WO2020097609A1 - Modulateurs du récepteur gpr139 - Google Patents

Modulateurs du récepteur gpr139 Download PDF

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Publication number
WO2020097609A1
WO2020097609A1 PCT/US2019/060788 US2019060788W WO2020097609A1 WO 2020097609 A1 WO2020097609 A1 WO 2020097609A1 US 2019060788 W US2019060788 W US 2019060788W WO 2020097609 A1 WO2020097609 A1 WO 2020097609A1
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hydrate
isotope
racemate
solvate
salt
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Robert M. Jones
Gary Brandt
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Neumora Therapeutics Inc
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Blackthorn Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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

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 G 12/13 .
  • the human GPR139 gene has been identified, and the human GPR139 protein (also known as hGPRgl or hGPCRl2) is a 345-amino acid orphan receptor located on chromosome 16r12.3.
  • 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):
  • R 101 , R 102 , R 103 , R 104 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , and R 112 are as defined herein below.
  • R 201 , R 202 , R 203 , R 204 , R 205 , R 208 , R 209 , R 210 , R 211 , R 212 , Q 206 , and Q 207 are as defined herein below.
  • compounds are provided having the structure of Formula (III):
  • R 301 , R 302 , R 303 , R 304 , R 305 , R 306 , R 307 , R 309 , R 310 , R 311 , and R 312 are as defined herein below.
  • R 401 , R 402 , R 403 , R 404 , R 405 , R 406 , R 407 , R 408 , R 409 , R 410 , R 411 , and R 412 , Q 409 , Q 410 and Q 412 are as defined herein below.
  • a pharmaceutical composition comprising a compound having the structure of Formula (I), Formula (II), Formula (III), or Formula (IV), 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), or Formula (IV), 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), or Formula (IV), 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), or Formula (IV), 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 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, n-propyl, n-butyl, n-pentyl-, n-hexyl, n-heptyl, and n-octyl groups.
  • branched lower alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Halo or “halogen” refers to fluorine, chlorine, bromine, and iodine.
  • Hydroxyloxy refers to–OH.
  • 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, ⁇ CF 3 , ⁇ CH 2 CF 3 , and the like.
  • Lower alkoxy refers to a lower alkyl as defined above joined by way of an oxygen atom (i.e., ⁇ O ⁇ (lower alkyl).
  • lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-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., ⁇ O ⁇ (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-l,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, norbomyl, 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.
  • 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, tetrahy dronaphthyl , and the like). In one embodiment, 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. For example, a dioxolanyl ring and a
  • benzdioxolanyl ring system (methylenedioxyphenyl 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,
  • 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, 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 (z.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 (z.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- stoi chi ometri c .
  • 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, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • compositions may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include,
  • 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, p-tol
  • 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.
  • compounds are provided having the structure of Formula (I):
  • R 101 is H or lower alkyl
  • R 102 is H, lower alkyl, or carbocyclyl
  • R 103 is H or lower alkyl
  • R 104 , R 109 , R 110 , R 111 , and R 112 are each, independently, H, halo, -CN, -S(O) n -R, -C(O)R, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, carbocyclyl, or heterocyclyl, where n is 0–2;
  • R 106 , R 107 , and R 108 are each, independently, H, halo, -CN, -NR2, -NRC(O)OR, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl, -O-carbocyclyl, -O-heterocyclyl, -NR-carbocyclyl, or -NR-heterocyclyl; and
  • each R is, independently, H, lower alkyl, or lower haloalkyl
  • R 104 , R 106 , R 107 , R 108 , R 109 , R 110 , R 111 , and R 112 are each, independently, optionally substituted by one or more R';
  • each R' is, independently, halo, -OH, lower alkyl, lower haloaklyl, or lower alkoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 102 is lower alkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 102 is methyl, ethyl, or isopropyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 102 is methyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 102 carbocycle.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 102 is C3-C6 cycloalkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 102 is cyclopropyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 103 is H.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 102 and R 103 together with the atom to which they are attached form C3-C6 cycloalkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 102 and R 103 together with the atom to which they are attached form cyclopropyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 109 , R 111 , and R 112 are H.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 is H, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, or C3-C6 cycloalkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 is methyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 is F or Cl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 is haloalkoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 is–OCF3.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 is cyclopropyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 110 is H, halo, or lower alkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 110 is H.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 110 is F or Cl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 110 is lower alkyl. In another embodiment, R 110 is methyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is H, halo, lower alkyl, lower alkoxy, carbocycle, or heterocycle.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is H.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is halo.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is F or Cl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is lower alkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is methyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is lower alkoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is methoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is carbocycle.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is C3-C6 cycloalkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is cyclopropyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is heterocycle.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 106 is
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is H, halo, lower alkyl, lower alkoxy, carbocycle, or heterocycle.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is H.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is halo.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is F or Cl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is lower alkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is methyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is lower alkoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is methoxy.
  • compounds having the structure of Formula (I) are provided or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is carbocycle.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is C3-C6 cycloalkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is cyclopropyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is heterocycle.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 107 is morpholino.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is H, halo, lower alkyl, lower haloalkyl, lower alkoxy, -NR 2 , carbocycle, heterocycle, or -NR-heterocyclyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is H. In one embodiment, compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is halo.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is I.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is Cl or F.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is lower alkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is methyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is lower haloalkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is–CF3.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is lower alkoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is methoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is -NR 2 .
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is–NHCH3 or -NHCH2CHF2.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is carbocycle.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is C3-C6 cycloalkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is cyclopropyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is heterocycle.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is morpholino.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 108 is -NR-heterocyclyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein .
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 101 is H.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 101 is methyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 111 is H or lower alkyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 111 is H.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 111 is lower alkyl. In another embodiment, R 111 methyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 112 is H.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 112 is halo.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 112 is F or Cl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 112 are each, independently, halo.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 is methyl and R 112 is F or Cl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 112 are each, independently, F or Cl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 112 are each, independently, halo, and R 106 , R 107 , and R 108 are each, independently, H, halo, lower alkyl, cycloalkyl, or lower alkoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 112 are each, independently, F or Cl, and R 106 , R 107 , and R 108 are each, independently, H, halo, lower alkyl, cycloalkyl, or lower alkoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 112 are each, independently, F or Cl, and R 106 is Cl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 112 are each, independently, F or Cl, and R 106 is cyclopropyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 112 each, independently, F or Cl, and R 106 is methoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 110 are each, independently, halo.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 110 are each, independently, F or Cl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 110 are each, independently, halo, and R 106 , R 107 , and R 108 are each, independently, H, halo, lower alkyl, cycloalkyl, lower alkoxy, -NR2, heterocycle, or -NR-heterocyclyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 110 are each, independently, F or Cl, and R 106 , R 107 , and R 108 are each, independently, H, halo, lower alkyl, cycloalkyl, lower alkoxy, -NR 2 , heterocycle, or -NR-heterocyclyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 110 are each, independently, F or Cl, and R 106 , R 107 , and R 108 are each, independently, H, F, Cl, or I.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 110 are each, independently, F or Cl, and R 106 , R 107 , and R 108 are each, independently, H or cyclopropyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 110 are each, independently, F or Cl, and R 106 , R 107 , and R 108 are each, independently, H or methyl.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 110 are each, independently, F or Cl, and R 106 , R 107 , and R 108 are each, independently, H or methoxy.
