WO2020097609A1 - Gpr139 receptor modulators - Google Patents

Gpr139 receptor modulators Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
hydrate
isotope
racemate
solvate
salt
Prior art date
Application number
PCT/US2019/060788
Other languages
French (fr)
Inventor
Robert M. Jones
Gary Brandt
Original Assignee
Blackthorn Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Blackthorn Therapeutics, Inc. filed Critical Blackthorn Therapeutics, Inc.
Publication of WO2020097609A1 publication Critical patent/WO2020097609A1/en

Links

Classifications

    • 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, ***e, 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).

Abstract

Compounds are provided that modulate the GPR139 receptor, compositions containing the same, and to methods of their preparation and use for treatment of a malcondition wherein modulation of the GPR139 receptor is medically indicated or beneficial. Such compounds have the structure of Formula (X) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R1, R2, R3, R4, R9, R10, R11, and R12, Q5, Q6, Q7 and Q8 are as defined herein.

Description

GPR139 RECEPTOR MODULATORS
FIELD OF THE INVENTION
The invention relates to modulators of the GPR139 receptor and to products containing the same, as well as to methods of their use and preparation.
BACKGROUND
G-protein coupled receptors (GPCRs) are the largest family of cell surface communicating molecules, and are associated with numerous physiological processes and disease conditions. GPCRs share high levels of homology and contain seven transmembrane helices separated by intra- and extracellular loops. They signal via heterotrimeric G proteins composed of Ga, b, and g subunits, and there are four major Ga protein subfamilies: Gq, Gs, Gi, and G12/13.
The human GPR139 gene has been identified, and the human GPR139 protein (also known as hGPRgl or 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. The consistent expression of GPR139 mRNA in the CNS of different species provides evidence that it plays specific roles in the modulation of brain functions, and GPR139 has been implicated as a potential drug target for any number of conditions, including diabetes, obesity and Parkinson's disease (Wang et al, Acta Pharmacologica Sinica, 36:874-878, 2015).
GPR139 has also been reported as having strong expression in the medial habenular nucleus of mice, which is involved in pain processing, reproductive behavior, nutrition, sleep -wake cycles, stress responses and learning. In view of recent findings showing calcifications in the pineal and habenula of patients suffering from schizophrenia, as well as altered activation of the habenula in such patients, modulators of GPR139 have also been identified as a target for treating schizophrenia and other CNS disorders such as depression (see WO2016/081736).
Due to its interest as a drug target, a number of groups have reported small molecule ligands, both agonists and antagonists, for GPR139. For example, Shi et al. (ACS Med Chem Lett 2:303-6, 2011) reported GPR139 receptor agonists in a calcium mobilization assay for CHO-K1 cell line stably expressing the human GPR139 for high-throughput screening. Hu et al. (J Biomol Screen 14:789-97, 2009) identified both agonists and antagonists of GPR139 after screening a large number of small molecules. Similarly, Wang et al. (Id.) identified GPR139 antagonists following a high- throughput screen, again using a calcium mobilization assay. Dvorak et al. (ACS Med Chem Lett 6(9): 1015-1018, 2015) focused on high-throughput screening to identify GPR139 agonists, and Isberg et al. (J Chem Inf Model 54(6): 1552-1557, 2014) employed computer-aided techniques to aid in the identification of GPR139 agonists.
Accordingly, compounds which serve to modulate the GPR139 receptor provide significant promise for the treatment of a variety of disorders. While advances have been made in this field, there remains a significant need for agents that modulate the GPR139 receptor, as well as for products containing the same, and for methods related to both their use and manufacture.
SUMMARY OF THE INVENTION
The present invention is directed to compounds that modulate the GPR139 receptor, to compositions containing the same, and to methods of their preparation and use for treatment of malconditions wherein modulation of the GPR139 receptor is medically indicated or beneficial. In one embodiment, the compound modulates the GPR139 receptor by agonizing the receptor; for example, by functioning as a GPR139 receptor agonist or as a GPR139 receptor partial agonist. In one embodiment, compounds are provided having the structure of Formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R101, R102, R103, R104, R106, R107, R108, R109, R110, R111, and R112 are as defined herein below.
In one embodiment, compounds are provided having the structure of Formula (II):
Figure imgf000004_0002
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R201, R202, R203, R204, R205, R208, R209, R210, R211, R212, Q206, and Q207 are as defined herein below. In one embodiment, compounds are provided having the structure of Formula (III):
Figure imgf000005_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R301, R302, R303, R304, R305, R306, R307, R309, R310, R311, and R312 are as defined herein below.
In one embodiment, compounds are provided having the structure of Formula (IV):
Figure imgf000005_0002
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R401, R402, R403, R404, R405, R406, R407, R408, R409, R410, R411, and R412, Q409 , Q410 and Q412 are as defined herein below.
In another embodiment, a pharmaceutical composition is provided comprising a compound having the structure of Formula (I), Formula (II), Formula (III), 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.
In another embodiment, use 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, for the manufacture of a medicament is provided.
In another embodiment, a method is provided for modulating the GPR139 receptor by contacting the receptor with an effective amount of a compound having the structure of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising the same. In more specific embodiments, the compound is a GPR139 receptor agonist or partial agonist.
In another embodiment, a method is provided for treatment of a condition for which modulation of the GPR139 receptor is medically indicated, comprising administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), Formula (II), Formula (III), 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.
In one embodiment, a method is provided for treating a neurobehavioral disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), Formula (II), Formula (III), 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.
In another embodiment, a method is provided for synthesis 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. DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the invention relates to compounds that modulate the GPR139 receptor, to products comprising the same, and to methods for their use and synthesis. A compound that "modulates" the GPR139 receptor (also referred to herein as a GPR139 "modulator") means that the compound interacts with the GPR139 receptor in a manner such that it functions as an agonist or antagonist to the receptor, or functions as a partial agonist, inverse agonist, or allosteric modulator, or any combination thereof. In one embodiment, the compound is a GPR139 agonist. In another embodiment, the compound is a GPR139 partial agonist. As used herein, "lower alkyl" means a straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms. Examples of straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl-, n-hexyl, n-heptyl, and n-octyl groups. Examples of 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. "Hydroxy" refers to–OH.
"Cyano"" refers to -CN.
"Lower haloalkyl" refers to a lower alkyl as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkyl groups include, but are not limited to, ˗CF3, ˗CH2CF3, and the like.
"Lower alkoxy" refers to a lower alkyl as defined above joined by way of an oxygen atom (i.e., ˗O˗(lower alkyl). Examples of 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). Examples of lower haloalkoxy groups include, but are not limited to, ˗OCF3, ˗OCH2CF3, and the like. "Cycloalkyl" refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring do not give rise to aromaticity. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclochexenyl, cyclohexa-l,3- dienyl, cycloheptenyl, and cyclooctenyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, 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. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons in the ring portions of the groups. The phrase "aryl groups" includes groups containing fused rings, such as fused aromatic- aliphatic ring systems (e.g., indanyl, tetrahy dronaphthyl , and the like). In one embodiment, aryl is phenyl or naphthyl, and in another embodiment aryl is phenyl.
"Carbocycle," "carbocyclyl" or "carbocyclic" refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi -electrons in the ring may give rise to aromaticity. In one embodiment, carbocycle includes cycloalkyl as defined above. In another embodiment, carbocycle includes aryl as defined above.
"Heterocycle," "heterocyclyl" or "heterocyclic" refers to aromatic and non-aromatic ring moieties containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P. In some embodiments, heterocyclyl includes 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom. For example, a dioxolanyl ring and a
benzdioxolanyl ring system (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,
benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,
thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.
"Heteroaryl" refers to aromatic ring moieties containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. "Isomer" is used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the invention. The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers." Single enantiomers of a pure compound are optically active (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. For example, the isolated isomer may be at least 80%, at least 82%, at least 84%, at least 86%, or at least 88% pure by weight. In other embodiments, the isolated isomer is at least 90% pure. In another embodiment, the isolated isomer is at least 95% pure, at least 98% pure, or at least 99% pure by weight.
"Substantially enantiomerically or diastereomerically" pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.
The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled "(±)" because it is not optically active (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. As the term is used herein a "hydrate" refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.
A "solvate" is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non- stoi chi ometri c . As the term is used herein a "solvate" refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.
"Isotope" refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formula (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has a number of isotopes, fluorine 18 is longest-lived. Thus, an isotope of a compound having the structure of Formula (I) includes, but not limited to, compounds of Formula (I) wherein one or more carbon 12 atoms are replaced by carbon- 13 and/or carbon- 14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine- 18.
"Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as "acid addition salts". Conversely, salts formed between bases in the cationic form and anions are referred to as "base addition salts."
Co-crystal forms of compounds having the structure of Formula (I) are also included within the scope of this invention; namely, solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts.
The term "pharmaceutically acceptable" refers an agent that has been approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to non-toxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).
Pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include
hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, b-hydroxybutyric,
salicylic, -galactaric, and galacturonic acid.
Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of compounds having the structure of Formula I, for example in their purification by recrystallization. In one embodiment, compounds are provided having the structure of Formula (I):
Figure imgf000013_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R101 is H or lower alkyl;
R102 is H, lower alkyl, or carbocyclyl;
R103 is H or lower alkyl;
or R102 and R103, together with the atom to which they are attached, form a C3-C6 cycloalkyl;
R104, R109, R110, R111, and R112 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;
R106, R107, and R108 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 R104, R106, R107, R108, R109, R110, R111, and R112 are each, independently, optionally substituted by one or more R'; and
each R' is, independently, halo, -OH, lower alkyl, lower haloaklyl, or lower alkoxy. 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 R102 is lower alkyl.
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 R102 is methyl, ethyl, or isopropyl.
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 R102 is methyl.
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 R102 carbocycle.
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 R102 is C3-C6 cycloalkyl.
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 R102 is cyclopropyl.
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 R103 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 R102 and R103 together with the atom to which they are attached form C3-C6 cycloalkyl.
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 R102 and R103 together with the atom to which they are attached form cyclopropyl. 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 R109, R111, and R112 are 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 R104 is H, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, or C3-C6 cycloalkyl.
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 R104 is methyl.
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 R104 is F or Cl.
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 R104 is haloalkoxy.
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 R104 is–OCF3.
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 R104 is cyclopropyl.
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 R110 is H, halo, or lower alkyl.
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 R110 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 R110 is F or Cl. 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 R110 is lower alkyl. In another embodiment, R110 is methyl.
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 R106 is H, halo, lower alkyl, lower alkoxy, carbocycle, or heterocycle.
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 R106 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 R106 is halo.
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 R106 is F or Cl.
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 R106 is lower alkyl.
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 R106 is methyl.
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 R106 is lower alkoxy.
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 R106 is methoxy.
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 R106 is carbocycle. 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 R106 is C3-C6 cycloalkyl.
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 R106 is cyclopropyl.
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 R106 is heterocycle.
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 R106 is
Figure imgf000017_0001
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 R107 is H, halo, lower alkyl, lower alkoxy, carbocycle, or heterocycle.
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 R107 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 R107 is halo.
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 R107 is F or Cl.
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 R107 is lower alkyl. 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 R107 is methyl.
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 R107 is lower alkoxy.
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 R107 is methoxy.
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 R107 is carbocycle.
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 R107 is C3-C6 cycloalkyl.
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 R107 is cyclopropyl.
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 R107 is heterocycle.
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 R107 is morpholino.
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 R108 is H, halo, lower alkyl, lower haloalkyl, lower alkoxy, -NR2, carbocycle, heterocycle, or -NR-heterocyclyl.
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 R108 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 R108 is halo.
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 R108 is I.
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 R108 is Cl or F.
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 R108 is lower alkyl.
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 R108 is methyl.
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 R108 is lower haloalkyl.
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 R108 is–CF3.
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 R108 is lower alkoxy.
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 R108 is methoxy.
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 R108 is -NR2. 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 R108 is–NHCH3 or -NHCH2CHF2.
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 R108 is carbocycle.
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 R108 is C3-C6 cycloalkyl.
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 R108 is cyclopropyl.
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 R108 is heterocycle.
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 R108 is morpholino.
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 R108 is -NR-heterocyclyl.
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
Figure imgf000020_0001
.
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 R101 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 R101 is methyl. 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 R111 is H or lower alkyl.
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 R111 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 R111 is lower alkyl. In another embodiment, R111 methyl.
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 R112 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 R112 is halo.
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 R112 is F or Cl.
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 R104 and R112 are each, independently, halo.
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 R104 is methyl and R112 is F or Cl.
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 R104 and R112 are each, independently, F or Cl.
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 R104 and R112 are each, independently, halo, and R106, R107, and R108 are each, independently, H, halo, lower alkyl, cycloalkyl, or lower alkoxy. 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 R104 and R112 are each, independently, F or Cl, and R106, R107, and R108 are each, independently, H, halo, lower alkyl, cycloalkyl, or lower alkoxy.
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 R104 and R112 are each, independently, F or Cl, and R106 is Cl.
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 R104 and R112 are each, independently, F or Cl, and R106 is cyclopropyl.
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 R104 and R112 each, independently, F or Cl, and R106 is methoxy.
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 R104 and R110 are each, independently, halo.
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 R104 and R110 are each, independently, F or Cl.
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 R104 and R110 are each, independently, halo, and R106, R107, and R108 are each, independently, H, halo, lower alkyl, cycloalkyl, lower alkoxy, -NR2, heterocycle, or -NR-heterocyclyl.
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 R104 and R110 are each, independently, F or Cl, and R106, R107, and R108 are each, independently, H, halo, lower alkyl, cycloalkyl, lower alkoxy, -NR2, heterocycle, or -NR-heterocyclyl. 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 R104 and R110 are each, independently, F or Cl, and R106, R107, and R108 are each, independently, H, F, Cl, or I.
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 R104 and R110 are each, independently, F or Cl, and R106, R107, and R108 are each, independently, H or cyclopropyl.
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 R104 and R110 are each, independently, F or Cl, and R106, R107, and R108 are each, independently, H or methyl.
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 R104 and R110 are each, independently, F or Cl, and R106, R107, and R108 are each, independently, H or methoxy.
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 R104 and R110 are each, independently, F or Cl, and R106, R107, and R108 are each, independently, H, -NHCH3, morpholino,
Figure imgf000023_0001
.
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
Representative Compounds
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
In one embodiment, compounds are provided having the structure of Formula (II):
Figure imgf000034_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R201 is H;
R202 is lower alkyl;
R203 is H;
R204, R209, R210, R211, and R212 are each, independently, H, halo, lower alkyl, lower alkoxy, or lower haloalkoxy;
Q206 is N and Q207 is CR207, or Q206 is CR206 and Q207 is N; R205, R206, R207, and R208 are each, independently, H, halo, -NR2, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl, -O-heterocyclyl, -NR-carbocyclyl, or -NR-heterocyclyl;
wherein R204, R205, R206, R207, R208, R209, R210, R211, and R212 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 Q207 is CR207, then R207 is not phenyl. In another embodiment, compounds are provided having the structure of Formula (II-A):
Figure imgf000035_0002
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R201, R202, R203, R204, R205, R207, R208, R209, R210, R211, R212 are as defined as above. In yet another embodiment, compounds are provided having the structure of Formula (II-B):
Figure imgf000035_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R201, R202, R203, R204, R205 , R206, R208, R209, R210, R211, R212 are as defined as above. 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 R202 is methyl, ethyl, or isopropyl.
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 R202 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 R203 is H.
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 R209 is H.
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 R211 is H.
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 R204 is halo, lower alkyl, or lower haloalkoxy.
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 R204 is H.
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 R204 is halo. In another embodiment, R204 is F or Cl.
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 R204 is lower alkyl. In another embodiment, R204 is lower alkyl. In another embodiment, R204 is methyl, ethyl, or isopropyl. In yet another embodiment, R204 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 R204 is lower haloalkoxy. In another embodiment, R204 is -OCF3. 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 R210 is H or halo.
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 R210 is H.
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 R210 is halo. In another embodiment, R210 is F or Cl.
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 R212 is H or halo.
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 R212 is H.
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 R212 is halo. In another embodiment, R212 is F or Cl.
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 R205 is H, lower alkyl, carbocycle, or heterocycle.
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 R205 is H.
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 R205 is lower alkyl. In another embodiment, R205 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 R205 is carbocycle. In another embodiment, R205 is C3-C6 cycloalkyl. In another embodiment, R205 is cyclopropyl.
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 R205 is heterocycle. In another embodiment, R205 is
Figure imgf000038_0001
.
In one embodiment, 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 R206 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
In one embodiment, 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 R206 is H.
In one embodiment, 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 R206 is halo. In another embodiment, R206 is Cl.
In one embodiment, 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 R206 is lower alkyl. In another embodiment, R206 is methyl.
In one embodiment, 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 R206 is lower alkoxy. In another embodiment, R206 is methoxy.
In one embodiment, 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 R206 is carbocycle. In another embodiment, R206 is C3-C6 cycloalkyl. In another embodiment R206 is cyclopropyl.
In one embodiment, 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 R207 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
In one embodiment, 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 R207 is H.
