Replacement pyrrolidinyl and piperidinyl compounds and related methods of treatment

Abstract

The present invention provides compounds useful for the treatment of narcolepsy or cataplexy in a subject in need of such treatment. 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 / 353,982, 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 its 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). Therefore, orexin-2 receptor agonists may be therapeutic agents for narcolepsy or other disorders exhibiting 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 on 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 coma, 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 associated with 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] wherein, ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, and further, the ring is unsubstituted or is substituted with 1 to 3 substituents each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen, X is N or CH, Y is S(=O)2, C(=O), or S(=O)(=NR e ), R e is selected from the group consisting of H, C1-C3 alkyl, or C3-C5 cycloalkyl, E is NR a R b , C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-7 membered heteroaryl, and C1-C3 alkylene-(5-7 membered heteroaryl), where C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10Aryl), 5- to 7-membered heteroaryl or C1-C3 alkylene-(5- to 7-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl, R a and R b are each independently selected from the group consisting of H, C1-C3 alkyl, C3-C5 cycloalkyl, and 4- to 7-membered heterocyclyl, where C1-C3 alkyl, C3-C5 cycloalkyl, or 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl, or, 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, where the 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , C1-C3 alkyl, C1-C3 alkoxyl or C1-C3 alkyl substituted with 1 to 3 halogen, 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), C(=O)-(CR c R d ) n -(5- to 10-membered heteroaryl), C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, C(=O)-O-(CRc R d ) n -(4 - to 7 - membered heterocyclyl), (CR c R d ) n -(C6 - C 10 aryl) and (CR c R d ) n -(5 - to 10 - membered heteroaryl) selected from the group consisting of, wherein C1 - C4 alkyl, C1 - C4 alkoxyl, C3 - C8 cycloalkyl, 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, R c and R d are each independently H, unsubstituted C1 - C3 alkyl, or C1 - C3 alkyl substituted with one or more halogens or deuteriums, n is 0, 1, or 2, Each of R2, R3, R4, R5, R6, R7, and R8 is independently H, halogen, unsubstituted C1 - C3 alkyl, or C1 - C3 alkyl substituted with one or more halogens or deuteriums, or, R3 and R6 together form unsubstituted C1 - C3 alkylene or C1 - C3 alkylene substituted with one or more halogens, or, R4 and R5 together form unsubstituted C1 - C3 alkylene or C1 - C3 alkylene substituted with one or more halogens, m is 0 or 1, p is 0, 1, 2, 3, or 4, Each R9 is independently selected from the group consisting of deuterium, halogen, hydroxyl, and cyano, provided that Y is S(=O)2, m is 1, E is NR a R b , C1 - C3 alkylene - NR a Rb , 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 alkylene-NR a R b , 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, C1-C3 alkyl, or C1-C3 alkoxy, R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), n is 0 or 1, R a and R b are each independently H or unsubstituted C1-C3 alkyl, Ring A is unsubstituted or substituted with 1 to 3 substituents each independently selected from C1-C3 alkyl or halogen, X is N.

[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 formula

[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 thereof, the method comprising administering to the subject a compound of formula I-A or I, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0013] Compounds useful for treating a subject's narcolepsy or cataplexy, such as compounds of formula I-A or I or pharmaceutically acceptable salts thereof, are provided herein.

[0014] In a non-limiting aspect, these compounds may 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 a subject's narcolepsy 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. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are well known and commonly employed in the art.

[0017] As used herein, the articles "a" and "an" refer to one or more than one (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 depending on the context in which it is used. When used herein in reference to measurable values such as amounts, durations, etc., the term "about" means to encompass variations 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 "treat", "treated", "treating", or "treatment" include a decrease 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 term "prevent" or "prevention" means the absence of the occurrence of a disorder or disease when it has not occurred, or the absence of the occurrence of a further disorder or disease when a disorder or disease has already occurred. 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, that 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 compounds 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 are 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. There are a number of techniques for administering compounds 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, dispersant, 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 be capable of performing 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, absorption delaying agents, etc. that are compatible with the activity of the compounds useful within the present invention and are physiologically acceptable to a patient. Auxiliary active compounds can also be incorporated into the composition. "Pharmaceutically acceptable carrier" can further include pharmaceutically acceptable salts of the compounds useful within the present invention. Other additional components 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 indicated 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 the first ring. Cycloalkyl also includes bicyclic structures that can be essentially bridged or spirocyclic, and each individual ring within the ring varies 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, having 1, 2 or 3 rings, such rings may be fused, and the fusion is defined above. Heterocyclyl also includes bicyclic structures that can be essentially bridged or spirocyclic, having each individual ring within the bicyclic varying from 3 to 8 atoms and 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, epoxyxyl, 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 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. 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 linked to the moiety designated via a different ring atom (i.e., shown or described without indication of a specific point of attachment), it is to be understood that all possible points are contemplated, via either a carbon atom or, for example, a trivalent nitrogen atom. 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, provided herein is a compound of formula I-A having the structure of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0045] In one embodiment of formula (I), ring A is a phenyl ring, and the ring is unsubstituted or is substituted with 1 to 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 is substituted with 1 to 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 to 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 to 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 to 2 substituents each independently selected from halogen.

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

[0051] In another embodiment of formula (I), ring A is a phenyl ring, and the ring is 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 ring is unsubstituted or substituted with 1 to 3 substituents each independently 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 ring is unsubstituted or substituted with 1 to 2 substituents each independently 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 ring is substituted with 1 to 2 substituents each independently 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 ring is substituted with 1 to 2 substituents each independently selected from C1-C3 alkyl or halogen.

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

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

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

[0060] In another embodiment of formula (I), ring A is a pyridazinyl 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.

[0061] In another embodiment of formula (I), ring A is a pyridazinyl 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.

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

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

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

[0066] In another embodiment of formula (I), ring A is a pyridazinyl ring, and the ring is monosubstituted with 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 rings are each independently substituted with 1 to 2 substituents 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 rings are each independently substituted with 1 to 2 substituents selected from C1-C3 alkyl or halogen.

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

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

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

[0074] In another embodiment of formula (I), ring A is a pyrazinyl 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.

[0075] In another embodiment of formula (I), ring A is a pyrazinyl 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.

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

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

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

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

[0081] In another embodiment of formula (I), ring A is a triazinyl 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.

[0082] In another embodiment of formula (I), ring A is a triazinyl 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.

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

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

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

[0087] In another embodiment of formula (I), ring A is a triazinyl ring, and the rings are mono-substituted 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 In another embodiment of formula (I), E is C1-C3 alkylene-NR a R bis. 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, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C1-C3 alkyl. In another embodiment of formula (I), E is c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkyl substituted with C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C3-C8 cycloalkyl. In another embodiment of formula (I), E is c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkyl substituted with C1-C3 alkoxyl, C3-C8 cycloalkyl. In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of formula (I), E is 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 unsubstituted 4- to 10-membered heterocyclyl. In another embodiment of formula (I), E is c R d , CF3, CHF2, CH2F, C1-C3 alkyl or 4- to 10-membered heterocyclyl substituted with C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(4- to 10-membered heterocyclyl). In another embodiment of formula (I), E is c R d, CF3, CHF2, CH2F, C1-C3 alkylene-(4-10 membered heterocyclyl) substituted with C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C6-C 10 aryl. In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , C6-C 10 -aryl substituted with CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is 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 , 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 unsubstituted 5-7 membered heteroaryl. In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , 5-7 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-(5-7 membered heteroaryl). In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , C1-C3 alkylene-(5-7 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), 4-10 membered heterocyclyl, or C1-C3 alkylene-(4-10 membered heterocyclyl), and C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, or C1-C3 alkylene-(4-10 membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , 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), 4-10 membered heterocyclyl, or C1-C3 alkylene-(4-10 membered heterocyclyl), and C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, or C1-C3 alkylene-(4-10 membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , 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 halogens, 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 halogens, hydroxyl, NR 10 , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. 10

[0096] In another embodiment of formula (I), E is 5-7 membered heteroaryl or C1-C3 alkylene-(5-7 membered heteroaryl). In another embodiment of formula (I), E is unsubstituted 5-7 membered heteroaryl or C1-C3 alkylene-(5-7 membered heteroaryl). In another embodiment of formula (I), E is 5-7 membered heteroaryl or C1-C3 alkylene-(5-7 membered heteroaryl) substituted with one or more halogens, 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 selected from the group consisting of 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 -(4-7 membered heterocyclyl), C(=O)-(CR c R d ) n -(C6-C 10 aryl), and C(=O)-(CR c R d ) n -(5-10 membered heteroaryl), and C1-C4 alkyl, C1-C4 alkoxyl, C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyl, or C1-C3 alkyl 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-Selected from the group consisting of C3-C8 cycloalkyl, C1-C4 alkyl, C1-C4 alkoxyl, or C3-C8 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums.

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

[0103] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkoxyl, and C1-C4 alkoxyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyl, or C1-C3 alkyl 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 to C8 cycloalkyl, and the C3 to C8 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1 to C3 alkyl, or C1 to C3 alkyl 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- to 7-membered heterocyclyl), and the 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1 to C3 alkyl, or C1 to C3 alkyl 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 to C 10 aryl), and the C6 to C 10 aryl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1 to C3 alkyl, or C1 to C3 alkyl 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), and the 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1 to C3 alkyl, or C1 to C3 alkyl substituted with one or more halogens or deuteriums.

[0108] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 5- to 7-membered heterocyclyl), wherein the 5- to 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.

[0109] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5- to 6-membered heterocyclyl), wherein the 5- to 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.

[0110] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), the 5-membered heterocyclyl being 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.

[0111] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), the 6-membered heterocyclyl being 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.

[0112] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a C6 aryl), wherein the 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), where the 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), where the 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), where 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 -(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. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, where 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. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n-(a 4- to 7-membered heterocyclyl), where the 4- to 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. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3-C5 cycloalkyl, where the C3-C5 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. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5- to 6-membered heterocyclyl), where the 5- to 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. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), where the 5-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. 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.

[0120] In another embodiment of formula (I), R1 is (CR c R d ) n -(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. 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, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[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, 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 the C6-C 10 aryl or 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 substituted with one or more halogens or deuterium, and further n is 0.

[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), and 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), wherein the C6-C 10 aryl or 5- to 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 deuteriums, and further n is 1.

[0123] In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl), and the C6-C 10 aryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl), and the C6-C 10 aryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums.

[0124] In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl), and the C6-C 10 aryl 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), and the C6-C 10Aryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, and further n is 0.

[0125] In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl), where 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), where C6-C 10 aryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, and further n is 1.

[0126] In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), where the 5- to 10-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), where the 5- to 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 deuteriums.

[0127] In another embodiment of formula (I), R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), where 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), where 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.

[0128] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 10-membered heteroaryl), where 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), where 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.

[0129] 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), where the phenyl or 5- to 7-membered heteroaryl is unsubstituted. 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), where the 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.

[0130] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR cR d ) n -(5- to 7-membered heteroaryl), wherein 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 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.

[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), wherein 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, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium, and further n is 1.

[0132] 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 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.

[0133] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), the 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 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 0.

[0134] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), 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), where 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 1.

[0135] 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, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is pyridazinyl. In another embodiment of formula (I), R1 is 3-pyridazinyl.

[0136] 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 -(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.

[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 1. In another embodiment of formula (I), R1 is (CR c R d ) n-(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.

[0138] In another embodiment of formula (I), R1 is (CR c R d ) n -(5-membered heteroaryl), where the 5-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(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.

[0139] In another embodiment of formula (I), R1 is (CR c R d ) n -(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 -(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.

[0140] In another embodiment of formula (I), R1 is (CR c R d ) n -(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, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, and further n is 1.

[0141] In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is independently H, 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, 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 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-C3 to 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 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)-(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)-(CR c R d ) n -C3 to C8 cycloalkyl, 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 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.

[0148] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3-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-C8 cycloalkyl, 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 -C3-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-C8 cycloalkyl, n is 1 or 2, 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 -(4-7 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 -(4-7 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 -(4-7 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)-(CRc R d ) n -(4- to 7-membered heterocyclyl), 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), 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-C3 alkyl. 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 halogen. 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 fluorine.

[0151] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(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 -(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 cR d ) n -(4- to 7-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 -(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.

