Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/56—Nitrogen atoms
  • C07D211/58—Nitrogen atoms attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
  • C07D211/98—Nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems

Definitions

• Orexin A and orexin B bind to orexin receptors.
• Orexin receptors are G protein-coupled receptors expressed preferentially 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 a variety of 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).
• Narcolepsy is a neurological disease that results in excessive daytime sleepiness, sudden bouts of muscular paralysis (cataplexy), and disrupted sleep patterns (Mahoney et al., Nature Reviews Neuroscience, 2019). It is known that narcolepsy is caused by the degeneration of orexin neurons. Narcoleptic symptoms can be modeled in transgenic mice engineered to degenerate orexin neurons, and their symptoms can be reversed by intraventricular administration of orexin peptides (Proc. Natl. Acad. Sci. USA, Vol.101, 4649-4654, 2004).
• orexin-2 receptor knockout mice have suggested that the orexin-2 receptor plays a preferential role in maintaining wakefulness (Cell, Vol.98, 437- 451, 1999, Neuron, Vol.38, 715-730, 2003).
• orexin-2 receptor agonists can 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).
• a compound having agonist activity at the orexin-2 receptor is hypothesized to be useful as a novel therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbance of consciousness such as coma and the like, narcolepsy syndrome, hypersomnolence syndrome characterized by hypersomnia (e.g., in Parkinson’s disease, Guillain-Barre syndrome or Kleine Levin syndrome), Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, or sepsis and the like.
• hypersomnia e.g., in Parkinson’s disease, Guillain-Barre syndrome or Kleine Levin syndrome
• Alzheimer’s disease e.g., in Parkinson’s disease, Guillain-Barre syndrome or Kleine Levin syndrome
• Alzheimer’s disease e.g., in Parkinson’s disease, Guillain-Barre syndrome or Kleine Levin syndrome
• Alzheimer’s disease e.g
• the present invention aims to provide substituted piperidino compounds having orexin-2 receptor agonist activity. Accordingly, in an initial aspect, the present invention provides a compound represented by Formula I-A or a pharmaceutically acceptable salt thereof:
• T is CR6 or N
• U is CR 5 or N
• V is CR4 or N
• W is CR 3 or N
• X is CR 2 or N; includes no more than 3 nitrogen atoms in the ring
• E is selected from the group consisting of NR a R b , C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-( C 3 -C 8 cycloalkyl), 4- to 10- membered heterocyclyl, and C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl) wherein the C 1 - C3 alkylene-NRaRb, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alky
• T is CR 6 or N
• U is CR5 or N
• V is CR 4 or N
• W is CR 3 or N
• E is selected from the group consisting of NRaRb, C 1 -C 3 alkylene-NRaRb, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10- membered heterocyclyl, and C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl) wherein the C1- C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2
• a pharmaceutical composition comprising a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• a method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• a method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• compounds e.g., the compounds of Formula I-A or I, or pharmaceutically acceptable salts thereof, that are useful in the treatment of narcolepsy or cataplexy in a subject.
• these compounds may modulate the orexin-2 receptor.
• the compounds provided herein are considered orexin-2 agonists.
• the compounds provided herein are useful in treatment of narcolepsy in a subject by acting as an agonist of the orexin-2 receptor. Definitions Listed below are definitions of various terms used to describe this invention.
• the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, including ⁇ 5%, ⁇ 1%, and ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
• the term “EC50” refers to the concentration of a compound required to achieve an effect that is 50% of the maximal observed effect of a compound.
• agonist refers to a compound that, when contacted with a target of interest (e.g., the orexin-2 receptor), causes an increase in the magnitude of a certain activity or function of the target compared to the magnitude of the activity or function observed in the absence of the agonist.
• a target of interest e.g., the orexin-2 receptor
• treatment includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
• the treatment comprises bringing into contact with the orexin-2 receptor an effective amount of a compound of the invention for conditions related to narcolepsy or cataplexy.
• the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.
• the term “patient,” “individual” or “subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the patient, subject, or individual is human.