  • compounds having the structure of Formula (I) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 104 and R 110 are each, independently, F or Cl, and R 106 , R 107 , and R 108 are each, independently, H, -NHCH 3 , morpholino, .
  • Representative compounds of Formula (I) 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
  • R 201 is H
  • R 202 is lower alkyl
  • R 203 is H
  • R 204 , R 209 , R 210 , R 211 , and R 212 are each, independently, H, halo, lower alkyl, lower alkoxy, or lower haloalkoxy;
  • Q 206 is N and Q 207 is CR 207 , or Q 206 is CR 206 and Q 207 is N;
  • R 205 , R 206 , R 207 , and R 208 are each, independently, H, halo, -NR 2 , lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl, -O-heterocyclyl, -NR-carbocyclyl, or -NR-heterocyclyl;
  • R 204 , R 205 , R 206 , R 207 , R 208 , R 209 , R 210 , R 211 , and R 212 are each, independently, optionally substituted by one or more R';
  • each R is, independently, H or lower alkyl
  • each R' is, independently, halo, lower alkyl, or -C(O)OR; wherein when Q 207 is CR 207 , then R 207 is not phenyl.
  • compounds are provided having the structure of Formula (II-A):
  • R 201 , R 202 , R 203 , R 204 , R 205 , R 207 , R 208 , R 209 , R 210 , R 211 , R 212 are as defined as above.
  • compounds are provided having the structure of Formula (II-B):
  • R 201 , R 202 , R 203 , R 204 , R 205 , R 206 , R 208 , R 209 , R 210 , R 211 , R 212 are as defined as above.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 202 is methyl, ethyl, or isopropyl.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 202 is methyl.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 203 is H.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 209 is H.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 211 is H.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 is halo, lower alkyl, or lower haloalkoxy.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 is H.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 is halo. In another embodiment, R 204 is F or Cl.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 is lower alkyl.
  • R 204 is lower alkyl.
  • R 204 is methyl, ethyl, or isopropyl.
  • R 204 is methyl.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 is lower haloalkoxy.
  • R 204 is -OCF3.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 210 is H or halo.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 210 is H.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 210 is halo. In another embodiment, R 210 is F or Cl.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 212 is H or halo.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 212 is H.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 212 is halo. In another embodiment, R 212 is F or Cl.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 205 is H, lower alkyl, carbocycle, or heterocycle.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 205 is H.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 205 is lower alkyl. In another embodiment, R 205 is methyl. In one embodiment, compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 205 is carbocycle. In another embodiment, R 205 is C 3 -C 6 cycloalkyl. In another embodiment, R 205 is cyclopropyl.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 205 is heterocycle. In another embodiment, R 205 is .
  • compounds having the structure of Formula (II) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 206 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
  • compounds having the structure of Formula (II) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 206 is H.
  • compounds having the structure of Formula (II) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 206 is halo. In another embodiment, R 206 is Cl.
  • compounds having the structure of Formula (II) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 206 is lower alkyl. In another embodiment, R 206 is methyl.
  • compounds having the structure of Formula (II) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 206 is lower alkoxy. In another embodiment, R 206 is methoxy.
  • compounds having the structure of Formula (II) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 206 is carbocycle.
  • R 206 is C 3 -C 6 cycloalkyl.
  • R 206 is cyclopropyl.
  • compounds having the structure of Formula (II) or (II-A) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 207 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
  • compounds having the structure of Formula (II) or (II-A) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 207 is H.
  • compounds having the structure of Formula (II) or (II-A) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 207 is halo. In another embodiment, R 207 is Cl.
  • compounds having the structure of Formula (II) or (II-A) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 207 is lower alkyl. In another embodiment, R 207 is methyl.
  • compounds having the structure of Formula (II) or (II-A) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 207 is lower alkoxy. In another embodiment, R 207 is methoxy.
  • R 207 is carbocycle. In another embodiment, R 207 is
  • R 207 is cyclopropyl.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is H, lower alkyl, lower haloalkyl, lower alkoxy, -NR2, carbocycle, heterocycle, substituted heterocycle, -O-heterocyclyl, substituted -O-heterocyclyl, or -NR-heterocyclyl.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is H.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is lower alkyl. In another embodiment, R 208 is methyl.
  • Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is lower haloalkyl.
  • R 208 is -CHF 2 .
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is lower alkoxy. In another embodiment, R 208 is methoxy.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is -NR2.
  • R 208 is -NHCH 3 .
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is carbocycle.
  • R 208 is C 3 -C 6 cycloalkyl.
  • R 208 is cyclopropyl.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is heterocycle. In another embodiment, R 208 is
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is substituted heterocycle.
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is -O-heterocyclyl. In another embodiment, R 208 is .
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is substituted -O-heterocyclyl. In another embodiment, .
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 208 is -NR-heterocyclyl. In another embodiment, R 208 is .
  • compounds having the structure of Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 201 is H.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 212 are halo, and R 205 , R 206 , and R 208 are each, independently, H, halo, lower alkoxy, carbocycle, or heterocycle.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 212 are F or Cl, and R 205 , R 206 , R 207 , and R 208 are each, independently, H, halo, lower alkoxy, carbocycle, or heterocycle.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 212 are halo, and R 205 is carbocycle, or heterocycle.
  • R 204 and R 212 are each, independently, F or Cl, and R 205 is cyclopropyl or .
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 212 are halo, and R 206 is halo, lower alkoxy, or carbocycle.
  • R 204 and R 212 are each, independently, F or Cl, and R 206 is Cl, methoxy, or cyclopropyl.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 212 are halo, and R 208 is lower alkoxy or carbocycle.
  • R 204 and R 212 are each, independently, F or Cl, and R 208 is methoxy or cyclopropyl.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 210 are halo. In another embodiment, R 204 and R 210 are F or Cl.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 210 are halo, and R 205 , R 207 , and R 208 are each, independently, H, halo, lower alkyl, lower alkoxy, -NR2, carbocycle, heterocycle, or -O-heterocyclyl.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 210 are F or Cl, and R 205 , R 207 , and R 208 are each, independently, H, halo, lower alkyl, lower alkoxy, -NR 2 , carbocycle, heterocycle, or -O-heterocyclyl.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 210 are halo, and R 205 is carbocycle or heterocycle.
  • R 204 and R 210 are each, independently, F or Cl, and R 205 is
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 210 are halo, and R 207 is halo, lower alkoxy, or carbocycle.
  • R 204 and R 210 are each, independently, F or Cl, and R 207 is Cl, methoxy, or cyclopropyl.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 and R 210 are halo, and R 208 is lower alkyl, lower alkoxy, -NR 2 , carbocycle, heterocycle, substituted heterocycle, -O-heterocyclyl, or substituted -O-heterocyclyl.
