WO2021127459A1 - Modulateurs du récepteur gpr139 - Google Patents

Modulateurs du récepteur gpr139 Download PDF

Info

Publication number
WO2021127459A1
WO2021127459A1 PCT/US2020/066044 US2020066044W WO2021127459A1 WO 2021127459 A1 WO2021127459 A1 WO 2021127459A1 US 2020066044 W US2020066044 W US 2020066044W WO 2021127459 A1 WO2021127459 A1 WO 2021127459A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
lower alkyl
compound
yield
reaction
Prior art date
Application number
PCT/US2020/066044
Other languages
English (en)
Inventor
Gray Edward Lee BRANDT
Adam James Davenport
Robert M. Jones
Pui Leng Loke
Robert Pace
Inaki MORAO
Simon Ellwood
Original Assignee
Blackthorn Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Blackthorn Therapeutics, Inc. filed Critical Blackthorn Therapeutics, Inc.
Publication of WO2021127459A1 publication Critical patent/WO2021127459A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to modulators of the GPR139 receptor and to products containing the same, as well as to methods of their use and preparation.
  • GPCRs G-protein coupled receptors
  • GPCRs are the largest family of cell surface communicating molecules and are associated with numerous physiological processes and disease conditions. GPCRs share high levels of homology and contain seven transmembrane helices separated by intra- and extracellular loops. They signal via heterotrimeric G proteins composed of Ga, b, and g subunits, and there are four major Ga protein subfamilies: Gq, Gs, Gi, and G12/13.
  • the human GPR139 gene has been identified, and the human GPR139 protein (also known as hGPRgl or hGPCR12) is a 345-amino acid orphan receptor located on chromosome 16pl2.3.
  • GPR139 is highly conserved among different species; for example, human, mouse and rat GPR139 protein sequences share greater than 94% identity at the amino acid level. Expression studies in mice have shown that transcription of GPR139 is more evident in the brain.
  • Human GPR139 mRNA is predominantly expressed in the fetal and adult central nervous system (CNS), especially in the basal ganglia and the hypothalamus, which are involved in movement control, regulation of food intake and metabolism.
  • CNS central nervous system
  • GPR139 mRNA in the CNS of different species provides evidence that it plays specific roles in the modulation of brain functions, and GPR139 has been implicated as a potential drug target for any number of conditions, including diabetes, obesity and Parkinson's disease (Wang et al, Acta Pharmacologica Sinica, 36:874-878, 2015).
  • GPR139 has also been reported as having strong expression in the medial habenular nucleus of mice, which is involved in pain processing, reproductive behavior, nutrition, sleep-wake cycles, stress responses and learning.
  • modulators of GPR139 have also been identified as a target for treating schizophrenia and other CNS disorders such as depression (see WO2016/081736).
  • the present invention is directed to compounds that modulate the GPR139 receptor, to compositions containing the same, and to methods of their preparation and use for treatment of malconditions wherein modulation of the GPR139 receptor is medically indicated or beneficial.
  • the compound modulates the GPR139 receptor by agonizing the receptor; for example, by functioning as a GPR139 receptor agonist or as a GPR139 receptor partial agonist.
  • compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1 , R 4 , R 5 , R 9 , R 10 , Q 6 , Q 7 , and Q 12 are as defined herein below.
  • compounds are provided having the structure of Formula (II): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1 , R 4 , R 5 , R 6 , R 9 , R 10 , and Q 12 are as defined herein below.
  • compounds are provided having the structure of Formula (V): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 9 , R 10 , and Q 12 are as defined herein below.
  • a pharmaceutical composition comprising a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, in combination with a pharmaceutically acceptable carrier, diluent, or excipient.
  • a method for modulating the GPR139 receptor by contacting the receptor with an effective amount of a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising the same.
  • the compound is a GPR139 receptor agonist or partial agonist.
  • a method for treatment of a condition for which modulation of the GPR139 receptor is medically indicated comprising administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject.
  • a method for treating a neurobehavioral disease or disorder comprising administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject.
  • a method for synthesis of a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.
  • the invention relates to compounds that modulate the GPR139 receptor, to products comprising the same, and to methods for their use and synthesis.
  • a compound that "modulates" the GPR139 receptor means that the compound interacts with the GPR139 receptor in a manner such that it functions as an agonist or antagonist to the receptor, or functions as a partial agonist, inverse agonist, or allosteric modulator, or any combination thereof.
  • the compound is a GPR139 agonist.
  • the compound is a GPR139 partial agonist.
  • lower alkyl means a straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms.
  • straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, «-propyl, «-butyl, «-pentyl-, «-hexyl, «-heptyl, and «-octyl groups.
  • branched lower alkyl groups include, but are not limited to, isopropyl, iso butyl , sec-butyl, /-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Halo or halogen refers to fluorine, chlorine, bromine, and iodine.
  • Lower haloalkyl refers to a lower alkyl as defined above with one or more hydrogen atoms replaced with halogen.
  • Examples of lower haloalkyl groups include, but are not limited to, -CF3, -CH2CF3, and the like.
  • Lower alkoxy refers to a lower alkyl as defined above joined by way of an oxygen atom ⁇ i.e., -0-(lower alkyl).
  • Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, //-propoxy, //-butoxy, isopropoxy, sec-butoxy, tert- butoxy, and the like.
  • Lower haloalkoxy refers to a lower haloalkyl as defined above joined by way of an oxygen atom ⁇ i.e., -0-(lower haloalkyl).
  • lower haloalkoxy groups include, but are not limited to, -OCF3, -OCH2CF3, and the like.
  • Cycloalkyl refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring do not give rise to aromaticity.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclochexenyl, cyclohexa-1,3- dienyl, cycloheptenyl, and cyclooctenyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.
  • Cycloalkylalkyl are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • “Aryl” groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons in the ring portions of the groups.
  • aryl groups includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).
  • fused aromatic-aliphatic ring systems e.g., indanyl, tetrahydronaphthyl, and the like.
  • aryl is phenyl or naphthyl, and in another embodiment aryl is phenyl.
  • Carbocycle refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring may give rise to aromaticity.
  • carbocycle includes cycloalkyl as defined above.
  • carbocycle includes aryl as defined above.
  • Heterocycle refers to aromatic and non aromatic ring moieties containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P.
  • heterocyclyl includes 3 to 20 ring members, whereas other such groups have 3 to 15 ring members.
  • At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom.
  • a dioxolanyl ring and a benzdioxolanyl ring system are both heterocyclyl groups within the meaning herein.