In one embodiment, 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 R207 is halo. In another embodiment, R207 is Cl.
In one embodiment, 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 R207 is lower alkyl. In another embodiment, R207 is methyl.
In one embodiment, 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 R207 is lower alkoxy. In another embodiment, R207 is methoxy.
In one embodiment, compounds having the structure of Formula (II) or (II-A) are provided wherein R207 is carbocycle. In another embodiment, R207 is
C3-C6 cycloalkyl. In another embodiment, R207 is cyclopropyl.
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 R208 is H, lower alkyl, lower haloalkyl, lower alkoxy, -NR2, carbocycle, heterocycle, substituted heterocycle, -O-heterocyclyl, substituted -O-heterocyclyl, or -NR-heterocyclyl.
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 R208 is H. 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 R208 is lower alkyl. In another embodiment, R208 is methyl.
In one embodiment, compounds having the structure of Formula
Formula (II), (II-A) or (II-B) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is lower haloalkyl. In another embodiment, R208 is -CHF2.
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 R208 is lower alkoxy. In another embodiment, R208 is methoxy.
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 R208 is -NR2. In another embodiment, R208 is -NHCH3.
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 R208 is carbocycle. In another embodiment, R208 is C3-C6 cycloalkyl. In another embodiment, R208 is cyclopropyl.
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 R208 is heterocycle. In another embodiment, R208 is
Figure imgf000040_0001
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 R208 is substituted heterocycle. In
another embodiment,
Figure imgf000041_0001
.
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 R208 is -O-heterocyclyl. In another embodiment, R208 is
Figure imgf000041_0002
.
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 R208 is substituted -O-heterocyclyl. In another embodiment,
Figure imgf000041_0003
.
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 R208 is -NR-heterocyclyl. In another embodiment, R208 is
Figure imgf000041_0004
.
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 R201 is H.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R212 are halo, and R205, R206, and R208 are each, independently, H, halo, lower alkoxy, carbocycle, or heterocycle.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R212 are F or Cl, and R205, R206, R207, and R208 are each, independently, H, halo, lower alkoxy, carbocycle, or heterocycle.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R212 are halo, and R205 is carbocycle, or heterocycle. In another embodiment, R204 and R212 are each, independently, F or Cl, and R205 is cyclopropyl or
Figure imgf000042_0001
.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R212 are halo, and R206 is halo, lower alkoxy, or carbocycle. In another embodiment, R204 and R212 are each, independently, F or Cl, and R206 is Cl, methoxy, or cyclopropyl.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R212 are halo, and R208 is lower alkoxy or carbocycle. In another embodiment, R204 and R212 are each, independently, F or Cl, and R208 is methoxy or cyclopropyl.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R210 are halo. In another embodiment, R204 and R210 are F or Cl.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R210 are halo, and R205, R207, and R208 are each, independently, H, halo, lower alkyl, lower alkoxy, -NR2, carbocycle, heterocycle, or -O-heterocyclyl.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R210 are F or Cl, and R205, R207, and R208 are each, independently, H, halo, lower alkyl, lower alkoxy, -NR2, carbocycle, heterocycle, or -O-heterocyclyl.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R210 are halo, and R205 is carbocycle or heterocycle. In another embodiment, R204 and R210 are each, independently, F or Cl, and R205 is
cyclopropyl
Figure imgf000043_0001
.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R210 are halo, and R207 is halo, lower alkoxy, or carbocycle. In another embodiment, R204 and R210 are each, independently, F or Cl, and R207 is Cl, methoxy, or cyclopropyl.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 and R210 are halo, and R208 is lower alkyl, lower alkoxy, -NR2, carbocycle, heterocycle, substituted heterocycle, -O-heterocyclyl, or substituted -O-heterocyclyl. In another embodiment, R204 and R210 are each, independently, F or
Cl, and R208 is methyl, methoxy, cyclopropyl,
Figure imgf000043_0002
,
Figure imgf000043_0003
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is lower alkyl or lower haloalkoxy, and R206 and R208 are each independently, H, lower alkyl, lower haloalkyl, or -N-heterocyclyl. In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is lower alkyl or lower haloalkoxy, and R206 is lower alkyl. In another embodiment, R204 is methyl or–OCF3, and R206 is methyl.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is lower haloalkoxy, and R208 is lower alkyl, lower haloalkyl, or -N-heterocyclyl. In another embodiment, R204 is–OCF3, and R208 is methyl,–CHF2, or
Figure imgf000044_0001
.
In one embodiment, compounds having the structure of Formula (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is halo, or lower alkyl, and R205 and R207 are lower alkyl. In another embodiment, R204 is Cl or methyl, and R205 and R207 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."
Table 2
Representative Compounds
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0002
In one embodiment, compounds are provided having the structure of Formula (III):
Figure imgf000055_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R301 is H or lower alkyl;
R302 is methyl and R303 is H;
R304, R309, R310, R311, and R312 are each, independently, H, halo, lower alkyl, lower alkoxy, lower haloalkoxy, or carbocyclyl;
R305, R306, and R307 are each, independently, H, halo, lower alkyl, lower alkoxy, or carbocyclyl; and
and wherein R304, R305, R306, R307, R309, R310, R311, and R312 are each, independently, optionally substituted by one or more R'; and
each R' is, independently, halo. 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 R302 is lower alkyl.
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 R302 is methyl.
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 R303 is H.
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 R309 is H.
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 R311 is H or lower alkyl.
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 R311 is H.
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 R311 is lower alkyl. In another embodiment, R311 is methyl.
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 R304 is halo, lower alkyl, lower haloalkoxy, or carbocycle.
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 R304 is H.
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 R304 is halo. In another embodiment, R304 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 R304 is lower alkyl. In another embodiment, R304 is methyl.
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 R304 is lower haloalkoxy. In another embodiment, R304 is–OCF3 or -OCHF2.
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 R304 is carbocycle. In another embodiment, R304 is
C3-C6 cycloalkyl. In another embodiment, R304 is cyclopropyl.
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 R310 is H or halo.
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 R310 is H.
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 R310 is halo. In another embodiment, R310 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 R312 is H or halo.
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 R312 is H.
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 R312 is halo. In another embodiment, R312 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 R305 is H, lower alkyl, or carbocycle.
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 R305 is H.
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 R305 is lower alkyl. In another embodiment, R305 is methyl.
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 R305 is carbocycle. In another embodiment, R305 is
C3-C6 cycloalkyl. In another embodiment, R305 is cyclopropyl.
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 R306 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
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 R306 is H.
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 R306 is halo. In another embodiment, R306 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 R306 is lower alkyl. In another embodiment, R306 is methyl.
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 R306 is lower alkoxy. In another embodiment, R306 is methoxy.
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 R306 is carbocycle. In another embodiment, R306 is
C3-C6 cycloalkyl. In another embodiment, R306 is cyclopropyl.
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 R307 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
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 R307 is H.
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 R307 is halo. In another embodiment, R307 is 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 R307 is lower alkyl. In another embodiment, R307 is methyl.
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 R307 is lower alkoxy. In another embodiment, R307 is methoxy.
In one embodiment, compounds having the structure of Formula (III) are provided wherein R307 is carbocycle. In another embodiment, R307 is C3-C6 cycloalkyl. In another embodiment, R307 is cyclopropyl.
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 R301 is H or lower alkyl.
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 R301 is H.
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 R301 is lower alkyl. In another embodiment, R301 is methyl.
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 R304, R310, R311, and R312 are each independently H, halo, lower alkyl, lower alkoxy, lower haloalkoxy or carbocyle.
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 R304 is halo, lower alkyl, lower haloalkoxy, or carbocyle, and R310 is halo. In another embodiment, R304 is Cl, methyl,–OCF3, or cyclopropyl, and R310 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 R304 is halo, and R311 is lower alkyl. In another embodiment, R304 is Cl and R311 is methyl.
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 R304 is lower haloalkoxy, and R312 is halo. In another embodiment, R304 is–OCHF2, and R312 is F.
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 R304 is halo, R310 halo, and R301 is lower alkyl. In another embodiment, R304 is Cl, R310 is F, and R301 is methyl.
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 R304, R310, and R312 are each independently H, halo, lower alkyl, lower alkoxy, lower haloalkoxy or carbocyle, and R305, R306, and R307 are each independently H, halo, lower alkyl, lower alkoxy, lower haloalkoxy, or carbocycle.
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 R304 is lower haloalkoxy, and R305 is lower alkyl. In another embodiment, R304 is–OCF3, and R305 is methyl.
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 R304 is halo, R305 is lower alkyl, and R307 is lower alkyl. In another embodiment, R304 is Cl, R305 is methyl, and R307 is methyl.
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 R304 is halo or lower haloalkoxy, and R306 is halo, lower alkyl, or lower alkoxy. In another embodiment, R304 is Cl or–OCF3, and R306 is F, methyl, or methoxy.
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 R304 is halo, lower alkyl, or lower haloalkoxy, and R307 is lower alkyl, or lower alkoxy. In another embodiment, R304 is Cl, methyl, or–OCF3, and R307 is methyl, or methoxy.
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 R304 is halo, R310 is halo, and R305 is lower alkyl or carbocycle. In another embodiment, R304 is F or Cl, R310 is F or Cl, and R305 is methyl or cyclopropyl.
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 R304 is halo or lower haloalkoxy, R310 is halo, and R306 is halo, lower alkyl, or carbocycle. In another embodiment, R304 is Cl or–OCF3, R310 is F, and R306 is F, Cl, methyl, or cyclopropyl.
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 R304 is halo, R310 is halo, and R307 is lower alkyl, lower alkoxy, or carbocycle. In another embodiment, R304 is F or Cl, R310 is F or Cl, and R307 is methyl, methoxy, or cyclopropyl.
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 R304 is halo, R310 is halo, and R306 is lower alkyl, and R307 is lower alkoxy. In another embodiment, R304 is Cl, R310 is F, and R306 is methyl, and R307 is methoxy.
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 R304 is halo, R312 is halo, and R306 is halo, lower alkyl, lower alkoxy, or carbocycle. In another embodiment, R304 is F or Cl, R312 is F or Cl, and R306 is F, Cl, methyl, methoxy, or cyclopropyl.
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 R304, R312, and R307 are halo. In another embodiment, R304 is F or Cl, R312 is F or Cl, and R307 is 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 R304 is halo, R312 is halo, R305 is lower alkyl, and R307 is lower alkyl. In another embodiment, R304 is Cl, R312 is F, R305 is methyl, and R307 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.”
Table 3
Representative Compounds
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0002
In one embodiment, compounds are provided having the structure of Formula (IV):
Figure imgf000072_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R401 is H or lower alkyl;
R402 is H, lower alkyl, or carbocyclyl;
R403 is H or lower alkyl;
or R402 and R403, together with the atom to which they are attached, form a C3-C6 cycloalkyl;
R404, R409, R410, R411, and R412 are each, independently, H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or aryl; Q409, Q410, and Q412 are each independently C or N;
R405, R406, R407, and R408 are each, independently, H, halo, -CN, -NR2, -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;
and wherein R404, R405, R406, R407, R408, R409, R410, R411, and R412 are each, independently, optionally substituted by one or more R'; and
each R' is, independently, halo, -OH, lower alkyl, lower haloaklyl, or lower alkoxy.
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 R402 is lower alkyl.
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 R402 is methyl.
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 R402 is carbocycle.
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 R402 is C3-C6 cycloalkyl.
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 R402 is cyclopropyl.
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 R403 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 R402 and R403, together with the atom to which they are attached, form a C3-C6 cycloalkyl.
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 R402 and R403, together with the atom to which they are attached, form cyclopropyl.
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 R409 is H or lower alkyl.
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 R409 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 R409 is lower alkyl.
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 R409 is methyl.
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 R411 is H, halo, or lower alkyl.
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 R411 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 R411 is halo.
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 R411 is F. 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 R411 is lower alkyl.
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 R411 is methyl.
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 R404 is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or aryl.
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 R404 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 R404 is halo.
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 R404 is F or Cl.
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 R404 is lower alkyl.
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 R404 is methyl.
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 R404 is lower alkoxy.
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 R404 is–OCH(CH3)2. 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 R404 is lower haloalkyl.
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 R404 is–CF3.
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 R404 is lower haloalkoxy.
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 R404 is–OCF3 or–OCHF2.
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 R404 is aryl.
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 R404 is phenyl.
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 R410 is H, halo, or lower alkyl.
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 R410 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 R410 is halo.
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 R410 is F or Cl. 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 R410 is lower alkyl.
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 R410 is methyl.
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 R412 is H or halo.
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 R412 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 R412 is halo.
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 R412 is F.
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 R405 is H, halo, lower alkoxy, heterocycle, or substituted heterocycle.
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 R405 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 R405 is halo.
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 R405 is F or Br. 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 R405 is lower alkoxy.
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 R405 is methoxy.
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 R405 is heterocycle.
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 R405 is
Figure imgf000078_0001
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 R405 is substituted heterocycle.
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 R405 is
Figure imgf000078_0002
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 R406 is H, halo, -CN, lower alkyl, lower alkoxy, or carbocycle.
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 R406 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 R406 is halo.
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 R406 is F, Cl, or Br.
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 R406 is -CN.
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 R406 is lower alkyl.
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 R406 is methyl.
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 R406 is lower alkoxy.
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 R406 is methoxy.
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 R406 is carbocycle.
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 R406 is C3-C6 cycloalkyl.
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 R406 is cyclopropyl. 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 R407 is H, halo, -CN, lower alkyl, lower alkoxy, carbocycle, substituted carbocycle, aryl, heterocycle, substituted heterocycle, -O-heterocyclyl, or -NR-heterocyclyl.
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 R407 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 R407 is halo.
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 R407 is F, Cl, or I.
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 R407 is -CN.
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 R407 is lower alkyl.
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 R407 is methyl.
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 R407 is lower alkoxy.
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 R407 is methoxy. 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 R407 is carbocycle.
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 R407 is C3-C6 cycloalkyl.
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 R407 is cyclopropyl or cyclobutyl.
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 R407 is substituted carbocycle.
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 R407 is
Figure imgf000081_0001
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 R407 is aryl.
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 R407 is phenyl.
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 R407 is heterocycle.
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 R407 is
Figure imgf000081_0002
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 R407 is substituted heterocycle.
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 R407 is
Figure imgf000082_0001
Figure imgf000082_0002
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 R407 is -O-heterocyclyl.
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 R407 is
Figure imgf000082_0003
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 R407 is -NR-heterocyclyl.
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 R407 is
Figure imgf000082_0004
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 R408 is H, halo, -NR2, -NRC(O)OR, lower alkoxy, heterocycle, or substituted heterocycle. 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 R408 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 R408 is halo.
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 R408 is F or Cl.
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 R408 is -NR2.
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 R408 is -NH2, -NHCH3, or
Figure imgf000083_0001
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 R408 is -NRC(O)OR.
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 R408 is -NHC(O)OC(CH3)3.
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 R408 is heterocycle.
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 R408 is
Figure imgf000083_0002
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 R408 is substituted heterocycle.
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 R408 is
Figure imgf000084_0001
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 R401 is H or lower alkyl.
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 R401 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 R401 is lower alkyl.
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 R401 is methyl.
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 R404, R410, and R411 are each independently H, halo, lower alkyl, or lower haloalkoxy.
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 R404 is halo, lower alkyl, or lower haloalkoxy, and R410 is halo or lower alkyl. 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 R404 is Cl, methyl, or–OCHF2, and R410 is F, Cl, or methyl.
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 R404 is halo, and R411 is halo or lower alkyl.
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 R404 is Cl, and R411 is F or methyl.
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 R404 and R401 are lower alkyl.
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 R404 is methyl, and R401 is methyl.
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 R404, R405, R406, R407, and R408 are each independently H, halo, -NR2, -NRC(O)OR, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, carbocycle, heterocycle, substituted heterocycle, or -O-heterocyclyl.
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 R404 is halo, lower alkyl, or lower haloalkoxy, and R405 is halo, lower alkoxy, heterocycle, or substituted heterocycle.
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 R404 is Cl, methyl, or–OCF3, and R405 is F, Br, methoxy,
Figure imgf000085_0001
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 R404 is halo, lower alkyl, lower haloalkyl, or lower haloalkoxy, and R406 is halo, lower alkyl, lower alkoxy, or carbocycle.
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 R404 is Cl, methyl,–CF3, or–OCF3, and R406 is F, Br, methyl, methoxy, or cyclopropyl.
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 R404 is lower alkyl or lower haloalkoxy, and R407 is halo, lower alkyl, lower alkoxy, heterocycle, substituted heterocycle, or -O-heterocyclyl.
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 R404 is methyl or–OCF3, and R407 is Cl, methyl, methoxy,
Figure imgf000086_0001
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 R404 is lower alkyl, and R408 is halo,–NR2,–NRC(O)OR, lower alkoxy, heterocycle, or substituted heterocycle.
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 R404 is methyl, and R408 is F, Cl, methoxy,–NH2,–NHCH3,
Figure imgf000086_0002
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 R404 and R410 are halo, and R401 is lower alkyl.
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 R404 is Cl, R410 is F, and R401 is methyl.
