Classifications

• • 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
  • C07D498/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
• • 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
• • 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
• • 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
  • C07D498/12—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 three hetero rings
  • C07D498/14—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
  • C07D498/12—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 three hetero rings
  • C07D498/18—Bridged systems

Definitions

• Orexin is a neuropeptide specifically produced in particular neurons located sparsely in the lateral hypothalamus and its surrounding area. Orexin consists of two subtypes, orexin A and orexin B.
• Both orexin A (OX-A) and orexin B (OX-B) are endogenous ligands of the orexin receptors, which are mainly present in the brain.
• Two orexin receptors have been cloned and characterized in mammals. They belong to the super family of G-protein coupled receptors: the orexin-1 receptor (OX or OX1R) is partially selective for OX-A and the orexin-2 receptor (OX2 or OX2R) is capable of binding OX-A as well as OX-B with similar affinity.
• the physiological actions in which orexins are presumed to participate are thought to be expressed via one or both of OX1 receptor and OX2 receptor as the two subtypes of orexin receptors.
• Orexins regulate states of sleep and wakefulness making the orexin system a target for potential therapeutic approaches to treat sleep disorders. Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior. Orexins have also been indicated as playing a role in arousal, emotion, energy homeostasis, reward, learning and memory. [0004] There is a need for compounds that modulate orexin receptors, as well as compositions and methods for treating a disease or disorder that is treatable by administration of an Orexin agonist.
• the present disclosure provides a compound of Formula (IA-1): or a pharmaceutically acceptable salt thereof, wherein: is phenyl, 5- or 6-membered heteroaryl, cycloalkyl, or heterocyclyl; V and Z are each independently –O–, –CR 8 R 9 –, or –NR 10 –; X is –O–, –CR 11 R 12 –, or –NR 13 –; Y is a bond, –O–, –CR8R9–, or –NR10–; A 5 and A 6 are each independently –O– or –CH 2 –; R1, R2, R3, R4, R8, R9, R11, and R12 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl; and/or R1 and R2 together with the atom to which they are attached form a carbocycle or heterocycle; and/or R 3 and R 4 together with the atom to which they are
• the present disclosure provides a compound of Formula (IB-1): or a pharmaceutically acceptable salt thereof, wherein: Ar is an aryl or heteroaryl linker; is phenyl, 5- or 6-membered heteroaryl, cycloalkyl, or heterocyclyl; V and Z are each independently –O–, –CR 8 R 9 –, or –NR 10 –; X is –O–, –CR11R12–, or –NR13–; Y is a bond, –O–, –CR8R9–, or –NR10–; R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R 11 , and R 12 are each independently H, halogen, alkyl, cycloalkyl, or heterocyclyl; and/or R 1 and R 2 together with the atom to which they are attached form a carbocycle or heterocycle; and/or R3 and R4 together with the atom to
• R 1 and R 2 are each independently H, halogen, or alkyl.
• R1 and R2 are each independently H or alkyl.
• the alkyl is methyl or ethyl.
• R1 and R2 are H.
• R1 and R2 are H or halogen.
• halogen is fluorine.
• R 1 and R 2 together with the carbon atom to which they are attached form a carbocycle or heterocycle.
• the carbocycle is a C3-6 cycloalkyl.
• the heterocycle is a 3- or 6-membered heterocycle.
• the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O, and S.
• R3 and R4 are each independently H, halogen, or alkyl.
• R3 and R4 are each independently H or alkyl.
• the alkyl is methyl or ethyl.
• R 3 and R 4 are H.
• R 3 and R 4 are halogen.
• the halogen is fluorine.
• R3 and R4 together with the carbon atom to which they are attached form a carbocycle or heterocycle.
• the carbocycle is a C 3-6 cycloalkyl.
• the heterocycle is a 3- or 6-membered heterocycle. In some embodiments, the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O, and S.
• R 5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene- heterocyclyl, heteroaryl, alkylene-heteroaryl, or alkylene–S(O) 2 –alkyl. In some embodiments, R 5 is alkyl or haloalkyl. In some embodiments, R5 is C1-5 alkyl or C1-5 haloalkyl.
• R5 is C1-5 alkyl, C3-6 cycloalkyl, C1-3 alkylene-(C3-6 cycloalkyl), 4- to 6-membered heterocyclyl, C 1-3 alkylene-(4- to 6-membered heterocyclyl), 5- or 6-membered heteroaryl, C 1-3 alkylene-(5- or 6-membered heteroaryl), or C 1-3 alkylene–S(O)2–C 1-3 alkyl.
• R5 is alkyl optionally substituted with one or more halogen.
• R5 is alkyl optionally substituted with one or more fluorine.
• R 5 is alkyl, C 1-5 alkyl, or C 1-5 haloalkyl. In some embodiments, R 5 is C 1-3 alkylene -cycloalkyl, C 1-3 alkylene-heterocyclyl, C1-3 alkylene-heteroaryl, or C1-3 alkylene –S(O)2–alkyl. In some embodiments, R5 is alkylene- cycloalkyl, alkylene-heterocyclyl, alkylene-heteroaryl, or alkylene–S(O)2–alkyl, and the alkylene is a methylene or ethylene.
• R 5 is alkylene-cycloalkyl, alkylene- heterocyclyl, alkylene-heteroaryl, or alkylene–S(O)2–alkyl, and the alkylene is a methylene.
• V is –O– or –CR8R9–. In some embodiments, V is –O– or –NR10– . In some embodiments, V is –O–. In some embodiments, V is –CR 8 R 9 –. In some embodiments, R 8 and R 9 are each independently H or alkyl. In some embodiments, R 8 and R 9 together with the carbon atom to which they are attached form a C3-6 cycloalkyl.
• Z is a –NR 10 – or –CR 8 R 9 –. In some embodiments, Z is –NR 10 –.
• R8 and R9 are each independently H or alkyl. In some embodiments, R8 and R9 together with the carbon atom to which they are attached form a C3-6 cycloalkyl.
• Ra is alkyl optionally substituted with one or more fluoride. In some embodiments, Ra is alkoxy optionally substituted with one or more fluoride. In some embodiments, R a is F, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CF3, CHCF2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCHCF2, or -CN. In some embodiments, Ra is F, CH3, CH2CH3, CH(CH3)2, CF3, CHCF2, or -CN. In some embodiments, q is 0 or 1. In some embodiments, q is 0. [0017] In some embodiments, m is 0 or 1.
• m is 0. [0018] In some embodiments, n is 0 or 1. In some embodiments, n is 1. [0019] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. [0020] In some embodiments, r is 0. In some embodiments, r is 1. [0021] In some embodiments, L is heteroaryl, –carbocyclyl-(CR 7 CR 7’ ) r -O–, or –heterocyclyl- (CR 7 CR 7’ ) r -O–.
• L is –carbocyclyl-(CH 2 ) r -O– or –heterocyclyl-(CH 2 ) r -O–.
• L has the structure , wherein A 5 and A 6 are each independently –O– or –CH2–.
• A5 is –O–.
• A5 is – CH2–.
• A6 is –O–.
• A6 is –CH2–.
• L is a –carbocyclyl-(CH 2 ) r -O–linker having the structure , wherein r is 0 or 1; s is 1 or 2; and t is 1 or 2. In some embodiments, s is 1 and t is 1. In some embodiments, s is 2 and t is 2. In some embodiments, L is a –carbocyclyl-(CH2)r-O–linker having the structure , wherein r is 0 or 1. [0022] In some embodiments, wherein R b is halogen, alkyl, or alkoxy; and u is 0, 1, or 2. In some embodiments, R b is halogen.
• the halogen is fluoride.
• Rb is F, CH3, CH2CH3, CH(CH3)2, CF3, CHCF2, -OCH3, -OCH2CH3, - OCH(CH 3 ) 2 , -OCF 3 , or -OCHCF 2 .
• u is 1. In some embodiments, u is 0. In some embodiments, .
• L is a 5- or 6-membered heteroaryl linker. In some embodiments, L is a 5- or 6-membered heteroaryl linker having 1 or 2 nitrogen atoms.
• L wherein R b is halogen, alkyl, or alkoxy; and u is 0 or 1.
• the present disclosure provides a compound of Formula (IC-1): or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R1, R2, R3, R4, R5, R6, , V, X, Y and Z are as defined herein; s is 1 or 2; and t is 0, 1 or 2.
• s is 1. In some embodiments, s is 2.
• t is 1. In some embodiments, t is 2.
• s is 1 and t is 1.
• s is 2 and t is 2.
• the present disclosure provides a compound of Formula (ID-1): or a pharmaceutically acceptable salt thereof, wherein m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , , V, X, Y and Z are defined herein.
• the compound of the present disclosure e.g., the compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), or Formula (IC-4)) is:
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula, (ID-4), Formula (II), or Tables 1-24) or a pharmaceutically acceptable salt thereof
• a compound disclosed herein e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC
• the term "about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value).
• “about 50” can mean 45 to 55
• "about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation.
• “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5.
• the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term "about” provided herein.