• the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
• the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
• pharmaceutically acceptable salt refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
• Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• pharmaceutically acceptable salt is not limited to a mono, or 1:1, salt.
• “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt.
• composition refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier.
• the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
• the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
• a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
• Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
• Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient.
• materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; 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; surface active agents; alginic acid; pyrogen-free water; isotonic saline
• “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
• the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
• Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
• alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C 1-6 alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl.
• C 1 -C 6 -alkyl examples include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.
• halo or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
• alkylene refers to divalent aliphatic hydrocarbyl groups, for example, having from 1 to 4 carbon atoms that are either straight-chained or branched.
• alkenyl denotes 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 the point of attachment to another group.
• Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, prop-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.
• alkynyl denotes 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 the point of attachment to another group.
• Alkynyl groups include, but are not limited to, for example, ethynyl, propynyl, prop-1-yn-2-yl, butynyl, 1-methyl-2-butyn-1-yl, heptynyl, octynyl and the like.
• alkoxy refers to the group –O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy and the like.
• cycloalkyl means a non-aromatic carbocyclic system that is partially or fully saturated having 1, 2 or 3 rings wherein such rings may be fused.
• 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 may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms.
• 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.
• heterocyclyl means a non-aromatic carbocyclic system containing 1, 2, 3 or 4 heteroatoms selected independently from N, O, and S and having 1, 2 or 3 rings wherein such rings may be fused, wherein fused is defined above.
• Heterocyclyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 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 also specifically includes, but is not limited to, epoxidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl
• bridged bicyclic heterocyclyl refers to non-aromatic heterocyclic ring systems in which two rings share more than two atoms.
• the bridged bicyclic ring system can be, for example, [3.2.1] bicyclic ring systems such as azabicyclo[3.2.1]octane or [3.1.1] bicyclic ring systems such as azabicyclo[3.1.1]heptane.
• aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be bonded or otherwise attached to a designated moiety through differing ring atoms (i.e., shown or described without denotation of a specific point of attachment), then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom.
• pyridinyl means 2-, 3- or 4-pyridinyl
• thiophenyl means 2- or 3-thiophenyl, and so forth.
• substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
• the present invention provides a compound represented by Formula I-A or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof; wherein: T is CR 6 or N; U is CR5 or N; V is CR4 or N; W is CR 3 or N; includes no more than 3 nitrogen atoms in the ring; E is selected from the group consisting of NRaRb, C 1 -C 3 alkylene-NRaRb, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10- membered heterocyclyl, and C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl) wherein the C1- C 3 alkylene-NR a R b , C 1 -C
• T is CR6 or N
• U is CR 5 or N
• V is CR4 or N
• W is CR 3 or N
• X is CR 2 or N; includes no more than 3 nitrogen atoms in the ring
• E is selected from the group consisting of NR a R b , C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4-to 10- membered heterocyclyl, and C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl) wherein the C 1 - C3 alkylene-NRaRb, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alky
• Formula (I) is selected from the group consisting , In another embodiment of Formula (I), is selected from the group In another embodiment of Formula In another embodiment of Formula . In another embodiment of Formula . In another embodiment of Formula . In another embodiment of Formula (I), . In another embodiment of Formula . In another embodiment of Formula (I), . In another embodiment of Formula . In another embodiment of Formula (I), . In another embodiment of Formula . In another embodiment of Formula ( . In another embodiment of Formula (I), . In another embodiment of Formula . In another embodiment of Formula ( . In another embodiment of Formula (I), . In another embodiment of Formula . In another embodiment of Formula . 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.
• 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. In another embodiment of Formula (I), p is 1 and R 14 is deuterium. In another embodiment of Formula (I), p is 1 and R 14 is halogen. In another embodiment of Formula (I), p is 1 and R 14 is fluorine. In another embodiment of Formula (I), p is 1 and R 14 is hydroxyl. In another embodiment of Formula (I), p is 1 and R 14 is cyano. In another embodiment of Formula (I), p is 2 and each R 14 is hydroxyl.
