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WO2021127459A1 - Gpr139 receptor modulators - Google Patents

Gpr139 receptor modulators Download PDF

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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
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mmol
lower alkyl
compound
yield
reaction
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French (fr)
Inventor
Gray Edward Lee BRANDT
Adam James Davenport
Robert M. Jones
Pui Leng Loke
Robert Pace
Inaki MORAO
Simon Ellwood
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Neumora Therapeutics Inc
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Blackthorn Therapeutics Inc
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    • 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.

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Abstract

Compounds are provided that modulate the GPR139 receptor, compositions containing the same, and to methods of their preparation and use for treatment of a malcondition wherein modulation of the GPR139 receptor is medically indicated or beneficial. Such compounds have the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1, R4, R5, R9, R10, Q6, Q7, and Q12 are as defined herein.

Description

GPR139 RECEPTOR MODULATORS
FIELD OF THE INVENTION
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.
BACKGROUND
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. The consistent expression of 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. In view of recent findings showing calcifications in the pineal and habenula of patients suffering from schizophrenia, as well as altered activation of the habenula in such patients, modulators of GPR139 have also been identified as a target for treating schizophrenia and other CNS disorders such as depression (see WO2016/081736).
Due to its interest as a drug target, a number of groups have reported small molecule ligands, both agonists and antagonists, for GPR139. For example, Shi et al. (ACS Med Chem Lett 2:303-6, 2011) reported GPR139 receptor agonists in a calcium mobilization assay for CHO-K1 cell line stably expressing the human GPR139 for high- throughput screening. Hu et al. (J Biomol Screen 14:789-97, 2009) identified both agonists and antagonists of GPR139 after screening a large number of small molecules. Similarly, Wang et al. (Id.) identified GPR139 antagonists following a high-throughput screen, again using a calcium mobilization assay. Dvorak et al. (ACS Med Chem Lett 6(9): 1015-1018, 2015) focused on high-throughput screening to identify GPR139 agonists, and Isberg et al. (J Chem Inf Model 54(6):1552-1557, 2014) employed computer-aided techniques to aid in the identification of GPR139 agonists.
Accordingly, compounds which serve to modulate the GPR139 receptor provide significant promise for the treatment of a variety of disorders. While advances have been made in this field, there remains a significant need for agents that modulate the GPR139 receptor, as well as for products containing the same, and for methods related to both their use and manufacture.
SUMMARY OF THE INVENTION
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. In one embodiment, 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.
In one embodiment, compounds are provided having the structure of Formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1, R4, R5, R9, R10, Q6, Q7, and Q12 are as defined herein below.
In one embodiment, compounds are provided having the structure of Formula (II):
Figure imgf000004_0004
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1, R4, R5, R6, R9, R10, and Q12 are as defined herein below.
In one embodiment, compounds are provided having the structure of Formula
(III):
Figure imgf000004_0002
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1, R4, R5, R7, R9, R10, and Q12 are as defined herein below.
In one embodiment, compounds are provided having the structure of Formula
(IV):
Figure imgf000004_0003
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1, R4, R5, R9, R10, and Q12 are as defined herein below.
In one embodiment, compounds are provided having the structure of Formula (V):
Figure imgf000005_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1, R4, R5, R6a, R6b, R7a, R7b, R9, R10, and Q12 are as defined herein below.
In another embodiment, a pharmaceutical composition is provided 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.
In another embodiment, use 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, for the manufacture of a medicament is provided.
In another embodiment, a method is provided 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. In more specific embodiments, the compound is a GPR139 receptor agonist or partial agonist.
In another embodiment, a method is provided 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.
In one embodiment, a method is provided 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.
In another embodiment, a method is provided 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.
DETAILED DESCRIPTION
As mentioned above, 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 (also referred to herein as a GPR139 "modulator") 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. In one embodiment, the compound is a GPR139 agonist. In another embodiment, the compound is a GPR139 partial agonist.
As used herein, "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. Examples of straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, «-propyl, «-butyl, «-pentyl-, «-hexyl, «-heptyl, and «-octyl groups. Examples of 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.
"Hydroxy" refers to -OH.
"Cyano"" refers to — CN.
"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). Examples of 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. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclochexenyl, cyclohexa-1,3- dienyl, cycloheptenyl, and cyclooctenyl groups. In some embodiments, 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. In some embodiments, aryl groups contain 6-14 carbons in the ring portions of the groups. The phrase "aryl groups" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). In one embodiment, aryl is phenyl or naphthyl, and in another embodiment aryl is phenyl.
"Carbocycle," "carbocyclyl" or "carbocyclic" 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. In one embodiment, carbocycle includes cycloalkyl as defined above. In another embodiment, carbocycle includes aryl as defined above.
"Heterocycle," "heterocyclyl" or "heterocyclic" 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. In some embodiments, 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. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methyl enedioxy phenyl 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, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.
"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, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups.
"Isomer" 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. For example, the isolated isomer may be at least 80%, at least 82%, at least 84%, at least 86%, or at least 88% pure by weight. In other embodiments, the isolated isomer is at least 90% pure. In another embodiment, 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%.
The terms "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. As the term is used herein 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. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non- stoichiometric. As the term is used herein 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. For example, 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. Thus, 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. For example, salts formed between acids in their anionic form and cations are referred to as "acid addition salts". Conversely, salts formed between bases in the cationic form and anions are referred to as "base addition salts."
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.
The term "pharmaceutically acceptable" refers an agent that has been approved for human consumption and is generally non-toxic. For example, the term "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, Af, 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. Examples of 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, panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, / oluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, b-hydroxybutyric, salicylic, -galactaric, and galacturonic acid.
Although pharmaceutically unacceptable salts are not generally useful as medicaments, such 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.
In one embodiment, compounds are provided having the structure of Formula (I):
Figure imgf000012_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
Q6 is -N= when Q7 is =CR7- or =N , or Q7 is =N- when Q6 is -CR6= or -N=, or Q6 is CR6aR6b- when Q7 is -CR7aR7b-;
Q12 is CR12 orN;
R1 is H or lower alkyl;
R4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
R5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl; R6, R6a, R6b, R7, R7a, and R711 are each, independently, H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
R9, R10, and R12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R4 and R10 together with the atoms to which they are attached form a heterocycle; and wherein R4, R5, R6, R6a, R6b, R7, R7a, R7b, R9, R10, and R12 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.
In one embodiment of Formula (I), Q6 is -CR6=, Q7 is =N-, and compounds are provided having the structure of Formula (II):
Figure imgf000013_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
Q12 is CR12 orN;
R1 is H or lower alkyl;
R4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
R5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
R6 is H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
R9, R10, and R12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R4 and R10 together with the atoms to which they are attached form a heterocycle; and wherein R4, R5, R6, R9, R10, and R12 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. In one embodiment of Formula (I), Q6 is -N=, Q7 is =CR7-, and compounds are provided having the structure of Formula (III):
Figure imgf000014_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
Q12 is CR12 orN;
R1 is H or lower alkyl;
R4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
R5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
R7 is H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
R9, R10, and R12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R4 and R10 together with the atoms to which they are attached form a heterocycle; and wherein R4, R5, R7, R9, R10, and R12 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.
In one embodiment of Formula (I), Q6 is -N=, Q7 is =N , and compounds are provided having the structure of Formula (IV):
Figure imgf000014_0002
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
Q12 is CR12 orN;
R1 is H or lower alkyl;
R4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
R5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
R9, R10, and R12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R4 and R10 together with the atoms to which they are attached form a heterocycle; and wherein R4, R5, R9, R10, and R12 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.
In one embodiment of Formula (I), Q6 is -CR6aR6b-, Q7 is -CR7aR7b-, and compounds are provided having the structure of Formula (IV):
Figure imgf000015_0002
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
Q12 is CR12 orN;
R1 is H or lower alkyl;
R4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
R5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl; R6a,
Figure imgf000015_0001
R7 3 ancj j^7b are eacj^ independently, H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
R9, R10, and R12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R4 and R10 together with the atoms to which they are attached form a heterocycle; and wherein R4, R5, R6a, R6b, R7a, R7b, R9, R10, and R12 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.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R1 is H.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R1 is lower alkyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R1 is methyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or aryl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is halo.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is F or Cl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is lower alkyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is methyl. In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is lower alkoxy.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is -OCH(CH3)2.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is lower haloalkyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is -CF3.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is lower haloalkoxy.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 is -OCF3 or -OCHF2. In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is lower alkyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is methyl, ethyl, propyl, or butyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is lower haloalkyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is -CF3 or -CH2CF3.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is cycloalkylalkyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is carbocyclyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is aryl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is phenyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is cycloalkyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is cyclopropyl or cyclobutyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is heterocyclyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is heteroaryl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is pyridine, pyrimidine, pyrazolyl, orthiazolyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is tetrahydrofuranyl or tetrahydropyranyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is not substituted with R.
In one embomdiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is substituted with at least one R. In one embomdiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is substituted with halo.
In one embomdiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is substituted with lower alkyl.
In one embomdiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is substituted with carbocyclyl. lone embomdiment of Formulas (I), (II), (III), (IV) and (V) above, R5 is substituted with cycloalkyl.
In one embodiment of Formulas (I) and (II) above, R6 is H.
In one embodiment of Formulas (I) and (II) above, R6 is lower alkyl.
In one embodiment of Formulas (I) and (II) above, R6 is lower haloalkyl.
In one embodiment of Formulas (I) and (II) above, R6 is carbocyclyl.
In one embodiment of Formulas (I) and (II) above, R6 is aryl.
In one embodiment of Formulas (I) and (II) above, R6 is not phenyl.
In one embodiment of Formula (I) above, R6, R6a, R6b, R7, R7a, and R7b are each, independently, H, -S(0)2R, lower alkyl, lower haloalkyl, or heterocyclyl, where R is lower alkyl;
In one embodiment of Formula (I) above, R6, R6a, R6b, R7, R7a, and R7b are each, independently, H, -S(0)2R, lower alkyl, or lower haloalkyl, where R is lower alkyl;
In one embodiment of Formula (II) above, R6 is H, -S(0)2R, lower alkyl, lower haloalkyl, or heterocyclyl, where R is lower alkyl;
In one embodiment of Formula (II) above, R6 is H, -S(0)2R, lower alkyl, or lower haloalkyl, where R is lower alkyl;
In one embodiment of Formulas (I) and (II) above, R6 is heterocyclyl.
In one embodiment of Formulas (I) and (II) above, R6 is heteroaryl.
In one embodiment of Formulas (I) and (II) above, R6 is not substituted with R’.
In one embodiment of Formulas (I) and (II) above, R6 is substituted with at least one R’ .
In one embodiment of Formulas (I) and (II) above, R6 is substituted with halo.
In one embodiment of Formulas (I) and (II) above, R6 is substituted with -OH. In one embodiment of Formulas (I) and (II) above, R6 is substituted with lower alkyl.
In one embodiment of Formulas (I) and (II) above, R6 is substituted with lower haloaklyl.
In one embodiment of Formulas (I) and (III) above, R7 is H.
In one embodiment of Formulas (I) and (III) above, R7 is lower alkyl.
In one embodiment of Formulas (I) and (III) above, R7 is lower haloalkyl.
In one embodiment of Formulas (I) and (III) above, R7 is carbocyclyl.
In one embodiment of Formulas (I) and (III) above, R7 is cycoalkyl.
In one embodiment of Formulas (I) and (III) above, R7 is not substituted with R’. In one embodiment of Formulas (I) and (III) above, R7 is substituted with at least one R’ .
In one embodiment of Formulas (I) and (V) above, R6a, R6b, R7a, and R711 are each H.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R9 is H.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R10 is H.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R10 is halo.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R10 is chloro or flouro.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R10 is lower alkyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R10 is methyl. In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R10 is heterocyle.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R10 is morpholinyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 and R10 together with the atoms to which they are attached form a heterocycle. In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, R4 and R10 together with the atoms to which they are attached form 1,3-dioxolyl.
In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, Q12 is CR12 and R12 is H. In one embodiment of Formulas (I), (II), (III), (IV) and (V) above, Q12 is CR12 and R12 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.”
Table 1
Representative Compounds
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000022_0002
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000024_0002
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000028_0002
Figure imgf000028_0001
Figure imgf000029_0002
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000030_0002
Figure imgf000031_0002
Figure imgf000031_0001
In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, 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. When the active compound is mixed with 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. Some examples of 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. Similarly, 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. 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.
For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid solubility or serve as preservatives can also be included. Furthermore, injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, and the like can be employed.
For topical administration, the compounds of the present invention can be formulated using bland, moisturizing bases such as ointments or creams. If 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. If 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. Alternatively, sterile oils can be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non volatile, including natural or synthetic oils, fatty acids, mono-, di-, or tri-glycerides.
For injection, 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. For injection, 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. Thus, 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).
For nasal administration, the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application. 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.
For parenteral application, particularly suitable are 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.
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. In certain embodiments, 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.
In another embodiment, there are provided methods of making a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
In another embodiment, a method is provided for modulating the GPR139 receptor, and the method 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.
As used herein, 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. Thus, in one embodiment, the compound 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.
The term "agonism" is used herein to encompass compounds that interact in some way with a receptor and thereby function as an agonist, either by binding to the receptor at the binding site of its natural ligand or at locations other than the binding site. Thus, the phrase to "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).
Conversely, 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. Thus, 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.
In an embodiment, a method is provided for treatment of a malcondition in a subject for which modulation of the GPR139 receptor is medically indicated. Such method 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.
The phrase "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. In one embodiment, the malcondition for which modulation of the GPR139 receptor is medically indicated is a neurobehavioral disease or disorder. In a more specific embodiment, 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.
As used herein, 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.
The expression "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.
In certain embodiments, 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. Such 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.
In certain embodiments, 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.
In another embodiment, 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. In certain embodiments, 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.
In some embodiments, imaging and/or diagnostic methods are provided 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. In some aspects, the amount of the compound in the subject is quantified. In further aspects, a condition in the subject is detected via a detection of the compound in the subject. In certain embodiments, 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). In a particular aspect, the radiodiagnostic method is PET.
In one embodiment, methods of treatment are provided 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.
As mentioned above, 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.
In an embodiment, a method is provided 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. Examples of schizophrenia spectrum disorders include schizophrenia, schizoaffective disorder, psychotic states and memory disorders. In an embodiment, a method is provided for treatment of attention- deficit/hyperactivity disorder (ADHD), 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.
In an embodiment, a method is provided 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. In one embodiment, the anxiety disorder is a social anxiety disorder. In one embodiment, 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.
In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These 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. In addition to recurrent unexpected panic attacks, 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. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).
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 terrifying 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.
In an embodiment, a method is provided 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. In one embodiment, the disorder is a trauma- and stressor-related disorder. In one embodiment, the trauma- and stressor-related disorder is PTSD.
In an embodiment, a method is provided 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. Often 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. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.
In an embodiment, a method is provided 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. Examples of such disorders include major depressive disorder (MDD), drug-resistant depression, dysthymia, unipolar depression, and bipolar disorder. In an embodiment, a method is provided 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.
The terms "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. The term "treatment of depressive disorder with melancholic features" comprises treatment of both the depressive disorder and melancholic features associated herewith. In one embodiment, the mood disorder is anhedonia. In one embodiment, the mood disorder is major depression. In one embodiment, the mood disorder is seasonal affective disorder (SAD).
In an embodiment, a method is provided 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. As used herein, "autistic 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.
In an embodiment, a method is provided for treatment of an addictive disorder, including disorders related to substance abuse or addiction, 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.
In an embodiment, a method is provided 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. Other 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. In an embodiment, a method is provided 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.
In one embodiment, a method is provided 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.
In an embodiment, a method is provided 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.
In an embodiment, a method is provided 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.
In one embodiment, a method is provided 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. As described herein, sleep/wake disorders and circadian rhythm disorders can affect pain processing, sleep-awake cycles, stress response, and learning.
In one embodiment, a method is provided 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. In a preferred embodiment, a method is provided for treating the affective components of pain.
Compounds 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, can be synthesized using standard synthetic techniques known to those of skill in the art. To this end, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation(s) necessary. Generally, 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. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed. EXAMPLES
The invention is further illustrated by the following examples. The examples below are non-limiting are merely representative of various aspects of the invention. Solid and dotted wedges within the structures herein disclosed illustrate relative stereochemistry, with absolute stereochemistry depicted only when specifically stated or delineated.
General Methods
All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
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. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, 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.
All the starting materials and reagents are commercially available and were used as is. ¾ Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker instrument operating at 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (d) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad. 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)).
Chemical names were generated using the JChem for Excel naming software (Version 16.7.1800.1000) by Chem Axon Ltd. In some cases, generally accepted names of commercially available reagents were used in place of names generated by the naming software.
Abbreviations
The following abbreviations are used in the examples, while other abbreviations have their customary meaning in the art:
DCM: Diehl oromethane
DIPEA: N,N-Diisopropylethylamine
DMF: N,N-Dimethylformamide
DMSO: Dimethyl sulfoxide
EtOAc: Ethyl acetate
EtOH: Ethanol
Et3N: Triethylamine hr hour(s)
HATU: N-[(Dimethylamino)(3H-[l,2,3]triazolo[4,5- b ] py ri din-3 -y 1 oxy )m ethyl ene] -N- methylmethanaminium hexafluorophosphate
HC1: Hydrochloric acid
HPLC: high performance liquid chromatography
IPA: Isopropyl alcohol
K2CO3: Potassium carbonate
L: Liter
LCMS: liquid chromatography - mass spectrometry
M: Molar
MeOH: Methanol MeCN: Acetonitrile
MgSOr: Magnesium sulfate min: Minute(s) pL: Microliter mL: Millliliter
N2: Nitrogen
NaiCOr: Sodium carbonate
NaHCCb: Sodium bicarbonate
NaiSOr: Sodium sulfate
ME: Ammonia
NMR: nuclear magnetic resonance spectroscopy ppm: parts per million
RT: Room temperature
Rt: Retention time sat.: Saturated
TBME: tert-butyl methyl ether
THF: Tetrahydrofuran
Analytical LC-MS Methods
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® BEH™ 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-
1000
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.
Preparative HPLC
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 Al: 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 - 0.8 min 10% B, 0.8 - 14. 5 min 10 - 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 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.
EXAMPLE A
SYNTHESIS OF COMPOUNDS OF FORMULA (ID
Figure imgf000052_0001
General Reaction Schemes
Reaction Scheme A1
Figure imgf000053_0001
Reaction Scheme A2
Figure imgf000054_0001
Reaction Scheme A3
Figure imgf000054_0002
Reaction Scheme A5
Figure imgf000055_0001
Reaction Scheme A8
Figure imgf000055_0002
Reaction Scheme A9
Figure imgf000056_0003
Reaction Scheme Al l
Figure imgf000056_0001
Synthesis of 4-(6-methylpyridin-3-yl )-4.5-dihydro- l H- 1.2.4-triazol-5-one
(Intermediate Al)
Figure imgf000056_0002
(Intermediate Al)
Methyl hydrazinocarboxylate (250 mg, 2.77 mmol), (diethoxymethoxy)ethane (411 mg, 2.77 mmol) and 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. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting solid was suspended in MeOH (5 mL) and cooled in an ice bath for 10 minutes. The solid was collected by vacuum filtration and trituration with methanol afforded the title compound (74 mg, 12% yield). 1HNMR (250 MHz, DMSO-d6) d 12.03 (s, 1H), 8.74 (d, J = 2.3 Hz, 1H), 8.39 (s, 1H), 7.99 (dd, J = 8.4, 2.7 Hz, 1H), 7.39 (d, J =
8.4 Hz, 1H), 2.51 (s, 3H). LCMS (Analytical Method E) Rt= 0.80 min, MS (ESIpos): m/z= 177.2 [M+H]+, purity = 100%.
Using procedure described for Intermediate Al, the following intermediates were prepared.
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0002
Synthesis of 4-(bicvclori.l.l1pentan-l-yl|-4.5-dihydro-lH-1.2.4-triazol-5-one
(Intermediate A9)
Figure imgf000059_0001
(Intermediate A9) Methyl hydrazinocarboxylate (53 mg, 0.588 mmol) and 4-methylbenzenesulfonic acid;hydrate (3.0 mg, 0.0158 mmol) were suspended in methanol (1.5 mL), then diethoxymethoxyethane (98 pL, 0.589 mmol) was added. The mixture was sealed under nitrogen and stirred at 60 °C for 3 hr. The reaction was cooled to room temperature and sodium hydrogen carbonate (1.5 mg, 0.0179 mmol) was added, followed by bicyclo[l.l.l]pentan-l -amine hydrochloride (70 mg, 0.585 mmol) and triethylamine (88 pL, 0.63 mmol). The mixture was sealed and stirred at 110 °C for 16 hr. The reaction was concentrated in vacuo and the crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM), followed by purification with Biotage Isolera™ chromatography (silica gel, eluting with 0-100% TBME in heptane then 0-80% MeOH in TBME) to afford the title compound (38 mg, 41% yield). 1H NMR (500 MHz, Chloroform-d) d 10.8 (s, 1H), 7.3 (s, 1H), 2.6 (s, 1H), 2.3 (s, 6H). LCMS (Analytical Method E) Rt= 0.67 min, MS (ESIpos): m/z= 152.0 [M+H]+, purity = 95%.
Synthesis of 4-(5-fluoropyridin-2-vD-4.5-dihvdro-lH-E2.4-triazol-5-one
(Intermediate A10)
Figure imgf000060_0001
To a mixture of methyl hydrazinocarboxylate (1.61 g, 17.87 mmol) and 4- methylbenzenesulfonic acid (60 mg, 0.36 mmol) in methanol (20 ml) was added (di ethoxy methoxy)ethane (3 ml, 18.02 mmol). The mixture was sealed under nitrogen and stirred at 60°C for 4 hr. The reaction was cooled to room temperature and NaHC03 (0.03 g, 0.36 mmol) was added, followed by 5-fluoropyridin-2-amine (2 g, 17.84 mmol). The mixture was re-sealed under nitrogen and stirred at 110°C for 18 hr. The mixture was cooled to room temperature and concentrated in vacuo. The residue obtained was triturated with methanol then purified via Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM) to afford the first batch of the title compound (158 mg, 5% yield).
The intermediate isolated from chromatography fractions was suspended in n- butanol (5 ml) and stirred at 150°C for 4 hr. The reaction mixture was cooled to room temperature and triturated with methanol giving a second batch of solid (408 mg). This solid was combined with the first batch to give the title compound (566 mg, 18% yield). 1H NMR (500 MHz, DMSO-d6) d 12.1 (s, 1H), 8.5 (s, 1H), 8.5 (d, J = 3.1 Hz, 1H), 8.2 (dd, J = 9.1, 3.9 Hz, 1H), 8.0 (ddd, J = 9.1, 8.2, 3.1 Hz, 1H). LCMS (Analytical Method D) Rt= 0.71 min, MS (ESIpos): m/z= 181.0 [M+H]+, purity = 100%.
Synthesis of 4-(3.3-difluorocvclobutvO-4.5-dihvdro-lH-E2.4-triazol-5-one
(Intermediate A11)
Figure imgf000061_0001
To a mixture of methyl hydrazinocarboxylate (375 mg, 4.16 mmol) and 4- methylbenzenesulfonic acid (17 mg, 0.09 mmol) in MeOH (6 mL) was added (di ethoxy methoxy)ethane (695 mΐ, 4.17 mmol). The mixture was sealed under nitrogen and stirred at 60°C for 4 hr. The reaction was cooled to room temperature and neutralised with NaHC03 (7.5 mg, 0.09 mmol). A solution of 3,3-difluorocyclobutan-l-amine hydrochloride (600 mg, 4.18 mmol) and DIPEA (730 mΐ, 4.19 mmol) in MeOH (1 ml) was added and the mixture was sealed and stirred at 110°C for 16 hr. The reaction was concentrated in vacuo. Purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-10% MeOH in DCM) followed by trituration with acetonitrile afforded the title compound (307 mg, 17% yield). 1H NMR (250 MHz, DMSO-d6) d 11.72 (s, 1H), 8.00 (s, 1H), 4.44 - 4.28 (m, 1H), 3.09 - 2.78 (m, 4H). LCMS (Analytical Method D) Rt= 0.40 min, MS (ESIpos): m/z= 176.0 [M+H]+, purity = not determined (solvent front).