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 R404 and R406 are halo, and R402 and R403, together with the atom to which they are attached, form a C3-C6 cycloalkyl.
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 R404 is Cl, R406 is F, and R402 and R403, together with the atom to which they are attached, form cyclopropyl.
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 R410 and R406 are halo, and R402 and R403, together with the atom to which they are attached, form a C3-C6 cycloalkyl.
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 R410 is Cl, R406 is F, and R402 and R403, together with the atom to which they are attached, form cyclopropyl.
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 R404, R410, R405, R406, R407, and R408 are each independently H, halo, -CN, lower alkyl, lower alkoxy, carbocycle, substituted carbocycle, heterocycle, substituted heterocycle, or–N-heterocyclyl.
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 R404 is halo or lower alkyl, R410 is halo, and R405 is heterocycle or substituted heterocycle. 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 R404 is Cl or methyl, R410 is F or Cl, and R405 is
Figure imgf000088_0002
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 R404 is halo or lower alkyl, R410 is halo, and R406 is halo, -CN, lower alkyl, lower alkoxy, or carbocycle.
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 R404 is F, Cl, or methyl, R410 is F or Cl, and R406 is F, Cl, -CN, methyl, methoxy, or cyclopropyl.
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 R404 is halo or lower alkyl, R410 is halo, and R407 is halo,–CN, lower alkyl, lower alkoxy, carbocycle, substituted carbocycle, aryl, or -N-heterocyclyl.
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 R404 is F, Cl, or methyl, R410 is F or Cl, and R407 is F, Cl, I,–
CN, methyl, methoxy, or cyclopropyl, cyclobutyl, phenyl,
Figure imgf000088_0003
, or
Figure imgf000088_0001
.
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 R404 and R410 are halo, and R408 is heterocycle or substituted heterocycle.
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 R404 is Cl, R410 is F, and R408 is
Figure imgf000089_0001
or
Figure imgf000089_0002
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 R404, R409, and R411 are lower alkyl, and R407 is lower alkoxy.
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 R404, R409, and R411 are methyl, and R407 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.”
Table 4
Representative Compounds
Cpd. No. Structure
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0002
In one embodiment, compounds are provided having the structure of Formula (X):
Figure imgf000109_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q5 is N or CR5;
Q6 is N or CR6; Q7 is N or CR7;
Q8 is N or CR8;
R1 is H or lower alkyl;
R2 is H, lower alkyl, or carbocyclyl;
R3 is H or lower alkyl;
or R2 and R3, together with the atom to which they are attached, form a C3-C6 cycloalkyl;
R4, R9, R10, R11, and R12 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;
R5, R6, R7, and R8 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 R4, R6, R7, R8, R9, R10, R11, and R12 are each, independently, optionally substituted by one or more R'; and
each R' is, independently, halo, -OH, lower alkyl, lower haloaklyl, lower alkoxy, or -C(O)OR. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols,
polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl 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. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances, preserving agents, sweetening agents, or flavoring agents. The compositions can also be sterilized if desired.
The route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment, the oral route being preferred.
For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid solubility or serve as preservatives can also be included. Furthermore, injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, and the like can be employed.
For topical administration, the compounds of the present invention can be formulated using bland, moisturizing bases such as ointments or creams.
If a solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer’s solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di-, or tri-glycerides.
For injection, the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried, or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations can optionally contain stabilizers, pH modifiers, surfactants,
bioavailability modifiers, and combinations of these. The compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection can be in ampoules or in multi dose containers.
The formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations can also be formulated for controlled release or for slow release.
Compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections. Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
For nasal administration, the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application. The carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin
(phosphatidylcholine) or cyclodextrin, or preservatives such as parabens. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment and/or to minimize or avoid unwanted side effects associated with the treatment. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians' Desk Reference, incorporated herein by reference.
When used to prevent the onset of a malcondition, the compounds provided herein will be administered to a subject at risk for developing the same, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular malcondition generally include those that have a family history of the same, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the malcondition.
Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject's life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
In another embodiment, there are provided methods of making a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
In another embodiment, a method is provided for modulating the GPR139 receptor, and the method comprises contacting the receptor with an effective amount of a compound having the structure of any one of Formula (I), (II), (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.
As used herein, the phrase "modulating the GPR139 receptor" means that the compound interacts with the GPR139 receptor in a manner such that it functions as an agonist or antagonist to the receptor, or functions as a partial agonist, inverse agonist or allosteric modulator, or any combination thereof. Thus, in one embodiment, the compound is a GPR139 agonist, and in another embodiment is a GPR139 antagonist. In further embodiments, the compound is a partial agonist, inverse agonist or allosteric modulator or GPR139.
The term "agonism" is used herein to encompass compounds that interact in some way with a receptor and thereby function as an agonist, either by binding to the receptor at the binding site of its natural ligand or at locations other than the binding site. Thus, the phrase to "GPR139 agonism" is used herein to encompass compounds that interact in some way with the GPR139 receptor and thereby function as an agonist, either by binding to the GPR receptor at the binding site of its natural ligand, or at a location other than the binding site (i.e., allosteric binding).
Conversely, the term "antagonism" is used herein to encompass compounds that interact in some way with a receptor and thereby function as an antagonist, either by binding to the receptor at the binding site of its natural ligand or at locations other than the binding site. Thus, the phrase to "GPR139 antagonism" is used herein to encompass compounds that interact in some way with the GPR139 receptor and thereby function as an antagonist, either by binding to the GPR receptor at the binding site of its natural ligand, or at a location other than the binding site (i.e., allosteric binding). A partial agonist is compound that binds to and activates a receptor, but with reduced efficacy compared to a full agonist. In the presence of a full agonist, a partial agonist behaves as an effective competitive antagonist. An inverse agonist is a compound that binds to a receptor and induces an opposing pharmacological response to that of an agonist. An allosteric modulator is a compound that binds at a location distinct from the orthosteric site, or the site of action of the primary ligand, and exerts an indirect effect by influencing binding or efficacy of the primary ligand. Pure allostery exerts no effect on a protein in the absence of a primary ligand that either activates or deactivates a receptor.
In an embodiment, a method is provided for treatment of a malcondition in a subject for which modulation of the GPR139 receptor is medically indicated. Such method comprises administering to the subject an effective amount of a compound having the structure of any one of Formula (I), (II), (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.
The phrase "malcondition" is intended to broadly encompass any and all diseases, disorders, syndromes and/or symptoms wherein the GPR139 receptor plays a role in the same, such that a therapeutically beneficial effect can be achieved by modulation of the GPR139 receptor. In one embodiment, the malcondition for which modulation of the GPR139 receptor is medically indicated is a neurobehavioral disease or disorder. In a more specific embodiment, the neurobehavioral disease or disorder is schizophrenia, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, obsessive-compulsive disorder (OCD), and affective disorders such as depression, bipolar disorder, and anxiety disorders.
As used herein, a "subject" means both mammals and non-mammals. Mammals include, for example: humans; non-human primates (e.g., apes and monkeys); cattle; horses; sheep; and goats. Non-mammals include, for example, fish and birds.
"Treating" or "treatment" within the meaning herein refers to an alleviation of symptoms associated with a malcondition, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the malcondition in certain instances.
The expression "effective amount", when used to describe use of a compound for treating a subject suffering from a malcondition for which modulation of the GPR 139 receptor is medically indicated, refers to the amount of the compound sufficient to produce a beneficial therapeutic effect for the subject.
In certain embodiments, the present invention provides a method for modulating the GPR139 receptor with a compound having the structure of any one of Formula (I), (II), (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. Such contacting can take place in vitro, for example in carrying out an assay to determine the GPR139 activity of a compound undergoing experimentation related to a submission for regulatory approval.
In certain embodiments, the method for modulating the GPR 139 receptor can also be carried out in vivo; that is, within the living body of the subject. The compound of any one of Formula (I), (II), (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.
In another embodiment, 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. In certain embodiments, the isotope is a fluorine isotope. The compounds may be used for therapeutic purposes, or to diagnose or assess the progression of a malcondition in a subject for which modulation of the GPR139 receptor is medically indicated.
In some embodiments, imaging and/or diagnostic methods are provided comprising administering to a subject in need thereof the imaging agent described herein and detecting the compound comprised in the imaging agent in the subject. In some aspects, the amount of the compound in the subject is quantified. In further aspects, a condition in the subject is detected via a detection of the compound in the subject. In certain embodiments, the imaging is effected by a radiodiagnostic method. The radiodiagnostic method may be performed by any instrument capable of detecting radiation by the compounds. Exemplary radiodiagnostic methods include, but are not limited to, Positron Emission Tomography (PET), PET-Time-Activity Curve (TAC) or PET-Magnetic Resonance Imaging (MRI). In a particular aspect, the radiodiagnostic method is PET.
In one embodiment, methods of treatment are provided comprising administering a compound of any one of Formula (I), (II), (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.
As mentioned above, modulators of the GPR139 receptor provide significant promise for the treatment of malconditions which benefit from modulation of the GPR139 receptor, including the embodiment wherein the malcondition is a neurobehavioral disease or disorder, including schizophrenia, attention- deficit/hyperactivity disorder (ADHD), autism spectrum disorder, obsessive-compulsive disorder (OCD), and affective disorders such as depression, bipolar disorder, and anxiety disorders, or any combination thereof.
In an embodiment, a method is provided for treatment of schizophrenia spectrum disorders, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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. Examples of schizophrenia spectrum disorders include schizophrenia, schizoaffective disorder, psychotic states and memory disorders.
In an embodiment, a method is provided for treatment of attention- deficit/hyperactivity disorder (ADHD), comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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.
In an embodiment, a method is provided for treatment of anxiety disorders, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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. In one embodiment, the anxiety disorder is a social anxiety disorder. In one embodiment, the anxiety disorder is a phobia.
Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. A person suffering from generalized anxiety experiences non-specific persistent fear and worry and becomes overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.
In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attack’s potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).
The single largest category of anxiety disorders is that of Phobia, which includes all cases in which fear and anxiety are triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from social phobia, specific phobia, agoraphobia, phobia of an animal, or of a location, or of a bodily fluid.
In an embodiment, a method is provided for treatment of trauma- and stressor-related disorders comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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. In one embodiment, the disorder is a trauma- and stressor-related disorder. In one embodiment, the trauma- and stressor-related disorder is PTSD.
In an embodiment, a method is provided for treatment of obsessive- compulsive and related disorders comprising administering to a subject in need thereof an effective amount of a compound having the structure of of any one of Formula (I), (II), (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. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.
In an embodiment, a method is provided for treatment of a depressive disorder, depression, or depressive illness, or a combination thereof, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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. Examples of such disorders include major depressive disorder (MDD), drug-resistant depression, dysthymia, unipolar depression, and bipolar disorder.
In an embodiment, a method is provided for treatment of a mood disorder, or an affective disorder, or a combination thereof, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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.
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.
The terms "anhedonia" and "anhedonic symptom" are used interchangeably and is defined as the inability to experience pleasure from activities usually found enjoyable, e.g. exercise, hobbies, music, sexual activities or social interactions. The terms "anhedonia" and "anhedonic symptom" are closely related to criterion of "depressive disorder with melancholic features" which is defined in DSM-5 as melancholic depression characterized by a loss of pleasure in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early morning waking, psychomotor retardation, excessive weight loss, or excessive guilt. The term "treatment of depressive disorder with melancholic features" comprises treatment of both the depressive disorder and melancholic features associated herewith. In one embodiment, the mood disorder is anhedonia. In one embodiment, the mood disorder is major depression. In one embodiment, the mood disorder is seasonal affective disorder (SAD).
In an embodiment, a method is provided for treatment of an affective disorder, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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. As used herein, "autistic spectrum disorders" and "Autism spectrum disorders" are used interchangeably and refer to autism, monogenetic causes of autism such as synaptophathies, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome and the like.
In an embodiment, a method is provided for treatment of an addictive disorder, including disorders related to substance abuse or addiction, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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, ***e, opiate addiction, heroin addiction, benzodiazepines and the like.
In an embodiment, a method is provided for treatment of an opioid related disorder, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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.
In an embodiment, a method is provided for treatment of an eating disorder, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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.
In one embodiment, a method is provided for treatment of binge-eating disorder, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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.
In an embodiment, a method is provided for treatment of Parkinson's disease, including neuroprotection and/or disease modifying effects in Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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.
In an embodiment, a method is provided for treating cognitive impairment or behavioral disturbances associated with neurological disorders, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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.
In one embodiment, a method is provided for treating sleep or wake disorders or circadian rhythm disorders, or a combination thereof, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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. As described herein, sleep/wake disorders and circadian rhythm disorders can affect pain processing, sleep-awake cycles, stress response, and learning.
In one embodiment, a method is provided for treating pain, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formula (I), (II), (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. In a preferred embodiment, a method is provided for treating the affective components of pain.
Compounds having the structure of any one of Formula (I), (II), (II-A), (II-B), (III), or (IV), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, can be synthesized using standard synthetic techniques known to those of skill in the art. For example, compounds of the present invention can be synthesized using the general synthetic procedures set forth in Reaction Schemes I-1 through I-11, II-1 through II-10, III-1 through III-8, and IV-1 through IV-11.
To this end, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation(s) necessary. Generally, suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the
intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent.
Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed. Reaction Scheme I-1
Figure imgf000125_0001
Reagents and conditions: K2CO3, MeCN (LG denotes a leaving group, such as halogen). Reaction Scheme I-2
Figure imgf000125_0002
Reagents and conditions: i) hydrazine hydrate, EtOH; ii) benzophenone hydrazone, Pd2(dba)3, Xantphos or JohnPhos, sodium tert-butoxide, toluene; iii) concentrated HCl; iv) CDI, MeCN; v) 4-nitrophenyl carbonochloridate, Et3N, THF. Reaction Scheme I-3
Figure imgf000125_0003
Reagents and conditions: i) Pd/C, MeOH, DCM, hydrogen atmosphere; ii) R106-H/NaOMe, THF; wherein R106-H is, independently, lower alkoxy, lower haloalkoxy, -O-carbocyclyl, or -O-heterocyclyl. Reaction Scheme I-4
Figure imgf000126_0001
Reagents and conditions: i) R107-B(OH)2, Pd(OAc)2, K3PO4, tricyclohexylphosphine, toluene, H2O; ii) hydrazine hydrate, EtOH; iii) CDI, MeCN. Reaction Scheme I-5
Figure imgf000126_0002
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) R108-B(OR''')2, K3PO4, Pd(dppf)Cl2, THF, H2O; vii) R108-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-1-amine, piperidine, morpholine, and oxetan-3-amine); wherein R108-B(OR''')2 is, independently, R108-boronic acid, or R108-boronic ester (such as boronic acid pinacol ester); and wherein R108-H is, independently, lower alkoxy, lower haloalkoxy, -O-carbocyclyl, or -O-heterocyclyl. Reaction Scheme I-6
Figure imgf000127_0001
Reagents and conditions: i) K2CO3, MeCN; ii) R106-B(OR''')2, K3PO4, Pd(dppf)Cl2, THF, H2O; iii) LiOH• H2O, EtOH, H2O; iv) DIPEA, HATU, DCM or DMF or DCM/DMF mixtures; wherein R106-B(OR''')2 is, independently, R106-boronic acid or R106-boronic ester (including, but not limited to, boronic acid pinacol ester).(LG denotes a leaving group, such as halogen). Reaction Scheme I-7
Figure imgf000127_0002
Reagents and conditions: i) R106-B(OR''')2, K3PO4, THF, H2O,
Pd(dppf)Cl2; ii) NMP, HNR2 or HNRC(O)OR or HN(R'')2; wherein R106-B(OR''')2 is, independently, R106-boronic acid or R106-boronic ester (including, but not limited to, boronic acid pinacol ester); and wherein R'' is, "independently, H, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl. R106 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-8
Figure imgf000128_0003
Reagents and conditions: i) R108-B(OR''')2, K3PO4, THF, H2O,
Pd(dppf)Cl2; ii) NMP, HNR2 or HNRC(O)OR or HN(R’’)2; wherein R108-B(OR''')2 is, independently, R108-boronic acid or R108-boronic ester (including, but not limited to, boronic acid pinacol ester); and wherein R" is, independently, H, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl. R108 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
Figure imgf000128_0001
Reagents and conditions: i) R107-B(OR''')2, K3PO4, THF, H2O,
Pd(dppf)Cl2; ii) NMP, HNR2 or HNRC(O)OR or HN(R'')2; wherein R107-B(OR''')2 is, independently, R107-boronic acid or R107-boronic ester (including, but not limited to, boronic acid pinacol ester); and wherein R'' is, independently, H, lower alkyl, lower haloalkyl, carbocyclyl, or heterocyclyl. R107 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-10
Figure imgf000128_0002
Reagents and conditions: i) titanium tetraethoxide, (R)- tertbutylsulfinamide, DCM; ii) R2MgBr in ether, THF; iii) HCl/dioxane, 1,4-dioxane. Reaction Scheme I-11
Figure imgf000129_0001
Reagents and conditions: Et3N or Me3N, THF (LG denotes a leaving group). Reaction Scheme II-1
Figure imgf000129_0004
Reagents and conditions: Et3N, THF (LG denotes a leaving group, such as halogen). Reaction Scheme II-2
Figure imgf000129_0002
Reagents and conditions: CDI, MeCN. Reaction Scheme II-3
Figure imgf000129_0003
Reagents and conditions: i) CDI, MeCN; ii) 4-nitrophenyl
chloroformate, Et3N, THF. Reaction Scheme II-4
Figure imgf000130_0001
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
Figure imgf000130_0002
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, Et3N (as needed); ii) (a) NaH, tert-butyl 3-hydroxyazetidine-1- carboxylate, THF, (b) starting material, THF (HAL denotes halogen). Reaction Scheme II-6
Figure imgf000131_0001
Reagents and conditions: K2CO3, MeCN (LG denotes a leaving group, such as halogen). Reaction Scheme II-7
Figure imgf000131_0002
Reagents and conditions: K2CO3, MeCN (LG denotes a leaving group, such as halogen). Reaction Scheme II-8
Figure imgf000131_0003
Reagents and conditions: i) K2CO3, MeCN (LG denotes a leaving group, such as halogen); ii) TFA, DCM; iii) formaldehyde/H2O, STAB, DCM. Reaction Scheme II-9
Figure imgf000132_0001
Reagents and conditions: i) K2CO3, MeCN (LG denotes a leaving group, such as halogen); ii) TFA, DCM; iii) formaldehyde/H2O, STAB, DCM. Reaction Scheme II-10
Figure imgf000132_0002
Reagents and conditions: i) benzophenone hydrazone, Pd2(dba)3, JohnPhos, sodium tert-butoxide, toluene; ii) concentrated HCl; iii) CDI, MeCN, Et3N. Reaction Scheme III-1
Figure imgf000133_0001
Reagents and conditions: K2CO3, MeCN (LG denotes a leaving group, such as halogen). Reaction Scheme III-2
Figure imgf000133_0002
Reagents and conditions: i) R306-B(OH)2, Cs2CO3, toluene/H2O, Bis(cyclopentyldiphenylphosphane) dichloromethane dichloropalladium iron; ii) hydrazine hydrate, EtOH; iii) benzophenone hydrazone, sodium tert-butoxide, JohnPhos, Pd2(dba)3, toluene; iv) concentrated HCl; v) CDI, MeCN; vi) 4-nitrophenyl chloroformate, Et3N, THF. Reaction Scheme III-3
Figure imgf000133_0003
Reagents and conditions: i) benzophenone hydrazone, sodium tert- butoxide, JohnPhos, Pd2(dba)3, toluene; ii) concentrated HCl; iii) CDI, Et3N, MeCN. Reaction Scheme III-4
Figure imgf000134_0001
Reagents and conditions: i) hydrazine hydrate, EtOH; ii) CDI, MeCN. Reaction Scheme III-5
Figure imgf000134_0002
Reagents and conditions: CDI, MeCN. Reaction Scheme III-6
Figure imgf000134_0003
Reagents and conditions: CDI, MeCN. Reaction Scheme III-7
Figure imgf000134_0004
Reagents and conditions: i) titanium tetraethoxide, R- tertbutylsulfinamide, DCM; ii) R2MgBr in ether, THF; iii) HCl/dioxane, 1,4-dioxane. Reaction Scheme III-8
Figure imgf000135_0001
Reagents and conditions: Et3N or Me3N, THF. (LG denotes a leaving group, such as halogen). Reaction Scheme IV-1
Figure imgf000135_0002
Reagents and conditions: K2CO3, MeCN, DMF (as needed) (LG denotes a leaving group, such as halogen). Reaction Scheme IV-2
Figure imgf000135_0003
Reagents and conditions: i) K2CO3, MeCN (LG denotes a leaving group, such as halogen); ii) TFA, DCM; iii) DIPEA, HATU, DCM, DMF (as needed). Reaction Scheme IV-3
Figure imgf000136_0001
Reagents and conditions: i) K2CO3, MeCN (LG denotes a leaving group, such as halogen) (HAL denotes halogen); ii) R407-OH, Pd(OAc)2, Cs2CO3, JohnPhos, toluene; iii) R407-B(OR''')2, K2CO3, Pd(dppf)Cl2, THF, H2O; iv) TFA, DCM; v) DIPEA, HATU, DCM, DMF (as needed), wherein R407-B(OR''')2 is R407-boronic acid or R407-boronic ester (including, but not limited to, boronic acid pinacol ester). Reaction Scheme IV-4
Figure imgf000136_0002
Reagents and conditions: i) R405-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). Reaction Scheme IV-5
Figure imgf000137_0001
Reagents and conditions: i) R407-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). Reaction Scheme IV-6
Figure imgf000137_0002
Reagents and conditions: i) R408-OH, JohnPhos or Ad-BippyPhos, Pd(OAc)2, Cs2CO3, toluene; ii) tBuBrettPhos Pd G3, Cs2CO3, NMP, H2O, 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). Reaction Scheme IV-7
Figure imgf000138_0001
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/H2O; ii) K2CO3, 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/H2O, STAB, DCM, MeOH. (HAL denotes halogen.) Reaction Scheme IV-8
Figure imgf000139_0001
Reagents and conditions: i) 6-boc-1,6-diazaspiro[3.3]heptane
hemioxalate, Pd2dba3, Xantphos, sodium tert-butoxide, toluene (HAL denotes halogen); ii) TFA, DCM; iii) formaldehyde, STAB, DCM, MeOH. Reaction Scheme IV-9
Figure imgf000139_0002
Reagents and conditions: i) titanium tetraethoxide, R- tertbutylsulfinamide, DCM; ii) R2MgBr in ether, THF; iii) HCl/dioxane, 1,4-dioxane. Reaction Scheme IV-10
Figure imgf000139_0003
Reagents and conditions: Et3N, THF (LG denotes a leaving group, such as halogen). Reaction Scheme IV-11
Figure imgf000140_0001
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, Et3N, THF. EXAMPLES
The invention is further illustrated by the following examples. The examples below are non-limiting and are merely representative of various aspects of the invention. Solid and dotted wedges within the structures herein disclosed illustrate relative stereochemistry, with absolute stereochemistry depicted only when specifically stated or delineated. General Methods
All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art. The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to a person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using 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. In some cases, the compounds may be purified by preparative HPLC using methods as described.
Purification methods as described herein may provide compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to a person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
All the starting materials and reagents are commercially available and were used as is.1H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker instrument operating at 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (d) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad. Preparative HPLC purification was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996/2998 UV/VIS detector, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution UV directed system. The Waters 2767 liquid handler acted as both auto- sampler and fraction collector. The columns used for the preparative purification of the compounds were a Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl (10 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). Mobile phase 5-95% acetonitrile in water (0.1% formic acid) gradient, flow rate 2.0 mL/min, and 6.5 min run time. Method 2: The RP-HPLC column was Waters Xterra MS 5 pm C18 , 100 x 4.6mm. Mobile phase 5-95% acetonitrile in water (lOmM ammonium bicarbonate (ammonium hydrogen carbonate)).
Chemical names were generated using the JChem for Excel naming software (Version 16.7.1800.1000) by Chem Axon Ltd. In some cases, generally accepted names of commercially available reagents were used in place of names generated by the naming software. Abbreviations
The following abbreviations are used in the examples, while other abbreviations have their customary meaning in the art: Ad-BippyPhos: 5-[Di(1-adamantyl)phosphino]-1¢,3¢,5¢-triphenyl-1¢H- [1,4¢]bipyrazole
CDI: 1,1¢-Carbonyldiimidazole
Cs2CO3: Cesium carbonate
DCM: Dichloromethane
DIAD: Diisopropyl azodicarboxylate
DMF: N,N-Dimethylformamide
DMSO: Dimethyl sulfoxide
EtOAc: Ethyl acetate
EtOH: Ethanol
Et2O: Diethylether
Et3N: Triethylamine
h hour(s)
HATU: N-[(Dimethylamino)(3H-[1,2,3]triazolo[4,5- b]pyridin-3-yloxy)methylene]-N- methylmethanaminium hexafluorophosphate
HCl: Hydrochloric acid
HMBC: Heteronuclear Multiple Bond Correlation HPLC: high performance liquid chromatography IPA: Isopropyl alcohol
JohnPhos: (2-Biphenyl)di-tert-butylphosphine, (2-Biphenylyl)di- tert-butylphosphine, 2-(Di-tert- butylphosphino)biphenyl
K2CO3: Potassium carbonate
K3PO4: Tripotassium phosphate
Figure imgf000143_0001
: Liter
LCMS: liquid chromatography– mass spectrometry
M: Molar
MeOH: Methanol
MeCN: Acetonitrile
Me3N: Trimethylamine MgSO4: Magnesium sulfate
min: Minute(s)
µl: Microliter
ml: Milliliter
N2: Nitrogen
Na2CO3: Sodium carbonate
NaH Sodium hydride
NaHCO3: Sodium bicarbonate
Na2SO4: Sodium sulfate
NH3: Ammonia
NH4Cl: Ammonium chloride
NMP: N-Methyl-2-pyrrolidone
NMR: nuclear magnetic resonance spectroscopy Pd/C: Palladium on carbon
Pd(dppf)Cl2: [1,1´- Bis(diphenylphosphino)ferrocene]dichloropalladium(I I)
Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)
Pd(OAc)2: Palladium (II) acetate
ppm: parts per million
RT: Room temperature
Rt: Retention time
sat.: Saturated
TBME: tert-butyl methyl ether
tBu-BrettPhos: 2-(Di-tert-butylphosphino)-2¢,4¢,6¢-triisopropyl-3,6- dimethoxy-1,1¢-biphenyl
THF: Tetrahydrofuran
TFA: Trifluoroacetic acid Analytical LC-MS Methods
Analytical Method A: Column: Phenomenex Kinetix-XB C181.2 x 100 mm, 1.7 µm; 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 µL; 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 µm; 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 µL; 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 µm 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 µL; 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 µm 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 µL; 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 E: Column: Phenomenex Gemini-NX C182.0 x 50 mm, 3 µm; eluent A: 2 mM ammonium bicarbonate, buffered to pH 10, eluent B:
acetonitrile; gradient: 0 - 1.8 min 1 - 100% B, 1.8– 2.1 min 100% B, 2.1– 2.3 min 100 - 2% B, 2.3– 3.5 min 1% B; flow 1 mL/min; injection volume 3 µL; temperature:
40 °C; UV scan: 215 nm; PDA Spectrum range: 210-420nm step: 1nm; MSD signal settings- scan pos: 150-850.
Analytical Method F: Column: Phenomenex Gemini–NX C182.01 x 100 mm, 3 µm; 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 µL; 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
Biotage IsoleraTM chromatography system
(http://www.biotage.com/product-area/flash-purification) using pre-packed silica and pre-packed modified silica cartridges were employed.
Method 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 µm; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide;
gradient: 0– 0.8 min 10% B, 0.8– 14.5 min 10 - 95% B, 14.5 - 16.7 min 95% B; flow 40 mL/min; injection volume 1500 µL; temperature: 25 °C; UV scan: 215 nm.
Method A2: Instrument: pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281 or pump: Gilson 333 & 334; auto injector: Gilson GX281; UV detector: Gilson 155; collector: Gilson GX281; Column: Waters Xbridge C1830 x 100 mm, 10 µm; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide;
gradient: 0 - 1.1 min 30% B, 1.1 - 10.05 min 30 - 95% B, 10.05 - 11.5 min 95% B; flow 40 mL/min; injection volume 1500 µL; temperature: 25 °C; UV scan: 215 nm.
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 µm; 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 µL; 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 µm; eluent A: water + 0.1 vol% formic acid, eluent B:
acetonitrile + 0.1 vol% formic acid; gradient: 0– 1.1 min 30% B, 1.1– 10.05 min 30 - 95% B, 10.05– 11.5 min 95% B; flow 40 mL/min; injection volume 1500 µL;
temperature: 25 °C; UV scan: 215 nm.
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 µm; 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
Biotage IsoleraTM chromatography system
(http://www.biotage.com/product-area/flash-purification) using pre-packed silica and pre-packed modified silica cartridges were employed.
Method 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 µm; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide;
gradient: 0– 0.8 min 10% B, 0.8– 14.5 min 10 - 95% B, 14.5 - 16.7 min 95% B; flow 40 mL/min; injection volume 1500 µL; temperature: 25 °C; UV scan: 215 nm.
Method A2: Instrument: pump: Gilson 331 & 332; auto injector: Gilson GX281; UV detector: Gilson 159; collector: Gilson GX281 or pump: Gilson 333 & 334; auto injector: Gilson GX281; UV detector: Gilson 155; collector: Gilson GX281; Column: Waters Xbridge C1830 x 100 mm, 10 µm; eluent A: water + 0.2 vol% ammonium hydroxide, eluent B: acetonitrile + 0.2 vol% ammonium hydroxide;
gradient: 0 - 1.1 min 30% B, 1.1 - 10.05 min 30 - 95% B, 10.05 - 11.5 min 95% B; flow 40 mL/min; injection volume 1500 µL; temperature: 25 °C; UV scan: 215 nm.
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 µm; 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 µL; 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 µm; eluent A: water + 0.1 vol% formic acid, eluent B:
acetonitrile + 0.1 vol% formic acid; gradient: 0– 1.1 min 30% B, 1.1– 10.05 min 30 - 95% B, 10.05– 11.5 min 95% B; flow 40 mL/min; injection volume 1500 µL;
temperature: 25 °C; UV scan: 215 nm.
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 µm; 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;
temperature: 25 °C; UV scan: 215 nm.