• p is 2 and each R 14 is halogen. In another embodiment of Formula (I), p is 2 and each R 14 is fluorine.
• E is NR a R b . In another embodiment of Formula (I), E is C 1 -C 3 alkylene-NRaRb. In another embodiment of Formula (I), E is unsubstituted C 1 -C 3 alkyl, unsubstituted C 2 -C 4 alkenyl or unsubstituted C 2 -C 4 alkynyl.
• E is C 1 -C 3 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.
• E is unsubstituted C 1 -C 3 alkyl.
• E is C 1 -C 3 alkyl substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.
• E is unsubstituted C 3 -C 8 cycloalkyl.
• E is C 3 -C 8 cycloalkyl substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.
• E is unsubstituted C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl).
• E is C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl) substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.
• E is unsubstituted 4- to 10- membered heterocyclyl.
• E is 4- to 10-membered heterocyclyl substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.
• E is unsubstituted C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl).
• E is C 1 -C 3 alkylene-(4- to 10- membered heterocyclyl) substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C1- C 3 alkoxyl.
• E is C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, or C 1 - C3 alkylene-(4- to 10-membered heterocyclyl), wherein the C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, or C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl,
• E is C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, or C 1 -C 3 alkylene-(4- to 10- membered heterocyclyl), wherein the C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, or C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.
• E is C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), wherein the C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 3 alkylene- (C 3 -C 8 cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.
• R 1 is (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted.
• R 1 is (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
• R 1 is (CRcRd)n-(C6-C10 aryl) or (CRcRd)n-(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted and further wherein n is 0.
• R 1 is (CRcRd)n-(C6-C10 aryl) or (CRcRd)n-(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.
• R 1 is (CRcRd)n-(C6-C10 aryl) or (CRcRd)n-(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is unsubstituted and further wherein n is 1.
• R 1 is (CRcRd)n-(C6-C10 aryl) or (CRcRd)n-(5- to 10-membered heteroaryl) wherein the aryl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 1.
• R 1 is (CRcRd)n-(C6-C10 aryl) wherein the aryl is unsubstituted.
• R 1 is (CR c R d ) n -(C 6 -C 10 aryl) wherein the aryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C1- C3 alkyl substituted with one or more halogen or deuterium.
• R 1 is (CRcRd)n-(C6-C10 aryl) wherein the aryl is unsubstituted and further wherein n is 0.
• R 1 is (CR c R d ) n -(C 6 -C 10 aryl) wherein the aryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.
• R 1 is (CRcRd)n-(C6-C10 aryl) wherein the aryl is unsubstituted and further wherein n is 1.
• R 1 is (CRcRd)n-(C6-C10 aryl) wherein the aryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 1.
• R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the heteroaryl is unsubstituted.
• R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
• R 1 is (CRcRd)n-(5- to 10-membered heteroaryl) wherein the heteroaryl is unsubstituted and further wherein n is 0.
• R 1 is (CRcRd)n-(5- to 10-membered heteroaryl) wherein the heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.
• R 1 is (CRcRd)n-(5- to 10-membered heteroaryl) wherein the heteroaryl is unsubstituted and further wherein n is 1.
• R 1 is (CRcRd)n-(5- to 10-membered heteroaryl) wherein the heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 1.
• R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7- membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted.
• R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
• R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7- membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted and further wherein n is 0.
• R 1 is (CRcRd)n-(phenyl) or (CRcRd)n-(5- to 7- membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.
• R 1 is (CRcRd)n-(phenyl) or (CRcRd)n-(5- to 7- membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted and further wherein n is 1.
• R 1 is (CRcRd)n-(phenyl) or (CRcRd)n-(5- to 7- membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 1.
• R 1 is (CRcRd)n-(phenyl) or (CRcRd)n-(6- membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted.
• R 1 is (CRcRd)n-(phenyl) or (CRcRd)n-(6-membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
• R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6- membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted and further wherein n is 0.
• R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6- membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.
• R 1 is (CRcRd)n-(phenyl) or (CRcRd)n-(6- membered heteroaryl) wherein the phenyl or heteroaryl is unsubstituted and further wherein n is 1.
