Classifications

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  • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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  • 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
  • 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
  • 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
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • 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
  • C07D487/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

• Orexin A and orexin B bind to orexin receptors.
• Orexin receptors are G protein-coupled receptors expressed preferentially in the brain.
• 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).
• 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 piperidinyl and pyrrolidinyl 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:
• a pharmaceutical composition comprising a compound of any 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 “EC 50 ” 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 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
• 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.
• aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n + 2) delocalized ⁇ (pi) electrons, where n is an integer.
• aryl means an aromatic carbocyclic system containing 1, 2 or 3 rings, wherein such rings may be fused, wherein fused is defined above. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated.
• aryl includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl.
• aryl can include C6-C10 aryl, C6-C8 aryl, or C6 aryl (i.e., phenyl).
• heteroaryl means an 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.
• heteroaryl includes, but is not limited to, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like.
• 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.
• 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.
• ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, further wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen;
• X is N or CH;
• Re is selected from the group consisting of H, C1-C3 alkyl, or C3-C5 cycloalkyl;
• 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, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8
• ring A is a phenyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C 1 -C 3 alkyl, C3-C5 cycloalkyl, or halogen.
• ring A is a phenyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C3 alkyl, C 3 -C 5 cycloalkyl, or halogen.
• ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.
• ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C 1 -C 3 alkyl or halogen.
• ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from halogen.
• ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from F or Cl.
• ring A is a phenyl ring, wherein the ring is substituted with 1-2 F substituents.
• ring A is 3-fluorophenyl.
• ring A is a pyridinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C1-C3 alkyl, C 3 -C 5 cycloalkyl, or halogen.
• ring A is a pyridinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C1-C3 alkyl or halogen.
• ring A is a pyridinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from halogen.
• ring A is a pyridinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C1-C3 alkyl.
• ring A is a pyridinyl ring, wherein the ring is mono-substituted with C3-C5 cycloalkyl.
• ring A is a pyridazinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C1-C3 alkyl, C 3 -C 5 cycloalkyl, or halogen.
• ring A is a pyridazinyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.
• ring A is a pyridazinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or halogen.
• ring A is a pyridazinyl ring, wherein the ring is mono-substituted with C3-C5 cycloalkyl.
• ring A is a pyrimidinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C1-C3 alkyl, C 3 -C 5 cycloalkyl, or halogen.
• ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C1-C3 alkyl or halogen.
• ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from halogen.
• ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C1-C3 alkyl.
• ring A is a pyrazinyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl, or halogen.
• ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or halogen.
• ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C1-C3 alkyl or halogen.
• ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from halogen.
• ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C1-C3 alkyl.
• ring A is a triazinyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each independently selected from C 1 -C 3 alkyl, C3-C5 cycloalkyl, or halogen.
• ring A is a triazinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or halogen.
• ring A is a triazinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C1-C3 alkyl or halogen.
• ring A is a triazinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from halogen.
• ring A is a triazinyl ring, wherein the ring is substituted with 1-2 substituents, each independently selected from C1-C3 alkyl.
• ring A is a triazinyl ring, wherein the ring is mono-substituted with C3-C5 cycloalkyl.
• 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. 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.
• 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 R 9 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 R 9 is halogen. In another embodiment of Formula (I), p is 2 and each R 9 is fluorine.
• E is NRaRb. In another embodiment of Formula (I), E is C 1 -C 3 alkylene-NR a R b .
• E is unsubstituted C1-C3 alkyl, unsubstituted C2-C4 alkenyl or unsubstituted C2-C4 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, C1-C3 alkyl, or C1-C3 alkoxyl.
• E is unsubstituted C 1 -C 3 alkyl.
• E is C1-C3 alkyl substituted with one or more halogen, hydroxyl, NRcRd, CF3, CHF 2 , CH 2 F, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.
• E is unsubstituted C3-C8 cycloalkyl.
• E is C3-C8 cycloalkyl substituted with one or more halogen, hydroxyl, NR c R d , CF 3 , CHF 2 , CH 2 F, C 1 -C 3 alkyl, or C1-C3 alkoxyl.
• E is unsubstituted C1-C3 alkylene-(C3- C 8 cycloalkyl).
• E is C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl) substituted with one or more halogen, hydroxyl, NRcRd, CF3, CHF2, CH2F, C1-C3 alkyl, or C1-C3 alkoxyl.
• E is unsubstituted 4- to 10- membered heterocyclyl.
• E is 4- to 10-membered heterocyclyl substituted with one or more halogen, hydroxyl, NRcRd, CF3, CHF2, CH2F, C1- C 3 alkyl, or C 1 -C 3 alkoxyl.
• E is unsubstituted C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl).