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 µm; 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 chiral SFC (Method A): SFC Berger; Column: Daicel Chiralpak AD 4.6 x 250 mm, 5 µm; eluent A: carbon dioxide, eluent B: ethanol;
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 µm; 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
(Intermediate 1)
Figure imgf000149_0001
A solution of (S)-1-(4-methylphenyl)ethylamine (2.72 mL, 18.49 mmol) and triethylamine (3.86 mL, 27.73 mmol) in tetrahydrofuran (50 mL) was added slowly to an ice cold solution of bromoacetyl chloride (1.62 mL, 19.41 mmol) in
tetrahydrofuran (100 mL). The reaction was stirred for 2 hours then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated with diethyl ether. The solid material was collected by filtration, washed with diethyl ether and dried in vacuo to yield the title compound as a tan solid (3.56 g, 75% yield). 1H NMR (250 MHz, CDCl3) d 7.24 - 7.13 (m, 4H), 6.64 (s, 1H), 5.07 (p, J = 7.1 Hz, 1H), 3.95 - 3.81 (m, 2H), 2.34 (s, 3H), 1.52 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.03 min, MS (ESIpos): m/z 255.8, 257.8 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐[4‐(trifluoromethoxy)phenyl]ethyl]acetamide
(Intermediate 2)
Figure imgf000149_0002
Bromoacetyl chloride (106 µL, 1.28 mmol) was added slowly to an ice cold solution of (1S)-1-[4-(trifluoromethoxy)phenyl]ethylamine (250 mg, 1.22 mmol) and triethylamine (355 µL, 2.56 mmol) in tetrahydrofuran (10 mL). The reaction was stirred for 90 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with 0- 75% ethyl acetate/heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a beige solid (204 mg, 51% yield). 1H NMR (500 MHz, CDCl3) d 7.35 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.65 (s, 1H), 5.11 (p, J = 7.1 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 1.53 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 326.0, 327.9 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐(4‐chloro‐3‐fluorophenyl)ethyl]acetamide
(Intermediate 3)
Figure imgf000150_0001
A solution of bromoacetyl chloride (166 µL, 2 mmol) in tetrahydrofuran (5 mL) was added slowly to an ice cold suspension of (1S)-1-(4-chloro-3- fluorophenyl)ethylamine HCl (400 mg, 1.9 mmol) and triethylamine (556 µL, 4 mmol) in tetrahydrofuran (15 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with 0-75% tert-butyl methyl ether/heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a white solid (490 mg, 75% yield). 1H NMR (500 MHz, CDCl3) d 7.37 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 2.0, 9.9 Hz, 1H), 7.05 (dd, J = 2.0, 8.3 Hz, 1H), 6.69 - 6.59 (m, 1H), 5.05 (p, J = 7.2 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 1.51 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.10 min, MS (ESIpos): m/z 293.9, 295.9, 297.8 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐(3,4‐dichlorophenyl)ethyl]acetamide
(Intermediate 4)
Figure imgf000151_0001
A solution of bromoacetyl chloride (25 µL, 0.3 mmol) in tetrahydrofuran (0.5 mL) was added slowly to an ice cold solution of (1S)-1-(3,4- dichlorophenyl)ethylamine (55 mg, 0.29 mmol) and trimethylamine (85 µL, 0.61 mmol) in tetrahydrofuran (1.5 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo to yield the title compound as a yellow oil (63 mg, 70% yield). 1H NMR (500 MHz, CDCl3) d 7.45 - 7.37 (m, 2H), 7.16 (dd, J = 2.1, 8.3 Hz, 1H), 6.64 (s, 1H), 5.04 (p, J = 7.2 Hz, 1H), 3.94 - 3.84 (m, 2H), 1.51 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 309.7, 311.7, 313.7 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐(3‐chloro‐4‐methylphenyl)ethyl]acetamide
(Intermediate 5)
Figure imgf000151_0002
A solution of bromoacetyl chloride (74 µL, 0.89 mmol) in tetrahydrofuran (1 mL) was added slowly to an ice cold solution of (1S)-1-(3-chloro-4- methylphenyl)ethylamine HCl (175 mg, 0.85 mmol) and triethylamine (248 µL, 1.78 mmol) in tetrahydrofuran (7 mL). The reaction was stirred for 2 hours then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo to yield the title compound as a pale oil that solidified on standing (241 mg, 79% yield). 1H NMR (500 MHz, DMSO-d6) d 8.73 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.17 (dd, J = 1.7, 7.8 Hz, 1H), 4.84 (p, J = 7.1 Hz, 1H), 3.89 - 3.82 (m, 2H), 2.29 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.15 min, MS (ESIpos): m/z 289.95, 291.95 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐(4‐chloro‐3‐methylphenyl)ethyl]acetamide
(Intermediate 6)
Figure imgf000152_0001
A solution of bromoacetyl chloride (103 µL, 1.24 mmol) in THF (0.5 mL) was added dropwise to an ice cold solution of (1S)-1-(4-chloro-3- methylphenyl)ethanamine (200 mg, 1.18 mmol) and triethylamine (0.31 mL, 2.25 mmol). The reaction was stirred for 90 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with 0-40% ethyl acetate/heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as pale brown solid (45 mg, 12% yield). 1H NMR (500 MHz, CDCl3) d 7.24 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 8.2, 2.1 Hz, 1H), 6.58 (s, 1H), 4.97 (p, J = 7.1 Hz, 1H), 3.83 (m, 2H), 2.31 (s, 3H), 1.43 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 289.85, 291.85, 293.90 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐(4‐chloro‐2‐methylphenyl)ethyl]acetamide
(Intermediate 7)
Figure imgf000152_0002
A solution of bromoacetyl chloride (42 µL, 0.51 mmol) in
tetrahydrofuran (0.5 mL) was added slowly to an ice cold suspension of (1S)-1-(4- chloro-2-methylphenyl)ethylamine HCl (100 mg, 0.49 mmol) and triethylamine (175 µL, 1.26 mmol) in tetrahydrofuran (4.5 mL). The reaction was stirred for 90 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography, eluting with 0-75% ethyl acetate/heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a white solid (105 mg, 74%). 1H NMR (500 MHz, CDCl3) d 7.23 - 7.15 (m, 3H), 6.58 (s, 1H), 5.21 (p, J = 7.0 Hz, 1H), 3.89 (d, J = 13.8 Hz, 1H), 3.84 (d, J = 13.8 Hz, 1H), 2.36 (s, 3H), 1.48 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.10 min, MS (ESIpos): m/z 289.75, 291.70, 293.75 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐(4‐chlorophenyl)ethyl]acetamide
(Intermediate 8)
Figure imgf000153_0001
A solution of bromoacetyl chloride (421 µl, 5.06 mmol) in THF (2 mL) was added dropwise to an ice cold solution of (1S)-1-(4-chlorophenyl)ethanamine (750 mg, 4.82 mmol) and triethylamine (1.31 mL, 9.64 mmol) in tetrahydrofuran 30 mL. The reaction was stirred for 90 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The solid was triturated from diethyl ether to give the title compound as a pale brown solid (1.02 g, 75% yield). 1H NMR (250 MHz, CDCl3) d 7.40 - 7.18 (m, 4H), 6.66 (s, 1H), 5.09 (p, J = 7.1 Hz, 1H), 3.91 (d, J = 2.6 Hz, 2H), 1.54 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.07 min, MS (ESIpos): m/z 275.75, 277.65, 279.75 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐(3‐fluoro‐4‐methylphenyl)ethyl]acetamide
(Intermediate 9)
Figure imgf000154_0001
A solution of bromoacetyl chloride (150 µL, 1.80 mmol) in THF (3 mL) was added dropwise to an ice cold solution of (1S)-1-(3-fluoro-4- methylphenyl)ethanamine (250 mg, 1.63 mmol) and triethylamine (0.57 mL, 1.1 mmol) in THF (12 mL) over 10 mins. The reaction was stirred for 2 hours then quenched with water and extracted into ethyl acetate three times. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography eluting with 0%-70% EtOAc/heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a pale orange solid (280 mg, 63% yield). 1H NMR (500 MHz, CDCl3) d 7.16 (t, J = 7.8 Hz, 1H), 7.03 - 6.89 (m, 2H), 6.63 (s, 1H), 5.05 (p, J = 7.1 Hz, 1H), 3.95 - 3.80 (m, 2H), 2.25 (d, J = 1.5 Hz, 3H), 1.51 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method D) Rt= 1.07 min, MS (ESIpos): m/z 273.75, 275.75 [M+H]+. Synthesis of 2-bromo-N-[(S)-(4-chloro-3-fluorophenyl)(cyclopropyl)methyl]acetamide
(Intermediate 10)
Figure imgf000154_0002
The title compound was prepared in analogy to the procedure described for Intermediate 3, starting from (S)-(4-chloro-3- fluorophenyl)(cyclopropyl)methanamine hydrochloride. Yield = 94%. 1H NMR (250 MHz, CDCl3) d 7.36 (t, 1H), 7.20– 7.04 (m, 2H), 6.93– 6.76 (m, 1H), 4.39– 4.23 (m, 1H), 4.01– 3.80 (m, 2H), 1.26– 1.02 (m, 1H), 0.75– 0.58 (m, 2H), 0.55– 0.33 (m, 2H). LCMS (Analytical Method D) Rt= 1.14 min, MS (ESIpos): m/z 321.8 [M+H]+. Synthesis of 2-bromo-N-[(1S)-1-(4-chloro-3-fluorophenyl)propyl]acetamide
(Intermediate 11)
Figure imgf000155_0001
The title compound was prepared in analogy to the procedure described for Intermediate 3, starting from (1S)-1-(4-chloro-3-fluorophenyl)propan-1-amine hydrochloride. Yield = 11%. 1H NMR (250 MHz, CDCl3) d 7.37 (t, J = 7.9 Hz, 1H), 7.04 (t, J = 9.7 Hz, 2H), 6.65 (s, 1H), 4.80 (q, J = 7.4 Hz, 1H), 3.89 (d, J = 3.6 Hz, 2H), 1.83 (p, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). LCMS (Analytical Method D) Rt= 1.13 min, MS (ESIpos): m/z 309.7 [M+H]+. Syntheis of 2-bromo-N-[(1S)-1-(4-chloro-3-fluorophenyl)-2-methylpropyl]acetamide
(Intermediate 12)
Figure imgf000155_0002
The title compound was prepared in analogy to the procedure described for Intermediate 3, starting from (1S)-1-(4-chloro-3-fluorophenyl)-2-methylpropan-1- amine hydrochloride. Yield = 54%. 1H NMR (500 MHz, DMSO-d6) d 8.66 (d, J = 8.7 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.33 (dd, J = 10.7, 1.9 Hz, 1H), 7.15 (dd, J = 8.3, 1.9 Hz, 1H), 4.56 (t, J = 8.3 Hz, 1H), 3.96– 3.80 (m, 2H), 2.01– 1.90 (m, 1H), 0.89 (d, J = 6.7 Hz, 3H), 0.75 (d, J = 6.7 Hz, 3H). LCMS (Analytical Method D) Rt= 1.24 min, MS (ESIpos): m/z 323.9 [M+H]+. Synthesis of 2-bromo-N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]propanamide
(Intermediate 13)
Figure imgf000156_0001
To a mixture of (1S)-1-(4-Chloro-3-fluorophenyl)ethan-1-amine hydrochloride (100 mg, 0.48 mmol) and triethylamine (200 µl, 1.43 mmol) in THF (2 ml) at 0°C was added 2-bromopropanoyl chloride (50 µl, 0.49 mmol. The mixture was stirred under nitrogen for 3 h. The reaction was quenched with water and extracted with EtOAc. The organics were combined, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (148 mg, 96% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) d 8.73 (dd, J = 16.9, 7.6 Hz, 1H), 7.54 (q, J = 8.2 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.21 - 7.16 (m, 1H), 4.94 - 4.82 (m, 1H), 4.60 - 4.50 (m, 1H), 1.65 (dd, J = 10.0, 6.8 Hz, 3H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 307.9, 309.9 [M+H]+. Synthesis of 2-bromo-N-[1-(4-chlorophenyl)cyclopropyl]acetamide (Intermediate 14-1) and 2-chloro-N-[1-(4-chlorophenyl)cyclopropyl]acetamide (Intermediate 14-2)
Figure imgf000156_0002
To a suspension of 1-(4-chlorophenyl)cyclopropan-1-amine hydrochloride (200 mg, 0.98 mmol) in THF (5 ml) was added triethylamine (330 µl, 2.37 mmol). The mixture was cooled to 0 °C and 2-bromoacetyl chloride (90 µl, 1.08 mmol) was added. The solution was stirred at 0 °C for 5 min then allowed to warm to room temperature and stirred for 1 h. Additional triethylamine (140 µl, 1.0 mol) and 2- bromoacetyl chloride (45 µl, 0.54 mmol) was added and the mixture was stirred for further 1 h. The reaction was quenched with water and extracted with DCM. The organic phase was concentrated in vacuo and the resultant residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% EtOAc in heptanes) to afford a mixture of Intermediate 14-1 and 14-2 (145 mg, 51% yield). 1H NMR (500 MHz, CDCl3) d 7.26 (s, 2H), 7.21 - 7.16 (m, 2H), 7.13 - 7.01 (m, 1H), 3.84 (s, 2H), 1.31 - 1.23 (m, 4H). LCMS (Analytical Method D) Rt= 1.05 min, MS (ESIpos): m/z 287.8, 289.65 and 243.9, 245.9 [M+H]+. Synthesis of 2-bromo-N-[1-(3-chlorophenyl)cyclopropyl]acetamide (Intermediate 15-1) and 2-chloro-N-[1-(3-chlorophenyl)cyclopropyl]acetamide (Intermediate 15-2)
Figure imgf000157_0001
The mixture of the title compounds was prepared in analogous manner to that described for Intermediates 14-1 and 14-2. 1H NMR (500 MHz, CDCl3) d 7.24 - 7.16 (m, 3H), 7.15 - 7.11 (m, 1H), 3.86 (s, 2H), 1.31 (d, J = 3.4 Hz, 4H). LCMS (Analytical Method D) Rt= 1.05 min, MS (ESIpos): m/z 287.8, 289.65 and 243.9, 245.9 [M+H]+. Synthesis of (R)‐N‐[(1E)‐[3‐fluoro‐4‐(trifluoromethoxy)phenyl]methylidene]‐2‐ methylpropane‐2‐sulfinamide (Intermediate 16)
Figure imgf000157_0002
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. The aqueous layer was extracted into dichloromethane three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo to yield the title compound as a colorless oil (707 mg, 95% yield). 1H NMR (500 MHz, CDCl3) d 8.54 (d, J = 1.1 Hz, 1H), 7.75 (dd, J = 1.9, 10.2 Hz, 1H), 7.62 (dd, J = 1.3, 8.4 Hz, 1H), 7.45 - 7.40 (m, 1H), 1.27 (s, 9H). LCMS (Analytical Method D) Rt= 1.29 min, MS (ESIpos): m/z 311.8 [M+H]+. Synthesis of (R)‐N‐[(1S)‐1‐[3‐fluoro‐4‐(trifluoromethoxy)phenyl]ethyl]‐2‐
methylpropane‐2‐sulfinamide (Intermediate 17)
Figure imgf000158_0001
Methyl magnesium bromide in ether (3M, 1.14 mL) was added over 10 minutes to a -40 °C solution of (R)‐N‐[(1E)‐[3‐fluoro‐4‐(trifluoromethoxy)- phenyl]methylidene]‐2‐methylpropane‐2‐sulfinamide (Intermediate 16) (707 mg, 2.27 mmol) in tetrahydrofuran (15 mL). The reaction was stirred at this temperature for 4 hours then quenched by the slow addition of water. The mixture was partitioned between ethyl acetate and water and the aqueous layer extracted three times with ethyl acetate. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with 20- 100% tert-butyl methyl ether:heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a viscous oil (368 mg, 50% yield). 1H NMR (500 MHz, CDCl3) d 7.26 (s, 2H), 7.19 (dd, J = 2.0, 10.9 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 4.58 (q, J = 6.6 Hz, 1H), 3.32 (s, 1H), 1.52 (d, J = 6.7 Hz, 3H), 1.22 (s, 9H). LCMS (Analytical Method D) Rt= 1.19 min, MS (ESIpos): m/z 327.8 [M+H]+. Synthesis of (1S)‐1‐[3‐fluoro‐4‐(trifluoromethoxy)phenyl]ethan‐1‐amine hydrochloride
(Intermediate 18)
Figure imgf000159_0001
(R)-N-[(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]ethyl]-2-methyl- propane-2-sulfinamide (Intermediate 17) (368 mg, 1.09 mmol) was suspended in 1,4- dioxane (4.4 mL) and a HCl in dioxane (4M, 1.69 mL) was added. The reaction was stirred for 1 hour then concentrated in vacuo. The solid was triturated with heptane, the solid material collected by filtration and dried in vacuo to yield the title compound as a white solid (262 mg, 89% yield). 1H NMR (500 MHz, DMSO-d6) d 8.52 (s, 3H), 7.85 - 7.76 (m, 2H), 7.58 (d, J = 8.6 Hz, 1H), 4.59 (q, J = 6.8 Hz, 1H), 1.62 (d, J = 6.8 Hz, 3H). LCMS (Analytical Method B) Rt= 1.69 min, MS (ESIpos): m/z 224.1 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐[3‐fluoro‐4‐(trifluoromethoxy)phenyl]ethyl]acetamide
(Intermediate 19)
Figure imgf000159_0002
A suspension of (1S)‐1‐[3‐fluoro‐4‐(trifluoromethoxy)phenyl]ethan‐1‐ amine hydrochloride (Intermediate 18) (262 mg, 1.01 mmol) and triethylamine (421 µL, 3.03 mmol) in tetrahydrofuran (4 mL) was added dropwise to an ice cold solution of bromoacetyl chloride (88 µL, 1.06 mmol) in tetrahydrofuran (4 mL). The reaction was stirred for 1 hour then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography, eluting with 0- 100% tert-butyl methyl ether:heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a beige solid (150 mg, 43% yield). 1H NMR (500 MHz, CDCl3) d 7.31 - 7.27 (m, 1H), 7.16 (dd, J = 2.1, 10.7 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.70 - 6.60 (m, 1H), 5.08 (p, J = 7.1 Hz, 1H), 3.92 (d, J = 13.9 Hz, 1H), 3.88 (d, J = 13.9 Hz, 1H), 1.52 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method D) Rt= 1.14 min, MS (ESIpos): m/z 343.7 [M+H]+. Synthesis of (R)‐N‐[(1E)‐(4‐cyclopropylphenyl)methylidene]-2‐methylpropane‐2‐ sulfinamide (Intermediate 20)
Figure imgf000160_0001
(R)-2-methylpropane-2-sulfinamide (912 mg, 7.53 mmol) was added to a solution of 4-cyclopropylbenzaldehyde (1.0 g, 6.84 mmol) in CH2Cl2 (34 mL).