Synthesis of 4-(l-methyl-lH-pyrazol-4-vD-4.5-dihvdro-lH-E2.4-triazol-5-one (Intermediate A12)
Figure imgf000062_0001
(Intermediate A 12)
Diethoxymethoxy ethane (0.46 mL, 2.88 mmol) was added to a solution of methyl hydrazinocarboxylate (250 mg, 2.78 mmol) and 4-methylbenzenesulfonic acid (10 mg, 0.056 mmol) in (3 ml) in anhydrous methanol (5 mL) a pressure tube under nitrogen. The reaction was heated at 60 °C for 4 hr. The reaction was neutralised with sodium hydrogen carbonate (5 mg, 0.056 mmol), then evaporated in vacuo. To the residue was added 1- butanol (3 ml) and 1 -methyl- lH-pyrazol-4-amine (0.23 ml, 2.71 mmol). The mixture was heated at 120 °C for 3 hr. Upon standing at room temperature for 2 days, a precipitate was formed. The solid was collected by suction filtration and washed with ethyl acetate to afford the title compound (65 mg, 14% yield). lHNMR(500MHz, DMSO-d6) d 11.90
(s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.75 (d, J = 0.6 Hz, 1H), 3.87 (s, 3H). LCMS
(Analytical Method D) Rt= 0.28 min, MS (ESIpos): m/z= 166.0 [M+H]+, purity = not determined (solvent front).
Synthesis of 4-(2-methylpyrimidin-5-vO-4.5-dihvdro-lH-L2.4-triazol-5-one
(Intermediate A13)
Figure imgf000062_0002
(Intermediate A13)
Diethoxymethoxyethane (0.47 mL, 2.78 mmol) was added to a solution mixture of methyl hydrazinocarboxylate (250 mg, 2.78 mmol) and 4-methylbenzenesulfonic acid
(10 mg, 0.06 mmol) in anhydrous methanol (3 mL) a pressure tube under nitrogen. The reaction mixture was heated at 60 °C for 4 hr. The reaction was neutralised with sodium hydrogen carbonate (5 mg, 0.06 mmol), then concentrated in vacuo. To this residue was added 2-methylpyrimidin-5-amine (296 mg, 2.71 mmol) and n-butanol (3 mL). The mixture was heated at 120 °C for 3 hr. Upon cooling to room temperature, precipitate was formed, washed with EtOAc and was collected by suction filtration to yield the title compound (54 mg, 11% yield). 1HNMR (500 MHz, DMSO-d6) d 12.14 (s, 1H), 9.04 (s, 2H), 8.46 (s, 1H), 2.67 (s, 3H). LCMS (Analytical Method D) Rt= 0.30 min, MS
(ESIpos): m/z= 178.0 [M+H]+, purity = not determined (solvent front).
Synthesis of 4-(5-methyl-L3-thiazol-2-yl)-4,5-dihydro-lH-L2,4-triazol-5-one
(Intermediate A14)
Figure imgf000063_0001
Diethoxymethoxyethane (0.47 mL, 2.78 mmol) was added to a solution mixture of methyl hydrazinocarboxylate (250 mg, 2.78 mmol) and 4-methylbenzenesulfonic acid (10 mg, 0.06 mmol) in anhydrous methanol (3 mL) a pressure tube under nitrogen. The reaction mixture was heated at 60 °C for 4 hr. The reaction was neutralised with sodium hydrogen carbonate (5 mg, 0.06 mmol), then concentrated in vacuo. To this residue was added 5-methyl-l,3-thiazol-2-amine (309 mg, 2.71 mmol) and n-butanol. The mixture was heated at 120 °C for 3 hr. The reaction mixture was concentrated in vacuo, then triturated in EtOAc- heptane to afford the title compound (23 mg, 4% yield). 1H NMR (500 MHz, DMSO-d6) d 8.55 (s, 1H), 7.34 (s, 1H). LCMS (Analytical Method D) Rt= 0.80 min, MS (ESIpos): m/z= 183.0 [M+H]+, purity = 92%.
Synthesis of 4-(4-chlorophenyl )-4.5-dihydro- l H- l .2.4-triazol-5-one
(Intermediate A15)
Figure imgf000063_0002
A solution of methyl hydrazinocarboxylate (200 mg, 2.22 mmol), 4- methylbenzenesulfonic acid;hydrate (21 mg, 0.111 mmol) and tri ethyl orthoformate (0.37 mL, 2.22 mmol) in ethanol (2 mL) was heated to 60°C for 3 hours. 4-chloroaniline (283 mg, 2.22 mmol) was added followed by sodium ethoxide (21%, 2.0 mL, 4.44 mmol) and the reaction was heated to 100°C for 18 hours. The solid material was collected by filtration and washed with ethanol, then purified by preparative HPLC, Method B1 to afford the title compound as a white solid (20 mg, 5% yield). 1H NMR (500 MHz, DMSO-d6) d 12.03 (s, 1H), 8.40 (s, 1H), 7.76 - 7.73 (m, 2H), 7.59 - 7.55 (m, 2H)._LCMS (Analytical Method D) Rt= 0.87 min, MS (ESIpos): m/z= 195.8, 197.9 [M+H]+, purity = 87%.
Synthesis of 4-(6-methylpyridin-3-yl )-4.5-dihydro- l H- 1.2.4-triazol-5-one
(Intermediate A16)
Figure imgf000064_0001
(Intermediate A16) To a mixture of methyl hydrazinocarboxylate (200 mg, 2.22 mmol) and 4- methylbenzenesulfonic acid;hydrate (12 mg, 0.0631 mmol) in methanol (5 mL) was added diethoxymethoxyethane (370 pL, 2.22 mmol). The mixture was stirred at 60°C for 3 hr. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up in n-butanol (6 ml), then sodium hydrogen carbonate (6.0 mg, 0.0714 mmol) and 6-methylpyridin-3 -amine (241 mg, 2.23 mmol) were added. The mixture was sealed and stirred at 130°C for 18 hr. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified via Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM), followed by trituration with methanol to afford the title compound (10 mg, 2.5% yield) as a white solid. 1HNMR (400 MHz, DMSO-d6) d 12.0 (s, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 8.0 (d, J = 8.4 Hz, 1H), 7.4
(d, J = 8.3 Hz, 1H). LCMS (Analytical Method D) Rt= 0.22 min, MS (ESIpos): m/z= 170.0 [M+H]+, purity = not determined (solvent front). Synthesis of 4-(6-methoxypyridin-3-vO-3-methyl-4.5-dihvdro-lH-E2.4-triazol-5-one
(Intermediate A17)
Figure imgf000065_0001
(Intermediate A17)
Methyl hydrazinocarboxylate (218 mg, 2.42 mmol), 1,1,1 -tri ethoxy ethane
(392mg, 2.42 mmol) and 4-methylbenzenesulfonic acid hydrate (1:1) (7.41 mΐ, 0.05 mmol) were suspended in MeOH (5 ml) and stirred, under a nitrogen atmosphere, at 60 °C for 4 hr. The reaction mixture was cooled to room temperature and was added solid NaHCCb (10 mg), The solution was decanted into a pressure tube charged with 6- methoxypyridin-3 -amine (300 mg, 2.42 mmol). The tube was sealed, under a nitrogen atmosphere, and heated at 110 °C overnight for 16 hr. The reaction mixture was concentrated in vacuo. Purification by preparative HPLC, Method B 1 afforded the title compound (76 mg, 15% yield). 1HNMR (500 MHz, DMSO-r/6) d 11.62 (s, 1H), 8.28 - 8.17 (m, 1H), 7.79 (dd, J= 8.8, 2.7 Hz, 1H), 7.01 - 6.91 (m, 1H), 3.90 (s, 3H), 2.04 (s, 3H). LCMS (Analytical Method E) Rt= 1.04 min, MS (ESIpos): m/z= 207.2 [M+H]+, purity = 100%.
Synthesis of 4-cvclopropyl-3-methyl-4.5-dihydro-lH-E2.4-triazol-5-one
(Intermediate A18)
Figure imgf000065_0002
(Intermediate A18) 1,1,1-Tri ethoxy ethane (1.29 mL, 7.01 mmol) was added to a solution of methyl hydrazinocarboxylate (631 mg, 7.01 mmol) and 4-methylbenzenesulfonic acid (24 mg, 0.14 mmol) in MeOH (6 mL) in a pressure tube under N2. The reaction was heated at 60 °C for 4 hr. The reaction was neutralised with solid NaHCCb (6.6 mg, 0.08 mmol). The solution was decanted into a fresh pressure tube. Cyclopropanamine (485 mΐ, 7.01 mmol) was added and the reaction was heated at 110 °C for 18 hr. The reaction was allowed to cool to room temperature and concentrated. The resulting residue was triturated in MeOH to give the title compound as a white solid (281 mg, 29% yield). 1H NMR (250 MHz, DMSO-d6) d 11.17 (s, 1H), 2.82 - 2.66 (m, 1H), 2.18 (s, 3H), 0.92 - 0.83 (m, 4H). LCMS (Analytical Method B) Rt= 0.96 min, MS (ESIpos): m/z= 139.7 [M+H]+, purity = 97%.
Synthesis of 4-(5-fluoropyridin-2-vD-3-methyl-4.5-dihvdro-lH-L2.4-triazol-5-one
(Intermediate 19)
Figure imgf000066_0001
(Intermediate A19)
To a solution mixture of methyl hydrazinocarboxylate (200 mg, 2.22 mmol) and 4-methylbenzenesulfonic acid hydrate (13 mg, 0.0683 mmol) in ethanol (8 ml), was added 1,1,1 -tri ethoxy ethane (405 pL, 2.22 mmol). The mixture was sealed and stirred at 60°C for 4 hr, then cooled to room temperature and neutralised with sodium hydrogen carbonate (6.0 mg, 0.0714 mmol). 5-fluoropyridin-2-amine (250 mg, 2.23 mmol) was added and the mixture was sealed and stirred at 110°C for 16 hr. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up in n-butanol (8 ml) and the mixture was sealed and stirred at 150°C for 16 hr. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified via Biotage Isolera™ chromatography (silica gel, eluting with 0-100% TBME in heptane then 0-20% MeOH in TBME) to afford the title compound (67 mg, 15% yield). 1H NMR (500 MHz, DMSO-d6) d 11.7 (s, 1H), 8.6 (d, J = 3.1 Hz, 1H), 8.0 - 7.9 (m, 1H), 7.8 (dd, J = 8.9, 4.1 Hz, 1H), 2.2 (s, 3H). LCMS (Analytical Method D) Rt= 0.73 min, MS (ESIpos): m/z= 195.0 [M+H]+, purity = 100%.
Using procedure described for Intermediate A19, the following intermediate is are prepared.
Figure imgf000067_0002
Synthesis of 4-cvclopropyl-3-methyl-4.5-dihvdro-lH-E2.4-triazol-5-one
(Intermediate A20)
Figure imgf000067_0001
(Intermediate A20)
To a solution mixture of methyl hydrazinocarboxylate (200 mg, 2.22 mmol) and 4-methylbenzenesulfonic acid;hydrate (13 mg, 0.0683 mmol) in ethanol (8 ml) was added 1,1,1 -tri ethoxy ethane (405 gL, 2.22 mmol). The mixture was sealed and stirred at 60°C for 4 hr, then neutralised with sodium hydrogen carbonate (6.0 mg, 0.0714 mmol). 4- fluoroaniline (216 gL, 2.25 mmol) was added and the mixture was sealed and stirred at 110°C for 18 hr. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up in n-butanol (8 ml) and the mixture was sealed and stirred at 150°C for 16 hr. The mixture was cooled to room temperature and concentrated in vacuo. The resultant residue was partitioned between 1M aq HC1 and DCM. The organic phase was separated and concentrated in vacuo and the crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% TBME in heptane then 0-20% MeOH in TBME) to afford the title compound (122 mg, 24% yield). 1H NMR (500 MHz, DMSO-d6) d 11.6 (s, 1H), 7.5 - 7.4 (m, 2H), 7.4 - 7.3 (m, 2H), 2.0 (s, 3H). LCMS (Analytical Method B) Rt= 0.83 min, MS (ESIpos): m/z= 194.0 [M+H]+, purity = 85%.
Using procedure described for Intermediate A20, the following intermediate is prepared.
Figure imgf000068_0002
Synthesis of phenyl N-(5-chloropyridin-2-vOcarbamate
(Intermediate A21)
Figure imgf000068_0001
(Intermediate A21)
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). 1H NMR (500 MHz, DMSO-d6) d 9.32 (s, 1H), 7.87 (d, J = 2.7 Hz, 1H), 7.40 (dd, J = 8.8, 2.7 Hz, 1H), 7.15 (dd, J = 8.5, 7.4 Hz, 2H), 6.78 - 6.72 (m, 3H), 6.45 (dd, J = 8.8, 0.6 Hz, 1H). LCMS (Analytical Method D) Rt= 1.16 min, MS (ESIpos): m/z= 248.9, 250.9 [M+H]+, purity = 100%.
Synthesis of 3-amino-l-(5-chloropyridin-2-vOurea
(Intermediate A22)
Figure imgf000069_0002
(Intermediate A22) Hydrazine hydrate (0.18 mL, 3.70 mmol) was added to a suspension of phenyl N-
(5-chloro-2-pyridyl)carbamate (Intermediate A21) (460 mg, 1.85 mmol) in dichloromethane (5 mL). The reaction was heated to 50°C for 4 hours. No dissolution occurred and LCMS shows little reaction. Ethanol (10 mL) was added and the reaction heated to 75°C for 18 hours. The reaction was cooled and the solid material collected by filtration and washed with ethanol to yield the title compound (230 mg, 66% yield).
Synthesis of 4-(5-chloropyridin-2-yl )-4.5-dihydro- l H- l .2.4-triazol-5-one
(Intermediate A23)
Figure imgf000069_0001
(Intermediate A23) A mixture of l-amino-3-(5-chloro-2-pyridyl)urea (Intermediate A22) (50 mg,
0.268 mmol), triethylorthoformate (53 pL, 0.322 mmol) and p-toluenesulfonic acid monohydrate (2.5 mg, 0.0134 mmol) in ethanol (3 mL) was heated to 70°C for 3 hours. The mixture was cooled and the solid material collected by filtration to yield the title compound (35 mg, 66% yield). LCMS (Analytical Method D) Rt= 0.88 min, MS (ESIpos): m/z= 196.9, 198.9 [M+H]+, purity = 100%.
Synthesis of phenyl N-(4-fluoro-2-methylphenv0carbamate
(Intermediate A24)
Figure imgf000070_0001
(Intermediate A24)
To a mixture of 4-fluoro-2-methyl-aniline (250 mg, 2.00 mmol) and pyridine (195 uL, 2.41 mmol) in dichloromethane (8 mL) at 0°C was added phenyl chloroformate (250 pL, 1.99 mmol). The reaction was stirred for 2 hr and during this time the reaction warmed to r.t. The mixture was quenched with water and extracted with DCM. The organics were combined and concentrated in vacuo. Purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% EtOAc in heptanes) afforded the title compound (495 mg, 99% yield). 1H NMR (500 MHz, Methanol-d4) d 7.43 - 7.37 (m, 3H), 7.25 - 7.21 (m, 1H), 7.21 - 7.16 (m, 2H), 7.00 (dd, J = 9.4, 2.9 Hz, 1H), 6.92 (td, J = 8.5, 3.0 Hz, 1H), 2.33 (s, 3H). LCMS (Analytical Method D) Rt= 1.14 min, MS
(ESIpos): m/z= 246.0 [M+H]+, purity = 98%.
Synthesis of 3-amino-l-(4-fluoro-2-methylphenvDurea
(Intermediate A25)
Figure imgf000070_0002
(Intermediate A25) A mixture of phenyl N-(4-fluoro-2-methyl-phenyl)carbamate (Intermediate A24) (465 mg, 1.86 mmol) and hydrazine hydrate (180 uL, 3.71 mmol) was dissolved in ethanol (6 mL) and the solution was stirred at 75°C for 2 hr. The reaction was cooled to room temperature and left standing overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM) to afford the title compound (296 mg, 84% yield). 1H NMR (500 MHz, DMSO-d6) d 8.26 (s, 1H,), 7.78 (dd, J = 8.8, 5.7 Hz, 1H), 7.51 (s, 1H), 7.02 (dd, J = 9.6, 3.0 Hz, 1H), 6.94 (td, J = 8.7, 3.1 Hz, 1H), 4.42 (s, 2H), 2.20 (s, 3H). LCMS (Analytical Method E) Rt= 1.18 min, MS (ESIpos): m/z= 184.2 [M+H]+, purity = 97%.
Synthesis of 4-(4-fluoro-2-methylphenvO-4.5-dihvdro-lH-E2.4-triazol-5-one
(Intermediate A26)
Figure imgf000071_0001
(Intermediate A26)
To a suspension mixture of 1 -amino-3 -(4-fluoro-2-methyl-phenyl)urea (Intermediate A25) (255 mg, 1.39 mmol) and p-toluenesulfonic acid monohydrate (14 mg, 0.0736 mmol) in ethanol (5 ml) was added tri ethyl orthoformate (280 pL, 1.68 mmol) was added. The mixture was stirred at 110°C for 16 hr. The reaction was cooled to room temperature and concentrated in vacuo. Purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% TBME in heptane) afforded the title compound (135 mg, 49% yield). 1H NMR (500 MHz, DMSO-d6) d 11.89 (s, 1H), 8.03 (s, 1H), 7.36 (dd, J = 8.7, 5.5 Hz, 1H), 7.28 (dd, J = 9.6, 2.9 Hz, 1H), 7.17 (td, J = 8.5, 3.0 Hz, 1H), 2.17 (s, 3H). LCMS (Analytical Method D) Rt= 0.79 min, MS (ESIpos): m/z= 194.0 [M+H]+, purity = 97%.
Synthesis of phenyl N-G1 -(2.2.2-trifluoroethyl )- l H-pyrazol-4-yllcarbamate
(Intermediate A27)
Figure imgf000072_0001
(Intermediate A27)
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. Purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% TBME in heptane) afforded the title compound (195 mg, 65% yield). 1H NMR (500 MHz, DMSO-d6) d 10.12 (s, 1H), 7.86 (s, 1H), 7.53 (s, 1H), 7.44 - 7.39 (m, 2H), 7.27 - 7.22 (m, 1H), 7.21 - 7.18 (m, 2H), 5.09 (q, J = 9.1 Hz, 2H). LCMS (Analytical Method D) Rt= 1.04 min, MS (ESIpos): m/z= 285.9 [M+H]+, purity = 99%.
Synthesis of 3-amino-l- trifluoroethvD-lH-pyrazol-4-yl1urea
Figure imgf000072_0002
(Intermediate A28)
Figure imgf000072_0003
(Intermediate A28)
Hydrazine hydrate (60 pL, 1.24 mmol) was added to a solution of phenyl N-[l- (2,2,2-trifluoroethyl)pyrazol-4-yl]carbamate (175 mg, 0.614 mmol) in ethanol (3 ml). The reaction was heated to 75°C for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. Purification by trituration with DCM afforded the title compound (81 mg, 59% yield). 1H NMR (500 MHz, DMSO-d6) d 8.64 (s, 1H), 7.87 (s, 1H), 7.56 (s, 1H), 7.35 (s, 1H), 5.01 (q, J = 9.2 Hz), 4.28 (s, 2H). LCMS (Analytical Method D) Rt= 0.31 min, MS (ESIpos): m/z= 223.9 [M+H]+, purity = 99%. Synthesis of 4-PI -(2.2.2-trifluoroethyl )- l H-pyrazol-4-nP-
4.5-dihvdro-lH-E2.4-triazol-5-one
(Intermediate A29)
Figure imgf000073_0001
(Intermediate A29)
A mixture of l-amino-3-[l-(2,2,2-trifluoroethyl)pyrazol-4-yl]urea (Intermediate A28) (70 mg, 0.314 mmol), triethylorthoformate (65 pL, 0.391 mmol) and p- toluenesulfonic acid monohydrate (6 mg, 0.0315 mmol) were dissolved in ethanol (3 ml) was heated to 110°C for 16 hrs. The reaction was cooled to room temperature and concentrated in vacuo. Purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% TBME in heptane) afforded the title compound (49 mg, 60% yield). 1H NMR (500 MHz, DMSO-d6) d 11.92 (s, 1H), 8.33 (s, 1H), 8.32 (s, 1H), 7.97 (s, 1H), 5.19 (q, J = 9.1 Hz, 2H). LCMS (Analytical Method D) Rt= 0.67 min, MS (ESIpos): m/z= 233.9 [M+H]+, purity = 92%.
Synthesis of phenyl N-(2-chlorophenvDcarbamate
(Intermediate A30)
Figure imgf000073_0002
(Intermediate A30)
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 Isolera™ chromatography (silica gel, eluting with 0-100% TBME in heptane) afforded the title compound (472 mg, 88% yield). 1H NMR (500 MHz, DMSO-d6) d 9.69 (s, 1H), 7.63 (dd, J = 8.0, 1.4 Hz, 1H), 7.52 (dd, J = 8.0, 1.4 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.36 (td, J = 7.7, 1.5 Hz, 1H), 7.28 - 7.20 (m, 3H), 7.18 - 7.13 (m, 1H). LCMS (Analytical Method D) Rt= 1.20 min, MS (ESIpos): m/z= 247.9,249.9 [M+H]+, purity = 93%.
Using procedure described for Intermediate A30, the following intermediates are prepared.
Figure imgf000074_0001
Synthesis of 3-amino-l-(2-chlorophenvOurea (Intermediate A31)
Figure imgf000075_0001
(Intermediate A31)
Hydrazine hydrate (165 pL, 3.40 mmol) was added to a solution of phenyl N-(2- chlorophenyl)carbamate (450 mg, 1.69 mmol) in ethanol (5 ml). The reaction was heated to 75°C for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. Purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% EtOAc in heptane) afforded the title compound (197 mg, 61% yield). 1H NMR (500 MHz, DMSO-d6) d 9.1 (s, 1H), 8.3 - 8.2 (m, 1H), 7.9 (s, 1H), 7.4 (dd, J = 8.0, 1.4 Hz, 1H), 7.3 - 7.2 (m, 1H), 7.0 - 6.9 (m, 1H), 4.7 (s, 2H). LCMS (Analytical Method D) Rt= 0.81 min, MS (ESIpos): m/z= 185.9,187.9 [M+H]+, purity = 97%.
Using procedure described for Intermediate A31, the following intermediates are prepared.
Figure imgf000075_0002
Figure imgf000076_0002
Synthesis of 4-(2-chlorophenyl )-4.5-dihydro- l H- l .2.4-triazol-5-one
(Intermediate A32)
Figure imgf000076_0001
(Intermediate A32) A mixture of 1 -amino-3 -(2-chlorophenyl)urea (180 mg, 0.941 mmol), triethylorthoformate (169 pL, 1.14 mmol) and p-toluenesulfonic acid monohydrate (10 mg, 0.0526 mmol) were dissolved in ethanol (3 ml) was heated to 110°C for 16 hrs. The reaction was cooled to room temperature and concentrated in vacuo. Purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% TBME in heptane then 0-80% MeOH in heptane) followed by extraction of the product from 1M HC1 (aq) with 4:1 DCM:MeOH afforded the title compound (93 mg, 50% yield). 1H NMR (500 MHz, DMSO-d6) d 11.9 (s, 1H), 8.1 (d, J = 1.4 Hz), 7.7 - 7.7 (m, 1H), 7.6 - 7.6 (m, 1H), 7.6 - 7.5 (m, 2H). LCMS (Analytical Method D) Rt= 0.76 min, MS (ESIpos): m/z= 195.9,197.9 [M+H]+, purity = 98%.
Synthesis of 4-fluoro-N-r(methylcarbamov0aminolbenzamide (Intermediate A33)
Figure imgf000077_0001
(Intermediate A33)
To a suspension of N-methylhydrazinecarboxamide (112 mg, 1.26 mmol) and Et3N (211 pL, 1.51 mmol) in THF (6 mL) at 0 °C, under nitrogen, was added 4- fluorobenzoyl chloride (152 pL, 1.26 mmol) dropwise. The reaction was allowed to warm to room temperature over 18 hr. The resulting solid was triturated in DCM to give the title compound as a white solid (124 mg, 45% yield). 1H NMR (250 MHz, DMSO-d6) d 10.13 (s, 1H), 8.06 - 7.91 (m, 2H), 7.86 (s, 1H), 7.33 (t, J = 8.9 Hz, 2H), 6.43 (d, J = 4.4 Hz, 1H), 2.58 (d, J = 4.6 Hz, 3H). LCMS (Analytical Method D) Rt= 0.54 min, MS (ESIpos): m/z= 212.0 [M+H]+, purity = 97%.
Synthesis of 3-(4-fluorophenvO-4-methyl-4.5-dihvdro-lH-E2.4-triazol-5-one
(Intermediate A34)
Figure imgf000077_0002
(Intermediate A34) A pressure vial was charged with 4-fluoro-N-[(methylcarbamoyl)amino] benzamide (Intermediate A33) (124 mg, 0.59 mmol), 1.12 MNaOH (524 pL) and water (0.5 mL). The suspension was heated at 105 °C for 18 hr. The reaction was allowed to cool to room temperature. The aqueous phase was decanted from the precipitate. The precipitate was diluted with water (1 mL) and the pH was adjusted to pH 6 with IMaq HC1. The resulting suspension was sonicated and the solid was collected by filtration to give the title compound as a white solid (65 mg, 57% yield). 1HNMR (250 MHz, DMSO- d6) d 11.89 (s, 1H), 7.74 (ddd, J = 8.4, 5.3, 2.6 Hz, 2H), 7.43 - 7.30 (m, 2H), 3.23 (s, 3H). LCMS (Analytical Method D) Rt= 0.83 min, MS (ESIpos): m/z= 194.0 [M+H]+, purity = 100%.