  • Heterocyclyl groups also include fused ring species including those having fused aromatic and non-aromatic groups.
  • a heterocyclyl group also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl, and also includes heterocyclyl groups that have substituents, including but not limited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, bonded to one or more of the ring members.
  • a heterocyclyl group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl,
  • Heteroaryl refers to aromatic ring moieties containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridin
  • Racemic is used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the invention.
  • the isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers.”
  • Single enantiomers of a pure compound are optically active (i.e., they are capable of rotating the plane of plane polarized light and designated R or ri).
  • isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
  • the isolated isomer may be at least 80%, at least 82%, at least 84%, at least 86%, or at least 88% pure by weight.
  • the isolated isomer is at least 90% pure.
  • the isolated isomer is at least 95% pure, at least 98% pure, or at least 99% pure by weight.
  • substantially enantiomerically or diastereomerically pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.
  • racemate and “racemic mixture” refer to an equal mixture of two enantiomers.
  • a racemate is labeled “( ⁇ )” because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).
  • All compounds with an asterisk (*) adjacent to a tertiary or quaternary carbon are optically active isomers, which may be purified from the respective racemate and/or synthesized by appropriate chiral synthesis.
  • a “hydrate” is a compound that exists in combination with water molecules.
  • the combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is similar to a hydrate except that a solvent other that water is present.
  • a solvent other that water For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non- stoichiometric.
  • a “solvate” refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.
  • Isotope refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formula (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom.
  • carbon 12 the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons.
  • Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has a number of isotopes, fluorine 18 is longest-lived.
  • an isotope of a compound having the structure of Formula (I) includes, but not limited to, compounds of Formula (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine- 18.
  • Salt generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion.
  • acids in their anionic form and cations
  • bases in the cationic form and anions
  • Co-crystal forms of compounds having the structure of Formula (I) are also included within the scope of this invention; namely, solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts.
  • pharmaceutically acceptable refers an agent that has been approved for human consumption and is generally non-toxic.
  • pharmaceutically acceptable salt refers to non-toxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al ., Salt Selection for Basic Drugs, Int. J Pharm ., 33, 201-217, 1986) (incorporated by reference herein).
  • Pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, A f , l''-dibenzyl ethyl enedi amine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (A-methylglucamine), and procaine.
  • Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic,
  • salts may be useful, for example as intermediates in the synthesis of compounds having the structure of Formula I, for example in their purification by recrystallization.
  • compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
  • Q 12 is CR 12 orN
  • R 1 is H or lower alkyl
  • R 4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
  • R 5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
  • R 6 , R 6a , R 6b , R 7 , R 7a , and R 711 are each, independently, H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
  • R 9 , R 10 , and R 12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R 4 and R 10 together with the atoms to which they are attached form a heterocycle; and wherein R 4 , R 5 , R 6 , R 6a , R 6b , R 7 , R 7a , R 7b , R 9 , R 10 , and R 12 are each, independently, optionally substituted by one or more R'; and each R' is, independently, halo, OH, lower alkyl, lower haloaklyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl.
  • Q 12 is CR 12 orN
  • R 1 is H or lower alkyl
  • R 4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
  • R 5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
  • R 6 is H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
  • R 9 , R 10 , and R 12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R 4 and R 10 together with the atoms to which they are attached form a heterocycle; and wherein R 4 , R 5 , R 6 , R 9 , R 10 , and R 12 are each, independently, optionally substituted by one or more R; and each R' is, independently, halo, OH, lower alkyl, lower haloaklyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl.
  • Q 12 is CR 12 orN
  • R 1 is H or lower alkyl
  • R 4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
  • R 5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
  • R 7 is H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
  • R 9 , R 10 , and R 12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R 4 and R 10 together with the atoms to which they are attached form a heterocycle; and wherein R 4 , R 5 , R 7 , R 9 , R 10 , and R 12 are each, independently, optionally substituted by one or more R; and each R' is, independently, halo, OH, lower alkyl, lower haloaklyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl.
  • Q 12 is CR 12 orN
  • R 1 is H or lower alkyl
  • R 4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
  • R 5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
  • R 9 , R 10 , and R 12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R 4 and R 10 together with the atoms to which they are attached form a heterocycle; and wherein R 4 , R 5 , R 9 , R 10 , and R 12 are each, independently, optionally substituted by one or more R; and each R' is, independently, halo, OH, lower alkyl, lower haloaklyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl.
  • Q 6 is -CR 6a R 6b -
  • Q 7 is -CR 7a R 7b -
  • compounds are provided having the structure of Formula (IV): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
  • Q 12 is CR 12 orN
  • R 1 is H or lower alkyl
  • R 4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
  • R 5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
  • R 6a , R 7 3 ancj j ⁇ 7b are eacj ⁇ independently, H, -S(0) 2 R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
  • R 9 , R 10 , and R 12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R 4 and R 10 together with the atoms to which they are attached form a heterocycle; and wherein R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 9 , R 10 , and R 12 are each, independently, optionally substituted by one or more R'; and each R' is, independently, halo, OH, lower alkyl, lower haloaklyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl.
  • R 1 is H.
  • R 1 is lower alkyl
  • R 1 is methyl
  • R 4 is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or aryl.
  • R 4 is halo.
  • R 4 is F or Cl.
  • R 4 is lower alkyl.
  • R 4 is methyl. In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R 4 is lower alkoxy.
  • R 4 is -OCH(CH 3 )2.
  • R 4 is lower haloalkyl.
  • R 4 is -CF 3.
  • R 4 is lower haloalkoxy.
  • R 4 is -OCF 3 or -OCHF2.
