyridazinyl ring, and the rings are each independently substituted with 1 to 2 substituents selected from halogen.

[0065] In another embodiment of formula (I), ring A is a pyridazinyl ring, and the rings are each independently substituted with 1 to 2 substituents selected from C1-C3 alkyl.

[0066] In another embodiment of formula (I), ring A is a pyridazinyl ring, and the ring is monosubstituted with a C3-C5 cycloalkyl.

[0067] In another embodiment of formula (I), ring A is a pyrimidinyl ring, and the ring is unsubstituted or substituted with 1 to 3 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0068] In another embodiment of formula (I), ring A is a pyrimidinyl ring, and the ring is unsubstituted or substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0069] In another embodiment of formula (I), ring A is a pyrimidinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0070] In another embodiment of formula (I), ring A is a pyrimidinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl or halogen.

[0071] In another embodiment of formula (I), ring A is a pyrimidinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from halogen.

[0072] In another embodiment of formula (I), ring A is a pyrimidinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl.

[0073] In another embodiment of formula (I), ring A is a pyrimidinyl ring, and the ring is monosubstituted with a C3-C5 cycloalkyl.

[0074] In another embodiment of formula (I), ring A is a pyrazinyl ring, and the ring is unsubstituted or substituted with 1 to 3 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0075] In another embodiment of formula (I), ring A is a pyrazinyl ring, and the ring is unsubstituted or substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0076] In another embodiment of formula (I), ring A is a pyrazinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0077] In another embodiment of formula (I), ring A is a pyrazinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl or halogen.

[0078] In another embodiment of formula (I), ring A is a pyrazinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from halogen.

[0079] In another embodiment of formula (I), ring A is a pyrazinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl.

[0080] In another embodiment of formula (I), ring A is a pyrazinyl ring, and the ring is monosubstituted with C3-C5 cycloalkyl.

[0081] In another embodiment of formula (I), ring A is a triazinyl ring, and the ring is unsubstituted or substituted with 1 to 3 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0082] In another embodiment of formula (I), ring A is a triazinyl ring, and the ring is unsubstituted or substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0083] In another embodiment of formula (I), ring A is a triazinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.

[0084] In another embodiment of formula (I), ring A is a triazinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl or halogen.

[0085] In another embodiment of formula (I), ring A is a triazinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from halogen.

[0086] In another embodiment of formula (I), ring A is a triazinyl ring, and the ring is substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl.

[0087] In another embodiment of formula (I), ring A is a triazinyl ring, and the ring is monosubstituted with C3-C5 cycloalkyl.

[0088] In another embodiment of formula (I), p is 0. In another embodiment of formula (I), p is 1. In another embodiment of formula (I), p is 2. In another embodiment of formula (I), p is 3. In another embodiment of formula (I), p is 4. In another embodiment of formula (I), p is 0, 1 or 2. In another embodiment of formula (I), p is 0 or 1.

[0089] In another embodiment of formula (I), p is 1 and R9 is deuterium. In another embodiment of formula (I), p is 1 and R9 is halogen. In another embodiment of formula (I), p is 1 and R9 is fluorine. In another embodiment of formula (I), p is 1 and R9 is hydroxyl. In another embodiment of formula (I), p is 1 and R9 is cyano. In another embodiment of formula (I), p is 2 and each R9 is hydroxyl. In another embodiment of formula (I), p is 2 and each R9 is halogen. In another embodiment of formula (I), p is 2 and each R9 is fluorine.

[0090] In another embodiment of formula (I), E is NR a R b and is. In another embodiment of formula (I), E is C1-C3 alkylene-NR a R b and is. In another embodiment of formula (I), E is unsubstituted C1-C3 alkyl, unsubstituted C2-C4 alkenyl or unsubstituted C2-C4 alkynyl. In another embodiment of formula (I), E is 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 (I), E is unsubstituted C1-C3 alkyl. In another embodiment of formula (I), E is C1-C3 alkyl substituted with one or more halogens, hydroxyls, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C3-C8 cycloalkyl. In another embodiment of formula (I), E is C3-C8 cycloalkyl substituted with one or more halogens, hydroxyls, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of formula (I), E is C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogens, hydroxyls, NR c R d, CF3, CHF2, CH2F, C1-C3 alkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with C1-C3 alkoxyl. In another embodiment of formula (I), E is an unsubstituted 4- to 10-membered heterocyclyl. In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , a 4- to 10-membered heterocyclyl substituted with CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is an unsubstituted C1-C3 alkylene-(4- to 10-membered heterocyclyl). In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , a C1-C3 alkylene-(4- to 10-membered heterocyclyl) substituted with CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is an unsubstituted C6-C 10 aryl. In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , a C6-C 10 -aryl substituted with CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is an unsubstituted C1-C3 alkylene-(C6-C 10 aryl). In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , a C1-C3 alkylene-(C6-C 10 -aryl) substituted with CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is an unsubstituted 5- to 7-membered heteroaryl. In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R dis a 5- to 7-membered heteroaryl substituted with CF3, CHF2, CH2F, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(5- to 7-membered heteroaryl). In another embodiment of formula (I), E is one or more halogen, hydroxyl, NR c R d is C1-C3 alkylene-(5- to 7-membered heteroaryl) substituted with CF3, CHF2, CH2F, C1-C3 alkyl, or C1-C3 alkoxyl.

[0091] 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- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl), and C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d is substituted with CF3, CHF2, CH2F, C1-C3, or C1-C3 alkoxyl.

[0092] In another embodiment of formula (I), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl), and C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, or C1-C3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d is substituted with CF3, CHF2, CH2F, C1-C3 alkyl, or C1-C3 alkoxyl.

[0093] In another embodiment of formula (I), E is C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl), and C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl, or C1-C3 alkoxyl.

[0094] In another embodiment of formula (I), E is methyl. In another embodiment of formula (I), E is methyl substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is CF3. In another embodiment of formula (I), E is CHF2. In another embodiment of formula (I), E is CH2F. In another embodiment of formula (I), E is NH(CH3). In another embodiment of formula (I), E is N(CH3)2.

[0095] In another embodiment of formula (I), E is C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-7 membered heteroaryl or C1-C3 alkylene-(5-7 membered heteroaryl). In another embodiment of formula (I), E is unsubstituted C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl). In another embodiment of formula (I), E is C6-C c aryl or C1-C3 alkylene-(C6-C d aryl) substituted with one or more halogen, hydroxyl, NR 10 aryl or C1-C3 alkylene-(C6-C 10 aryl).

[0096] In another embodiment of formula (I), E is a 5- to 7-membered heteroaryl or C1-C3 alkylene-(5- to 7-membered heteroaryl). In another embodiment of formula (I), E is an unsubstituted 5- to 7-membered heteroaryl or C1-C3 alkylene-(5- to 7-membered heteroaryl). In another embodiment of formula (I), E is a 5- to 7-membered heteroaryl or C1-C3 alkylene-(5- to 7-membered heteroaryl) substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl.

[0097] In another embodiment of formula (I), Y is S(=O)2. In another embodiment of formula (I), Y is C(=O). In another embodiment of formula (I), Y is S(=O)(=NR e ).

[0098] In another embodiment of formula (I), X is N. In another embodiment of formula (I), X is CH.

[0099] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, C(=O)-C1-C4 alkoxyl, C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C6-C 10 aryl), and C(=O)-(CR c R d ) n -(5- to 10-membered heteroaryl), and is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxyl, C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl, C6-C 10Aryl, or 5- to 10-membered heteroaryl, is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0100] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, C(=O)-C1-C4 alkoxyl, and C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, selected from the group consisting of, and C1-C4 alkyl, C1-C4 alkoxyl, or C3-C8 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0101] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C6-C 10 aryl) and C(=O)-(CR c R d ) n -(5- to 10-membered heteroaryl), selected from the group consisting of, and 4- to 7-membered heterocyclyl, C6-C 10 aryl or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0102] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, and C1-C4 alkyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0103] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkoxyl, and the C1-C4 alkoxyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0104] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, and the C3-C8 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0105] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(4-7 membered heterocyclyl), and the 4-7 membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0106] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl), and the C6-C 10 aryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0107] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(5 to 10-membered heteroaryl), where the 5 to 10-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0108] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5 to 7-membered heterocyclyl), where the 5 to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0109] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5 to 6-membered heterocyclyl), where the 5 to 6-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0110] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), where the 5-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0111] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), where the 6-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0112] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), where C6 aryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0113] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C8 aryl), and C8 aryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0114] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C 10 aryl), and C 10 aryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0115] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5-6 membered heteroaryl), and the 5-6 membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0116] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 5-membered heteroaryl), where the 5-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0117] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heteroaryl), where the 6-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0118] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 7-membered heteroaryl), where the 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0119] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl or C(=O)-O-(CR c R d ) n -(a 4-7-membered heterocyclyl), where the C3-C8 cycloalkyl or 4-7-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0120] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n-C3-C8 cycloalkyl, and C3-C8 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(4-7 membered heterocyclyl), and 4-7 membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3-C5 cycloalkyl, and C3-C5 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(5-6 membered heterocyclyl), and 5-6 membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(5 membered heterocyclyl), and 5 membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n-(a 6-membered heterocyclyl), where the 6-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0121] In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl) or (CR c R d ) n -(a 5- to 10-membered heteroaryl), where the C6-C 10 aryl or 5- to 10-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl) or (CR c R d ) n -(a 5- to 10-membered heteroaryl), where the C6-C 10 aryl or 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0122] In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl) or (CR c R d ) n -(a 5- to 10-membered heteroaryl), where the C6-C 10 aryl or 5- to 10-membered heteroaryl is unsubstituted and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl) or (CR c R d ) n-(a 5- to 10-membered heteroaryl), where C6-C 10 The aryl or 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 0.

[0123] In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl) or (CR c R d ) n -(a 5- to 10-membered heteroaryl), where C6-C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl) or (CR c R d ) n -(a 5- to 10-membered heteroaryl), where C6-C 10 The aryl or 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 1.

[0124] In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl), where C6-C 10 The aryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl), where C6-C 10 The aryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0125] In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl), C6-C 10 aryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl), C6-C 10 aryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 0.

[0126] In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl), C6-C 10 aryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl), C6-C 10 aryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 1.

[0127] In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), and the 5- to 10-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n-(a 5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0128] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums and further n is 0.

[0129] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums and further n is 1.

[0130] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(a 5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CRc R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0131] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), the phenyl or 5- to 7-membered heteroaryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium, and further n is 0.

[0132] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), the phenyl or 5- to 7-membered heteroaryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n-(5- to 7-membered heteroaryl), wherein phenyl or 5- to 7-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 1.

[0133] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein phenyl or 6-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein phenyl or 6-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0134] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), phenyl or 6-membered heteroaryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein phenyl or 6-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 0.

[0135] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium, and further n is 1.