  • R 204 and R 210 are each, independently, F or
  • R 208 is methyl, methoxy, cyclopropyl, ,
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 is lower alkyl or lower haloalkoxy, and R 206 and R 208 are each independently, H, lower alkyl, lower haloalkyl, or -N-heterocyclyl.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 is lower alkyl or lower haloalkoxy, and R 206 is lower alkyl.
  • R 204 is methyl or–OCF 3
  • R 206 is methyl.
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 is lower haloalkoxy, and R 208 is lower alkyl, lower haloalkyl, or -N-heterocyclyl.
  • R 204 is–OCF 3
  • R 208 is methyl,–CHF2, or .
  • compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 204 is halo, or lower alkyl, and R 205 and R 207 are lower alkyl.
  • R 204 is Cl or methyl, and R 205 and R 207 are methyl.
  • Representative compounds of Formula (II) include the compounds listed in Table 2 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.”
  • R 301 is H or lower alkyl
  • R 302 is methyl and R 303 is H;
  • R 304 , R 309 , R 310 , R 311 , and R 312 are each, independently, H, halo, lower alkyl, lower alkoxy, lower haloalkoxy, or carbocyclyl;
  • R 305 , R 306 , and R 307 are each, independently, H, halo, lower alkyl, lower alkoxy, or carbocyclyl;
  • R 304 , R 305 , R 306 , R 307 , R 309 , R 310 , R 311 , and R 312 are each, independently, optionally substituted by one or more R';
  • each R' is, independently, halo.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 302 is lower alkyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 302 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 303 is H.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 309 is H.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 311 is H or lower alkyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 311 is H.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 311 is lower alkyl. In another embodiment, R 311 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, lower alkyl, lower haloalkoxy, or carbocycle.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is H.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo. In another embodiment, R 304 is F or Cl. In one embodiment, compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is lower alkyl. In another embodiment, R 304 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is lower haloalkoxy.
  • R 304 is–OCF 3 or -OCHF2.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is carbocycle. In another embodiment, R 304 is
  • R 304 is cyclopropyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 310 is H or halo.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 310 is H.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 310 is halo. In another embodiment, R 310 is F or Cl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 312 is H or halo.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 312 is H.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 312 is halo. In another embodiment, R 312 is F or Cl. In one embodiment, compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 305 is H, lower alkyl, or carbocycle.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 305 is H.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 305 is lower alkyl. In another embodiment, R 305 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 305 is carbocycle. In another embodiment, R 305 is
  • R 305 is cyclopropyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 306 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 306 is H.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 306 is halo. In another embodiment, R 306 is F or Cl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 306 is lower alkyl. In another embodiment, R 306 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 306 is lower alkoxy. In another embodiment, R 306 is methoxy.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 306 is carbocycle. In another embodiment, R 306 is
  • R 306 is cyclopropyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 307 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 307 is H.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 307 is halo. In another embodiment, R 307 is Cl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 307 is lower alkyl. In another embodiment, R 307 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 307 is lower alkoxy. In another embodiment, R 307 is methoxy.
  • R 307 is carbocycle.
  • R 307 is C3-C6 cycloalkyl.
  • R 307 is cyclopropyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 301 is H or lower alkyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 301 is H.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 301 is lower alkyl. In another embodiment, R 301 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 , R 310 , R 311 , and R 312 are each independently H, halo, lower alkyl, lower alkoxy, lower haloalkoxy or carbocyle.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, lower alkyl, lower haloalkoxy, or carbocyle, and R 310 is halo.
  • R 304 is Cl, methyl,–OCF 3 , or cyclopropyl, and R 310 is F or Cl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, and R 311 is lower alkyl. In another embodiment, R 304 is Cl and R 311 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is lower haloalkoxy, and R 312 is halo.
  • R 304 is–OCHF2, and R 312 is F.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, R 310 halo, and R 301 is lower alkyl.
  • R 304 is Cl
  • R 310 is F
  • R 301 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 , R 310 , and R 312 are each independently H, halo, lower alkyl, lower alkoxy, lower haloalkoxy or carbocyle, and R 305 , R 306 , and R 307 are each independently H, halo, lower alkyl, lower alkoxy, lower haloalkoxy, or carbocycle.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is lower haloalkoxy, and R 305 is lower alkyl.
  • R 304 is–OCF 3
  • R 305 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, R 305 is lower alkyl, and R 307 is lower alkyl.
  • R 304 is Cl, R 305 is methyl, and R 307 is methyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo or lower haloalkoxy, and R 306 is halo, lower alkyl, or lower alkoxy.
  • R 304 is Cl or–OCF 3
  • R 306 is F, methyl, or methoxy.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, lower alkyl, or lower haloalkoxy, and R 307 is lower alkyl, or lower alkoxy.
  • R 304 is Cl, methyl, or–OCF3, and R 307 is methyl, or methoxy.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, R 310 is halo, and R 305 is lower alkyl or carbocycle.
  • R 304 is F or Cl
  • R 310 is F or Cl
  • R 305 is methyl or cyclopropyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo or lower haloalkoxy, R 310 is halo, and R 306 is halo, lower alkyl, or carbocycle.
  • R 304 is Cl or–OCF3
  • R 310 is F
  • R 306 is F, Cl, methyl, or cyclopropyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, R 310 is halo, and R 307 is lower alkyl, lower alkoxy, or carbocycle.
  • R 304 is F or Cl
  • R 310 is F or Cl
  • R 307 is methyl, methoxy, or cyclopropyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, R 310 is halo, and R 306 is lower alkyl, and R 307 is lower alkoxy.
  • R 304 is Cl
  • R 310 is F
  • R 306 is methyl
  • R 307 is methoxy.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, R 312 is halo, and R 306 is halo, lower alkyl, lower alkoxy, or carbocycle.
  • R 304 is F or Cl
  • R 312 is F or Cl
  • R 306 is F, Cl, methyl, methoxy, or cyclopropyl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 , R 312 , and R 307 are halo.
  • R 304 is F or Cl
  • R 312 is F or Cl
  • R 307 is Cl.
  • compounds having the structure of Formula (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 304 is halo, R 312 is halo, R 305 is lower alkyl, and R 307 is lower alkyl.
  • R 304 is Cl
  • R 312 is F
  • R 305 is methyl
  • R 307 is methyl.
  • Representative compounds of Formula (III) include the compounds listed in Table 3 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.”