Synthesis of 3-cvclopropyl-4-methyl-4.5-dihvdro-lH-L2.4-triazol-5-one
(Intermediate A35)
Figure imgf000078_0001
(Intermediate A35)
A mixture of cyclopropanecarboxylic acid (175 pL, 2.34 mmol), HATU (1100 mg, 2.89 mmol) and DIPEA (1.22 mL, 7.03 mmol) were dissolved in DMF (5 mL). The mixture was stirred at room temperature for 30 minutes. N-Methylhydrazinecarboxamide (220 mg, 2.47 mmol) was added and the mixture was stirred for 18 hr. The reaction mixture was concentrated in vacuo and the crude product was purified via Biotage Isolera™ chromatography (silica gel, eluting with 0-80% MeOH in DCM), followed by trituration with DCM afforded the title compound (118 mg, 26% yield). 1H NMR (500 MHz, DMSO-d6) d 9.63 (s, 1H), 7.68 (s, 1H), 6.27 - 6.17 (m, 1H), 2.54 (d, J = 4.6 Hz, 3H), 1.60 - 1.51 (m, 1H), 0.73 - 0.66 (m, 4H). LCMS (Analytical Method B) Rt= 0.65 min, MS (ESIpos): m/z= 157.5 [M+H]+, purity =not determined (solvent front). Synthesis of 3-cvclopropyl-4-methyl-4.5-dihydro-lH-E2.4-triazol-5-one
(Intermediate A36)
Figure imgf000079_0001
(Intermediate A36)
A mixture of N-[(methylcarbamoyl)amino]cyclopropanecarboxamide (Intermediate A35), (118 mg, 0.6 mmol) water (0.5 mL) and 1M aqNaOH (602 pL) was stirred at 100°C for 9 hr. The mixture was cooled to room temperature and acidified to pH ~ 3 with 1M aq HC1, then extracted with DCM three times. The organic phases were combined and concentrated in vacuo. The aqueous phase was also concentrated in vacuo. Both residues were combined and purified via Biotage Isolera™ chromatography (silica gel, eluting with 0-15% MeOH in DCM) to afford the title compound (38 mg, 36% yield). 1HNMR (500 MHz, DMSO-d6) d 11.27 (s, 1H), 3.16 (s, 3H), 1.85 - 1.77 (m, 1H), 0.90 - 0.85 (m, 2H), 0.77 - 0.74 (m, 2H). LCMS (Analytical Method D) Rt= 0.40 min, MS (ESIpos): m/z= 140.1 [M+H]+, purity =not determined (solvent front).
Synthesis of 4-methyl-3-(oxan-4-vD-4.5-dihydro-lH-E2.4-triazol-5-one
(Intermediate A37)
Figure imgf000079_0002
(Intermediate A37)
A mixture of oxane-4-carboxylic acid (250 mg, 1.92 mmol), HATU (875 mg, 2.3 mmol) and DIPEA (1.0 mL, 5.74 mmol) were dissolved in DMF (5 mL) and the solution was stirred at room temperature for 30 minutes. N-Methylhydrazinecarboxamide (200 mg, 2.24 mmol) was added and the mixture was stirred for 2 hr. The mixture was concentrated in vacuo and the crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM), followed by trituration from EtOAc, to afford the title compound (255 mg, 57% yield). 1H NMR (500 MHz, DMSO-d6) d 9.40 (d, J = 1.8 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 6.18 (d, J = 4.6 Hz, 1H), 3.89 - 3.82 (m, 2H), 3.30 - 3.26 (m, 2H), 2.55 (d, J = 4.6 Hz, 3H), 2.43 - 2.35 (m, 1H), 1.65 - 1.50 (m, 4H). LCMS (Analytical Method D) Rt= 0.22 min, MS (ESIpos): m/z= 202.0 [M+H]+, purity =not determined (solvent front).
Synthesis of 4-methyl-3-(oxan-4-vO-4.5-dihvdro-lH-E2.4-triazol-5-one
(Intermediate A38)
Figure imgf000080_0001
(Intermediate A38)
N-[(methylcarbamoyl)amino]oxane-4-carboxamide (Intermediate A37) (240 mg, 1.03 mmol) was suspended in water (0.5 mL) and 1M NaOH (1.04 mL) was added. The mixture was sealed and stirred at 100°C for 16 hr. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM) to afford the title compound (155 mg, 82% yield). 1H NMR (500 MHz, DMSO-d6) d 11.39 (s, 1H), 3.89 (ddd, J = 11.4, 3.8, 2.3 Hz, 2H), 3.46 - 3.38 (m, 2H), 3.12 (s, 3H), 2.91 - 2.82 (m, 1H), 1.81 - 1.73 (m, 2H), 1.67 - 1.55 (m, 2H). LCMS (Analytical Method D) Rt= 0.37 min, MS (ESIpos): m/z= 184.0 [M+H]+, purity = not determined (solvent front).
Synthesis of 5-fluoro-N-r(methylcarbamovDaminolpyridine-2-carboxamide
(Intermediate A39)
Figure imgf000081_0001
(Intermediate A39)
A mixture of 5-fluoropyridine-2-carboxylic acid (320 mg, 2.27 mmol), HATU (1.02 g, 2.68 mmol) and DIPEA (1.2 mL, 6.87 mmol) in DMF (6 mL) and stirred at room temperature for 15 minutes, then N-methylhydrazinecarboxamide (200 mg, 2.24 mmol) was added. The mixture was stirred for 3 hr, then concentrated in vacuo. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0- 20% MeOH in DCM) to afford the title compound (334 mg, 63% yield). 1H NMR (500 MHz, DMSO-d6) d 10.2 - 10.1 (m, 1H), 8.7 (d, J = 2.9 Hz, 1H), 8.1 (dd, J = 8.8, 4.6 Hz, 1H), 7.9 - 7.9 (m, 2H), 6.3 (d, J = 4.4 Hz, 1H), 2.6 (d, J = 4.6 Hz, 3H). LCMS (Analytical Method D) Rt= 0.38 min, MS (ESIpos): m/z= 213.0 [M+H]+, purity =not determined (solvent front).
Synthesis of 3-(5-fluoropyridin-2-vO-4-methyl-4.5-dihvdro-lH- triazol-5-one
(Intermediate A40)
Figure imgf000081_0002
Figure imgf000081_0003
(Intermediate A40)
To a suspension of 5-fluoro-N-[(methylcarbamoyl)amino]pyridine-2- carboxamide (330 mg, 1.40 mmol) (Intermediate A39) in water (2 mL) was added 1 M aq sodium hydroxide (1.4 mL, 1.40 mmol). The mixture was sealed under nitrogen and stirred at 100 °C for 4 hr. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-15% MeOH in DCM) to afford the title compound (245 mg, 90% yield). 1H NMR (500 MHz, DMSO-d6) 5 12.1 (s, 1H), 8.7 (d, J = 2.9 Hz, 1H), 8.0 (dd, J = 8.9, 4.5 Hz, 1H), 7.9 (td, J = 8.8, 2.9 Hz, 1H), 3.5 (s, 3H). LCMS (Analytical Method D) Rt= 0.79 min, MS (ESIpos): m/z= 195.0 [M+H]+, purity =not determined (solvent front).
Synthesis of l-methyl-N-r(methylcarbamovDaminol-lH-pyrazole-4-carboxamide
(Intermediate A41)
Figure imgf000082_0001
(Intermediate A41)
A mixture of l-methylpyrazole-4-carboxylic acid (285 mg, 2.26 mmol), HATU (1.02 g, 2.68 mmol) and DIPEA (1.2 mL, 6.87 mmol) in DMF (6 ml) was stirred at room temperature for 15 minutes, then N-methylhydrazinecarboxamide (200 mg, 2.24 mmol) was added and the mixture was stirred for 3 hr. The reaction was concentrated in vacuo. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM) to afford the title compound (467 mg, 63% yield). 1H NMR (500 MHz, DMSO-d6) d 9.7 (s, 1H), 8.2 (s, 1H), 7.9 (s, 1H), 7.8 (s, 1H), 6.4 (d, J = 4.4
Hz, 1H), 3.9 (s, 3H), 2.6 (d, J = 4.6 Hz, 3H). LCMS (Analytical Method D) Rt= 0.24 min, MS (ESIpos): m/z= 198.0 [M+H]+, purity =not determined (solvent front).
Synthesis of 4-methyl-3-( l -methyl- 1 H-pyrazol-4-yl )-4.5-dihydro- l H- l .2.4-triazol-5- one
(Intermediate A42)
Figure imgf000083_0001
(Intermediate A42).
To a suspension of l-methyl-3-[(l-methylpyrazole-4-carbonyl)amino]urea (Intermediate A41) (460 mg, 1.40 mmol) was in water (2 mL) was added 1 M aq sodium hydroxide (1.4 mL, 1.40 mmol). The mixture was sealed under nitrogen and stirred at 100 °C for 4 hr. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified via Biotage Isolera™ chromatography (silica gel, eluting with 0-15% MeOH in DCM) to afford the title compound (118 mg, 47% yield). 1HNMR (500 MHz, DMSO-d6) 5 11.6 (s, 1H), 8.2 (s, 1H), 7.8 (d, J = 0.7 Hz, 1H), 3.9 (s, 3H), 3.2 (s, 3H). LCMS (Analytical Method D) Rt= 0.43 min, MS (ESIpos): m/z= 180.0 [M+H]+, purity =100%.
Using procedure described for Intermediate A42, the following intermediates are prepared.
Figure imgf000083_0002
Figure imgf000084_0002
Synthesis of 2.2.2-trifluoro-N-r(methyl carbamoyl )amino1acetamide
(Intermediate A43)
Figure imgf000084_0001
(Intermediate A43)
To a suspension mixture of N-methylhydrazinecarboxamide (200 mg, 2.24 mmol) and N,N-dimethylpyridin-4-amine (25 mg, 0.205 mmol) in THF (5 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (343 pL, 2.47 mmol) dropwise at 0°C. The mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo. The crude product was purified via Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM) to give the title compound (370 mg, 85% yield). 1H NMR (500 MHz, DMSO-d6) d 11.0 (s, 1H), 8.2 (s, 1H), 6.5 - 6.5 (m, 1H), 2.6 (d, J = 4.6 Hz, 3H). LCMS (Analytical Method D) Rt= 0.25 min, MS (ESIpos): m/z= 186.0 [M+H]+, purity =not determined (solvent front). Using procedure described for Intermediate A43, the following intermediates are prepared.
Figure imgf000085_0002
Synthesis of 4-methyl-3-(trifluoromethyl)-4.5-dihvdro- l H- l triazol-5-one
Figure imgf000085_0001
(Intermediate A44)
Figure imgf000086_0001
(Intermediate A44)
To a suspension of 2,2,2-trifluoro-N-[(methylcarbamoyl)amino]acetamide (Intermediate A43) (340 mg, 1.75 mmol) in water (2 mL) was added 1 M aq sodium hydroxide (1.80 mL, 1.80 mmol). The mixture was sealed and stirred at 100°C for 24 hr. The reaction was cooled to room temperature and acidified to pH 1 with 1M aq HC1, then extracted with DCM/ MeOH (9:1). The product remained in the aqueous phase, which was then concentrated in vacuo. The crude product was dry loaded to silica and purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM) to afford the title compound (15 mg, 5% yield). 1HNMR (500 MHz, Methanol-d4) d 3.4 - 3.4 (m, 3H). LCMS (Analytical Method D) Rt= 0.68 min, MS (ESIpos): m/z= 167.9
[M+H]+, purity = 100%.
Using procedure described for Intermediate A44, the following intermediates are prepared.
Figure imgf000086_0002
Figure imgf000087_0001
Synthesis of N-IYcvclopropylcarbamovOamino -fluorobenzamide
(Intermediate A45)
Figure imgf000088_0001
(Intermediate A45)
To a suspension of 4-fluorobenzohydrazide (250 mg, 1.62 mmol) in THF (5 mL) was added isocyanatocyclopropane (120 pL, 1.72 mmol). The mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered and the precipitate washed with THF, then collected and dried in vacuo to afford the title compound (250 mg, 62% yield). 1H NMR (500 MHz, DMSO-d6) d 9.28 (s, 1H), 7.65 (s, 1H), 6.49 (s, 1H), 5.32 (s, 1H,), 3.86 (d, J = 12.7 Hz, 2H), 2.44 (s, 1H), 0.64 - 0.47 (m, 2H), 0.36 (s, 2H). LCMS (Analytical Method D) Rt= 0.75 min, MS (ESIpos): m/z= 238.0 [M+H]+, purity = 100%.
Synthesis of 4-cvclopropyl-3-(4-fluorophenyl )-4.5-dihydro- l H- l .2.4-triazol-5-one
(Intermediate A46)
Figure imgf000088_0002
(Intermediate A46)
To a suspension of N-[(cyclopropylcarbamoyl)amino]-4-fluorobenzamide (200 mg, 0.84 mmol)in water (0.5 mL) was added 1M aq NaOH (855 pL) was added. The mixture was sealed under nitrogen and stirred at 100°C for 24 hr. The mixture was concentrated in vacuo and dry loaded onto silica, then purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM) to afford the title compound (106 mg, 57% yield). 1HNMR (500 MHz, DMSO-d6) d 11.77 (s, 1H), 7.84 -
7.78 (m, 2H), 7.37 - 7.31 (m, 2H, H12, H14), 3.11 - 3.05 (m, 1H), 0.89 - 0.78 (m, 2H), 0.60 - 0.50 (m, 2H). LCMS (Analytical Method D) Rt= 0.91 min, MS (ESIpos): m/z= 220.0 [M+H]+, purity = 100%.
Synthesis of tert-butyl 2-r4-(4-fluorophenvD-5-oxo-4.5- dihydro- 1H- 1 2.4-triazol- 1 -yllacetate
(Intermediate A47)
Figure imgf000089_0001
(Intermediate A47)
To a mixture of 4-(4-fluorophenyl)-4,5-dihydro-lH-l,2,4-triazol-5-one (200 mg, 1.12 mmol) and potassium carbonate (230 mg, 1.66 mmol) in acetonitrile (3 mL) was added tert-butyl 2-bromoacetate (180 pL, 1.22 mmol). The mixture was stirred at 60°C for 18 hr. The reaction was cooled to room temperature and diluted with water, then extracted with EtOAc. The organic phase was concentrated in vacuo and the crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0- 100% EtOAc in heptane) to afford the title compound (325 mg, 99% yield). 1H NMR (500 MHz, DMSO-d6) d 8.50 (s, 1H), 7.75 - 7.71 (m, 2H), 7.41 - 7.35 (m, 2H), 4.53 (s,
2H), 1.43 (s, 9H). LCMS (Analytical Method D) Rt= 1.06 min, MS (ESIpos): m/z= 316.0 [M+H]+, purity = 100%.
Synthesis of 2-14-(4-fluorophenyl )-5-oxo-4.5-dihydro- l H- l 2.4-triazol - 1 -yll acetic acid
(Intermediate A48)
Figure imgf000089_0002
(Intermediate A48)
To a solution of tert-butyl 2-[4-(4-fluorophenyl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-l-yl] acetate (300 mg, 1.02 mmol) DCM (2 mL) was added trifluoroacetic acid (1.5 mL, 19.6 mmol). The mixture was stirred at room temperature for 18 hr. The reaction was concentrated in vacuo to afford the title compound (240 mg, 99% yield). 1H NMR (500 MHz, DMSO-d6) d 13.16 (s, 1H), 8.50 (s, 1H), 7.77 - 7.71 (m, 2H), 7.42 - 7.34 (m, 2H), 4.54 (s, 2H). LCMS (Analytical Method D) Rt= 0.75 min, MS (ESIpos): m/z= 237.9 [M+H]+, purity = 100%.
Synthesis of N-r(cvclopropylcarbamovDaminol-2-hvdroxyacetamide
(Intermediate A49)
Figure imgf000090_0001
(Intermediate A49) To a suspension of 2-hydroxyacetohydrazide (250 mg, 2.78 mmol) in THF (5 mL) was added isocyanatocyclopropane (200 pL, 2.87 mmol). The mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered. The precipitate was washed with THF and after thorough drying afforded the title compound (285 mg, 53% yield).1H NMR (500 MHz, DMSO-d6) d 9.28 (s, 1H), 7.65 (s, 1H), 6.49 (s, 1H), 5.32 (s, 1H), 3.86 (d, J = 12.7 Hz, 2H), 2.44 (s, 1H), 0.64 - 0.47 (m, 2H), 0.36 (s, 2H). LCMS (Analytical
Method D) Rt= 0.19 min, MS (ESIpos): m/z= 174.0 [M+H]+, purity = not determined (solvent front).
Synthesis of 4-cvclopropyl-3-(hvdroxymethyl )-4.5-dihydro- l H- l .2.4-triazol-5-one (Intermediate A50)
Figure imgf000090_0002
(Intermediate A50) To a suspension of N-[(cyclopropylcarbamoyl)amino]-2-hydroxyacetamide (Intermediate A49) (480 mg, 2.77 mmol) in water (0.5 mL) was added 1M aq NaOH (2.8 mL). The mixture was sealed under nitrogen and stirred at 100 °C for 18 hr. The reaction was cooled to room temperature and concentrated in vacuo. Purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-80% MeOH in DCM) afforded the title compound (395 mg, 87% yield). 1H NMR (500 MHz, DMSO-d6) d 11.4 (s, 1H), 5.4 (s, 1H), 4.5 - 4.2 (m, 2H), 2.8 - 2.7 (m, 1H), 1.0 - 0.8 (m, 4H). LCMS (Analytical Method D) Rt= 0.23 min, MS (ESIpos): m/z= 156.0 [M+H]+, purity = not determined (solvent front).
Synthesis of N-(r(4-fluorophenvDcarbamovnamino|-2-hvdroxyacetamide
(Intermediate A51)
Figure imgf000091_0001
(Intermediate A51)
To a solution of 2-hydroxyacetohydrazide (250 mg, 2.78 mmol) in THF (5 mL) was added l-fluoro-4-isocyanatobenzene (325 pL, 2.86 mmol). The mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered and the solid was collected to afford the title compound (404 mg, 64% yield). 1H NMR (500 MHz, DMSO-d6) d 9.5 (s, 1H), 8.7 (s, 1H), 8.0 (s, 1H), 7.5 - 7.4 (m, 2H), 7.1 - 7.0 (m, 2H), 5.4 (t, J = 5.3 Hz, 1H), 3.9 (d, J = 5.5 Hz, 2H).
Synthesis of 4-(4-fluorophenyl )-3 -(hydroxymethyl )-4.5-dihydro-l H- l .2.4-triazol-5-one
(Intermediate A52)
Figure imgf000092_0001
(Intermediate A52)
To a suspension of N-{[(4-fluorophenyl)carbamoyl]amino}-2-hydroxyacetamide (395 mg, 1.74 mmol) in water (0.5 mL) was added 1M aq NaOH (1.76 mL). The mixture was sealed and stirred at 100°C for 3 hr. The reaction was cooled to room temperature then concentrated in vacuo. Purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-50% MeOH in DCM) afforded the title compound (208 mg, 54% yield). 1HNMR (500 MHz, DMSO-d6) d 7.5 - 7.5 (m, 2H), 7.4 - 7.3 (m, 2H), 4.2 (s, 2H). LCMS (Analytical Method D) Rt= 0.56 min, MS (ESIpos): m/z= 210.0 [M+H]+, purity = 100%. Synthesis of 4-methyl-3-(methylsulfanyl )-4.5-dihydro- l H- l .2.4-triazol-5-one
(Intermediate A53)
Figure imgf000092_0002
(Intermediate A53)
Iodomethane (52 pL, 0.839 mmol) was added to a suspension of 4-methyl-3- sulfanyl-lH-l,2,4-triazol-5-one (0.10 g, 0.762 mmol) and potassium carbonate (211 mg, 1.52 mmol) in ethanol (5 mL). A pale yellow colour was observed and the reaction was stirred for 2 hours. The solid material was removed by filtration, washing with ethanol and the filtrate concentrated in vacuo. The residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-10% MeOH in DCM) to give the title compound (110 mg, 97% yield). 1H NMR (500 MHz, DMSO-d6) d 3.06 (s, 3H), 2.48 (s, 3H). LCMS (Analytical Method D) Rt= 0.51 min, MS (ESIpos): m/z= 145.9 [M+H]+, purity = 98%. Synthesis of 3-methanesulfonyl-4-methyl-4.5-dihvdro-lH-L2.4-triazol-5-one
(Intermediate A54)
Figure imgf000093_0001
(Intermediate A54) m-Chloroperbenzoic acid (55%, 238 mg, 0.758 mmol) was added to an ice cold solution of 4-methyl-3-(methylsulfanyl)-4,5-dihydro-lH-l,2,4-triazol-5-one (Intermediate A53) (110 mg, 0.76 mmol) in dichloromethane (5 mL). The reaction was stirred for 2 hours then concentrated in vacuo to give a residue. The residue was taken up in dichloromethane (10 mL) and cooled in ice/water then m-chloroperbenzoic acid (55%, 238 mg, 0.758 mmol) was added. The reaction was stirred for 6 hours (warmed to room temperature over this time) then concentrated in vacuo. The residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-10% MeOH in DCM) to give the title compound (88 mg, 66% yield). 1H NMR (500 MHz, DMSO-d6) d 12.75 (s, 1H), 3.45 (s, 3H), 3.33 (s, 3H).
Synthesis of 2-bromo-N-r(lS)-l-(4-methylphenvDethvHacetamide
(Intermediate A55)
Figure imgf000093_0002
(Intermediate A55)
A solution of (S)-l-(4-methylphenyl)ethylamine (2.72 mL, 18.49 mmol) and triethylamine (3.86 mL, 27.73 mmol) in tetrahydrofuran (50 mL) was added slowly to an ice cold solution of bromoacetyl chloride (1.62 mL, 19.41 mmol) in tetrahydrofuran (100 mL). The reaction was stirred for 2 hours then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was triturated with diethyl ether. The solid material was collected by filtration, washed with diethyl ether and dried in vacuo to yield the title compound as a tan solid (3.56 g, 75% yield). ¾ NMR (250 MHz, CDCb) d 7.24 - 7.13 (m, 4H), 6.64 (s, 1H), 5.07 (p, J = 7.1 Hz, 1H), 3.95 - 3.81 (m, 2H), 2.34 (s, 3H), 1.52 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.03 min, MS (ESIpos): m/z 255.8, 257.8 [M+H]+.
Synthesis of 2-bromo-N-r(lS)-l-r4-(trifluoromethoxy)phenyllethyllacetamide
(Intermediate A56)
Figure imgf000094_0001
Bromoacetyl chloride (106 pL, 1.28 mmol) was added slowly to an ice cold solution of (lS)-l-[4-(trifluoromethoxy)phenyl]ethylamine (250 mg, 1.22 mmol) and triethylamine (355 pL, 2.56 mmol) in tetrahydrofuran (10 mL). The reaction was stirred for 90 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-75% ethyl acetate/heptane to yield the title compound as a cream solid (204 mg, 51% yield). ¾ NMR (500 MHz, CDCb) d 7.35 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.65 (s, 1H), 5.11 (p, J = 7.1 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 1.53 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 326.0, 327.9 [M+H]+.
Synthesis of 2-bromo-N-r(l S)-l-(4-chloro-3-fluorophenvDethyllacetamide
(Intermediate A57)
Figure imgf000095_0001
A solution of bromoacetyl chloride (166 pL, 2 mmol) in tetrahydrofuran (5 mL) was added slowly to an ice cold suspension of (lS)-l-(4-chloro-3- fluorophenyl)ethylamine HC1 (400 mg, 1.9 mmol) and triethylamine (556 pL, 4 mmol) in tetrahydrofuran (15 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-75% tertbutylmethylether/heptane to yield the title compound as a white solid (490 mg, 75% yield). ¾ NMR (500 MHz, CDCb) d 7.37 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 2.0, 9.9 Hz, 1H), 7.05 (dd, J = 2.0, 8.3 Hz, 1H), 6.69 - 6.59 (m, 1H), 5.05 (p, J = 7.2 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 1.51 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.10 min, MS (ESIpos): m/z 293.9, 295.9, 297.8 [M+H]+.