• R 1 is (CRcRd)n-(phenyl) or (CRcRd)n-(6- membered heteroaryl) wherein the phenyl or heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 1.
• each of R2, R 3 , R4, R5, and R6, when present, is, independently, selected from the group consisting of H, halogen, hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen.
• each of R 2 , R 3 , R 4 , R 5 , and R 6 when present, is, independently, selected from the group consisting of H, halogen, hydroxyl, and unsubstituted C 1 -C 3 alkyl.
• each of R2, R 3 , R4, R5, and R6, when present, is, independently, selected from the group consisting of H, halogen, and unsubstituted C1- C3alkyl.
• each of R2, R 3 , R4, R5, and R6, when present, is, independently, selected from H or halogen.
• each of R2, R 3 , R4, R5, and R6, when present, is, independently, selected from H or fluorine.
• each of R 2 , R 3 , R 4 , R 5 , and R 6 when present, is, independently, selected from H or chlorine.
• each of R 2 , R 3 , R 4 , R 5 , and R 6 when present, is, independently, selected from H or unsubstituted C 1 alkyl.
• each of R2, R 3 , R4, R5, and R6, when present, is, independently, selected from H or hydroxyl.
• each of R2, R 3 , R4, R5, and R6, when present, is H.
• each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, independently, H, halogen, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
• R 8 and R 11 together, form an unsubstituted C 1 -C 3 alkylene or a C 1 -C 3 alkylene substituted with one or more halogen.
• R 8 and R 11 together, form an unsubstituted C2 alkylene or a C2 alkylene substituted with one or more halogen.
• R 8 and R 11 together, form an azabicyclo[3.2.1]octanyl bridged bicyclic heterocyclyl.
• R 9 and R 10 together, form an unsubstituted C 1 -C 3 alkylene or a C 1 -C 3 alkylene substituted with one or more halogen.
• R 9 and R 10 together, form an unsubstituted C2 alkylene or a C2 alkylene substituted with one or more halogen.
• R 9 and R 10 together, form an azabicyclo[3.2.1]octanyl bridged bicyclic heterocyclyl.
• each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, independently, H, halogen, or unsubstituted C 1 -C 3 alkyl.
• each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, independently, H, fluorine, or unsubstituted C 1 -C 3 alkyl.
• each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, independently, H, halogen, or unsubstituted C 1 alkyl.
• each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, independently, H or unsubstituted C1 alkyl. In another embodiment of Formula (I), each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is, independently, H or halogen. In another embodiment of Formula (I), each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• each of R2, R 3 , R4, R5, and R6, when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• each of R2, R 3 , R4, R5, and R6, when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• each of R2, R 3 , R 4 , R 5 , and R 6 when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• each of R2, R 3 , R4, R5, and R6, when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CRcRd)n-(5- to 10-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CRcRd)n-(5- to 10- membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl), each of R 2 , R 3 , R4, R5, and R6, when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CRcRd)n-(5- to 7-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CRcRd)n-(5- to 7-membered heteroaryl), each of R2, R 3 , R4, R5, and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CRcRd)n-(5- to 7-membered heteroaryl), each of R2, R 3 , R4, R5, and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CRcRd)n-(5- to 7-membered heteroaryl), each of R2, R 3 , R4, R5, and R6, when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CRcRd)n-(6-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CRcRd)n-(6-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CRcRd)n-(6- membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CR c R d ) n -(6-membered heteroaryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CRcRd)n-(6-membered heteroaryl), n is 0, each of R2, R 3 , R4, R5, and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CRcRd)n-(6-membered heteroaryl), n is 0, each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, each of R2, R 3 , R4, R5, and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, each of R2, R 3 , R4, R5, and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CRcRd)n-(6-membered heteroaryl), n is 1, each of R2, R 3 , R4, R5, and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CRcRd)n-(6-membered heteroaryl), n is 1, each of R2, R 3 , R4, R5, and R6, when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CRcRd)n-(C6-C10 aryl), each of R2, R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CRcRd)n-(C6-C10 aryl), each of R2, R 3 , R4, R5, and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 - C3 alkyl.