  • R 401 is H or lower alkyl
  • R 402 is H, lower alkyl, or carbocyclyl
  • R 403 is H or lower alkyl
  • R 404 , R 409 , R 410 , R 411 , and R 412 are each, independently, H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or aryl; Q 409 , Q 410 , and Q 412 are each independently C or N;
  • R 405 , R 406 , R 407 , and R 408 are each, independently, H, halo, -CN, -NR 2 , -NRC(O)OR, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl, -O-carbocyclyl, -O-heterocyclyl, or -NR-heterocyclyl; and
  • each R is, independently, H, lower alkyl, or lower haloalkyl
  • R 404 , R 405 , R 406 , R 407 , R 408 , R 409 , R 410 , R 411 , and R 412 are each, independently, optionally substituted by one or more R';
  • each R' is, independently, halo, -OH, lower alkyl, lower haloaklyl, or lower alkoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 402 is lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 402 is methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 402 is carbocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 402 is C 3 -C 6 cycloalkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 402 is cyclopropyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 403 is H.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 402 and R 403 , together with the atom to which they are attached, form a C 3 -C 6 cycloalkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 402 and R 403 , together with the atom to which they are attached, form cyclopropyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 409 is H or lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 409 is H.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 409 is lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 409 is methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 411 is H, halo, or lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 411 is H.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 411 is halo.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 411 is F.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 411 is lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 411 is methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or aryl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is H.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is halo.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is F or Cl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is lower alkoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is–OCH(CH3)2.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is lower haloalkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is–CF 3 .
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is lower haloalkoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is–OCF 3 or–OCHF 2 .
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is aryl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is phenyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 410 is H, halo, or lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 410 is H.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 410 is halo.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 410 is F or Cl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 410 is lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 410 is methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 412 is H or halo.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 412 is H.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 412 is halo.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 412 is F.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 405 is H, halo, lower alkoxy, heterocycle, or substituted heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 405 is H.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 405 is halo.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 405 is F or Br.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 405 is lower alkoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 405 is methoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 405 is heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 405 is substituted heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is H, halo, -CN, lower alkyl, lower alkoxy, or carbocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is H. In one embodiment, compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is halo.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is F, Cl, or Br.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is -CN.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is lower alkoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is methoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is carbocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is C3-C6 cycloalkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 406 is cyclopropyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is H, halo, -CN, lower alkyl, lower alkoxy, carbocycle, substituted carbocycle, aryl, heterocycle, substituted heterocycle, -O-heterocyclyl, or -NR-heterocyclyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is H.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is halo.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is F, Cl, or I.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is -CN.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is lower alkoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is methoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is carbocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is C 3 -C 6 cycloalkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is cyclopropyl or cyclobutyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is substituted carbocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is aryl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is phenyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,
  • R 407 is In one embodiment, compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is substituted heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is -O-heterocyclyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 407 is -NR-heterocyclyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 408 is H, halo, -NR 2 , -NRC(O)OR, lower alkoxy, heterocycle, or substituted heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 408 is H.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 408 is halo.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 408 is F or Cl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 408 is -NR 2 .
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 408 is -NH2, -NHCH3, or
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 408 is -NRC(O)OR.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 408 is -NHC(O)OC(CH3)3.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 408 is heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,
  • R 408 is In one embodiment, compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 408 is substituted heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 401 is H or lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 401 is H.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 401 is lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 401 is methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 , R 410 , and R 411 are each independently H, halo, lower alkyl, or lower haloalkoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is halo, lower alkyl, or lower haloalkoxy, and R 410 is halo or lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is Cl, methyl, or–OCHF2, and R 410 is F, Cl, or methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is halo, and R 411 is halo or lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is Cl, and R 411 is F or methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 and R 401 are lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is methyl, and R 401 is methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 , R 405 , R 406 , R 407 , and R 408 are each independently H, halo, -NR2, -NRC(O)OR, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, carbocycle, heterocycle, substituted heterocycle, or -O-heterocyclyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is halo, lower alkyl, or lower haloalkoxy, and R 405 is halo, lower alkoxy, heterocycle, or substituted heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is Cl, methyl, or–OCF3, and R 405 is F, Br, methoxy,
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is halo, lower alkyl, lower haloalkyl, or lower haloalkoxy, and R 406 is halo, lower alkyl, lower alkoxy, or carbocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is Cl, methyl,–CF3, or–OCF3, and R 406 is F, Br, methyl, methoxy, or cyclopropyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is lower alkyl or lower haloalkoxy, and R 407 is halo, lower alkyl, lower alkoxy, heterocycle, substituted heterocycle, or -O-heterocyclyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is methyl or–OCF3, and R 407 is Cl, methyl, methoxy,
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is lower alkyl, and R 408 is halo,–NR 2 ,–NRC(O)OR, lower alkoxy, heterocycle, or substituted heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is methyl, and R 408 is F, Cl, methoxy,–NH 2 ,–NHCH 3 ,
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 and R 410 are halo, and R 401 is lower alkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is Cl, R 410 is F, and R 401 is methyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 and R 406 are halo, and R 402 and R 403 , together with the atom to which they are attached, form a C 3 -C 6 cycloalkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is Cl, R 406 is F, and R 402 and R 403 , together with the atom to which they are attached, form cyclopropyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 410 and R 406 are halo, and R 402 and R 403 , together with the atom to which they are attached, form a C 3 -C 6 cycloalkyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 410 is Cl, R 406 is F, and R 402 and R 403 , together with the atom to which they are attached, form cyclopropyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 , R 410 , R 405 , R 406 , R 407 , and R 408 are each independently H, halo, -CN, lower alkyl, lower alkoxy, carbocycle, substituted carbocycle, heterocycle, substituted heterocycle, or–N-heterocyclyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is halo or lower alkyl, R 410 is halo, and R 405 is heterocycle or substituted heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is Cl or methyl, R 410 is F or Cl, and R 405 is
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is halo or lower alkyl, R 410 is halo, and R 406 is halo, -CN, lower alkyl, lower alkoxy, or carbocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is F, Cl, or methyl, R 410 is F or Cl, and R 406 is F, Cl, -CN, methyl, methoxy, or cyclopropyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is halo or lower alkyl, R 410 is halo, and R 407 is halo,–CN, lower alkyl, lower alkoxy, carbocycle, substituted carbocycle, aryl, or -N-heterocyclyl.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 is F, Cl, or methyl, R 410 is F or Cl, and R 407 is F, Cl, I,–
  • CN methyl, methoxy, or cyclopropyl, cyclobutyl, phenyl, , or .
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 and R 410 are halo, and R 408 is heterocycle or substituted heterocycle.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope,
  • R 404 is Cl
  • R 410 is F
  • R 408 is or
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 , R 409 , and R 411 are lower alkyl, and R 407 is lower alkoxy.
  • compounds having the structure of Formula (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 404 , R 409 , and R 411 are methyl, and R 407 is methoxy.
  • Representative compounds of Formula (IV) include the compounds listed in Table 4 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.”