  • R 5 is lower alkyl.
  • R 5 is methyl, ethyl, propyl, or butyl.
  • R 5 is lower haloalkyl.
  • R 5 is -CF 3 or -CH2CF3.
  • R 5 is cycloalkylalkyl.
  • R 5 is carbocyclyl
  • R 5 is aryl
  • R 5 is phenyl
  • R 5 is cycloalkyl
  • R 5 is cyclopropyl or cyclobutyl.
  • R 5 is heterocyclyl
  • R 5 is heteroaryl
  • R 5 is pyridine, pyrimidine, pyrazolyl, orthiazolyl.
  • R 5 is tetrahydrofuranyl or tetrahydropyranyl.
  • R 5 is not substituted with R.
  • R 5 is substituted with at least one R. In one embomdiment of Formulas (I), (II), (III), (IV) and (V) above, R 5 is substituted with halo.
  • R 5 is substituted with lower alkyl.
  • R 5 is substituted with carbocyclyl. lone embomdiment of Formulas (I), (II), (III), (IV) and (V) above, R 5 is substituted with cycloalkyl.
  • R 6 is H.
  • R 6 is lower alkyl
  • R 6 is lower haloalkyl.
  • R 6 is carbocyclyl
  • R 6 is aryl
  • R 6 is not phenyl.
  • R 6 , R 6a , R 6b , R 7 , R 7a , and R 7b are each, independently, H, -S(0)2R, lower alkyl, lower haloalkyl, or heterocyclyl, where R is lower alkyl;
  • R 6 , R 6a , R 6b , R 7 , R 7a , and R 7b are each, independently, H, -S(0)2R, lower alkyl, or lower haloalkyl, where R is lower alkyl;
  • R 6 is H, -S(0)2R, lower alkyl, lower haloalkyl, or heterocyclyl, where R is lower alkyl;
  • R 6 is H, -S(0)2R, lower alkyl, or lower haloalkyl, where R is lower alkyl;
  • R 6 is heterocyclyl
  • R 6 is heteroaryl
  • R 6 is not substituted with R’.
  • R 6 is substituted with at least one R’ .
  • R 6 is substituted with halo.
  • R 6 is substituted with -OH. In one embodiment of Formulas (I) and (II) above, R 6 is substituted with lower alkyl.
  • R 6 is substituted with lower haloaklyl.
  • R 7 is H.
  • R 7 is lower alkyl
  • R 7 is lower haloalkyl.
  • R 7 is carbocyclyl
  • R 7 is cycoalkyl
  • R 7 is not substituted with R’. In one embodiment of Formulas (I) and (III) above, R 7 is substituted with at least one R’ .
  • R 6a , R 6b , R 7a , and R 711 are each H.
  • R 9 is H.
  • R 10 is H.
  • R 10 is halo.
  • R 10 is chloro or flouro.
  • R 10 is lower alkyl.
  • R 10 is methyl. In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R 10 is heterocyle.
  • R 10 is morpholinyl
  • R 4 and R 10 together with the atoms to which they are attached form a heterocycle. In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R 4 and R 10 together with the atoms to which they are attached form 1,3-dioxolyl.
  • Q 12 is CR 12 and R 12 is H. In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, Q 12 is CR 12 and R 12 is H.
  • Representative compounds of Formulas (I), (II), (III), (IV) and (V) include the compounds listed in Table 1 below, as well as pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, and salts thereof. To this end, representative compounds are identified herein by their respective “Compound Number”, which is sometimes abbreviated as “Compound No.”, “Cpd. No.” or “No.”
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention together with at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose, and polyvinylpyrrolidone.
  • the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
  • auxiliary agents which do not deleteriously react with the active compounds.
  • Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances, preserving agents, sweetening agents, or flavoring agents.
  • the compositions can also be sterilized if desired.
  • the route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment, the oral route being preferred.
  • the carrier will typically comprise sterile water, although other ingredients that aid solubility or serve as preservatives can also be included.
  • injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, and the like can be employed.
  • the compounds of the present invention can be formulated using bland, moisturizing bases such as ointments or creams.
  • a solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or non- aqueous liquid suspension or solution.
  • injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent.
  • Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent.
  • Acceptable solvents or vehicles include sterilized water, Ringer’s solution, or an isotonic aqueous saline solution.
  • sterile oils can be employed as solvents or suspending agents.
  • the oil or fatty acid is non volatile, including natural or synthetic oils, fatty acids, mono-, di-, or tri-glycerides.
  • the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried, or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations of these.
  • the compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection can be in ampoules or in multi-dose containers.
  • the formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the formulations can also be formulated for controlled release or for slow release.
  • compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections. Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide- polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application.
  • a liquid carrier preferably an aqueous carrier
  • the carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician.
  • Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment and/or to minimize or avoid unwanted side effects associated with the treatment.
  • Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians' Desk Reference, incorporated herein by reference.
  • the compounds provided herein When used to prevent the onset of a malcondition, the compounds provided herein will be administered to a subject at risk for developing the same, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Subjects at risk for developing a particular malcondition generally include those that have a family history of the same, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the malcondition.
  • Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject's life.
  • the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
  • a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable carrier or diluent is suitable for oral administration.
  • the methods can further include the step of formulating the composition into a tablet or capsule.
  • the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration.
  • the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
  • a method for modulating the GPR139 receptor comprises contacting the receptor with an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising the same.
  • the phrase "modulating the GPR139 receptor” means that the compound interacts with the GPR139 receptor in a manner such that it functions as an agonist or antagonist to the receptor, or functions as a partial agonist, inverse agonist or allosteric modulator, or any combination thereof.
  • the compound in one embodiment, is a GPR139 agonist, and in another embodiment is a GPR139 antagonist. In further embodiments, the compound is a partial agonist, inverse agonist or allosteric modulator or GPR139.
  • GPR139 agonism is used herein to encompass compounds that interact in some way with the GPR139 receptor and thereby function as an agonist, either by binding to the GPR receptor at the binding site of its natural ligand or at locations other than the binding site.
  • GPR139 agonism is used herein to encompass compounds that interact in some way with the GPR139 receptor and thereby function as an agonist, either by binding to the GPR receptor at the binding site of its natural ligand, or at a location other than the binding site (i.e., allosteric binding).
  • the term “antagonism” is used herein to encompass compounds that interact in some way with a receptor and thereby function as an antagonist, either by binding to the receptor at the binding site of its natural ligand or at locations other than the binding site.