[0152] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(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 -(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 -(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 -(5-membered heterocyclyl), 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 -(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.

[0154] 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.

[0155] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(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 -(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 -(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 -(6-membered heterocyclyl), 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 -(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.

[0157] 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)-(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.

[0158] 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 10is 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.

[0159] 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 10 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), 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), n is 0, 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 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 cR d ) n -(C6~C 10 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~C 10 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~C 10 aryl), n is 1 or 2, 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 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.

[0162] In another embodiment of formula (I), R1 is C(=O)-(CR c Rd ) 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.

[0163] 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.

[0164] 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 -(5-7 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 -(5-7 membered heteroaryl), 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), 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 -(5-7 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-(a 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 -(a 5- to 7-membered heteroaryl), n is 0, 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 -(a 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 -(a 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 -(a 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 -(a 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.

[0167] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 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-(a 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 -(a 5-membered heteroaryl), 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 5-membered heteroaryl), 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 -(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 a 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.

[0169] 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 -(a 5-membered heteroaryl), n is 1 or 2, 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 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 -(a 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 -(a 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 -(a 6-membered heteroaryl), 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), 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.

[0172] 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.

[0173] 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-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)-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)-O-(CR c R d ) n -C3-C8 cycloalkyl, 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, 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.

[0175] 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.

[0176] In another embodiment of formula (I), R1 is C(=O)-O-(CR c Rd ) n -(a 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 -(a 4- to 7-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 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.

[0177] 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-(4- to 7-membered heterocyclyl), n is 0, 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 -(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 -(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 -(4- to 7-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 -(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.

[0179] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(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 -(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.

[0180] 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 a 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 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 -(a 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 -(a 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-(a 6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0185] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 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 -(a 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 -(a 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 c R d ) n -(a 5- to 10-membered heteroaryl), 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 -(a 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 -(a 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 -(a 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 (CRc R d ) n -(5- to 7-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 -(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.

[0188] 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.

[0189] 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.

[0190] 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 10is 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.

[0191] 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.

[0192] 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.

[0193] 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.

[0194] Each of the embodiments described herein with respect to the compounds of formula I also applies to the compounds of formula I-A.

[0195] According to Formula I-A or I in this specification, when Ring A is pyridinyl, the position of the pyridinyl N atom is specified as shown below.

Chemical formula

Chemical formula

[0196] Furthermore, according to Formula I-A or I in this specification, when Ring A is pyridazinyl, the position of the pyridazinyl N atom is specified as shown below.

Chemical formula

Chemical formula

[0197] Furthermore, according to Formula I-A or I in this specification, when Ring A is pyrimidinyl, the position of the pyrimidinyl N atom is specified as shown below.

Chemical formula

Chemical formula

[0198] Furthermore, according to Formula I-A or I in this specification, when Ring A is pyrazinyl, the position of the pyrazinyl N atom is specified as shown below.

Chemical formula

[0199] Furthermore, according to Formula I-A or I in this specification, when Ring A is triazinyl, the position of the triazinyl N atom is specified as shown below. [Chemistry] or [Chemistry]

[0200] All other variables described in Formulas I-A and I are as defined above.

[0201] 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 referred to collectively or individually herein as "the compounds of the invention" or "the compounds provided herein". [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

[0202] The disclosed compounds have one or more stereocenters, and each stereocenter can independently exist in either the R configuration or the 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, positional isomers and stereoisomers, or combinations thereof, having the therapeutically useful properties described herein.

[0203] The preparation of the optically active form 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.

[0204] In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0205] 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 typically found in nature while having the same atomic number as the atoms in the compounds described herein. 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 35It includes, but is not limited to, S. 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., an increase in in vivo half-life or a decrease in required dosage). In another embodiment, the compounds described herein are 2 include H (i.e., deuterium) isotopes.

[0206] In yet another embodiment, 11 C, 18 F, 15 O and 13 substitution with positron-emitting isotopes such as N is useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. The isotope-labeled compound is prepared by any suitable method or process that uses a suitable isotope-labeled reagent in place of the unlabeled reagent used in other methods.

[0207] 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 Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999), and March, Advanced Organic Chemistry 5th Ed., (Wiley 1992) (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.

[0208] The compounds described herein are synthesized starting from compounds available from commercial sources or using any suitable procedure prepared using the procedures described herein.

[0209] Therapeutic methods The compounds of the 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 invention or a pharmaceutical composition comprising a compound of the invention. In one embodiment of the methods described herein, the subject is a human. In one aspect, the compounds provided herein are useful for treating a disease or condition by acting as an agonist of the orexin 2 receptor.

[0210] The compounds of the 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.

[0211] In one embodiment, the compounds of the 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 invention. In one embodiment, the compounds of the invention can be used to treat hypersomnia of a subject.

[0212] 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 ameliorating one or more of the following symptoms or diseases of various neurological and psychiatric diseases associated with changes in sleep / arousal 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, Moebius 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 encephalopathy in subjects having the same), lethargy, loss of consciousness, obesity (e.g., malignant obesity, exogenous obesity, hyperinsulinemic obesity, cytoplasmic hypertrophy, endoplasmic reticulum steatosis, 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 disturbance, jet lag, jet lag syndrome, shift worker sleep disorder, sleep disorders, night terrors, depression, major depressive disorder, sleepwalking disorder, enuresis, sleep disorders, 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., daytime excessive 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 disorders, 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).

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[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 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.

[0218] In another aspect, the compounds of the present invention have orexin 2 receptor agonist activity and are useful as prophylactic or therapeutic agents for cancer and / or daytime excessive somnolence or fatigue associated with chemotherapy.

[0219] In another embodiment, the present invention provides a method for 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.

[0220] In another embodiment, the present invention provides a method for treating narcolepsy type 1 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.

[0221] In another embodiment, the present invention provides a method for treating narcolepsy type 2 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.

[0222] In another embodiment, the present invention provides a method for treating narcolepsy and daytime excessive somnolence 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.

[0223] In another embodiment, the present invention provides a method for treating narcolepsy, cataplexy and daytime excessive somnolence 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.

[0224] In another embodiment, the present invention provides a method for treating narcolepsy and cataplexy 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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 and / or administered in a therapeutically effective amount.

[0233] Administration / Dosage / Formulation In another aspect, a pharmaceutical composition comprising at least one compound of the present invention together with a pharmaceutically acceptable carrier is provided herein.

[0234] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention may vary so as to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0235] In particular, the selected dosage level depends on various factors including the activity of the particular compound being used, 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 similar factors well known in the medical arts.

[0236] A physician or veterinarian, who is skilled in the art, e.g., an internist or veterinarian, can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can initiate administration of the pharmaceutical composition by administering the disclosed compound at a level lower than that required to achieve the desired therapeutic effect and to increase the dosage gradually until the desired effect is achieved.

[0237] 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 being 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 unique 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.

[0238] 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.

[0239] 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 can be 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.

[0240] Any route of administration of the compositions of the present invention includes oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. The 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, the preferred route of administration is oral.

[0241] 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 powders 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.

[0242] 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.

[0243] 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 may be used, optionally containing other formulating agents such as suspending, stabilizing or dispersing agents.

[0244] 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 are 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.

[0245] 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 a range of values, are also contemplated by this application. 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.

Examples

[0246] Example 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 conventional techniques of organic synthesis, cell biology, cell culture, molecular biology, transgenic biology, microbiology, and immunology, which are within the skill of one of ordinary skill in the art, unless otherwise specified.

[0247] 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 on December 20, 2021 and PCT Application No. PCT / US21 / 64484 filed on December 21, 2021. Both of these are hereby expressly incorporated by reference in their entirety.

[0248] In the following synthetic examples, the following abbreviations can be used. DCM = dichloromethane MeOH = methanol EtOH = ethanol DIPEA or DIEA = N,N - diisopropylethylamine PE = petroleum ether EtOAc = ethyl acetate TFA = trifluoroacetic acid THF = tetrahydrofuran DMSO = dimethyl sulfoxide i - PrOH = isopropanol Boc = tert - butyloxycarbonyl Ms = methanesulfonyl Bn = benzyl Bz = benzoyl Et = ethyl Ph = phenyl min = minute h = hour n - BuLi = n - butyllithium Boc2O = di - tert - butyl dicarbonate DMAP = 4 - (dimethylamino)pyridine TEA = triethylamine SM = starting material (CH2O)n = paraformaldehyde HATU = 1 - [bis(trimethylamino)methylene]-1H - 1,2,3 - triazolo[4,5 - b]pyridinium 3 - oxide hexafluorophosphate DMF = Dimethylformamide Pd(OH)2 = Palladium hydroxide PEPPSI = Pyridine-Enhanced Precatalyst Preparation Stabilization Initiation

Chem.

Chem.

Chem.

[0249] A solution of lithium tri-sec-butylborohydride (L-selectride) (104.0 mL, 1 mol, 2.0 eq, 104.0 mmol) in THF was added dropwise to a stirred mixture of 4-(3-fluorophenyl)cyclohexan-1-one (10.0 g, 1 eq, 52.02 mmol) in THF (100 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 6 h. The reaction was quenched by adding EtOH (40 mL) and H2O (10 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 30 min. A solution of NaOH (100 mL, 2N) and H2O2 (40 mL) was added and the resulting mixture was stirred at 0 °C for 30 min. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with EtOAc / PE (1 / 20) to give (1s,4s)-4-(3-fluorophenyl)cyclohexan-1-ol (10.0 g, 51.5 mmol, 99.0%) as a solid. 1H NMR (400 MHz, Chloroform-d) δ 7.33 - 7.20 (m, 2H), 7.05 - 6.79 (m, 3H), 4.16 (p, J = 3.0 Hz, 1H), 2.56 (td, J = 11.8, 5.8 Hz, 1H), 1.97 - 1.83 (m, 4H), 1.70 (tp, J = 8.9, 2.3 Hz, 5H). MR (400 MHz, Methanol-d4) δ 8.66 (s, 1H), 8.47 (d, J = 5.4 Hz, 1H), 7.57 (d, J = 5.4 Hz, 1H), 4.81 (s, 2H). [Chemical formula]

[0250] (1s,4s)-4-(3-Fluorophenyl)cyclohexan-1-ol (26.7 g, 1 eq, 137 mmol) in a solution of chlorotrimethylsilane (14.9 g, 260 mL, 1 eq, 137 mmol), (CH2O) n(4.54 g, 1.1 equivalents, 151 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification.

Chemical formula

[0251] To a solution of 1-benzylpiperidin-4-one (18.9 g, 100 mmol, 1 equivalent) and 1-phenylethan-1-amine (12.1 g, 100 mmol, 1 equivalent) in toluene (600 mL) was added MgSO4 (2 equivalents), and the mixture was stirred at room temperature overnight. The solid was filtered off, and the filtrate was concentrated to give the imine as the crude product, which was used in the next step without further purification.