[0136] In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), and the 6-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), and the 6-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium. In another embodiment of formula (I), R1 is pyridazinyl. In another embodiment of formula (I), R1 is 3-pyridazinyl.

[0137] In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), and the 6-membered heteroaryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n-(a 6-membered heteroaryl), where the 6-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 0.

[0138] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 6-membered heteroaryl), the 6-membered heteroaryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 6-membered heteroaryl), where the 6-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 1.

[0139] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5-membered heteroaryl), the 5-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5-membered heteroaryl), where the 5-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0140] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5-membered heteroaryl), where the 5-membered heteroaryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n-(a 5-membered heteroaryl), where the 5-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 0.

[0141] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5-membered heteroaryl), where the 5-membered heteroaryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5-membered heteroaryl), where the 5-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 1.

[0142] In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is independently H, a halogen, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums. In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is independently H, a halogen, or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is independently H or a halogen. In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is independently H or fluorine. In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is independently H or C1-C3 alkyl. In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is H.

[0143] In another embodiment of formula (I), R3 and R6 together form unsubstituted C1-C3 alkylene or C1-C3 alkylene substituted with one or more halogens. In another embodiment of formula (I), R3 and R6 together form unsubstituted C2 alkylene or C2 alkylene substituted with one or more halogens. In another embodiment of formula (I), R3 and R6 together form azabicyclo[3.2.1]octanyl-bridged bicyclic heterocyclyl.

[0144] In another embodiment of formula (I), R4 and R5 together form unsubstituted C1-C3 alkylene or C1-C3 alkylene substituted with one or more halogens. In another embodiment of formula (I), R4 and R5 together form unsubstituted C2 alkylene or C2 alkylene substituted with one or more halogens. In another embodiment of formula (I), R4 and R5 together form azabicyclo[3.2.1]octanyl-bridged bicyclic heterocyclyl.

[0145] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, and each of R2, R3, R4, R5, R6, R7 and R8 is H. In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, and each of R2, R3, R4, R5, R6, R7 and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, and each of R2, R3, R4, R5, R6, R7 and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, and each of R2, R3, R4, R5, R6, R7 and R8 is H or fluorine.

[0146] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkoxyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkoxyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkoxyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkoxyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0147] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0148] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0149] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0150] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(4 to 7-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(4 to 7-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(4 to 7-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(4 to 7-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0151] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(4 to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(4 to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or a halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0152] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or a halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0153] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0154] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0155] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0156] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0157] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0158] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CRc R d ) n is -(6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0159] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0160] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10is aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl) and n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl) and n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0161] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl) and n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl) and n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl) and n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl) and n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0162] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0163] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(C6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0164] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0165] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5-7 membered heteroaryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5-7 membered heteroaryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(5- to 7-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0166] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0167] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(5- to 7-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0168] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0169] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 5-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0170] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(5-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0171] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0172] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0173] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0174] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7 and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n-C3 to C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0175] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0176] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n-C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0177] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(4 to 7-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(4 to 7-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(4 to 7-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n-(a 4- to 7-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0178] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0179] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d )n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or a halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0180] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or a halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0181] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n-(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0182] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0183] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d )n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0184] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0185] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0186] In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR cR d ) n -(5- to 10-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0187] In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 7-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 7-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 7-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 7-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0188] In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n-(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0189] In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0190] In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n-(6-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0191] In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0192] In another embodiment of formula (I), R1 is (CR c R d ) n-(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0193] In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0194] In another embodiment of formula (I), R1 is (CR c R d )n -(C6 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0195] Each of the embodiments described herein for the compounds of formula I also applies to the compounds of formula I-A.

[0196] According to formula I-A or I herein, when ring A is pyridinyl, the position of the pyridinyl N atom is specified as shown below.

Chemical formula

Chemical formula

[0197] Furthermore, according to formula I-A or I herein, when ring A is pyridazinyl, the position of the pyridazinyl N atom is specified as shown below.

Chemical formula

Chemical formula

[0198] Furthermore, according to Formula I-A or I herein, when ring A is pyrimidinyl, the position of the pyrimidinyl N atom is specified as shown below.

Chemical formula

Chemical formula

[0199] Furthermore, according to Formula I-A or I herein, when ring A is pyrazinyl, the position of the pyrazinyl N atom is specified as shown below.

Chemical formula

[0200] Furthermore, according to Formula I-A or I herein, when ring A is triazinyl, the position of the triazinyl N atom is specified as shown below.

Chemical formula

Chemical formula

[0201] All other variables described in Formulas I-A and I are as defined above.

[0202] Certain embodiments of the compounds of Formula I-A or I, or pharmaceutically acceptable salts thereof, are shown in Table 1 below. The compounds of Formula I-A or I, or pharmaceutically acceptable salts thereof, and the compounds of Table 1, or pharmaceutically acceptable salts thereof, may be collectively or individually referred to herein 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

[0203] The disclosed compounds have one or more stereocenters, each of which may independently exist in either the R or S configuration. In one embodiment, the compounds described herein exist in optically active form or racemic form. It should be understood that the compounds described herein include racemates, optically active forms, positional isomers, and stereoisomers, or combinations thereof, having the therapeutically useful properties described herein.

[0204] The preparation of the optically active forms is achieved by any suitable method including, by way of non-limiting example, resolution of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In one embodiment, a mixture of two or more isomers is utilized as the disclosed compounds described herein. In another embodiment, pure isomers are utilized as the disclosed compounds described herein. In another embodiment, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means including stereoselective synthesis, enantioselective synthesis, or separation of mixtures of enantiomers or diastereomers. Resolution of the compounds and their isomers is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0205] In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0206] The compounds described herein also include isotopically labeled compounds in which one or more atoms have an atomic mass or mass number different from the atomic mass or mass number usually found in nature while having the same atomic number as the atom replaced. Examples of isotopes suitable for inclusion in the compounds described herein include 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I,13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S are included, but not limited to these. In one embodiment, the isotope-labeled compound is useful for drug or substrate tissue distribution studies. In another embodiment, substitution with a heavier isotope such as deuterium confers greater metabolic stability (e.g., increased in vivo half-life or decreased required dose). In another embodiment, the compounds described herein contain 2 H (i.e., deuterium) isotopes.

[0207] In yet another embodiment, 11 C, 18 F, 15 O and 13 substitution with positron-emitting isotopes such as N are useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. The isotope-labeled compounds are prepared by any suitable method or process using a suitable isotope-labeled reagent in place of the unlabeled reagent used in other methods.

[0208] The specific compounds described herein, and other compounds encompassed by one or more of the formulas described herein having different substituents, are described herein, e.g., 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 thThey are synthesized using techniques and materials 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 such disclosures). General methods for preparing compounds as described herein are varied by the use of appropriate reagents and conditions for introducing the various moieties found in the formulas as provided herein.

[0209] The compounds described herein are synthesized starting from compounds available from commercial sources or using any suitable procedure prepared using the procedures described herein.

[0210] Treatment methods The compounds of the present invention can be used in a method for treating a disease or condition of a subject, the method comprising administering to the subject a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. In one embodiment of the methods described herein, the subject is human. In one aspect, the compounds provided herein are useful for treating a disease or condition by acting as an agonist of the orexin 2 receptor.

[0211] The compounds of the present invention can be used to treat a disease or condition selected from the group consisting of narcolepsy, cataplexy or hypersomnia in a subject in need thereof.

[0212] In one embodiment, the compounds of the present invention can be used to treat narcolepsy in a subject. In one embodiment, the cataplexy of a subject can be treated using the compounds of the present invention. In one embodiment, the compounds of the present invention can be used to treat hypersomnia of a subject.

[0213] The orexin 2 receptor is important in a wide range of biological functions. This suggests that the orexin 2 receptor plays a role in diverse disease processes in humans or other species. The compounds of the present invention are useful for treating, preventing or improving one or more of the following symptoms or diseases of various neurological and psychiatric diseases associated with changes in sleep / awake function. This includes narcolepsy, narcolepsy with cataplexy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome characterized by hypersomnia (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Möbius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, multisystem atrophy, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen encephalitis, Wernicke encephalitis, limbic encephalitis, or Hashimoto's encephalopathy in subjects having the same), lethargy, loss of consciousness, obesity (e.g., malignant obesity, exogenous obesity, hyperinsulinemic obesity, cytoplasmic polysomia, endoplasmic reticulum lipomatosis, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, diet-induced obesity, hypogonadal obesity, general obesity, simple obesity, or central obesity), insulin resistance syndrome, Alzheimer's disease, disorders of consciousness such as lethargy, side effects and complications of anesthesia, sleep disorders, excessive daytime sleepiness, sleep disorders, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep disorder, jet lag, jet lag syndrome, shift worker sleep disorder, sleep disorder, night terrors, depression, major depressive disorder, sleepwalking disorder, enuresis, sleep disorder, Alzheimer's disease, sunburn, diseases related to the circadian rhythm, fibromyalgia, conditions resulting from decreased sleep quality, overeating, binge 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, cholestasis, cholelithiasis, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, polysyndactyly, craniopharyngioma, Prader-Willi syndrome, Froehlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities,Reduced fertility, infertility, male hypogonadism, sexual and reproductive dysfunction, such as hirsutism in women, fetal disorders associated with obesity in pregnant women, gastrointestinal motility disorders such as gastroesophageal reflux associated with pessimism, obesity hypoventilation syndrome (Pickwickian 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 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, schizophrenia, systemic lupus erythematosus, traumatic brain injury, facial flushing, night sweats, genital / urinary diseases, diseases related to sexual function or reproductive ability, thymus disorders, bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder (PTSD), separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant brain deficits, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorders related to muscle contracture, delirium, amnestic disorder, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, drug-induced parkinsonism syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tic symptoms, restless legs syndrome, dystonia, attention deficit hyperactivity disorder (ADHD), behavioral disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, weakness, and traumatic brain injury (TBI).

[0214] In particular, it is useful as a therapeutic or prophylactic agent for treating or preventing narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome characterized by hypersomnia (e.g., in Parkinson's disease, Guillain - Barré syndrome or Kleine - Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with osteopenia, sepsis, disorders of consciousness such as coma, anesthesia, etc. or side effects and complications caused by anesthetic antagonists, etc.

[0215] In one embodiment, the compound of the present invention has orexin 2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for narcolepsy.

[0216] In another aspect, the compound of the present invention is useful as a prophylactic or therapeutic agent for type 1 narcolepsy. In another aspect, the compound of the present invention is useful as a prophylactic or therapeutic agent for type 2 narcolepsy. In another aspect, the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy and excessive daytime sleepiness. In another aspect, the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy, cataplexy, and excessive daytime sleepiness. In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy and cataplexy. In another aspect, the compound of the present invention is useful as a prophylactic or therapeutic agent for excessive daytime sleepiness. In another aspect, the compound of the present invention is useful as a prophylactic or therapeutic agent for idiopathic hypersomnia. In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for obstructive sleep apnea.