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. NaHCO3 and the resulting mixture was stirred at RT for 30 min. The mixture was extracted three times with CH2Cl2. The combined organics were washed with brine, dried over MgSO4 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). 1H NMR (250 MHz, CDCl3) d 8.54 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 1.95 (ddd, J = 13.3, 8.4, 5.1 Hz, 1H), 1.25 (s, 9H), 1.13– 1.01 (m, 2H), 0.78 (dt, J = 6.9, 4.7 Hz, 2H). LCMS (Analytical Method D) Rt= 1.30 min, MS (ESIpos): m/z 250.0
[M+H]+. Synthesis of (R)‐N‐[(1S)‐1‐(4‐cyclopropylphenyl)ethyl]‐2‐methylpropane‐2‐ sulfinamide
(Intermediate 21)
Figure imgf000161_0001
Methyl magnesium bromide (3M in Et2O, 2.47 mL, 7.40 mmol) was added slowly to a -40 °C solution of (R)-N-[(1E)-(4-cyclopropylphenyl)methylidene]-2- methylpropane-2-sulfinamide (Intermediate 20) (1.2 g, 4.93 mmol) in THF (45 mL). The reaction was stirred for 90 minutes then additional methyl magnesium bromide (3M in Et2O, 1.64 mL, 4.90 mmol) was added slowly and stirring continued for a further 2 hours. The reaction was warmed to -15 °C and stirring continued for a further 4 hours. The reaction was quenched by addition of water and the aqueous layer was extracted with EtOAc three times. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by
chromatography eluting with 7-100% tert-butyl methyl ether:heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a white solid (986 mg, 75% yield). 1H NMR (250 MHz, CDCl3) d 7.21 (d, J = 8.2 Hz, 2H), 7.08– 6.97 (m, 2H), 4.53 (qd, J = 6.7, 3.8 Hz, 1H), 3.27 (d, J = 3.3 Hz, 1H), 1.88 (ddd, J = 13.5, 8.4, 5.1 Hz, 1H), 1.52 (d, J = 6.7 Hz, 3H), 1.19 (s, 9H), 1.01– 0.90 (m, 2H), 0.73– 0.63 (m, 2H). LCMS (Analytical Method D) Rt= 1.18 min, MS (ESIpos): m/z 266.0 [M+H]+. Synthesis of (1S)‐1‐(4‐cyclopropylphenyl)ethan‐1‐amine hydrochloride
(Intermediate 22)
Figure imgf000162_0001
Hydrogen chloride in 1,4-dioxane (4M, 5.5 mL) was added to a suspension of (R)-N-[(1S)-1-(4-cyclopropylphenyl)ethyl]-2-methylpropane-2- sulfinamide (Intermediate 21) (986 mg, 3.71 mmol) in 1,4-dioxane (25 mL). The reaction was stirred for 1 hour then concentrated in vacuo. The residue was triturated with diethyl ether and the solid material collected by filtration and dried in vacuo to yield the title compound as a white solid (541 mg, 74% yield). 1H NMR (250 MHz, DMSO-d6) d 8.37 (s, 3H), 7.36 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 4.32 (q, J = 6.8 Hz, 1H), 1.92 (ddd, J = 13.5, 8.4, 5.1 Hz, 1H), 1.48 (d, J = 6.8 Hz, 3H), 1.01– 0.90 (m, 2H), 0.72– 0.61 (m, 2H). LCMS (Analytical Method B) Rt= 1.64 min, MS (ESIpos): m/z 162.2 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐(4‐cyclopropylphenyl)ethyl]acetamide
(Intermediate 23)
Figure imgf000162_0002
Bromoacetyl chloride (44 µL, 0.53 mmol) was added to an ice cold solution of (1S)‐1‐(4‐cyclopropylphenyl)ethan‐1‐amine hydrochloride (Intermediate 22) (100 mg, 0.51 mmol) and triethylamine (211 µL, 1.52 mmol) in tetrahydrofuran (4 mL). The reaction was stirred for 45 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by
chromatography (10 g, silica), eluting with 0-100% tert-butyl methyl ether:heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a white solid (83 mg). 1H NMR (500 MHz, CDCl3) d 7.21 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.62 (d, J = 5.2 Hz, 1H), 5.06 (p, J = 7.1 Hz, 1H), 3.90 (d, J = 13.8 Hz, 1H), 3.85 (d, J = 13.8 Hz, 1H), 1.92 - 1.85 (m, 1H), 1.51 (d, J = 6.9 Hz, 3H), 0.98 - 0.93 (m, 2H), 0.70 - 0.66 (m, 2H). LCMS (Analytical Method D) Rt= 1.13 min, MS (ESIpos): m/z 281.9, 283.8 [M+H]+. Synthesis of 4‐cyclopropyl‐3‐fluorobenzaldehyde
(Intermediate 24)
Figure imgf000163_0001
A mixture of 4-bromo-3-fluorobenzaldehyde (2.00 g, 9.85 mmol), cyclopropylboronic acid (888 mg, 10.34 mmol), tricyclohexylphosphine (1.38 g, 4.93 mmol), palladium acetate (331 mg, 0.49 mmol) and potassium phosphate (4.18 g, 19.7 mmol) in toluene (30 mL) and water (5 mL) was heated to 80 °C for 18 hours. After cooling, the solid material was removed by filtration and the filtrate partitioned between toluene and aq. sat. NaHCO3. The aqueous later was extracted with toluene twice. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with 2-20% EtOAc in heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compounds as a yellow oil (1.02 g, 58% yield). 1H NMR (250 MHz, CDCl3) d 9.91 (d, J = 1.9 Hz, 1H), 7.56 (dd, J = 7.9, 1.5 Hz, 1H), 7.50 (dd, J = 10.0, 1.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 2.26– 2.10 (m, 1H), 1.17– 1.07 (m, 2H), 0.87– 0.81 (m, 2H). LCMS (Analytical Method D) Rt= 1.16 min, MS (ESIpos): m/z 164.95 [M+H]+. Synthesis of (R)‐N‐[(1E)‐(4‐cyclopropyl‐3‐fluorophenyl)methylidene]‐2‐ methylpropane‐2‐sulfinamide (Intermediate 25)
Figure imgf000164_0001
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 CH2Cl2 (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. The residue was purified by chromatography eluting with 2- 30% EtOAc in heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a yellow oil (1.26 g, 71% yield). 1H NMR (250 MHz, CDCl3) d 8.50 (d, J = 1.3 Hz, 1H), 7.57– 7.43 (m, 2H), 6.95 (t, J = 7.7 Hz, 1H), 2.16 (ddd, J = 13.8, 8.5, 5.2 Hz, 1H), 1.26 (s, 9H), 1.13– 1.03 (m, 2H), 0.81 (dt, J = 6.8, 4.7 Hz, 2H). LCMS (Analytical Method D) Rt= 1.35 min, MS (ESIpos): m/z 267.9 [M+H]+. Synthesis of (R)‐N‐[(1S)‐1‐(4‐cyclopropyl‐3‐fluorophenyl)ethyl]‐2‐methylpropane‐2‐ sulfinamide (Intermediate 26)
Figure imgf000164_0002
Methyl magnesium bromide (3M in Et2O, 2.4 mL, 7.1 mmol) was slowly added to a -40 °C solution of (R)-N-[(1E)-(4-cyclopropyl-3-fluorophenyl)methylidene]- 2-methylpropane-2-sulfinamide (Intermediate 25) (1.26 g, 4.71 mmol) in THF (45 mL). The reaction was stirred for 2 h then additional methyl magnesium bromide (3M in Et2O, 1.6 mL, 4.7 mmol) was added slowly 5 min and the reaction was stirred at -30 °C for a further 2h. Additional methyl magnesium bromide (3M in Et2O, 1.0 mL, 3.0 mmol) was added slowly over 3 min and the reaction was stirred at -20 °C for a further 30 min. The reaction was quenched by addition of water and extracted with EtOAc three times. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with 7- 100% TBME in heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a white solid (861 mg, 64% yield). 1H NMR (250 MHz, CDCl3) d 7.03– 6.92 (m, 2H), 6.84 (t, J = 7.9 Hz, 1H), 4.52 (dd, J = 6.5, 3.2 Hz, 1H), 3.27 (s, 1H), 2.06 (ddd, J = 13.6, 8.6, 5.3 Hz, 1H), 1.50 (d, J = 6.7 Hz, 3H), 1.21 (s, 9H), 1.02– 0.91 (m, 2H), 0.76– 0.66 (m, 2H). LCMS (Analytical Method D) Rt= 1.22 min, MS (ESIpos): m/z 284.0 [M+H]+. Synthesis of (1S)‐1‐(4‐cyclopropyl‐3‐fluorophenyl)ethan‐1‐amine hydrochloride
(Intermediate 27)
Figure imgf000165_0001
Hydrogen chloride in 1,4-dioxane (4M, 3.0 mL) was added to a suspension of (R)-N-[(1S)-1-(4-cyclopropyl-3-fluorophenyl)ethyl]-2-methylpropane-2- sulfinamide (Intermediate 26) (861 mg, 3.04 mmol) in 1,4-dioxane (20 mL). The reaction was stirred for 1h then concentrated in vacuo. The residue was triturated with Et2O, the solid material collected by filtration and dried in vacuo to yield the title compound as a white solid (508 mg, 78% yield). 1H NMR (250 MHz, DMSO-d6) d 8.49 (s, 3H), 7.33 (dd, J = 11.6, 1.7 Hz, 1H), 7.23 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (t, J = 8.1 Hz, 1H), 4.36 (q, J = 6.8 Hz, 1H), 2.03 (ddd, J = 13.7, 8.4, 5.2 Hz, 1H), 1.48 (d, J = 6.8 Hz, 3H), 1.04– 0.92 (m, 2H), 0.77– 0.66 (m, 2H). LCMS (Analytical Method B) Rt= 1.66 min, MS (ESIpos): m/z 180.2 [M+H]+. Synthesis of 2‐bromo‐N‐[(1S)‐1‐(4‐cyclopropyl‐3‐fluorophenyl)ethyl]acetamide
(Intermediate 28)
Figure imgf000166_0001
Bromoacetyl chloride (40 µL, 0.49 mmol) was added to an ice cold solution of (1S)‐1‐(4‐cyclopropyl‐3‐fluorophenyl)ethan‐1‐amine hydrochloride
(Intermediate 27) (100 mg, 0.46 mmol) and triethylamine (193 µL, 1.39 mmol) in tetrahydrofuran (4 mL). The reaction was stirred for 45 minutes then quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with 0-100% tert-butyl methyl ether:heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a colorless oil that solidified on standing (80 mg, 57% yield). 1H NMR (500 MHz, CDCl3) d 7.01 - 6.93 (m, 2H), 6.87 (t, J = 7.9 Hz, 1H), 6.62 (d, J = 5.0 Hz, 1H), 5.04 (p, J = 7.0 Hz, 1H), 3.90 (d, J = 13.9 Hz, 1H), 3.86 (d, J = 13.9 Hz, 1H), 2.09 - 2.02 (m, 1H), 1.50 (d, J = 6.9 Hz, 3H), 0.99 - 0.95 (m, 2H), 0.72– 0.68 (m, 2H). LCMS (Analytical Method D) Rt= 1.16 min, MS (ESIpos): m/z 299.8, 301.8 [M+H]+. Synthesis of 6‐methyl‐2H,3H‐[1,2,4]triazolo[4,3‐b]pyridazin‐3‐one
(Intermediate 29)
Figure imgf000166_0002
A mixture of 3-hydrazinyl-6-methylpyridazine (0.25 g, 2.0 mmol) and CDI (0.28 g, 1.7 mmol) in acetonitrile (5 mL) was stirred at 80 oC for 1h. The reaction mixture was allowed to cool to room temperature. The precipitate was removed by filtration. The filtrate was concentrated. The resulting residue was triturated in MeCN to afford 30 mg (9% yield) of the title compound as a brown solid. 1H NMR (250 MHz, DMSO-d6) d 12.64 (s, 1H), 7.70 (d, J = 9.7 Hz, 1H), 7.03 (d, J = 9.7 Hz, 1H), 2.39 (s, 3H). LCMS (Analytical Method D) Rt= solvent front, MS (ESIpos): m/z= 151
[M+H]+. Synthesis of 3‐hydrazinyl‐5‐methylpyridazine
(Intermediate 30)
Figure imgf000167_0001
A solution of 3-chloro-5-methylpyridazine (0.15 g, 1.2 mmol) and hydrazine hydrate (569 µL, 11.7 mmol) in EtOH (2.5 mL) was heated to 60 °C for 22 h. The reaction was cooled and allowed to stand at room temperature for 24 h then concentrated. The residue was loaded onto an SCX-2 cartridge, primed with MeOH. The cartridge was washed sequentially with DCM/MeOH then eluted 2M ammonia in MeOH. The basic fraction was concentrated to afford the title compound as a brown oil (120 mg, 83% yield). 1H NMR (250 MHz, DMSO-d6) d 8.32 (d, J = 1.8 Hz, 1H), 7.74 (s, 1H), 6.85 - 6.76 (m, 1H), 2.20 - 2.15 (m, 3H). LCMS (Analytical Method D) Rt= 0.14, MS (ESIpos): m/z= 124.9 [M+H]+. Synthesis of 7‐methyl‐2H,3H‐[1,2,4]triazolo[4,3‐b]pyridazin‐3‐one
(Intermediate 31)
Figure imgf000168_0001
A solution of 3‐hydrazinyl‐5‐methylpyridazine (120 mg, 1.0 mmol) (Intermediate 30) and CDI (188 mg, 1.2 mmol) in acetonitrile (7.5 mL) was heated to 80 °C for 90 min then cooled and concentrated. The residue was triturated with acetonitrile to yield 57 mg (39% yield) of the title compound as a grey solid. 1H NMR (500 MHz, DMSO-d6) d 12.54 (s, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.54 - 7.48 (m, 1H), 2.24 (d, J = 1.2 Hz, 3H). LCMS (Analytical Method D) Rt= solvent front, MS
(ESIpos): m/z= 150.85 [M+H]+. Synthesis of 8‐methyl‐2H,3H‐[1,2,4]triazolo[4,3‐b]pyridazin‐3‐one
(Intermediate 32)
Figure imgf000168_0002
A mixture of 3-hydrazinyl-4-methylpyridazine (250 mg, 1.0 mmol) and CDI (0.29 g, 1.8 mmol) in acetonitrile (5 mL) was stirred at 60 °C for 1 h. The reaction was allowed to cool to room temperature. The resulting precipitate was removed by filtration. The filtrate was concentrated. The residue was triturated in MeCN to give 17 mg (10% yield) of the title compound as an orange solid. 1H NMR (250 MHz, DMSO- d6) d 12.72 (s, 1H), 8.14 (d, J = 3.5 Hz, 1H), 6.95 (s, 1H), 2.31 (s, 3H). LCMS (Analytical Method D) Rt= solvent front, MS (ESIpos): m/z= 151.00 [M+H]+. Synthesis of 2H,3H‐[1,2,4]triazolo[4,3‐b]pyridazin‐3‐one
(Intermediate 33)
Figure imgf000169_0001
A mixture of 6‐chloro‐2H,3H‐[1,2,4]triazolo[4,3‐b]pyridazin‐3‐one (Intermediate 33-1) (200 mg, 1.2 mmol) and Pd/C (10%, 20 mg) in methanol (10mL) and dichloromethane (10mL) was stirred under an atmosphere of hydrogen for 12 h. The atmosphere was replaced with nitrogen and the mixture flushed through a pad of celite, washing with MeOH. The filtrate was concentrated. The residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-10% MeOH in DCM) to give 61 mg (38% yield) of the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) d 12.75 (s, 1H), 8.22 (dd, J = 1.5, 4.0 Hz, 1H), 7.77 (dd, J = 1.5, 9.7 Hz, 1H), 7.08 (dd, J = 4.0, 9.7 Hz, 1H). Synthesis of 6‐methoxy‐2H,3H‐[1,2,4]triazolo[4,3‐b]pyridazin‐3‐one
(Intermediate 34)
Figure imgf000169_0002
5.4M Sodium methoxide in MeOH (271 µL) was added to a suspension of 6‐chloro‐2H,3H‐[1,2,4]triazolo[4,3‐b]pyridazin‐3‐one (Intermediate 33-1) (50 mg, 0.29 mmol) in THF (2 mL). The reaction was heated at 65 °C for 1.5 h, then cooled and diluted with EtOAc. The solid was collected by filtration, washed with EtOAc and dried to yield the title compound 73 mg (99% yield) as a yellow solid. 1H NMR (250 MHz, D2O) d 7.54 (d, J = 9.9 Hz, 1H), 6.65 (d, J = 9.9 Hz, 1H), 3.93 (s, 3H). LCMS
(Analytical Method D) Rt= 0.62, MS (ESIpos): m/z= 166.8 [M+H]+. Synthesis of 3-hydrazinyl-4-(trifluoromethyl)pyridazine
(Intermediate 35)
Figure imgf000170_0001
A solution of 3-chloro-4-(trifluoromethyl)pyridazine (183 mg, 1 mmol) and hydrazine hydrate (489 µl, 10.03 mmol) in ethanol (2.5 mL) was heated to 60 °C for 4 hours. The mixture was cooled and concentrated in vacuo. The residue was loaded onto an SCX-2 ion exchange cartridge, primed with methanol. The cartridge was washed sequentially with methanol then 2M ammonia in methanol. The basic fraction was concentrated in vacuo to yield the title compound (170 mg, 57% yield). LCMS (Analytical Method D) Rt= solvent front, MS (ESIpos): m/z= 179 [M+H]+. Synthesis of 8-(trifluoromethyl)-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one
(Intermediate 36)
Figure imgf000170_0002
A mixture of 3-hydrazinyl-4-(trifluoromethyl)pyridazine (Intermediate 35) (170 mg, 0.57 mmol) and carbonyl diimidazole (111 mg, 0.69 mmol) in acetonitrile (4 mL) was heated to 80 °C for 4 hours. The reaction was cooled and concentrated in vacuo. The residue was purified by preparative HPLC, Method B1. The relevant fractions were combined and concentrated in vacuo to yield the title compound (74 mg, 63% yield). 1H NMR (250 MHz, DMSO-d6) d 13.03 (s, 1H), 8.38 (d, J = 4.2 Hz, 1H), 7.62 - 7.54 (m, 1H). LCMS (Analytical Method D) Rt= 0.54 min, MS (ESIpos): m/z= 204.8 [M+H]+. Synthesis of 6-chloro-3-hydrazinylpyridazin-4-amine
(Intermediate 37)
Figure imgf000171_0001