• E is C1- C 3 alkylene-(4- to 10-membered heterocyclyl) substituted with one or more halogen, hydroxyl, NRcRd, CF3, CHF2, CH2F, C1-C3 alkyl, or C1-C3 alkoxyl.
• E is unsubstituted C 6 -C 10 aryl.
• E is C 6 - C10 aryl substituted with one or more halogen, hydroxyl, NRcRd, CF3, CHF2, CH2F, C1-C3 alkyl, or C 1 -C 3 alkoxyl.
• E is unsubstituted C 1 -C 3 alkylene-(C6-C10 aryl).
• E is C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 3 alkylene-(C3-C8 cycloalkyl), wherein the C1-C3alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene- (C3-C8 cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , CF 3 , CHF 2 , CH 2 F, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.
• E is methyl.
• E is methyl substituted with one or more halogen, hydroxyl, NR c R d , CF 3 , CHF 2 , CH2F, C1-C3 alkyl, or C1-C3 alkoxyl.
• E is CF3.
• E is CHF 2 .
• E is CH2F.
• E is NH(CH3).
• E is N(CH 3 ) 2 .
• E is C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 7-membered heteroaryl or C 1 -C 3 alkylene-(5- to 7-membered heteroaryl).
• E is unsubstituted C6-C10 aryl or C1-C3 alkylene-(C6-C10 aryl).
• R1 is (CRcRd)n-(C6-C10 aryl) or (CRcRd)n-(5- to 10-membered heteroaryl) wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is unsubstituted and further wherein n is 0.
• R1 is (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the C 6 -C 10 aryl or 5- to 10-membered 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 (CR c R d ) n -(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the C6-C10 aryl or 5- to 10-membered 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 C6-C10 aryl or 5- to 10-membered heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium and further wherein n is 1.
• R1 is (CRcRd)n-(C6-C10 aryl) wherein the C6- C10 aryl is unsubstituted.
• R1 is (CRcRd)n-(C6-C10 aryl) wherein the C6-C10 aryl is substituted with one or more halogen, hydroxyl, unsubstituted C1- C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.
• R 1 is (CR c R d ) n -(C 6 -C 10 aryl) wherein the C 6 - C10 aryl is unsubstituted and further wherein n is 0.
• R1 is (CR c R d ) n -(C 6 -C 10 aryl) wherein the C 6 -C 10 aryl is substituted with one or more halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.
• R1 is (CRcRd)n-(C6-C10 aryl) wherein the C6- C 10 aryl is unsubstituted and further wherein n is 1.
• R 1 is (CRcRd)n-(C6-C10 aryl) wherein the C6-C10 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 5- to 10-membered heteroaryl is unsubstituted.
• R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
• R1 is (CRcRd)n-(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl is unsubstituted and further wherein n is 0.
• R1 is (CRcRd)n-(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.
• R1 is (CRcRd)n-(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl is unsubstituted and further wherein n is 1.
• R1 is (CRcRd)n-(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium and further wherein n is 1.
• R1 is (CRcRd)n-(phenyl) or (CRcRd)n-(5- to 7- membered heteroaryl) wherein the phenyl or 5- to 7-membered heteroaryl is unsubstituted.
• R1 is (CRcRd)n-(phenyl) or (CRcRd)n-(5- to 7-membered heteroaryl) wherein the phenyl or 5- to 7-membered heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.
• R 1 is (CR c R d ) n -(phenyl) or (CRcRd)n-(5- to 7-membered heteroaryl) wherein the phenyl or 5- to 7-membered 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 -(6- membered heteroaryl) wherein the phenyl or 6-membered heteroaryl is unsubstituted.
• R 1 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 halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.
• R1 is (CRcRd)n-(phenyl) or (CRcRd)n-(6- membered heteroaryl) wherein the phenyl or 6-membered heteroaryl is unsubstituted and further wherein n is 0.
• R1 is (CRcRd)n-(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or 6-membered heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.
• R1 is (CRcRd)n-(phenyl) or (CRcRd)n-(6- membered heteroaryl) wherein the phenyl or 6-membered heteroaryl is unsubstituted and further wherein n is 1.
• R1 is (CRcRd)n-(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or 6-membered heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium and further wherein n is 1.
• R1 is (CRcRd)n-(6-membered heteroaryl) wherein the 6-membered heteroaryl is unsubstituted.
• R1 is (CRcRd)n-(6-membered heteroaryl) wherein the 6-membered heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.
• R 1 is pyridazinyl.
• R1 is 3-pyridazinyl.
• R 1 is (CR c R d ) n -(6-membered heteroaryl) wherein the 6-membered heteroaryl is unsubstituted and further wherein n is 0.
• R 1 is (CR c R d ) n -(6-membered heteroaryl) wherein the 6- membered heteroaryl is substituted with one or more halogen, hydroxyl, unsubstituted C1-C3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium and further wherein n is 0.