Synthesis of 2-bromo-N-r(l S)-l-(3-fluoro-4-methylphenvDethvHacetamide
(Intermediate A58)
Figure imgf000095_0002
(Intermediate A58)
A solution of bromoacetyl chloride (150 pL, 1.80 mmol) in THF (3 mL) was added dropwise to an ice cold solution of (lS)-l-(3-fluoro-4-methylphenyl)ethanamine (250 mg, 1.63 mmol) and triethylamine (0.57 mL, 1.1 mmol) in THF (12 mL) over 10 mins. The reaction was stirred for 2 hours then quenched with water and extracted into ethyl acetate three times. The combined organics were washed with brine, dried over Na2SC>4 and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0%-70% EtOAc/heptane to yield the title compound as a pale orange solid (280 mg, 63% yield). 1H NMR (500 MHz, Chloroform-d) d 7.16 (t, J = 7.8 Hz, 1H), 7.03 - 6.89 (m, 2H), 6.63 (s, 1H), 5.05 (p, J = 7.1 Hz, 1H), 3.95 - 3.80 (m, 2H), 2.25 (d, J = 1.5 Hz, 3H), 1.51 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt=
1.07 min, MS (ESIpos): m/z 273.75, 275.75 [M+H]+.
Synthesis of 2-bromo-N-rO S)-l-(3.4-difluorophenvOethvnacetamide
(Intermediate A59)
Figure imgf000096_0001
(Intermediate A59)
A solution mixture of (lS)-l-(3,4-difluorophenyl)ethan-l-amine (250 mg, 1.59 mmol) in THF (5 ml) and triethylamine (675 pL, 4.85 mmol) was cooled to 0°C. Bromoacetyl chloride (150 pL, 1.8 mmol) was added slowly. The mixture was stirred at this temperature for 1 hr. The reaction was quenched with water and extracted with EtOAc three times. The organic phases were combined and concentrated in vacuo. The crude product was purified by flash chromatography (silica, gradient of 0-100% TBME in heptane) to afford the title compound as an off-white solid (370 mg, 84% yield). 1H NMR (500 MHz, DMSO-d6) d 8.75 (d, J = 7.6 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.19 - 7.11 (m, 1H), 4.92 - 4.83 (m, 1H), 3.91 - 3.83 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.02 min, MS (ESIpos): m/z 277.9, 279.9 [M+H]+.
Synthesis of 2-chloro-N-r(lS)-l-(3.4-difluorophenv0ethyllacetamide
(Intermediate A60)
Figure imgf000097_0001
(Intermediate A60)
A suspension of (lS)-l-(3,4-difluorophenyl)ethylamine hydrochloride (350 mg, 1.80 mmol) and triethylamine (0.770 mL, 5.53 mmol) in THF (4 mL) was added slowly to an ice cold solution of 2-chloroacetyl chloride (0.140 mL, 2.34 mmol) in THF (7 mL) . The reaction was stirred for 2 hours then the reaction was quenched with water
(10 mL) and extracted into EtOAc (3 x 25 mL). The combined organics were dried over MgSCri and concentrated in vacuo. The residue was purified by chromatography, silica gel, eluting with 0-100% tertbutylmethyl ether/heptane. The relevant fractions were combined and concentrated to yield the title compound as a pale brown solid (200 mg, 47% yield). ¾ NMR (500 MHz, DMSO-d6) d 8.67 (d, J = 7.7 Hz, 1H), 7.42 - 7.34 (m,
2H), 7.18 - 7.13 (m, 1H), 4.90 (p, J = 7.1 Hz, 1H), 4.08 (s, 2H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.02 min, MS (ESIpos): m/z 233.8, 235.9 [M+H]+.
Synthesis of 2-Bromo-N-r(l S)- l -(3.4-dichlorophenyl iethyllacetamide
(Intermediate A61)
Figure imgf000097_0002
A solution of bromoacetyl chloride (25 pL, 0.3 mmol) in tetrahydrofuran (0.5 mL) was added slowly to an ice cold solution of (lS)-l-(3,4- dichlorophenyl)ethylamine (55 mg, 0.29 mmol) and trimethylamine (85 pL, 0.61 mmol) in tetrahydrofuran (1.5 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo to yield the title compound as a yellow oil (63 mg, 70% yield). ¾NMR (500 MHz, CDCb) d 7.45 - 7.37 (m, 2H), 7.16 (dd, J = 2.1, 8.3 Hz, 1H), 6.64 (s, 1H), 5.04 (p, J = 7.2 Hz, 1H), 3.94 - 3.84 (m, 2H), 1.51 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 309.7, 311.7, 313.7 [M+H]+.
Synthesis of 2-Bromo-N-r(l S)-l-(4-chloiO-3-methylphenvDethyl1acetamide
(Intermediate A62)
Figure imgf000098_0001
A solution of bromoacetyl chloride (103 pL, 1.24 mmol) in THF (0.5 mL) was added dropwise to an ice cold solution of (lS)-l-(4-chlorophenyl)ethanamine (200 mg, 1.18 mmol) and triethylamine (0.31 mL, 2.25 mmol). The reaction was stirred for 90 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-40% ethyl acetate/heptane to yield the title compound as pale brown solid (45 mg, 12% yield). ¾ NMR (500 MHz, Chloroform-d) d 7.24 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 8.2, 2.1 Hz, 1H), 6.58 (s, 1H), 4.97 (p, J = 7.1 Hz, 1H), 3.83 (m, 2H), 2.31 (s, 3H), 1.43 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 289.85, 291.85, 293.90 [M+H]+.
Synthesis of (R)-N-r(3-chloro-4-fluorophenvDmethylenel-2-methyl-propane-2- sulfmamide
(Intermediate A63)
Figure imgf000099_0001
(Intermediate A63)
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. The aqueous layer was extracted into dichloromethane three times, the combined organics washed with brine, dried over MgSCb and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-100% ethyl acetate: heptane to yield the title compound as a colourless oil (3.11 g, 92% yield). ¾NMR (500 MHz, DMSO-d6) d 8.55 (s, 1H), 8.17 (dd, J = 7.3, 2.1 Hz, 1H), 8.01 - 7.96 (m, 1H), 7.58 (t, J = 8.9 Hz, 1H), 1.18 (s, 9H). LCMS (Analytical Method D) Rt= 1.26 min, MS (ESIpos): m/z 261.9, 263.9 [M+H]+.
Synthesis of (R)-N-r(3-chloro-4-fluorophenyl)methylenel-
2-methyl-propane-2-sulfmamide (Intermediate A64)
Figure imgf000099_0002
3 (Intermediate A64)
1M Methyl magnesium bromide in THF (15.0 mL) was added dropwise to a -40 °C solution of (R)-N-[(3-chloro-4-fluorophenyl)methylene]-2-methyl-propane- 2-sulfmamide (Intermediate A63) (3.10 g, 11.6 mmol) in tetrahydrofuran (30 mL). The reaction was stirred at this temperature for 3 hours then allowed to warm slowly to room temperature. After stirring for 16 hours the reaction was quenched by the slow addition of water. The mixture was partitioned between ethyl acetate and water and the aqueous layer extracted three times with ethyl acetate. The combined organics were washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by chromatography, silica gel, eluting with 0-100% tert-butyl methyl ethenheptane to yield the title compound as a viscous oil (1.07 g, 33% yield). ¾ NMR (500 MHz, DMSO-d6) d 7.57 - 7.54 (m, 1H), 7.34 - 7.37 (m, 2H), 5.44 (d, J = 5.5 Hz, 1H), 4.43 (p, J = 6.7 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.10 (s, 9H). LCMS (Analytical Method A) Rt= 3.17 min, MS (ESIpos): m/z 278.1, 280.1 [M+H]+.
Synthesis of (lS)-l-(3-chloro-4-fluorophenvDethylamine hydrochloride
(Intermediate A65)
Figure imgf000100_0001
(Intermediate A65)
4M HCI in dioxane (15 mL) was added to a solution of (R)-N-[(3-chloro- 4-fluorophenyl)methylene]-2-methyl-propane-2-sulfmamide (Intermediate A64) (1.36 g, 4.91 mmol) in 1,4-dioxane (10 mL). The reaction was stirred for 4 hours then concentrated in vacuo to yield the title compound as a white solid (668 mg, 65%). ¾ NMR (500 MHz, DMSO) d 8.68 (s, 3H), 7.84 (dd, J = 7.1, 2.2 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.51 - 7.46 (m, 1H), 4.43 (q, J = 6.4 Hz, 1H), 1.51 (d, J = 6.8 Hz, 3H). LCMS (Analytical Method D) Rt= 0.72 min, MS (ESIpos): m/z 174, 176 [M+H]+.
Synthesis of 2-chloro-N-IYl S)-l-(3-chloro-4-fluorophenvDethyl1acetamide
(Intermediate A66)
Figure imgf000101_0001
(Intermediate A66)
A suspension of (lS)-l-(3-chloro-4-fluorophenyl)ethylamine hydrochloride (Intermediate A65) (668 mg, 3.18 mmol) and triethylamine (1.10 mL, 7.95 mmol) in THF (10 mL) was added slowly to an ice cold solution of 2-chloroacetyl chloride (0.250 mL, 4.18 mmol) in THF (10 mL). The reaction was stirred for 2 hours then additional 2-chloroacetyl chloride (0.250 mL, 4.18 mmol) was added and the reaction stirred for an additional 1 hour. The reaction was quenched with water (10 mL) and extracted into EtOAc (3 x 25 mL). The combined organics were dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-100% tertbutylmethyl ether/heptane to yield the title compound as a pale brown solid (775 mg, 98% yield). ¾ NMR (500 MHz, DMSO-d6) d 8.69 (d, J = 7.7 Hz, 1H), 7.52 (dd, J = 7.2, 2.1 Hz, 1H), 7.37 (t, J = 8.9 Hz, 1H), 7.34 - 7.30 (m, 1H), 4.91 (p, J = 7.1 Hz, 1H), 4.11 - 4.05 (m, 2H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.08 min, MS (ESIpos): m/z 249.9, 251.9 [M+H]+.
Synthesis of N l-(L3-benzodioxol-5-vnethyll-2-chloro-acetamide
Figure imgf000101_0002
(Intermediate A67)
Figure imgf000101_0003
(Intermediate A67)
A suspension of (lS)-l-(l,3-benzodioxol-5-yl)ethanamine hydrochloride (225 mg, 1.12 mmol) and triethylamine (0.390 mL, 2.51 mmol) in THF (2.5 mL) was added slowly to an ice cold solution of 2-chloroacetyl chloride (0.085 mL, 1.42 mmol) in THF (2.5 mL) . The reaction was stirred for 2 hours then the reaction was quenched with water (10 mL) and extracted into EtOAc (3 x 25 mL). The combined organics were dried over MgSCri and concentrated in vacuo. The residue was purified by chromatography, silica gel, eluting with 0-10% methanol/dichloromethane. The relevant fractions were combined and concentrated to yield the title compound as a pale brown solid (198 mg, 73% yield). ¾ NMR (500 MHz, DMSO-d6) d 8.55 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 1.7 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.77 (dd, J = 8.1, 1.5 Hz, 1H), 5.97 (s, 2H), 4.83 (p, J = 7.1 Hz, 1H), 4.07 - 4.02 (m, 2H), 1.33 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method E) Rt= 0.46 min, MS (ESIpos): m/z 241.9, 243.9 [M+H]+.
Synthesis of 6-Chloro-5-fluoropyridine-3-carbaldehvde
(Intermediate A68)
Figure imgf000102_0001
(Intermediate A68)
A solution of 5-bromo-2-chloro-3-fluoropyridine (10 g, 47.5 mmol) in diethyl ether (150 mL) was cooled in a dry ice/acetone bath. 2.5M Butyllithium in hexane (26.6 mL) was added over 20 minutes and the reaction stirred for 30 minutes. N,N- Dimethylformamide (18.4 mL, 237.6 mmol) was added over 10 minutes and stirring continued for 30 minutes. The reaction was quenched by addition of water and warmed to room temperature. The mixture was partitioned between ethyl acetate and water and the aqueous layer extracted into ethyl acetate three times. The combined organics were washed with brine, dried over MgSCri and concentrated in vacuo. The residue was crystallised from ethyl acetate/heptane (1:10) to give a portion of the title compound as an orange solid (120 mg). The filtrate was purified by chromatography (100 g, silica), eluting with 0-40% ethyl acetate/heptane to give a yellow solid (3.34 g, 36% yield). 1H NMR (250 MHz, CDC13) d 10.11 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 1.8 Hz, 1H), 7.92 (dd, J = 1.9, 7.6 Hz, 1H). LCMS (Analytical Method D) Rt= 0.88 min, MS (ESIpos): m/z 177.9, 180.1 [hydrate M+H]+; Purity= 92%.
Synthesis of 5-Fluoro-6-methylpyridine-3-carbaldehvde (Intermediate A69)
Figure imgf000103_0001
(Intermediate A69)
A mixture of 6-chloro-5-fluoropyridine-3-carbaldehyde (Intermediate
A68) (3.3 g, 17.0 mmol), 3.5Mtrimethylboroxine in THF (2.91 ml), potassium carbonate (4.69 g, 33.9 mmol) and Pd(PPh3)4 (0.98 g, 0.85 mmol) in 1,4-dioxane (30 mL) was degassed by sparging with nitrogen. The mixture was heated to 80°C for 24 hours then cooled and filtered through a short pad of celite. The filtrate was concentrated in vacuo to yield a residue. The residue was purified by chromatography (100 g, silica), eluting with 0-40% ethyl acetate/heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound (640 mg, 27% yield). 1H NMR (250 MHz, CDC13) d 10.08 (d, J = 2.3 Hz, 1H), 8.77 (s, 1H), 7.77 (dd, J = 1.7, 8.9 Hz, 1H), 2.64 (d, J = 3.0 Hz, 3H). LCMS (Analytical Method D) Rt= 0.80 min, MS (ESIpos): m/z 139.9 [M+H]+; Purity= 100%.
Synthesis of (R)-N-r(lE)-(5-fluoro-6-methylpyridin-3-vDmethylidenel-
2-methylpropane-2-sulfinamide
(Intermediate A70)
Figure imgf000103_0002
(Intermediate A70)
To a solution of 5-fluoro-6-methylpyridine-3-carbaldehyde (Intermediate A69) (889 mg, 6.39 mmol) in dichloromethane (60 mL) was added R- tertButylsulfmamide (852 mg, 7.03 mmol) followed by titanium tetraethoxide (3.15 mL, 12.8 mmol). The reaction was stirred for 24 hours then saturated NaHCCh (aq, 30 mL) was added. The mixture was stirred vigorously for 1 hour then filtered through a pad of celite. The filtrate was extracted into dichloromethane three times, the combined organics washed with brine, dried over MgSCE and concentrated in vacuo to yield the title compound as a yellow oil (1.38 g, 89% yield). 1H NMR (250 MHz, CDC13) d 8.66 (s, 1H), 8.62 (d, J = 1.8 Hz, 1H), 7.81 (dd, J = 1.6, 9.5 Hz, 1H), 2.60 (d, J = 3.0 Hz, 3H), 1.26 (s, 9H). LCMS (Analytical Method D) Rt= 1.08 min, MS (ESIpos): m/z 243.0 [M+H]+; Purity= 94%.
Synthesis of (RVN-Kl SV l-(5-fhioro-6-methylpyridin-3-vDethvH- 2-methylpropane-2-sulfmamide (Intermediate A71)
Figure imgf000104_0001
(Intermediate A71)
3M Methyl magnesium bromide in ether (2.84 ml) was added slowly to a solution cooled (-60°C) of (R)-N-[(lE)-(5-fluoro-6-methylpyridin-3-yl)methylidene]-2- methylpropane-2-sulfmamide (1.38 g, 5.68 mmol) in tetrahydrofuran (40 mL). The reaction was warmed to -40°C and stirred for 5 hours. The reaction was quenched by slow addition of water and warmed to room temperature. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgS04 and concentrated in vacuo to give a residue. The residue was triturated with toluene, the solid material collected by filtration and dried in vacuo to yield the title compound as a white solid (460 mg, 31% yield). 1H NMR (500 MHz, Chloroform-d) d 8.28 (s, 1H), 7.29 (dd, J = 10.1, 1.8 Hz, 1H), 4.61 (qd, J = 6.7, 3.3 Hz, 1H), 3.33 (d, J = 2.7 Hz, 1H), 2.52 (d, J = 2.9 Hz, 3H), 1.55 (d, J = 6.7 Hz, 3H), 1.21 (s, 9H). LCMS (Analytical Method D) Rt= 0.93 min, MS (ESIpos): m/z 259.0 [M+H]+Purity= 94%.
Synthesis of -l-(5-fluoro-6-methylpyridin-3-vDethan-l-amine dihydrochloride
Figure imgf000104_0002
(Intermediate A72) HCI HCI
Figure imgf000105_0001
(Intermediate A72)
4M HC1 in dioxane (2.67 mL) was added to a solution of (R)-N-[(1S)-1- (5-fluoro-6-methylpyridin-3-yl)ethyl]-2-methylpropane-2-sulfmamide (Intermediate A71). (460 mg, 1.78 mmol) A thick white precipitate rapidly formed. The reaction was stirred for 45 minutes. The mixture was concentrated in vacuo to yield the title compound as a colourless oil (404 mg, quantitative yield).
EXAMPLE Al-1
Synthesis of N-r(lS)-l-(4-chloro-3-fhaorophenvOethyll-2-r4-(4-fluorophenvO- 5-oxo-4.5-dihvdro-lH-E2.4-triazol-l-yllacetamide (Compound Al-1)
Figure imgf000105_0002
To a solution of 2-bromo-N-[(lS)-l-(4-chloro-3-fluorophenyl)ethyl] acetamide (Intermediate A57) (43 mg, 0.14 mmol) and 4-(4-fluorophenyl)-4, 5 -dihydro- lH-l,2,4-triazol-5-one (25 mg, 0.14 mmol) in DMF (1 mL) was added potassium carbonate (58 mg, 0.42 mmol). The reaction was heated at 60 °C for 1 hr. The reaction was allowed to cool to room temperature. Water (5 mL) was added. The resulting suspension was sonicated and filtered affording the title compound as a white solid (40 mg, 73% yield). 1HNMR (500 MHz, DMSO-d6) d 8.64 (d, J = 7.6 Hz, 1H), 8.48 (s, 1H), 7.80 - 7.67 (m, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.20 (dd, J = 8.3, 1.7
Hz, 1H), 4.93 (p, J = 7.2 Hz, 1H), 4.46 (s, 1H), 4.45 (s, 1H), 1.37 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt= 3.66 min, MS (ESIpos): m/z= 392.95, 394.95 [M+H]+, Purity = 100%.
EXAMPLES Al-2 THROUGH Al-19 Synthesis of Compounds Al-2 through Compound Al-19
Each of Compounds Al-2 through Al-19 as listed in Table 2 were prepared according to the method of Example Al-1, using the intermediates listed in the “Synthesis” column for such compounds. The final compounds were purified by preparative HPLC Methods, Al, A2, B1 or B2; or flash chromatography; or precipitation from specified solvent.
Table 2
Representative Compounds of Formula (II)
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
EXAMPLE A2-1
Synthesi s ofN-IYlSVl -(4-chloro-3 -fluorophenvOethyll -2- G 4-(5 -fluoropyridin-2-vO-5 - oxo-4.5-dihydro- l H-l .2.4-triazol- 1 -yllacetamide (Compound A2-1)
Figure imgf000115_0001
(Compound A2-1)
A mixture of 4-(5-fluoro-2-pyridyl)-lH-l,2,4-triazol-5-one (Intermediate A10) (220 mg, 1.21 mmol), 2-bromo-N-[(lS)-l-(4-chloro-3-fluoro- phenyl)ethyl]acetamide (Intermediate A57) (400 mg, 1.34 mmol) and potassium carbonate (300 mg, 2.17 mmol) in acetonitrile (5 mL) was stirred at 60°C for 3 hr. The reaction mixture was cooled to room temperature and diluted with water, then extracted with EtOAc. The organic phase was concentrated in vacuo. Purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% EtOAc in heptanes), followed by trituration with MeOH/MeCN afforded the title compound.1H NMR (500 MHz, DMSO-d6) d 8.7 (d, J = 7.7 Hz, 1H), 8.6 (s, 1H), 8.5 (d, J = 3.0 Hz, 1H), 8.2 (dd, J = 9.1, 4.0 Hz, 1H), 8.0 - 8.0 (m, 1H), 7.5 (t, J = 8.1 Hz, 1H), 7.4 (dd, J = 10.7, 1.9 Hz, 1H), 7.2 (dd, J = 8.3, 1.8 Hz, 1H), 5.0 - 4.9 (m, 1H), 4.5 - 4.4 (m, 2H), 1.4 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt= 3.01 min, MS (ESIpos): m/z= 394.2, 396.2 [M+H]+, Purity = 100%.
EXAMPLES A2-2 THROUGH A2-36 Synthesis of Compounds A2-2 through Compound A2-36 Each of Compounds A2-2 through A2-36 as listed in Table 3 were prepared according to the method of Example A2-1, using the intermediates listed in the “Synthesis” column for such compounds. The final compounds were purified by preparative HPLC Methods, Al, A2, B1 or B2; or flash chromatography; or precipitation from specified solvent. Each of Compounds A2-37 through A2-60 as listed in Table 3 are prepared according to the method of Example A2-1, using the intermediates listed in the “Synthesis” column for such compounds.
Table 3
Representative Compounds of Formula (II)
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
EXAMPLE A3
Synthesi s ofN-IYlSVl -(5 -fluoro-6-methylpyridin-3 -vOethyll -2- G 4-(4-fluorophenv0-5 - oxo-4.5-dihydro- l H-l .2.4-triazol- 1 -yllacetamide (Compound A3)
Figure imgf000136_0001
(Compound A3)
To a mixture of 2-[4-(4-fluorophenyl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-l-yl] acetic acid (Intermediate A48) (40 mg, 0.17 mmol) and HATU (80 mg, 0.21 mmol) in DMF (1 mL) was added DIPEA (90 pL, 0.52 mmol). The mixture was stirred at room temperature for 20 minutes, then (1 S)-l-(5-fluoro-6-methylpyridin-3-yl)ethan-l- amine (Intermediate A45) (35 mg, 0.19 mmol) was added. The mixture was stirred for 1 hr. The reaction mixture was purified directly by preparative HPLC, Method B1 to give the title compound (35 mg, 54% yield). 1H NMR (500 MHz, DMSO-d6) d 8.66 (d, J = 7.5 Hz, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.76 - 7.70 (m, 2H), 7.57 (dd, J = 10.8, 1.7 Hz, 1H), 7.42 - 7.33 (m, 2H), 4.98 (p, J = 7.1 Hz, 1H), 4.48 (d, J = 16.6 Hz, 1H), 4.44 (d, J =
16.6 Hz, 1H), 2.42 (d, J = 2.9 Hz, 3H), 1.41 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method A) Rt= 1.92 min, MS (ESIpos): m/z= 374 [M+H]+, purity = 98%.
EXAMPLES A4 AND A5
Synthesis of N-r(lS)-l-(4-chloro-3-fluorophenv0ethyll-2-r4-methyl-3-(morpholin-4- vn-5-oxo-4.5-dihvdro-lH-E2.4-triazol-l-yllacetamide (Compound A4)
Figure imgf000137_0001
(Compound A4) and
Synthesis of N-r(lS)-l-r4-chloro-3-(morpholin-4-vDphenvHethyll-2-(3- methanesulfonyl-4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)acetamide
(Compound A5)
Figure imgf000137_0002
(Compound A5)
A mixture of N-[(lS)-l-(4-chloro-3-fluorophenyl)ethyl]-2-(3- methanesulfonyl-4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)acetamide (Example A2-31) (60 mg, 0.154 mmol) and morpholine (134 pL, 1.54 mmol) in N- Methyl-2-pyrrolidone (0.1 mL) was heated to 180°C for 14 hours under microwave irradiation. The mixture was cooled and purified by preparative HPLC, Method B2 to afford two main fractions.
Fraction 1 was further purified by chromatography (silica, pipette column), eluting with 0-20% methanol/dichloromethane to afford of N-[(lS)-l-(4- chloro-3-fluorophenyl)ethyl]-2-[4-methyl-3-(morpholin-4-yl)-5-oxo-4,5-dihydro-lH- l,2,4-triazol-l-yl]acetamide (Compound A4) (4 mg, 5% yield). 1H NMR (500 MHz, Methanol -d4) d 7.43 - 7.38 (m, 1H), 7.23 (dd, J = 10.4, 2.0 Hz, 1H), 7.15 (dd, J = 8.3, 2.0 Hz, 1H), 5.01 (q, J = 7.0 Hz, 1H), 4.41 (s, 2H), 3.81 - 3.76 (m, 4H), 3.21 (s, 3H), 3.13 - 3.08 (m, 4H), 1.46 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method A) Rt= 2.42 min, MS (ESIpos): m/z= 398.1.2, 400.1 [M+H]+, Purity = 96%.