• administer refers to administering a compound or pharmaceutically acceptable salt of the compound or a composition or formulation comprising the compound or pharmaceutically acceptable salt of the compound to a patient.
• pharmaceutically acceptable salt includes both acid and base addition salts.
• Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.
• a salt for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.
• Base addition salts include but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e.
• lysine and arginine dicyclohexylamine and the like examples include metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like.
• metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like.
• ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
• organic bases examples include lysine, arginine, guanidine, diethanolamine, choline and the like.
• acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
• treating refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.
• effective amount and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound, or a salt thereof, (or pharmaceutical composition containing the compound or salt) that, when administered to a patient, is capable of performing the intended result.
• the “effective amount” can vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated. [0038]
• the term "therapeutically effective” applied to a dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.
• carrier or “vehicle” as used interchangeably herein encompasses carriers, excipients, adjuvants, and diluents or a combination of any of the foregoing, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body.
• the carrier includes nanoparticles of organic and inorganic nature.
• C 1 -C 6 alkyl is intended to encompass C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1- 6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
• Alkyl or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond.
• Alkyls comprising any number of carbon atoms from 1 to 12 are included.
• An alkyl comprising up to 12 carbon atoms is a C 1 -C 12 alkyl
• an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl
• an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl
• an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl.
• a C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls, and C 1 alkyl (i.e., methyl).
• a C 1 -C 6 alkyl includes all moieties described above for C 1 -C 5 alkyls but also includes C 6 alkyls.
• a C 1 -C 10 alkyl includes all moieties described above for C 1 -C 5 alkyls and C1-C6 alkyls, but also includes C7, C8, C9 and C10 alkyls.
• a C1-C12 alkyl includes all the foregoing moieties, but also includes C 11 and C 12 alkyls.
• Non-limiting examples of C 1 -C 12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t- butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.
• an alkyl group can be optionally substituted.
• Alkylene or “alkylene chain” refers to a fully saturated, straight, or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms.
• C 1 -C 12 alkylene include methylene, ethylene, propylene, n-butylene, and the like.
• the alkylene chain is attached to the rest of the molecule through a single bond and to a radical group (e.g., those described herein) through a single bond.
• the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.
• alkenyl or “alkenyl group” refers to a straight or branched hydrocarbon chain having from two to twelve carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included.
• An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl
• an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl
• an alkenyl group comprising up to 6 carbon atoms is a C 2 -C 6 alkenyl
• an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl.
• a C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls.
• a C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C 6 alkenyls.
• a C 2 -C 10 alkenyl includes all moieties described above for C 2 -C 5 alkenyls and C 2 -C 6 alkenyls, but also includes C 7 , C 8 , C 9 and C 10 alkenyls.
• a C 2 - C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls.
• Non- limiting examples of C 2 -C 12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2- heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4- octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-n
• alkenyl group can be optionally substituted.
• alkenylene or “alkenylene chain” refers to an unsaturated, straight or branched divalent hydrocarbon chain radical having one or more olefins and from two to twelve carbon atoms.
• C 2 -C 12 alkenylene include ethenylene, propenylene, n-butenylene, and the like.
• the alkenylene chain is attached to the rest of the molecule through a single bond and to a radical group (e.g., those described herein) through a single bond.
• alkenylene chain can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.
• Alkynyl or “alkynyl group” refers to a straight or branched hydrocarbon chain having from two to twelve carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included.
• An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl
• an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl
• an alkynyl group comprising up to 6 carbon atoms is a C 2 -C 6 alkynyl
• an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl.
• a C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls.
• a C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes C 6 alkynyls.
• a C 2 -C 10 alkynyl includes all moieties described above for C 2 -C 5 alkynyls and C 2 -C 6 alkynyls, but also includes C 7 , C 8 , C 9 and C 10 alkynyls.
• a C 2 - C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls.
• Non- limiting examples of C 2 -C 12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkynyl group can be optionally substituted.
• Alkynylene or “alkynylene chain” refers to an unsaturated, straight or branched divalent hydrocarbon chain radical having one or more alkynes and from two to twelve carbon atoms.
• Non- limiting examples of C2-C12 alkynylene include ethynylene, propynylene, n-butynylene, and the like.
• alkynylene chain is attached to the rest of the molecule through a single bond and to a radical group (e.g., those described herein) through a single bond.
• the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain having a suitable valency.
• an alkynylene chain can be optionally substituted.
• Alkoxy refers to a group of the formula -OR a where R a is an alkyl, alkenyl or alkynyl as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.
• Aryl refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, and which is attached to the rest of the molecule by a single bond.
• the aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
• Aryls include, but are not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the “aryl” can be optionally substituted.
• “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
• “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon, and which is attached to the rest of the molecule by a single bond. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring.
• Carbocyclic rings can include aryls and cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.
• “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spirocyclic ring systems, having from three to twenty carbon atoms (e.g., having from three to ten carbon atoms) and which is attached to the rest of the molecule by a single bond.
• Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• the cyclohexyl ring is depicted by the structure: , wherein the stereochemistry is as provided in the compound disclosed herein.
• Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.
• Cycloalkenyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting solely of carbon and H atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
• Monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like.
• Polycyclic cycloalkenyls include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.
• Cycloalkynyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
• Monocyclic cycloalkynyl include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.
• “Haloalkyl” refers to an alkyl, as defined above, that is substituted by one or more halo radicals, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
• Heterocyclyl refers to a stable saturated or unsaturated 3- to 20-membered ring which consists of two to nineteen carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and which is attached to the rest of the molecule by a single bond.
• Heterocyclyl or heterocyclic rings include heterocyclylalkyls, heterocyclylalkenyls, and hetercyclylalkynyls.
• the heterocyclyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spirocyclic ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially or fully saturated.
• heterocyclyl examples include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholin
• Heteroaryl refers to a 5- to 20-membered ring system comprising hydrogen atoms, one to nineteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, at least one aromatic ring, and which is attached to the rest of the molecule by a single bond.
• the heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized.
• Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
• Heterocyclylalkyl refers to a radical of the formula -R b -R e where R b is an alkylene, alkenylene, or alkynylene group as defined above and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.
• Optically active compounds can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
• Techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
• HPLC high pressure liquid chromatography
• the compounds of the present disclosure are stereopure, meaning that the compound exists as a single enantiomer and a single diastereomer (when more than one stereocenter is present).
• a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
• the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
• substituted means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and/or heteroaryl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamine
• “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple- bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
• a higher-order bond e.g., a double- or triple- bond
• nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
• R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
• “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N- heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group.
• a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
• “ ” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond.
• the specific point of attachment to the non-depicted chemical entity can be specified by inference.
• the compound CH 3 -R 3 wherein R 3 ” infers that when R 3 is “XY”, the point of attachment bond is the same bond as the bond by which R 3 is depicted as being bonded to CH 3 .
• the present disclosure provides macrocyclic compounds that are agonists of the orexin type 2 receptor as well as pharmaceutical compositions thereof and uses thereof in treating various diseases and disorders.
• the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: L is a linker selected from aryl, heteroaryl, –carbocyclyl-(CR7CR7’)r-O–, and – heterocyclyl-(CR 7 CR 7’ ) r -O–, wherein –carbocyclyl-(CR 7 CR 7’ ) r -O– and –heterocyclyl- (CR 7 CR 7’ ) r -O— have the following orientation: ; is phenyl, 5- or 6-membered heteroaryl, cycloalkyl, or heterocyclyl; V and Z are each independently –O–, –CR 8 R 9 –, or –NR 10 –; X is –O–, –CR11R12–, or –NR13–; Y is a bond, –O–, –CR 8 R 9 –, or
• linker L is aryl, heteroaryl, –carbocyclyl-(CH2)r-O–, or – heterocyclyl-(CH2)r-O—, wherein –carbocyclyl-(CH2)r-O–, and –heterocyclyl-(CH2)r-O— have the following orientation: defined herein.
• linker L is aryl, heteroaryl, –cycloalkyl-O–, and –heterocyclyl-O—, wherein –cycloalkyl-O– and –heterocyclyl-O— have the following orientation: .
• the present disclosure provides a compound of Formula (I-1): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, R1, R2, R3, R4, R5, R 6 , L, , V, X, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (I-2): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, , V, X, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IA): (IA) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , are as defined herein.
• the present disclosure provides a compound of Formula (IA-1): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, , V, X, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IA-2): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m, n, p, R1, R2, R3, R4, R5, R 6 , , V, X, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IB): or a pharmaceutically acceptable salt thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, Ar, , V, X, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IB-1): or a pharmaceutically acceptable salt thereof, wherein m, n, p, R1, R2, R3, R4, R5, R6, Ar, , V, X, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IB-2): or a pharmaceutically acceptable salt thereof, wherein m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Ar, , V, X, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IC-1): [0075] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , , V, X, Y and Z are as defined herein; s is 1 or 2; and t is 0, 1 or 2. [0076] In some embodiments, s is 1. In some embodiments, s is 2. [0077] In some embodiments, t is 1. In some embodiments, t is 2. [0078] In some embodiments, s is 1 and t is 1. In some embodiments, s is 2 and t is 2.