• R 1 is (CR c R d ) n -(6-membered heteroaryl) wherein the 6-membered heteroaryl is unsubstituted and further wherein n is 1.
• R1 is (CRcRd)n-(5-membered heteroaryl) wherein the 5-membered 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 -(5-membered heteroaryl) wherein the 5-membered heteroaryl is unsubstituted and further wherein n is 0.
• R1 is (CR c R d ) n -(5- to 10-membered heteroaryl) and each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H or unsubstituted C1-C3 alkyl.
• R1 is (CRcRd)n-(5- to 10- membered heteroaryl) and each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H or halogen.
• R1 is (CRcRd)n-(5- to 10-membered heteroaryl) and each of R2, R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H or fluorine.
• R1 is (CRcRd)n-(5- to 7-membered heteroaryl) and each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.
• R 1 is (CR c R d ) n -(5- to 7-membered heteroaryl) and each of R 2 , R 3 , R4, R5, R6, R7, and R8 is H or fluorine.
• R 1 is (CR c R d ) n -(6-membered heteroaryl) and each of R2, R3, R4, R5, R6, R7, and R8 is H.
• R1 is (CRcRd)n-(6-membered heteroaryl) and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.
• R1 is (CRcRd)n-(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H.
• R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H or unsubstituted C1-C3 alkyl.
• R1 is (CRcRd)n-(6- membered heteroaryl), n is 0, and each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H or halogen.
• R1 is (CRcRd)n-(6-membered heteroaryl), n is 0, and each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H or fluorine.
• R1 is (CRcRd)n-(6-membered heteroaryl), n is 1 or 2, and each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.
• R 1 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.
• R1 is (CRcRd)n-(C6-C10 aryl) and each of R2, R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.
• R 1 is (CR c R d ) n -(C 6 - C10 aryl) and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl.
• R1 is (CRcRd)n-(C6-C10 aryl) and each of R2, R3, R4, R5, R 6 , R 7 , and R 8 is H or halogen.
• R 1 is (CR c R d ) n -(C 6 - C10 aryl) and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.
• R 1 is (CR c R d ) n -(C 6 aryl) and each of R 2 , R 3 , R4, R5, R6, R7, and R8 is H.
• R1 is (CRcRd)n-(C6 aryl) and each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H or unsubstituted C 1 -C 3 alkyl.
• R1 is (CRcRd)n-(C6 aryl) and each of R2, R3, R4, R5, R6, R7, and R 8 is H or halogen.
• R 1 is (CR c R d ) n -(C 6 aryl) and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.
• R 1 is (CR c R d ) n -(C 6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H.
• R1 is (CRcRd)n-(C6 aryl), n is 0, and each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H or unsubstituted C 1 -C 3 alkyl.
• R1 is (CRcRd)n-(C6 aryl), n is 0, and each of R2, R3, R4, R 5 , R 6 , R 7 , and R 8 is H or halogen.
• 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.
• 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 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 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 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.
• the subject is administered a compound of Formula I-A.
• 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.
• 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.
• 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.
• 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
• Compound 65 was synthesized using method 6 (11.5 mg, 19.8 ⁇ mol, 26.5 %, 92.1% purity) as a semi-solid.
• LCMS: m/z (ES+), [M+Na]+ 558.0.
• Example 2 Human OX 2 R IP1 assay T-Rex CHO cells stably overexpressing the human orexin-2 receptor (OX 2 R) are induced overnight with 1 ⁇ g/mL of doxycycline in a T225 flask.24 hours post induction, cells are lifted with accutase and plated into a 384-well proxy plate at 30,000 cells/well.
• Cells are then treated with different test compounds in 1X stimulation buffer containing 10 mM Hepes, 1 mM CaCl 2 , 0.5 mM MgCl 2 , 4.2 mM KCl, 146 mM NaCl, 5.5 mM glucose, and 50 mM LiCl, pH 7.4, for 1 hr at 37 degrees C.
• 1X stimulation buffer containing 10 mM Hepes, 1 mM CaCl 2 , 0.5 mM MgCl 2 , 4.2 mM KCl, 146 mM NaCl, 5.5 mM glucose, and 50 mM LiCl, pH 7.4, for 1 hr at 37 degrees C.
• detection mix which is composed of IP1-d2 and anti-IP1-cryptate diluted in lysis buffer as well as 1X stimulation buffer.
• the plates are allowed to incubate for 1 hour at room temperature and are then read in the EnVision® multimode plate reader, measuring inositol phosphate
• 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 EC50 values reported in Table 2 were obtained according to the human OX2R IP1 assay described above. Data are the mean EC 50 values ⁇ S.E.M. Table 2.

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