  • Q 6 is N or CR 6
  • Q 7 is N or CR 7 ;
  • Q 8 is N or CR 8 ;
  • R 1 is H or lower alkyl
  • R 2 is H, lower alkyl, or carbocyclyl
  • R 3 is H or lower alkyl
  • R 4 , R 9 , R 10 , R 11 , and R 12 are each, independently, H, halo, -CN,
  • n 0–2;
  • R 5 , R 6 , R 7 , and R 8 are each, independently, H, halo, -CN, -NR2, -NRC(O)OR, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl, -O-carbocyclyl, -O-heterocyclyl, -NR-carbocyclyl, or -NR-heterocyclyl; and
  • each R is, independently, H, lower alkyl, or lower haloalkyl; and wherein R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , 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, or -C(O)OR.
  • the invention provides 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.
  • the active compound 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.
  • 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 di stearate, 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.
  • 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.
  • 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,
  • 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
  • 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), (II- A), (II- B), (III), (IV), or (X), 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.
  • 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), (II- A), (II-B), (III), (IV), or (X), 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 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), (II-A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X), 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), (II- A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X), 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), (II-A), (II- B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X), 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), (II- A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X), 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), (II- A), (II-B), (III), (IV), or (X), 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), (II- A), (II-B), (III), (IV), or (X), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a
  • 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 (MOD); 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), (II- A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X) 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), (II-A), (II- B), (III), (IV), or (X), 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.
  • 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), (II-A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X) 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), (II-A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X), 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), (II-A), (II-B), (III), (IV), or (X), 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.
  • reaction may be carried out in any suitable solvent, or other reagents to perform the transformation(s) necessary.
  • suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the
  • a given reaction may be carried out in one solvent or a mixture of more than one solvent.
  • Reagents and conditions i) hydrazine hydrate, EtOH; ii) benzophenone hydrazone, Pd 2 (dba) 3 , Xantphos or JohnPhos, sodium tert-butoxide, toluene; iii) concentrated HCl; iv) CDI, MeCN; v) 4-nitrophenyl carbonochloridate, Et3N, THF.
  • Reagents and conditions i) Pd/C, MeOH, DCM, hydrogen atmosphere; ii) R 106 -H/NaOMe, THF; wherein R 106 -H is, independently, lower alkoxy, lower haloalkoxy, -O-carbocyclyl, or -O-heterocyclyl.
  • Reagents and conditions i) hydrazine hydrate; ii) formic acid; iii) Pd/C, DIPEA, EtOH, MeOH, DCM, hydrogen atmosphere; iv) 3-methylbutyl nitrite, diiodomethane, MeCN; v) selenium dioxide, nitrobenzene; vi) R 108 -B(OR''')2, K3PO4, Pd(dppf)Cl2, THF, H2O; vii) R 108 -H/NaOMe, THF; viii) NMP, morpholine or HNR2 or HNRC(O)OR or HN(R'') 2 ; wherein each R'' is, independently, H, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl (examples include methylamine, methyl, difluoroethyl, 3-oxetane, and 2,2-difluoroethan
  • Reagents and conditions i) K 2 CO 3 , MeCN; ii) R 106 -B(OR''') 2 , K 3 PO 4 , Pd(dppf)Cl2, THF, H2O; iii) LiOH• H2O, EtOH, H2O; iv) DIPEA, HATU, DCM or DMF or DCM/DMF mixtures; wherein R 106 -B(OR''') 2 is, independently, R 106 -boronic acid or R 106 -boronic ester (including, but not limited to, boronic acid pinacol ester).(LG denotes a leaving group, such as halogen).
  • Reagents and conditions i) R 106 -B(OR''') 2 , K 3 PO 4 , THF, H 2 O,
  • R 106 -B(OR''')2 is, independently, R 106 -boronic acid or R 106 -boronic ester (including, but not limited to, boronic acid pinacol ester); and wherein R'' is, "independently, H, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl.
  • R 106 examples include, but are not limited to, methylamine, 2,2-difluoroethan-1-amine, piperidine, morpholine, and oxetan-3-amine (HAL denotes halogen).
  • Reagents and conditions i) R 108 -B(OR''')2, K3PO4, THF, H2O,
  • Pd(dppf)Cl 2 ii) NMP, HNR 2 or HNRC(O)OR or HN(R’’) 2 ; wherein R 108 -B(OR''') 2 is, independently, R 108 -boronic acid or R 108 -boronic ester (including, but not limited to, boronic acid pinacol ester); and wherein R" is, independently, H, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl.
  • R 108 examples include, but are not limited to, methylamine, 2,2-difluoroethan-1-amine, piperidine, morpholine, and oxetan-3-amine) (HAL denotes halogen.) Reaction Scheme I-9
  • Reagents and conditions i) R 107 -B(OR''') 2 , K 3 PO 4 , THF, H 2 O,
  • R 107 -B(OR''')2 is, independently, R 107 -boronic acid or R 107 -boronic ester (including, but not limited to, boronic acid pinacol ester); and wherein R'' is, independently, H, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl.
  • R 107 examples include, but are not limited to, methylamine, 2,2-difluoroethan-1-amine, piperidine, morpholine, and oxetan-3-amine (HAL denotes halogen).
  • Reagents and conditions i) ditertbutyldicarbonate, THF; ii) ⁇ 1,3-bis[2,6- bis(propan-2-yl)phenyl]imidazolidin-2-yl ⁇ (difluoromethyl)silver, DPEPhos, Pd(dba) 2 , toluene. (HAL denotes halogen.) Reaction Scheme II-5
  • Reagents and conditions i) THF, HN(R'')2, wherein R" are each independently H, lower alkyl, cycloalkyl, or heterocycle, or substituted heterocycle (examples include methylamine, piperidine, oxetan-3-amine, and tert-butyl piperazine- 1-carboxylate, Et 3 N (as needed); ii) (a) NaH, tert-butyl 3-hydroxyazetidine-1- carboxylate, THF, (b) starting material, THF (HAL denotes halogen). Reaction Scheme II-6
  • Reagents and conditions i) R 306 -B(OH)2, Cs2CO3, toluene/H2O, Bis(cyclopentyldiphenylphosphane) dichloromethane dichloropalladium iron; ii) hydrazine hydrate, EtOH; iii) benzophenone hydrazone, sodium tert-butoxide, JohnPhos, Pd 2 (dba) 3 , toluene; iv) concentrated HCl; v) CDI, MeCN; vi) 4-nitrophenyl chloroformate, Et3N, THF. Reaction Scheme III-3
  • Reagents and conditions i) K2CO3, MeCN (LG denotes a leaving group, such as halogen) (HAL denotes halogen); ii) R 407 -OH, Pd(OAc) 2 , Cs 2 CO 3 , JohnPhos, toluene; iii) R 407 -B(OR''')2, K2CO3, Pd(dppf)Cl2, THF, H2O; iv) TFA, DCM; v) DIPEA, HATU, DCM, DMF (as needed), wherein R 407 -B(OR''') 2 is R 407 -boronic acid or R 407 -boronic ester (including, but not limited to, boronic acid pinacol ester). Reaction Scheme IV-4
  • Reagents and conditions i) R 405 -OH, Pd(OAc) 2 , JohnPhos or Ad- BippyPhos, Cs2CO3, toluene; ii) NMP, HNR’R’’, wherein R’ and R” are each independently H, lower alkyl, substituted lower alkyl, cycloalkyl, heterocycle, or a substituted heterocycle (examples include piperidine, piperazine, morpholine, azetidin- 3-ol, 1-methylpiperazine, 3,3-difluoroazetidine, 3-methylmorpholine) (HAL denotes halogen).