Chemical formula

[0252] To a stirred mixture of diethylamine (6.0 g, 8.5 mL, 1.2 eq, 82 mmol) in THF (200 mL), a solution of n-BuLi (40 mL, 1.2 eq, 82 mmol) was added dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 hour. To the above mixture, a solution of 1-benzyl-N-(1-phenylethyl)piperidin-4-imine (20 g, 1 eq, 68 mmol) in THF (50 mL) was added dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for an additional 1 hour. To the above mixture, a solution of 1-((1s,4s)-4-(chloromethoxy)cyclohexyl)-3-fluorobenzene (22 g, 1.3 eq, 89 mmol) in THF (50 mL) was added dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for an additional 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution at 0 °C. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel to afford 1-benzyl-3-((((1s,4s)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-one (28 g, 71 mmol, 100%) as an oil.LCMS: m / z (ES+), [M+H]+ = 396; 1H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.27 (m, 5H), 7.25 - 7.20 (m, 1H), 7.03 - 6.77 (m, 3H), 3.76 (dd, J = 9.6, 4.8 Hz, 1H), 3.70 (d, J = 13.1 Hz, 1H), 3.61 (d, J = 13.1 Hz, 1H), 3.56 (p, J = 3.0 Hz, 1H), 3.46 (dd, J = 9.6, 8.3 Hz, 1H), 3.28 (ddd, J = 11.3, 5.7, 2.4 Hz, 1H), 3.07 - 2.97 (m, 1H), 2.93 - 2.81 (m, 1H), 2.59 (dddd, J = 13.5, 10.7, 5.6, 1.3 Hz, 1H), 2.50 (td, J = 10.8, 3.3 Hz, 2H), 2.46 - 2.32 (m, 2H), 1.97 (dq, J = 14.1, 3.7, 2.9 Hz, 2H), 1.66 (tdd, J = 13.0, 11.7, 3.4 Hz, 2H), 1.61 - 1.51 (m, 2H), 1.51 - 1.45 (m, 1H), 1.45 - 1.38 (m, 1H).。 [Chemistry]

[0253] To a solution of 1-benzyl-3-((((1s,4s)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-one (5.00 g, 1 equivalent, 12.6 mmol) in MeOH (100 mL) was added ZnCl2 (68.9 mg, 722 μL, 0.7 mol, 0.04 equivalent, 506 μmol) at 0 °C. The resulting mixture was stirred at 0 °C for 10 minutes. To the above mixture were added NaBH3CN (4.77 g, 6 equivalents, 75.8 mmol) and HCOONH4 (15.9 g, 20 equivalents, 253 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for an additional 4 hours. The reaction was stopped by adding saturated aqueous NH4Cl solution at 0 °C. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS: m / z (ES+), [M+H]+ = 397.3 [Chemical formula]

[0254] To a solution of 1-benzyl-3-((((1s,4s)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-amine (5.00 g, 1 equivalent, 12.6 mmol) in DCM (20 mL) were added triethylamine (2.55 g, 3.51 mL, 2.0 equivalents, 25.2 mmol) and Boc2O (4.13 g, 4.22 mL, 1.5 equivalents, 18.9 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography to give tert-butyl (1-benzyl-3-((((1s,4s)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-yl)carbamate (4.9 g, 9.9 mmol, 78%) as an oil. LCMS: m / z (ES+), [M+H]+ = 497.30

[0255] The crude product was purified by achiral-SFC using the following conditions: column: Triart Diol-HILIC, 3 × 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: ACN:MeOH = 4:1; flow rate: 100 mL / min; gradient: isocratic 15% B; column temperature (°C): 35; backpressure (bar): 100; wavelength: 220 nm; RT1 (min): 3.48; RT2 (min): 4.78.

[0256] The solvent was evaporated to obtain tert-butyl ((3R,4S)-1-benzyl-3-(((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-yl)carbamate (6a) (6g, 0.01 mol, 30%) 1H NMR (400 MHz, DMSO-d6) δ 7.34 - 7.24 (m, 5H), 7.20 (m, 1H), 7.04 - 6.93 (m, 3H), 6.78 (d, J = 7.8 Hz, 1H), 5.76(s,0H), 3.62 (s, 1H), 3.42 (d, J = 7.4 Hz, 2H), 2.56 (d, J = 11.2 Hz, 3H), 2.19 (s, 2H), 2.03 (s, 1H), 1.88 (dd, J = 26.6, 13.3 Hz, 2H), 1.66-1.54 (m, 3H), 1.54-1.40 (m, 3H), 1.34 (s, 9H) and tert-butyl ((3R,4R)-1-benzyl-3-(((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-yl)carbamate (6b) as an oil (10g, 20 mmol, 50%) 1H NMR (400 MHz, DMSO-d6) δ 7.31 (s, 1H), 7.28 (d, J = 4.4 Hz, 4H), 7.28 - 7.17 (m, 1H), 7.04 - 6.95 (m, 3H), 6.76 (d, J = 8.8 Hz, 1H), 5.76(s,1H), 3.51-3.36 (m, 3H), 3.28-3.14 (m, 2H), 2.99 (d, J = 10.9 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 1.89 (dt, J = 23.4, 13.3 Hz, 2H), 1.79 (d, J =11.2 Hz, 1H), 1.71 (d, J = 8.6 Hz, 1H), 1.64-1.53 (m, 1H), 1.48 (d, J = 13.1 Hz, 2H), 1.45-1.37 (m, 1H), 1.35 (s, 9H).

Chemical formula

[0257] To a solution of tert-butyl ((3R,4S)-1-benzyl-3-(((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-yl)carbamate (1.00 g, 1 equivalent, 2.01 mmol) in 2-propanol (20 mL) was added palladium (429 mg, 10% by weight, 0.2 equivalent, 403 μmol) and Pd(OH)2 (283 mg, 10% by weight, 0.1 equivalent, 201 μmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 8 hours under a hydrogen atmosphere using a hydrogen balloon. The reaction solution was filtered through a Celite pad and concentrated under reduced pressure to obtain a crude product. The crude product was used as such in the next step without further purification. LCMS: m / z (ES+), [M+H]+ = 407.1

Chemical formula

[0258] A solution of tert-butyl ((3R,4S)-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-yl)carbamate (650 mg, 1 equiv, 1.60 mmol) and 3-bromopyridazine (381 mg, 1.5 equiv, 2.40 mmol) in DMSO (8 mL) was added with Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (134 mg, 0.1 equiv, 160 μmol) and cesium carbonate (1.04 g, 2 equiv, 3.20 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 4 h. The resulting mixture was diluted with H2O (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography to give tert-butyl ((3R,4S)-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-1-(pyridazin-3-yl)piperidin-4-yl)carbamate (415 mg, 0.81 mmol, 51%, purity 90%) as an oil.

[0259] LCMS: m / z (ES+), [M+H]+ = 485.45. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.4, 1.2 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.21 (dd, J = 9.4, 1.3 Hz, 1H), 7.09 - 6.94 (m, 4H), 3.92 (s, 1H), 3.86 - 3.75 (m, 1H), 3.74 - 3.61 (m,2H), 3.60 - 3.51 (m, 1H), 3.44 (dd, J = 9.3, 6.5 Hz, 2H), 3.27 (dd, J = 9.3, 7.4 Hz, 1H), 2.57 (d, J = 11.7 Hz, 1H), 2.16 - 2.08 (m, 1H), 1.91 (t, J = 12.7 Hz, 2H), 1.77 - 1.59 (m, 4H), 1.49 (d, J= 28.8 Hz, 4H), 1.38 (s, 9H). [Chemistry]

[0260] TFA (1 g, 1 mL, 0.01 mol) was added to a stirred solution of tert-butyl ((3R,4S)-3-((((1s,4S)-4-(3-fluorophenyl) cyclohexyl) oxy) methyl)-1-(pyridazin-3-yl) piperidin-4-yl) carbamate (350 mg, 1 equivalent, 722 μmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred at 25 °C for 30 minutes. The pH was adjusted to 8 by adding saturated aqueous Na2CO3 solution at 0 °C. Water (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product (300 mg), which was used directly in the next step without further purification. LCMS: m / z (ES+), [M+H]+ = 385.3 [Chemistry]

[0261] tert-Butyl ((3R,4S)-1-benzyl-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-yl)carbamate (10.0 g, 1 equivalent, 20.13 mmol) was added to a solution of HCl (12.54 g, 25.17 mL, 4 mol, 5 equivalents, 100.7 mmol) in 1,4-dioxane (50 mL). The resulting mixture was stirred at 25 °C for 1 hour. The resulting solution was evaporated under reduced pressure. The mixture was basified to pH 8 with sodium carbonate solution. The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (3R,4S)-1-benzyl-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-amine (7.52 g, 18.4 mmol, 91.2%, purity 96.8%) as an oil. LCMS (SNB54-875): m / z (ES+), [M+H]+ = 397.1

Chemical Structure

[0262] (3R,4S)-1-Benzyl-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-amine (1.00 g, 1 equivalent, 2.52 mmol) and TEA (766 mg, 1.05 mL, 3 equivalents, 7.57 mmol) in DCM (25 mL) were added dropwise with dimethylsulfamoyl chloride (543 mg, 1.5 equivalents, 3.78 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 16 hours. The resulting solution was evaporated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM = 1 / 15) to give the product (1.19 g, 2.35 mmol, 64.0%, purity 99.5%) as an oil. LCMS (SNB54-877): m / z (ES+), [M+H]+ = 504.15

Chemical Structure

[0263] To a solution of the above sulfamide starting material (1.19 g, 1 eq, 2.36 mmol) in i-PrOH (30 mL) were added Pd(OH)₂ (332 mg, 20% wt, 0.2 eq, 473 μmol) and Pearlman's catalyst (503 mg, 10% wt, 0.2 eq, 473 μmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 16 h under a hydrogen atmosphere using a hydrogen balloon. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain a crude product. LCMS (SNB54-878): m / z (ES+), [M+H]+ = 414.1 The compound of the present invention Compounds 1 and 2

Chemical formula

[0264] Method 1: To a solution of (3R,4S)-3-((((1S,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-1-(pyridazin-3-yl)piperidin-4-amine (200 mg, 1 eq, 520 μmol) and DCM (5 mL) were added TEA (158 mg, 217 μL, 3 eq, 1.56 mmol) and dimethylsulfamoyl chloride (314 mg, 4.2 eq, 2.18 mmol). The resulting mixture was stirred at 25 °C for 1 day. LCMS showed 29.7% of the product and 26.8% of the SM. Water (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography using the following conditions (110 mg, 0.21 mmol). The crude product was purified by preparative chiral HPLC using TFA as an additive. The organic solvent was evaporated and subsequently lyophilized to obtain Compound 2 (22.3 mg, 44.5 μmol, 21.9%, purity 98.1%) as a solid, and Compound 1 (4.6 mg, 9.5 μmol, 46%, purity 99.6%) as a by-product. Compound 1: LCMS(SNB83-674A1): m / z (ES+), [M+H]+ = 481.2. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (dd, J = 4.3, 1.3 Hz, 1H), 7.35 (dd, J = 9.4, 4.3 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.00 (dt, J = 7.7, 1.2 Hz, 1H), 6.95 - 6.82 (m, 2H), 4.36 (dt, J = 9.4, 4.6 Hz, 1H), 4.30 - 4.14 (m, 2H), 3.57 (d, J = 7.0 Hz, 3H), 3.49 (dd, J = 13.6, 3.4 Hz, 1H), 3.36 (ddd, J = 13.4, 9.3, 4.1 Hz, 1H), 2.56 (tt, J = 11.9, 3.5 Hz, 1H), 2.44 (tq, J = 5.8, 3.5, 2.8 Hz, 1H), 2.06 - 1.84 (m, 4H), 1.82 - 1.65 (m, 2H), 1.65 - 1.48 (m, 4H). Compound 2: LCMS (SNB83 - 679A1): m / z (ES+), [M+H]+ = 492.2. 1H NMR (400 MHz, Methanol - d4) δ 8.42 (dd, J = 4.3, 1.3 Hz, 1H), 7.34 (dd, J = 9.4, 4.3 Hz, 1H), 7.31 - 7.16 (m, 2H), 7.03 (dt, J = 7.8, 1.4 Hz, 1H), 6.94 (dt, J = 10.6, 2.1 Hz, 1H), 6.91 - 6.82 (m, 1H), 4.15 (dt, J = 13.0, 5.0 Hz, 1H), 4.00 (ddd, J = 13.6, 6.0, 1.5 Hz, 1H), 3.79 - 3.66 (m, 2H), 3.61 - 3.48 (m, 3H), 3.43 (ddd, J = 13.1, 8.5, 4.1 Hz, 1H), 2.80 (s, 6H), 2.62 - 2.51 (m, 1H), 2.37 - 2.27 (m, 1H), 2.04 (d, J = 12.8 Hz, 2H), 1.99 - 1.67 (m, 4H), 1.66 - 1.49 (m, 4H). Compound 3 [Chem.]

[0265] Compound 3 was synthesized using Method 1. LCMS: m / z (ES+), [M+H]+ = 478.15. 1H NMR (400 MHz, Methanol-d4) δ 8.42 (dd, J = 4.3, 1.3 Hz, 1H), 7.34 (dd, J = 9.4, 4.3 Hz, 1H), 7.32 - 7.21 (m, 2H), 7.03 (dt, J = 7.8, 1.2 Hz, 1H), 6.94 (dt, J = 10.5, 2.1 Hz, 1H), 6.91 - 6.81 (m, 1H), 4.17(dt, J = 12.9, 4.9 Hz, 1H), 4.02 (ddd, J = 13.6, 5.8, 1.3 Hz, 1H), 3.71 (td, J = 8.8, 8.1, 4.8 Hz, 2H), 3.60 - 3.50 (m, 3H), 3.50 - 3.37 (m, 1H), 2.66 (s, 3H), 2.62 - 2.51 (m, 1H), 2.33 (s, 1H), 2.04 (d, J = 12.6 Hz, 2H), 1.99 - 1.69 (m, 4H), 1.65 - 1.50 (m, 4H), 1.39 - 1.25 (m, 1H). Compound 4

Chem.