  • the phrase to "GPR139 antagonism” is used herein to encompass compounds that interact in some way with the GPR139 receptor and thereby function as an antagonist, either by binding to the GPR receptor at the binding site of its natural ligand, or at a location other than the binding site (i.e., allosteric binding).
  • a partial agonist is compound that binds to and activates a receptor, but with reduced efficacy compared to a full agonist. In the presence of a full agonist, a partial agonist behaves as an effective competitive antagonist.
  • An inverse agonist is a compound that binds to a receptor and induces an opposing pharmacological response to that of an agonist.
  • An allosteric modulator is a compound that binds at a location distinct from the orthosteric site, or the site of action of the primary ligand, and exerts an indirect effect by influencing binding or efficacy of the primary ligand. Pure allostery exerts no effect on a protein in the absence of a primary ligand that either activates or deactivates a receptor.
  • a method for treatment of a malcondition in a subject for which modulation of the GPR139 receptor is medically indicated comprises administering to the subject an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for duration sufficient to provide a beneficial effect to the subject.
  • malcondition is intended to broadly encompass any and all diseases, disorders, syndromes and/or symptoms wherein the GPR139 receptor plays a role in the same, such that a therapeutically beneficial effect can be achieved by modulation of the GPR139 receptor.
  • the malcondition for which modulation of the GPR139 receptor is medically indicated is a neurobehavioral disease or disorder.
  • the neurobehavioral disease or disorder is schizophrenia, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, obsessive- compulsive disorder (OCD), and affective disorders such as depression, bipolar disorder, and anxiety disorders.
  • a "subject” means both mammals and non-mammals. Mammals include, for example: humans; non-human primates (e.g., apes and monkeys); cattle; horses; sheep; and goats. Non-mammals include, for example, fish and birds. "Treating” or “treatment” within the meaning herein refers to an alleviation of symptoms associated with a malcondition, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the malcondition in certain instances.
  • an effective amount when used to describe use of a compound for treating a subject suffering from a malcondition for which modulation of the GPR 139 receptor is medically indicated, refers to the amount of the compound sufficient to produce a beneficial therapeutic effect for the subject.
  • the present invention provides a method for modulating the GPR139 receptor with a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, by contacting the receptor with a suitable amount of the compound to modulate the receptor.
  • contacting can take place in vitro , for example in carrying out an assay to determine the GPR139 activity of a compound undergoing experimentation related to a submission for regulatory approval.
  • the method for modulating the GPR 139 receptor can also be carried out in vivo ; that is, within the living body of the subject.
  • the compound of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, can be supplied to the living organism via one of the routes as described above ( e.g ., orally) or can be provided locally within the body tissues. In the presence of the compound, modulation of the receptor takes place, and the effect thereof can be studied.
  • a compound of any one of Formula (I), (II), (III), (IV), or (V), is an imaging agent, wherein the compound contains an isotope, such as isotopes of I, F, O, N and C.
  • the isotope is a fluorine isotope.
  • the compounds may be used for therapeutic purposes, or to diagnose or assess the progression of a malcondition in a subject for which modulation of the GPR139 receptor is medically indicated.
  • imaging and/or diagnostic methods comprising administering to a subject in need thereof the imaging agent described herein and detecting the compound comprised in the imaging agent in the subject.
  • the amount of the compound in the subject is quantified.
  • a condition in the subject is detected via a detection of the compound in the subject.
  • the imaging is effected by a radiodiagnostic method.
  • the radiodiagnostic method may be performed by any instrument capable of detecting radiation by the compounds. Exemplary radiodiagnostic methods include, but are not limited to, Positron Emission Tomography (PET), PET-Time- Activity Curve (TAC) or PET -Magnetic Resonance Imaging (MRI).
  • PET Positron Emission Tomography
  • TAC PET-Time- Activity Curve
  • MRI PET -Magnetic Resonance Imaging
  • the radiodiagnostic method is PET.
  • methods of treatment comprising administering a compound of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, alone or in combination with another pharmacologically active agent or second medicament, to a subject having a malcondition for which modulation of the GPR139 receptor is medically indicated.
  • modulators of the GPR139 receptor provide significant promise for the treatment of malconditions which benefit from modulation of the GPR139 receptor, including the embodiment wherein the malcondition is a neurobehavioral disease or disorder, including schizophrenia, attention- deficit/hyperactivity disorder (ADHD), autism spectrum disorder, obsessive-compulsive disorder (OCD), and affective disorders such as depression, bipolar disorder, and anxiety disorders, or any combination thereof.
  • ADHD attention- deficit/hyperactivity disorder
  • OCD obsessive-compulsive disorder
  • affective disorders such as depression, bipolar disorder, and anxiety disorders, or any combination thereof.
  • a method for treatment of schizophrenia spectrum disorders comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • schizophrenia spectrum disorders include schizophrenia, schizoaffective disorder, psychotic states and memory disorders.
  • a method for treatment of attention- deficit/hyperactivity disorder comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • ADHD is a mental disorder of the neurodevelopmental type, and is characterized by problems paying attention, excessive activity, or difficulty controlling behavior which is not appropriate for a person's age.
  • a method for treatment of anxiety disorders comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety.
  • Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders, including generalized anxiety disorder, panic disorder, substance/medication-induced anxiety disorder, phobia, social anxiety disorder, and separation anxiety disorder.
  • the anxiety disorder is a social anxiety disorder.
  • the anxiety disorder is a phobia.
  • Generalized anxiety disorder is a common chronic disorder characterized by long- lasting anxiety that is not focused on any one object or situation. A person suffering from generalized anxiety experiences non-specific persistent fear and worry and becomes overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.
  • panic disorder a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing.
  • panic attacks defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent.
  • a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attack’s potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes.
  • the single largest category of anxiety disorders is that of Phobia, which includes all cases in which fear and anxiety are triggered by a specific stimulus or situation.