• s is 1 or 2 and t is 1. In some embodiments, s is 1 or 2 and t is 2. In some embodiments, s is 1 and t is 1 or 2. In some embodiments, s is 2 and t is 1 or 2. [0079] In some embodiments, the present disclosure provides a compound of Formula (IC-2): , or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, s, t, R1, R2, R3, R4, R5, R6, , V, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IC-2a): , or a pharmaceutically acceptable salt thereof, wherein p, r, R5, , V, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IC-2b): or a pharmaceutically acceptable salt thereof, wherein p, r, R5, , V, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IC-2c): or a pharmaceutically acceptable salt thereof, wherein m, p, R1, R2, R3, R4, R5, R6, , V, X, Y and Z are defined herein.
• the present disclosure provides a compound of Formula (IC-2d): or a pharmaceutically acceptable salt thereof, wherein m, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , , V, X, Y and Z are defined herein.
• the present disclosure provides a compound of Formula (IC-2e): or a pharmaceutically acceptable salt thereof, wherein q, R a , and R 5 are as defined herein.
• the present disclosure provides a compound of Formula (IC-2f): , or a pharmaceutically acceptable salt thereof, wherein q, R a , and R 5 are as defined herein.
• R a is H, halogen, or alkyl; and q is 1 or 2.
• Ra is H, F, or Me and q is 0 or 1.
• Ra is F or Me and q is 1.
• Ra is F and q is 1.
• the present disclosure provides a compound of Formula (IC-2g): or a pharmaceutically acceptable salt thereof, wherein R 5 is as defined herein.
• the present disclosure provides a compound of Formula (IC-2h): , or a pharmaceutically acceptable salt thereof, wherein R5 is as defined herein.
• the present disclosure provides a compound of Formula (IC-3): (IC-3), or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, s, t, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, X, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IC-3a): or a pharmaceutically acceptable salt thereof, wherein m, n, p, q, r, s, t, Ra, R1, R2, R3, R4, R5, R6, V, X, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (IC-3b): or a pharmaceutically acceptable salt thereof, wherein m, n, p, q, r, s, t, R a , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, X, Y and Z are as defined herein.
• Ra is H, halogen, or alkyl; and q is 1 or 2.
• R a is H, F, or Me and q is 0 or 1.
• R a is F or Me and q is 1.
• R a is F and q is 1.
• the present disclosure provides a compound of Formula (IC-4): , [0094] or a pharmaceutically acceptable salt thereof, wherein m, n, p, q, r, s, t, R a , R 1 , R 2 , R 3 , R 4 , R5, R6, V, X, Y and Z are as defined herein.
• the present disclosure provides a compound of Formula (ID-1): , or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , , V, X, Y and Z are defined herein.
• the present disclosure provides a compound of Formula (ID-2): , or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , , V, Y and Z are defined herein.
• the present disclosure provides a compound of Formula (ID-3): , or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, and Z are defined herein.
• the present disclosure provides a compound of Formula (ID-4): , [0099] or a pharmaceutically acceptable salt thereof, wherein m, n, p, r, Rb, R1, R2, R3, R4, R5, R6, V, and Z are defined herein.
• linker L is aryl, –carbocyclyl-(CH 2 ) r -O–, and –heterocyclyl-(CH 2 ) r - O–, wherein r is 0 or 1.
• L is –carbocyclyl-(CH 2 ) r -O– or –heterocyclyl- (CH2)r-O–, wherein r is 0 or 1.
• L is –carbocyclyl-(CH2)r-O–, wherein r is 0 or 1.
• L is –heterocyclyl-(CH 2 ) r -O–, wherein r is 0 or 1. In some embodiments, r is 0 and L is –carbocyclyl-O– or –heterocyclyl-O–.
• the carbocyclyl is a C3-6 cycloalkyl. In some embodiments, the carbocyclyl is cyclohexyl or cyclobutyl. In some embodiments, the carbocyclyl is cyclohexyl. In some embodiments, the carbocyclyl is cyclobutyl. In some embodiments, the carbocyclyl is , wherein x is 1, 2, 3, or 4.
• the heterocyclyl is a 4- to 6-membered heterocyclyl.
• the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O, and S.
• L is a –carbocyclyl-O– or – heterocyclyl-O– linker having the structure , wherein A5 and A6 are each independently –O– or –CH2–.
• A5 is –O–.
• A5 is – CH 2 –.
• a 6 is –O–.
• a 6 is –CH 2 –.
• L has the structure .
• L has the structure .
• L has the structure , wherein x is 1, 2, 3, or 4. In some embodiments, L has the structure . In some embodiments, L has the structure . In some embodiments, L has the structure . In some embodiments, L is a –carbocyclyl-(CH2)r-O–linker having the structure , wherein r is 0 or 1; s is 1 or 2; and t is 1 or 2. In some embodiments, s is 1 and t is 1. In some embodiments, s is 2 and t is 2. In some embodiments, L is a –carbocyclyl-(CH2)r-O–linker having the structure , wherein r is 0 or 1.
• L is a –carbocyclyl- (CH 2 ) r -O–linker having the structure , wherein r is 0 or 1. In some embodiments, L is a –carbocyclyl-(CH 2 ) r -O–linker having the structure , wherein r is 0 or 1. In some embodiments, L is a –carbocyclyl-(CH 2 ) r -O–linker having the structure , wherein r is 0. In the above embodiments, * represents the point of a .
• L is a –carbocyclyl-O– or –heterocyclyl-O– linker having the structure , wherein A 5 and A 6 are each independently –O– or –CH 2 –, and * represents the point of attachment to .
• A5 is –O–.
• a 5 is –CH 2 –.
• a 6 is –O–.
• a 6 is –CH 2 –.
• L is an aryl linker having the structure , wherein Rb is halogen, alkyl, or alkoxy; and u is 0, 1, or 2. In some embodiments, Rb is halogen.
• the halogen is fluoride. In some embodiments, u is 1. In some embodiments, u is 0. In some embodiments, the aryl linker i . [0103] In some embodiments, L is a 5- or 6-membered heteroaryl linker. In some embodiments, L is a 5- or 6-membered heteroaryl linker having 1 or 2 nitrogen atoms. In some embodiments, linker L is a heteroaryl linker having the structure , wherein R b is halogen, alkyl, or alkoxy; and u is 0 or 1. In some embodiments, u is 0. In some embodiments, u is 1.
• R1, R2, R3, R4, R8, R9, R11, and R12 are each independently H, halogen, alkyl, or cycloalkyl.
• R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R 11 , and R 12 are each independently H, halogen, or alkyl.
• the alkyl is a C1-5alkyl.
• the alkyl is methyl, ethyl, or isopropyl.
• the cycloalkyl is a C 3-6 cycloalkyl.
• the cycloalkyl is a cyclopropyl.
• R 1 and R 2 are each independently H, halogen, or alkyl.
• R1 and R2 are each independently H or alkyl.
• R1 and R2 are alkyl.
• the alkyl is methyl or ethyl.
• R1 and R2 are H.
• R 1 and R 2 are H or halogen.
• halogen is fluoride.
• R 1 and R 2 together with the carbon atom to which they are attached form a carbocycle or heterocycle.
• the carbocycle is a C3-6 cycloalkyl.
• R 3 and R 4 are halogen. In some embodiments, the halogen is fluoride. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a carbocycle or heterocycle. In some embodiments, the carbocycle is a C3-6 cycloalkyl. In some embodiments, the carbocycle is a cyclopropyl. In some embodiments, the heterocycle is a 3- or 6- membered heterocycle. In some embodiments, the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O, and S.
• R5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene- heterocyclyl, aryl, heteroaryl, alkylene-heteroaryl, or alkylene-S(O)2-alkyl.
• R 5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, aryl, heteroaryl, alkylene-heteroaryl, or alkylene-S(O)2-alkyl, each of which is optionally substituted with one or more halogen, C1-5 alkyl, C1-5 haloalkyl, -O-C1-5 alkoxy, and/or -CN.
• R5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heteroaryl, or alkylene-heteroaryl.
• R5 is C1-5 alkyl, C3-6 cycloalkyl, (C1-3 alkylene)-C3-6 cycloalkyl, 4- to 6-membered heterocyclyl, (C1-3 alkylene)-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, or (C 1-3 alkylene)-(5- to 6-membered heteroaryl).
• R 5 is alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or alkylene-heterocyclyl.
• R5 is C1-5 alkyl, C3-6 cycloalkyl, (C1-3 alkylene)-C3-6 cycloalkyl, 4- to 6-membered heterocyclyl, or (C 1-3 alkylene)-(4- to 6-membered heterocyclyl).
• R 5 is cycloalkyl, heterocyclyl, or heteroaryl.
• R5 is cycloalkyl or heterocyclyl.
• R5 is heteroaryl.
• R5 is a C1-5 alkyl, optionally substituted with one or more halogen and/or hydroxy.