Fraction 2 was further purified by preparative HPLC, Method C3 to afford N-[(lS)-l-[4-chloro-3-(morpholin-4-yl)phenyl]ethyl]-2-(3-methanesulfonyl-4-methyl- 5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)acetamide (Compound A5). 1H NMR (400 MHz, DMSO-d6) d 8.65 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 8.2, 2.0 Hz, 1H), 4.89 (p, J = 7.0 Hz, 1H), 4.58 - 4.47 (m, 2H), 3.74 (t, J = 4.5 Hz, 4H), 3.46 (s, 3H), 3.39 (s, 3H), 2.98 (q, J = 4.0 Hz, 4H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt= 2.48 min, MS (ESIpos): m/z458.2, 460.2
[M+H]+, Purity = 98%.
EXAMPLE B
SYNTHESIS OF COMPOUNDS OF FORMULA (IIG)
Figure imgf000138_0001
General Reaction Schemes Reaction Scheme B1
Figure imgf000138_0002
Reaction Scheme B2
Figure imgf000139_0002
Reaction Scheme B4
Figure imgf000139_0003
Reaction Scheme B6
Figure imgf000139_0001
Reaction Scheme B7
Figure imgf000140_0001
Synthesis of (2E)-2-(2-phenylhvdrazin-l-ylidene)acetic acid (Intermediate Bl)
Figure imgf000140_0003
(Intermediate Bl)
Glyoxylic acid hydrate (0.94 g, 10.17 mmol) was added to a solution of phenyl hydrazine (1 g, 9.25 mmol) in water (30 mL). An aq solution of HC1 (12 M, 1.15 mL) was added and the mixture stirred at room temperature. A precipitate rapidly formed. After 1 hour the solid material was collected by filtration, washed with water and dried in vacuo to yield the title compound as a pale brown solid (1.45 g, 86% yield). 1H NMR
(500 MHz, DM SO) d 12.24 (s, 1H), 11.12 (s, 1H), 7.30 - 7.25 (m, 2H), 7.14 - 7.10 (m,
3H), 6.93 - 6.87 (m, 1H). LCMS (Analytical Method D) Rt= 0.71 min, MS (ESIpos): m/z= 164.8 [M+H]+, Purity = 93%.
Synthesis of l-phenyl-4.5-dihvdro-lH-E2.4-triazol-5-one
(Intermediate B2)
Figure imgf000140_0002
(Intermediate B2)
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 mΐ, 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). 1HNMR (250 MHz, DMSO) d 11.95 (s, 1H), 8.10 (s, 1H), 7.94 - 7.85 (m, 2H), 7.48 - 7.39 (m, 2H), 7.25 - 7.16 (m, 1H). LCMS (Analytical Method D) Rt= 0.81 min, MS (ESIpos): m/z= 162.0 [M+H]+, Purity = 100%.
Synthesis of (2E)-2-r2-(4-fluorophenv0hvdrazin-l-ylidenelacetic acid
(Intermediate B3)
Figure imgf000141_0001
(Intermediate B3)
Glyoxylic acid hydrate (0.4 g, 4.36 mmol) was added to a suspension of (4- fluorophenyl)hydrazine (0.5 g, 3.96 mmol) and 12 M hydrochloric acid (0.5 ml) in water (15 mL). The reaction was stirred at room temperature. A thick precipitate rapidly formed and additional water (5 mL) was added. After 1 hour the solid material was collected by filtration, washed with water and dried in vacuo to yield the title compound (623 mg, 78% yield). 1HNMR (500 MHz, DMSO) d 12.24 (s, 1H), 11.14 (s, 1H), 7.13 - 7.09 (m,
5H). LCMS (Analytical Method D) Rt= 0.96 min, MS (ESIpos): m/z= 182.9 [M+H]+, Purity = 100%.
Synthesis of 1 -(4-fluorophenyl )-4.5-dihydro- l H- l .2.4-triazol-5-one
(Intermediate B4)
Figure imgf000141_0002
(Intermediate B4)
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. The solid material was collected by filtration, washed with 2 M aq HC1 and dried in vacuo to yield the title compound (290 mg, 47% yield). 1H NMR (500 MHz, DMSO) d 11.97 (s, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.32 - 7.26 (m, 2H). LCMS (Analytical Method D) Rt= 0.85 min, MS (ESIpos): m/z= 179.9 [M+H]+, Purity = 84%.
Synthesis of (2E)-2-r2-(4-fluorophenvDhvdrazin-l-ylidenelpropanoic acid
(Intermediate B5)
Figure imgf000142_0001
(Intermediate B5)
12 M Hydrochloric acid (0.77 mL) was added to a suspension of 4-
(fluoropheny)hydrazine HC1 (1 g, 6.15 mmol) and pyruvic acid (0.6 g, 6.77 mmol) in water (18 mL). The reaction was stirred for 10 minutes. A thick precipitate was formed. Additional portion of water (5 mL) was added and stirring continued for 1 hour. The solid material was collected by filtration, washed with water and dried in vacuo to yield the title compound (823 mg, 68% yield).1H NMR (250 MHz, DMSO) d 9.76 (s, 1H), 7.39 - 7.30 (m, 2H), 7.10 (t, J = 8.9 Hz, 2H), 2.02 (s, 3H). LCMS (Analytical Method D) Rt= 0.96 min, MS (ESIpos): m/z= 197.9 [M+H]+, Purity = 59%.
Synthesis of 1 -(4-fluorophenyl )-3-methyl-4.5-dihydro- l H- l .2.4-triazol-5-one
(Intermediate B6)
Figure imgf000143_0001
(Intermediate B6)
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). 1HNMR (250 MHz, DMSO) d 7.93 - 7.82 (m, 2H), 7.31 - 7.19 (m, 2H), 2.17 (s, 3H). LCMS (Analytical MethodD) Rt= 0.92 min, MS (ESIpos): m/z= 193.9 [M+H]+, Purity = 100%.
Synthesis of tert-butyl 2-1 1 -(4-fluorophcnyl)-5-o\o-4.5-dihvdro- 1 H- 1.2.4-triazol-4-yl I acetate
(Intermediate B7)
Figure imgf000143_0002
(Intermediate B7) l-(4-fluorophenyl)-4,5-dihydro-lH-l,2,4-triazol-5-one (Intermediate B4) (160 mg, 0.89 mmol) and potassium carbonate (185 mg, T34 mmol) were suspended in acetonitrile (3 mL), then tert-butyl 2-bromoacetate (145 pL, 0.98 mmol) was added. The mixture was stirred at 60°C for 2 hr. The reaction was cooled to room temperature and diluted with water, then extracted with EtOAc. The organic phase was concentrated in vacuo and the crude product was purified via Biotage Isolera™ chromatography (silica gel, eluting with 0-100% EtOAc in heptane) to afford the title compound (236 mg, 90% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) d 8.23 (s, 1H), 7.93 - 7.88 (m, 2H), 7.35 - 7.29 (m, 2H), 4.48 (s, 2H), 1.44 (s, 9H). LCMS (Analytical Method D) Rt= 1.13 min, MS (ESIpos): m/z= 238.0 [M+H]+, Purity = 100%.
Synthesis of (2-ri-(4-fluorophenvD-5-oxo-4.5-dihvdrc>-lH-1.2.4-triazol-4-yl1acetic acid (Intermediate B8)
Figure imgf000144_0001
(Intermediate B8)
To a solution of tert-butyl2-[l-(4-fluorophenyl)-5-oxo-4, 5-dihydro- 1H- 1,2,4- triazol-4-yl]acetate (Intermediate B7) (220 mg, 0.75 mmol) in DCM (1.5 ml) was added trifluoroacetic acid (1 mL, 13.07 mmol). The reaction mixture was stirred at room temperature for 18 hr. The reaction was concentrated in vacuo to afford the title compound (119 mg, 66% yield). 1H NMR (500 MHz, DMSO-d6) d 13.36 (s, 1H), 8.23 (s, 1H), 7.94 - 7.87 (m, 2H), 7.35 - 7.28 (m, 2H), 4.49 (s, 2H). LCMS (Analytical Method D) Rt= 0.84 min, MS (ESIpos): m/z= 237.9 [M+H]+, Purity = 99%.
Synthesis of ethyl N-GP E )-cvcl opropyl (ethoxy imethylidenelcarbam ate
(Intermediate B9)
Figure imgf000144_0002
(Intermediate B9)
Ethyl chloroformate (64 pL, 0.67 mmol) was added dropwise to an ice cold solution of ethyl cyclopropanecarboximidate hydrochloride (100 mg, 0.67 mmol) and diisopropylethylamine (298 pL, 1.67 mmol) in dichloromethane (3 mL). The reaction was stirred for 18 hours then concentrated in vacuo. The residue was suspended in diethyl ether, the solid material removed by filtration and the filtrate concentrated in vacuo to yield the title compound as a colourless oil (110 mg, 89% yield). 1H NMR (250 MHz, Chloroform-d) d 4.24 (q, J = 7.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 1.82 (tt, J = 8.1, 4.8 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.11 - 1.03 (m, 2H), 0.95 - 0.79 (m, 2H). LCMS (Analytical Method D) Rt= 1.08 min, MS (ESIpos): m/z= 186.0 [M+H]+, Purity = 100%.
Synthesis of 3-cvclopropyl-l-(4-fluorophenvD-4.5-dihvdro-lH-E2.4-triazol-5-one
(Intermediate BIO)
Figure imgf000145_0001
A mixture of ethyl N-[(lE)-cyclopropyl(ethoxy)methylidene]carbamate
(Intermediate B9) (110 mg, 0.59 mmol), (4-fluorophenyl)hydrazine HC1 (97 mg, 0.59 mmol) and triethylamine (99 pL, 0.71 mmol) in toluene (3 mL) was heated to 50°C for 1 hour. Additional triethylamine (99 pL, 0.71 mmol) was added and the reaction heated to 90°C for 18 hours. The reaction was cooled and quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCE and concentrated in vacuo. The residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 15-80% ethyl acetate/heptane) to yield the title compound as a white solid (75 mg, 58% yield). 1H NMR (500 MHz, DMSO-d6) d 11.78 (s, 1H), 7.86 (dd, J = 9.2, 4.9 Hz, 2H), 7.25 (t, J = 8.9 Hz, 2H), 1.85 (tt, J = 8.4, 5.1 Hz, 1H), 1.00 - 0.95 (m, 2H), 0.92 - 0.88 (m, 2H). LCMS (Analytical Method D) Rt=
1.00 min, MS (ESIpos): m/z= 219.9 [M+H]+, Purity = 100%.
Synthesis of ethyl N-G(1Z)-1 -ethoxyethylidenelcarbamate (Intermediate Bl l)
Figure imgf000146_0002
(Intermediate Bll)
To a stirred mixture of ethyl ethanecarboximidate hydrochloride (250 mg, 2.02 mmol) and DIPEA (875 pL, 5.01 mmol) in DCM (3 mL) at 0°C was added chloro(ethoxy)methanone (200 pL, 2.1 mmol). The mixture was stirred for 8 hr then concentrated in vacuo. The crude product was triturated with diethyl ether. The white solid produced was filtered off and the filtrate was concentrated in vacuo to give the title compound (240 mg, 71% yield). 1H NMR (500 MHz, DMSO-d6) d 4.1 (q, 2H), 4.1 (q, 2H), 2.0 (s, 3H), 1.2 - 1.2 (m, 6H). LCMS (Analytical Method D) Rt= 1.09 min, MS (ESIpos): m/z= 160.0 [M+H]+, Purity = 87%.
Synthesis of l-cvclopropyl-3-methyl-4.5-dihydro-lH-E2.4-triazol-5-one
(Intermediate B 12)
Figure imgf000146_0001
(Intermediate B 12)
To a solution of ethyl N-[(lZ)-l-ethoxyethylidene]carbamate (Intermediate B11) (230 mg, 1.44 mmol) in toluene (4 mL) was added DIPEA (550 pL, 3.15 mmol), then cyclopropylhydrazine dihydrochloride (210 mg, 1.45 mmol). The mixture was stirred at 100 °C for 18 hr. The reaction mixture was concentrated in vacuo and purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-10% MeOH in DCM) followed by re-purification by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% MeOH in TBME) afforded the title compound (216 mg, 86% yield). 1H NMR (500 MHz, DMSO-d6) d 3.1 - 3.1 (m, 1H), 1.4 - 1.2 (m, 7H). LCMS (Analytical Method D) Rt= 0.35 min, MS (ESIpos): m/z= 140.0 [M+H]+.
Synthesis of N-GP S 1 -(4-chloro-3 -fluorophenyl)ethvn-2-(5-oxo-4.5-dihydro- 1H- 1.2.4- triazol-4-vDacetamide (Intermediate B13)
Figure imgf000147_0001
(Intermediate B13)
A mixture of 2,4-dihydro-3H-l,2,4-triazol-3-one (50 mg, 0.588 mmol), 2-bromo- N-[(lS)-l-(4-chloro-3-fluoro-phenyl)ethyl]acetamide (180 mg, 0.611 mmol) and potassium carbonate (120 mg, 0.868 mmol) in DMSO (2 mL) was stirred at 70°C for 16 hr. The reaction was cooled to room temperature and diluted with water, resulting in formation of a precipitate. The precipitate was filtered off and was purified by preparative HPLC, Method B1 to afford N-[(lS)-l-(4-chloro-3-fluorophenyl)ethyl]-2-[l-({[(lS)-l- (4-chloro-3-fluorophenyl)ethyl]carbamoyl}methyl)-5-oxo-4, 5-dihydro- 1H- 1,2, 4-triazol- 4-yl]acetamide (8 mg, 3% yield) as a white solid. The resultant filtrate was purified by preparative HPLC, MethodBl to afford N-[(lS)-l-(4-chloro-3-fluorophenyl)ethyl]-2-(5- oxo-4,5-dihydro-lH-l,2,4-triazol-4-yl)acetamide (Intermediate B 13) (43 mg, 22% yield) as a white solid. 1HNMR(500 MHz, DMSO-d6) d 11.6 (s, 1H), 8.7 (d,J = 7.6 Hz, 1H), 7.8 (s, 1H), 7.5 (t, J = 8.1 Hz, 1H), 7.4 (dd,J = 10.7, 1.9 Hz, 1H), 7.2 (dd,J = 8.3, 1.9 Hz, 1H), 4.9 - 4.9 (m, 1H, HI 5), 4.3 - 4.2 (m, 2H), 1.4 (d,J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 0.92 min, MS (ESIpos): m/z= 289.9, 300.9 [M+H]+, Purity = 91%.
Synthesis of 2-bromo-N-r -l-r4-(trifluoromethoxy)phenyllethyllacetamide
Figure imgf000147_0002
(Intermediate B 14)
Figure imgf000148_0001
Bromoacetyl chloride (106 pL, 1.28 mmol) was added slowly to an ice cold solution of (lS)-l-[4-(trifluoromethoxy)phenyl]ethylamine (250 mg, 1.22 mmol) and triethylamine (355 pL, 2.56 mmol) in tetrahydrofuran (10 mL). The reaction was stirred for 90 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-75% ethyl acetate/heptane to yield the title compound as a cream solid (204 mg, 51% yield). ¾ NMR (500 MHz, CDCb) d 7.35 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.65 (s, 1H), 5.11 (p, J = 7.1 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.87 (d, J
= 13.9 Hz, 1H), 1.53 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 326.0, 327.9 [M+H]+.
Synthesis of 2-bromo-N-rO S)-l-(4-chloro-3-fluorophenvDethyllacetamide (Intermediate B 15)
Figure imgf000148_0002
A solution of bromoacetyl chloride (166 pL, 2 mmol) in tetrahydrofuran (5 mL) was added slowly to an ice cold suspension of (lS)-l-(4-chloro-3- fluorophenyl)ethylamine HC1 (400 mg, 1.9 mmol) and triethylamine (556 pL, 4 mmol) in tetrahydrofuran (15 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-75% tertbutylmethylether/heptane to yield the title compound as a white solid (490 mg, 75% yield). ¾ NMR (500 MHz, CDCb) d 7.37 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 2.0, 9.9 Hz, 1H), 7.05 (dd, J = 2.0, 8.3 Hz, 1H), 6.69 - 6.59 (m, 1H), 5.05 (p, J = 7.2 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 1.51 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.10 min, MS (ESIpos): m/z 293.9, 295.9, 297.8 [M+H]+.
Synthesis of 2-bromo-N-r(lS)-l-(4-methylphenyl)ethyllacetamide
(Intermediate B 16)
Figure imgf000149_0001
(Intermediate B 16)
A solution of (S)-l-(4-methylphenyl)ethylamine (2.72 mL, 18.49 mmol) and triethylamine (3.86 mL, 27.73 mmol) in tetrahydrofuran (50 mL) was added slowly to an ice cold solution of bromoacetyl chloride (1.62 mL, 19.41 mmol) in tetrahydrofuran (100 mL). The reaction was stirred for 2 hours then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was triturated with diethyl ether. The solid material was collected by filtration, washed with diethyl ether and dried in vacuo to yield the title compound as a tan solid (3.56 g, 75% yield). ¾ NMR (250 MHz, CDCb) d 7.24 - 7.13 (m, 4H), 6.64 (s, 1H), 5.07 (p, J = 7.1 Hz, 1H), 3.95 - 3.81 (m, 2H), 2.34 (s, 3H), 1.52 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.03 min, MS (ESIpos): m/z 255.8, 257.8 [M+H]+.
Synthesis of 2-bromo-N-r(l S)-l-(3-fluoro-4-methylphenyl)ethyllacetamide
(Intermediate B 17)
Figure imgf000150_0001
(Intermediate B 17)
A solution of bromoacetyl chloride (150 pL, 1.80 mmol) in THF (3 mL) was added dropwise to an ice cold solution of (lS)-l-(3-fluoro-4-methylphenyl)ethanamine (250 mg, 1.63 mmol) and triethylamine (0.57 mL, 1.1 mmol) in THF (12 mL) over 10 mins. The reaction was stirred for 2 hours then quenched with water and extracted into ethyl acetate three times. The combined organics were washed with brine, dried over Na2SC>4 and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0%-70% EtOAc/heptane to yield the title compound as a pale orange solid (280 mg, 63% yield). ¾ NMR (500 MHz, Chloroform-d) d 7.16 (t, J = 7.8 Hz, 1H), 7.03 - 6.89 (m, 2H), 6.63 (s, 1H), 5.05 (p, J = 7.1 Hz, 1H), 3.95 - 3.80 (m, 2H), 2.25 (d, J = 1.5 Hz, 3H), 1.51 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.07 min, MS (ESIpos): m/z 273.75, 275.75 [M+H]+.
Synthesis of 2-bromo-N-r(l S)- l -(3.4-difluorophenyl iethyllacetamide
(Intermediate B 18)
Figure imgf000150_0002
(Intermediate B 18)
A solution mixture of (lS)-l-(3,4-difluorophenyl)ethan-l-amine (250 mg, 1.59 mmol) in THF (5 mL) and triethylamine (675 pL, 4.85 mmol) was cooled to 0°C. Bromoacetyl chloride (150 pL, 1.8 mmol) was added slowly. The mixture was stirred at this temperature for 1 hr. The reaction was quenched with water and extracted with EtOAc three times. The organic phases were combined and concentrated in vacuo. The crude product was purified by flash chromatography (silica, gradient of 0-100% TBME in heptane) to afford the title compound as an off-white solid (370 mg, 84% yield). 1H NMR (500 MHz, DMSO-d6) d 8.75 (d, J = 7.6 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.19 - 7.11 (m, 1H), 4.92 - 4.83 (m, 1H), 3.91 - 3.83 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.02 min, MS (ESIpos): m/z 277.9, 279.9 [M+H]+.
Synthesis of 6-Chloro-5-fluoropyridine-3-carbaldehvde
(Intermediate B 19)
Figure imgf000151_0001
(Intermediate B 19)
A solution of 5-bromo-2-chloro-3-fluoropyridine (10 g, 47.5 mmol) in diethyl ether (150 mL) was cooled in a dry ice/acetone bath. 2.5M Butyllithium in hexane (26.6 mL) was added over 20 minutes and the reaction stirred for 30 minutes. N,N- Dimethylformamide (18.4 mL, 237.6 mmol) was added over 10 minutes and stirring continued for 30 minutes. The reaction was quenched by addition of water and warmed to room temperature. The mixture was partitioned between ethyl acetate and water and the aqueous layer extracted into ethyl acetate three times. The combined organics were washed with brine, dried over MgSCri and concentrated in vacuo. The residue was crystallised from ethyl acetate/heptane (1:10) to give a portion of the title compound as an orange solid (120 mg). The filtrate was purified by chromatography (100 g, silica), eluting with 0-40% ethyl acetate/heptane to give a yellow solid (3.34 g, 36% yield). 1H NMR (250 MHz, CDC13) d 10.11 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 1.8 Hz, 1H), 7.92 (dd, J = 1.9, 7.6 Hz, 1H). LCMS (Analytical Method D) Rt= 0.88 min, MS (ESIpos): m/z 177.9, 180.1 [hydrate M+H]+; Purity= 92%.
Synthesis of 5-Fluoro-6-methylpyridine-3-carbaldehvde
(Intermediate B20)
Figure imgf000152_0001
(Intermediate B20)
A mixture of 6-chloro-5-fluoropyridine-3-carbaldehyde (Intermediate B19) (3.3 g, 17.0 mmol), 3.5M trimethylboroxine in THF (2.91 ml), potassium carbonate (4.69 g, 33.9 mmol) and Pd(PPh3)4 (0.98 g, 0.85 mmol) in 1,4-dioxane (30 mL) was degassed by sparging with nitrogen. The mixture was heated to 80°C for 24 hours then cooled and filtered through a short pad of celite. The filtrate was concentrated in vacuo to yield a residue. The residue was purified by chromatography (100 g, silica), eluting with 0-40% ethyl acetate/heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound (640 mg, 27% yield). 1H NMR (250 MHz, CDC13) d 10.08 (d, J = 2.3 Hz, 1H), 8.77 (s, 1H), 7.77 (dd, J = 1.7, 8.9 Hz, 1H), 2.64 (d, J = 3.0 Hz, 3H). LCMS (Analytical Method D) Rt= 0.80 min, MS (ESIpos): m/z 139.9 [M+H]+; Purity= 100%.
Synthesis of (R)-N-r(lE)-(5-fluoro-6-methylpyridin-3-vOmethylidenel- 2-methylpropane-2-sulfmamide (Intermediate B21)
Figure imgf000152_0002
(Intermediate B21)
To a solution of 5-fluoro-6-methylpyridine-3-carbaldehyde (Intermediate B20) (889 mg, 6.39 mmol) in dichloromethane (60 mL) was added R-tertButylsulfinamide (852 mg, 7.03 mmol) followed by titanium tetraethoxide (3.15 mL, 12.8 mmol). The reaction was stirred for 24 hours then saturated NaHCCb (aq, 30 mL) was added. The mixture was stirred vigorously for 1 hour then filtered through a pad of celite. The filtrate was extracted into dichloromethane three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo to yield the title compound as a yellow oil (1.38 g, 89% yield). lHNMR (250 MHz, CDC13) d 8.66 (s, 1H), 8.62 (d, J = 1.8 Hz, 1H), 7.81 (dd, J = 1.6, 9.5 Hz, 1H), 2.60 (d, J = 3.0 Hz, 3H), 1.26 (s, 9H). LCMS (Analytical Method D) Rt= 1.08 min, MS (ESIpos): m/z 243.0 [M+H]+; Purity= 94%.
Synthesis of (RVN-IYl SVl-(5-fluoro-6-methylpyridin-3-vDethyll- 2-methylpropane-2-sulfmamide (Intermediate B22)
Figure imgf000153_0001
(Intermediate B22)
3M Methyl magnesium bromide in ether (2.84 ml) was added slowly to a solution cooled (-60°C) of (R)-N-[(lE)-(5-fluoro-6-methylpyridin-3-yl)methylidene]-2- methylpropane-2-sulfmamide (1.38 g, 5.68 mmol) in tetrahydrofuran (40 mL). The reaction was warmed to -40°C and stirred for 5 hours. The reaction was quenched by slow addition of water and warmed to room temperature. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCE and concentrated in vacuo to give a residue. The residue was triturated with toluene, the solid material collected by filtration and dried in vacuo to yield the title compound as a white solid (460 mg, 31% yield). 1H NMR (500 MHz, Chloroform-d) d 8.28 (s, 1H), 7.29 (dd, J = 10.1, 1.8 Hz, 1H), 4.61 (qd, J = 6.7, 3.3 Hz, 1H), 3.33 (d, J = 2.7 Hz, 1H), 2.52 (d, J = 2.9 Hz, 3H), 1.55 (d, J = 6.7 Hz, 3H), 1.21 (s, 9H). LCMS (Analytical Method D) Rt= 0.93 min, MS (ESIpos): m/z 259.0 [M+H]+Purity= 94%.
Synthesis of -l-(5-fluoro-6-methylpyridin-3-vDethan-l-amine dihydrochloride
Figure imgf000153_0002
(Intermediate B23) HCI HCI
Figure imgf000154_0001
(Intermediate B23)
4M HC1 in dioxane (2.67 mL) was added to a solution of (R)-N-[(l S)-l-(5-fluoro- 6-methylpyridin-3-yl)ethyl]-2-methylpropane-2-sulfmamide (460 mg, 1.78 mmol). A thick white precipitate rapidly formed. The reaction was stirred for 45 minutes. The mixture was concentrated in vacuo to yield the title compound as a colourless oil (404 mg, quantitative yield).