• R 1 is (CRcRd)n-(C6-C10 aryl), each of R2, R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CRcRd)n-(C6-C10 aryl), each of R2, R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CR c R d ) n -(C 6 aryl), each of R 2 , R 3 , R 4 , R5, and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CR c R d ) n -(C 6 aryl), each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CR c R d ) n -(C 6 aryl), each of R 2 , R 3 , R 4 , R 5 , and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CRcRd)n-(C6 aryl), each of R2, R 3 , R4, R5, and R6, when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CRcRd)n-(C6 aryl), n is 0, each of R2, R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CRcRd)n-(C6 aryl), n is 0, each of R2, R 3 , R4, R5, and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CRcRd)n-(C6 aryl), n is 0, each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CRcRd)n-(C6 aryl), n is 0, each of R 2 , R 3 , R 4 , R 5 , and R 6 , when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CR c R d ) n -(C 6 aryl), n is 1, each of R 2 , R 3 , R4, R5, and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CR c R d ) n -(C 6 aryl), n is 1, each of R 2 , R 3 , R 4 , R 5 , and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CR c R d ) n -(C 6 aryl), n is 1, each of R2, R 3 , R4, R5, and R6, when present, is H, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CR c R d ) n -(C 6 aryl), n is 1, each of R2, R 3 , R4, R5, and R6, when present, is H and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CRcRd)n-(6-membered heteroaryl), n is 0, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CRcRd)n-(6-membered heteroaryl), n is 0, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CR c R d ) n -(6- membered heteroaryl), n is 0, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CR c R d ) n -(6-membered heteroaryl), n is 1, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CRcRd)n-(6- membered heteroaryl), n is 1, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CRcRd)n-(6-membered heteroaryl), n is 1, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CRcRd)n-(C6 aryl), n is 0, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CRcRd)n- (C 6 aryl), n is 0, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CRcRd)n-(C6 aryl), n is 0, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CRcRd)n-(C6 aryl), n is 0, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• R 1 is (CR c R d ) n -(C 6 aryl), n is 1, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H.
• R 1 is (CRcRd)n- (C 6 aryl), n is 1, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or unsubstituted C 1 -C 3 alkyl.
• R 1 is (CRcRd)n-(C6 aryl), n is 1, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or halogen.
• R 1 is (CRcRd)n-(C6 aryl), n is 1, and each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is H or fluorine.
• Table 1 Compounds of Formula I-A or I, or pharmaceutically acceptable salts thereof, and compounds of Table 1, or pharmaceutically acceptable salts thereof, collectively or individually are sometimes referred to herein as “compounds of the invention” or “compounds provided herein”. Table 1
• the disclosed compounds possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration.
• compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with 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 compound described herein.
• a pure isomer is utilized as the disclosed compound described herein.
• compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis or separation of a mixture of enantiomers or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
• the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
• Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S.
• isotopically-labeled compounds are useful in drug or substrate tissue distribution studies.
• substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
• the compounds described herein include a 2 H (i.e., deuterium) isotope.
• substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
• PET Positron Emission Topography
• the compounds of the invention can be used in a method of treating a disease or condition in a subject, said method comprising administering to the subject a compound of the invention, or a pharmaceutical composition comprising a compound of the invention.
• the subject is human.
• the compounds provided herein are useful in treatment of a disease or condition by acting as an agonist of the orexin-2 receptor.
• 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.
• the compounds of the invention can be used to treat narcolepsy in a subject.
• the compounds of the invention can be used to treat cataplexy in a subject.
• the compounds of the invention can be used to treat hypersomnia in a subject.
• Orexin-2 receptors are important in a wide range of biological functions.
• the compound of the present invention is useful for treating, preventing, or ameliorating the risk of one or more of the following symptoms or diseases of various neurological and psychiatric diseases associated with alterations in sleep/wake function.