• R 5 is cyclopropyl or cyclobutyl, each of which is optionally substituted with one or more halogen and/or C1-3 haloalkyl. In some embodiments, R5 is a cyclopropyl or cyclobutyl. In some embodiments, R 5 is a cyclopropyl or cyclobutyl, each of which is optionally substituted with one or more halogen and/or C 1-3 haloalkyl. In some embodiments, R 5 is a 4- to 6-membered heterocyclyl.
• the R5 is an oxetane, tetrahydrofuran, tetrahydropyran, morpholine, or thiomorpholine, each of which is optionally substituted with a C 1-3 haloalkyl.
• R5 is phenyl.
• R5 is a 5- or 6-membered heteroaryl.
• R 5 is 5- or 6-membered nitrogen-containing heteroaryl.
• R5 is 5-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.
• R5 is heteroaryl, optionally substituted with one or more halogen and/or C1-5 alkyl. In some embodiments, R5 is heteroaryl optionally substituted with one .
• the alkylene is a C 1-3 alkylene. In some embodiments, the alkylene is -CH2-. In some embodiments, R5 is optionally substituted with one or more halogen, - OH, -O-alkyl, -CN, and/or alkyl.
• R5 is optionally substituted with one or more F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -CN, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CF 3 and/or CHF 2.
• R 5 is optionally substituted with one or more F, CH3, CH2CH3, CH(CH3)2, -CN, CF3 and/or CHF2.
• R5 is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
• the alkyl is a C1-5alkyl.
• the alkyl is methyl, ethyl, or isopropyl.
• the cycloalkyl is a C3-6cycloalkyl.
• the aryl is a phenyl.
• the heterocyclyl is a 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms selected from the group consisting of N, O, and S.
• the heteroaryl is a 5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O, and S.
• V is –O– or –CR8R9–.
• V is –O– or –NR10–. In some embodiments, V is –O–. In some embodiments, V is –CR 8 R 9 –. In some embodiments, R 8 and R 9 are each independently H or alkyl.
• X is –O– or –NR13–. In some embodiments, X is –O– or –CR11R12– . In some embodiments, X is –CR11R12– or –NR13–. In some embodiments, X is –CR11R12–. In some embodiments, X is –CH 2 –.
• Y is a bond, –CR 8 R 9 –, or –NR 10 –. In some embodiments, Y is a bond, –O–, or –CR8R9–. In some embodiments, Y is a bond or –CR8R9–. In some embodiments, Y is a bond. In some embodiments, Y is a –CR 8 R 9 –. In some embodiments, Y is –CH 2 –. [0116] In some embodiments, Z is a –NR 10 – or –CR 8 R 9 –. In some embodiments, Z is –NR 10 –. In some embodiments, R8 and R9 are each independently H or alkyl.
• R8 and R9 together with the carbon atom to which they are attached form a C3-6 cycloalkyl.
• R 10 is H or alkyl.
• the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the alkyl is methyl.
• V-(X) p -Y-Z is –O-(CH 2 ) p -CH 2 -CH 2 – or –O-(CH 2 ) p -CH 2 –, wherein p is 0 or 1.
• V-(X) p -Y-Z is –O-(CH 2 ) p -CH 2 -O–, wherein p is 1.
• V-(X) p -Y-Z is –O-CH 2 -CH 2 -O–.
• V-(X) p -Y-Z is –O-CH 2 -O– .
• V-(X)p-Y-Z is –O-CH2-. In some embodiments, V-(X)p-Y-Z is –O-CH2- CH2-. [0118] In some embodiments, V-(X) p -Y-Z does not comprise an –O-O– or –N-N– bond. [0119] In some embodiments, R 8 and R 9 are each independently H, halogen, or alkyl. In some embodiments, R8 and R9 are each independently H or alkyl. In some embodiments, R8 and R9 are alkyl. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, R 8 and R 9 are each independently H or halogen.
• R 8 and R 9 are H.
• R8 and R9 are halogen.
• the halogen is fluoride.
• R8 and R9 together with the carbon atom to which they are attached form a carbocycle or heterocycle.
• the carbocycle is a C 3-6 cycloalkyl.
• the carbocycle is a cyclopropyl.
• the heterocycle is a 3- or 6-membered heterocycle.
• the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O, and S.
• R10 is H, alkyl, or cycloalkyl.
• R 10 is H or alkyl.
• R 10 is alkyl.In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is methyl, ethyl, or isopropyl. In some embodiments, the alkyl is methyl. In some embodiments, the cycloalkyl is a C 3-6 cycloalkyl. [0121] In some embodiments, R 11 and R 12 are each independently H, halogen, or alkyl. In some embodiments, R11 and R12 are each independently H or alkyl. In some embodiments, R11 and R12 are alkyl. In some embodiments, the alkyl is methyl or ethyl.
• R11 and R12 are each independently H or halogen. In some embodiments, R 11 and R 12 are H. In some embodiments, R11 and R12 are halogen. In some embodiments, the halogen is fluoride. In some embodiments, R11 and R12 together with the carbon atom to which they are attached form a carbocycle or heterocycle. In some embodiments, the carbocycle is a C 3-6 cycloalkyl. In some embodiments, the carbocycle is a cyclopropyl. In some embodiments, the heterocycle is a 3- or 6- membered heterocycle. In some embodiments, the heterocycle comprises 1 or 2 heteroatoms selected from the group consisting of N, O, and S.
• Ra is each independently F, CH3, CH2CH3, CH(CH3)2, CF3, CHCF2, -OCH3, -OCH2CH3, -OCH(CH3)2, - OCF 3 , -OCHCF 2 , or -CN.
• R a is each independently F, CH 3 , CH 2 CH 3 , CF 3 , CHF 2 , -OCH 3 , -OCF 3 , or -OCHF 2 .
• R a is each independently F, CH 3 , CH2CH3, CH(CH3)2, CF3, CHCF2, or -CN.
• Ra is each independently F or CH 3 .
• each R a is F.
• q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 2. , . [0124] In some embodiments, is a 5-membered heteroaryl. In some embodiments, is 5- membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the 5-membered heteroaryl . some embodiments, is a 6-membered heteroaryl. In some embodiments, is a 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.
• is a 6-membered heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.
• the 6-membered heteroaryl is: , , , , , , or , wherein Ra is each independently halogen, alkyl, -CN, or alkoxy; and q is 0, 1, or 2.
• the 6-membered heteroaryl is: , wherein Ra is each independently halogen, alkyl, -CN, or alkoxy; and q is 0, 1, or 2.
• each independently halogen or alkyl is selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.
• the 6-membered heteroaryl is: , , , , , , or , wherein Ra is each independently halogen, alkyl, -CN, or alkoxy; and
• Ra is each independently halogen or C1-5 alkyl. In some embodiments, Ra is each independently F, CH3, CH2CH3, CH(CH3)2, CF3, CHCF 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -OCHCF 2 , or -CN. In some embodiments, R a is each independently F, CH3, CH2CH3, CF3, CHF2, -OCH3, -OCF3, or -OCHF2. In some embodiments, Ra is each independently F, CH3, CH2CH3, CH(CH3)2, CF3, CHCF2, or -CN. In some embodiments, R a is each independently F or CH 3 .
• each R a is F. In some embodiments, each R a is CH 3 . In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. [0125] In some embodiments, is: , , , , , , , , or . In [0126] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. [0127] In some embodiments, n is 0 or 1. In some embodiments, n is 1. [0128] In some embodiments, the sum of m and n is from 1 to 3. In some embodiments, the sum of m and n is 1 or 2.
• m is 0 and n is 1 or 2. In some embodiments, m is 1 and n is 0, 1, or 2. In some embodiments, n is 0 and m is 1 or 2. In some embodiments, n is 1 and m is 0, 1, or 2. In some embodiments, m is 0 and n is 1; n is 0 and m is 1; or m is 1 and n is 1. In some embodiments, m is 1 and n is 1. In some embodiments, m is 0 and n is 1. In some embodiments, n is 0 and m is 1. [0129] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.
• R1 and R2 are each independently H or alkyl
• R3 and R4 are H
• X is ⁇ CH2 ⁇
• V is ⁇ O ⁇
• Y is a bond or ⁇ CH2 ⁇
• Z is ⁇ O ⁇
• ⁇ CH2 ⁇ or ⁇ N(alkyl) ⁇
• m is 0 or 1
• n is 0 or 1
• p is 0 or 1.
• R1 and R2 are each independently H or alkyl
• R3 and R4 are H
• X is ⁇ CH2 ⁇
• V is ⁇ O ⁇
• Y is a bond or ⁇ CH2 ⁇
• Z is ⁇ O ⁇
• m is 0 or 1
• n is 0 or 1
• p is 0 or 1.
• R 1 and R 2 are each independently H or alkyl
• R 3 and R 4 are H
• X is ⁇ CH2 ⁇
• V is ⁇ O ⁇
• Y is a bond or ⁇ CH2 ⁇
• Z is ⁇ CH2 ⁇ or ⁇ O ⁇
• m is 0 or 1
• n is 0 or 1
• p is 0 or 1.