Synthesis of N-r(lS)-l-(1.3-benzodioxol-5-vnethyl1-2-chloro-acetamide
(Intermediate B24)
Figure imgf000154_0002
(Intermediate B24)
A suspension of (lS)-l-(l,3-benzodioxol-5-yl)ethanamine hydrochloride (225 mg, 1.12 mmol) and triethylamine (0.390 mL, 2.51 mmol) in THF (2.5 mL) was added slowly to an ice cold solution of 2-chloroacetyl chloride (0.085 mL, 1.42 mmol) in THF (2.5 mL) . The reaction was stirred for 2 hours then the reaction was quenched with water (10 mL) and extracted into EtOAc (3 x 25 mL). The combined organics were dried over MgSCri and concentrated in vacuo. The residue was purified by chromatography, silica gel, eluting with 0-10% methanol/dichloromethane. The relevant fractions were combined and concentrated to yield the title compound as a pale brown solid (198 mg, 73% yield). 1HNMR (500 MHz, DMSO-d6) d 8.55 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 1.7 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.77 (dd, J = 8.1, 1.5 Hz, 1H), 5.97 (s, 2H), 4.83 (p, J = 7.1 Hz, 1H), 4.07 - 4.02 (m, 2H), 1.33 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method E) Rt= 0.46 min, MS (ESIpos): m/z 241.9, 243.9 [M+H]+.
EXAMPLE B2-1
Synthesis of 2-(5-oxo- 1 -phenyl-4 5-dihydro- 1H- 1.2.4-triazol-4-vD-N-r (1 SV 1 -G4-
(trifluoromethoxy)phenyl 1 ethyl 1 acetami de
(Compound B2-1)
Figure imgf000155_0001
A mixture of phenyl-4, 5-dihydro-lH-l, 2, 4-triazol-5-one (30 mg, 0.19 mmol), 2- brorno-N-[(lS)-l-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (Intermediate B14) (61 mg, 0.19 mmol) and potassium carbonate (77.18 mg, 0.56 mmol) in acetonitrile (2 mL) was heated to 80°C for 1 hour. The reaction was cooled and quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCE and concentrated in vacuo. The residue was purified by preparative HPLC, Method B2 to yield the title compound (49 mg, 65% yield). 1H NMR (500 MHz, DM SO) d 8.80 (d, J = 7.7 Hz, 1H), 8.17 (s, 1H), 7.89 (dd, J = 1.1, 8.7 Hz, 2H), 7.49 - 7.43 (m, 4H), 7.33 (d, J = 8.0 Hz, 2H), 7.26 - 7.21 (m, 1H), 4.97 (p, J = 7.0 Hz, 1H), 4.47 - 4.38 (m, 2H), 1.39 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt= 3.38 min, MS (ESIpos): m/z= 407 [M+H]+, Purity = 99%.
EXAMPLES B2-2 THROUGH B2-13 Synthesis of Compounds B2-2 through Compound B2-13 Each of Compounds B2-2 through B2-13 as listed in Table 4 were prepared according to the method of Example B2-1, using the intermediates listed in the “Synthesis” column for such compounds. The final compounds were purified by preparative HPLC Methods, Al, A2, B1 or B2; or flash chromatography; or precipitation from specified solvent.
Table 4 Representative Compounds of Formula (III)
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0002
EXAMPLE B3
Synthesis of 2-ri-(4-fluorophenvn-5-oxo-4.5-dihvdro-lH-E2.4-triazol-4-yl1-N- GP S)-l-(4-methylphenvDethvnacetamide (Compound B3)
Figure imgf000160_0001
(Compound B3)
Potassium carbonate (58 mg, 0.42 mmol) was added to a solution of l-(4- fluorophenyl)-4,5-dihydro-lH-l,2,4-triazol-5-one (Intermediate B4) (25 mg, 0.14 mmol) and 2-bromo-N-[(lS)-l-(4-methylphenyl)ethyl]acetamide (Intermediate B16) (36 mg, 0.14 mmol) in DMF (1 ml). The reaction was heated at 60 °C for 1 hr. The reaction was allowed to cool to room temperature. Water (5 ml) was added and the suspension was sonicated and filtered. The resulting solid was triturated in MeOH/water affording the title compound as a white solid (29 mg, 59% yield). 1H NMR (500 MHz, DMSO-d6) d 8.68 (d, J = 7.9 Hz, 1H), 8.17 (s, 1H), 7.95 - 7.82 (m, 2H), 7.34 - 7.27 (m, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 4.89 (p, J = 7.0 Hz, 1H), 4.40 (s, 1H), 4.39 (s, 1H), 2.27 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt= 3.75 min, MS (ESIpos): m/z= 355 [M+H]+, Purity = 100%.
EXAMPLE B4
Synthesi s ofN- -(5 -fluoro-6-methylpyridin-3 -vOethyll -2- G 1 -(4-fluorophenvO-5 -
Figure imgf000161_0001
oxo-4.5-dihydro-l H-l triazol-4-yllacetamide
Figure imgf000161_0002
(Compound B4)
Figure imgf000161_0003
(Compound B4)
A mixture of 2-[l-(4-fluorophenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-4- yljacetic acid (Intermediate B8) (40 mg, 0.17 mmol), HATU (80 mg, 0.21 mmol) and DIPEA (90 mΐ, 0.52 mmol) in DMF (1 ml) was stirred at room temperature for 20 min, then (lS)-l-(5-fluoro-6-methylpyridin-3-yl)ethan-l-amine (35 mg, 0.19 mmol) was added. The mixture was stirred for 1 hr. The reaction mixture was purified directly via preparative HPLC, Method B1 to give the title compound (6 mg, 9% yield) as an off- white solid. 1H NMR (500 MHz, DMSO-d6) d 8.80 (d, J = 7.5 Hz, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.93 - 7.86 (m, 2H), 7.57 (dd, J = 10.8, 1.7 Hz, 1H), 7.34 - 7.28 (m, 2H), 4.97 (p, J = 7.1 Hz, 1H), 4.44 - 4.41 (m, 2H), 2.41 (d, J = 2.9 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt= 2.28 min, MS (ESIpos): m/z= 374 [M+H]+, Purity = 94%. EXAMPLE B5
Synthesis of N-r(lS)-l-(4-chloro-3-fhiorophenvDethvH-2-ri-(cvclopropylmethvD-5- oxo-4.5-dihydro- l H-l .2.4-triazol-4-yllacetamide
(Compound B5)
Figure imgf000162_0001
(Compound B5)
To a stirred mixture of N-[(lS)-l-(4-chloro-3-fluorophenyl)ethyl]-2-(5-oxo-4,5- dihydro-lH-l,2,4-triazol-4-yl)acetamide (Intermediate B13) (35 mg, 0.117 mmol) and potassium carbonate (25 mg, 0.181 mmol) in acetonitrile (1 ml) was added bromomethylcyclopropane (14 pL, 0.144 mmol). The mixture was stirred at 60°C for 4 hr. The reaction was retreated with bromomethylcyclopropane (14 pL, 0.144 mmol) and stirred at 70°C for 7 hr. The reaction was cooled to room temperature and diluted with water, then extracted with EtOAc. The organics were concentrated in vacuo and the crude product was purified by preparative HPLC, Method B1 to afford the title compound (16 mg, 39% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) d 8.7 (d, J = 7.6 Hz, 1H), 7.8 (s, 1H), 7.5 (dd, J = 8.1 Hz, 1H), 7.4 (dd, J = 10.6, 2.0 Hz, 1H), 7.2 (dd, J = 8.3, 1.9 Hz, 1H), 4.9 (p, J = 7.2 Hz, 1H), 4.3 - 4.3 (m, 2H), 3.5 (d, J = 6.9 Hz, 2H), 1.4 (d, J = 7.0 Hz, 3H), 1.1 - 1.0 (m, 1H), 0.5 - 0.4 (m, 2H), 0.3 - 0.2 (m, 2H). LCMS (Analytical Method C) Rt= 3.53 min, MS (ESIpos): m/z= 353.0, 355.0 [M+H]+, Purity = 100%.
EXAMPLE C
Figure imgf000162_0002
Figure imgf000163_0001
General Reaction Schemes
Reaction Scheme Cl
Figure imgf000163_0002
Reaction Scheme C3
Figure imgf000163_0003
Reaction Scheme C5
Figure imgf000164_0003
Reaction Scheme C7
Figure imgf000164_0001
Reaction Scheme C9
Figure imgf000164_0002
Synthesis of l-(4-fluorophenvO-4.5-dihvdro-lH-E2.3.4-tetrazol-5-one
(Intermediate Cl)
Figure imgf000165_0002
(Intermediate Cl)
A mixture of l-fluoro-4-isocyanatobenzene (400 pL, 3.52 mmol) and azidotrimethylsilane (930 pL, 7.07 mmol) was sealed under nitrogen and the mixture stirred at 90°C for 18 hr. The reaction was cooled to room temperature and the volatiles removed, affording the title compound (595 mg, 89% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) d 14.7 (s, 1H), 7.9 - 7.8 (m, 2H), 7.4 - 7.4 (m, 2H). LCMS
(Analytical Method D) Rt= 0.92 min, MS (ESIpos): m/z= (not detected), purity = 72%.
Synthesis of 1 -(4-chlorophenyl )-4.5-dihydro- l H- l 2.3.4-tetrazol-5-one
(Intermediate C2)
Figure imgf000165_0001
A mixture of 4-chlorophenylisocyanate (400 mg, 2.6 mmol) and azidotrimethylsilane (691 pL, 5.21 mmol) was heated to 95°C for 18 hours. The reaction was cooled and concentrated in vacuo. The residue was triturated with methanol and the solid material collected by filtration to yield the title compound as a white solid (400 mg, 78% yield). 1H NMR (250 MHz, DMSO-d6) d 14.79 (s, 1H), 7.90 (d, J = 8.9 Hz, 2H),
7.63 (d, J = 8.9 Hz, 2H).
Using procedure described for Intermediate C2, the following intermediates are prepared.
Figure imgf000166_0002
Synthesis of l-(2.2.2-trifluoroethvO-4.5-dihvdro-lH-E2.3.4-tetrazol-5-one
(Intermediate C3)
Figure imgf000166_0001
(Intermediate C3)
A mixture of l,l,l-trifluoro-2-isocyanatoethane (200 pL, 1.6 mmol) and azidotrimethylsilane (425 pL, 3.23 mmol) was sealed under nitrogen and the mixture stirred at 90°C for 18 hr. The mixture was cooled to room temperature and the volatiles removed to give the title compound (265 mg, 93% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) d 4.9 (q, J = 9.1 Hz, 2H). LCMS (Analytical Method D) Rt= 0.64 min, MS (ESIpos): m/z= (not detected), purity = 94%.
Using procedure described for Intermediate C3, the following intermediate is prepared.
Figure imgf000167_0005
Synthesis of 1 -(propan-2-yl )-4.5-dihydro- 1 H- l tetrazol-5-one
Figure imgf000167_0001
(Intermediate C4)
Figure imgf000167_0002
(Intermediate C4)
A mixture of 2-isocyanatopropane (230 pL, 2.34 mmol) and azidotrimethylsilane (770 pL, 5.85 mmol) was stirred at 90°C for 18 hr. The mixture was cooled to room temperature and volatiles removed to give the title compound (87 mg, 25% yield) as an off-white solid. 1H NMR (250 MHz, DMSO-d6) d 4.4 - 4.3 (m, 1H), 1.4 (d, J = 6.7 Hz, 6H). LCMS (Analytical Method D) Rt= 0.69 min, MS (ESIpos): m/z= 128.9 [M+H]+, purity = 34%.
Synthesis of 1 -(2-methylpropyl )-4.5-dihydro- l H- l tetrazol-5-one
Figure imgf000167_0003
(Intermediate C5)
Figure imgf000167_0004
(Intermediate C5)
3-Methylbutanoyl chloride (250 pL, 2.02 mmol) was added to ice cold azido(trimethyl)silane (1.6 mL, 12.1 mmol). The reaction was stirred for 45 minutes then heated to 60°C for 1 hour. The reaction was heated to 90°C for 18 hours then concentrated in vacuo. The residue was purified by preparative HPLC, Method B2 to afford the title compound (18 mg, 6% yield). 1H NMR (500 MHz, DMSO-d6) d 3.67 (d, J = 7.1 Hz, 2H), 2.06 (dq, J = 13.6, 6.8 Hz, 1H), 0.88 (d, J = 6.7 Hz, 6H). LCMS (Analytical Method D) Rt= 0.83 min, MS (ESIpos): m/z=143.0 [M+H]+, purity = 100%.
Synthesis of l-(3.3-difluorocvclobutyr)-4.5-dihvdro-lH-E2.3.4-tetrazol-5-one
(Intermediate C6)
Figure imgf000168_0001
3,3-Difluorocyclobutanecarbonyl chloride (100 mg, 0.647 mmol) was added to ice cold azido(trimethyl)silane (0.51 mL, 3.88 mmol). The reaction was stirred for 45 minutes then heated to 60°C for 1 hour. The reaction was heated to 90°C for 18 hours then concentrated in vacuo to yield the title compound (104 mg, 91% yield). 1H NMR (500 MHz, DMSO-d6) d 4.72 - 4.64 (m, 1H), 3.19 - 3.12 (m, 4H). LCMS (Analytical Method D) Rt= 0.76 min, MS (ESIneg): m/z=174.8 [M-H]-, purity = 74%.
Using procedure described for Intermediate C6, the following intermediates are prepared.
Figure imgf000168_0002
Figure imgf000169_0003
Synthesis of 1 -(cvclopropylmethyl )-4.5-dihydro- l H- l tetrazol-5-one
Figure imgf000169_0001
(Intermediate C7)
Figure imgf000169_0002
(IntermediateCl)
A mixture of (isocyanatomethyl)cyclopropane (200 mΐ, 2.06 mmol) and azidotrimethylsilane (680 pL, 5.17 mmol) was stirred at 90°C for 18 hr. The mixture was cooled to room temperature and the volatiles removed to afford the crude title compound. The product was used in the next step without purification.
Synthesis of 1 -GG1 -tert-butyl-1 H- l 2.3.4-tetrazol-5-yl )sulfanyllpropan-2-ol
(Intermediate C8)
Figure imgf000170_0001
(Intermediate C8)
2-Methyloxirane (40 pL, 0.569 mmol) was added to an ice cold suspension of 4- tert-butyl-lH-tetrazole-5-thione (75 mg, 0.474 mmol) and sodium hydroxide (23 mg, 0.569 mmol) in ethanol (1 mL) and water (0.1 mL). The reaction was stirred for 4 hours then quenched into water and acidified with HC1 (aq). The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine/HCl, dried over MgS04 and concentrated in vacuo. The residue was purified by preparative HPLC, Method B2 to give the title compound as a colourless oil (70 mg, 68% yield). 1H NMR (500 MHz, DMSO-d6) d 5.10 (d, J = 5.0 Hz, 1H), 3.96 (hept, J = 6.2 Hz, 1H), 3.44 (dd, J = 12.9, 4.8 Hz, 1H), 3.35 (dd, J = 12.9, 7.0 Hz, 1H), 1.68 (s, 9H), 1.18 (d, J = 6.2 Hz, 3H). LCMS (Analytical Method D) Rt= 0.89 min, MS (ESIpos): m/z= 236.8 [M+H]+, purity = 87%.
Synthesis of 1 -tert-butyl-4.5-dihydro- l H- l 2.3.4-tetrazol-5-one
(Intermediate C9)
Figure imgf000170_0002
(Intermediate C9)
Sodium hydroxide (111 mg, 0.971 mmol) was added to a solution of l-[(l-tert- butyl-lH-l,2,3,4-tetrazol-5-yl)sulfanyl]propan-2-ol (Intermediate C8) (70 mg, 0.324 mmol) and the reaction heated to 70°C for 1 hour. The reaction was cooled and diluted with water (2 mL). The solution was acidified with HC1 (aq) leading to a white precipitate forming. The suspension was filtered but all material passed through the sinter. The sinter was rinsed with methanol and water and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC, Method B 1 to give the title compound as a white solid (35 mg, 76% yield). 1H NMR (500 MHz, DMSO-d6) d 1.54 (s, 9H). LCMS (Analytical Method D) Rt= 0.82 min, MS (ESIpos): m/z= 143.0 [M+H]+, purity = 97%. Synthesis of methyl 2-r4-(4-fluorophenv0-5-oxo-4.5-dihydro-
1 H- l 2.3.4-tetrazol- l -yll acetate
(Intermediate CIO)
Figure imgf000171_0001
(Intermediate CIO)
A mixture of 4-fluorophenylisocyanate (166 mΐ, 1.46 mmol) and methyl 2- azidoacetate (168 mg, 1.46 mmol) in n-octane (1 mL) was heated to 125°C for 18 hours. The mixture was cooled and concentrated in vacuo. The residue was purified by flash chromatography (25 g, silica), eluting with 0-100% ethyl acetate/heptane to yield the title compound a white solid (24 mg, 7% yield). 1H NMR (250 MHz, Chloroform-d) d 7.99 - 7.90 (m, 2H), 7.22 - 7.14 (m, 2H), 4.82 (s, 2H), 3.84 (s, 3H). Using procedure described for Intermediate C6, the following intermediates are prepared.
Figure imgf000171_0002
Synthesis of 2-r4-(4-fluorophenv0-5-oxo-4.5-dihydro- 1 H- l .2.3.4-tetrazol- l -yllacetic acid (Intermediate Cl l)
Figure imgf000172_0002
(Intermediate Cl l) 2M aq lithium hydroxide (119 pL, 0.238 mmol) was added to a solution of methyl
2-[4-(4-fluorophenyl)-5-oxo-4,5-dihydro-lH-l,2,3,4-tetrazol-l-yl]acetate (30 mg, 0.119 mmol) (Intermediate CIO) in tetrahydrofuran (1 mL) and methanol (0.1 mL). The reaction was stirred for 2 hours then quenched into water. The aqueous layer was adjusted to pH 2 with HC1 (aq) and extracted into ethyl acetate three times. The combined organics were dried over MgS04 and concentrated in vacuo to yield the title compound (26 mg, 80% yield). 1H NMR (250 MHz, DMSO-d6) d 7.95 - 7.86 (m, 2H), 7.46 (t, J = 8.9 Hz, 2H), 4.92 (s, 2H). LCMS (Analytical Method D) Rt= 0.89 min, MS (ESIpos): m/z= 236.8 [M+H]+, purity = 87%.
Using procedure described for Intermediate C6, the following intermediate is prepared (in the R , S or racemic form as desired).
Figure imgf000172_0003
Synthesis of ethyl 2-(5-oxo-4.5-dihydro- l H- l tetrazol- l -yl iacetate
Figure imgf000172_0001
(Intermediate Cl 2)
Figure imgf000173_0002
(Intermediate Cl 2)
A mixture of ethyl 2-isocyanatoacetate (0.8 ml, 7.13 mmol) and azidotrimethylsilane (2 mL, 15.2 mmol) were split in 4 vials, and the mixture was heated at 90°C for 16 hr. The reaction mixtures were cooled to room temperature, combined and concentrated in vacuo. The residue was purified by flash chromatography (25 g, silica) eluting with 0-10% MeOH in DCM to afford the title compound (644 mg, 48% yield) as a white solid. 1HNMR (250 MHz, DMSO-d6) d 4.9 (s, 2H), 4.2 (q, J = 7.1 Hz, 2H), 1.2 (t, J = 7.1 Hz, 3H). LCMS (Analytical Method D) Rt= 0.61 min, MS (ESIpos): m/z= 173.0 [M+H]+, purity = 91%.
Synthesis of ethyl 2-(4-r(3.3-difluorocvclobutvOmethvn-5-oxo-4.5-dihydro-
1 H- l 2.3.4-tetrazol- l -yl i acetate
(Intermediate Cl 3)
Figure imgf000173_0001
To a mixture of 3-(bromomethyl)-l,l-difluoro-cyclobutane (100 mg, 0.541 mmol) and ethyl 2-(5-oxo-4,5-dihydro-lH-l,2,3,4-tetrazol-l-yl)acetate (Intermediate C12) (100 mg, 0.529 mmol) in acetonitrile (2 ml) was added potassium carbonate (110 mg, 0.796 mmol) and the mixture was sealed under nitrogen and stirred at 60°C for 18 hr. The reaction was cooled to room temperature and diluted with water, then extracted with EtOAc. The organics were concentrated in vacuo to afford the title compound (135 mg, 91% yield) as a yellow oil. 1H NMR (500 MHz, DMSO-d6) d 4.9 (s, 2H), 4.2 - 4.2 (m, 2H), 4.1 (d, J = 6.9 Hz, 2H), 2.8 - 2.6 (m, 3H), 2.5 - 2.4 (m, 2H), 1.2 - 1.2 (m, 3H). LCMS (Analytical Method D) Rt= 1.03 min, MS (ESIpos): m/z= 277.0 [M+H]+, purity = 98%.
Synthesis of 2-(4 difluorocvclobutvDmethyl1-5-oxo-4.5-dihvdrc>-
Figure imgf000174_0001
1 H- tetrazol- 1-yl i acetic acid
Figure imgf000174_0002
(Intermediate Cl 4)
Figure imgf000174_0003
Ethyl 2-{4-[(3,3-difluorocyclobutyl)methyl]-5-oxo-4,5-dihydro-lH-l,2,3,4- tetrazol-l-yl} acetate (Intermediate C13) (100 mg, 0.362 mmol) was dissolved in ethanol (1.5 mL) and 1 M aq lithium hydroxide (400 pL, 0.4 mmol) was added. The mixture was stirred at room temperature for 18 hr. The reaction was diluted with water and acidified to pH 1 with 1 M aq HC1, then extracted with DCM. The organics were concentrated in vacuo to afford the title compound (71 mg, 67% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) d 4.8 (s, 2H), 4.1 (d, J = 7.0 Hz, 2H), 2.7 - 2.7 (m, 2H), 2.6 - 2.5 (m, 1H), 2.5 - 2.4 (m, 2H). LCMS (Analytical Method D) Rt= 0.84 min, MS (ESIpos): m/z=
249.0 [M+H]+, purity = 85%.
Synthesis of ethyl 2-G4-G1 -cyclopropyl ethyl )-5-oxo-4.5-dihydro- 1 H- l 2.3.4-tetrazol- l -yll acetate
(Intermediate Cl 5)
Figure imgf000174_0004
(Intermediate Cl 5) Diisopropyl azodicarboxylate (114 uL, 0.582 mmol) was added to a solution of ethyl 2-(5-oxo-lH-tetrazol-4-yl)acetate (91%, 100 mg, 0.529 mmol), 1- cyclopropylethanol (52 uL, 0.529 mmol) and triphenylphosphine (153 mg, 0.582 mmol) in THF (5 mL). The reaction was stirred for 2 hours then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by chromatography (10 g, silica), eluting with 0-10% methanol/dichloromethane, followed by purification by preparative HPLC, Method B2 to yield the title compound as a colourless oil (40 mg, 32% yield). 1H NMR (500 MHz, Chloroform-d) d 4.72 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 3.60 (dq, J = 9.4, 6.9 Hz, 1H), 1.60 (d, J = 6.9 Hz, 3H), 1.39 - 1.32 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.71 - 0.65 (m, 1H), 0.55 - 0.49 (m, 1H), 0.45 - 0.38 (m, 1H), 0.38 - 0.32 (m, 1H). LCMS (Analytical Method D) Rt= 1.04 min, MS (ESIneg): m/z=241.0 [M+H]+, purity = 100%.
Synthesis of 2-r4-(l-cvclopropylethv0-5-oxo-4.5-dihvdro-
1 H-l tetrazol- l -yllacetic acid
Figure imgf000175_0001
(Intermediate Cl 6)
Figure imgf000175_0002
(Intermediate Cl 6)
2M aq lithium hydroxide (125 uL, 0.250 mmol) was added to a solution of ethyl 2-[4-(l-cyclopropylethyl)-5-oxo-4,5-dihydro-lH-l,2,3,4-tetrazol-l-yl]acetate (Intermediate C15) (40 mg, 0.17 mmol) in a mixture of THF (2 mL) and methanol (0.5 mL). The reaction was stirred for 5 hours then quenched by addition of 4 M hydrogen chloride (4M in dioxane) (83 pL, 0.33 mmol). The mixture was concentrated in vacuo to afforded the title compound (assume quantitative yield).