  • Reagents and conditions i) R 407 -OH, Pd(OAc) 2 , JohnPhos or Ad- BippyPhos, Cs2CO3, toluene; ii) NMP, HNR’R’’, wherein R’ and R” are each independently H, lower alkyl, substituted lower alkyl, cycloalkyl, or heterocycle substituted heterocycle (examples include piperidine, morpholine, oxetan-3-amine, 1- methylpiperazine, 4-methoxypiperidine, (3R)-piperidin-3-ol, (3S)-piperidin-3-ol) (HAL denotes halogen).
  • Reagents and conditions i) R 408 -OH, JohnPhos or Ad-BippyPhos, Pd(OAc) 2 , Cs 2 CO 3 , toluene; ii) tBuBrettPhos Pd G3, Cs 2 CO 3 , NMP, H 2 O, HNR’R’’; iii) Pd2dba3, Xantphos, sodium tert-butoxide, toluene, HNR’R”; wherein R’ and R” are each independently H, lower alkyl, substituted lower alkyl, cycloalkyl, or heterocycle, or tert-butyl carbamate (examples include methylamine, 2,2-difluoroethanamine, morpholine) (HAL denotes halogen).
  • Reagents and conditions i) tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate, Cs2CO3, Pd(dppf)Cl2, dioxane/H 2 O; ii) K 2 CO 3 , MeCN (LG denotes a leaving group, such as halogen); iii) palladium on charcoal, EtOH, DCM, hydrogen atmosphere; iv) (a) HCl/dioxane, 1,4- dioxane, (b) TFA, DCM; v) formaldehyde/H 2 O, STAB, DCM, MeOH. (HAL denotes halogen.) Reaction Scheme IV-8
  • Reagents and conditions i) hydrazine hydrate, EtOH; ii) benzophenone hydrazone, Pd(OAc)2, BINAP, phenyl boronic acid, sodium tert-butoxide, toluene; iii) concentrated HCl; iv) CDI, MeCN or DCM; v) 4-nitrophenyl chloroformate, Et 3 N, THF.
  • 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.
  • the compounds may be purified by chromatography, particularly flash column chromatography, using prepacked silica gel cartridges (e.g., Biotage SNAP cartridges 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.
  • 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 pm 21.2 x 150 mm, 10 mm) or Waters Xbridge Phenyl (10 mm 19 x 150 mm, 5 mm).
  • 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 analyzed 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 pm C18 (2), (100 x 4.6mm).
  • Ad-BippyPhos 5-[Di(1-adamantyl)phosphino]-1 ⁇ ,3 ⁇ ,5 ⁇ -triphenyl-1 ⁇ H- [1,4 ⁇ ]bipyrazole
  • CDI 1,1 ⁇ -Carbonyldiimidazole
  • DIAD Diisopropyl azodicarboxylate
  • HATU N-[(Dimethylamino)(3H-[1,2,3]triazolo[4,5- b]pyridin-3-yloxy)methylene]-N- methylmethanaminium hexafluorophosphate
  • HMBC Heteronuclear Multiple Bond Correlation
  • HPLC high performance liquid chromatography
  • IPA Isopropyl alcohol
  • Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)
  • tBu-BrettPhos 2-(Di-tert-butylphosphino)-2 ⁇ ,4 ⁇ ,6 ⁇ -triisopropyl-3,6- dimethoxy-1,1 ⁇ -biphenyl
  • Analytical Method A Column: Phenomenex Kinetix-XB C181.2 x 100 mm, 1.7 ⁇ m; 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 ⁇ L; temperature: 40 °C; UV scan: 215 nm; PDA Spectrum range: 200-400 nm step: 1 nm; MSD signal settings- scan pos: 150-850.
  • Analytical Method B Column: Waters UPLC® CSHTM C182.1 x 100 mm, 1.7 ⁇ m; eluent A: 2 mM ammonium bicarbonate, buffered to pH10, 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 ⁇ L; temperature: 40 °C; UV scan: 215 nm; PDA Spectrum range: 200-400 nm step: 1 nm; MSD signal settings- scan pos: 150-850.
  • Analytical Method C Column: Waters Atlantis dC182.1 x 100 mm, 3 ⁇ m 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 ⁇ L; temperature: 40 °C; UV scan: 215 nm; PDA Spectrum range: 200-400 nm step: 1 nm; MSD signal settings- scan pos: 150-1000.
  • Analytical Method D Column: Kinetex Core-Shell C182.1 x 50 mm, 5 ⁇ m 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 ⁇ L; temperature: 40 °C; UV scan: 215 nm; PDA Spectrum range: 210-420 nm step: 1 nm; MSD signal settings- scan pos: 100-1000.
  • Analytical Method F Column: Phenomenex Gemini–NX C182.01 x 100 mm, 3 ⁇ m; eluent A: 2 mM ammonium bicarbonate, buffered to pH 10, eluent B: acetonitrile; gradient: 0 - 5.5 min 5 - 100% B, 5.5– 5.9 min 100% B, 5.9 - 5.92 min 100 - 5% B, 5.92– 7.00 min 5% B; flow 0.5 mL/min; injection volume 3 ⁇ L; temperature: 40 °C; UV scan: 215 nm; PDA Spectrum range: 210-400 nm step: 1 nm; MSD signal settings- scan pos: 150-850.
  • Preparative HPLC Preparative HPLC
  • Method A1 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 C1830 x 100 mm, 10 ⁇ m; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide;
  • 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 C1830 x 100 mm, 10 ⁇ m; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide;
  • Method B1 Instrument pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281; Column: Waters Sunfire C1830 x 100 mm, 10 ⁇ m; eluent A: water + 0.1 vol% formic acid, eluent B:
  • Method B2 Instrument pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281; Column: Waters Sunfire C1830 x 100 mm, 10 ⁇ m; eluent A: water + 0.1 vol% formic acid, eluent B:
  • Method D Instrument pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281; Column: Waters X-Bridge C1819 x 100 mm, 5 ⁇ m; eluent A: water + 0.1 vol% formic acid, eluent B: acetonitrile + 0.1 vol% formic acid; gradient: 0.0 - 1.9 min 5% B, 1.9– 2.0 min 5 - 35% B, 2.0– 16.0 min 35 - 45% B, 16.0– 16.1 min 45 - 95% B, 16.1 - 18.0 min 95% B; 18.0 - 18.1 min 95 - 5 % B; 18.1– 20.0 min 5 % B, flow 20 mL/min; temperature: 25 °C; UV scan: 215 nm.