• R1 and R2 are each independently H or alkyl
• R3 and R4 are H
• X is ⁇ CH 2 ⁇
• V is ⁇ O ⁇
• Y is a bond or ⁇ CH 2 ⁇
• Z is ⁇ CH 2 ⁇
• m is 0 or 1
• p is 0 or 1.
• R 1 and R 2 are each independently H or alkyl
• R 3 and R 4 are H
• X is ⁇ CH2 ⁇
• V is ⁇ O ⁇
• Y is a bond
• Z is ⁇ CH2 ⁇
• m is 0 or 1
• n is 1, and p is 0.
• L is –carbocyclyl-O– or –heterocyclyl-O–
• R 1 and R 2 are each independently H or alkyl
• R3 and R4 are H
• X is ⁇ CH2 ⁇
• V is ⁇ O ⁇
• Y is a bond or ⁇ CH2 ⁇
• Z is ⁇ O ⁇ , ⁇ CH2 ⁇ , ⁇ CH(Me) ⁇ , or ⁇ N(alkyl) ⁇
• m is 0 or 1
• n is 0 or 1
• p is 0 or 1.
• L is –carbocyclyl-O– or –heterocyclyl-O–
• R 1 and R 2 are each independently H or alkyl
• R3 and R4 are H
• X is ⁇ CH2 ⁇
• V is ⁇ O ⁇
• Y is a bond or ⁇ CH2 ⁇
• Z is ⁇ CH2 ⁇ or ⁇ O ⁇
• m is 0 or 1
• n is 0 or 1
• p is 0 or 1.
• L is , wherein A 5 and A 6 are each independently ⁇ CH2 ⁇ or ⁇ O ⁇ , R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is ⁇ CH2 ⁇ , V is ⁇ O ⁇ , Y is a bond or ⁇ CH2 ⁇ , Z is ⁇ O ⁇ , ⁇ CH2 ⁇ , ⁇ CH(Me) ⁇ , or ⁇ N(alkyl) ⁇ , m is 0 or 1, n is 0 or 1, and p is 0 or 1.
• L is , wherein A 5 and A 6 are each independently ⁇ CH2 ⁇ or ⁇ O ⁇ , R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is ⁇ CH2 ⁇ , V is ⁇ O ⁇ , Y is a bond or ⁇ CH2 ⁇ , Z is ⁇ CH2 ⁇ or ⁇ O ⁇ , m is 0 or 1, n is 0 or 1, and p is 0 or 1.
• L is phenyl or heteroaryl having 1 or 2 N atoms
• L is , wherein A5 and A6 are each independently ⁇ CH2 ⁇ or ⁇ O ⁇ , R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is ⁇ CH2 ⁇ , V is ⁇ O ⁇ , Y is a bond or ⁇ CH2 ⁇ , Z is ⁇ O ⁇ , ⁇ CH 2 ⁇ , ⁇ CH(Me) ⁇ , or ⁇ N(alkyl) ⁇ , m is 0 or 1, n is 0 or 1, and p is 0 or 1.
• L is phenyl or heteroaryl having 1 or 2 N atoms
• L is , wherein A 5 and A 6 are each independently ⁇ CH 2 ⁇ or ⁇ O ⁇
• R 1 and R 2 are each independently H or alkyl
• R3 and R4 are H
• X is ⁇ CH2 ⁇
• V is ⁇ O ⁇
• Y is a bond or ⁇ CH2 ⁇
• Z is ⁇ CH 2 ⁇ or ⁇ O ⁇
• m is 0 or 1
• n is 0 or 1
• p is 0 or 1.
• L is , wherein r is 0 or 1, s is 1, and t is 1,
• R 1 and R 2 are each independently H or alkyl, R 3 and R 4 are H,
• X is ⁇ CH 2 ⁇
• V is ⁇ O ⁇
• Y is a bond or ⁇ CH 2 ⁇
• Z is ⁇ CH 2 ⁇ or ⁇ O ⁇
• m is 0 or 1
• n is 0 or 1
• p is 0 or 1.
• Ra and q are as defined herein, L is , R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is ⁇ CH2 ⁇ , V is ⁇ O ⁇ , Y is a bond or ⁇ CH2 ⁇ , Z is ⁇ CH2 ⁇ or ⁇ O ⁇ , m is 0 or 1, n is 1, and p is 0. In some embodiments, m is 1.
• R a and q are as defined herein, L is , R 1 and R 2 are each independently H or alkyl, R 3 and R 4 are H, X is ⁇ CH 2 ⁇ , V is ⁇ O ⁇ , Y is a bond or ⁇ CH 2 ⁇ , Z is ⁇ CH 2 ⁇ or ⁇ O ⁇ , m is 0 or 1, n is 1, and p is 0. In some embodiments, m is 1.
• R a and q are as defined herein, L is , R 1 and R 2 are each independently H or alkyl, R 3 and R 4 are H, X is ⁇ CH 2 ⁇ , V is ⁇ O ⁇ , Y is a bond or ⁇ CH 2 ⁇ , Z is ⁇ CH 2 ⁇ or ⁇ O ⁇ , m is 0 or 1, n is 1, and p is 0. In some embodiments, m is 1.
• Ra and q are as defined herein, L is , R1 and R2 are each independently H or alkyl, R3 and R4 are H, X is ⁇ CH2 ⁇ , V is ⁇ O ⁇ , Y is a bond or ⁇ CH2 ⁇ , Z is ⁇ CH2 ⁇ , m is 1, n is 1, and p is 0 or 1.
• Ra and q are as defined herein, L is , R1 and R2 are each independently H or alkyl, R 3 and R 4 are H, R 5 is as defined herein, R 6 is H, X is ⁇ CH 2 ⁇ , V is ⁇ O ⁇ , Y is a bond or ⁇ CH 2 ⁇ , Z is ⁇ CH 2 ⁇ , m is 0 or 1, n is 1, and p is 0 or 1.
• Ra and q are as defined herein, L is , R1 and R2 are each independently H or alkyl, R3 and R4 are H, R5 is as defined herein, R 6 is H, X is ⁇ CH 2 ⁇ , V is ⁇ O ⁇ , Y is a bond, Z is ⁇ CH 2 ⁇ , m is 1, n is 1, and p is 0.
• R1 and R2 are each independently H or alkyl, R3 and R4 are H, R5 is as defined herein, R6 is H, X is ⁇ CH2 ⁇ , V is ⁇ O ⁇ , Y is a bond, Z is ⁇ CH2 ⁇ , m is 1, n is 1, and p is 0.
• R 3 and R 4 are H
• R 5 is as defined herein
• R 6 is H
• X is ⁇ CH 2 ⁇
• V is ⁇ O ⁇
• Y is a bond
• Z is ⁇ CH2 ⁇
• m is 1, n is 1, and p is 0.
• R 1 and R 2 are each independently H or alkyl
• R 3 and R 4 are H
• R 5 is as defined herein
• R6 is H
• X is ⁇ CH2 ⁇
• V is ⁇ O ⁇
• Y is a bond
• Z is ⁇ CH2 ⁇
• m is 1, n is 1, and p is 0.
• Ra and q are as defined herein, L is , R1 and R2 are each independently H R 6 is H, X is ⁇ CH 2 ⁇ , V is ⁇ O ⁇ , Y is a bond or ⁇ CH 2 ⁇ , Z is ⁇ CH 2 ⁇ , m is 0 or 1, n is 1, and p is 0 or 1.
• R a and q are as defined herein, , R 1 and R 2 are each independently H or alkyl, R 3 and R 4 are H, R 5 is , ⁇ CH 2 ⁇ , Z is ⁇ CH 2 ⁇ , m is 0 or 1, n is 1, and p is 0 or 1.
• Ra and q are as defined herein, L is , R1 and R2 are each independently H ⁇ O ⁇ , Y is a bond or ⁇ CH 2 ⁇ , Z is ⁇ CH 2 ⁇ , m is 0 or 1, n is 1, and p is 0 or 1.
• L , R 1 and R 2 are each independently H or alkyl, R 3 and R 4 are H, R 5 is bond, Z is ⁇ CH 2 ⁇ , m is 1, n is 1, and p is 0.
• R3 and R4 are H
• R5 is , , or , R6 is H
• X is ⁇ CH 2 ⁇
• V is ⁇ O ⁇
• Y is a bond
• Z is ⁇ CH 2 ⁇
• m is 1
• n is 1
• p is 0.
• L is , wherein Rb is halogen, alkyl, or alkoxy, and u is 0, 1, or 2
• R1 and R2 are each independently H or alkyl
• R 3 and R 4 are H
• X is ⁇ CH 2 ⁇
• V is ⁇ O ⁇
• Y is a bond or ⁇ CH 2 ⁇
• Z is ⁇ O ⁇ , ⁇ CH 2 ⁇ , ⁇ CH(Me) ⁇ , or ⁇ N(alkyl) ⁇
• m is 0 or 1
• n is 0 or 1
• p is 0 or 1.