A suspension of 3,6-dichloropyridazin-4-amine (500 mg, 3.05 mmol) in hydrazine hydrate (1:1) (2.23 ml, 45.7 mmol) was stirred at 105 oC for 40 min. The reaction was allowed to cool to 0 oC and quenched with ice. The resulting precipitate was triturated in cold water and collected by filtration to give title compound (380 mg, 58% yield). 1H NMR (250 MHz, DMSO-d6) d 7.28 (s, 1H), 6.38 (s, 1H), 6.26 (s, 2H), 4.23 (s, 3H). LCMS (Analytical Method B) Rt= 0.65 min, MS (ESIpos): m/z= 160.0 [M+H]+. Synthesis of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-8-amine
(Intermediate 38)
Figure imgf000171_0002
A pressure tube was charged with 6-chloro-3-hydrazinylpyridazin-4- amine (Intermediate 37) (380 mg, 2.38 mmol) and formic acid (1.17 mL, 30.96 mmol). The reaction was stirred at 100 oC for 3h. The reaction was allowed to cool to room temperature. The resulting solid was triturated in water to give the title compound (267 mg, 62% yield). 1H NMR (250 MHz, DMSO-d6) d 9.38 (s, 1H), 7.93 (s, 2H), 6.14 (s, 1H). LCMS (Analytical Method D) Rt= 0.73 min, MS (ESIpos): m/z= 169.9 [M+H]+. Synthesis of [1,2,4]triazolo[4,3-b]pyridazin-8-amine
(Intermediate 39)
Figure imgf000172_0001
A flask was charged with 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-8- amine ) (Intermediate 38) (0.94 g, 5.54 mmol, EtOH (72 ml), MeOH (36 ml), DCM (36 ml) and diisopropylethylamine (2374.98 µl, 13.3 mmol). The flask was evacuated and flushed with nitrogen (x 3). Pd (10% wt on carbon) (10%, 176.95 mg, 0.17 mmol) was added. The flask was flushed evacuated and flushed with nitrogen (x 3) and then evacuated and flushed with hydrogen (x 3). The reaction was stirred under an atmosphere of hydrogen for 18 h. The reaction was filtered through celite rinsing with EtOAc and the filtrate was concentrated. The residue was diluted with water (50 ml) and extracted with EtOAc (3 x 60 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (463 mg, 62% yield). 1H NMR (250 MHz, DMSO-d6) d 9.37 (s, 1H), 8.04 (d, J = 5.4 Hz, 1H), 7.44 (s, 2H), 6.09 (d, J = 5.4 Hz, 1H). Synthesis of 8-iodo-[1,2,4]triazolo[4,3-b]pyridazine
(Intermediate 40)
Figure imgf000172_0002
3-Methylbutyl nitrite (178 µl, 1.32 mmol) was added to a suspension of [1,2,4]triazolo[4,3-b]pyridazin-8-amine (Intermediate 39) (40 mg, 0.3 mmol) in diiodomethane (1.39 ml, 17.17 mmol) and MeCN (6 ml). The reaction was heated at 90 oC for 1 h. The reaction was allowed to cool to room temperature then concentrated in vacuo. The resulting residue was diluted with water (5 ml) and extracted with DCM (3 x 10 ml). The combined organic extracts were dried (hydrophobic frit) and concentrated. The resulting solid was triturated in DCM to give the product (23 mg, 29% yield). 1H NMR (250 MHz, DMSO-d6) d 9.79 (s, 1H), 8.22 (d, J = 4.6 Hz, 1H), 7.94 (d, J = 4.6 Hz, 1H). LCMS (Analytical Method D) Rt= 0.71 min, MS (ESIpos): m/z= 246.8 [M+H]+. Synthesis of 8-iodo-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one
(Intermediate 41)
Figure imgf000173_0001
A pressure tube was charged with 8-iodo-[1,2,4]triazolo[4,3- b]pyridazine (Intermediate 40) (597 mg, 2.43 mmol), selenium dioxide (404 mg, 3.64 mmol) and nitrobenzene (9 ml). The reaction was heated at 165 oC for 2.5 hr. The reaction was allowed to cool to room temperature, sonicated and filtered. The precipitate was washed with the minimum volume of EtOH and then water. Water (20 ml) was added to the precipitate and the suspension was heated at 110 oC for 10 min. The remaining precipitate was removed by filtration. The aqueous filtrate was concentrated to give the title compound (274 mg, 38% yield). 1H NMR (500 MHz, DMSO-d6) d 12.89 (s, 1H), 7.84 (d, J = 4.3 Hz, 1H), 7.71 (d, J = 4.3 Hz, 1H). LCMS (Analytical Method A) Rt= 0.99 min, MS (ESIpos): m/z= 263.0 [M+H]+. Synthesis of 8-methoxy-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one
(Intermediate 42)
Figure imgf000173_0002
Sodium methoxide in methanol (5.4M, 176.7 µl) was added dropwise to a suspension of 8-iodo-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one (Intermediate 41) (50 mg, 0.19 mmol) in THF (2 ml). The reaction was stirred at 65 oC for 40 min. The reaction was allowed to cool to room temperature. The resulting precipitate was collected by filtration. The precipitate was then diluted with 0.5M aq. solution of HCl (1 ml). The resulting suspension was concentrated to give the title compound (44 mg, >90% yield). 1H NMR (500 MHz, DMSO-d6) d 12.72 (s, 1H), 8.13 (d, J = 5.1 Hz, 1H), 6.54 (d, J = 5.1 Hz, 1H), 3.99 (s, 3H). Synthesis of 3-chloro-5-cyclopropylpyridazine
(Intermediate 43)
Figure imgf000174_0001
5-Bromo-3-chloropyridazine (250 mg, 1.29 mmol), cyclopropylboronic acid (122 mg, 1.42 mmol), Pd(OAc)2 (28.41 mg, 0.13 mmol), tripotassium phosphate (550 mg, 2.59 mmol) and PCy3 (180 mg, 0.64 mmol) were suspended in toluene/water (9:1, 5 ml) and the mixture was de-gassed with nitrogen for 5 min, then sealed and stirred at 100 °C for 8 h. The reaction was cooled to room temperature, diluted with EtOAc and partitioned with 1M aq NaOH. The organic phase was separated and concentrated in vacuo. The crude product was purified by Biotage Isolera™
chromatography (silica gel, eluting with 0-100% EtOAc in heptane) to afford the title compound (91 mg, 44% yield). 1H NMR (500 MHz, DMSO-d6) d 9.07 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 2.05 - 1.98 (m, 1H), 1.21 - 1.15 (m, 2H), 1.04 - 0.98 (m, 2H). LCMS (Analytical Method D) Rt= 0.87 min, MS (ESIpos): m/z= 155, 157
[M+H]+. Synthesis of 5-cyclopropyl-3-hydrazinylpyridazine
(Intermediate 44)
Figure imgf000175_0001
3-Chloro-5-cyclopropylpyridazine (Intermediate 43) (110 mg, 0.71 mmol) was dissolved in ethanol (2 ml) and hydrazine hydrate (340 µl, 6.98 mmol) was added. The solution was sealed under nitrogen and stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-20% gradient of DCM and 20% 7M ammonia MeOH in DCM) to give the title compound (58 mg, 52% yield). 1H NMR (500 MHz, CDCl3) d 8.33 (d, J = 1.9 Hz, 1H), 6.89 - 6.39 (m, 2H), 3.98 - 3.42 (m, 2H), 1.81 - 1.73 (m, 1H), 1.12 - 1.05 (m, 2H), 0.84 - 0.78 (m, 2H). LCMS
(Analytical Method D) Rt= 0.30 min (solvent front), MS (ESIpos): m/z= 151.0
[M+H]+. Synthesis of 7-cyclopropyl-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one
(Intermediate 45)
Figure imgf000175_0002
5-Cyclopropyl-3-hydrazinylpyridazine (Intermediate 44) (58 mg, 0.37 mmol) and 1-(1H-imidazole-1-carbonyl)-1H-imidazole (65 mg, 0.4 mmol) were dissolved in acetonitrile (2 ml) and the solution was stirred under nitrogen at 60 °C for 2 h. The reaction mixture was concentrated in vacuo. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting 0-20% gradient of 2M ammonia MeOH/ DCM) to afford the title compound (85 mg, >90% yield). 1H NMR (500 MHz, Methanol-d4) d 8.06 (d, J = 2.0 Hz, 1H), 7.26 - 7.22 (m, 1H), 2.00 - 1.93 (m, 1H), 1.19 - 1.08 (m, 2H), 0.97 - 0.87 (m, 2H). LCMS (Analytical Method D) Rt= 0.76 min, MS (ESIpos): m/z= 177.0 [M+H]+. Synthesis of 3-[2-(diphenylmethylidene)hydrazin-1-yl]-5-methoxypyridazine
(Intermediate 46)
Figure imgf000176_0001
3-Chloro-5-methoxypyridazine (500 mg, 3.46 mmol), benzophenone hydrazone (815 mg, 4.15 mmol), JohnPhos (155 mg, 0.52 mmol) and Pd2(dba)3 (160 mg, 0.17 mmol) were suspended in toluene and the mixture was de-gassed with nitrogen for 10 min. Sodium tert-butoxide (475 mg, 4.94 mmol) was added and the mixture was sealed under nitrogen and stirred at 100 °C for 4 h. The reaction mixture was allowed to cool to room temperature, filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting 0-100% EtOAc in heptane) to afford the desired product (412 mg, 33% yield). 1H NMR (500 MHz, CDCl3) d 8.50 (s, 1H), 8.41 (d, J = 2.7 Hz, 1H), 7.60 - 7.50 (m, 5H), 7.37 - 7.30 (m, 5H), 7.11 (d, J = 2.7 Hz), 3.97 (s, 3H). LCMS (Analytical Method D) Rt= 1.06 min, MS (ESIpos): m/z= 305.0 [M+H]+. Synthesis of 3-hydrazinyl-5-methoxypyridazine dihydrochloride
(Intermediate 47)
Figure imgf000177_0001
3-[2-(Diphenylmethylidene)hydrazin-1-yl]-5-methoxypyridazine (Intermediate 46) (412 mg, 1.15 mmol) was dissolved in 12M HCl (5 ml) and the mixture was stirred at 65 °C for 18 hr. The reaction mixture was allowed to cool to room temperature and wash with DCM (3 x 10 ml). The aqueous phase was
concentrated in vacuo. The residue was triturated with acetonitrile to afford the title compound (162 mg, 95% yield). 1H NMR (500 MHz, Methanol-d4) d 8.35 (s, 1H), 6.91 (s, 1H), 4.05 (s, 3H). LCMS (Analytical Method D) Rt= 0.16 min (solvent front), MS (ESIpos): m/z= 140.9 [M+H]+. Synthesis of 7-methoxy-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one
(Intermediate 48)
Figure imgf000177_0002
3-Hydrazinyl-5-methoxypyridazine dihydrochloride (Intermediate 47) (162 mg, 1.1 mmol) and 1-(1H-imidazole-1-carbonyl)-1H-imidazole (190 mg, 1.17 mmol) were suspended in acetonitrile (4 ml) and the mixture was stirred at 60 °C for 1 h. After standing at RT for 2 days, then reaction mixture was filtered and precipitate collected. The precipitate was purified by Biotage Isolera™ chromatography (silica gel, eluting 0-20% 7N ammonia MeOH in DCM) to give the title compound (80 mg, 44% yield). 1H NMR (500 MHz, DMSO-d6) d 12.31 (s, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 3.84 (s, 3H). LCMS (Analytical Method D) Rt= 0.44 min (solvent front), MS (ESIpos): m/z= 167.0 [M+H]+. Synthesis of 5-chloro-3-[2-(diphenylmethylidene)hydrazin-1-yl]pyridazine
(Intermediate 49)
Figure imgf000178_0001
A mixture of 3,5-dichloropyridazine (500 mg, 3.36 mmol), benzophenone hydrazone (659 mg, 3.36 mmol), Pd2dba3 (108 mg, 0.12 mmol), Xantphos (136.03 mg, 0.23 mmol) and sodium tert-butoxide (387.1mg, 4.03 mmol) in toluene (20 mL) was degassed by sparging with nitrogen. The mixture was heated to 100 °C for 2 hours then cooled and quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (25 g, silica), eluting with 0-100% ethyl acetate/heptane to yield the title compound (410 mg, 40% yield). 1H NMR (500 MHz, DMSO-d6) d 9.46 (s, 1H), 8.80 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.66– 7.54 (m, 5H), 7.41– 7.36 (m, 5H). LCMS (Analytical Method A) Rt= 3.93 min, MS (ESIpos): m/z= 309.1 [M+H]+. Synthesis of 5-chloro-3-hydrazinylpyridazine dihydrochloride
(Intermediate 50)
Figure imgf000178_0002
A solution of 5-chloro-3-[2-(diphenylmethylidene)hydrazin-1- yl]pyridazine (Intermediate 49) (26 mg, 0.08 mmol) in concentrated HCl (12M, 2 mL) was heated to 65 °C for 18 hours. The mixture was cooled and partitioned between dichloromethane and water. The organic layer was extracted three times with water and the aqueous layer concentrated in vacuo to yield the title compound as a yellow solid (26 mg, 99% yield). 1H NMR (500 MHz, DMSO-d6) d 8.87 (d, J = 1.7 Hz, 2H), 7.47 (s, 2H). Synthesis of 7-chloro-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one
(Intermediate 51)
Figure imgf000179_0001
5-Chloro-3-hydrazinylpyridazine dihydrochloride (Intermediate 50) (90%, 1 g, 4.14 mmol) and 1-(1H-imidazole-1-carbonyl)-1H-imidazole (0.74 g, 4.55 mmol) were suspended in acetonitrile (40 ml) under nitrogen and the mixture was stirred at 60 °C for 2 h. The reaction was cooled to room temperature, then in an ice/water bath. A brown precipitate was filtered off and washed with acetonitrile. The precipitate was partitioned between water and EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc twice. The organics were combined and concentrated in vacuo. LCMS showed that the previous acetonitrile filtrate contained the majority of the desired product. The filtrate was combined with the organics and concentrated in vacuo. The resultant solid was purified chromatography (silica; 0-100% MeOH in DCM) to give the title compound (148 mg, 21% yield). 1H NMR (500 MHz, DMSO-d6) d 12.81 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H). LCMS (Analytical Method D) Rt= 0.45 min, MS (ESIpos): 170.85, 172.30 [M+H]+. Synthesis of 3-chloro-6-hydrazinyl-4,5-dimethylpyridazine
(Intermediate 52)
Figure imgf000180_0001
Hydrazine hydrate (2.7 ml, 56 mmol) was added to a solution of 3,6- dichloro-4,5-dimethylpyridazine (1g, 5.65 mmol) in ethanol (15 mL) and the reaction heated to 80 °C for 18 hr. Upon cooling to room temperature, precipitation occurred. The solid was collected by suction filtration to afford the title compound (870 mg, 89% yield). 1H NMR (250 MHz, DMSO-d6) d 7.65 (s, 1H), 4.35 (s, 2H), 2.22 (s, 3H), 2.04 (s, 3H). LCMS (Analytical Method D) Rt= 0.30 min (solvent front), MS (ESIpos): 172.9 [M+H]+. Synthesis of 6-chloro-7,8-dimethyl-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one
(Intermediate 53)
Figure imgf000180_0002
4-Nitrophenyl carbonochloridate (291 mg, 1.45 mmol) in dry THF (1.25 ml) was added dropwise to an ice-cold solution of 3-chloro-6-hydrazinyl-4,5- dimethylpyridazine (Intermediate 52) (250 mg, 1.45 mmol) and triethylamine (222 µl, 1.59 mmol) in dry THF (9 ml). The reaction was stirred at room temperature under nitrogen for 18 h. The reaction mixture was concentrated in vacuo. The residue was triturated with EtOAc-heptane to afford the title compound (125 mg, 38% yield). 1H NMR (500 MHz, DMSO-d6) d 12.54 (s, 1H), 8.06 (s, 1H), 2.24– 2.21 (m, 3H), 2.20– 2.16 (m, 3H). LCMS (Analytical Method D) Rt= 0.80 min, MS (ESIpos): 199.0
[M+H]+. Synthesis of 7,8-dimethyl-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one
(Intermediate 54)
Figure imgf000181_0001
A solution of 6-chloro-7,8-dimethyl-2H,3H-[1,2,4]triazolo[4,3- b]pyridazin-3-one (Intermediate 53) (125 mg, 0.63 mmol) and 10% palladium on charcoal (11 mg) in methanol (5 mL) and dichloromethane (5 mL) was stirred under an atmosphere of hydrogen for 12 h. The vessel was flushed with nitrogen and filtered through a pad of celite. The filtrate was concentrated. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-3% MeOH in DCM), to give the title compound (36 mg, 35% yield). 1H NMR (500 MHz, DMSO-d6) d 12.54 (s, 1H), 8.06 (s, 1H), 2.24– 2.21 (m, 3H), 2.20– 2.16 (m, 3H). LCMS (Analytical Method D) Rt= 0.59 min, MS (ESIpos): 165.0 [M+H]+. Synthesis of ethyl 2-{6-chloro-3-oxo-2H,3H-[1,2,4]-triazolo[4,3-b]pyridazin-2- yl}acetate