[0266] A solution of tert-butyl ((3R,4S)-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-yl)carbamate (500 mg, 1 equivalent, 1.23 mmol) in DCM (0.5 mL) was added with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (354 mg, 1.5 equivalents, 1.84 mmol), 1-fluorocyclobutane-1-carboxylic acid (218 mg, 1.5 equivalents, 1.84 mmol), 1-hydroxy-1H-benzotriazole (249 mg, 254 μL, 1.5 equivalents, 1.84 mmol) and diisopropylethylamine (477 mg, 638 μL, 3 equivalents, 3.69 mmol). The resulting mixture was stirred at 25 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography to obtain tert-butyl ((3R,4S)-1-(1-fluorocyclobutane-1-carbonyl)-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-yl)carbamate (522 mg, 0.90 mmol, 73%, purity 87%) as a solid. LCMS: m / z (ES+), [M+H]+ = 507

[0267] HCl (360 mg, 241 μL, 10 equivalents, 9.87 mmol) was added to a solution of tert-butyl ((3R,4S)-1-(1-fluorocyclobutane-1-carbonyl)-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-yl)carbamate (500 mg, 1 equivalent, 987 μmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 25 °C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 9 with Na2CO3 and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was used in the next step. LCMS: m / z (ES+), [M+H]+ = 407

[0268] To a solution of ((3R,4S)-4-amino-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-1-yl)(1-fluorocyclobutyl)methanone (100 mg, 1 equivalent, 246 μmol) in MeOH (2 mL) was added 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (96.9 mg, 1.2 equivalents, 295 μmol) at 0 °C. The resulting mixture was stirred at 25 °C for 12 h. The resulting mixture was concentrated under reduced pressure. Water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was used in the next step. LCMS: m / z (ES+), [M + H]+ = 489

[0269] To a solution of ((3R,4S)-1-(1-fluorocyclobutane-1-carbonyl)-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-4-yl)sulfamoyl fluoride (120 mg, 1 equivalent, 246 μmol) in MeOH (2 mL) were added DMAP (9.00 mg, 0.3 equivalent, 73.7 μmol), TEA (74.6 mg, 103 μL, 3 equivalents, 737 μmol) and dimethylamine (210 mg, 10.5 equivalents, 2.58 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 12 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography to obtain the product as a solid as a mixture of isomers (48 mg, 93 μmol, 21%, purity 99%). This mixture was purified by preparative chiral HPLC. The solvent was evaporated to obtain compound 4 (9.8 mg, 18 μmol, 16%, purity 94.0%) as a solid. LCMS: m / z (ES+), [M + H]+ = 514.2. 11H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.20 (m, 1H), 7.10 - 6.94 (m, 2H), 6.86 (q, J = 8.3 Hz, 1H), 4.04 - 3.81 (m, 2H), 3.72 (s, 2H), 3.66 - 3.54 (m, 2H), 3.54 - 3.33 (m, 3H), 2.78 (d, J = 1.6 Hz, 8H), 2.43 (dt, J = 20.9, 10.5 Hz, 2H), 2.14 (d, J = 71.6 Hz, 3H), 1.97 - 1.69 (m, 5H), 1.59 (t, J = 12.2 Hz, 5H). Compound 5

Chem.

[0270] Compound 5 (13.9 mg, purity 92.6%, solid) was synthesized using the same method as described for Compound 4. LCMS: m / z (ES+), [M+H]+ = 512. 1 1H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.19 (m, 1H), 7.10 - 6.92 (m, 2H), 6.87 (t, J = 8.3 Hz, 1H), 4.01 - 3.34 (m, 13H), 2.78 (d, J = 5.4 Hz, 6H), 2.59 (q, J = 12.7 Hz, 1H), 2.29 - 1.96(m, 5H), 1.92 - 1.69 (m, 4H), 1.61 (dd, J = 21.2, 13.6 Hz, 4H). Compound 6

Chem.

[0271] Method 2: To a solution of ((3R,4S)-4-amino-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-1-yl)(1-fluorocyclobutyl)methanone (130 mg, 1 equivalent, 320 μmol) and TEA (97.1 mg, 134 μL, 3 equivalents, 959 μmol) in DCM (1.5 mL) was added methanesulfonic anhydride (83.6 mg, 1.5 equivalents, 480 μmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC to give compound 6 (100 mg, 197 μmol, 61.5%, purity 94.5%). LCMS: m / z (ES+), [M+H]+ = 485.2. 1 H NMR (400 MHz, Methanol-d4) δ 7.32 - 7.18 (m, 1H), 7.13 - 6.94 (m, 2H), 6.86 (q, J = 7.4 Hz, 1H), 3.99 (dd, J = 61.0, 13.7 Hz, 1H), 3.81 (d, J = 29.2 Hz, 1H), 3.75 - 3.53 (m, 3H), 3.53 - 3.35 (m, 2H), 3.22 (d, J = 33.4 Hz, 1H), 3.00 (d, J = 3.8 Hz, 3H), 2.72 (d, J = 10.3 Hz, 2H), 2.64 - 2.32 (m, 3H), 2.28 - 1.98 (m, 3H), 1.97 - 1.68 (m, 5H), 1.68 - 1.45 (m, 5H). Compound 7

Chemical Structure

[0272] Compound 7 was synthesized as a solid using Method 2 (22.8 mg, 47.1 μmol, 22.7%, purity 99.7%). LCMS: m / z (ES+), [M+H]+ = 483.2. 11H NMR (400 MHz, Methanol-d4) δ 7.31 - 6.81 (m, 4H), 4.01 (dt, J = 34.8, 8.2 Hz, 1H), 3.90 - 3.37 (m, 12H), 3.01 (d, J = 6.9 Hz, 3H), 2.59 (dt, J = 15.6, 11.9 Hz, 1H), 2.27 - 1.96 (m, 5H), 1.93 - 1.69 (m, 4H), 1.60 (td, J = 9.6, 3.8 Hz, 4H). Compound 8

Chem.

[0273] Compound 8 was synthesized as a solid using Method 1 (60 mg, 0.11 mmol, 38%, purity 95%). LCMS: m / z (ES+), [M+H]+ = 504.1 11H NMR (400 MHz, Methanol-d4) δ 8.42 (dd, J = 4.3, 1.3 Hz, 1H), 7.34 (dd, J = 9.4, 4.3 Hz, 1H), 7.32 - 7.17 (m, 2H), 7.03 (d, J = 7.7 Hz, 1H), 6.95 (dd, J = 10.8, 2.5 Hz, 1H), 6.87 (td, J = 8.6, 2.6 Hz, 1H), 4.17 - 4.09 (m, 1H), 3.97 (dd, J = 13.5, 6.1 Hz, 1H), 3.86 (t, J = 7.7 Hz, 4H), 3.79 (dt, J = 8.6, 4.3 Hz, 1H), 3.67 (dd, J = 9.5, 5.6 Hz, 1H), 3.56 (dt, J = 8.3, 3.5 Hz, 2H), 3.53 - 3.39 (m, 2H), 2.57 (s, 1H), 2.33 (s, 1H), 2.21 (p, J = 7.6 Hz, 2H), 2.04 (d, J = 13.5 Hz, 2H), 1.96 - 1.68 (m, 3H), 1.60 (t, J = 13.2 Hz, 3H), 1.54 (d, J = 13.0 Hz, 1H), 1.29 (s, 1H). Compound 9

Chem.

[0274] Method 3: To a solution of (3R,4S)-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-1-(pyridazin-3-yl)piperidin-4-amine (250 mg, 1 equiv, 650 μmol) in acetonitrile (4 mL) were added trifluoromethanesulfonate (116 mg, 1.2 equiv, 780 μmol) and 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium (140 mg, 1.2 equiv, 780 μmol) at 0 °C. The resulting mixture was stirred at 25 °C for 4 h. The resulting mixture was diluted with H2O (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS: m / z (ES+), [M+H]+ = 467.0

[0275] To a solution of ((3R,4S)-3-((((1s,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-1-(pyridazin-3-yl)piperidin-4-yl)sulfamoyl fluoride (125 mg, 1 equiv, 268 μmol), triethylamine (81.3 mg, 3 equiv, 804 μmol) and DMAP (9.82 mg, 0.3 equiv, 80.4 μmol) in acetonitrile (25 mL) was added N-methylcyclopropanamine (22.9 mg, 1.2 equiv, 322 μmol) under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 4 h. The resulting mixture was diluted with H2O (300 mL) and extracted with DCM (3 × 300 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography to give the product as a solid as a mixture of isomers (60 mg, 0.11 mmol, 41%, purity 95.3%). This mixture was purified by chiral HPLC to give Compound 9. LCMS: m / z (ES+), [M+H]+ = 518.1 11H NMR (400 MHz, Methanol-d4) δ 8.42 (dd, J = 4.4, 1.4 Hz, 2H), 7.38 - 7.21 (m, 6H), 7.03 (d, J = 7.6 Hz, 2H), 6.98 - 6.83 (m, 3H), 4.18 (d, J = 13.4 Hz, 1H), 4.03 (dd, J = 13.4, 5.9 Hz, 2H), 3.74 (m, 4H), 3.57 (s, 2H), 3.55 - 3.47 (m, 3H), 3.40 (m, 2H), 2.85 (s, 6H), 2.57 (t, J = 11.9 Hz, 2H), 2.38 (t, J = 5.3 Hz, 1H), 2.04 (d, J = 13.6 Hz, 4H), 1.95 - 1.85 (m, 3H), 1.84 - 1.67 (m, 2H), 1.58 (q, 8H), 1.29 (s, 1H), 0.73 (d, J = 6.5 Hz, 8H). Compound 10

Chem.

[0276] Compound 10 was synthesized as a solid using Method 2 (6.4 mg, 12 μmol, 46%, purity 94.0%). LCMS: m / z (ES+), [M+H]+ = 489.1. 11H NMR (400 MHz, Methanol-d4) δ 8.33 (dd, J = 4.3, 1.3 Hz, 1H), 7.25 (dd, J = 9.4, 4.3 Hz, 1H), 7.22 - 7.11 (m, 2H), 6.93 (d, J = 7.7 Hz, 1H), 6.84 (dt, J = 10.3, 2.1 Hz, 1H), 6.77 (m, 1H), 3.98 (dt, J = 11.5, 5.1 Hz, 1H), 3.84 - 3.73 (m, 2H), 3.64 - 3.52 (m, 2H), 3.51 - 3.37 (m, 2H), 3.29 (s, 8H), 2.59 - 2.49 (m, 1H), 2.48 (s, 2H), 2.22 (s, 1H), 1.94 (d, J = 14.1 Hz, 3H), 1.83 (dd, J = 7.2, 4.4 Hz, 1H), 1.75 - 1.62 (m, 1H), 1.50 (s, 4H), 1.48 - 1.41 (m, 1H), 1.33 - 1.22 (m, 1H), 1.20 (s, 5H), 1.19 (s, 2H), 1.05 - 0.90 (m, 3H), 0.80 (t, J = 6.8 Hz, 1H). Compound 11

Chem.

[0277] Compound 11 was synthesized as a solid using Method 2 (7.1 mg). LCMS: m / z (ES+), [M+H]+ = 499.0. 11H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 2H), 8.50 (d, J = 4.2 Hz, 1H), 7.31 (dd, J = 9.3, 4.8 Hz, 2H), 7.22 (d, J = 9.2 Hz, 1H), 7.09 - 6.94 (m, 5H), 3.85 (s, 3H), 3.78 - 3.66 (m, 2H), 3.62 (s, 3H), 3.53 - 3.43 (m, 3H), 3.30 (s, 3H), 2.57 (s, 1H), 2.13 (s, 2H), 2.08 (s, 1H), 1.93 (d, J = 13.2 Hz, 4H), 1.74 (d, J = 13.3 Hz, 6H), 1.66 (d, J = 13.8 Hz, 1H), 1.53 (s, 1H), 1.50 (s, 8H). Compound 12

Chem.