• L is , wherein Rb is halogen, alkyl, or alkoxy, and u is 0, 1, or 2
• R1 and R2 are each independently H or alkyl
• R 3 and R 4 are H
• X is ⁇ CH 2 ⁇
• V is ⁇ O ⁇
• Y is a bond or ⁇ CH 2 ⁇
• Z is ⁇ O ⁇
• m is 0 or 1
• n is 0 or 1
• p is 0 or 1.
• phenyl is phenyl, wherein Rb is halogen, alkyl, or alkoxy, and u is 0, 1, or 2, R 1 and R 2 are each independently H or alkyl, R 3 and R 4 are H, X is ⁇ CH2 ⁇ , V is ⁇ O ⁇ , Y is a bond or ⁇ CH2 ⁇ , Z is ⁇ O ⁇ , ⁇ CH2 ⁇ , ⁇ CH(Me) ⁇ , or ⁇ N(alkyl) ⁇ , m is 0 or 1, n is 0 or 1, and p is 0 or 1. [0160] In some embodiments, the compounds disclosed herein are a racemic mixture. In some embodiments, the compounds disclosed herein are enriched in one enantiomer.
• the compounds disclosed herein are enriched in one enantiomer and substantially free of the opposite enantiomer.
• the compounds disclosed herein have an enantiomeric excess of about or greater than about 55%, about or greater than about 60%, about or greater than about 65%, about or greater than about 70%, about or greater than about 75%, about or greater than about 80%, about or greater than about 85%, about or greater than about 90%, about or greater than about 91%, about or greater than about 92%, about or greater than about 93%, about or greater than about 94%, about or greater than about 95%, about or greater than about 96%, about or greater than about 97%, about or greater than about 98%, about or greater than about 98.5%, about or greater than about 99%, about or greater than about 99.5%, or more, including all subranges and values therebetween.
• the compounds of the present disclosure are provided as a mixture of diastereomers. In some embodiments, a diastereomer of a compound of the present disclosure is provided substantially free of other possible diastereomer(s).
• the present disclosure includes tautomers of any compounds described herein. [0161] In some embodiments, provided herein is one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. [0162] In some embodiments, provided herein is one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or an enantiomer thereof.
• provided herein is one or more compounds selected from Table 1 or a pharmaceutically acceptable salt thereof, or a diastereomer, or mixture of diastereomers thereof.
• provided herein is one or more compounds selected from Table 1.
• provided herein is one or more pharmaceutically acceptable salts of a compound selected from Table 1. Table 1.
• Compounds of the Disclosure [0166] In some embodiments, the present disclosure provides a compound, e.g., a compound of Formula (I), having the structure:
• the compound of the present disclosure is a compound provided in Tables 3-24. In some embodiments, the compound of the present disclosure is a compound provided in Tables 3-24 that has “A” (EC 50 ⁇ 100 nM) or “B” activity (EC 50 between 100 nM and 1,000 nM). In some embodiments, the compound of the present disclosure is a compound provided in Tables 3-24 that has “A” activity.
• the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 6 , R a , m, n, and p are as defined herein: R14 is C1-5 haloalkyl; and s and t are each independently 1 or 2. [0169] In some embodiments, R 14 is CF 3 or CHF 2 . [0170] In some embodiments, R a is F.
• R1 and R2 are each H; R6 is H or CH3; R14 is CF3 or CHF2; Ra is F; m and n are each 1; p is 0 or 1; q is 0 or 1; and s and t are each 2.
• R 1 and R 2 are each H; R 6 is H; R 14 is CF 3 or CHF 2 ; R a is F; m and n are each 1; p is 0; q is 0 or 1; and s and t are each 2.
• the compound of Formula (II) is a compound having a structure provided in Table 2 or a pharmaceutically acceptable salt thereof. Table 2.
• the compound of present disclosure e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC- 2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula, (ID-4), or Formula (II), excludes the compounds disclosed in WO2021/108628 and WO2022/232025.
• compositions for modulating orexin receptor (e.g., orexin type 2 receptor) in a subject.
• a pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC- 2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula, (ID-4), Formula (II), or Tables 1-24) or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition comprises a therapeutically effective amounts of one or more compounds of the present disclosure (e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula, (ID-4), Formula (II), or Tables 1-24) or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition as described herein, comprises a compound selected from Table 1, or a pharmaceutically acceptable salt thereof or stereoisomer thereof. In some embodiments, a pharmaceutical composition, as described herein, comprises a compound selected from Table 2, or a pharmaceutically acceptable salt thereof or stereoisomer thereof. In some embodiments, a pharmaceutical composition, as described herein, comprises a compound selected from any one of Tables 1-24, or a pharmaceutically acceptable salt thereof.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula, (ID-4), Formula (II), or Tables 1-24), or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.
• a compound disclosed herein e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-2), Formula
• a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC- 2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID- 2), Formula (ID-3), Formula, (ID-4), Formula (II), or Tables 1-24) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or adjuvant is provided.
• a pharmaceutically acceptable salt thereof e.g., a pharmaceutically acceptable excipient or adjuvant
• a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprise a pharmaceutically acceptable carrier.
• a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent.
• suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions.
• suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.
• the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques.
• Intraarterial and intravenous injection as used herein includes administration through catheters.
• the compounds of the present disclosure are administered in a therapeutically effective amount.
• the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
• Methods of Use [0181]
• the compounds of the present disclosure find use in any number of methods. For example, in some embodiments the compounds are useful in methods for modulating an orexin receptor, e.g., orexin type 2 receptor.
• the present disclosure provides the use of any one of the foregoing compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID- 3), Formula, (ID-4), Formula (II), or Tables 1-24 or a pharmaceutically acceptable salt thereof, for modulating orexin receptor (e.g., orexin type 2 receptor) activity.
• orexin receptor e.g., orexin type 2 receptor
• modulating orexin receptor (e.g., orexin type 2 receptor) activity is in a mammalian cell.
• Modulating orexin receptor (e.g., orexin type 2 receptor) activity can be in a subject in need thereof (e.g., a mammalian subject, such as a human) and for treatment of any of the described conditions or diseases.
• the modulating orexin receptor (e.g., orexin type 2 receptor) activity is binding.
• the modulating orexin receptor (e.g., orexin type 2 receptor) activity is agonizing or stimulating the orexin receptor.
• the present disclosure provides methods of treating a disease or disorder that is treatable by administration of an Orexin agonist, the method comprising administering a therapeutically effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula, (ID-4), Formula (II), or Tables 1-24) to a subject in need thereof.
• compounds of the present disclosure e.g., compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (
• the present disclosure provides methods of treating a disease or disorder that is treatable by administration of an Orexin agonist, the method comprising administering a composition comprising a therapeutically effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula (I), Formula (I-1), Formula (I- 2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID- 3), Formula, (ID-4), Formula (II), or Tables 1-24) to a subject in need thereof.
• a composition comprising a therapeutically effective amount of one or more compounds of the present disclosure (e
• the compounds of the present disclosure are used for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with orexin receptors, including one or more of the following conditions or diseases: narcolepsy, narcolepsy syndrome accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, hypersomnia accompanied by daytime hypersomnia, interrupted sleep, sleep apnea, hypersomnia associated with sleep apnea, nocturnal myoclonus, disturbances of consciousness, such as coma, REM sleep interruptions, jet-lag, excessive daytime sleepiness, shift workers' sleep disturbances, dyssomnias, sleep disorders, sleep disturbances, hypersomnia associated with depression, emotional/mood disorders, drug use
• narcolepsy
• compounds of the present disclosure are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Parkinson’s disease, Guillain-Barre syndrome and 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.
• narcolepsy idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms
• hypersomnia syndrome accompanied by daytime hypersomnia e.g., Parkinson’s disease, Guill
• a compound of the present disclosure e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC- 2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula, (ID-4), Formula (II), or Tables 1-24), a pharmaceutically acceptable salt thereof, or a composition thereof is used to treat diseases or disorders or symptoms associated with excessive sleepiness in a subject in need thereof.
• a pharmaceutically acceptable salt thereof, or a composition thereof is used to treat diseases or disorders or symptoms associated with excessive sleepiness in a subject in need thereof.
• the excessive sleepiness is caused by any one of the following: insufficient quality or quantity of night time sleep; misalignments of the body’s circadian pacemaker with the environment (e.g., caused by requirement to remain awake at night for employment such as shift work or personal obligations such as caretaker for sick, young or old family members), such as jet lag, shift work and other circadian rhythm sleep disorders; another underlying sleep disorder, such as narcolepsy (e.g., narcolepsy type 1, narcolepsy type 2, probable narcolepsy), sleep apnea (e.g., obstructive sleep apnea, obstructive sleep apnea with use of continuous positive airway pressure), idiopathic hypersomnia, idiopathic excessive sleepiness, and restless legs syndrome; disorders, such as clinical depression or atypical depression; tumors; head trauma; anemia; kidney failure; hypothyroidism; injury to the central nervous system; drug abuse; genetic vitamin
• a compound of the present disclosure e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC- 2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula, (ID-4), Formula (II), or Tables 1-24), a pharmaceutically acceptable salt thereof, or a composition thereof is used to treat any one of the following: shift work disorder; shift work sleep disorder; and jet lag syndrome.