[0217] In another aspect, the compound of the present invention has orexin 2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for hypersomnia in Parkinson's disease.

[0218] In another aspect, the compound of the present invention has orexin 2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for hypersomnia. In another aspect, the compound of the present invention has orexin 2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for excessive daytime sleepiness associated with Parkinson's disease.

[0219] In another aspect, the compounds of the present invention have orexin 2 receptor agonist activity and are useful as a prophylactic or therapeutic agent for cancer and / or daytime excessive somnolence or fatigue associated with chemotherapy.

[0220] In another embodiment, the present invention provides a method of treating narcolepsy in a subject in need of treatment for narcolepsy, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0221] In another embodiment, the present invention provides a method of treating type 1 narcolepsy in a subject in need of treatment for type 1 narcolepsy, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0222] In another embodiment, the present invention provides a method of treating type 2 narcolepsy in a subject in need of treatment for type 2 narcolepsy, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0223] In another embodiment, the present invention provides a method of treating narcolepsy and daytime excessive somnolence in a subject in need of treatment for narcolepsy and daytime excessive somnolence, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0224] In another embodiment, the present invention provides a method of treating narcolepsy, cataplexy and daytime excessive somnolence in a subject in need of treatment for narcolepsy, cataplexy and daytime excessive somnolence, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0225] In another embodiment, the present invention provides a method of treating narcolepsy and cataplexy in a subject in need of treatment for narcolepsy and cataplexy, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0226] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness in a subject in need of treatment for excessive daytime sleepiness, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

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

[0228] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and idiopathic hypersomnia in a subject in need of treatment for excessive daytime sleepiness and idiopathic hypersomnia, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0229] In another embodiment, the present invention provides a method for treating obstructive sleep apnea in a subject in need of treatment for obstructive sleep apnea, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

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

[0231] In any of the methods described herein, a compound of formula I is administered to the subject. In any of the methods described herein, a compound of formula I-A is administered to the subject.

[0232] Each of the embodiments described herein with respect to the use of a compound of formula I is also applicable to a compound of formula I-A.

[0233] In any of the compositions or methods described herein, the compound of formula I-A or I or a pharmaceutically acceptable salt thereof is present in and / or administered in a therapeutically effective amount.

[0234] Administration / Dosage / Formulation In another aspect, pharmaceutical compositions comprising at least one compound of the invention together with a pharmaceutically acceptable carrier are provided herein.

[0235] The actual dosage level of the active ingredient in the pharmaceutical compositions of the invention may vary so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0236] In particular, the dosage level selected will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0237] A physician, e.g., a physician or veterinarian, who is a person skilled in the art, can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can initiate administration of the pharmaceutical composition at a level lower than the level disclosed in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0238] In certain embodiments, it is particularly advantageous to formulate the compounds in dosage unit form for ease of administration and uniformity of dosage. As used herein, a dosage unit form refers to physically discrete units suitable as unit dosages for the patient to be treated, each unit calculated to contain a predetermined quantity of the disclosed compounds so as to produce the desired therapeutic effect in relation to the required pharmaceutical vehicle. The dosage unit forms of the invention are determined by and directly depend on (a) the particular characteristics of the disclosed compounds and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such disclosed compounds for the treatment of narcolepsy or cataplexy in a patient.

[0239] In one embodiment, the compounds of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition of the invention comprises a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0240] In some embodiments, the dosage of the disclosed compounds is from about 1 mg to about 1,000 mg. In some embodiments, the dosage of the disclosed compounds used in the compositions described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 20 mg, or less than about 10 mg. For example, the dosage is about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or about 600 mg.

[0241] Any route of administration of the compositions of the present invention includes oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. Compounds for use in the present invention can be formulated for administration by any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., intravaginal and perivaginal), (intra)nasal and (trans)rectal), intravesical, intralung, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intratracheal, inhalation, and topical administration. In one embodiment, a preferred route of administration is oral.

[0242] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelcaps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma, lozenges, creams, pastes, plasters, lotions, disks, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, and the like. It should be understood that the formulations and compositions that may be useful in the present invention are not limited to the specific formulations and compositions described herein.

[0243] For oral application, tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions can contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may or may not be coated, or they may be coated by known techniques for elegance or to delay the release of the active ingredient. Formulations for oral use can also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0244] For parenteral administration, the disclosed compounds can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration as a bolus dose or by continuous infusion. Suspensions, solutions or emulsions in oily or aqueous vehicles, optionally containing other formulating agents such as suspending, stabilizing or dispersing agents, may be used.

[0245] One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this invention and covered by the appended claims. For example, modifications to reaction times, reaction sizes / volumes, and experimental reagents such as solvents, catalysts, pressures, atmospheric conditions such as nitrogen atmosphere, and reducing / oxidizing agents, including but not limited to these, are within the scope of this application using recognized alternatives in the art and no more than routine experimentation.

[0246] Whenever values and ranges are provided herein, it is to be understood that all values and ranges subsumed by these values and ranges are meant to be included within the scope of this invention. Further, all values falling within these ranges, as well as the upper or lower limits of ranges of values, are also contemplated by this application.

[0247] The following examples further illustrate aspects of the invention. However, they are in no way intended to limit the teachings or disclosure of the invention described herein.

[0248] The present invention is further illustrated by the following examples, which should not be construed as further limitations. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, molecular biology, transgenic biology, microbiology, and immunology, which are within the skill of the art.

[0249] General Procedures Example 1: Synthetic Procedure The synthetic procedures for preparing the compounds of the present invention are readily available to those skilled in the art. Unless otherwise specified, starting materials were generally obtained from commercial sources. Synthetic procedures for related compounds can be found, for example, in U.S. Patent Application No. 17 / 556,295, filed December 20, 2021, and PCT Application No. PCT / US21 / 64484, filed December 21, 2021. Both of these are hereby expressly incorporated by reference in their entirety.

[0250] In the following synthetic examples, the following abbreviations can be used. DCM = dichloromethane MeOH = methanol THF = tetrahydrofuran PPh3 = triphenylphosphine DIAD = diisopropyl azodicarboxylate DME = 1,2-dimethoxyethane tBuXphos = 2-di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl EA = ethyl acetate HATU = 1-[bis(trimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate DIEA = N,N-diisopropylethylamine NMP = 1-methyl-2-pyrrolidinone EDCI = 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide HOBt = 1-hydroxybenzotriazole STAB = sodium triacetoxyborohydride BH3.THF = borane tetrahydrofuran ACN = acetonitrile PE = petroleum ether EtOAc = ethyl acetate DMF = dimethylformamide LiOH = lithium hydroxide min = minute h = hour NaH = Sodium hydride Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) DMSO = Dimethyl sulfoxide Boc = tert-Butyloxycarbonyl Ms = Methanesulfonyl Bn = Benzyl Et = Ethyl Cbz = Carboxybenzyl TEA = Triethylamine [Chemical formula] Intermediate [Chemical formula]

[0251] A solution of 4-bromopyridine-3-olate (1 g, 5.747 mmol, 1.00 equivalent), (cis-4-phenylcyclohexyl)methanol (1.42 g, 7.462 mmol, 1.3 equivalents), and PPh3 (3.01 g, 11.476 mmol, 2 equivalents) in THF (2 mL) was added with DIAD (2.28 mL, 11.501 mmol, 2 equivalents) at 0 °C. The resulting solution was stirred at 70 °C for 2 hours. The resulting solution was concentrated and then purified by silica gel chromatography (0 - 30% ethyl acetate / petroleum ether) to obtain the product 4-bromo-3-[(cis-4-phenylcyclohexyl)methoxy]pyridine as a solid (1 g, 50% yield). LCMS: m / z (ES+), [M+H] + = 346 [Chemical formula]

[0252] A solution of 4-bromo-3-[(cis-4-phenylcyclohexyl)methoxy]pyridine (1 g, 2.89 mmol, 1 equiv) in DME (20 mL) was added with methanesulfonamide (1.38 g, 14.508 mmol, 5 equiv), Cs2CO3 (1.41 g, 4.328 mmol, 1.5 equiv), Pd2(dba)3 (264.45 mg, 0.289 mmol, 0.1 equiv) and tBuXphos (245.3 mg, 0.578 mmol, 0.2 equiv) under N2 atmosphere. The resulting solution was stirred at 80 °C overnight. The obtained mixture was concentrated and purified by silica gel chromatography (0 - 20% MeOH / DCM) to obtain the product N-(3-[[cis-4-phenylcyclohexyl]methoxy]pyridin-4-yl)methanesulfonamide as a solid (977 mg, yield 94%). LCMS: m / z (ES+), [M+H] + = 361

Chemical formula

[0253] To a solution of N-(3-[[cis-4-phenylcyclohexyl]methoxy]pyridin-4-yl)methanesulfonamide (562 mg, 1.559 mmol, 1 equiv) in ACN (10 mL) was added benzyl bromide (0.19 mL, 1.597 mmol, 1.02 equiv) at room temperature. The resulting solution was stirred at 80 °C overnight. The mixture was concentrated and purified by reverse-phase chromatography to obtain 1-benzyl-4-methanesulfonamido-3-[(cis-4-phenylcyclohexyl)methoxy]pyridin-1-ium-1-yl)-lambda2-bromide (474 mg, yield 67.3%) as a solid. LCMS: m / z (ES+), [M] + = 451

Chemical formula

[0254] A solution of (1-benzyl-4-methanesulfonamido-3-[[cis-4-phenylcyclohexyl]methoxy]-1λ4-pyridin-1-ium-1-yl)-λ2-bromide (474 mg, 0.892 mmol, 1 equiv) in THF (40 mL) was added with LiAlH4 (270.8 mg, 7.134 mmol, 8 equiv) at 0 °C. The resulting solution was stirred at 70 °C for 1 h. The reaction was quenched with MeOH (2 mL) at 0 °C and then filtered. The filtrate was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford N-[1-benzyl-3-[(cis-4-phenylcyclohexyl)methoxy]-2H-pyridin-4-yl]methanesulfonamide (500 mg, crude) as an oil. LCMS: m / z (ES+), [M+1] + = 453

Chemical formula

[0255] (N-[1-benzyl-3-[(cis-4-phenylcyclohexyl)methoxy]-4H-pyridin-4-yl]methanesulfonamide (500 mg, 1.10 mmol, 1.00 equiv) and Pd(OH)2 / C (499.5 mg) in EA (20 mL) were stirred at room temperature for 20 h under a H2 atmosphere. The mixture was filtered, the filtrate was concentrated, and purified by reverse-phase chromatography to afford N-[cis-3-[(cis-4-phenylcyclohexyl)methoxy]piperidin-4-yl]-methanesulfonamide (200 mg, 49.4%) as an oil. LCMS: m / z (ES+), [M+1] + = 367 The compound of the present invention Compound 37