[0278] Compound 12 was synthesized as a white solid using Method 3 (1.01 mg). LCMS: m / z (ES+), [M+H]+ = 540.1. 11H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 4.4, 1.3 Hz, 1H), 7.38 - 7.21 (m, 3H), 7.02 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 10.6 Hz, 1H), 6.87 (t, J = 8.7 Hz, 1H), 4.23 (t, J = 12.3 Hz, 3H), 4.10 (d, J = 13.1 Hz, 1H), 3.97 - 3.81 (m, 2H), 3.68 - 3.55 (m, 3H), 3.48 (t, J = 8.8 Hz, 2H), 2.57 (t, J = 12.0 Hz, 1H), 2.34 (s, 1H), 2.02 (s, 1H), 1.90 (dd, J = 11.3, 6.8 Hz, 2H), 1.78 (dd, J = 24.5, 12.4 Hz, 2H), 1.62 - 1.50 (m, 3H), 1.27 (d, J = 12.6 Hz, 2H). Compound 13

Chem.

[0279] Method 4: To a solution of the piperidine intermediate (200.0 mg, 1 equiv, 483.6 μmol) and 3,3-difluorocyclopentane-1-carboxylic acid (108.9 mg, 1.5 equiv, 725.4 μmol) in DCM (10 mL) was added HATU (275.8 mg, 1.5 equiv, 725.4 μmol) and DIEA (187.5 mg, 253 μL, 3 equiv, 1.451 mmol). The resulting mixture was stirred at 25 °C for 2 h. The resulting solution was evaporated under reduced pressure. The residue was purified by Prep-TLC to give the crude product (185.0 mg, 333 μmol, 68.9%, purity 98.3%) as an oil. LCMS(SNB54-888): m / z (ES+), [M+H]+ = 546.1 11H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.22 (m, 1H), 7.05 (dd, J = 15.1, 7.7 Hz, 1H), 7.01 - 6.91 (m, 1H), 6.90 - 6.82 (m, 1H), 4.06 - 3.75 (m, 2H), 3.75 - 3.57 (m, 3H), 3.56 - 3.32 (m, 4H), 2.78 (d, J = 5.7 Hz, 6H), 2.66 - 2.32 (m, 2H), 2.32 - 1.97 (m, 7H), 1.94 - 1.69 (m, 5H), 1.61 (m, J = 12.1, 10.9 Hz, 4H). Compound 14 [Chem.]

[0280] Compound 14 was synthesized using Method 3. LCMS: m / z (ES+), [M+H] + = 520.10. 11H NMR (400 MHz, Methanol-d4) δ 8.42 (dd, J = 4.3, 1.3 Hz, 1H), 7.38 - 7.16 (m, 3H), 7.05 - 6.82 (m, 3H), 4.18 (dt, J = 13.6, 4.7 Hz, 1H), 4.03 (ddd, J = 13.6, 6.0, 1.5 Hz, 1H), 3.68 (ddd, J = 13.8, 9.1, 4.8 Hz, 2H), 3.60 - 3.46 (m, 3H), 3.40 (ddd, J = 13.1, 8.8, 3.9 Hz, 1H), 3.28 (d, J = 7.1 Hz, 2H), 2.57 (tt, J = 12.1, 3.5 Hz, 1H), 2.36 - 2.25 (m, 1H), 2.09 - 1.97 (m, 2H), 1.96 - 1.66 (m, 4H), 1.57 (tdd, J = 17.4, 9.9, 3.5 Hz, 4H), 1.35 - 1.26 (m, 1H), 1.20 (t, J = 7.1 Hz, 6H). Compound 15

Chem.

[0281] Compound 15 was synthesized as a solid using Method 2 (20.0 mg, 35.7 μmol, 27.2%, purity 95.3%). LCMS: m / z (ES+), [M+H]+ = 534.3. 11H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 4.3, 1.3 Hz, 1H), 7.41 - 7.21 (m, 3H), 7.03 (dd, J = 7.6, 1.4 Hz, 1H), 6.98 - 6.82 (m, 2H), 5.22 (s, 1H), 4.16 (dd, J = 13.5, 5.7 Hz, 1H), 4.00 (dd, J = 13.5, 5.9 Hz, 1H), 3.81 - 3.69 (m, J = 5.5, 4.9 Hz, 5H), 3.60 - 3.42 (m, 6H), 3.24 - 3.12 (m, 4H), 2.57 (t, J = 11.9 Hz, 1H), 2.33 (s, 1H), 2.04 (d, J = 13.4 Hz, 2H), 1.99 - 1.67 (m, 4H), 1.58 (q, J = 14.4 Hz, 3H), 1.35 (t, J = 7.3 Hz, 5H). Compound 16

Chem.

[0282] Compound 16 was synthesized using Method 1. LCMS: m / z (ES+), [M+Na]+ = 494.20. 1 1H NMR (400 MHz, Methanol-d4) δ 7.32 - 7.19 (m, 1H), 7.12 - 6.93 (m, 2H), 6.92 - 6.81 (m, 1H), 3.87 - 3.33 (m, 10H), 2.77 (s, 6H), 2.56 (d, J = 12.8 Hz, 1H), 2.25 - 1.94 (m, 3H), 1.90 - 1.68 (m, 4H), 1.60 (d, J = 13.7 Hz, 4H). Compound 17

Chem.

[0283] Compound 17 was synthesized using Method 3 (60 mg, 0.11 mmol, 42%, purity 93.8%). LCMS: m / z (ES+), [M+H]+ = 504.1. 1 H NMR (400 MHz, Methanol-d4) δ 8.42 (dd, J = 4.3, 1.4 Hz, 1H), 7.38 - 7.21 (m, 2H), 7.03 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 10.3 Hz, 1H), 6.87 (t, J = 8.6 Hz, 1H), 4.23 (d, J = 12.6 Hz, 1H), 4.09 (dd, J = 13.5, 5.5 Hz, 1H), 3.74 (dd, J = 9.6, 5.6 Hz, 2H), 3.59 - 3.50 (m, 2H), 3.50 - 3.42 (m, 1H), 2.57 (t, J = 12.2 Hz, 1H), 2.37 (s, 1H), 2.03 (s, 3H), 1.89 (s, 1H), 1.78 (t, J = 13.4 Hz, 1H), 1.57 (d, J = 14.8 Hz, 4H), 1.35 (t, J = 7.3 Hz, 1H), 0.67 - 0.59 (m, 4H). Compound 18

Chemical Structure

[0284] Compound 18 was synthesized as an oil using Method 1 (80 mg, 0.14 mmol, 41%, purity 90.5%). LCMS: m / z (ES+), [M+H]+ = 522.2. 11H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 4.3, 1.3 Hz, 1H), 7.42 - 7.19 (m, 3H), 7.09 - 6.83 (m, 2H), 5.41 - 5.14 (m, 1H), 4.19 - 4.04 (m, 3H), 3.95 (dddd, J = 20.6, 9.6, 4.1, 1.2 Hz, 3H), 3.81 (dt, J = 8.6, 4.4 Hz, 1H), 3.70 - 3.43 (m, 5H), 2.57 (t, J = 12.0 Hz, 1H), 2.33 (s, 1H), 2.04 (d, J = 13.4 Hz, 2H), 1.95 - 1.67 (m, 4H), 1.67 - 1.48 (m, 4H), 1.39 - 1.27 (m, 1H). Compound 19

Chem.

[0285] Compound 19 was synthesized as a solid using Method 2 (14.5 mg, 29.4 μmol, 19%, purity 96.7%). LCMS: m / z (ES+), [M+H]+ = 477.05. 1HNMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 7.44 - 7.19 (m, 3H), 7.09 - 6.99 (m, 1H), 6.99 - 6.81 (m, 2H), 4.09 (dt, J = 11.4, 5.3 Hz, 1H), 3.95 - 3.80 (m, 2H), 3.68 (dd, J = 9.5, 6.0 Hz, 1H), 3.65 - 3.56 (m, 2H), 3.55 - 3.46 (m, 2H), 3.24 - 3.09 (m, 2H), 2.64 - 2.51 (m, 1H), 2.31 (s, 1H), 2.09 - 1.99 (m, 2H), 1.96 - 1.83 (m, 2H), 1.76 (dtd, J = 25.6, 12.9, 3.7 Hz, 2H), 1.58 (dt, J = 16.5, 13.0 Hz, 4H), 1.34 (dt, J = 20.1, 7.3 Hz, 4H). Compound 20

Chem.

[0286] Compound 20 was synthesized as a solid using Method 2 (10.2 mg, 19.7 μmol, 25%, purity 97.3%). LCMS: m / z (ES+), [M+H] + = 503.0. 1HNMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 4.4, 1.3 Hz, 1H), 7.34 (dd, J = 9.4, 4.3 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.03 (dt, J = 7.8, 1.4 Hz, 1H), 6.94 (dt, J = 10.6, 2.1 Hz, 1H), 6.90 - 6.83 (m, 1H), 4.12 - 3.93 (m, 2H), 3.92 - 3.77 (m, 2H), 3.70 - 3.55 (m, 3H), 3.55 - 3.43 (m, 2H), 2.64 - 2.53 (m, 1H), 2.53 - 2.40 (m, 2H), 2.39 - 2.23 (m, 3H), 2.10 - 1.95 (m, 4H), 1.91 - 1.69 (m, 4H), 1.67 - 1.51 (m, 4H), 1.29 (d, J = 4.1 Hz, 1H). Compound 21

Chem.

[0287] Compound 21 was synthesized as a solid using Method 2 (11.1 mg, 22.6 μmol, 37%, purity 99.9%). LCMS: m / z (ES+), [M+H]+ = 491.25. 1HNMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 4.4, 1.3 Hz, 1H), 7.40 - 7.18 (m, 3H), 7.02 (d, J = 7.7 Hz, 1H), 6.97 - 6.82 (m, 2H), 4.16 (dd, J = 13.1, 6.0 Hz, 1H), 3.98 (dd, J = 13.6, 6.0 Hz, 1H), 3.84 (dt, J = 8.6, 4.7 Hz, 1H), 3.70 (dd, J = 9.5, 6.0 Hz, 1H), 3.61 - 3.52 (m, 2H), 3.52 - 3.40 (m, 2H), 3.29 - 3.21 (m, 1H), 2.64 - 2.51 (m, 1H), 2.32 (s, 1H), 2.03 (d, J = 13.6 Hz, 2H), 1.94 - 1.83 (m, 2H), 1.82 - 1.68 (m, 2H), 1.65 - 1.50 (m, 4H), 1.37 (t, J = 7.0 Hz, 6H). Compound 22 [Chem.]

[0288] Compound 22 was synthesized as a solid using Method 3 (6.2 mg, 97.5%, 10.8 μmol). LCMS: m / z (ES+), [M+H]+ = 572.25. 11H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 4.4, 1.3 Hz, 1H), 7.40 - 7.20 (m, 3H), 7.11 - 6.76 (m, 3H), 4.24 - 3.99 (m, 3H), 3.98 - 3.84 (m, 3H), 3.79 (dt, J = 8.7, 4.5 Hz, 1H), 3.69 - 3.38 (m, 6H), 2.65 - 2.50 (m, 1H), 2.33 (s, 1H), 2.13 - 1.98 (m, 2H), 1.95 - 1.68 (m, 4H), 1.66 - 1.48 (m, 4H), 1.36 - 1.22 (m, 1H). Compound 23 [Chem.]