  • Preparative HPLC Preparative HPLC
  • Method A1 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 C1830 x 100 mm, 10 ⁇ m; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide;
  • 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 C1830 x 100 mm, 10 ⁇ m; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide;
  • Method B1 Instrument pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281; Column: Waters Sunfire C1830 x 100 mm, 10 ⁇ m; 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 ⁇ L; 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 C1830 x 100 mm, 10 ⁇ m; eluent A: water + 0.1 vol% formic acid, eluent B:
  • Method C Instrument pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281; Column: Waters X-Bridge C1819 x 100 mm, 5 ⁇ m; eluent A: water + 0.1 vol% formic acid, eluent B: acetonitrile + 0.1 vol% formic acid; gradient: 0– 2 min 5% B, 2– 16 min 5 - 12% B, 16– 18 min 12 - 95% B, 18 -18.1 min 95– 5% B, 18.1 -20 min 5% B; flow 20 mL/min;
  • Method D Instrument pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281; Column: Waters X-Bridge C1819 x 100 mm, 5 ⁇ m; eluent A: water + 0.1 vol% formic acid, eluent B: acetonitrile + 0.1 vol% formic acid; gradient: 0.0 - 1.9 min 5% B, 1.9– 2.0 min 5 - 35% B, 2.0– 16.0 min 35 - 45% B, 16.0– 16.1 min 45 - 95% B, 16.1 - 18.0 min 95% B; 18.0 - 18.1 min 95 - 5 % B; 18.1– 20.0 min 5 % B, flow 20 mL/min; temperature: 25 °C; UV scan: 215 nm.
  • isocratic gradient 30% B; flow 50 mL/min; injection volume 1mL, temperature 40 °C, UV scan 230 nm.
  • Method F Instrument pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281; Column: Waters X-Bridge C1819 x 100 mm, 5 ⁇ m; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide; gradient: 0 - 1.9 min 5% B, 2– 16 min 28 - 38% B, 16 - 18 min 95% B; flow 20 mL/min; temperature: 25 °C; UV scan: 215 nm. Synthesis of Intermediates Synthesis of 2 ⁇ bromo ⁇ N ⁇ [(1S) ⁇ 1 ⁇ (4 ⁇ methylphenyl)ethyl]acetamide
  • Titanium tetraethoxide (1.18 mL, 4.81 mmol) was added to a mixture of 3-fluoro-4-(trifluoromethoxy)benzaldehyde (500 mg, 2.4 mmol) and R- tertbutylsulfinamide (320 mg, 2.64 mmol) in dichloromethane (20 mL). The reaction was stirred for 72 hours. The reaction was quenched by addition of saturated NaHCO3 (aq, 10 mL). The mixture was stirred vigorously for 30 minutes. The precipitate was removed by filtration and the filtrate partitioned between dichloromethane and water.
  • Titanium tetraethoxide (2.9 mL, 13.7 mmol) was added and the resulting solution was stirred at RT for 16h. The reaction was quenched by addition of aq. sat. NaHCO 3 and the resulting mixture was stirred at RT for 30 min. The mixture was extracted three times with CH 2 Cl 2 . The combined organics were washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by chromatography eluting with 2- 30% ethyl acetate/heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a yellow oil (1.23 g, 72% yield).
  • Titanium tetraethoxide (2.6 mL, 12.5 mmol) was added to a solution of 4-cyclopropyl-3-fluorobenzaldehyde (Intermediate 24) (1.02 g, 6.23 mmol) and (R)-2- methylpropane-2-sulfinamide (831 mg, 6.85 mmol) in CH 2 Cl 2 (34 mL) and the reaction was stirred for 72 hours. The reaction was quenched by addition of aq. sat. NaHCO3 and the resulting mixture was stirred at RT for 30 min. The mixture was extracted with CH2Cl2 three times. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo.
  • a pressure tube was charged with ethyl 2- ⁇ 6-chloro-3-oxo-2H,3H- [1,2,4]triazolo[4,3-b]pyridazin-2-yl ⁇ acetate (Intermediate 55) (275 mg, 1.07 mmol), cyclopropylboronic acid (110.45 mg, 1.29 mmol), K 3 PO 4 (455 mg, 2.14 mmol) and THF / H2O (7.5 ml) and degassed with N2 for 5 min. Pd(dppf)Cl2 (156.81 mg, 0.21 mmol) was added. The tube was flushed with N 2 and sealed. The reaction was stirred at 75 o C for 6 h.
  • the reaction was re-treated with cyclopropylboronic acid (11 mg, 0.13 mmol) and Pd(dppf)Cl 2 (15.68 mg, 0.02 mmol).
  • the reaction was degassed with N 2 and sealed. Stirring was continued at 75 o C for another 1 hr.
  • the reaction was concentrated in vacuo.
  • the residue was diluted with water (10 ml) and extracted with EtOAc (3 x 10 ml).
  • the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo.
  • the crude product was purified by Biotage IsoleraTM chromatography (silica gel, eluting with 0-3% MeOH in DCM) to give the title compound (87 mg, 30% yield).
  • a pressure tube was charged with benzophenone hydrazine (1.07 g, 5.4 mmol), 2-chloro-5-methylpyrazine (500 mg, 3.9 mmol), sodium tert-butoxide (523 mg, 5.4 mmol), JohnPhos (34.8 mg, 0.12 mmol), Pd 2 (dba) 3 (35.6 mg, 0.04 mmol) and degassed toluene (6 mL).
  • the suspension was degassed further with N2 and sealed.
  • the reaction was heated at 90 o C for 5 h.
  • the reaction was allowed to cool to room temperature and was quenched with water (20 mL).
  • the reaction was neutralized with 1M HCl(aq).
  • the mixture was extracted with EtOAc (3 x 20 mL).
  • a pressure tube was charged with tert-butyl 8-chloro-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyrazine-2-carboxylate (195 mg, 0.7 mmol) (Intermediate 65), ⁇ 1,3-bis[2,6-bis(propan-2-yl)phenyl]imidazolidin-2-yl ⁇ (difluoromethyl)silver (516 mg, 0.9 mmol), DPEPhos (19 mg, 0.04 mmol), Pd(dba)2 (41 mg, 0.07 mmol) and degassed toluene (20 mL). The suspension was degassed further and then sealed under N2.
  • a pressure tube was charged with 8-chloro-2H,3H-[1,2,4]triazolo[4,3- a]pyrazin-3-one (100 mg, 0.57 mmol) (Intermediate 60), oxetan-3-amine (43 mg, 0.57 mmol), Et 3 N (88 ⁇ L, 0.63 mmol) and dry THF (2 mL).
  • the reaction was stirred under nitrogen at 80 °C for 1 h.
  • the reaction stirred at 80 °C for 1 h.
  • the reaction was re-treated oxetan-3-amine (43 mg, 0.57 mmol).
  • the reaction stirred at 80 °C for 1 h.
  • the reaction was allowed to cool to room temperature and the resulting precipitate was collected by filtration.