Chemical formula

[0256] Method 1: To a solution of N-[cis-3-[(cis-4-phenylcyclohexyl)methoxy]piperidin-4-yl]methanesulfonamide (112 mg, 0.306 mmol, 1 eq) in DMF (4 mL) were added cyclopropanecarboxylic acid (39.46 mg, 0.458 mmol, 1.5 eq), DIEA (78.99 mg, 0.611 mmol, 2 eq) and HATU (174.28 mg, 0.458 mmol, 1.5 eq) at room temperature. The resulting solution was stirred at room temperature for 2 h. After work-up, the crude material was purified by preparative HPLC to give N-[cis-1-cyclopropanecarbonyl-3-[(cis-4-phenylcyclohexyl)methoxy]piperidin-4-yl]methanesulfonamide (86 mg, 65% yield) as a solid as a mixture of isomers. This isomer mixture was purified by preparative chiral HPLC to give Compound 37 (36.5 mg, 42% yield) (absolute configuration not confirmed) as a solid. LCMS: m / z (ES+), [M+1] + = 435 1 H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.22 (m, 4H), 7.14 -7.12 (m, 1H), 4.79 - 4.20 (m, 2H), 3.84 3.80 (m, 1H), 3.66 - 3.64 (m, 3H), 3.47 - 3.35 (m, 1H), 3.02 (s, 3H), 2.92 - 2.90 (m, 1H), 2.70 - 2.51(m,1H), 2.16 - 1.75 (m, 6H), 1.74 - 1.53 (m, 6H), 0.87 - 0.75 (m, 4H). Compound 38

Chemical Structure

[0257] N-(cis-3-((cis-4-Phenylcyclohexyl)methoxy)piperidin-4-yl)methanesulfonamide (100.00 mg, 0.273 mmol, 1.00 eq), TEA (82.82 mg, 0.819 mmol, 3 eq) and 1-chloro-2-methyl-1-oxopropan-2-yl acetate (89.81 mg, 0.546 mmol, 2 eq) in DCM (2.00 mL) were added to an 8 mL vial at 0 °C. The resulting mixture was stirred at room temperature for 1 h under an argon atmosphere. The reaction was quenched with water. The resulting mixture was extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1-(4-methanesulfonamido-3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-1-yl)-2-methyl-1-oxopropan-2-yl acetate (130 mg, 96.3%) as a foam. LCMS: m / z (ES+), [M+H] + = 495

[0258] To a 50 mL round-bottom flask were added 2-methyl-1-(cis-4-(methylsulfonamido)-3-((cis-4-phenylcyclohexyl)methoxy)piperidin-1-yl)-1-oxopropan-2-yl acetate (130.00 mg, 0.263 mmol, 1.00 eq) and LiOH·H2O (55.14 mg, 1.314 mmol, 5.00 eq) in THF (3.00 mL) and H2O (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature overnight under an argon atmosphere. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (130 mg) was purified by preparative HPLC to give the crude product (70 mg, 59%) as a solid. This crude product (70 mg) was purified by CHIRAL-Prep-HPLC to give Compound 38 (17.1 mg, 24%) as a solid. LCMS: m / z (ES+), [M+H] + = 453 1 1H NMR (400 MHz, DMSO-d6) δ 7.27 (d, J = 4.5 Hz, 4H), 7.16 (h, J= 4.1 Hz, 1H), 6.87 (s, 1H), 5.34 (s, 1H), 4.58 (s, 2H), 3.64 (d, J = 103.3 Hz, 4H), 3.26 (s, 1H), 2.95 (s, 3H), 2.80 (d, J = 18.4 Hz, 1H), 2.52 (s, 1H), 1.97 (s, 1H), 1.84 - 1.64 (m, 4H), 1.56 (s, 4H), 1.48 (s, 2H), 1.29 (d, J = 9.6 Hz, 6H). Compound 39

Chem.

[0259] To an 8 mL vial, N-(cis-3-((cis-4-phenylcyclohexyl)methoxy)piperidin-4-yl)methanesulfonamide (90.0 mg, 0.246 mmol, 1.00 equiv), DIEA (95.21 mg, 0.737 mmol, 3 equiv) and 2-chloro-1,3-oxazole (50.83 mg, 0.491 mmol, 2.00 equiv) were added at room temperature in NMP (2.00 mL). The resulting mixture was stirred at 120 °C overnight under an argon atmosphere. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by preparative HPLC to give N-(cis-1-(oxazol-2-yl)-3-((cis-4-phenylcyclohexyl)methoxy)piperidin-4-yl)methanesulfonamide (60 mg, 56.3%) as a solid.

[0260] The above product (60 mg) was purified by CHIRAL-Prep-HPLC to give Compound 39 (10.6 mg, 18%) as a solid. LCMS: m / z (ES+), [M+H] + = 434 1 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 1.0 Hz, 1H), 7.28 (dd, J = 8.0, 6.9 Hz, 2H), 7.25 - 7.20 (m, 2H), 7.19 - 7.13 (m, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 1.0 Hz, 1H), 4.12 - 4.00 (m, 1H), 3.83 (dd, J = 13.3, 5.0 Hz, 1H), 3.68 - 3.50 (m, 3H), 3.45 (dd, J = 9.0, 7.0 Hz, 1H), 3.21 - 3.07 (m, 2H), 2.96 (s, 3H), 2.52(s, 1H), 1.91 - 1.77 (m, 2H), 1.71 (d, J = 11.0 Hz, 1H), 1.67 - 1.54 (m, 5H), 1.53 - 1.38 (m, 3H). Compounds 40 and 41

Chemical Structure

[0261] Method 2: To a solution of N-(cis-3-(((1s,4S)-4-phenylcyclohexyl)methoxy)piperidin-4-yl)methanesulfonamide (200 mg, 0.546 mmol, 1 equiv) and TEA (165.65 mg, 1.637 mmol, 3 equiv) in DCM (10 mL) was added methyl chloroformate (103.12 mg, 1.091 mmol, 2 equiv) at 0 °C. The resulting solution was stirred at room temperature for 2.5 h. The reaction was quenched with water (20 mL). The resulting mixture was extracted with dichloromethane (3 × 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC to give methyl-cis-4-(methylsulfonamido)-3-(((1s,4S)-4-phenylcyclohexyl)methoxy)piperidine-1-carboxylate (102 mg, 44% yield) as a solid. The above substance was purified by preparative chiral HPLC to give Compound 40 (36.0 mg (35% yield) as a solid and Compound 41 (35.6 mg, 34% yield) as a solid. Compound 40: LCMS: m / z (ES+), [M+NH4] + = 442 1 1H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.27 (m, 4H), 7.19 - 7.09 (m, 1H), 4.41 - 4.34 (m, 1H), 4.10 - 4.05 (m, 1H), 3.90 - 3.81 (m, 1H), 3.72 - 3.62 (m, 5H), 3.52 - 3.46 (m, 1H), 3.00 (s, 5H), 2.60 (s, 1H), 2.05 (s, 1H), 1.92 - 1.87 (m, 4H), 1.74 - 1.61 (m, 6H). Compound 41: LCMS: m / z (ES+), [M+NH4] + = 442 11H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.27 (m, 4H), 7.19 - 7.09 (m, 1H), 4.41 - 4.34 (m, 1H), 4.10 - 4.05 (m, 1H), 3.90 - 3.81 (m, 1H), 3.72 - 3.62 (m, 5H), 3.52 - 3.46 (m, 1H), 3.00 (s, 5H), 2.60 (s, 1H), 2.05 (s, 1H), 1.92 - 1.87 (m, 4H), 1.74 - 1.61 (m, 6H). Compound 42

Chem.

[0262] Method 3: A mixture of N-[(3R,4S)-3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (100.00 mg, 0.273 mmol, 1.00 equiv), EDCI (78.45 mg, 0.409 mmol, 1.5 equiv), HOBt (55.30 mg, 0.409 mmol, 1.5 equiv), DIEA (105.79 mg, 0.819 mmol, 3 equiv) and 1-methoxycyclobutane-1-carboxylic acid (53.26 mg, 0.409 mmol, 1.5 equiv) in DCM (1.00 mL) was stirred at room temperature for 3 h. The residue was purified by Prep-TLC (PE / EtOAc 2:1) to give the crude product (100 mg, 76.57%) as a solid. This crude product was purified by chiral HPLC to give Compound 42 (43 mg) as a solid. LCMS: m / z (ES+), [M+H] + =479.25 1H NMR (400 MHz, Methanol-d4) δ 7.26 (dd, J = 5.5, 3.9 Hz, 4H), 7.15 (tq, J = 5.0, 3.3, 2.9 Hz, 1H), 4.83 (dt, J = 14.1, 3.0 Hz, 1H), 4.19 (dp, J = 13.8, 2.8 Hz, 1H), 3.89 (t, J = 8.6 Hz, 1H), 3.79 - 3.58 (m, 2H), 3.44 (dd, J = 8.8, 6.8 Hz, 1H), 3.16 (s, 2H), 3.21 - 3.06 (m, 2H), 3.01 (d, J = 4.5 Hz, 3H), 2.84 (dd, J = 14.0, 1.4 Hz, 1H), 2.63 (tt, J = 12.1, 4.0 Hz, 1H), 2.61 - 2.46 (m, 1H), 2.33 - 2.16 (m, 1H), 2.19 - 2.07 (m, 1H), 2.04 (dt, J = 8.3, 4.4 Hz, 1H), 1.98 - 1.84 (m, 1H), 1.85 (s, 2H), 1.82 (ddt, J = 12.9, 7.8, 4.1 Hz, 1H), 1.80 - 1.66 (m, 2H), 1.70 - 1.55 (m, 2H), 1.61 (s, 2H), 1.37 - 1.28 (m, 1H). Compounds 43 and 44

Chem.

[0263] Compounds 43 and 44 were synthesized using Method 3.

[0264] Compound 43: (12.6 mg) Solid. LCMS72: m / z (ES+), [M+H] + =465.2 11H NMR (400 MHz, Methanol-d4) δ 7.32 - 7.22 (m, 5H), 7.19 - 7.10 (m, 2H), 4.70 (d, J = 14.0 Hz, 1H), 4.16 (d, J = 14.1 Hz, 1H), 3.90 (t, J = 8.7 Hz, 1H), 3.86 - 3.73 (m, 1H), 3.67 (s, 2H), 3.42 (dd, J= 8.7, 6.5 Hz, 1H), 3.21 (d, J = 14.4 Hz, 1H), 3.02 (s, 1H), 3.01 (s, 4H), 2.90 (d, J = 13.8 Hz, 1H), 2.74 (s, 2H), 2.59 (d, J = 11.2 Hz, 3H), 2.12 (dq, J = 39.6, 9.7 Hz, 4H), 1.98 - 1.81 (m, 2H), 1.84 - 1.77 (m, 1H), 1.70 (s, 9H), 1.68 (s, 1H), 1.62 (s, 2H), 1.54 (dt, J = 17.0, 8.7 Hz, 1H), 1.38 - 1.29 (m, 1H).