[0289] Compound 23 was synthesized as a solid using Method 3 (7.6 mg, 0.014 mmol, 90% purity). LCMS: m / z (ES+), [M+H]+ = 518.30. 11H NMR (400 MHz, Methanol-d4) δ 8.42 (dd, J = 4.4, 1.3 Hz, 1H), 7.34 (dd, J = 9.4, 4.3 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.03 (d, J = 7.7 Hz, 1H), 6.99 - 6.91 (m, 1H), 6.87 (td, J = 8.5, 2.5 Hz, 1H), 4.12 (s, 1H), 4.03 - 3.87 (m, 3H), 3.78 (dt, J = 8.8, 4.3 Hz, 1H), 3.67 (dd, J = 9.4, 5.5 Hz, 1H), 3.60 - 3.53 (m, 2H), 3.53 - 3.46 (m, 2H), 3.46 - 3.39 (m, 2H), 2.65 (td, J = 15.4, 14.8, 7.7 Hz, 2H), 2.56 (d, J = 12.0 Hz, 1H), 2.33 (s, 1H), 2.04 (d, J = 13.6 Hz, 2H), 1.95 - 1.79 (m, 3H), 1.79 - 1.68 (m, 2H), 1.58 (q, J = 14.1 Hz, 4H), 1.35 - 1.26 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H). Compound 24 [Chem.]

[0290] Compound 24 was synthesized as a solid using Method 3 (11.3 mg, 20.6 μmol, 9.61%, purity 99.6%). LCMS: m / z (ES+), [M+H] + = 547.2. 11H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, 1H), 7.34 (dd, 1H), 7.31 - 7.20 (m, 2H), 7.06 - 6.99 (m, 1H), 6.98 - 6.91 (m, 1H), 6.90 - 6.83 (m, 1H), 4.23 - 4.11 (m, 1H), 4.01 (dd, 1H), 3.79 - 3.72 (m, 1H), 3.69 (dd, 1H), 3.60 - 3.54 (m, 1H), 3.54 - 3.47 (m, 1H), 3.47 - 3.36 (m, 1H), 3.24 (t, 4H), 2.64 - 2.45 (m, 5H), 2.31 (s, 4H), 2.04 (d, 2H), 1.97 - 1.83 (m, 2H), 1.83 - 1.67 (m, 2H), 1.67 - 1.49 (m, 4H), 1.31 (d, 2H). Compound 25

Chem.

[0291] Compound 25 was synthesized as a solid using Method 3 (21.6 mg, 38.8 μmol, 32%, purity 99.4%). LCMS: m / z (ES+), [M+H]+ = 552.15. 1H NMR (400 MHz, Chloroform-d) δ 8.57 (dd, J = 4.5, 1.2 Hz, 1H), 7.26 - 7.20 (m, 2H), 7.02 (d, J = 7.7 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.90 - 6.83 (m, 1H), 6.46 (d, J = 5.4 Hz, 1H), 5.99 (td, J = 56.1, 4.8 Hz, 1H), 4.14 (dd, J = 13.7, 6.0 Hz, 1H), 4.01 (td, J = 8.6, 3.9 Hz, 3H), 3.84 (ddd, J = 11.6, 9.2, 4.8 Hz, 4H), 3.69 (dd, J = 9.9, 4.1 Hz, 2H), 3.64 - 3.56 (m, 1H), 3.37 (ddd, J = 12.8, 8.5, 3.6 Hz, 1H), 3.03 - 2.88 (m, 1H), 2.53 (dd, J = 13.1, 7.4 Hz, 1H), 2.38 (s, 1H), 2.06 (ddt, J = 21.5, 12.9, 4.3 Hz, 3H), 1.94 (ddt, J = 9.9, 6.3, 3.5 Hz, 2H), 1.73 - 1.63 (m, 4H), 1.54 (pd, J = 11.6, 6.2 Hz, 2H). Compound 26 [Chem.]

[0292] Compound 26 was synthesized as a solid using Method 3 (17.5 mg, purity 99.7%). LCMS: m / z (ES+), [M+H]+ = 518.2. 11H NMR (400 MHz, Methanol-d4) δ 8.33 (dd, J = 4.3, 1.4 Hz, 1H), 7.24 (dd, J = 9.4, 4.3 Hz, 1H), 7.21 - 7.11 (m, 2H), 6.93 (d, J = 7.9 Hz, 1H), 6.85 (dt, J = 10.6, 2.1 Hz, 1H), 6.77 (m, 1H), 4.12 - 4.01 (m, 1H), 3.96 - 3.86 (m, 1H), 3.68 (dt, J = 8.8, 4.3 Hz, 1H), 3.61 (dd, J = 9.5, 5.5 Hz, 1H), 3.50 - 3.38 (m, 3H), 3.34 (m, 1H), 2.53 - 2.43 (m, 1H), 2.22 (s, 1H), 1.94 (d, J = 13.3 Hz, 2H), 1.83 (m, 4H), 1.79 (dd, J = 10.2, 5.5 Hz, 1H), 1.78 - 1.58 (m, 2H), 1.50 (s, 3H), 1.45 (d, J = 13.6 Hz, 1H), 1.26 - 1.17 (m, 2H). Compound 27

Chem.

[0293] Compound 27 was synthesized as a solid using Method 3 (9.7 mg, 17 μmol, 4.02%, purity 99.7%). LCMS: m / z (ES+), [M+H] + = 559.25. 11H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, 1H), 7.34 (dd, 1H), 7.31 - 7.21 (m, 2H), 7.03 (d, 1H), 6.99 - 6.92 (m, 1H), 6.91 - 6.83 (m, 1H), 4.17 - 4.07 (m, 1H), 3.96 (dd, 1H), 3.91 (s, 4H), 3.80 - 3.73 (m, 1H), 3.65 (dd, 1H), 3.60 - 3.52 (m, 2H), 3.52 - 3.40 (m, 2H), 2.64 - 2.52 (m, 1H), 2.30 (s, 3H), 2.03 (d, 2H), 1.95 - 1.82 (m, 2H), 1.82 - 1.68 (m, 2H), 1.67 - 1.50 (m, 4H), 1.31 (d, 3H). Compound 28

Chem.

[0294] Compound 28 was synthesized as a solid using Method 3 (17.4 mg, 31.7 μmol, 26%, purity 97.7%). LCMS: m / z (ES+), [M+H] + = 536.2. 1 1H NMR (400 MHz, Methanol-d4) δ 8.42 (d, 1H), 7.40 - 7.20 (m, 3H), 7.03 (d, 1H), 6.99 - 6.91 (m, 1H), 6.91 - 6.82 (m, 1H), 4.59 (d, 1H), 4.52 - 4.43 (m, 1H), 4.12 (d, 1H), 4.02 - 3.87 (m,3H), 3.84 - 3.62 (m, 4H), 3.61 - 3.38 (m, 4H), 3.00 - 2.81 (m, 1H), 2.62 - 2.49 (m, 1H), 2.33 (s, 1H), 2.09 - 1.97 (m, 2H), 1.97 - 1.83 (m, 2H), 1.82 - 1.20 (m, 9H). Compound 29

Chem.

[0295] Compound 29 was synthesized as a solid using Method 3 (10.4 mg, 18.7 μmol, 26%, purity 99.6%). LCMS: m / z (ES+), [M+H]+ = 554.2. 1H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 4.3, 1.3 Hz, 1H), 7.34 (dd, J = 9.4, 4.3 Hz, 1H), 7.31 - 7.22 (m, 2H), 7.02 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 10.5 Hz, 1H), 6.87 (t, J = 9.0 Hz, 1H), 4.15 (d, J = 13.7 Hz, 1H), 3.98 (dd, J = 13.7, 6.1 Hz, 1H), 3.82 (dd, J = 8.5, 4.5 Hz, 1H), 3.70 - 3.64 (m, 2H), 3.62 (s, 1H), 3.58 (d, J = 5.1 Hz, 2H), 3.56 - 3.41 (m, 5H), 2.57 (t, J = 12.2 Hz, 1H), 2.50 - 2.37 (m, J = 14.1, 7.3 Hz, 2H), 2.33 (s, 1H), 2.04 (d, J = 13.7 Hz, 2H), 1.94 - 1.84 (m, 2H), 1.83 - 1.68 (m, 2H), 1.58 (q, J = 14.6 Hz, 4H), 0.10 (s, 1H). Compound 30

Chem.

[0296] Compound 30 was synthesized as a solid using Method 3 (10.2 mg, 18.7 μmol, 25.5%). LCMS: m / z (ES+), [M+H]+ = 547.3. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.4 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.36 - 7.19 (m, 3H), 7.02 (dt, J = 23.5, 9.0 Hz, 3H), 3.99 (dt, J = 12.1, 5.5 Hz, 1H), 3.79 (dd, J = 13.3, 6.9 Hz, 1H), 3.69 (q, J = 7.0, 6.4 Hz, 3H), 3.63 - 3.57 (m, 3H), 3.48 (q, J = 9.2, 7.4 Hz, 3H), 3.27 (s, 1H), 2.99 (p, J = 6.7 Hz, 1H), 2.58 (d, J = 12.2 Hz, 1H), 2.15 (s, 1H), 2.05 (s, 6H), 1.93 (d, J = 13.3 Hz, 2H), 1.81 - 1.61 (m, 4H), 1.60 - 1.40 (m, 4H). Compound 31 [Chem.]

[0297] Compound 31 was synthesized as a solid using Method 3 (19.8 mg, purity 94.6%). LCMS: m / z (ES+), [M+H]+ = 538.1. 11H NMR (400 MHz, Methanol-d4) δ 8.33 (dd, J = 4.3, 1.4 Hz, 2H), 7.29 - 7.22 (m, 1H), 7.23 (s, 2H), 7.26 - 7.12 (m, 4H), 6.93 (d, J = 7.7 Hz, 2H), 6.89 - 6.81 (m, 2H), 6.77 (m, 2H), 4.62 - 4.51 (m, 2H), 4.19 (m, 5H), 4.06 - 3.98 (m, 2H), 3.85 (dt, J = 8.9, 7.4 Hz, 6H), 3.71 (dt, J = 8.6, 4.4 Hz, 2H), 3.56 (dd, J = 9.4, 5.5 Hz, 2H), 3.53 - 3.44 (m, 1H), 3.47 (s, 3H), 3.43 - 3.32 (m, 4H), 2.48 (t, J = 12.0 Hz, 3H), 2.24 (s, 3H), 1.93 (s, 4H), 1.85 - 1.76 (m, 3H), 1.75 - 1.58 (m, 3H), 1.52 (d, J = 14.5 Hz, 7H), 1.47 (d, J = 3.1 Hz, 2H), 1.45 - 1.31 (m, 1H), 1.21 (d, J = 16.6 Hz, 2H), 1.11 (t, J = 7.1 Hz, 1H), 0.88 (t, J = 7.4 Hz, 1H). Compound 44 [Chem.]

[0298] Compound 44 was synthesized as a solid using Method 4 (29.2 mg, 56.0 μmol, 33%, purity 97.5%). LCMS: m / z (ES+), [M+H]+ = 509.1. 11H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.61 (s, 1H), 7.26 - 7.20 (m, 1H), 7.03 - 6.99 (m, 1H), 6.94 (dt, J = 10.4, 2.1 Hz, 1H), 6.87 (tdd, J = 8.4, 2.6, 1.0 Hz, 1H), 6.44 (s, 1H), 4.05 (dd, J = 13.7, 6.4 Hz, 2H), 3.84 - 3.60 (m, 6H), 2.81 (s, 6H), 2.59 - 2.48 (m, 1H), 2.32 (d, J = 3.8 Hz, 1H), 2.03 (d, J = 13.8 Hz, 3H), 1.90 (dq, J = 10.2, 3.4 Hz, 1H), 1.74 - 1.64 (m, 4H), 1.59 - 1.48 (m, 2H). Compound 45

Chem.

[0299] Compound 45 was synthesized as a solid using Method 4 (14.9 mg, 26.8 μmol, 14.1%, purity 94.4%). LCMS: m / z (ES+), [M+H]+ = 525.0. 1H NMR (400 MHz, Methanol-d4) δ 9.09 (s, 1H), 8.23 (s, 1H), 7.28 - 7.21 (m, J = 8.0, 6.1 Hz, 1H), 7.04 - 6.82 (m, 3H), 3.97 (d, J = 14.6 Hz, 2H), 3.83 - 3.73 (m, J = 12.4, 5.7, 4.6 Hz, 2H), 3.70 - 3.60 (m, J = 9.6, 5.7 Hz, 2H), 3.50 (d, J = 45.9 Hz, 2H), 2.78 (s, 6H), 2.52 (d, J = 12.1 Hz, 1H), 2.33 - 2.24 (m, J = 8.9, 4.1 Hz, 1H), 2.01 (s, 1H), 1.93 - 1.47 (m, 9H). Compound 46 [Chem.]