• narcolepsy narcolepsy with cataplexy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnolence syndrome characterized by hypersomnia (e.g., in subjects with Kleine Levin syndrome, major depression with hypersomnia, Lewy body dementia, Parkinson’s disease, progressive supranuclear paralysis, Prader-Willi syndrome, Mobius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, multiple systems atrophy, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen’s encephalitis, Wernicke’s encephalitis, limbic encephalitis, or Hashimoto’s encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity
• the compound of the present invention is useful as a therapeutic or prophylactic drug for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnolence syndrome characterized by hypersomnia (e.g., in Parkinson’s disease, Guillain-Barre syndrome or Kleine Levin syndrome), Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness such as coma and the like, side effects and complications due to anesthesia, and the like, or anesthetic antagonist.
• hypersomnia e.g., in Parkinson’s disease, Guillain-Barre syndrome or Kleine Levin syndrome
• Alzheimer’s disease e.g., in Parkinson’s disease, Guillain-Barre syndrome or Kleine Levin syndrome
• Alzheimer’s disease e.g., in Parkinson’s disease, Guillain-Barre syndrome or Kleine Levin syndrome
• the compound of the present invention has orexin-2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for narcolepsy.
• the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy type-1.
• the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy type-2.
• the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy and excessive daytime sleepiness.
• the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy, cataplexy, and excessive daytime sleepiness.
• the compound of the present invention is useful as a prophylactic or therapeutic agent for narcolepsy and cataplexy. In another embodiment, the compound of the present invention is useful as a prophylactic or therapeutic agent for excessive daytime sleepiness. In another embodiment, 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. In another embodiment, 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.
• 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 embodiment, 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. In another embodiment, 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 or fatigue associated with cancer and/or chemotherapy. In another embodiment, the present invention provides a method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating narcolepsy type-1 in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating narcolepsy type-2 in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating narcolepsy and excessive daytime sleepiness in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating narcolepsy, cataplexy, and excessive daytime sleepiness in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating narcolepsy and cataplexy in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating excessive daytime sleepiness in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating idiopathic hypersomnia in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating excessive daytime sleepiness and idiopathic hypersomnia in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating obstructive sleep apnea in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating excessive daytime sleepiness and obstructive sleep apnea in a subject in need thereof comprising administering to the subject a compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof.
• the subject is administered a compound of Formula I-A.
• the subject is administered a compound of Formula I.
• Each of the embodiments described herein with respect to the use of compounds of Formula I also applies to compounds of Formula I-A.
• the compound of Formula I-A or I, or a pharmaceutically acceptable salt thereof is present and/or administered in a therapeutically effective amount.
• a pharmaceutical composition comprising at least one compound of the invention, together with a pharmaceutically acceptable carrier.
• Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
• the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
• a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
• the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
• the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a disclosed compound for the treatment of narcolepsy or cataplexy in a patient.
• the compounds of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
• the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
• the dose of a disclosed compound is from about 1 mg to about 1,000 mg.
• a dose of a disclosed compound used in 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.
• a dose is about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or about 600 mg.
• routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
• the compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
• the preferred route of administration is oral.
• suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
• compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
• excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
• the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
• the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion.
• Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.
• reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
• experimental reagents such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents
• Desired product could be detected by TLC.
• 1 H-NMR 400 MHz, Chloroform-d
• Example 1.2 Into a 20 mL sealed tube were added N-(3-[[(4-bromocyclohex-3-en-1- yl)oxy]methyl]-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (200.00 mg, 0.450 mmol, 1.00 equiv.), Na2CO3 (143.10 mg, 1.350 mmol, 3.00 equiv.), 3-fluorophenylboronic acid (94.46 mg, 0.675 mmol, 1.50 equiv.), dioxane (4.00 mL), water (1.00 mL) and Pd(dppf)Cl 2 (19.76 mg, 0.027 mmol, 0.06 equiv.) at room temperature.