Synthesis of ethyl 2-r4-(cvclopropyl ethyl )-5-oxo-4.5-dihydro- 1 H- l 2.3.4-tetrazol- l -yll acetate (Intermediate Cl 7)
Figure imgf000176_0001
(Intermediate Cl 7)
To a mixture of ethyl 2-(5-oxo-4,5-dihydro-lH-l,2,3,4-tetrazol-l-yl)acetate (100 mg, 0.529 mmol) and potassium carbonate (110 mg, 0.796 mmol) in acetonitrile (2 ml), was added bromomethylcyclopropane (62 pL, 0.639 mmol) and the mixture was sealed under nitrogen and stirred at 60°C for 6 hr. The reaction was cooled to room temperature and diluted with water, then extracted with EtOAc. The organics were combined and concentrated in vacuo to afford the title compound (115 mg, 86% yield) as a yellow oil. 1HNMR (500 MHz, DMSO-d6) d 4.9 (s, 2H), 4.2 (q, J = 7.0 Hz, 2H), 3.8 (d, J = 7.2 Hz, 2H1.2 - 1.2 (m, 4H), 0.6 - 0.5 (m, 2H), 0.4 - 0.3 (m, 2H). LCMS (Analytical Method D)
Rt= 1.02 min, MS (ESIneg): m/z=227.0 [M+H]+, purity = 90%.
Synthesis of ethyl 2-r4-(cvclopropyl ethyl )-5-oxo-4.5-dihydro-
1 H-l 2.3.4-tetrazol-l -yll acetate (Intermediate Cl 8)
Figure imgf000176_0002
(Intermediate Cl 8)
1M Lithium hydroxide (400 pL, 0.4 mmol) was added to a solution of ethyl 2-[4- (cyclopropylmethyl)-5-oxo-tetrazol-l-yl]acetate (Intermediate C17) (90%, 82 mg, 0.326 mmol) in ethanol (2 ml). The mixture was stirred for 3 hrs then concentrated in vacuo. The residue was partitioned between DCM and water and acidified to pH 1 with 2M HC1. The organic phase was separated and the aqueous extracted with DCM. The organics were combined and concentrated in vacuo to afford the title compound as a yellow oil (58 mg, 90%). lHNMR (500 MHz, Chloroform-d) d 6.8 (s, 1H), 4.8 (s, 2H), 3.8 (d, J = 7.3 Hz, 2H), 1.3 (m, 1H), 0.6 - 0.6 (m, 2H), 0.4 (m, 2H). LCMS (Analytical Method D) Rt= 0.64 min, MS (ESIpos): m/z= 199.0 [M+H]+.
Synthesis of 2-bromo-N- -l-(4-methylphenvDethyl1acetamide
Figure imgf000177_0001
(Intermediate Cl 9)
Figure imgf000177_0002
(Intermediate Cl 9)
A solution of (S)-l-(4-methylphenyl)ethylamine (2.72 mL, 18.49 mmol) and triethylamine (3.86 mL, 27.73 mmol) in tetrahydrofuran (50 mL) was added slowly to an ice cold solution of bromoacetyl chloride (1.62 mL, 19.41 mmol) in tetrahydrofuran (100 mL). The reaction was stirred for 2 hours then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was triturated with diethyl ether. The solid material was collected by filtration, washed with diethyl ether and dried in vacuo to yield the title compound as a tan solid (3.56 g, 75% yield). ¾ NMR (250 MHz, CDCb) d 7.24 - 7.13 (m, 4H), 6.64 (s, 1H), 5.07 (p, J = 7.1 Hz, 1H), 3.95 - 3.81 (m, 2H), 2.34 (s, 3H), 1.52 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.03 min, MS (ESIpos): m/z 255.8, 257.8 [M+H]+.
Synthesis of 2-bromo-N-r(lS)-l-r4-(trifluoromethoxy)phenyllethyllacetamide
(Intermediate C20)
Figure imgf000177_0003
(Intermediate C20) Bromoacetyl chloride (106 pL, 1.28 mmol) was added slowly to an ice cold solution of (lS)-l-[4-(trifluoromethoxy)phenyl]ethylamine (250 mg, 1.22 mmol) and triethylamine (355 pL, 2.56 mmol) in tetrahydrofuran (10 mL). The reaction was stirred for 90 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-75% ethyl acetate/heptane to yield the title compound as a cream solid (204 mg, 51% yield). ¾ NMR (500 MHz, CDCb) d 7.35 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.65 (s, 1H), 5.11 (p, J = 7.1 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 1.53 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 326.0, 327.9 [M+H]+.
Synthesis of 2-bromo-N-rO S)-l-(4-chloro-3-fluorophenvDethyllacetamide
(Intermediate C21)
Figure imgf000178_0001
A solution of bromoacetyl chloride (166 pL, 2 mmol) in tetrahydrofuran (5 mL) was added slowly to an ice cold suspension of (lS)-l-(4-chloro-3- fluorophenyl)ethylamine HC1 (400 mg, 1.9 mmol) and triethylamine (556 pL, 4 mmol) in tetrahydrofuran (15 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-75% tertbutylmethylether/heptane to yield the title compound as a white solid (490 mg, 75% yield). ¾ NMR (500 MHz, CDCb) d 7.37 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 2.0, 9.9 Hz, 1H), 7.05 (dd, J = 2.0, 8.3 Hz, 1H), 6.69 - 6.59 (m, 1H), 5.05 (p, J = 7.2 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 1.51 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.10 min, MS (ESIpos): m/z 293.9, 295.9, 297.8 [M+H]+.
Synthesis of 2-bromo-N-r(l S)-l-(3-fluoro-4-methylphenvDethvnacetamide
(Intermediate C22)
Figure imgf000179_0001
(Intermediate C22)
A solution of bromoacetyl chloride (150 pL, 1.80 mmol) in THF (3 mL) was added dropwise to an ice cold solution of (lS)-l-(3-fluoro-4-methylphenyl)ethanamine (250 mg, 1.63 mmol) and triethylamine (0.57 mL, 1.1 mmol) in THF (12 mL) over 10 mins. The reaction was stirred for 2 hours then quenched with water and extracted into ethyl acetate three times. The combined organics were washed with brine, dried over Na2SC>4 and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0%-70% EtOAc/heptane to yield the title compound as a pale orange solid (280 mg, 63% yield). ¾ NMR (500 MHz, Chloroform-d) d 7.16 (t, J = 7.8 Hz, 1H), 7.03 - 6.89 (m, 2H), 6.63 (s, 1H), 5.05 (p, J = 7.1 Hz, 1H), 3.95 - 3.80 (m, 2H), 2.25 (d, J = 1.5 Hz, 3H), 1.51 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.07 min, MS (ESIpos): m/z 273.75, 275.75 [M+H]+.
Synthesis of 2-Bromo-N-r(l S)- l -(3.4-dichlorophenyl iethyllacetamide (Intermediate C23)
Figure imgf000179_0002
A solution of bromoacetyl chloride (25 pL, 0.3 mmol) in tetrahydrofuran (0.5 mL) was added slowly to an ice cold solution of (lS)-l-(3,4-dichlorophenyl)ethylamine (55 mg, 0.29 mmol) and trimethylamine (85 pL, 0.61 mmol) in tetrahydrofuran (1.5 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo to yield the title compound as a yellow oil (63 mg, 70% yield). ¾NMR (500 MHz, CDCb) d 7.45 - 7.37 (m, 2H), 7.16 (dd, J = 2.1, 8.3 Hz, 1H), 6.64 (s, 1H), 5.04 (p, J = 7.2 Hz, 1H), 3.94 - 3.84 (m, 2H), 1.51 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 309.7, 311.7, 313.7 [M+H]+.
Synthesis of 2-Bromo-N-rO S)-l-(4-chloro-3-methylphenvDethyllacetamide
(Intermediate C24)
Figure imgf000180_0001
A solution of bromoacetyl chloride (103 pL, 1.24 mmol) in THF (0.5 mL) was added dropwise to an ice cold solution of (lS)-l-(4-chlorophenyl)ethanamine (200 mg, 1.18 mmol) and triethylamine (0.31 mL, 2.25 mmol). The reaction was stirred for 90 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-40% ethyl acetate/heptane to yield the title compound as pale brown solid (45 mg, 12% yield). ¾ NMR (500 MHz, Chloroform-d) d 7.24 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 8.2, 2.1 Hz, 1H), 6.58 (s, 1H), 4.97 (p, J = 7.1 Hz, 1H), 3.83 (m, 2H), 2.31 (s, 3H), 1.43 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 289.85, 291.85, 293.90 [M+H]+. Synthesis of 2-chloro-N-r(l S)- l -(3.4-difluorophenyl iethyll acetamide
(Intermediate C25)
Figure imgf000181_0002
(Intermediate C25)
A suspension of (lS)-l-(3,4-difluorophenyl)ethylamine hydrochloride (350 mg, 1.80 mmol) and triethylamine (0.770 mL, 5.53 mmol) in THF (4 mL) was added slowly to an ice cold solution of 2-chloroacetyl chloride (0.140 mL, 2.34 mmol) in THF (7 mL) . The reaction was stirred for 2 hours then the reaction was quenched with water (10 mL) and extracted into EtOAc (3 x 25 mL). The combined organics were dried over MgSCri and concentrated in vacuo. The residue was purified by chromatography, silica gel, eluting with 0-100% tertbutylmethyl ether/heptane. The relevant fractions were combined and concentrated to yield the title compound as a pale brown solid (200 mg, 47% yield). ¾ NMR (500 MHz, DMSO-d6) d 8.67 (d, J = 7.7 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.18 - 7.13 (m, 1H), 4.90 (p, J = 7.1 Hz, 1H), 4.08 (s, 2H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.02 min, MS (ESIpos): m/z 233.8, 235.9 [M+H]+.
Synthesis of 2-bromo-N-r(lR)-l-(4-chloro-3-fluorophenvnethyllacetamide
(Intermediate C26)
Figure imgf000181_0001
(Intermediate C26)
2-Bromoacetyl chloride (0.079 mL, 0.952 mmol) was added to an ice cold suspension of (lR)-l-(4-chloro-3-fluorophenyl)ethan-l-amine hydrochloride (200 mg, 0.952 mmol) and triethylamine (0.40 mL, 2.86 mmol) in tetrahydrofuran (5 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography, silica gel eluting with 15-100% tert butylmethyl ether / heptane to yield the title compound (90 mg, 32% yield). 1H NMR (500 MHz, DMSO-d6) d 8.77 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.34 (dd, J = 10.7, 2.0 Hz, 1H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 4.88 (p, J = 7.1 Hz, 1H), 3.88 (d, J = 11.1 Hz, 1H), 3.86 (d, J = 11.1 Hz, 1H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.02 min, MS (ESIpos): m/z 233.8, 235.9 [M+H]+.
Synthesis of 2-bromo-N- -l-(4-chlorophenvDethyllacetamide
Figure imgf000182_0001
(Intermediate C27)
Figure imgf000182_0002
(Intermediate C27)
A solution of bromoacetyl chloride (421 pL, 5.06 mmol) in THF (2 mL) was added dropwise to an ice cold solution of (lS)-l-(4-chlorophenyl)ethanamine (750 mg, 4.82 mmol) and triethylamine (1.31 mL, 9.64 mmol) in tetrahydrofuran 30 mL. The reaction was stirred for 90 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The solid was triturated from diethyl ether to give the title compound as a pale brown solid (1.02 g, 75% yield). ¾ NMR (250 MHz, Chloroform-d) d 7.40 - 7.18 (m, 4H), 6.66 (s, 1H), 5.09 (p, J = 7.1 Hz, 1H), 3.91 (d, J = 2.6 Hz, 2H), 1.54 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.07 min, MS (ESIpos): m/z 275.75, 277.65, 279.75 [M+H]+.
Synthesis of N-r(lS)-l-(l,3-benzodioxol-5-yl)ethyll-2-chloro-acetamide
(Intermediate C28)
Figure imgf000183_0001
(Intermediate C28)
A suspension of (lS)-l-(l,3-benzodioxol-5-yl)ethanamine hydrochloride (225 mg, 1.12 mmol) and triethylamine (0.390 mL, 2.51 mmol) in THF (2.5 mL) was added slowly to an ice cold solution of 2-chloroacetyl chloride (0.085 mL, 1.42 mmol) in THF (2.5 mL) . The reaction was stirred for 2 hours then the reaction was quenched with water
(10 mL) and extracted into EtOAc (3 x 25 mL). The combined organics were dried over MgSCri and concentrated in vacuo. The residue was purified by chromatography, silica gel, eluting with 0-10% methanol/dichloromethane. The relevant fractions were combined and concentrated to yield the title compound as a pale brown solid (198 mg, 73% yield). ¾NMR (500 MHz, DMSO-d6) d 8.55 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 1.7
Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.77 (dd, J = 8.1, 1.5 Hz, 1H), 5.97 (s, 2H), 4.83 (p, J = 7.1 Hz, 1H), 4.07 - 4.02 (m, 2H), 1.33 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method E) Rt= 0.46 min, MS (ESIpos): m/z 241.9, 243.9 [M+H]+.
Synthesis of 2-bromo-N-r(l S)-l-(3.4-difluorophenvOethvnacetamide
(Intermediate C29)
Figure imgf000183_0002
(Intermediate C29)
A solution mixture of (lS)-l-(3,4-difluorophenyl)ethan-l-amine (250 mg, 1.59 mmol) in THF (5 mL) and triethylamine (675 pL, 4.85 mmol) was cooled to 0°C. Bromoacetyl chloride (150 pL, 1.8 mmol) was added slowly. The mixture was stirred at this temperature for 1 hr. The reaction was quenched with water and extracted with EtOAc three times. The organic phases were combined and concentrated in vacuo. The crude product was purified by flash chromatography (silica, gradient of 0-100% TBME in heptane) to afford the title compound as an off-white solid (370 mg, 84% yield). 1H NMR (500 MHz, DMSO-d6) d 8.75 (d, J = 7.6 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.19 - 7.11 (m, 1H), 4.92 - 4.83 (m, 1H), 3.91 - 3.83 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.02 min, MS (ESIpos): m/z 277.9, 279.9 [M+H]+.
Synthesis of (R)-N-r(3-chloro-4-fluorophenv0methylenel-
2-methyl-propane-2-sulfmamide
(Intermediate C30)
Figure imgf000184_0001
(Intermediate C30)
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. The aqueous layer was extracted into dichloromethane three times, the combined organics washed with brine, dried over MgSCb and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-100% ethyl acetate: heptane to yield the title compound as a colourless oil (3.11 g, 92% yield). ¾NMR (500 MHz, DMSO-d6) d 8.55 (s, 1H), 8.17 (dd, J = 7.3, 2.1 Hz, 1H), 8.01 - 7.96 (m, 1H), 7.58 (t, J = 8.9 Hz, 1H), 1.18 (s, 9H). LCMS (Analytical Method D) Rt= 1.26 min, MS (ESIpos): m/z 261.9, 263.9 [M+H]+.
Synthesis of (R)-N-r(3-chloro-4-fluorophenyl)methylenel-
2-methyl-propane-2-sulfmamide (Intermediate C31)
Figure imgf000185_0002
(Intermediate C31)
1M Methyl magnesium bromide in THF (15.0 mL) was added dropwise to a -40 °C solution of (R)-N-[(3-chloro-4-fluorophenyl)methylene]-2-methyl-propane-2- sulfmamide (Intermediate C30) (3.10 g, 11.6 mmol) in tetrahydrofuran (30 mL). The reaction was stirred at this temperature for 3 hours then allowed to warm slowly to room temperature. After stirring for 16 hours the reaction was quenched by the slow addition of water. The mixture was partitioned between ethyl acetate and water and the aqueous layer extracted three times with ethyl acetate. The combined organics were washed with brine, dried over MgSCL and concentrated in vacuo. The residue was purified by chromatography, silica gel, eluting with 0-100% tert-butyl methyl ethenheptane to yield the title compound as a viscous oil (1.07 g, 33% yield). ¾ NMR (500 MHz, DMSO-d6) d 7.57 - 7.54 (m, 1H), 7.34 - 7.37 (m, 2H), 5.44 (d, J = 5.5 Hz, 1H), 4.43 (p, J = 6.7 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.10 (s, 9H). LCMS (Analytical Method A) Rt= 3.17 min, MS (ESIpos): m/z 278.1, 280.1 [M+H]+.
Synthesis of (lSVl-(3-chloro-4-fluorophenvOethylamine hydrochloride
(Intermediate C32)
Figure imgf000185_0001
(Intermediate C32)
4M HCI in dioxane (15 mL) was added to a solution of (R)-N-[(3-chloro- 4-fluorophenyl)methylene]-2-methyl-propane-2-sulfmamide (Intermediate C31) (1.36 g, 4.91 mmol) in 1,4-dioxane (10 mL). The reaction was stirred for 4 hours then concentrated in vacuo to yield the title compound as a white solid (668 mg, 65%). ¾ NMR (500 MHz, DMSO) d 8.68 (s, 3H), 7.84 (dd, J = 7.1, 2.2 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.51 - 7.46 (m, 1H), 4.43 (q, J = 6.4 Hz, 1H), 1.51 (d, J = 6.8 Hz, 3H). LCMS (Analytical Method D) Rt= 0.72 min, MS (ESIpos): m/z 174, 176 [M+H]+.
Synthesis of 2-chloro-N- -l-(3-chloro-4-fluorophenvDethyl1acetamide
Figure imgf000186_0001
(Intermediate C33)
Figure imgf000186_0002
(Intermediate C33)
A suspension of (lS)-l-(3-chloro-4-fluorophenyl)ethylamine hydrochloride (Intermediate C32) (668 mg, 3.18 mmol) and tri ethyl amine (1.10 mL, 7.95 mmol) in THF (10 mL) was added slowly to an ice cold solution of 2-chloroacetyl chloride (0.250 mL, 4.18 mmol) in THF (10 mL). The reaction was stirred for 2 hours then additional 2-chloroacetyl chloride (0.250 mL, 4.18 mmol) was added and the reaction stirred for an additional 1 hour. The reaction was quenched with water (10 mL) and extracted into EtOAc (3 x 25 mL). The combined organics were dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-100% tertbutylmethyl ether/heptane to yield the title compound as a pale brown solid (775 mg, 98% yield). ¾ NMR (500 MHz, DMSO-d6) d 8.69 (d, J = 7.7 Hz, 1H), 7.52 (dd, J = 7.2, 2.1 Hz, 1H), 7.37 (t, J = 8.9 Hz, 1H), 7.34 - 7.30 (m, 1H), 4.91 (p, J = 7.1 Hz, 1H), 4.11 - 4.05 (m, 2H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.08 min, MS (ESIpos): m/z 249.9, 251.9 [M+H]+.
Synthesis of 2-chloro-N-r(l S)-l-(4-chloro-2-methylphenvDethvnacetamide
(Intermediate C34)
Figure imgf000187_0001
(Intermediate C34)
2-Chloroacetyl chloride (40 pL, 0.499 mmol) was added to an ice cold solution of (lS)-l-(4-chloro-2-methylphenyl)ethan-l -amine hydrochloride (98 mg, 0.475 mmol) and triethylamine (166 pL, 1.19 mmol) in THF (5 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate, the combined organics were washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-100% tertbutylmethylethenheptane to afford the title compound as a white solid (80 mg, 66% yield). ¾ NMR (500 MHz, DMSO-d6) d 8.67 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.27 - 7.21 (m, 2H), 5.01 (p, J = 7.0 Hz, 1H), 4.03 (s, 2H), 2.31
(s, 3H), 1.32 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.13 min, MS (ESIpos): m/z 245.9, 247.9, 249.9 [M+H]+, purity = 97%.
Synthesis of (R)-N-r(lE)-(4-chloro-2-fluorophenv0methylidenel-
2-methylpropane-2-sulfmamide
(Intermediate C35)
Figure imgf000187_0002
(Intermediate C35)
To a solution of 4-chloro-2-fluorobenzaldehyde (2.00 g, 12.6 mmol) and ({R})-2-methylpropane-2-sulfmamide (1.68 g, 13.9 mmol) DCM (40 mL), was added tetraethoxytitanium (5.3 mL, 25.3 mmol) and the mixture was stirred at room temperature for 3 hr. A saturated solution of sodium bicarbonate (40 ml) was added. The mixture was stirred vigorously for 10 min, then the solid material removed by filtration, washing with DCM. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organics were concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-100% EtO Ac in heptane to afford the title compound (2.95 g, 79% yield) as a white solid. ¾ NMR (500 MHz, DMSO-d6) d 8.64 (s, 1H), 8.01 (t, J = 8.2 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.46 (dd, J = 8.5, 1.9 Hz, 1H), 1.18 (s, 9H). LCMS (Analytical Method D) Rt= 1.24 min, MS (ESIpos): m/z 261.9, 263.9
[M+H]+, purity = 88%.
Synthesis of -l-(4-chloro-2-fluorophenvDethyll-
Figure imgf000188_0001
2-methylpropane-2-sulfmamide (Intermediate C36)
Figure imgf000188_0003
2-methylpropane-2-sulfmamide (Intermediate C37)
Figure imgf000188_0002
(Intermediate C37)
3M Methyl magnesium bromide in THF (5.0 mL) was added dropwise to a -40 °C solution of (R)-N-[(4-chloro-2-fluorophenyl)methylene]-2-methyl-propane-2- sulfmamide (Intermediate C35) (2.90 g, 11.1 mmol) in tetrahydrofuran (40 mL). The reaction was stirred at this temperature for 2 hours then allowed to warm slowly to room temperature. After stirring for 1 hour the reaction was quenched by the slow addition of water. The mixture was partitioned between ethyl acetate and water and the aqueous layer extracted three times with ethyl acetate. The combined organics were washed with brine, dried over MgSCri and concentrated in vacuo. The residue was purified by chromatography, silica gel, eluting with 0-100% tert-butyl methyl ethenheptane to yield the title compounds as white solids (Intermediate C36) (100 mg, 3%) and (Intermediate C37) (60 mg, 2%).
Intermediate C36: ¾ NMR (400 MHz, DMSO-d6) d 7.50 (t, J = 8.3 Hz, 1H), 7.37 (dd, J = 10.3, 2.1 Hz, 1H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H), 5.49 (d, J = 5.7 Hz, 1H), 4.64 (p, J = 6.7 Hz, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.09 (s, 9H). LCMS (Analytical Method D) Rt= 1.14 min, MS (ESIpos): m/z 277.9, 279.9 [M+H]+, purity = 100%.
Intermediate C37: lHMR (500 MHz, DMSO-d6) d 7.6 - 7.5 (m, 1H), 7.4 (dd, J = 10.3, 2.0 Hz, 1H), 7.3 (dd, J = 8.3, 2.0 Hz, 1H), 5.8 (d, J = 7.8 Hz, 1H), 4.6 (p, J = 7.0 Hz, 1H), 1.4 (d, J = 6.8 Hz, 3H), 1.1 (s, 9H). LCMS (Analytical Method D) Rt= 1.14 min, MS (ESIpos): m/z 277.9, 279.9 [M+H]+, purity = 100%.
Synthesis of (lS)-l-(4-chloro-2-fluorophenv0ethan-l -amine hydrochloride
(Intermediate C38)
Figure imgf000189_0001
(Intermediate C38)
4 M hydrogen chloride (0.72 mL, 2.89 mmol) was added to a solution of (R)-N-[(lS)-l-(4-chloro-2-fluoro-phenyl)ethyl]-2-methyl-propane-2-sulfmamide (Intermediate 36) (134 mg, 0.482 mmol) in 1,4-dioxane (2 mL). The reaction was stirred for 20 hours then additional 4 M hydrogen chloride (0.72 mL, 2.89 mmol) was added and stirring continued for 4 hours. The mixture was concentrated in vacuo and the residue repeatedly taken up in toluene and concentrated in vacuo to yield the title compound as an off white solid. The crude product was progressed directly to the next step. LCMS (Analytical Method D) Rt= 0.66 min, MS (ESIpos): m/z 156.9, 158.9 [M+H]+, purity = 87%. Synthesis of 2-chloro-N-IY 1 SI- 1 -(4-chloro-2-fluorophenvDethyllacetamide
(Intermediate C39)
Figure imgf000190_0001
(Intermediate C39) 2-Chloroacetyl chloride (40 pL, 0.505 mmol) was added to an ice cold solution of (lS)-l-(4-chloro-2-fluoro-phenyl)ethanamine;hydrochloride (Intermediate C38) (101 mg, 0.481 mmol) and triethylamine (168 pL, 1.20 mmol) in THF (4 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate, the combined organics were washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-80% tertbutylmethylether/heptane to afford the title compound as a white solid (93 mg, 77% yield). ¾ NMR (400 MHz, DMSO-d6) d 8.75 (d, J = 7.4 Hz, 1H), 7.44 _ 7.36 (m, 2H), 7.29 (dd, J = 8.4, 2.0 Hz, 1H), 5.07 (p, J = 7.1 Hz, 1H), 4.07 (s, 2H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.07 min, MS (ESIpos): m/z 247.9, 251.9, 253.8 [M+H]+, purity = 100%.