[0300] Compound 46 was synthesized as a solid using Method 4 (34.0 mg, 63.8 μmol, 26.4%, purity 97.9%). LCMS: m / z (ES+), [M+H]+ = 522.2. 11H NMR (400 MHz, Chloroform-d) δ 7.59 (s, 1H), 7.26 - 7.20 (m, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.94 (dd, J = 10.5, 2.5 Hz, 1H), 6.86 (td, J = 8.4, 2.6 Hz, 1H), 6.28 (s, 1H), 4.00 (dd, J = 14.3, 7.0 Hz, 2H), 3.84 - 3.60 (m, 9H), 2.81 (s, 6H), 2.52 (dd, J = 12.9, 7.5 Hz, 1H), 2.29 (s, 1H), 2.10 - 1.99 (m, 3H), 1.90 - 1.85 (m, 1H), 1.73 - 1.65 (m, 4H), 1.61 - 1.50 (m, 2H). Compound 47

Chem.

[0301] Compound 47 was synthesized as an oil using Method 4 (37.7 mg, 75.2 μmol, 34.1%, purity 99.6%). LCMS: m / z (ES+), [M+H]+ = 500.1. 1 1H NMR (400 MHz, Methanol-d4) δ 7.27 - 7.20 (m, 1H), 7.10 - 6.90 (m, 2H), 6.86 (td, J = 8.7, 2.6 Hz, 1H), 3.96 (d, J = 41.4 Hz, 2H), 3.79 - 3.58 (m, 4H), 3.50 (dd, J = 9.6, 7.7 Hz, 1H), 2.79 (s, 6H), 2.58 (t, J = 13.4 Hz, 1H), 2.29 - 2.20 (m, 1H), 2.04 (d, J = 11.2 Hz, 2H), 1.80 (q, J = 12.9 Hz, 4H), 1.60 (d, J = 12.7 Hz, 4H), 1.36 - 1.12 (m, 5H). Compound 48 [Chem.]

[0302] Compound 48 was synthesized as a solid using Method 1 (40.1 mg, 72.8 μmol, 31.6%, purity 94.7%). LCMS: m / z (ES+), [M+H]+ = 522.2 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J = 6.4 Hz, 2H), 7.07 (s, 1H), 6.99 (t, J = 8.4, 8.4 Hz, 1H), 6.43 - 5.94 (m, 1H), 4.28 (t, J = 15.3, 15.3 Hz, 2H), 3.51 (d, J = 34.8 Hz, 7H), 3.30 (s, 1H), 2.67 (s, 6H), 2.50 (s, 2H), 1.97 (d, J = 32.2 Hz, 3H), 1.66 (d, J = 29.3 Hz, 4H), 1.52 (s, 4H). Compound 49 [Chem.]

[0303] Compound 49 was synthesized as a solid using Method 4 (35.4 mg, 66.9 μmol, 26.2%, purity 98.6%). LCMS: m / z(ES+), [M+H]+ = 522.25 11H NMR (400 MHz, Methanol-d4) δ 7.44 (d, J = 29.4 Hz, 1H), 7.25 (s, 1H), 7.09 - 6.80 (m, 3H), 6.50 (d, J = 26.8 Hz, 1H), 3.91 (s, 4H), 3.85 - 3.33 (m, 7H), 2.78 (s, 6H), 2.57 (d, J = 26.6Hz, 1H), 2.26 (d, J = 33.1 Hz, 1H), 2.07 (s, 1H), 1.98 - 1.72 (m, 4H), 1.53 (d, J = 21.7 Hz, 5H), 1.36 - 1.22 (m, 1H). Compound 50

Chem.

[0304] Compound 50 was synthesized as an oil using Method 1 (26.5 mg, 51.0 μmol, 21.2%, purity 96.2%). LCMS: m / z (ES+), [M+H]+ = 500.2 1 1H NMR (400 MHz, DMSO-d6) δ 7.30 (td, J = 13.4, 12.2, 7.6 Hz, 2H), 7.15 - 6.92 (m, 3H), 4.87 - 4.58 (m, 1H), 3.67 - 3.40 (m, 6H), 3.32 - 3.19 (m, 2H), 2.66 (s, 6H), 2.58 (s, 1H), 1.95 (d, J = 12.3 Hz, 3H), 1.70 (s, 2H), 1.55 (d, J = 20.0 Hz, 6H), 1.14 (d, J = 6.2 Hz, 6H). Compound 51

Chem.

[0305] Compound 51 was synthesized as a solid using Method 4 (16.4 mg, 30.8 μmol, 16.2%, purity 98.7%). LCMS: m / z (ES+), [M+H]+ = 525.2 1H NMR (400 MHz, Methanol-d4) δ 7.29 - 7.21 (m, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.96 (t, J = 9.3 Hz, 1H), 6.92 - 6.81 (m, 1H), 3.83 - 3.59 (m, 6H), 3.55 - 3.39 (m, 3H), 3.20 - 3.11 (m, 1H), 2.78 (d, J = 4.8 Hz, 6H), 2.58 (dd, J = 14.5, 11.0 Hz, 1H), 2.38 (d, J = 7.2 Hz, 4H), 2.33 - 2.25 (m, 1H), 2.25 - 2.13 (m, 1H), 2.06 (s, 2H), 1.94 - 1.71 (m, 7H), 1.61 (t, J = 12.1 Hz, 4H). Compound 52

Chemical Structure

[0306] Compound 52 was synthesized as a solid using Method 4 (10.1 mg, 18.0 μmol, 15.1%, purity 97.5%). LCMS: m / z (ES+), [M+H]+ = 523.1 11H NMR (400 MHz, Chloroform-d) δ 7.23 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.93 (dt, J = 10.4, 2.1 Hz, 1H), 6.87 (t, J = 8.4 Hz, 1H), 6.45 (s, 1H), 5.72 (s, 1H), 3.85 (dd, J = 13.6, 7.3 Hz, 1H), 3.72 - 3.55 (m, 9H), 3.41 (s, 1H), 2.81 (s, 6H), 2.69 (dd, J = 16.8, 6.7 Hz, 1H), 2.54 (d, J = 9.4 Hz, 2H), 2.18 (s, 1H), 2.04 (s, 2H), 1.83 (s, 1H), 1.71 (s, 2H), 1.25 (s, 1H). Compounds 53 and 54

Chemical Structure

[0307] Compounds 53 and 54 were synthesized as solids using Method 4 (14.6 mg, 28.1 μmol, 11.8%, purity 98.950%). Compound 53: LCMS: m / z (ES+), [M+H]+ = 514.2 11H NMR (400 MHz, Methanol-d4) δ 7.26 (tt, J = 8.0, 5.7 Hz, 1H), 7.10 - 6.92 (m, 2H), 6.91 - 6.82 (m, 1H), 5.18 - 4.91 (m, 1H), 3.90 (ddd, J = 26.9, 13.2, 6.0 Hz, 1H), 3.73 - 3.66 (m, 1H), 3.63 (dq, J = 6.3, 2.3 Hz, 2H), 3.61 - 3.51 (m, 2H), 3.47 (dd, J = 9.5, 7.1 Hz, 1H), 3.39 (ddd, J = 18.9, 10.7, 4.6 Hz, 2H), 2.77 (d, J = 4.5 Hz, 6H), 2.73 - 2.25 (m, 5H), 2.18 (dd, J = 9.7, 4.4 Hz, 1H), 2.12 - 1.98 (m, 2H), 1.91 - 1.69 (m, 4H), 1.69 - 1.49 (m, 4H). Compound 54 LCMS: m / z(ES+), [M+H]+ = 514.2 1 1H NMR (400 MHz, Methanol-d4) δ 7.32 - 7.21 (m, 1H), 7.11 - 6.92 (m, 2H), 6.92 - 6.80 (m, 1H), 3.85 (s, 1H), 3.65 (td, J = 17.7, 15.1, 9.6 Hz, 4H), 3.48 (tt, J = 19.0, 10.5 Hz, 3H), 2.92 (dt, J = 16.8, 8.1 Hz, 1H), 2.78 (d, J = 4.7 Hz, 6H), 2.61 (d, J = 29.2 Hz, 3H), 2.47 (t, J = 8.5 Hz, 1H), 2.35 (dd, J = 29.5, 10.2 Hz, 1H), 2.18 (s, 1H), 2.12 - 1.96 (m, 2H), 1.91 - 1.70 (m, 4H), 1.64 (d, J = 27.4 Hz, 4H). Compound 55 [Chem.]

[0308] Method 5: Pyridine (115 mg, 117 μL, 6 eq, 1.45 mmol) was added to a stirred solution of morpholine (42.1 mg, 2 eq, 484 μmol) in DCM (2 mL). Triphosgene (71.8 mg, 45 μL, 1 eq, 242 μmol) was added to the mixture solution at 0 °C. The mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to give a crude intermediate. A solution of the starting piperidine intermediate (100 mg, 1 eq, 242 μmol) and TEA (73.4 mg, 101 μL, 3 eq, 725 μmol) in DCM (2 mL) was added to the mixture. The resulting mixture was stirred for 1 h. The reaction was monitored by LCMS. The residue was purified by Prep-TLC, followed by chiral HPLC to give compound 55 (10.6 mg, 19.7 μmol, 10.4%, purity 98.0%) as an oil. LCMS: m / z (ES+), [M+H]+ = 527.25 11H NMR (400 MHz, Chloroform-d) δ 7.26 - 7.20 (m, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.94 (dt, J = 10.5, 2.1 Hz, 1H), 6.87 (td, J = 8.5, 2.6 Hz, 1H), 6.25 (d, J = 5.2 Hz, 1H), 3.78 (dd, J = 9.8, 7.7 Hz, 1H), 3.72 - 3.67 (m, 5H), 3.63 (dd, J = 6.0, 4.0 Hz, 2H), 3.53 (dd, J = 13.6, 6.2 Hz, 2H), 3.30 - 3.22 (m, 5H), 3.14 (ddd, J = 12.9, 8.2, 3.4 Hz, 1H), 2.80 (s, 6H), 2.59 - 2.47 (m, 1H), 2.30 - 2.22 (m, 1H), 2.03 (d, J = 14.0 Hz, 2H), 1.94 (tt, J = 8.5, 4.0 Hz, 1H), 1.85 - 1.77 (m, 1H), 1.73 - 1.65 (m, 4H), 1.55 (q, J = 14.8, 13.9 Hz, 2H). Compounds 56 and 57

Chemical Structure

[0309] Compounds 56 and 57 were synthesized as solids using Method 3 (10.3 mg, 17.3 μmol, 13%, purity 99.1%). Compound 56 LCMS: m / z (ES+), [M+H]+ = 589.3 11H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 4.3, 1.3 Hz, 1H), 7.34 (dd, J = 9.4, 4.3 Hz, 1H), 7.31 - 7.22 (m, 2H), 7.03 (dt, J = 7.7, 1.3 Hz, 1H), 6.95 (dt, J = 10.6, 2.1 Hz, 1H), 6.92 - 6.83 (m, 1H), 4.20 - 4.09 (m, 1H), 4.05 - 3.96 (m, 1H), 3.79 (dt, J = 8.7, 4.3 Hz, 1H), 3.70 (dd, J = 9.5, 5.6 Hz, 1H), 3.62 - 3.40 (m, 6H), 3.34 (dd, J = 10.0, 3.3 Hz, 2H), 3.16 - 3.02 (m, 2H), 2.64 - 2.51 (m, 1H), 2.33 (s, 1H), 2.23 (s, 4H), 2.09 - 1.99 (m, 2H), 1.97 - 1.68 (m, 5H), 1.66 - 1.50 (m, 4H), 1.28 (s, 2H), 1.07 (dd, J = 6.6, 3.1 Hz, 6H). Compound 57 LCMS: m / z (ES+), [M+H]+ = 589.3 11H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 4.3, 1.3 Hz, 1H), 7.34 (dd, J = 9.4, 4.3 Hz, 1H), 7.30 - 7.21 (m, 2H), 7.03 (m, J = 7.7, 1.3 Hz, 1H), 6.95 (m, J = 10.6, 2.1 Hz, 1H), 6.92 - 6.83 (m, 1H), 4.22 - 4.11 (m, 1H), 4.00 (dd, J = 13.6, 6.1 Hz, 1H), 3.79 (m, J = 8.7, 4.3 Hz, 1H), 3.70 (dd, J = 9.5, 5.6 Hz, 1H), 3.63 - 3.41 (m, 6H), 3.41 - 3.32 (m, 2H), 3.17 - 2.98 (m, 2H), 2.64 - 2.51 (m, 1H), 2.37 (d, J = 28.9 Hz, 1H), 2.24 (s, 4H), 2.03 (t, J = 8.5 Hz, 2H), 1.96 - 1.67 (m, 5H), 1.67 - 1.48 (m, 4H), 1.30 (d, J = 16.7 Hz, 1H), 1.07 (dd, J = 6.6, 3.1 Hz, 6H). Compound 58 [Chem.]