• Example 1.3 Into a 500 mL 3-necked round-bottom flask were added 4-phenylcyclohexan-1-one (15.00 g, 86.087 mmol, 1.00 equiv.), THF (130.00 mL), and L-selectride (129.08 mL, 679.021 mmol, 7.02 equiv.) at room temperature. The resulting mixture was stirred for 16 hr at room temperature under nitrogen atmosphere. Then, water (0.16 mL, 8.609 mmol, 0.10 equiv.) and EtOH (0.10 mL, 2.171 mmol, 0.02 equiv.) were added.
• the crude product (2.0 g) was purified by Prep-HPLC with the following conditions (Column: XBridge® (Waters Technologies Corp., Milford, Massachusetts) Prep OBD C18 Column, 30 ⁇ 150mm 5um; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 52 B to 86 B in 8 min; 254/220 nm) to afford (cis)-N-(1- benzyl-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidin-4-yl)methanesulfonamide (420 mg, 17.5%) as a solid.
• Example 1.4 (Compound 19) To a stirred mixture of N-((3R,4S)-3-[[(4-phenylcyclohexyl)oxy]methyl]piperidin-4- yl)methanesulfonamide (50.00 mg, 0.136 mmol, 1.00 equiv.) and 2-fluoropyrimidine (20.07 mg, 0.205 mmol, 1.50 equiv.) in DMSO (10 mL) was added K2CO3 (47.13 mg, 0.341 mmol, 2.5 equiv.) at room temperature under air atmosphere. The resulting mixture was stirred for 2 hr at room temperature under nitrogen atmosphere.
• Example 1.5 (Compound 37) To a solution of N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4- yl)methanesulfonamide (200 mg, 1.00 equiv., 546 micromol) in acetophenone (393 mg, 6.00 equiv., 3.27 mmol) were added titanium(IV) isopropoxide (620 mg, 662 microL, 2.18 mmol, 4.00 equiv.). The reaction mixture was stirred at 25 degrees C for 30 minutes.
• Example 1.6 (Compound 39) To a solution of N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4- yl)methanesulfonamide (100 mg, 273 micromol, 1.00 equiv.) and picolinaldehyde (117 mg, 1.09 mmol, 4.00 equiv.) in methanol (5 mL) were added diisopropylethylamine (106 mg, 143 microL, 819 micromol, 3.00 equiv.) and sodium triacetoxyborohydride (578 mg, 2.73 mmol, 10.0 equiv.).
• Example 1.7 (Compound 44) To a solution of N-((3R,4S)-3-((((1s,4S)-4-phenylcyclohexyl)oxy)methyl)piperidin-4- yl)methanesulfonamide (33 mg, 90 micromol, 1.00 equiv.) and 5-chloro[1,2,4]triazolo[1,5- c]pyrimidine (17 mg, 0.11 mmol, 1.2 equiv.) in DMSO (1.5 mL) was added K 2 CO 3 (25 mg, 0.18 mmol, 2.0 equiv.). The resulting mixture was stirred for 18 hr at 120 degrees C and then filtered.
• Example 1.8 To a suspension of NaH (53.0 mg, 60% weight, 1.32 mmol, 1.00 equiv.) in THF (10 mL) was added 1-benzyl-3-((((1S,4S)-4-phenylcyclohexyl)oxy)methyl)piperidine-4-one (500 mg, 1.32 mmol, 1.00 equiv.) in THF (10 mL) at 0 degrees C. The resulting mixture was stirred for 30 minutes at 0 degrees C. To the reaction was added a solution of methyl iodide (0.166 mL, 0.376 grams, 2.65 mmol, 2.00 equiv.) in THF (10 mL) dropwise at 0 degrees C under nitrogen atmosphere.
• Example 2 Human OX 2 R IP1 assay T-Rex CHO cells stably overexpressing the human orexin-2 receptor (OX 2 R) were induced overnight with 1 ⁇ g/mL of doxycycline in a T225 flask.24 hours post induction, cells were lifted with accutase and plated into a 384-well proxy plate at 30,000 cells/well.
• Cisbio IP1 is a cell-based functional assay quantifying the accumulation of inositol monophosphate (IP), a metabolite released as a result of orexin 2 receptor activation through the phospholipase C-Gq signaling pathway.