  • Sufferers typically anticipate cosmic consequences from encountering the object of their fear, which can be anything from social phobia, specific phobia, agoraphobia, phobia of an animal, or of a location, or of a bodily fluid.
  • a method for treatment of trauma- and stressor- related disorders comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • Trauma- and stressor-related disorders include disorders which result from exposure to a traumatic or stressful event.
  • Current psychiatric diagnostic criteria recognize a variety of trauma- and stressor-related disorders including reactive attachment disorder, disinhibited social engagement disorder, posttraumatic stress disorder (PTSD), acute stress disorder, and adjustment disorders.
  • Post-traumatic stress disorder or PTSD is a trauma- and stressor-related disorder which results from exposure to a traumatic or stressful event.
  • Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even a serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.
  • the disorder is a trauma- and stressor-related disorder.
  • the trauma- and stressor-related disorder is PTSD.
  • a method for treatment of obsessive-compulsive and related disorders comprising administering to a subject in need thereof an effective amount of a compound having the structure of of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • Obsessive-compulsive disorder (OCD) and related disorders are primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals).
  • the OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist.
  • the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm.
  • the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness.
  • sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.
  • a method for treatment of a depressive disorder, depression, or depressive illness, or a combination thereof comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • disorders include major depressive disorder (MDD), drug-resistant depression, dysthymia, unipolar depression, and bipolar disorder.
  • a method for treatment of a mood disorder, or an affective disorder, or a combination thereof comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • Examples of a mood disorder or an affective disorder include major depressive disorder (MDD); bipolar disorder; anhedonia; dysthymia; major depression, Psychotic major depression (PMD), or psychotic depression; postpartum depression; seasonal affective disorder (SAD); and catatonic depression, a rare and severe form of major depression involving disturbances of motor behavior and other symptoms.
  • anhedonia and “anhedonic symptom” are used interchangeably and is defined as the inability to experience pleasure from activities usually found enjoyable, e.g. exercise, hobbies, music, sexual activities or social interactions.
  • the terms “anhedonia” and “anhedonic symptom” are closely related to criterion of "depressive disorder with melancholic features” which is defined in DSM-5 as melancholic depression characterized by a loss of pleasure in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early morning waking, psychomotor retardation, excessive weight loss, or excessive guilt.
  • treatment of depressive disorder with melancholic features comprises treatment of both the depressive disorder and melancholic features associated herewith.
  • the mood disorder is anhedonia.
  • the mood disorder is major depression.
  • the mood disorder is seasonal affective disorder (SAD).
  • a method for treatment of an affective disorder comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • Affective disorders such as disorders of stress, mood, and behavioral disorders, include stress-related affective disorders, obsessive compulsive disorder, autistic spectrum disorders, Personality disorders, ADHD, panic attacks and the like.
  • autism spectrum disorders and “Autism spectrum disorders” are used interchangeably and refer to autism, monogenetic causes of autism such as synaptophathies, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome and the like.
  • a method for treatment of an addictive disorder comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • Disorders related to substance abuse or addiction as described herein can include gambling, drug addiction, drug abuse, alcohol dependence, alcohol abuse, withdrawal, hyperalgia from withdrawal, substance-induced depression and mood disorders induced by substances such as alcohol, nicotine, amphetamine, methamphetamine, cocaine, opiate addiction, heroin addiction, benzodiazepines and the like.
  • a method for treatment of an opioid related disorder comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • Opioid related disorders as described herein can include opioid use disorder, opioid intoxication, opioid withdrawal, other opioid-induced disorders, and the like.
  • opioid-induced disorders as described herein can include opioid-induced depressive disorder, opioid-induced anxiety disorder, opioid-induced sleep disorder, and opioid-indueced sexual dysfunction, and the like.
  • a method for treatment of an eating disorder comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • Eating disorders as described herein can include pica, rumination disorder, avoidant/restrictive food intake disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, and the like.
  • a method for treatment of binge-eating disorder comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • a method for treatment of Parkinson's disease including neuroprotection and/or disease modifying effects in Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • a method for treating cognitive impairment or behavioral disturbances associated with neurological disorders comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • Behavioral disturbances associated with neurological disorders as described herein can include sleep disorders, apathy, anhedonia, and avolition.
  • Neurological disorders as described herein can include Alzheimer's disease and Parkinson's disease.
  • a method for treating sleep or wake disorders or circadian rhythm disorders, or a combination thereof comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • sleep/wake disorders and circadian rhythm disorders can affect pain processing, sleep-awake cycles, stress response, and learning.
  • a method for treating pain comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
  • a method is provided for treating the affective components of pain.
  • suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures).
  • a given reaction may be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular work-up following the reaction may be employed.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to a person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for Compound prepacked silica gel cartridges, e.g.
  • the compounds may be purified by preparative HPLC using methods as described.
  • Purification methods as described herein may provide compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to a person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • Preparative HPLC purification was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996/2998 UV/VIS detector, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution UV directed system.
  • the Waters 2767 liquid handler acted as both auto-sampler and fraction collector.
  • the columns used for the preparative purification of the compounds were a Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl (10 p 21.2 150 mm, 10 pm) or W aters Xbridge Phenyl (10 pm 19 x 150 mm, 5 pm). Appropriate focused gradients were selected based on acetonitrile and methanol solvent systems under either acidic or basic conditions.