[0265] Compound 44: (11 mg) solid. LCMS: m / z (ES+), [M+H] + =465.2 1H NMR (400 MHz, Methanol-d4) δ 7.32 - 7.22 (m, 5H), 7.14 (s, 1H), 4.70 (d, J = 14.1 Hz, 1H), 4.16 (d, J = 14.0 Hz, 1H), 3.90 (t, J = 8.7 Hz, 1H), 3.76 (d, J = 7.6 Hz, 1H), 3.65 (d, J = 16.6 Hz, 3H), 3.42 (dd, J = 8.7, 6.4 Hz, 1H), 3.19 (s, 1H), 3.01 (s, 3H), 2.90 (d, J = 14.0 Hz, 1H), 2.74 (s, 2H), 2.59 (d, J = 10.2 Hz, 2H), 2.16 (dt, J = 19.5, 9.9 Hz, 1H), 2.07 (q, J = 9.8, 8.6 Hz, 2H), 1.98 - 1.77 (m, 3H), 1.69 (s, 8H), 1.68 (s, 1H), 1.64 - 1.49 (m, 1H), 1.32 (q, J = 7.7, 7.0 Hz, 1H), 0.12 (s, 1H). Compounds 45 and 46

Chemical Structure

[0266] Compounds 45 and 46 were synthesized using Method 3.

[0267] Compound 45: (90 mg, 71%) solid. 1 H NMR (400 MHz, Methanol-d 4) δ 7.27 (d, J = 5.6 Hz, 4H), 7.14 (s, 1H), 4.93 (d, J = 5.9 Hz, 2H), 4.81 (d, J = 14.5 Hz, 1H), 4.34 (dd, J = 5.9, 18.7 Hz, 2H), 3.91 (t, J = 8.8 Hz, 1H), 3.71 - 3.61 (m, 2H), 3.42 - 3.36 (m, 1H), 3.20 - 3.09 (m, 2H), 3.02 (d, J = 4.8 Hz, 3H), 2.82 (d, J = 14.2 Hz, 1H), 2.58 (s, 1H), 2.08 (s, 1H), 1.98 - 1.85 (m, 2H), 1.77 (d, J = 13.5 Hz, 3H), 1.72 - 1.60 (m, 8H). LCMS: m / z (ES+), [M+H] + = 465.2

[0268] Compound 46: (10 mg, 7%) solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.27 (d, J = 4.5 Hz, 4H), 7.16 (t, J = 4.1 Hz, 1H), 6.95 (dd, J = 7.2, 19.8 Hz, 1H), 4.76 (t, J = 5.5 Hz, 2H), 4.59 (d, J = 13.8 Hz, 1H), 4.24 (dd, J = 5.8, 9.7 Hz, 2H), 3.76 (t, J = 9.0 Hz, 1H), 3.55 (s, 2H), 3.28 (dd, J = 5.9, 8.6 Hz, 1H), 3.07 (t, J = 12.8 Hz, 1H), 2.95 (d, J = 6.0 Hz, 4H), 2.76 (d, J = 13.9 Hz, 1H), 1.99 (s, 1H), 1.79 (t, J = 11.4 Hz, 1H), 1.70 (t, J = 13.8 Hz, 3H), 1.64 - 1.54 (m, 5H), 1.50 (s, 5H). LCMS: m / z (ES+), [M+H] + = 465.2 Compounds 47 and 48

Chemical formula

[0269] Method 4: THF (2.00 ml) was added dropwise to a stirred mixture of NaH (39.72 mg, 0.99 mmol, 2.80 equiv, 60%) and ionone (218.84 mg, 0.993 mmol, 2.80 equiv) at 0 °C under a nitrogen atmosphere. After stirring for about 5 minutes, the ice bath was removed and the solution was warmed to room temperature over 10 minutes. A certain portion (volume = 1.2 mL, 0.60 mmol, 1.5 equiv) of this solution was transferred to a dry 7 mL vial. The resulting mixture was concentrated under reduced pressure. To the above mixture, Pd-PEPPSI-IPentCl o-picoline (29.80 mg, 0.035 mmol, 0.10 equiv), N-[(3R,4S)-3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (130.00 mg, 0.355 mmol, 1.00 equiv) and 3-bromo-1-methylpyrazole (57.11 mg, 0.355 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) were stirred at 120 °C overnight under a nitrogen atmosphere. After the starting materials were consumed, the residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to obtain the crude product (120 mg) as a solid. The crude product (120 mg) was purified by preparative chiral HPLC to obtain Compound 47 and Compound 48.

[0270] Compound 47: (13.8 mg, 18.65%) solid. LCMS: m / z (ES+), [M+H]+ = 447 1H NMR (400 MHz, Methanol-d4) δ 7.32 (d, J = 2.2 Hz, 1H), 7.26 (t, J = 7.4 Hz, 2H), 7.22 - 7.17 (m, 2H), 7.14 (t, J = 7.2 Hz, 1H), 5.72 (t, J = 1.9 Hz, 1H), 3.76 (q, J = 7.9, 7.2 Hz, 2H), 3.69 - 3.66 (m, 5H), 3.62 - 3.47 (m, 2H), 3.06 (m, 1H), 3.02- 2.90 (m, 5H), 2.61 - 2.52 (m, 1H), 2.08 (ddd, J =23.4, 9.8, 3.9 Hz, 2H), 1.83 (dp, J = 17.3, 5.9, 4.1 Hz, 3H), 1.75 - 1.55 (m, 6H), 1.32 (t, J = 7.3 Hz, 3H).

[0271] Compound 48: (12.3 mg, 16.62%) solid. LCMS: m / z (ES+), [M+H]+ = 447.10 1H NMR (400 MHz, Methanol-d4) δ 7.32 (d, J = 2.2 Hz, 1H), 7.26 (t, J = 7.4 Hz, 2H), 7.22 - 7.17 (m, 2H), 7.14 (t, J = 7.2 Hz, 1H), 5.72 (t, J = 1.9 Hz, 1H), 3.76 (q, J = 7.9, 7.2 Hz, 2H),3.69 - 3.66 (m, 5H), 3.62 - 3.47 (m, 2H), 3.06 (m, 1H), 3.02- 2.90 (m, 5H), 2.61 - 2.52 (m, 1H), 2.08 (ddd, J =23.4, 9.8, 3.9 Hz, 2H), 1.83 (dp, J = 17.3, 5.9, 4.1 Hz, 3H), 1.75 - 1.55 (m, 6H), 1.32 (t, J = 7.3 Hz, 3H). Compounds 49 and 50 [Chemical Structure]

[0272] Compound 49 and Compound 50 were synthesized using Method 3.

[0273] Compound 49: (93.1 mg, 33.2%) solid. LCMS: m / z (ES+), [M+H]+ = 467.0 1 H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.20 (m, 4H), 7.17 - 7.12 (m, 1H), 4.79 (d, 1H), 3.92 (d, 2H), 3.77 - 3.61 (m, 2H), 3.40 - 3.34 (m, 1H), 3.24 - 3.14 (m, 1H), 3.01 (d, 3H), 2.89 (d, 1H), 2.70 (d, 2H), 2.56 (s, 1H), 2.41 (dp, 2H), 1.92 (d, 3H), 1.81 - 1.71 (m, 3H), 1.67 (d, 3H), 1.63 - 1.49 (m, 3H).

[0274] Compound 50: (75.5 mg, 26.96%) solid. LCMS: m / z (ES+), [M+H]+ = 467.0 1 H NMR (400 MHz, Methanol-d4) δ 7.31 - 7.23 (m, 4H), 7.14 (d, 1H), 4.79 (d, 1H), 3.96 - 3.62 (m, 4H), 3.40 - 3.35 (m, 1H), 3.20 (d, 1H), 3.01 (d, 3H), 2.89 (d, 1H), 2.70 (s, 2H), 2.56 (s, 1H), 2.41 (dt, 2H), 2.09 (d, 1H), 1.97 - 1.84 (m, 3H), 1.76 (d, 3H), 1.68 (d, 3H), 1.61 - 1.51 (m, 2H). Compounds 51 and 52

Chemical Structure

[0275] To a stirred solution of N-[(3R,4S)-3-[[(1S,4S)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (200.00 mg, 0.546 mmol, 1.00 equiv) in MeOH (5 mL), ZnCl2 (0.74 mg, 0.005 mmol, 0.01 equiv) and NaBH3CN (51.44 mg, 0.819 mmol, 1.50 equiv) were added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 3 h under a nitrogen atmosphere. The residue was filtered through a silica gel column using DCM / MeOH (20:1). The crude product (54 mg) was purified by preparative HPLC, followed by chiral HPLC to give the product.

[0276] Compound 51: (1.5 mg, 0.65%) solid. LCMS: m / z (ES+), [M+H]+ = 423.20 1H-NMR (400 MHz, Methanol-d4) δ 7.26 (d, J = 6.0 Hz, 3H), 7.15 (td, J = 5.9, 2.9 Hz, 1H), 4.75 - 4.55 (m, 5H), 3.77 - 3.69 (m, 1H), 3.69 - 3.48 (m, 3H), 3.00 (s, 3H), 2.76 (s, 1H), 2.61 (s,2H), 2.21 (s, 2H), 2.08 (s, 1H), 2.04 - 1.94 (m, 1H), 1.90 (d, J = 11.4 Hz, 2H), 1.82 - 1.64 (m, 6H).

[0277] Compound 52: (0.6 mg, 0.26%). LCMS: m / z (ES+), [M+H]+ = 423.20 1H-NMR (E05570-026): (400 MHz, Methanol-d4) δ 7.26 (d, J = 6.0 Hz, 3H), 7.15 (td, J = 5.9, 2.9 Hz, 1H), 4.75 - 4.55 (m, 5H), 3.77 - 3.69 (m, 1H), 3.69 - 3.48 (m, 3H), 3.00 (s, 3H), 2.76 (s, 1H), 2.61 (s, 2H), 2.21 (s, 2H), 2.08 (s, 1H), 2.04 - 1.94 (m, 1H), 1.90 (d, J = 11.4 Hz, 2H), 1.82 - 1.64 (m, 6H). Compounds 53 and 54

Chem.

[0278] Compounds 53 and 54 were synthesized using Method 4.

[0279] Compound 53: (6.3 mg) was obtained as a solid. LCMS: m / z (ES+), [M+H]+ = 447.1 1H NMR (400 MHz, Methanol-d4) δ 7.28 - 7.22 (m, 2H), 7.22 - 7.11 (m, 3H), 6.82 (d, J = 1.5 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 4.60 (s, 1H), 3.73 (t, J = 8.7 Hz, 2H), 3.70 - 3.64 (m, 1H), 3.60 (dd, J = 9.1, 6.8 Hz, 1H), 3.53 (s, 3H), 3.46 (dd, J = 12.6, 5.0 Hz, 1H), 3.24 (d, J = 12.3 Hz, 1H), 3.03 (s, 3H), 2.96 (dd, J = 20.7, 10.7 Hz, 2H), 2.58 (s, 1H), 2.13 (ddd, J = 23.3, 11.4, 7.7 Hz, 2H), 1.94 - 1.79 (m, 3H), 1.65 (dt, J = 25.9, 8.0 Hz, 6H), 1.31 (s, 2H).