• IP inositol monophosphate
• This is a competitive immunoassay in which the IP1 produced by the cells upon receptor activation competes with the IP1 analog coupled to the 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 IP1 concentration produced.
• the EC 50 values reported in Table 2 were obtained according to the human OX 2 R IP1 assay described above.
• MDCK-MDR1 Permeability Assay The bidirectional permeability (Apical to Basal and Basal to Apical directions) of test compounds in MDCK-MDR 1 cells were evaluated using MDCK-MDR 1 cells seeded in Solvo PreadyPortTM MDCK 96-well plate. Once the plate was received from ReadyCell (Barcelona, Spain), it was treated as per PreadyPortTM user’s manual.
• test compound (3 ⁇ M) co-dosed with LY (Lucifer Yellow) (100 ⁇ M) in HBSS (Hank’s Balanced Salt Solution) assay buffer was added to the donor side (A) while 250 ⁇ L of HBSS buffer was added to the receiver side (B).
• HBSS Hank’s Balanced Salt Solution
• 255 ⁇ L of test compound (3 ⁇ M) in HBSS assay buffer was added to the donor side (B) while 75 ⁇ L of HBSS buffer containing LY (100 ⁇ M) was added to the receiver side (A).
• the plate was placed in an incubator set at 37 degrees C.
• the efflux ratio (ER) was measured by dividing the Papp (basolateral to apical direction) by P app (apical to basolateral direction). It is a general measure of the involvement of active processes. An ER > 2 is considered positive for active transport.
• Percent Recovery 100 where: V R : Volume of the receiver compartment (mL) VD: Volume of the donor compartment (mL) C N : Concentration of dosing solution ( ⁇ M) collected after 10 minutes of incubation C R final : Receiver concentration at the end of the incubation ( ⁇ M) CD final : Donor concentration at the end of the incubation ( ⁇ M) The data reported in Table 3 were obtained according to the MDCK-MDR 1 permeability assay described above. Table 3.
• Example 4 Hepatocytes Stability Assay In vitro metabolic stability was assessed using cryopreserved hepatocytes from male Sprague Dawley rats and a pool of 50 mixed gender humans (BioIVT, Baltimore, MD).
• the incubation mixtures were prepared by mixing 250 ⁇ L of pre-warmed KHB (Krebs-Henseleit buffer) containing 2 ⁇ 10 6 cell/mL of hepatocytes with 250 ⁇ L of pre-warmed KHB buffer containing 2 ⁇ M of test compounds in a 48-well plate, giving a final concentration of 1 ⁇ M test compound (0.1% DMSO) and 1 ⁇ 10 6 cell/mL of hepatocytes.
• the reaction mixture was incubated at 37 degrees C.
• a 50 ⁇ L aliquot of incubation mixture was taken at time points (0, 15, 30, 60, 120 and 240 minutes) and transferred into a 96-well plate containing 300 ⁇ L ice-cold acetonitrile (containing 30 ng/mL of labetalol and 10 ng/mL of Naltrexone-d3 as internal standards) and immediately placed in ice to terminate the reaction. Samples were centrifuged, and supernatants were transferred into 96-well plates for liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis to monitor the depletion of the test compound.
• LC-MS/MS tandem mass spectrometry
• Example 5 Assessment of Wake Promotion in Sprague-Dawley Rats Wake promotion was assessed using electroencephalography (EEG) and electromyography (EMG) in adult male Sprague-Dawley rats. All rats (Charles River Laboratories, Raleigh, NC, USA) were intraperitoneally implanted with telemetry devices (F50-EEE, Data Sciences International Inc., MN, USA) under isoflurane anesthesia. For EEG, stainless steel screws were implanted over frontal cortex and parietal cortex, and reference screws were placed over cerebellum. Additionally, an electrode was placed in neck muscle for EMG. Rats were given carprofen post-surgery and underwent a 7 to 10-day recovery period.
• EEG electroencephalography
• EMG electromyography
• ZT5 zeitgeber time 5

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