  • the modifiers used under acidic/basic conditions were formic acid (0.1% V/V) and ammonium bicarbonate (10 mM) respectively.
  • the purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm, and triggered a threshold collection value at 260 nm and, when using the Fractionlynx, the presence of target molecular ion as observed under APi conditions. Collected fractions were analysed by LCMS (Waters Acquity systems with Waters SQD). Normal phase flash column chromatography was performed utilizing a Biotage Isolera system. The silica gel columns were purchased from either Interchim or Biotage.
  • the mobile phase was either ethyl acetate in hexanes or methanol in dichloromethane with various ratios, and the fraction collection was triggered by UV absorbance at 254 nm.
  • Analytical high-performance liquid chromatography-mass spectrometry (HPLC-MS) was performed utilizing HP or Waters DAD + Micromass ZQ, single quadrupole LC-MS or Quattro Micro LC-MS-MS.
  • Method 1 The RP-HPLC column was Phenomenex Luna 5 mih Cl 8 (2), (100 x 4.6mm). Mobile phase 5-95% acetonitrile in water (0.1% formic acid) gradient, flow rate 2.0 mL/min, and 6.5 min run time.
  • Method 2 The RP-HPLC column was Waters Xterra MS 5 mih C18, 100 x 4.6mm. Mobile phase 5-95% acetonitrile in water (lOmM ammonium bicarbonate (ammonium hydrogen carbonate)).
  • DIPEA N,N-Diisopropylethylamine
  • HATU N-[(Dimethylamino)(3H-[l,2,3]triazolo[4,5- b ] py ri din-3 -y 1 oxy )m ethyl ene] -N- methylmethanaminium hexafluorophosphate
  • MgSOr Magnesium sulfate min: Minute(s) pL: Microliter mL: Millliliter
  • Analytical Method A Column: Phenomenex Kinetix-XB C18 1.2 x 100 mm, 1.7 pm; eluent A: water + 0.1 vol% formic acid, eluent B: acetonitrile + 0.1 vol% formic acid; gradient: 0 - 5.3 min 5 - 100% B, 5.3 - 5.8 min 100% B, 5.8 - 5.82 min 100 - 5% B, 5.82 - 7.00 min 5% B; flow 0.6 mL/min; injection volume 1 pL; temperature: 40 °C; UV scan: 215 nm; PDA Spectrum range: 200-400nm step: lnm; MSD signal settings- scan pos: 150-850.
  • Analytical Method B Column: Waters UPLC® BEHTM C18 2.1 x 100 mm, 1.7 pm; eluent A: 2mM ammonium carbonate, buffered to pHIO, eluent B: acetonitrile; gradient: 0 - 5.3 min 5 - 100% B, 5.3 - 5.8 min 100% B, 5.8 - 5.82 min 100 - 5% B; 5.82- 7.00 min 5%B; flow 0.6 mL/min; injection volume 2 pL; temperature: 40 °C; UV scan: 215 nm; PDA Spectrum range: 200-400nm step: lnm; MSD signal settings- scan pos: 150-850.
  • Analytical Method C Column: Waters Atlantis dC182.1 x 100 mm, 3 pm eluent A: water + 0.1 vol% formic acid, eluent B: acetonitrile + 0.1 vol% formic acid; gradient: 0 - 5.0 min 5 - 100% B, 5.0 - 5.4 min 100% B, 5.4 - 5.42 min 100 - 5% B, 5.42 - 7.00 min 5% B; flow 0.6 mL/min; injection volume 3 pL; temperature: 40 °C; UV scan: 215 nm; PDA Spectrum range: 200-400nm step: lnm; MSD signal settings- scan pos: 150-
  • Analytical Method D Column: Kinetex Core-Shell Cl 8 2.1 x 50 mm, 5 mih eluent A: water + 0.1 vol% formic acid, eluent B: acetonitrile + 0.1 vol% formic acid; gradient: 0 - 1.2 min 5 - 100% B, 1.3 - 1.3 min 100% B, 1.3 - 1.31 min 100 - 5% B, 1.31 - 1.65 min 5% B; flow 1.2 mL/min; injection volume 3 pL; temperature: 40 °C; UV scan: 215 nm; PDA Spectrum range: 210-420nm step: lnm; MSD signal settings- scan pos: 100 1000
  • Analytical Method E Column: Phenomenex Gemini -NX C182.0 x 50 mm, 3 pm; eluent A: 2mM ammonium hydroxide, buffered to pHIO, eluent B: acetonitrile; gradient: 0 - 1.8 min 1 - 100% B, 1.8 - 2.1 min 100% B, 2.1 - 2.3 min 100 - 1% B; flow 1 mL/min; injection volume 3 pL; temperature: 40 °C; UV scan: 215 nm; PDA Spectrum range: 210-420nm step: lnm; MSD signal settings- scan pos: 150-850.
  • Biotage IsoleraTM chromatography system http://www.biotage.com/ product- area/flash-purification) using pre-packed silica and pre-packed modified silica cartridges were employed.
  • Method A2 Instrument: pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281 or pump: Gilson 333 & 334; auto injector: Gilson GX281; UV detector: Gilson 155; collector: Gilson GX281; Column: Waters Xbridge C18 30 x 100 mm, 10 pm; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide; gradient: 0 - 1.1 min 30% B, 1.1 - 10.05 min 30 - 95% B, 10.05 - 11.5 min 95% B; flow 40 mL/min; injection volume 1500 pL; temperature: 25 °C; UV scan: 215 nm.
  • Method B 1 Instrument pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281; Column: Waters Sunfire C18 30 x 100 mm, 10 pm; eluent A: water + 0.1 vol% formic acid, eluent B: acetonitrile + 0.1 vol% formic acid; gradient: 0 - 0.8 min 10% B, 0.8 - 14.5 min 5 - 95% B, 14.5 - 16.7 min 95% B; flow 40 mL/min; injection volume 1500 pL; temperature: 25 °C; UV scan: 215 nm.
  • Method B2 Instrument pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281; Column: Waters Sunfire C18 30 x 100 mm, 10 pm; eluent A: water + 0.1 vol% formic acid, eluent B: acetonitrile + 0.1 vol% formic acid; gradient: 0 - 1.1 min 30% B, 1.1 - 10.05 min 30 - 95% B, 10.05 - 11.5 min 95% B; flow 40 mL/min; injection volume 1500 pL; temperature: 25 °C; UV scan: 215 nm.
  • Method Cl Column: Waters Xbridge C18 30 x 100 mm, 5 pm; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide; gradient: 0 - 2.0 min 5% B, 2.0 - 2.5 min 5 - 25% B, 2.5 - 22.5 min 25% - 40% B, 22.5 - 23 min 40 - 100% B, 25 - 25.5 % B 100%- 5% B; flow 20 mL/min; temperature: 25 °C; UV scan: 215 nm.
  • Method C2 Column: Waters Xbridge C18 30 x 100 mm, 5 mih; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide; gradient: 0 - 2.0 min 5% B, 2.0 - 2.5 min 5 - 35% B, 2.5 - 14.5 min 35 - 50% B, 14.5 - 15.0 min 50 - 100% B, 15.0 - 17.0 min 100% B, 17.0 - 17.5 min 100 - 5% B, flow 40 mL/min; temperature: 25 °C; UV scan: 215 nm.
  • Method C3 Column: Waters Xbridge C18 30 x 100 mm, 5 pm; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide; gradient: 0 - 2.0 min 5% B, 2.0 - 2.5 min 5 - 25% B, 2.5 - 16.5 min 25 - 40% B, 16.5 - 17.0 min 40 - 95% B, 17.0 - 19.0 min 95% B, 19.0 - 19.5 min 95 - 5% B, flow 40 mL/min; temperature: 25 °C; UV scan: 215 nm.
  • Method C4 Column: Waters Xbridge C18 100 x 19 mm, 5 pm; eluent A: water + 0.1 vol% formic acid, eluent B: acetonitrile + 0.1 vol% formic acid; gradient: 0 - 1.9 min 5% B, 1.9 - 2.0 min 5 - 40% B, 2.0 - 16.0 min 40% -50% B, 16.0 - 16.1 min 50 - 95% B, 16.1 - 18.0 min 95% B, 18.0 - 18.1min 95-5% B, 18.1 - 20.0 min 5% B; flow 20 mL/min; temperature: 25 °C; UV scan: 215 nm.
  • Methyl hydrazinocarboxylate 250 mg, 2.77 mmol
  • (diethoxymethoxy)ethane (411 mg, 2.77 mmol)
  • 4-methylbenzenesulfonic acid hydrate (1:1) (12 mg, 0.06 mmol) were suspended in MeOH (5 mL) and stirred, under a nitrogen atmosphere, at 60 °C for 4 hours. After this time, the reaction mixture was cooled to room temperature and quenched with solid NaHCCb (10 mg). The NaHCCb was filtered off. The resulting filtrate was transferred to a pressure tube charged with 6-methylpyri din-3 -amine (300 mg, 2.77 mmol). The tube was sealed, under a nitrogen atmosphere, and heated at 110 °C for 16 hours.
  • Phenyl chloroformate (0.24 mL, 1.94 mmol) was added slowly to an ice cold solution of 2-amino-5-chloropyridine (250 mg, 1.94 mmol) and pyridine (0.19 mL, 2.33 mmol) in di chi orom ethane (10 mL). A thick white precipitate rapidly formed. The reaction was stirred for 3 hours then quenched into dilute sodium bicarbonate (aq). The solid material was collected by filtration to give the title compound (460mg, 95% yield).