[0280] Compound 54: (8.8 mg, 98%) solid. LCMS: m / z (ES+), [M+H]+ = 447.3 11H NMR (400 MHz, Methanol-d4) δ 7.28 - 7.22 (m, 2H), 7.22 - 7.11 (m, 3H), 6.82 (d, J = 1.5 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 4.60 (s, 1H), 3.73 (t, J = 8.7 Hz, 2H), 3.70 - 3.64 (m, 1H), 3.60 (dd, J = 9.1, 6.8 Hz, 1H), 3.53 (s, 3H), 3.46 (dd, J = 12.6, 5.0 Hz, 1H), 3.24 (d, J = 12.3 Hz, 1H), 3.03 (s, 3H), 2.96 (dd, J = 20.7, 10.7 Hz, 2H), 2.58 (s, 1H), 2.13 (ddd, J= 23.3, 11.4, 7.7 Hz, 2H), 1.94 - 1.79 (m, 3H), 1.65 (dt, J = 25.9, 8.0 Hz, 6H), 1.31 (s, 2H). Compounds 55 and 56

Chem.

[0281] To a stirred solution of N-(3-(((1s,4s)-4-phenylcyclohexyl)methoxy)piperidin-4-yl)methanesulfonamide (150.00 mg, 0.409 mmol, 1.00 equiv) in DMF (10.00 mL) was added 3-chloropyridazine (70.31 mg, 0.614 mmol, 1.50 equiv) and CsF (124.33 mg, 0.819 mmol, 2.00 equiv). The mixture was stirred at 120 °C for 48 h. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) to give the product (50 mg, 27.48%) as a mixture of isomers. This mixture was purified by chiral HPLC to give the following:

[0282] Compound 55: (6.3 mg, 90.00%) solid. LCMS: m / z (ES+), [M+H]+ = 445.1 1 1H NMR (E05616 - 059): (400 MHz, Methanol - d4) δ 8.38 (dd, J = 4.2, 1.5 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.29 - 7.23 (m, 2H), 7.22 - 7.11 (m, 3H), 4.68 (d, J = 14.4 Hz, 1H), 4.34 (d, J = 13.8 Hz, 1H), 3.76 - 3.68 (m, 3H), 3.54 - 3.46 (m, 1H), 3.26 - 3.14 (m, 2H), 3.03 (s, 3H), 2.51 (s, 1H), 2.01 (dd, J = 13.1, 9.1 Hz, 1H), 1.89 (s, 1H), 1.85 - 1.78 (m, 1H), 1.74 (d, J = 11.7 Hz, 1H), 1.69 - 1.56 (m, 4H), 1.49 (d, J = 6.1 Hz, 3H), 1.31 (s, 1H).

[0283] Compound 56: (3 mg) solid. LCMS: m / z (ES+), [M+H]+ = 445.1 1H NMR (E05616 - 059): (400 MHz, Methanol - d4) δ 8.38 (dd, J = 4.2, 1.5 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.29 - 7.23 (m, 2H), 7.22 - 7.11 (m, 3H), 4.68 (d, J = 14.4 Hz, 1H), 4.34 (d, J = 13.8 Hz, 1H), 3.76 - 3.68 (m, 3H), 3.54 - 3.46 (m, 1H), 3.26 - 3.14 (m, 2H), 3.03 (s, 3H), 2.51 (s, 1H), 2.01 (dd, J = 13.1, 9.1 Hz, 1H), 1.89 (s, 1H), 1.85 - 1.78 (m, 1H), 1.74 (d, J = 11.7 Hz, 1H), 1.69 - 1.56 (m, 4H), 1.49 (d, J = 6.1 Hz, 3H), 1.31 (s, 1H). Compounds 57 and 58 [Chemical formula]

[0284] To a stirred solution of N-(3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl)methanesulfonamide (100.0 mg, 0.273 mmol, 1.00 equiv) and oxetan-3-carbaldehyde (35.2 mg, 0.409 mmol, 1.50 equiv) in MeOH (6.00 mL) was added STAB (86.7 mg, 0.409 mmol, 1.50 equiv) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) to afford the product (60 mg, 50.37%) as a solid as a mixture of isomers. This mixture was purified by chiral HPLC to afford the following:

[0285] Compound 57: (25 mg, 42%) oil. LCMS: m / z (ES+), [M+H]+ = 437.25 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.34 - 7.20 (m, 4H), 7.19 - 7.08 (m, 1H), 4.82 - 4.77 (m, 2H), 4.43 (t, J = 6.2 Hz, 2H), 3.75 - 3.50 (m, 4H), 3.30 - 3.24 (m, 1H), 2.99 (s, 3H), 2.75 (d, J = 4.1Hz, 3H), 2.69 - 2.56 (m, 2H), 2.29 (d, J = 9.5 Hz, 2H), 2.11 - 1.92 (m, 2H), 1.90 - 1.80 (m, 2H), 1.70 (m, 7H).

[0286] Compound 58: (20 mg, 33%) oil. LCMS: m / z (ES+), [M+H]+ = 437.20 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.32 - 7.21 (m, 4H), 7.15 (t, J = 2.2 Hz, 1H), 4.81 (d, J = 5.8 Hz, 2H), 4.43 (t, J = 6.2 Hz, 2H), 3.75 - 3.49 (m, 4H), 3.30 - 3.23 (m, 1H), 2.99 (s, 3H), 2.85 - 2.72 (m, 3H), 2.62 (d, J = 9.5 Hz, 2H), 2.29 (d, J = 10.0 Hz, 2H), 2.12 - 2.01 (m, 1H), 2.01 - 1.91 (m, 1H), 1.91 - 1.80 (m, 2H), 1.78 - 1.64 (m, 7H). Compounds 59 and 60

Chemical Structure

[0287] Compounds 59 and 60 were synthesized using Method 4.

[0288] Compound 59: (10 mg, 23%) solid. LCMS: m / z (ES+), [M+H]+ = 447 1H NMR (400 MHz, Methanol-d4) δ 7.35 - 7.18 (m, 5H), 7.18 - 7.11 (m, 1H), 6.39 (d, 1H), 3.87 - 3.79 (m, 1H), 3.71 (dt, 1H), 3.67 - 3.56 (m, 6H), 3.39 - 3.35 (m, 1H), 3.02 (s, 3H), 2.93 - 2.87 (m, 1H), 2.82 (dd, 1H), 2.61 - 2.52 (m, 1H), 2.10 (dt, 2H), 1.91 - 1.79 (m, 3H), 1.69 (dd, 6H).

[0289] Compound 60: (10 mg, 23%) solid. LCMS: m / z (ES+), [M+H]+ = 447 1 1H NMR (400 MHz, Methanol-d4) δ 7.36 - 7.18 (m, 5H), 7.18 - 7.09 (m, 1H), 6.39 (d, 1H), 3.79 (dd, 1H), 3.71 (dd, 1H), 3.68 - 3.57 (m, 5H), 3.37 (s, 1H), 3.02 (s, 3H), 2.92 - 2.77 (m, 2H), 2.58 (dd, 1H), 2.10 (dt, 2H), 1.94 - 1.81 (m, 3H), 1.69 (dd, 6H). Compounds 61, 62, 63 and 64

Chemical Structure

[0290] N-[(3S,4R)-3-[[(1S,4S)-4-Phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (100.0 mg, 0.273 mmol, 1.00 equiv) and 1-(oxetan-3-yl)ethanone (81.95 mg, 0.819 mmol, 3.00 equiv) were added to a stirred solution in MeOH (3 mL) of ZnCl2 (37.19 mg, 0.273 mmol, 1.00 equiv) and NaBH3CN (51.44 mg, 0.819 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for an additional overnight. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) to give the product as a solid as a mixture of isomers (100 mg, 81%).

[0291] The crude product (96 mg) was purified by preparative chiral HPLC to give the following.

[0292] Compound 61: (30 mg, 31.25%) solid. LCMS: m / z (ES+), [M+H]+ = 451 1 1H NMR (400 MHz, Methanol-d4) δ 7.27 (s, 4H), 7.15 (t, 1H), 4.73 (dt, 2H), 4.61 (t, 1H), 4.44 (t, 1H), 3.67 - 3.51 (m, 4H), 3.25 - 3.10 (m, 1H), 3.09 - 2.98 (m, 1H), 2.98 (s, 3H), 2.82 (dd, 1H), 2.61 (s, 2H), 2.46 (dd, 1H), 2.35 (d, 1H), 1.94 (dt, 1H), 1.85 (t, 2H), 1.79 - 1.62 (m, 7H), 0.95 (d, 3H).

[0293] Compound 62: (20 mg, 21%) solid. LCMS: m / z (ES+), [M+H]+ = 451 11H NMR (400 MHz, Methanol-d4) δ 7.35 - 7.21 (m, 4H), 7.15 (t, 1H), 4.72 (dd, 2H), 4.61 (t, 1H), 4.44 (t, 1H), 3.69 (dd, 1H), 3.62 - 3.47 (m, 3H), 3.20 (dd, 1H), 3.11 - 2.93 (m, 4H), 2.81 (s, 1H), 2.65 (dt, 2H), 2.55 - 2.47 (m, 1H), 2.30 (dd, 1H), 2.05 (d, 1H), 1.88 (dt, 3H), 1.79 - 1.64 (m, 7H), 1.40.

[0294] Compound 63: (12 mg, 30%) solid. LCMS: m / z (ES+), [M+H]+ = 451.2 1H NMR(E05616 - 153): (400 MHz, Methanol-d4) δ7.32 - 7.22 (m, 4H), 7.18 - 7.12 (m, 1H), 4.73 (ddd, J = 8.1, 6.0, 4.0 Hz, 2H), 4.61 (t, J = 6.4 Hz, 1H), 4.47 (t, J = 6.4 Hz, 1H), 3.71 (t, J = 8.4 Hz, 1H), 3.60 (dd, J = 16.4, 7.4 Hz, 3H), 3.24 (s, 1H), 3.17 - 3.03 (m, 1H), 2.99 (s, 3H), 2.96 - 2.69 (m, 2H), 2.61 (dt, J = 11.3, 5.9 Hz, 2H), 2.40 (s, 1H), 2.06 (s, 1H), 1.87 (d, J = 10.2 Hz, 3H), 1.82 - 1.60 (m, 7H), 1.31 (d, J = 3.5 Hz, 1H), 0.97 (d, J = 41.5 Hz, 3H).