Synthesis of (lR)-l-(4-chloro-2-fluorophenvDethan-l -amine hydrochloride
(Intermediate C40)
Figure imgf000190_0002
(Intermediate C40) 4 M hydrogen chloride (0.22 mL, 0.864 mmol) was added to a solution of (R)-N-[(lR)-l-(4-chloro-2-fluoro-phenyl)ethyl]-2-methyl-propane-2-sulfmamide (Intermediate C37) (40 mg, 0.144 mmol) in 1,4-dioxane (1 mL). The reaction was stirred for 20 hours then additional 4 M hydrogen chloride (0.22 mL, 0.864 mmol) added and the reaction stirred for a further 3 hours. The mixture was concentrated in vacuo and the residue repeatedly taken up in toluene and concentrated in vacuo to yield the title compound as an off white solid. The crude product was progressed directly to the next step. LCMS (Analytical Method D) Rt= 0.70 min, MS (ESIpos): m/z 156.9, 158.9 [M+H]+, purity = 87%.
Synthesis of 2-chloro-N-r(lR)-l-(4-chloro-2-fluorophenv0ethvnacetamide
(Intermediate C41)
Figure imgf000191_0001
(Intermediate C41)
2-Chloroacetyl chloride (13 pL, 0.160 mmol) was added to an ice cold solution of (lR)-l-(4-chloro-2-fluoro-phenyl)ethanamine;hydrochloride (Intermediate C40) (32 mg, 0.152 mmol) and triethylamine (53 pL, 0.381 mmol) in THF (1.5 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate, the combined organics were washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography, silica gel, eluting with 0-80% tertbutylmethylether/heptane to afford the title compound as a white solid (36 mg, 95% yield). ¾ NMR (400 MHz, DMSO-d6) d 8.75 (d, J = 7.5 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.29 (dd, J = 8.3, 1.9 Hz, 1H), 5.07 (p, J = 7.1 Hz, 1H), 4.07 (s, 2H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.07 min, MS (ESIpos): m/z 247.9, 251.9, 253.8 [M+H]+, purity = 100%.
EXAMPLE Cl-1
Synthesis of N-r(lS)-l-(4-chloro-3-fluorophenvDethyl1-2-(4-cvclopropyl-5-oxo-4.5- dihydro-1 H- l 2.3.4-tetrazol-l -yl iacetamide
(Compound Cl-1)
Figure imgf000192_0001
(Compound Cl-1)
A mixture of l-cyclopropyl-4,5-dihydro-lH-l,2,3,4-tetrazol-5-one (0.64 g, 5.09 mmol), 2-bromo-N-[(lS)-l-(4-chloro-3-fluoro-phenyl)ethyl]acetamide (Intermediate C21) (1.50 g, 5.09 mmol) and potassium carbonate (2.11 g, 15.3 mmol) in acetonitrile (20 mL) was heated to 60°C for 2 hours. The reaction was cooled and quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. The residue was triturated with ethyl acetate, the solid material collected by filtration and washed with ethyl acetate to yield a white solid (1.3 g) which was further purified by flash chromatography, silica gel, eluting with 0-10% methanol/dichloromethane to yield the title compound as a white solid (1.15 g). Chromatography fractions with lower purity was further purified by Preparative HPLC, Method B1 to give the title compound (85 mg). Both batches of products were combined in acetonitrile and concentrated in vacuo to give the title compound white solid (1.21 g, 70% yield). 1HNMR (500 MHz, DMSO- d6) d 8.80 (d, J = 7.5 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.37 (dd, J = 10.7, 1.9 Hz, 1H), 7.20 (dd, J = 8.3, 1.9 Hz, 1H), 4.91 (p, J = 6.9 Hz, 1H), 4.69 (d, J = 16.8 Hz, 1H), 4.64 (d, J = 16.8 Hz, 1H), 1.37 (d, J = 7.0 Hz, 3H), 1.07 - 1.03 (m, 2H), 1.01 (t, J = 3.3 Hz, 2H). LCMS (Analytical Method A) Rt= 2.88 min, MS (ESIpos): m/z= 340.2,342.2 [M+H]+, Purity = 99%.
EXAMPLES Cl -2 THROUGH Cl -47
Synthesis of Compounds Cl -2 through Compound Cl -47
Each of Compounds Cl-2 through Cl-29 as listed in Table 5 were prepared according to the method of Example Cl, using the intermediates listed in the “Synthesis” column for such compounds. The final compounds were purified by preparative HPLC Methods, Al, A2, B1 or B2.
Table 5 Representative Compounds of Formula (IV)
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
EXAMPLE C2
Synthesis of N-r(lS)-l-(4-methylphenvDethyl1-2-(5-oxo-4-phenyl-
4.5-dihydro- 1 H- l tetrazol- l -yl lacetamide
Figure imgf000207_0001
(Compound C2)
Figure imgf000207_0002
(Compound C2)
A suspension of l-phenyl-4,5-dihydro-lH-l,2,3,4-tetrazol-5-one (50 mg, 0.308 mmol), 2-bromo-N-[(lS)-l-(4-methylphenyl)ethyl]acetamide (87 mg, 0.34 mmol) and cesium carbonate (301 mg, 0.93 mmol) in DMF (2 mL) was heated to 60°C for 1 hour. The reaction mixture was cooled and quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with water, brine, dried over Na2S04, filtered and concentrated in vacuo. Purification by preparative HPLC, Method B2 afforded the title compound (15 mg, 17% yield). 1H NMR (500 MHz, DMSO-d6) d 8.77 (d, J = 7.8 Hz, 1H), 7.92 - 7.79 (m, 2H), 7.60 (t, J = 8.0 Hz, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 4.91 (p, J = 7.0 Hz, 1H), 4.77 (s, 2H), 2.28 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C)
Rt= 4.1 min, MS (ESIpos): m/z= 338 [M+H]+, Purity = 100%.
EXAMPLE C3 Synthesis of N-r(lS)-l-(2H-E3-benzodioxol-5- 2-
Figure imgf000207_0003
r4-(4-fluorophenyl )-5-oxo-4.5-dihydro- l H- l tetrazol- l -yllacetamide
Figure imgf000207_0004
(Compound C3)
Figure imgf000207_0005
(Compound C3) 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50%, 85 uL, 0.142 mmol) was added to a mixture of 2-[4-(4-fluorophenyl)-5-oxo-tetrazol-l- yljacetic acid (26 mg, 0.0950 mmol), (lS)-l-(2H-l,3-benzodioxol-5-yl)ethan-l-amine hydrochloride (21 mg, 0.104 mmol) and triethylamine (44 pL, 0.313 mmol) in DMF (1.5 mL). The reaction was stirred for 2 hours then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri and concentrated in vacuo. Purification by preparative HPLC, Method B2 followed by Method C2 to afford the title compound (15 mg, 41% yield). 1H NMR (500 MHz, DMSO-d6) d 8.72 (d, J = 7.8 Hz, 1H), 7.89 (dd, J = 9.2, 4.8 Hz, 2H), 7.44 (t, J = 8.9 Hz, 2H), 6.91 (d, J = 1.7 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.79 (dd, J = 8.1, 1.5 Hz, 1H), 5.98 (s, 2H), 4.86 (p, J = 7.0 Hz, 1H), 4.77 - 4.74 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt= 3.06 min, MS (ESIpos): m/z= 386 [M+H]+, Purity = 100%. EXAMPLE C4-1
Synthesis ofN-r(lSVl-(4-chloro-3-fluorophenvOethyll-2-(4-r(3.3- difluorocvclobutvDmethyl1-5-oxo-4.5-dihydro- 1H- 1 tetrazol- 1 -yl lacetamide
Figure imgf000208_0001
(Compound C4-1)
Figure imgf000208_0002
(Compound C4-1) To a solution mixture of 2-[4-[(3,3-difluorocyclobutyl)methyl]-5-oxo- tetrazol-l-yl] acetic acid (30 mg, 0.103 mmol), (lS)-l-(4-chloro-3-fluorophenyl)ethan-l- amine hydrochloride (22 mg, 0.105 mmol) and triethylamine (45 pL, 0.323 mmol) in DMF (1 mL), was added 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (80 pL, 0.134 mmol) and the mixture was stirred for 2 hr at room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was concentrated in vacuo and the crude product was purified via preparative HPLC, Method B1 followed by preparative HPLC, Method C3 to afford the title compound (14 mg, 34% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) d 8.8 (d, J = 7.6 Hz, 1H), 7.5 (t, J = 8.1 Hz, 1H), 7.4 (dd, J = 10.7, 1.9 Hz, 1H), 7.2 (d, J = 1.9 Hz, 1H), 4.9 (p,
1H), 4.7 (d, 1H), 4.7 (d, 1H), 4.1 (d, J = 7.0 Hz, 2H), 2.7 - 2.6 (m, 2H), 2.6 - 2.5 (m, 1H), 2.5 - 2.4 (m, 2H), 1.4 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt= 3.23 min, MS (ESIpos): m/z= 404.2, 406.2 [M+H]+, Purity = 100%. EXAMPLES C4-2 AND C4-3
Synthesis of (R)-N-((S)-\ -(4-chloro-3-f1uorophenyl iethyl )-2-(4-(4-fluorophenyl )-5-oxo- 4.5-dihydro- tetrazol- l -yl ipropanamide (Compound C4-2)
Figure imgf000209_0001
and
(S)-N-((S)- \ -(4-chloro-3-f1uorophenyl iethyl )-2-(4-(4-f1uorophenyl )-5-oxo-4.5-dihydro- 1 //-tetrazol-1 -yl ipropanamide (Compound C4-3)
Compounds C4-2 through C4-3 as listed in Table 6 are prepared according to the method of Example C4, using the intermediates listed in the “Synthesis” column for such compounds. The final compounds are purified by preparative HPLC Methods, Al, A2, B1 or B2.
Table 6
Representative Compounds of Formula (IV)
Figure imgf000209_0002
Figure imgf000210_0002
EXAMPLE C5
Synthesis of N-r(lS)-l-(4-chloro-3-fluorophenv0ethyll-2-r4-(cvclopropylmethyr)-5- oxo-4.5-dihydro- 1H- 1 2.3.4-tetrazol- 1 -yllacetamide
(Compound C5)
Figure imgf000210_0001
(Compound C5)
To a mixture of 2-[4-(cyclopropylmethyl)-5-oxo-4,5-dihydro-lH-l,2,3,4- tetrazol-l-yl] acetic acid (25 mg, 0.126 mmol), (lS)-l-(4-chloro-3-fluorophenyl)ethan-l- amine hydrochloride (30 mg, 0.143 mmol) and triethylamine (60 pL, 0.431 mmol) in DMF (1 mL) was added 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50%, 110 pL, 0.185 mmol) and the mixture was stirred for 2 hr at room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was concentrated in vacuo and the crude product was purified by preparative HPLC, Method B1 to afford the title compound (24 mg, 54% yield) as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.8 (d, J = 7.5 Hz, 1H), 7.5 (t, J = 8.1 Hz, 1H), 7.4 (dd, J = 10.7, 2.0 Hz, 1H), 7.2 (dd, J = 8.3, 2.0 Hz, 1H), 4.9 (p, J = 7.2 Hz, 1H), 4.7 (d, J = 16.9 Hz, 1H), 4.7 (d, J = 16.9 Hz, 1H), 3.8 (d, J = 7.2 Hz, 2H), 1.4 (d, J = 7.0 Hz, 3H), 1.2 - 1.1 (m, 1H), 0.6 - 0.5 (m, 2H), 0.4 - 0.3 (m, 2H). LCMS (Analytical Method A) Rt= 3.07 min, MS (ESIpos): m/z= 354.2, 356.2 [M+H]+, Purity = 100%.
EXAMPLE C6
Synthesis of N-r(lS)-l-(4-chloro-3-fluorophenv0ethyll-2-r4-(l-cvclopropylethv0-5- oxo-4.5-dihydro- 1H- 1 2.3.4-tetrazol-l -yllacetamide (Compound C6)
Figure imgf000211_0001
(Compound C6)
A mixture of [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethyl-ammonium;hexafluorophosphate (66 mg, 0.174 mmol), N-ethyl-N-isopropyl- propan-2-amine (73 pL, 0.523 mmol) and 2-[4-(l-cyclopropylethyl)-5-oxo-4,5-dihydro- lH-l,2,3,4-tetrazol-l-yl]acetic acid (Intermediate C16) (37 mg, 0.174 mmol) was stirred for 5 minutes. (lS)-l-(4-chloro-3-fluorophenyl)ethan-l-amine hydrochloride (37 mg, 0.174 mmol) was added and stirring continued for 2 hours. The reaction was quenched into water, the aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSCri. The residue was purified by preparative HPLC, Method B 1 to yield the title compound (8 mg, 13% yield) as an off white solid.1H NMR (400 MHz, DMSO-d6) d 8.83 (d, J = 7.5 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 10.7 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 4.90 (p, J = 7.0 Hz, 1H), 4.74 - 4.63 (m, 2H), 3.63 - 3.57 (m, 1H), 1.47 (d, J = 6.9 Hz, 3H), 1.37 (d, J = 7.0 Hz, 3H), 1.29 - 1.20 (m, 1H), 0.57 (td, J = 8.6, 3.8 Hz, 1H), 0.47 - 0.35 (m, 2H), 0.27 (dd, J = 9.4, 4.8 Hz, 1H). LCMS (Analytical Method A) Rt= 3.29 min, MS (ESIpos): m/z= 412.2, 414.1 [M+H]+, Purity = 97%. EXAMPLE D
SYNTHESIS OF COMPOUNDS OF FORMULA (VI
Figure imgf000212_0001
Synthesis of tert-butyl-2-(2-oxo-3-phenylimidazolidin-l-vD acetate (Intermediate Dl)
Figure imgf000212_0002
(Intermediate Dl)
To as stirred suspension of l-phenylimidazolidin-2-one (300 mg, 1.85 mmol) in DMF (3 ml) at room temperature was added NaH (60%, 111 mg, 2.77 mmol). The resulting suspension was stirred for 5 min then tert-butyl bromoacetate (0.35 ml, 2.4 mmol) was added. The reaction was stirred for 1 hr then quenched with water and extracted with EtOAC. The organic extracts were washed with water and brine, dried (NaiSCri), filtered and concentrated in vacuo to give the title compound as an off-white solid (530 mg, 97% yield). ¾ NMR (250 MHz, DMSO-d6) d 7.64 - 7.50 (m, 2H), 7.40 - 7.25 (m, 2H), 7.10 - 6.94 (m, 1H), 3.91 (s, 2H), 3.84 (m, 2H), 3.54 (m, 2H), 1.44 (s,
9H). LCMS (Analytical Method D) Rt= 1.16 min, MS (ESIpos): m/z 221.3 [M-Boc+H]+.
Synthesis of 2-(2 oxo-3-phenylimidazolidin-l-vD acetic acid (Intermediate D2)
Figure imgf000212_0003
(Intermediate D2)
A solution of tert-butyl 2-(2-oxo-3-phenylimidazolidin-l-yl)acetate (Intermedaite Dl) (94%, 530 mg, 1.8 mmol) in 25% TFA in DCM (5.3 ml) was stirred at room temperature for 16 hrs. The reaction was concentrated in vacuo then triturated in DCM to afford the title compound as a white solid (268 mg, 66% yield). ¾ NMR (500 MHz, DMSO-d6) d 12.79 (s, 1H), 7.56 (m, 2H), 7.36 - 7.27 (m, 2H), 7.05 - 6.90 (m, 1H), 3.93 (s, 2H), 3.83 (m, 2H), 3.54 (m, 2H). LCMS (Analytical Method D) Rt= 0.89 min, MS (ESIpos): m/z 221.3 [M+H]+.
Synthesis of N- -l-(4-methylphenvDethyll-2-(2-oxo-3phenylimidazolidin-l-
Figure imgf000213_0001
vDacetamide (Compound Dl)
Figure imgf000213_0002
(Compound Dl) To a stirred solution of 2-(2-oxo-3-phenylimidazolidin-l-yl)acetic acid
(Intermediate D2) (130 mg, 0.59 mmol), (lS)-l-(4methylphenyl)ethan-l -amine (96 mΐ, 0.65 mmol) and DIPEA (232 mΐ, 1.3 mmol) in DMF (3.0 ml) was added HATU (269 mg, 0.71 mmol). The reaction was stirred at room temperature for 3 days then concentrated in vacuo. The residue was dissolved in DCM and washed with sat. NaHCCh (aq). The aqueous layer was extracted with DCM. The combined organic extracts were dried through a hydrophobic frit and concentrated in vacuo. The crude product was purified by preparative HPLC (Method Bl) to afford the title compound as a white solid (136 mg, 68% yield). ¾ NMR (250 MHz, Chloroform-d) d 7.59 - 7.45 (m, 2H), 7.41 - 7.30 (m, 2H), 7.23 - 7.03 (m, 5H), 6.59 - 6.38 (m, 1H), 5.21 - 4.98 (m, 1H), 4.09 - 3.74 (m, 4H), 3.68 - 3.41 (m, 2H), 2.31 (s, 3H), 1.48 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method
C) Rt= 3.81 min, MS (ESIpos): m/z 338.1 [M+H]+.
EXAMPLE E
ACTIVITY DATA Human GPR139 FLIPR™ Assay
FLIPR™ 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 (FLIPR1 tl RA", Molecular Devices, 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 mΐ/ 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 (FLIPR™ 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 mΐ/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 FLIPRtetra® and 10 mΐ/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:
Figure imgf000214_0001
The efficacy of saturating concentrations of the agonist JNJ63533054 (Sigma Aldrich, St Louis, MO, 20 mM) was set as maximal response (100% Emax) and the bottom defined by the signal achieved with 0.1 % DMSO. Activity expressed as ECso of representative compounds against the GPR139 receptor is provided in Table 7 below. With respect to GPR139 activity: "++++" denotes an ECso of less than 100 nM; "+++" denotes an ECso of from 100 nM to less than 500 nM; "++" denotes an ECso of from 500 nM to less than 1000 nM; and "+" denotes an ECso of 1000 nM or more. Efficacy of representative compounds with respect to the agonist JNJ63533054: "++++" denotes a %Emax of more than 80%; "+++" denotes a %Emax from 50% to less than 80%; "++" denotes a %Emax from 25% to less than 50%; and "+" denotes a %Emax less than 25%. Table 7
Human GPR139 ECso and % Emax FLIPR Assay Results
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Rat GPR139 FLIPR™ Assay
For the rat GPR139 FLIPR™ 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 (FLIPRtetra®, 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. All assays were run with cells frozen at a low passage number (< 20), thawed, plated in assay media without selection antibiotics at 20000 cells/ 50 mΐ/ 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 (FLIPR™ Calcium 5 Assay Kit, Molecular Devices #R8187) was prepared according to the manufacturer guidelines (in HBSS Buffer, 20 mM HEPES pH 7.4). Cells were equilibrated at room temperature for 30 minutes, and then loaded with 50 mΐ/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™11^® and 10 mΐ/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:
Figure imgf000219_0001
The efficacy of saturating concentrations of the agonist JNJ63533054 (Sigma Aldrich,
St Louis, MO, 20 mM) was set as maximal response (100% Emax) and the bottom defined by the signal achieved with 0. 1 % DMSO. Activity expressed as ECso of representative compounds against the GPR139 receptor is provided in Table 8 below. With respect to GPR139 activity: "++++" denotes an ECso of less than 100 nM; "+++" denotes an ECso of from 100 nM to less than 500 nM; "++" denotes an ECso of from 500 nM to less than 1000 nM; and "+" denotes an ECso of 1000 nM or more. Efficacy of representative compounds with respect to the agonist JNJ63533054: "++++" denotes a %Emax of more than 80%; "+++" denotes a %Emax from 50% to less than 80%; "++" denotes a %Emax from 25% to less than 50%; and "+" denotes a %Emax less than 25%.
Table 8 Rat GPR139 ECso and % Emax FLIPR Assay Results
Figure imgf000219_0002
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Human GPR139 PathHunter™ b-Arrestin Assay
PathHunter™ 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) and 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. All assays were run with cells frozen at a low passage number (< 12), thawed and plated in Cell plating reagent 2 (DiscoverX, Fremont, CA) at 10000 cells/ 20 mΐ/ well in a 384 well plate and incubated at 37 °C, 5% CO2 overnight. Cell plates were equilibrated for 30 min at RT (room temperature) before treatment with compounds (5 mΐ/well of 5x final concentrations) for 90 min at RT. Plates were then incubated for 3 h at RT with detection solution (DiscoverX, Fremont, CA), and the chemiluminescence signal was detected using an Envision plate reader (Perkin Elmer, Waltham, MA) in luminscence mode (measurement time 0.1 s). For data analysis, concentration-response data of test and reference agonists were fitted to the four-parameter logistic equation:
Figure imgf000223_0001
The efficacy of saturating concentrations of the agonist JNJ63533054 (20 mM) was set as maximal response (100% Emax) and the bottom defined by the signal achieved with 0.1 % DMSO.
Activity expressed as EC so of representative compounds against the GPR139 receptor is provided in Table 9 below. With respect to GPR139 activity: "++++" denotes an EC50 of less than 100 nM; "+++" denotes an EC50 of from 100 nM to less than 500 nM; "++" denotes an EC50 of from 500 nM to less than 1000 nM; and "+" denotes an EC50 of 1000 nM or more. Efficacy of representative compounds with respect to the agonist JNJ63533054: "++++" denotes a %Emax of more than 80%; "+++" denotes a %Emax from 50% to less than 80%; "++" denotes a %Emax from 25% to less than 50%; and "+" denotes a %Emax less than 25%.
Table 9 Human GPR139 ECso and % Emax b-arrestin Assay Results
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, including U.S. Provisional Patent Application No. 62/951,853, filed on December 20, 2019, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above- detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

1. The compound of claim 1, having the structure of Formula (I):
Figure imgf000228_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
Q6 is -N= when Q7 is =CR7- or =N , or
Q7 is =N- when Q6 is -CR6= or -N=, or
Q6 is CR6aR6b- when Q7 is -CR7aR7b-;
Q12 is CR12 orN;
R1 is H or lower alkyl;
R4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
R5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
R6, R6a, R6b, R7, R7a, and R711 are each, independently, H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
R9, R10, and R12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R4 and R10 together with the atoms to which they are attached form a heterocycle; and wherein R4, R5, R6, R6a, R6b, R7, R7a, R7b, R9, R10, and R12 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.
2. The compound of claim 1, wherein Q6 is -CR6=, Q7 is =N-, and having the structure of Formula (II):
Figure imgf000229_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
Q12 is CR12 orN;
R1 is H or lower alkyl;
R4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
R5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
R6 is H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
R9, R10, and R12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R4 and R10 together with the atoms to which they are attached form a heterocycle; and wherein R4, R5, R6, R9, R10, and R12 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.
3 The compound of claim 1, wherein Q6 is -N=, Q7 is =CR7-, and having the structure of Formula (III):
Figure imgf000229_0002
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q12 is CR12 orN;
R1 is H or lower alkyl;
R4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
R5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
R7 is H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
R9, R10, and R12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R4 and R10 together with the atoms to which they are attached form a heterocycle; and wherein R4, R5, R7, R9, R10, and R12 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.
4. The compound of claim 1, wherein Q6 is -N=, Q7 is =N-, and having the structure of Formula (IV):
Figure imgf000230_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
Q12 is CR12 orN;
R1 is H or lower alkyl;
R4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
R5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl; R9, R10, and R12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R4 and R10 together with the atoms to which they are attached form a heterocycle; and wherein R4, R5, R9, R10, and R12 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.
5. The compound of claim 1, wherein Q6 is -CR6aR6b-, Q7 is -CR7aR7b-, and having the structure of Formula (V):
Figure imgf000231_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
Q12 is CR12 orN;
R1 is H or lower alkyl;
R4 is halo, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy;
R5 is lower alkyl, lower haloalkyl, cycloalkylalkyl, carbocyclyl, or heterocyclyl;
R6a,
Figure imgf000231_0002
independently, H, -S(0)2R, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl, where R is lower alkyl;
R9, R10, and R12 are each, independently, H, halo, lower alkyl, or heterocyclyl; or R4 and R10 together with the atoms to which they are attached form a heterocycle; and wherein R4, R5, R6a, R6b, R7a, R7b, R9, R10, and R12 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.
6. The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the compound has a structure as set forth in Tabel 1.
7. A pharmaceutical composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
8. A method for modulating the GPR139 receptor, comprising contacting the GPR139 receptor with an effective amount of a compound of any one of claims 1-6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition of claim 7.
9. A method for treating a GPR139 dependent condition, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition of claim 7, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
10. A method for treating a neurobehavioral disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition of claim 7, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
11. The method of claim 10, wherein the neurobehavioral disease or disorder is schizophrenia, ADHD, autism, compulsive-like alcohol drinking, or an affective disorder.
12. A method for treating an eating disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition of claim 7, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
13. The method of claim 12, wherein the eating disorder is binge-eating disorder.
14. A method of treating an opioid-use disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition of claim 7, at a frequency and for a duration sufficient to provide a beneficial effect to the subject.
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