  • Phenyl chloroformate (132 pL, 1.05 mmol) was added to an ice cold solution of l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-amine (165 mg, 0.999 mmol) and pyridine (100 pL, 1.24 mmol) in DCM (3 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into DCM three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo.
  • Phenyl chloroformate 250 pL, 1.99 mmol was added to an ice cold solution of 2-chloroaniline (206 pL, 1.96 mmol) and pyridine (190 pL, 2.35 mmol) in DCM (6 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into DCM three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. Purification by Biotage IsoleraTM chromatography (silica gel, eluting with 0-100% TBME in heptane) afforded the title compound (472 mg, 88% yield).
  • Titanium tetraethoxide (15.30 mL, 25.3 mmol) was added to a mixture of 3-chloro-4-fluorobenzaldehyde (2.00 g, 12.6 mmol) and R-tertbutylsulfmamide (1.68 g, 13.9 mmol) in dichloromethane (40 mL). The reaction was stirred for 20 hours. The reaction was quenched by addition of saturated NaHCCb (aq, 40 mL). The mixture was stirred vigorously for 30 minutes. The precipitate was removed by filtration and the filtrate partitioned between dichloromethane and water.
  • Diphenylphosphorylazide (655 pL, 3.05 mmol) was added to a suspension of (2E)-2-(2-phenylhydrazin-l-ylidene)acetic acid (500 mg, 3.05 mmol) and triethylamine (424 m ⁇ , 3.05 mmol) in toluene (15 mL).
  • the reaction was heated to 90°C for 1 hour then cooled and quenched into 10% aqueous KOH solution (aq).
  • the solution was acidified to pH with HC1 (aq) and allowed to stand for 2 hours.
  • the solid material was collected by filtration, washed with water and dried in vacuo to yield the title compound as a pale brown solid (131 mg, 27% yield).
  • Diphenylphosphorylazide (735 pL, 3.42 mmol) was added to a solution of (2E)- 2-[2-(4-fluorophenyl)hydrazin-l-ylidene]acetic acid (623 mg, 3.42 mmol) and triethylamine (476 pL, 3.42 mmol) in toluene (15 mL).
  • the reaction was slowly heated to 90°C for 1 hour then cooled and quenched into 10% KOH solution (aqueous).
  • the mixture was then cautiously acidified to pHl with HC1 and allowed to stand at room temperature for 90 minutes.
  • Diphenylphosphorylazide (899 pL, 4.18 mmol) was added to a suspension of (2E)-2-[2-(4-fluorophenyl)hydrazin-l-ylidene]propanoic acid (820 mg, 4.18 mmol) and triethylamine (581 pL, 4.18 mmol) in toluene (20 mL). The reaction was heated to 90°C for 1 hour then cooled and quenched into 10% KOH solution (aqueous). The mixture was cautiously acidified to pH 1 with HC1 and allowed to stand for 1 hour. The solid material was collected by filtration, washed with water and dried in vacuo to the title compound (329 mg, 41% yield).
  • Titanium tetraethoxide (15.30 mL, 25.3 mmol) was added to a mixture of 3- chloro-4-fluorobenzaldehyde (2.00 g, 12.6 mmol) and R-tertbutylsulfinamide (1.68 g, 13.9 mmol) in dichloromethane (40 mL). The reaction was stirred for 20 hours. The reaction was quenched by addition of saturated NaHCCb (aq, 40 mL). The mixture was stirred vigorously for 30 minutes. The precipitate was removed by filtration and the filtrate partitioned between dichloromethane and water.
  • FLIPRTM technology was used to test compounds on a CHO-K1 cell line (Chinese Hamster ( Cricetulus griseus ) Ovary cells, initiated from a biopsy of an adult Chinese hamster by T. T. Puck in 1957) stably expressing human GPR139 (PathHunter ® CHO- K1 human GPR139 b-Arrestin cell line; DiscoverX, Fremont, CA; cat. 93-0954C2), by measuring the intracellular calcium fluxes induced by increasing concentrations of test and reference compounds in the Fluorometric Imaging Plate Reader Tetra (FLIPR 1 tl RA ", Molecular Devices, CA).
  • CHO-K1 cell line Choinese Hamster ( Cricetulus griseus ) Ovary cells, initiated from a biopsy of an adult Chinese hamster by T. T. Puck in 1957
  • human GPR139 PathHunter ® CHO- K1 human GPR139 b-Arrestin cell line
  • DiscoverX Fremont, CA
  • Cells were cultured at 37 °C, 5% CO2 in Cell Culture Kit-107 (DiscoverX, #92-3107G) for no more than 20 passages. All assays were run with cells previously frozen at a low passage number ( ⁇ 20), thawed, plated in assay media without selection antibiotics at 20000 cells/ 50 m ⁇ / well in a 384 well plate (Corning 384-Well CellBIND black, clear bottom, polystyrene barcoded plates) and incubated at 37 °C, 5% CO2 overnight.
  • the Calcium 5 dye solution (FLIPRTM Calcium 5 Assay Kit, Molecular Devices, San Jose CA, #R8187) was prepared according to the manufacturer guidelines (in HBSS Buffer, Hanks' Balanced Salt Solution, 20 mM HEPES, hydroxy ethyl piperazineethanesulfonic acid; pH 7.4). Cells were equilibrated at room temperature for 30 minutes, and then loaded with 50 m ⁇ /well of Calcium 5 dye solution supplemented with 2.5 mM Probenecid for 60 minutes at room temperature in the dark. Cell and compound plates were transferred into the FLIPR tetra® and 10 m ⁇ /well of the test compound solutions (6X) were automatically dispensed into the cell plates. The fluorescence intensity reflecting intracellular calcium changes was recorded before and after compound addition with an excitation and emission wavelengths of 470-495 nm and 515-575 nm, respectively. Fluorescence intensity raw data were fitted to the four- parameter logistic equation:
  • rat GPR139 FLIPRTM assay a stably expressing CHO-K1 rat GPR139 cell line was generated de novo by transfecting rGPR139 into parental CHO-K1 cells. Compounds were tested by measuring the intracellular calcium fluxes induced by increasing concentrations of test and reference compounds in the Fluorometric Imaging Plate Reader Tetra (FLIPR tetra® , Molecular Devices, CA). Cells were cultured at 37 °C, 5% CO2 in Nutrient Mixture F-12 Ham, 5% FBS (fetal bovine serum), 2 mM L- Glutamine, 1 mg/ml G-418 for no more than 20 passages.
  • FLIPR tetra® Fluorometric Imaging Plate Reader Tetra
  • PathHunterTM B-Arrestin assay technology was used to test compounds on a CHO-K1 cell line stably expressing GPR139 (PathHunter® CHO-K1 human GPR139 b- Arrestin cell line; DiscoverX, Fremont, CA; # 93-0954C2). Cells were treated with compounds and a B-galactosidase fragment, which complements a second B- galactosidase fragment tagged to GPR139. The chemiluminescence signal achieved by b-galactosidase fragment complementation was measured on an Envision plate reader (Perkin Elmer, Waltham, MA).
  • the GPR139 profile was evaluated by testing increasing concentrations of the test compounds, comparing the response to the maximum activation achieved with reference agonist JNJ63533054 (Sigma Aldrich, St Louis, MO, 20 mM).
  • EC50 the concentration of a compound that causes half-maximal response in a functional assay
  • Emax the maximum possible effect for an agonist in a concentration-response curve
  • Hill slope were calculated from raw luminescence intensity data using a four- parameter logistic equation.
  • Cells were maintained in Cell culture kit 107 (DiscoverX, Fremont, CA) and subcultured at 80-90 % confluency.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés qui modulent le récepteur GPR139, des compositions les contenant, et leurs procédés de préparation et d'utilisation pour le traitement d'une maladie dans laquelle la modulation du récepteur GPR139 est indiquée ou bénéfique du point de vue médical. De tels composés présentent la structure de formule (I), ou un isomère, racémate, hydrate, solvate, isotope ou sel pharmaceutiquement acceptables de ceux-ci, où R1, R4, R5, R9, R10, Q6, Q7, et Q12 sont tels que définis selon l'invention.
PCT/US2020/066044 2019-12-20 2020-12-18 Modulateurs du récepteur gpr139 WO2021127459A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201962951843P 2019-12-20 2019-12-20
US62/951,843 2019-12-20