[0295] Compound 64: (13 mg, 32.5%) solid. LCMS: m / z (ES+), [M+H]+ = 451.2 1H NMR (E05616-154): (400 MHz, Methanol-d4) δ 7.30 - 7.22 (m, 4H), 7.15 (ddd, J = 8.6, 6.0, 2.2 Hz, 1H), 4.78 - 4.69 (m, 2H), 4.61 (t, J = 6.4 Hz, 1H), 4.45 (t, J = 6.3 Hz, 1H), 3.72 - 3.48 (m, 4H), 3.20 (d, J = 8.0 Hz, 1H), 3.06 (q, J = 7.3 Hz, 1H), 2.99 (s, 3H), 2.84 (d, J = 22.3 Hz, 1H), 2.62 (d, J = 8.6 Hz, 2H), 2.47 (d, J = 39.2 Hz, 2H), 2.08 - 1.91 (m, 2H), 1.84 (td, J = 11.5, 9.5, 5.2 Hz, 2H), 1.71 (p, J = 7.9 Hz, 7H), 1.39 - 1.27 (m, 1H), 1.05 - 0.88 (m, 3H). Compounds 65 and 66 [Chemical Structure]

[0296] Compounds 65 and 66 were synthesized using Method 3.

[0297] Compound 65: (27.7 mg, 25.18%) solid. LCMS: m / z (ES+), [M + H]+ = 449.6 11H NMR (400 MHz, Methanol-d4) δ 7.33 - 7.23 (m, 4H), 7.18 - 7.13 (m, 1H), 4.61 (s, 1H), 3.91 (dt, 1H), 3.77 (dt, 1H), 3.70 - 3.59 (m, 2H), 3.50 - 3.35 (m, 2H), 3.19 - 3.10 (m, 1H), 3.01 (d, 3H), 2.81 (d, 1H), 2.58 (s, 1H), 2.38 - 2.31 (m, 1H), 2.26 - 2.04 (m, 3H), 1.97 - 1.60 (m, 11H).

[0298] Compound 66: (32.3 mg, 29%) solid. LCMS: m / z (ES+), [M+H]+ = 449.6 1 1H NMR (400 MHz, Methanol-d4) δ 7.32 - 7.25 (m, 4H), 7.17 - 7.12 (m, 1H), 4.77 (d, 1H), 4.60 (s, 1H), 3.91 (dt, 1H), 3.77 (dt, 1H), 3.70 - 3.59 (m, 2H), 3.47 - 3.35 (m, 2H), 3.18 - 3.10 (m, 1H), 3.01 (d, 3H), 2.81 (d, 1H), 2.58 (s, 1H), 2.41 - 2.14 (m, 3H), 2.08 - 1.62 (m, 13H), 1.31 (s, 1H). Compounds 67 and 68

Chemical Structure

[0299] Compounds 67 and 68 were synthesized using Method 3.

[0300] Compound 67: (22.9 mg, 22.9%) solid. LCMS: m / z (ES+), [M+H]+ = 453.5 11H NMR (400 MHz, Methanol-d4) δ 7.26 (d, 4H), 7.15 (h, 1H), 4.73 (d, 1H), 4.45 (d, 1H), 3.87 (s, 1H), 3.74 - 3.64 (m, 2H), 3.47 (s, 1H), 3.02 (s, 3H), 2.57 (s, 1H), 2.06 (s, 2H), 1.79 (s, 4H), 1.70 - 1.50 (m, 5H), 1.39 - 1.12 (m, 5H).

[0301] Compound 68: (22.9 mg, 22.9%) solid. LCMS (E05569 - 095): m / z (ES+), [M+H]+ = 453.59; NH4HCO3, HPLC tR = 1.689 min. 1 1H NMR (400 MHz, Methanol-d4) δ 7.26 (d, 4H), 7.14 (dt, 1H), 4.73 (d, 1H), 4.32 (s, 1H), 3.87 (s, 1H), 3.69 (d, 2H), 3.02 (s, 4H), 2.97 - 2.51 (m, 2H), 2.06 (s, 4H), 1.73 - 1.51 (m, 7H), 1.25 (d, 5H). Compounds 69 and 70

Chemical formula

[0302] A stirred solution of N-[(3R,4S)-1-(1-fluorocyclobutanecarbonyl)-3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (95.00 mg, 0.204 mmol, 1.00 equiv) and BH3·THF (4.00 mL, 41.796 mmol, 205.29 equiv) was stirred at room temperature for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The above

[0303] MeOH (5.00 mL) was added portionwise to the mixture at room temperature. The resulting mixture was stirred at 50 °C for an additional overnight. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc 1:1) to give N-[(3R,4S)-1-[(1-fluorocyclobutyl)methyl]-3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (91 mg, 98.75%) as a solid. The crude product (91 mg) was purified by preparative CHIRAL-HPLC to give the following.

[0304] Compound 69: (35 mg, 39%) oil. LCMS: m / z (ES+), [M+H]+ = 452.6 1 H NMR (400 MHz, Methanol-d4) δ 7.26 (d, 4H), 7.16 (d, 1H), 3.73 (d, 1H), 3.62 - 3.47 (m, 3H), 2.99 (d, 4H), 2.77 (d, 1H), 2.71 (d, 1H), 2.67 - 2.55 (m, 2H), 2.42 (d, 2H), 2.30 - 2.12 (m, 4H), 2.11 - 1.94 (m, 2H), 1.85 (td, 3H), 1.69 (td, 7H), 1.58 - 1.43 (m, 1H), 1.31 (s, 1H).

[0305] Compound 70: (30 mg, 33%) oil. LCMS: m / z (ES+), [M+H]+ = 452.6 11H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.21 (m, 4H), 7.15 (dt, 1H), 3.73 (dt, 1H), 3.65 - 3.48 (m, 3H), 2.99 (d, 4H), 2.77 (d, 1H), 2.74 - 2.68 (m, 1H), 2.67 - 2.56 (m, 2H), 2.42 (t, 2H), 2.22 (dt, 4H), 2.05 (d, 1H), 2.02 - 1.93 (m, 1H), 1.93 - 1.76 (m, 3H), 1.76 - 1.60 (m, 7H), 1.52 (d, 1H).

[0306] Example 2: Human OX2R IP1 Assay T-Rex CHO cells that stably overexpress human orexin 2 receptor (OX2R) are induced overnight using 1 μg / mL doxycycline in a T225 flask. 24 hours after induction, the cells are lifted with Accutase and plated at 30,000 cells / well in a 384-well ProxiPlate. The cells are then treated with different test compounds for 1 hour at 37 °C in 1× 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 is stopped by adding a detection mixture consisting of lysis buffer and IP1-d2 and anti-IP1 cryptate diluted in 1× stimulation buffer. The plate is incubated at room temperature for 1 hour and then read on an EnVision® multimode plate reader to measure inositol phosphate levels.

[0307] Cisbio IP1 is a cell-based functional 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 coupled to a d2 fluorophore (acceptor) for binding to an anti-IP1 monoclonal antibody labeled with Eu cryptate (donor). The measured HTRF-FRET-based signal is inversely proportional to the concentration of IP1 produced.

[0308] The EC reported in Table 2 50 values were obtained according to the above-described human OX2R IP1 assay. The data are mean EC 50 values ± S.E.M.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

[0309] Although the present invention has been specifically shown and described with reference to its preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. Compound of formula (I-A): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof During the ceremony, Ring A is selected from the group consisting of phenyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, and triazinyl, and furthermore, the ring is either unsubstituted or each is independently C １ ~C ３ Alkyl, C ３ ~C ５ It is substituted with 1 to 3 substituents selected from cycloalkyl or halogens. X is N or CH, Y is S (=O) ２ , C (=O), or S (=O) (=NR ｅ ) and R ｅ is selected from the group consisting of H, C １ -C ３ alkyl or C ３ -C ５ cycloalkyl, E is NR ａ R ｂ , C １ ~C ３ Alkylene-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 membered heterocyclyl), C ６ ~C １０ Ariel, C １ ~C ３ Alkylene-(C) ６ ~C １０ aryl), 5-7 member heteroaryl and C １ ~C ３ Selected from the group consisting of alkylene-(5-7 member heteroaryl), where C １ ~C ３ Alkylene-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 membered heterocyclyl), C ６ ~C １０ Ariel, C １ ~C ３ Alkylene-(C) ６ ~C １０ aryl), 5-7 member heteroaryl or C １ ~C ３ Alkylene-(5-7 member heteroaryl) is unsubstituted or contains one or more halogens, hydroxyl, NR ｃ R ｄ CF ３ CHF ２ ,CH ２ F, C １ ~C ３ Alkyl or C １ ~C ３ Substituted with alkoxyl, R ａ and R ｂ These are H and C, respectively, independently. １ ~C ３ Alkyl, C ３ ~C ５ Selected from the group consisting of cycloalkyl and 4- to 7-membered heterocyclyl, where the C １ ~C ３ Alkyl, C ３ ~C ５ Cycloalkyl or 4- to 7-membered heterocyclyl may be unsubstituted or may contain one or more halogens, hydroxyl, or C １ ~C ３ Alkyl, or C １ ~C ３ Substituted with alkoxyl, Alternatively, R ａ and R ｂ together with the N atom to which they are attached form a 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl, wherein said 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyl, NR ｃ R ｄ , C １ -C ３ alkyl, C １ -C ３ alkoxyl or C １ -C ３ alkyl substituted with 1 to 3 halogens, R １ is C(=O)-C １ ~C ４ Alkyl, C(=O)-C １ ~C ４ Alkoxyl, C(=O)-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ Cycloalkyl, C(=O)-(CR ｃ R ｄ ) ｎ - (4-7 member heterocyclyl), C(=O)-(CR ｃ R ｄ ) ｎ - (C ６ ~C １０ Ayl), C(=O)-(CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), C(=O)-O-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ Cycloalkyl, C(=O)-O-(CR ｃ R ｄ ) ｎ - (4-7 member heterocyclyl), (CR ｃ R ｄ ) ｎ - (C ６ ~C １０ (Aryl) and (CR ｃ R ｄ ) ｎ - Selected from the group consisting of (5-10 member heteroaryls), in the formula, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxyl, C ３ ~C ８ Cycloalkyl, 4-7 membered heterocyclyl, C ６ ~C １０ The aryl or 5-10 membered heteroaryl is unsubstituted or contains one or more halogens, hydroxyl, and unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ It is substituted with alkyl, R ｃ and R ｄ These are H and unsubstituted C, respectively, independently. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ It is alkyl, n is 0, 1, or 2. R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ Each of these is independently H, halogen, and unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ It is alkyl, Alternatively, R ３ and R ６ They come together as non-substituted C １ ~C ３ C substituted with alkylene or one or more halogens １ ~C ３ Forming alkylenes, Alternatively, R ４ and R ５ They come together as non-substituted C １ ~C ３ C substituted with alkylene or one or more halogens １ ~C ３ Forming alkylenes, m is either 0 or 1. p is 0, 1, 2, 3, or 4. Each R ９ These are independently selected from the group consisting of deuterium, halogens, hydroxyl, and cyano. A compound of formula (I-A) or a pharmaceutically acceptable salt thereof.