  • the crude solid was purified by Biotage
  • a pressure tube was charged with benzophenone hydrazone (1.07 g, 5.4 mmol), 2-chloro-5-methylpyrimidine (0.50 g, 3.9 mmol), sodium tert-butoxide (0.52 g, 5.4 mmol), JohnPhos (35 mg, 0.12 mmol), Pd2(dba)3 (36 mg, 0.04 mmol) and degassed toluene (6 mL).
  • the suspension was degassed further with N 2 and sealed.
  • the reaction was heated at 90 o C for 5 h.
  • the reaction was allowed to cool to room temperature and was quenched with water (10 mL).
  • the reaction was neutralised with 1M HCl(aq).
  • a pressure tube was charged with benzophenone hydrazine (1.71 g, 8.7 mmol), 2-chloro-4-methoxypyrimidine (900 mg, 6.2 mmol), sodium tertbutoxide (838 mg, 8.7 mmol), JohnPhos (55.7 mg, 0.19 mmol), Pd2(dba)3 (57.0 mg, 0.06 mmol) and degassed toluene (11 mL).
  • the suspension was degassed further with N 2 and sealed.
  • the reaction was heated at 90 o C for 5 h.
  • the reaction was allowed to cool to room temperature and was quenched with water (20 mL).
  • the reaction was neutralised with 1M HCl (aq) and extracted with EtOAc (3 x 40 mL).

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Abstract

L'invention concerne des composés qui modulent le récepteur GPR139, des compositions les contenant, et leurs procédés de préparation et d'utilisation pour le traitement d'une maladie dans laquelle la modulation du récepteur GPR139 est indiquée ou bénéfique du point de vue médical. De tels composés ont la structure de formule (X) ou un isomère, racémate, hydrate, solvate, isotope, ou sel pharmaceutiquement acceptable de ceux-ci, R1, R2, R3, R4, R9, R10, R11 et R12, Q5, Q6, Q7 et Q8 étant tels que définis dans la description.
PCT/US2019/060788 2018-11-09 2019-11-11 Modulateurs du récepteur gpr139 Ceased WO2020097609A1 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US201862758451P 2018-11-09 2018-11-09
US201862758445P 2018-11-09 2018-11-09
US62/758,451 2018-11-09
US62/758,445 2018-11-09
US201862760849P 2018-11-13 2018-11-13
US201862760839P 2018-11-13 2018-11-13
US201862760847P 2018-11-13 2018-11-13
US201862760841P 2018-11-13 2018-11-13
US62/760,847 2018-11-13
US62/760,849 2018-11-13
US62/760,839 2018-11-13
US62/760,841 2018-11-13

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Cited By (8)

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WO2021234450A1 (fr) * 2020-05-22 2021-11-25 Takeda Pharmaceutical Company Limited Dérivés de 1-((1h-pyrazol-4-yl)méthyl)-3-(phényl)-1,3-dihydro-2h-imidazol-2-one et composés apparentés servant d'antagonistes de gpr139 pour le traitement de la dépression, par exemple
WO2021234451A1 (fr) * 2020-05-22 2021-11-25 Takeda Pharmaceutical Company Limited Dérivés de 3-((1h-pyrazol-4-yl)méthyl)-6'-(phényl)-2h-(1,2'-bipyridin)-2-one et composés apparentés servant d'antagonistes de gpr139 pour une utilisation dans une méthode de traitement de la dépression, par exemple
WO2023165263A1 (fr) * 2022-03-01 2023-09-07 上海科技大学 Composé de pyrrolotriazinone, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
WO2023165262A1 (fr) * 2022-03-01 2023-09-07 上海科技大学 Composé hétérocyclique contenant un thiéno-azote, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
WO2023147336A3 (fr) * 2022-01-26 2023-09-28 University Of Florida Research Foundation, Incorporated Modulateurs à petites molécules du complexe gpr139
CN117396480A (zh) * 2021-03-26 2024-01-12 奥弗恩制药公司 吡唑并嘧啶酮化合物
WO2024087783A1 (fr) * 2022-10-28 2024-05-02 浙江友宁生物医药科技有限公司 Agoniste du récepteur gpr139, son procédé de préparation et son application
US12370192B2 (en) 2019-09-16 2025-07-29 Takeda Pharmaceutical Company Limited Azole-fused pyridazin-3(2H)-one derivatives

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12370192B2 (en) 2019-09-16 2025-07-29 Takeda Pharmaceutical Company Limited Azole-fused pyridazin-3(2H)-one derivatives
WO2021234450A1 (fr) * 2020-05-22 2021-11-25 Takeda Pharmaceutical Company Limited Dérivés de 1-((1h-pyrazol-4-yl)méthyl)-3-(phényl)-1,3-dihydro-2h-imidazol-2-one et composés apparentés servant d'antagonistes de gpr139 pour le traitement de la dépression, par exemple
WO2021234451A1 (fr) * 2020-05-22 2021-11-25 Takeda Pharmaceutical Company Limited Dérivés de 3-((1h-pyrazol-4-yl)méthyl)-6'-(phényl)-2h-(1,2'-bipyridin)-2-one et composés apparentés servant d'antagonistes de gpr139 pour une utilisation dans une méthode de traitement de la dépression, par exemple
JP2023528281A (ja) * 2020-05-22 2023-07-04 武田薬品工業株式会社 例えばうつ病の治療方法において使用するためのｇｐｒ１３９拮抗薬としての３－（（１ｈ－ピラゾール－４－イル）メチル）－６’－（フェニル）－２ｈ－（１，２’－ビピリジン）－２－オン誘導体および関連化合物
JP7734153B2 (ja) 2020-05-22 2025-09-04 武田薬品工業株式会社 例えばうつ病の治療方法において使用するためのｇｐｒ１３９拮抗薬としての３－（（１ｈ－ピラゾール－４－イル）メチル）－６’－（フェニル）－２ｈ－（１，２’－ビピリジン）－２－オン誘導体および関連化合物
US12590086B2 (en) 2020-05-22 2026-03-31 Takeda Pharmaceutical Company Limited 3-((1H-pyrazol-4-yl)methyl)-6′-(phenyl)-2H-(1,2′-bipyridin)-2-one derivatives and related compounds as GPR139 antagonists for use in a method of treatment of e.g. depression
CN117396480A (zh) * 2021-03-26 2024-01-12 奥弗恩制药公司 吡唑并嘧啶酮化合物
WO2023147336A3 (fr) * 2022-01-26 2023-09-28 University Of Florida Research Foundation, Incorporated Modulateurs à petites molécules du complexe gpr139
WO2023165263A1 (fr) * 2022-03-01 2023-09-07 上海科技大学 Composé de pyrrolotriazinone, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
WO2023165262A1 (fr) * 2022-03-01 2023-09-07 上海科技大学 Composé hétérocyclique contenant un thiéno-azote, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
WO2024087783A1 (fr) * 2022-10-28 2024-05-02 浙江友宁生物医药科技有限公司 Agoniste du récepteur gpr139, son procédé de préparation et son application

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