Publications (1)

Publication Number Publication Date
WO2021127459A1 true WO2021127459A1 (fr) 2021-06-24

Family

ID=76478560

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2020/066044 WO2021127459A1 (fr) 2019-12-20 2020-12-18 Modulateurs du récepteur gpr139

Country Status (1)

Country Link
WO (1) WO2021127459A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114349774A (zh) * 2021-12-23 2022-04-15 凯美克(上海)医药科技有限公司 一种双环[1.1.1]戊基角位硼酸酯类化合物的制备方法
WO2023165262A1 (fr) * 2022-03-01 2023-09-07 上海科技大学 Composé hétérocyclique contenant un thiéno-azote, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
CN114349774B (zh) * 2021-12-23 2024-06-04 凯美克(上海)医药科技有限公司 一种双环[1.1.1]戊基角位硼酸酯类化合物的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130005704A1 (en) * 2006-05-23 2013-01-03 Bayer Pharma Aktiengesellshaft Substituted arylimidazolone and triazolone as inhibitors of vasopressin receptors
US20160145218A1 (en) * 2014-11-20 2016-05-26 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazine modulators of gpr139

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130005704A1 (en) * 2006-05-23 2013-01-03 Bayer Pharma Aktiengesellshaft Substituted arylimidazolone and triazolone as inhibitors of vasopressin receptors
US20160145218A1 (en) * 2014-11-20 2016-05-26 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazine modulators of gpr139

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem 24 April 2017 (2017-04-24), ANONYMOUS: "SID 333860224", XP055838293, Database accession no. 333860224 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114349774A (zh) * 2021-12-23 2022-04-15 凯美克(上海)医药科技有限公司 一种双环[1.1.1]戊基角位硼酸酯类化合物的制备方法
CN114349774B (zh) * 2021-12-23 2024-06-04 凯美克(上海)医药科技有限公司 一种双环[1.1.1]戊基角位硼酸酯类化合物的制备方法
WO2023165262A1 (fr) * 2022-03-01 2023-09-07 上海科技大学 Composé hétérocyclique contenant un thiéno-azote, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation

Similar Documents

Publication Publication Date Title
AU2018223058B2 (en) Bipyrazole derivatives as jak inhibitors
CN103415519B (zh) 作为β-分泌酶(BACE)抑制剂有用的6，7-二氢-吡唑[1，5-a]吡嗪-4-基胺衍生物
JP6014155B2 (ja) ビアリールエーテルスルホンアミドおよび治療剤としてのそれらの使用
US11987588B2 (en) Modulators of the beta-3 adrenergic receptor useful for the treatment or prevention of heart failure and disorders related thereto
CN113811300A (zh) Tead转录因子的新型小分子抑制剂
CN112292375A (zh) 取代的烷氧基吡啶基吲哚磺酰胺类
WO2019101086A1 (fr) Inhibiteur de ssao/vap-1 halo-allylamine et son utilisation
US11124494B2 (en) Aryl heterocyclic piperidinone formyl peptide 2 receptor and formyl peptide 1 receptor agonists
EA020275B1 (ru) Морфолинотиазолы в качестве позитивных аллостерических модуляторов альфа 7
EP3679043B1 (fr) Antagonistes du récepteur de la vasopressine, produits et procédés associés
JP7350759B2 (ja) ニューロトロフィンに関連する疾患を治療するためのトリアジン誘導体
WO2020097609A1 (fr) Modulateurs du récepteur gpr139
JP2021520340A (ja) 化合物およびｐｄｅ４活性剤としてのそれらの使用
CN112292373A (zh) 作为RORγt的调节剂的吡啶基吡唑类
KR20240015622A (ko) 심장 근절 억제제
CN117642416A (zh) 分拣蛋白活性调节剂
CN112513032A (zh) 作为trk受体的调节剂的4-取代的苯基-1,3,5-三嗪衍生物
WO2021127459A1 (fr) Modulateurs du récepteur gpr139
US10550080B2 (en) Acyl sulfonamide NaV1.7 inhibitors
JP6831376B2 (ja) トリアゾール誘導体
JP6298172B2 (ja) Ｇｐｒ１４２アゴニスト化合物
JP5694959B2 (ja) 三位で置換された３−ベンゾフラニル−インドール−２−オン誘導体、この調製およびこの治療的使用
JP2022512373A (ja) 置換キサンチン誘導体
JP7408662B2 (ja) 置換キサンタン誘導体
RU2816837C2 (ru) Производные триазина для лечения заболеваний, связанных с нейротрофинами

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20903548

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20903548

Country of ref document: EP

Kind code of ref document: A1