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

3. Ring A is a phenyl ring, and the ring is unsubstituted, or each is independently C １ ~C ３ Alkyl, C ３ ~C ５ The compound according to claim 1 or 2, which is substituted with one to three substituents selected from cycloalkyl or halogen.

4. The compound according to claim 1 or 2, wherein ring A is a phenyl ring, and each ring is independently substituted with one or two substituents selected from halogens.

5. The compound according to claim 1 or 2, wherein ring A is phenyl or 3-fluorophenyl.

6. Ring A is a pyridinyl ring, and the ring is unsubstituted, or C １ ~C ３ Alkyl, C ３ ~C ５ The compound according to claim 1 or 2, which is substituted with one to three substituents independently selected from cycloalkyl or halogen.

7. Ring A is a pyridazinyl ring, and the ring is unsubstituted, or each is independently C １ ~C ３ Alkyl, C ３ ~C ５ The compound according to claim 1 or 2, which is substituted with one to three substituents selected from cycloalkyl or halogen.

8. Ring A is a pyrimidinyl ring, and the ring is unsubstituted, or each is independently C １ ~C ３ Alkyl, C ３ ~C ５ The compound according to claim 1 or 2, which is substituted with one to three substituents selected from cycloalkyl or halogen.

9. Ring A is a pyrazinyl ring, and the ring is unsubstituted, or each is independently C １ ~C ３ Alkyl, C ３ ~C ５ The compound according to claim 1 or 2, which is substituted with one to three substituents selected from cycloalkyl or halogen.

10. Ring A is a triazinyl ring, and the ring is unsubstituted, or each is independently C １ ~C ３ Alkyl, C ３ ~C ５ The compound according to claim 1 or 2, which is substituted with one to three substituents selected from cycloalkyl or halogen.

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

12. E is NR ａ R ｂ The compound according to claim 1 or 2.

13. E is C １ ~C ３ Alkylene-NR ａ R ｂ The compound according to claim 1 or 2.

14. E is an unsubstituted C １ ~C ３ Alkyl, unsubstituted C ２ ~C ４ Alkenyl or unsubstituted C ２ ~C ４ The compound according to claim 1 or 2, wherein E is an alkynyl, or a C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

15. E is unsubstituted C １ ~C ３ The compound according to claim 1 or 2, wherein E is alkyl, or a C1-C3 alkyl substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl, or C1-C3 alkoxyl.

16. E is unsubstituted C ３ ~C ８ The compound according to claim 1 or 2, wherein E is a cycloalkyl or a C3-C8 cycloalkyl substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl or C1-C3 alkoxyl.

17. E is unsubstituted C １ ~C ３ Alkylene-(C) ３ ~C ８ The compound according to claim 1 or 2, wherein E is a cycloalkyl or a C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl or C1-C3 alkoxyl.

18. The compound according to claim 1 or 2, wherein E is an unsubstituted 4- to 10-membered heterocycline, or E is a 4- to 10-membered heterocycline substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C 1-C 3 alkyl, or C 1-C 3 alkoxyl.

19. E is unsubstituted C １ ~C ３ The compound according to claim 1 or 2, wherein E is an alkylene-(4-10 membered heterocycline) or a C1-C3 alkylene-(4-10 membered heterocycline) substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl, or C1-C3 alkoxyl.

20. E is unsubstituted C ６ ~C １０ The compound according to claim 1 or 2, wherein E is an aryl or a C6-C10-aryl substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl, or C1-C3 alkoxyl.

21. E is unsubstituted C １ ~C ３ Alkylene-(C) ６ ~C １０ The compound according to claim 1 or 2, wherein E is an aryl or a C1-C3 alkylene-(C6-C10-aryl) substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl or C1-C3 alkoxyl.

22. The compound according to claim 1 or 2, wherein E is an unsubstituted 5- to 7-membered heteroaryl, or E is a 5- to 7-membered heteroaryl substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C 1-C 3 alkyl, or C 1-C 3 alkoxyl.

23. E is unsubstituted C １ ~C ３ The compound according to claim 1 or 2, wherein E is an alkylene-(5-7 member heteroaryl) or a C1-C3 alkylene-(5-7 member heteroaryl) substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl, or C1-C3 alkoxyl.

24. The compound according to claim 1 or 2, wherein E is methyl, or E is methyl substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl, or C1-C3 alkoxyl.

25. The compound according to claim 1 or 2, wherein E is CF3, CHF2, or CH2F.

26. E is NH (CH ３ The compound according to claim 1 or 2, wherein it is either N(CH3)2 or N(CH3)2.

27. Y is S (=O) ２ The compound according to claim 1 or 2.

28. The compound according to claim 1 or 2, wherein Y is C (=O).

29. The compound according to claim 1 or 2, wherein X is CH.

30. R １ However, C(=O)-C １ ~C ４ Alkyl, C(=O)-C １ ~C ４ Alkoxyl, C(=O)-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ Cycloalkyl, C(=O)-(CR ｃ R ｄ ) ｎ - (4-7 member heterocyclyl), C(=O)-(CR ｃ R ｄ ) ｎ - (C ６ ~C １０ aryl), and C(=O)-(CR ｃ R ｄ ) ｎ - Selected from the group consisting of (5-10 member heteroaryls), C １ ~C ４ Alkyl, C １ ~C ４ Alkoxyl, C ３ ~C ８ Cycloalkyl, 4-7 membered heterocyclyl, C ６ ~C １０ The aryl or 5-10 membered heteroaryl is unsubstituted, or one or more halogens, hydroxyls, and unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

31. R １ C(=O)-C １ ~C ４ Alkyl, and the C １ ~C ４ The alkyl group is unsubstituted, or it contains one or more halogens, hydroxyls, and unsubstituted C atoms. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

32. R １ C(=O)-C １ ~C ４ It is an alkoxyl, and the C １ ~C ４ The alkoxyl is unsubstituted, or one or more halogens, hydroxyls, and unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

33. R １ is C(=O)-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ It is a cycloalkyl, and the C ３ ~C ８ The cycloalkyl group is unsubstituted, or it contains one or more halogens, hydroxyls, and unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

34. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (4-7 member heterocycline), where the 4-7 member heterocycline is unsubstituted, or contains one or more halogens, hydroxyl, and unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

35. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (C ６ ~C １０ It is aryl, and the C ６ ~C １０ The aryl is unsubstituted, or one or more halogens, hydroxyls, and unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

36. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), and the 5-10 member heteroaryl is unsubstituted, or one or more halogens, hydroxyl, and unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

37. R １ is C(=O)-O-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ It is a cycloalkyl, and the C ３ ~C ８ The cycloalkyl group is unsubstituted, or it contains one or more halogens, hydroxyls, and unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ Substituted with alkyl, or R1 is C(=O)-O-(CR c R d) n-(4-7 member heterocyclil), and the 4-7 member heterocyclil is either unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium. or R1 is a C(=O)-O-(CR c R d)n-C3-C5 cycloalkyl group, and the C3-C5 cycloalkyl group is either unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium. or R1 is C(=O)-O-(CR c R d) n-(5-6 member heterocyclyl), and the 5-6 member heterocyclyl is either unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium. or R1 is C(=O)-O-(CR c R d) n-(5-membered heterocyclyl), and the 5-membered heterocyclyl is either unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium. or The compound according to claim 1 or 2, wherein R1 is C(=O)-O-(CR c R d) n-(6-membered heterocyclyl), and the 6-membered heterocyclyl is either unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

38. R １ But (CR ｃ R ｄ ) ｎ - (C ６ ~C １０ (Aryl) or (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), and the above C ６ ~C １０ The compound according to claim 1 or 2, wherein the aryl or 5-10 membered heteroaryl is unsubstituted, or the C6-C10 aryl or 5-10 membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

39. R １ But (CR ｃ R ｄ ) ｎ The compound according to claim 1 or 2, wherein the compound is a (six-membered heteroaryl), and the six-membered heteroaryl is unsubstituted, or the six-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

40. R １ C(=O)-C １ ~C ４ It is alkyl, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ Each of them is either H or unsubstituted C １ ~C ３ The compound according to claim 1 or 2, wherein it is alkyl.

41. R １ C(=O)-C １ ~C ４ It is an alkoxy, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ Each of them is either H or unsubstituted C １ ~C ３ The compound according to claim 1 or 2, wherein it is alkyl.

42. R １ is C(=O)-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ It is a cycloalkyl, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ Each of them is either H or unsubstituted C １ ~C ３ A compound according to any one of claims 1 to 94, wherein it is alkyl.

43. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (4-7 member heterocyclyl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

44. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (5-membered heterocycline), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

45. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (6-membered heterocycline), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

46. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (C ６ ~C １０ aryl) and R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

47. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (C ６ aryl) and R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

48. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (5-7 member heteroaryl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

49. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (5-membered heteroaryl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

50. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (6-membered heteroaryl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

51. R １ is C(=O)-O-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ It is a cycloalkyl, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

52. R １ is C(=O)-O-(CR ｃ R ｄ ) ｎ - (4-7 member heterocyclyl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

53. R １ is C(=O)-O-(CR ｃ R ｄ ) ｎ - (5-membered heterocycline), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

54. R １ is C(=O)-O-(CR ｃ R ｄ ) ｎ - (6-membered heterocycline), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

55. R １ But (CR ｃ R ｄ ) ｎ - (5-7 member heteroaryl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

56. R １ But (CR ｃ R ｄ ) ｎ - (C ６ ~C １０ aryl) and R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

57. R １ The compound according to claim 1 or 2, wherein is 3-pyridazinyl.

58. R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ Each of these is independently H, halogen, or unsubstituted C. １ ~C ３ The compound according to claim 1 or 2, wherein it is alkyl.

59. R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

60. The following: 【Chemistry 3-1】 【Chemistry 2-2】 [Chemistry 2-3] 【Chemistry 2-4】 【Chemistry 2-5】 【Chemistry 2-6】 and 【Transformation 3】 A compound according to claim 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

61. A pharmaceutical composition comprising a compound according to any one of claims 1 to 60 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

62. Use of a compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, or a composition thereof, for the manufacture of a pharmaceutical product for narcolepsy.

63. Use of a compound or a pharmaceutically acceptable salt thereof, or a composition thereof, according to any one of claims 1 to 60, for the manufacture of a pharmacopoeias for cataplexy.

64. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, or a composition thereof, for use in a method of treating narcolepsy in a subject requiring treatment for narcolepsy.

65. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, or a composition thereof, for use in a method of treating cataplexy in a subject requiring treatment for cataplexy.

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