• the methods and uses herein are used to treat any one of the following: narcolepsy type 1, narcolepsy type 2, probable narcolepsy, idiopathic hypersomnia, idiopathic excessive sleepiness, hypersomnia, hypersomnolence, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with use of continuous positive airway pressure); or disturbance of consciousness such as coma and the like; and narcolepsy syndrome accompanied by narcolepsy- like symptoms; hypersomnolence or hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Parkinson’s disease, Guillain-Barre syndrome and Kleine Levin syndrome); excessive daytime sleepiness in Parkinson’s disease, Prader-Willi Syndrome, depressions (depression, atypical depression, major depressive disorder, treatment resistant depression), ADHD, sleep apnea syndrome (
• Narcolepsy e.g., narcolepsy type 1, narcolepsy type 2, probable narcolepsy
• the excessive sleepiness is excessive daytime sleepiness or excessive sleepiness during working hours, or excessive sleepiness or reduced quantity of sleep which is caused by requirement to remain awake at night for employment (e.g., shift work) or personal obligations (e.g., caretaker for sick, young or old family members).
• the subject suffers from the diseases or disorders or symptoms associated with excessive sleepiness.
• the subject is sleep-deprived subject, subject with excessive sleepiness, subject with disruptive regular sleep cycle, or subject with a need to decrease sleepiness.
• the present disclosure provides methods for decreasing or treating excessive sleepiness.
• the excessive sleepiness is caused by narcolepsy type 1, narcolepsy type 2 or idiopathic hypersomnia.
• the excessive sleepiness is caused by obstructive sleep apnea despite the use of continuous positive airway pressure (CPAP).
• CPAP continuous positive airway pressure
• methods for increasing wakefulness in a subject in need thereof is provided.
• the orexin level in the subject is not compromised or partially compromised.
• a compound of the present disclosure e.g., a compound of Formula (I), Formula (I- 1), Formula (I-2
• a compound of the present disclosure e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-3), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID- 3), Formula, (ID-4), Formula (II), or Tables 1-24
• a pharmaceutically acceptable salt thereof is used to treat a subject with a sleep disorder, to treat a sleep disorder, or to treat the symptoms of a sleep disorder.
• a method for the treatment of narcolepsy in a subject in need thereof comprising administering a compound of the present disclosure (e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula, (ID-4), or Tables 1-24), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• a compound of the present disclosure e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (I
• a compound of the present disclosure e.g., a compound of Formula (I), Formula (I- 1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC- 2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID- 2), Formula (ID-3), Formula, (ID-4), Formula (II), or Tables 1-24), or a pharmaceutically acceptable salt thereof, is used to treat a subject with narcolepsy, to treat narcolepsy, or to treat the symptoms of narcolepsy.
• a pharmaceutically acceptable salt thereof is used to treat a subject with narcolepsy, to treat n
• a method for the treatment of idiopathic hypersomnia (IH) in a subject in need thereof comprising administering a compound of the present disclosure (e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula, (ID-4), Formula (II), or Tables 1-24), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• a compound of the present disclosure e.g., a compound of Formula (I), Formula (I-1), Formula
• a compound of the present disclosure e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IA-1), Formula (IA-2), Formula (IB), Formula (IB-1), Formula (IB-2), Formula (IC-1), Formula (IC-2), Formula (IC-2a), Formula (IC-2b), Formula (IC-2c), Formula (IC-2d), Formula (IC-2e), Formula (IC-2f), Formula (IC-2g), Formula (IC-2h), Formula (IC-3), Formula (IC-3a), Formula (IC-3b), Formula (IC-4), Formula (ID-1), Formula (ID-2), Formula (ID-3), Formula, (ID-4), Formula (II), or Tables 1-24), or a pharmaceutically acceptable salt thereof, is used to treat a subject with IH, to treat IH, or to treat the symptoms of IH.
• a pharmaceutically acceptable salt thereof is used to treat a subject with IH, to treat IH, or to treat the symptoms of IH.
• reaction products can be purified by generally known methods including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol and the like or preparative reverse phase high pressure liquid chromatography.
• IP-1 ACCUMULATION ASSAY IP-1 ACCUMULATION ASSAY
• hOX1-CHO and hOX2-CHO cells were seeded into white 384-well plates at a density of 20,000 cells/well in Hank’s Balanced Salt Solution (HBSS) containing 20 mM HEPES pH 7.4, 50 mM, LiCl and 0.1% and Bovine Serum Albumin (BSA).
• HBSS Hank’s Balanced Salt Solution
• BSA Bovine Serum Albumin
• Compounds of the invention were tested in 11 point concentration response curves (CRC) serially diluted in neat DMSO at 200-fold concentrations and added by Echo acoustic liquid handling (Labcyte) to the cells (0.5% DMSO final in the assay).
• CRC 11 point concentration response curves
• IP1-d2 tracer and anti-IP1-cryptate were diluted in lysis buffer according to the manufacturer’s descriptions and added to the cells.
• time-resolved fluorescence HTRF
• HTRF ratio A665/A615x10 4
• EC 50 Mean data of EC 50 are calculated from at least two independent experiments performed in duplicate.
• EC 50 Category A corresponds to compounds displaying an EC50 ⁇ 100nM, Category B between 100nM and 1,000nM, Category C between 1,000nM and 10,000nM and Category D above 10,000 nM
• SYNTHESIS OF INTERMEDIATE 1 [0206] 1-tert-butyl-4-ethyl-3-oxo-2-( ⁇ [(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]- oxy ⁇ methyl)-piperidine-1,4-dicarboxylate [0207] In a flask, a 2.4M solution of nBuLi in heptane (79 mL, 0.191 mol) was added to a stirred solution of N-(propan-2-yl)propan-2-amine (26 mL, 0.188 mol) in anhydrous THF (90 mL) at - 78
• the reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (2 x 200 mL) and brine (200 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the crude material. The latter was purified by column chromatography using a silica cartridge (0-50% EtOAc in heptane) to afford the title compound (7.03 g, 14.25 mmol, 54% yield) as an orange oil.
• the resulting solution was stirred for 1 h, then it was concentrated in vacuo to afford the crude material.
• the mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried (MgSO 4 ), filtered and concentrated in vacuo to afford the crude product.
• the crude material was purified by column chromatography using a silica cartridge (0-40% 3:1 EtOAc/EtOH in heptane) to afford the title compound (5.9 g, 17.0 mmol, 65% yield) as a white solid.
• the mixture was diluted with DCM (200 mL), then washed with saturated aqueous. NaHCO 3 (100 mL), 1 M aq. Na 2 S 2 O 3 (100 mL), and 1M aq. Na 2 CO 3 (100 mL).
• the organic phase was dried by passing through a hydrophobic filter and concentrated in vacuo to give the crude product.
• the crude material was purified by column chromatography using a silica cartridge (0-100% 3:1 EtOAc/EtOH in heptane) to afford the title compound (4.1 g, 11.94 mmol, 75% yield) as a pale-yellow solid.
• Method B A solution of 2,2,2-trifluoroethanamine (125 mg, 1.26 mmol), Ti(OEt) 4 (191 mg, 0.839 mmol) and Intermediate 8 (150 mg, 0.420 mmol) in anhydrous THF (5 mL) was heated to 70 °C for 16 h. The reaction mixture was cooled to room temperature, then sodium borohydride (254 mg, 6.71 mmol) was added and the mixture was stirred for 3h. The reaction was quenched with water (15 mL) and diluted with EtOAc (15 mL). The mixture was filtered through a pad of Celite and extracted with EtOAc (2 x 20 mL).
• the suspension was degassed by several vacuum/N 2(g) cycles and then by bubbling N 2(g) through the mixture for 10 minutes.
• the mixture was stirred at 105 °C for 16 h, then it was cooled to room temperature and saturated aqueous NaHCO3 solution was added.
• the mixture was extracted three times with EtOAc.
• the combined organic layers were dried by filtering through a hydrophobic frit (Phase Separator) and concentrated in vacuo.
• the product was purified by column chromatography using a silica cartridge (0-20% EtOAc in cHex) to afford the title compound (7.3 g, 14.73 mmol, 49% yield) as a yellow oil.
• Procedure B A solution of the appropriate amine (0.500 mmol), macrocyclic ketone intermediate (0.170 mmol), and Ti(OEt)4 (0.07 mL, 0.330 mmol) in THF (4.912 mL) was heated to 70 °C overnight. Then sodium cyanoborohydride (164.24 mg, 2.66 mmol) was added and the mixture stirred for 5 h at room temperature. Water was added and the mixture was extracted three times with DCM. The combined organic layers were dried (Na2SO4) and evaporated in vacuo.