[0310] Method 6: To a stirred mixture of phenyl (3R,4S)-4-(((N,N-dimethylsulfamoyl)amino)-3-((((1S,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidine-1-carboxylate (90.0 mg, 1 equiv, 169 μmol) and (1-fluorocyclopropyl)methanol (45.6 mg, 3 equiv, 506 μmol) in DMF (2 mL) was added sodium hydride (24.3 mg, 6 equiv, 1.01 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for an additional 2 h. The residue was purified by Prep-TLC, followed by prep~CHIRAL reverse phase column to afford Compound 58 (16.4 mg, 30.5 μmol, 26.9%, purity 98.5%) as a semi-solid. LCMS: m / z (ES+), [M+H]+ = 530.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (qd, J = 7.1, 6.2, 4.4 Hz, 2H), 7.13 - 6.93 (m, 3H), 4.30 (d, J = 23.1 Hz, 2H), 3.72 - 3.45 (m, 6H), 3.40 (t, J = 5.9 Hz, 1H), 2.67 (s, 6H), 2.57 (t, J = 12.2 Hz, 1H), 1.97 (d, J = 31.6 Hz, 3H), 1.81 - 1.58 (m, 4H), 1.58 - 1.43 (m, 4H), 1.02 (s, 2H), 0.86 - 0.72 (m, 2H). Compound 59

Chemical formula

[0311] Compound 59 was synthesized as a solid using Method 6 (10.4 mg, 19.7 μmol, 14.8%, purity 99.8%). LCMS: m / z (ES+), [M+H]+ = 527.2. 11H NMR (400 MHz, Methanol-d4) δ 7.26 (q, J = 7.4 Hz, 1H), 7.12 - 6.80 (m, 3H), 3.76 (s, 2H), 3.64 (q, J = 4.2 Hz, 5H), 3.49 (s, 1H), 3.36 (s, 1H), 3.13 (d, J = 29.6 Hz, 2H), 2.78 (s, 6H), 2.60 (s, 1H), 2.34 (d, J = 11.3 Hz, 3H), 2.12 (d, J = 53.0 Hz, 3H), 1.93 - 1.70 (m, 4H), 1.61 (d, J = 13.3 Hz, 4H). Compound 60

Chem.

[0312] Compound 60 was synthesized as an oil using Method 1 (14.4 mg, 28.8 μmol, 14.3%, purity 99.4%). LCMS: m / z (ES+), [M+H]+ = 498.2. 1 1H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.19 (m, 2H), 7.13 - 6.90 (m, 3H), 3.96 (s, 1H), 3.52 (d, J = 19.5 Hz, 6H), 3.29 - 3.20 (m, 2H), 2.66 (s, 6H), 2.58 (t, J = 10.6, 10.6 Hz, 1H), 2.09 - 1.84 (m, 3H), 1.70 (d, J = 12.4 Hz, 2H), 1.62 - 1.39 (m, 6H), 0.55 (d, J = 32.1 Hz, 4H). Compound 61

Chem.

[0313] Compound 61 was synthesized as a solid using Method 5 (15.7 mg, 28.3 μmol, 31%, purity 98.7%). LCMS: m / z (ES+), [M+H]+ = 547.0. 1H NMR (400 MHz, Methanol-d4) δ 7.29 - 7.22 (m, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 10.6 Hz, 1H), 6.89 - 6.83 (m, J = 8.6, 2.5 Hz, 1H), 3.84 - 3.72 (m, 1H), 3.70 - 3.47 (m, 9H), 3.26 (d, J = 3.4 Hz, 1H), 3.20 - 3.12 (m, J = 9.2, 8.7, 4.2 Hz, 1H), 2.77 (s, 6H), 2.58 (t, J = 12.0 Hz, 1H), 2.34 - 2.18 (m, 3H), 2.04 (d, J = 13.2 Hz, 2H), 1.87 - 1.68 (m, 4H), 1.60 (d, J = 12.7 Hz, 4H). Compound 62

Chemical Structure

[0314] Compound 62 was synthesized as a solid using Method 5 (6.8 mg, 13 μmol, 23%, purity 99.5%). LCMS: m / z (ES+), [M+H]+ = 533.20. 1H NMR (400 MHz, Methanol-d4) δ 7.26 (q, J = 7.4 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 10.6 Hz, 1H), 6.86 (t, J = 8.2 Hz, 1H), 4.44 - 4.20 (m, J = 39.7, 11.7 Hz, 4H), 3.73 - 3.56 (m, 5H), 3.48 (t, J = 8.8 Hz, 1H), 3.40 - 3.33 (m, J = 13.5, 3.5 Hz, 1H), 3.24 (d, J = 12.8 Hz, 1H), 2.77 (s, 6H), 2.58 (t, J = 11.4 Hz, 1H), 2.19 (s, 1H), 2.06 (d, J = 13.5 Hz, 2H), 1.87 - 1.71 (m, 4H), 1.68 - 1.52 (m, J = 20.6, 11.9 Hz, 4H). Compound 63

Chem.

[0315] Compound 63 was synthesized as an oil using Method 3 (16.7 mg, purity 98.3%). LCMS: m / z (ES+), [M+H]+ = 536.1. 11H NMR (400 MHz, Methanol-d4) δ 8.42 (dd, J = 4.4, 1.3 Hz, 1H), 7.34 (dd, J = 9.3, 4.3 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.03 (d, J = 7.7 Hz, 1H), 6.94 (dd, J = 10.5, 2.2 Hz, 1H), 6.91 - 6.82 (m, 1H), 4.19 - 4.11 (m, 1H), 3.99 (dd, J = 13.7, 6.0 Hz, 1H), 3.72 (m, 2H), 3.62 - 3.51 (m, 4H), 3.55 - 3.48 (m, 1H), 3.37 (dd, J = 9.8, 6.5 Hz, 8H), 2.89 (s, 3H), 2.62 - 2.52 (m, 1H), 2.33 (s, 1H), 2.04 (d, J = 13.6 Hz, 2H), 1.96 - 1.68 (m, 3H), 1.58 (m, 4H). Compound 64 [Chem.]

[0316] Using Method 3 (14.1 mg, purity 95.0%), Compound 64 was synthesized as an oil. LCMS: m / z (ES+), [M+H]+ = 524.1. 11H NMR (400 MHz, Methanol-d4) δ 8.33 (d, J = 4.3 Hz, 1H), 7.24 (dd, J = 9.4, 4.3 Hz, 1H), 7.21 - 7.11 (m, 2H), 6.93 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 10.9 Hz, 1H), 6.77 (td, J = 8.4, 2.6 Hz, 1H), 4.56 (t, J = 4.9 Hz, 1H), 4.50 - 4.41 (m, 1H), 4.06 (dd, J = 12.7, 6.3 Hz, 1H), 3.91 (dd, J = 13.6, 5.9 Hz, 1H), 3.64 (dd, J = 8.7, 4.5 Hz, 1H), 3.63 - 3.53 (m, 1H), 3.51 - 3.33 (m, 5H), 3.31 (dt, J = 8.5, 4.3 Hz, 1H), 3.25 (s, 2H), 2.82 (s, 3H), 2.53 - 2.42 (m, 1H), 2.23 (s, 1H), 1.94 (d, J = 13.7 Hz, 2H), 1.87 - 1.58 (m, 3H), 1.56 - 1.41 (m, 4H), 1.19 (s, 0H). Compound 65 [Chem.]

[0317] Compound 65 was synthesized as a semi-solid using Method 6 (11.5 mg, 19.8 μmol, 26.5%, purity 92.1%). LCMS: m / z (ES+), [M+Na]+ = 558.0. 11H NMR (400 MHz, DMSO-d6) δ 7.31 (m, J = 7.1, 6.2, 4.3 Hz, 2H), 7.18 - 6.91 (m, 3H), 6.08 (m, J = 55.0, 19.1 Hz, 1H), 4.91 (d, J = 6.6 Hz, 1H), 3.56 (s, 5H), 2.67 (s, 6H), 2.59 (d, J = 12.2 Hz, 1H), 1.97 (d, J = 30.5 Hz, 3H), 1.80 - 1.41 (m, 8H), 1.20 (t, J = 10.9 Hz, 3H). Compound 66 [Chem.]

[0318] Compound 66 was synthesized as a semi-solid using Method 6 (27.9 mg, 51.2 μmol, 34.3%, purity 99.7%). LCMS: m / z (ES+), [M+H]+ = 544.3. 1 1H NMR (400 MHz, Methanol-d4) δ 7.25 (m, J = 7.9, 6.0 Hz, 1H), 7.01 (d, J = 31.4 Hz, 2H), 6.90 - 6.82 (m, 1H), 4.33 - 4.17 (m, 2H), 3.77 (d, J = 34.1 Hz, 2H), 3.68 - 3.60 (m, 3H), 3.54 - 3.33 (m, 3H), 2.77 (s, 6H), 2.57 (t, J = 11.0 Hz, 1H), 2.34 - 2.12 (m, 5H), 2.05 (d, J = 13.5 Hz, 2H), 1.77 (dd, J = 7.8, 4.4 Hz, 5H), 1.65 - 1.47 (m, 5H).

[0319] Example 2: Human OX2R IP1 Assay T-Rex CHO cells that stably overexpress human orexin 2 receptor (OX2R) are induced overnight in a T225 flask using 1 μg / mL doxycycline. Twenty-four 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.

[0320] 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.

[0321] The EC 50 values reported in Table 2 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

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

[0322] 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 defined by the appended claims.

Claims

1. Compounds 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, where the 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 Forms alkylene, 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 Forms alkylene, m is 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. however, Y is S (=O) ２ And, m is 1, 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-membered to 10-membered heterocyclyl, or C １ ~C ３ Alkylene-(4-membered to 10-membered heterocycline), and the above 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-membered to 10-membered heterocyclyl, or C １ ~C ３ Alkylene-(4- to 10-membered heterocyclyl) is either unsubstituted or has one or more halogens, hydroxyl, C １ ~C ３ Alkyl, or C １ ~C ３ It is substituted with alkoxy, R １ However, (CR ｃ R ｄ ) ｎ - (C ６ ~C １０ (Aryl) or (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl) n is 0 or 1, R ａ and R ｂ However, each independently, H or unsubstituted C １ ~C ３ It is alkyl, Ring A is either unsubstituted, or each independently, C １ ~C ３ If substituted with 1 to 3 substituents selected from alkyl or halogen, X is N. A compound of formula I-A or a pharmaceutically acceptable salt thereof.

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

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 3, wherein ring A is a phenyl ring, and each of the rings is independently substituted with one or two substituents selected from halogens.

5. The compound according to claim 4, wherein ring A is 3-fluorophenyl.

6. Ring A is a pyridinyl 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.

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 It is an aryl, or E is 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 C substituted with alkoxyl ６ ~C １０ - The compound according to claim 1 or 2, wherein it is an aryl compound.

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. E is CF ３ The compound according to claim 1 or 2, which is CHF2 or CH2F.

26. E is NH (CH ３ The compound according to claim 1 or 2, wherein the compound is 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, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls 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 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 alkoxyl, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ Each of them is 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 H or unsubstituted C １ ~C ３ The compound according to claim 1 or 2, 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 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.

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 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.

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 independently consists of H, halogen, and 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 58, wherein each of them is H.

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

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 or a pharmaceutically acceptable salt thereof, or a composition thereof, according to any one of claims 1 to 60, 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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