• Procedure C The appropriate macrocyclic ketone intermediate (0.170 mmol) and the appropriate amine (0.170 mmol) were suspended in DCM (2 mL). Sodium triacetoxyborohydride (148 mg, 0.700 mmol) and Na 2 SO 4 (50 mg, 0.350 mmol) were added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO 3 solution. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
• Procedure D The appropriate macrocyclic ketone intermediate (0.140 mmol) and the appropriate amine (0.280 mmol) were suspended together in THF (1.4 mL) then sodium triacetoxyborohydride (176 mg, 0.830 mmol) was slowly added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, saturated aqueous NH4Cl solution and brine. The organic layer was dried (Na 2 SO 4 ) and evaporated in vacuo.
• Procedure E The appropriate macrocyclic ketone intermediate (0.190 mmol), the appropriate amine (0.390 mmol) and sodium triacetoxyborohydride (123 mg, 0.580 mmol) were dissolved in DCM (1.3 mL). The mixture was stirred for 3 h at room temperature. EtOAc was added and the suspension was filtered to remove inorganic salts. The filtrate was washed with saturated aqueous NH4Cl solution, dried (Na2SO4) and evaporated in vacuo. [0286] The products listed in the following table were obtained using the procedures above were purified using the most suitable method between direct or inverse phase column chromatography or using a SCX cartridge.
• ketone intermediates were synthetized using a similar synthetic route to that described for Intermediate 23.
• Stereoisomers were separated by chiral HPLC purification using appropriate chiral columns and combinations of solvent mixtures; Chiralpak columns (AD-H, AS-H, IC, ID), Chiralcel columns (OD-H, OJ-H); solvent mixture of n-Hexane / EtOH, n-Hexane / (EtOH + 0.1% iPrNH2), n-Hexane / (EtOH/MeOH 1:1 + 0.1% iPrNH2), or by chiral SFC purification using appropriate chiral columns and combinations of solvent mixtures; Chiralpak columns (AD-H, ID), MeOH + 0.1% iPrNH 2 or EtOH + 0.1% iPrNH 2 as modifier.
• Example 205 [0291] Rel-2-( ⁇ [(1s,15S,16R,19s)-3,6-difluoro-10-oxo-8,18-dioxa-11-azatetracyclo [17.2.2.02,7.011,16]tricosa-2(7),3,5-trien-15-yl]amino ⁇ methyl)benzonitrile
• the organic layer was dried (Na2SO4), filtered and evaporated in vacuo.
• the intermediate was purified by column chromatography using a C18 cartridge (0-30% MeCN + 0.1% HCOOH in H 2 O + 0.1% HCOOH).
• the intermediate obtained (63.0 mg, 0.130 mmol) was dissolved in methanol (6 mL).
• Ammonium formate (161 mg, 2.55 mmol) and 10% wt. Pd/C (15 mg, 0.140 mmol) were added and the mixture was stirred at 70 °C overnight.
• the suspension was filtered, and the filtrate was evaporated in vacuo.
• the residue was dissolved in EtOAc and washed with water, dried (Na 2 SO 4 ), filtered and evaporated in vacuo.
• Example 202 To a solution of Example 202 (50 mg, 0.110 mmol) in DCM (3 mL), formaldehyde (0.41 mL, 0.110 mmol) and triethylamine (0.05 mL, 0.330 mmol) were added, followed by sodium triacetoxyborohydride (47 mg, 0.220 mmol). The mixture was stirred at room temperature overnight. Saturated aqueous NaHCO3 solution was added and the mixture was extracted with DCM. The combined organic layer was dried (Na2SO4), filtered and evaporated in vacuo. The product was purified by preparative HPLC to afford the title compound (1.7 mg, 0.004 mmol, 3% yield) as a white solid.
• the reaction mixture was stirred while sodium triacetoxyborohydride (1309 mg, 6.18 mmol) was added portionwise over 1 h and then stirred at room temperature for 1 h.
• the mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution and brine.
• the organic layer was dried (Na 2 SO 4 ), filtered and then concentrated in vacuo.
• the residue was dissolved in EtOH (37.2 mL) and then ammonium formate (5842 mg, 92.64 mmol) followed by palladium on Carbon 10% wet (3286 mg, 1.54 mmol) were added to the reaction mixture.
• Example 211 3- ⁇ [(1s,15R,16R,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo [17.2.2.02,7.011,16]tricosa-2(7),3,5-trien-15-yl]amino ⁇ propanenitrile [0308]
• Example 212 3- ⁇ [(1s,15S,16R,19s)-3-fluoro-10-oxo-8,18-dioxa-11-azatetracyclo [17.2.2.02,7.011,16]tricosa-2(7),3,5-trien-15-yl]amino ⁇ propanenitrile
• Example 213 Rel-4,4,4-trifluoro-3- ⁇ [(1s,15R,16R,19s)-3-fluoro-10-oxo-8,18-dioxa-11- azatetracyclo[17.2.2.02,7.011,16]tricosa-2(7),3,5-trien-15-yl]amino ⁇ butanenitrile [0312]
• Example 214 Rel-4,4,4-trifluoro-3- ⁇ [(1s,15S,16S,19s)-3-fluoro-10-oxo-8,18-dioxa-11- azatetracyclo[17.2.2.02,7.011,16]tricosa-2(7),3,5-trien-15-yl]amino ⁇ butanenitrile [0313]
• Example 215 4,4,4-trifluoro-3- ⁇
• reaction mixture was stirred at this temperature for 1 h. After complete consumption of the starting material, the reaction mixture was warmed to room temperature and further DIPEA (0.11 mL, 0.620 mmol) was added. N,N-dimethylamine hydrochloride (51 mg, 0.620 mmol) was added to the reaction mixture and it was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and then washed with saturated aqueous NH 4 Cl solution, saturated aqueous NaHCO 3 solution and brine. The organic phase was dried over (Na 2 SO 4 ), filtered and then concentrated to dryness in vacuo.
• Example 229 40 °C
• Examples 235 and 236 80 °C
• Examples 232 and 233, 237 60 °C
• Examples 231 and 234 100 °C
• Example 230 120 °C
• triethylamine (2 eq.) was also added to the reaction mixture.
• MeCN was used as reaction solvent.
• Stereoisomers were separated by chiral purification using appropriate chiral columns and combinations of solvent mixtures. Table 13.
• Example 242 60 °C
• Examples 244, 245, 250 and 254 120 °C
• Examples 246 and 253 80 °C
• Example 249 150 °C
• Stereoisomers were separated by chiral SFC purification using appropriate chiral columns and eluent modifiers; Chiralpak columns (AD-H); methanol + 0.1 % isopropylamine. Table 15.
• Example 259 [0349] Rel-(1s,15S,16R,19s)-4-fluoro-15- ⁇ [1-(6-oxo-1,6-dihydropyridin-2-yl)ethyl]amino ⁇ - 8,18-dioxa-11-azatetracyclo[17.2.2.02,7.011,16]tricosa-2(7),3,5-trien-10-one [0350] A mixture of Example 258 (20 mg, 0.040 mmol), sodium iodide (12 mg, 0.080 mmol) and chloro(trimethyl)silane (5 uL, 0.040 mmol) in MeCN (1 mL) was shaken at 85 °C for 1.5 h.
• the mixture was diluted with DCM (30 mL), then washed with saturated aqueous NaHCO3 solution (30 mL), 1 M aqueous Na2S2O3 solution (30 mL), and 1M aqueous Na2CO3 solution (30 mL).
• the organic layer was dried by passing through a hydrophobic frit (Phase Separator) and concentrated to dryness to give the crude product.
• the crude product was purified by column chromatography (0-40% 3:1 EtOAc/EtOH in heptane) to afford the title compound (807 mg) as a white solid.
• the mixture was degassed again by bubbling N2(g) through the mixture for 10 minutes and stirred at 80 °C for 1 h. After cooling the mixture to room temperature, the suspension was diluted with EtOAc and washed with water and brine. The organic phase was filtered through a hydrophobic frit (Phase Separator) and concentrated in vacuo. The residue was purified by column chromatography using a silica cartridge (0-15% EtOAc in cHex) to afford the title compound (519 mg, 0.939 mmol, 93% yield) as a colorless oil.
• Example 279 was synthetized using a similar procedure to that described for Example 269 to afford the title compound (40 mg, 0.085 mmol, 35% yield) as a white solid.
• Enantiomers were separated by chiral SFC purification using Chiralcel OD-H column and 10% (ethanol + 0.1% isopropylamine) as modifier. Table 21.
• Example 283 (1s,15S,16S,19s)-15- ⁇ [(2R)-1,1,1-trifluoropropan-2-yl]amino ⁇ -8,18-dioxa- 11-azatetracyclo[17.1.1.02,7.011,16]henicosa-2(7),3,5-trien-10-one [0472]
• Example 284 (1s,15S,16R,19s)-15- ⁇ [(2R)-1,1,1-trifluoropropan-2-yl]amino ⁇ -8,18-dioxa- 11-azatetracyclo[17.1.1.02,7.011,16]henicosa-2(7),3,5-trien-10-one [0473]
• Example 285 (1s,15R,16S,19s)-15- ⁇ [(2R)-1,1,1-trifluoropropan-2-yl

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