(Intermediate 55)
Figure imgf000181_0002
A suspension of 6-chloro-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one (Intermediate 33-1) (194 mg, 1.14 mmol), ethyl bromoacetate (126.13 µl, 1.14 mmol), and K2CO3 (157.2 mg, 1.14 mmol) in MeCN (6 ml) was stirred at 60 °C for 90 min. The reaction was allowed to cool to room temperature, diluted with water (1 ml) and extracted with EtOAc (3 x 5 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the title compound (275 mg, 90% yield). 1H NMR (250 MHz, DMSO-d6) d 7.96 (d, J = 9.9 Hz, 1H), 7.31 (d, J = 9.9 Hz, 1H), 4.86 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H). LCMS (Analytical Method D) Rt= 0.85 min, MS (ESIpos): m/z 256.9, 258.9 [M+H]+,. Synthesis of ethyl 2-{6-cyclopropyl-3-oxo-2H,3H-[1,2,4]-triazolo[4,3-b]-pyridazin-2- yl}acetate (Intermediate 56)
Figure imgf000182_0001
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), K3PO4 (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 N2 and sealed. The reaction was stirred at 75 oC for 6 h. The reaction was re-treated with cyclopropylboronic acid (11 mg, 0.13 mmol) and Pd(dppf)Cl2 (15.68 mg, 0.02 mmol). The reaction was degassed with N2 and sealed. Stirring was continued at 75 oC 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 Isolera™ chromatography (silica gel, eluting with 0-3% MeOH in DCM) to give the title compound (87 mg, 30% yield). LCMS (Analytical Method D) Rt= 0.89 min, MS (ESIpos): m/z 263 [M+H]+. Another peak corresponding to the methyl ester also observed: Rt= 0.82 min, MS (ESIpos): m/z 249 [M+H]+. Synthesis of 2-{6-cyclopropyl-3-oxo-2H,3H-[1,2,4]-triazolo[4,3-b]pyridazin-2- yl}acetic acid (Intermediate 57)
Figure imgf000183_0001
To a stirred solution of ethyl 2-{6-cyclopropyl-3-oxo-2H,3H- [1,2,4]triazolo[4,3-b]pyridazin-2-yl}acetate (Intermediate 56) (87 mg, 0.33 mmol) in ethanol (7 ml) and water (3 ml) was added LiOH• H2O (28 mg, 0.66 mmol). The reaction was stirred at room temperature for 18 hr. The reaction was concentrated. The residue was dissolved in water (10 ml) and acidified with 1M HCl to pH 1. The aqueous layer was extracted with DCM (3 x 10 ml). The combined organic extracts were dried (hydrophobic frit) and concentrated to give the crude product. The acidic aqueous was added to the crude product and concentrated to give the title compound (106 mg). 1H NMR (250 MHz, DMSO-d6) d 13.23 (s, 1H), 7.74 (d, J = 9.8 Hz, 1H), 7.07 (d, J = 9.8 Hz, 1H), 4.69 (s, 2H), 2.19– 2.04 (m, 1H), 1.06 (dt, J = 7.8, 2.5 Hz, 2H), 1.00 (dt, J = 5.0, 2.9 Hz, 2H). LCMS (Analytical Method D) Rt= 0.71 min, MS (ESIpos): m/z 235 [M+H]+. Synthesis of 2H,3H‐[1,2,4]triazolo[4,3‐c]pyrimidin‐3‐one
(Intermediate 58)
Figure imgf000183_0002
A mixture of 4-hydrazinylpyrimidine (250 mg, 2.3 mmol) and CDI (442 mg, 2.7 mmol) in acetonitrile (10 mL) was heated to 80 °C for 2.5 h. The reaction was cooled and the precipitate collected by filtration and washed with acetonitrile to yield 221 mg (61% yield) of the title compound as a tan solid.1H NMR (500 MHz, DMSO- d6) d 12.56 (s, 1H), 8.72 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 7.0 Hz, 1H), 7.17 (dd, J = 1.6, 7.0 Hz, 1H). Synthesis of 5,7‐dimethyl‐2H,3H‐[1,2,4]triazolo[4,3‐c]pyrimidin‐3‐one
(Intermediate 59)
Figure imgf000184_0001
A mixture of 4-hydrazinyl-2,6-dimethylpyrimidine (150 mg, 1.1 mmol) and CDI (211 mg, 1.3 mmol) in acetonitrile (5 mL) was heated to 80 °C for 2.5 h. The reaction was cooled and the precipitate was collected by filtration, washed with acetonitrile and dried to yield 85 mg (43% yield) of the title compound as a tan solid. 1H NMR (500 MHz, DMSO-d6) d 12.25 (s, 1H), 6.75 (s, 1H), 2.72 (s, 3H), 2.19 (d, J = 0.8 Hz, 3H). LCMS (Analytical Method D) Rt= 0.59, MS (ESIpos): m/z= 164.9 [M+H]. Synthesis of 8‐chloro‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrazin‐3‐one
(Intermediate 60)
Figure imgf000184_0002
To a stirred solution of 2-chloro-3-hydrazinylpyrazine (1.17 g, 8.1 mmol) and Et3N (1.24 mL, 8.9 mmol) in dry THF (57 mL), under N2 at 0 oC, was added dropwise a solution of 4-nitrophenyl chloroformate (1.63 g, 8.1 mmol) in dry THF (6 mL). The reaction was allowed to warm to room temperature for 18 h. The reaction was filtered. The precipitate was discarded. The filtrate was concentrated. The residue was triturated in the minimum volume of DCM to afford 983 mg (63% yield) of the title compound as a beige solid.1H NMR (500 MHz, DMSO-d6) d 13.07 (s, 1H), 7.91 (d, J = 4.8 Hz, 1H), 7.33 (d, J = 4.8 Hz, 1H). LCMS (Analytical Method D) Rt= 0.47 min, MS (ESIpos): m/z= 170.80, 172.80 [M+H]+. Synthesis of 8‐methyl‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrazin‐3‐one
(Intermediate 61)
Figure imgf000185_0001
CDI (235 mg, 1.5 mmol) was added to a solution of 2-hydrazinyl-3- methylpyrazine (150 mg, 1.2 mmol) in MeCN (6 mL). The reaction was heated to 80 °C for 2 h. The mixture was cooled and the solid material collected by filtration, washing with acetonitrile to afford 102 mg (45% yield) of the title compound as an orange solid. 1H NMR (250 MHz, DMSO-d6) d 12.92 (s, 1H), 7.71 (d, J = 4.9 Hz, 1H), 7.38 (d, J = 4.9 Hz, 1H). LCMS (Analytical Method D) Rt= solvent front, MS (ESIpos): m/z= 151.60 [M+H]+. Synthesis of 2‐[2‐(diphenylmethylidene)hydrazin‐1‐yl]‐5‐methylpyrazine
(Intermediate 62)
Figure imgf000185_0002
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), Pd2(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 oC 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). The combined organic extracts were washed with brine (40 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-16% EtOAc in heptane) to give 950 mg (85% yield) of the title compound as a white solid.1H NMR (500 MHz, CDCl3) d 8.81 (d, J = 1.1 Hz, 1H), 8.02 (s, 1H), 7.85 (s, 1H), 7.62– 7.55 (m, 4H), 7.54– 7.50 (m, 1H), 7.38– 7.33 (m, 4H), 7.33– 7.30 (m, 1H), 2.46 (s, 3H). LCMS (Analytical Method D) Rt= 1.30 min, MS (ESIpos): m/z= 288.90 [M+H]+. Synthesis of 2‐hydrazinyl‐5‐methylpyrazine dihydrochloride
(Intermediate 63)
Figure imgf000186_0001
A suspension of 2-[2-(diphenylmethylidene)hydrazin-1-yl]-5- methylpyrazine (950 mg, 3.3 mmol) (Intermediate 62) in conc HCl (14 mL) was heated to 65 °C for 6 h. The reaction was allowed to cool to room temperature, filtered and washed with DCM (3 x 10 mL). The aqueous layer was concentrated to give 597 mg (92% yield) of the title compound as a yellow solid.1H NMR (500 MHz, DMSO-d6) d 10.34 (s, 3H), 9.57 (s, 1H), 8.22 (d, J = 1.4 Hz, 1H), 8.15 (s, 1H), 2.40 (s, 3H). LCMS (Analytical Method D) Rt= 0.17 min, MS (ESIpos): m/z= 124.90 [M+H]+. Synthesis of 6‐methyl‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrazin‐3‐one
(Intermediate 64)
Figure imgf000187_0001
To a suspension of 2‐hydrazinyl‐5‐methylpyrazine dihydrochloride (436 mg, 2.2 mmol) (Intermediate 63) and Et3N (616 µL, 4.43 mmol) in MeCN (5.3 mL) was added CDI (431 mg, 2.7 mmol). The reaction was stirred at 80 oC for 1.5 h. The reaction was cooled to 0 oC and the resulting precipitate collected by filtration. The solid was triturated in a mixture of water (2 mL) and EtOAc (2 mL) to give 206 mg (62% yield) of the title compound as a red solid.1H NMR (250 MHz, DMSO-d6) d 12.88 (s, 1H), 8.84 (d, J = 1.6 Hz, 1H), 7.82– 7.51 (m, 1H), 2.29 (d, J = 1.0 Hz, 3H). LCMS (Analytical Method B) Rt= 0.51 min, MS (ESIpos): m/z= 150.6 [M+H]+. [ca. 90%]. Synthesis of tert‐butyl 8‐chloro‐3‐oxo‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrazine‐2‐ carboxylate
(Intermediate 65)
Figure imgf000187_0002
To a stirred solution of 8-chloro-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-3- one (200 mg, 1.2 mmol) (Intermediate 60) in THF (4 mL) was added
ditertbutyldicarbonate (269 mg, 1.2 mmol). The reaction was stirred at room temperature for 18 h. N,N-dimethylpyridin-4-amine (14 mg, 0.12 mmol) was added and the reaction was stirred for 2 h. The reaction was diluted with water (4 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried
(Na2SO4), filtered and concentrated. The crude product was purified by Biotage Isolera™ chromatography (silica gel, using 0-43% EtOAc in heptane as eluent) to give 205 mg (65% yield) of the tile compound as a white solid.1H NMR (250 MHz, DMSO- d6) d 12.55 (s, 1H), 8.44 (d, J = 3.0 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 3.80 (s, 3H). LCMS (Analytical Method D) Rt= 1.01 min, MS (ESIpos): m/z= 170.90, 172.90 [M- BOC+H]+. Synthesis of 8‐(difluoromethyl)‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrazin‐3‐one
(Intermediate 66)
Figure imgf000188_0001
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. The reaction was heated at 80 oC for 4.5 h. The reaction was concentrated. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0- 10% MeOH in DCM) to give the title compound as a black solid (660 mg, 66% yield). 19F NMR (235 MHz, DMSO-d6) d -122.49 (d, J = 52.5 Hz, 2F). LCMS (Analytical Method D) Rt= 0.45 min, MS (ESIpos): m/z= 186.80 [M+H]+. Synthesis of 8‐(piperidin‐1‐yl)‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrazin‐3‐one
(Intermediate 67)
Figure imgf000189_0001
To a suspension of 8-chloro-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-3-one (50 mg, 0.29 mmol) (Intermediate 60) in THF (1 mL) was added piperidine (29 µL, 0.29 mmol). The reaction was stirred at 80 oC for 90 min. The reaction was allowed to cool to room temperature and filtered. The solid was diluted with water (1 mL) and EtOAc (3 mL) and sonicated. The resulting suspension was sonicated. The precipitate was collected by filtration affording 30 mg (42% yield) of the title compound as a beige solid.1H NMR (250 MHz, DMSO-d6) d 12.72 (s, 1H), 7.13 (d, J = 4.7 Hz, 1H), 7.04 (d, J = 4.7 Hz, 1H), 4.13– 3.87 (m, 4H), 1.77– 1.44 (m, 6H). LCMS (Analytical Method D) Rt= 0.71 min, MS (ESIpos): m/z= 219.90 [M+H]+. Synthesis of tert‐butyl 4‐{3‐oxo‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrazin‐8‐yl}piperazine‐
1‐carboxylate (Intermediate 68)
Figure imgf000190_0001
To a suspension of 8-chloro-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-3-one (100 mg, 0.59 mmol) (Intermediate 60) in THF (2 mL) was added Et3N (90 µL, 0.64 mmol) and tert-butyl piperazine-1-carboxylate (109 mg, 0.59 mmol). The reaction was sonicated and then stirred at 80 oC for 30 min. The reaction was allowed to cool to room temperature, diluted with water (1 mL) and EtOAc (3 mL). The resulting suspension was sonicated. The precipitate was collected by filtration affording 87 mg (42% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 12.85 (s, 1H), 7.19 (d, J = 4.7 Hz, 1H), 7.05 (d, J = 4.7 Hz, 1H), 4.11– 3.88 (m, 4H), 3.53– 3.37 (m, 4H), 1.42 (s, 9H). LCMS (Analytical Method D) Rt= 0.99 min, MS (ESIpos): m/z= 321.10 [M+H]+. Synthesis of tert-butyl 4-[2-({[(1S)-1-(4-chloro-3- fluorophenyl)ethyl]carbamoyl}methyl)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-8- yl]piperazine-1-carboxylate
(Intermediate 69)
Figure imgf000190_0002
A suspension of 2-bromo-N-[(1S)-1-(4-chloro-3- fluorophenyl)ethyl]acetamide (Intermediate 3) (55.17 mg, 0.19 mmol), tert-butyl 4-{3- oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-8-yl}piperazine-1-carboxylate (Intermediate 68) (60 mg, 0.19 mmol) and K2CO3 (78 mg, 0.56 mmol) in acetonitrile (5 ml) was stirred at 60 °C for 40 min. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-3% MeOH in DCM) to give the title compound as a white solid (81 mg, 74% yield).1H NMR (500 MHz, DMSO-d6) d 8.62 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.34 (dd, J = 10.6, 1.7 Hz, 1H), 7.27 (d, J = 4.7 Hz, 1H), 7.23– 7.15 (m, 1H), 7.11 (d, J = 4.7 Hz, 1H), 4.95 (p, J = 7.1 Hz, 1H), 4.68 (d, J = 16.7 Hz, 1H), 4.62 (d, J = 16.7 Hz, 1H), 4.01– 3.89 (m, 4H), 3.52– 3.39 (m, 4H), 1.42 (s, 9H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.19 min, MS (ESIpos): m/z= 534.05, 537.05 [M+H]+. Synthesis of 8‐[(oxetan‐3‐yl)amino]‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrazin‐3‐one
(Intermediate 70)
Figure imgf000191_0001
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), Et3N (88 µL, 0.63 mmol) and dry THF (2 mL). The reaction was stirred under nitrogen at 80 °C for 1 h. The reaction stood at room temperature for 18 h and was then re-treated oxetan-3-amine (43 mg, 0.57 mmol). 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
Isolera™ chromatography (silica gel, eluting with 0-6% MeOH in DCM) to give 23 mg (18% yield) of the title compound as a solid.1H NMR (500 MHz, DMSO-d6) d 12.72 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.13 (d, J = 4.8 Hz, 1H), 6.95 (d, J = 4.9 Hz, 1H), 5.08 - 5.01 (m, 1H), 4.76 (t, J = 6.9 Hz, 2H), 4.64 (t, J = 6.5 Hz, 2H). LCMS
(Analytical Method D) Rt= 0.39 min, MS (ESIpos): m/z= 207.85 [M+H]+. Synthesis of tert‐butyl 3‐({3‐oxo‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrazin‐8‐
yl}oxy)azetidine‐1‐carboxylate (Intermediate 71)
Figure imgf000192_0001
To a stirred suspension of NaH (60%, 35 mg, 0.88 mmol) in THF (2 mL), under N2 at 0 oC, was added tert-butyl 3-hydroxyazetidine-1-carboxylate (51 mg, 0.29 mmol). The reaction was stirred at room temperature for 1 h. The reaction was cooled to 0 oC and a suspension of 8-chloro-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-3-one (50 mg, 0.29 mmol) (Intermediate 60) in THF (2 mL) was added in one portion. The reaction was stirred at room temperature for 2 h. The reaction was heated at 66 oC for 18 h. The reaction was allowed to cool to room temperature and quenched with saturated NH4Cl (aq) solution. The pH was adjusted to pH 7 with 1M HCl (aq) and extracted with DCM (3 x 6 mL). The combined organic extracts were dried
(hydrophobic frit) and concentrated. The crude product was triturated in EtOAc to give the title compound as a brown solid (19 mg, 19% yield).1H NMR (500 MHz, DMSO- d6) d 11.09 (s, 1H), 7.53 (d, J = 4.9 Hz, 1H), 7.02 (d, J = 4.9 Hz, 1H), 5.42 (tt, J = 6.6, 3.9 Hz, 1H), 4.37– 4.17 (m, 2H), 4.02– 3.82 (m, 2H), 1.39 (s, 9H). LCMS (Analytical Method D) Rt= 0.97 min, MS (ESIpos): m/z= 251.95 [M-tBu+H]+. Synthesis of tert-butyl 3-{[2-({[(1S)-1-(4-chloro-3- fluorophenyl)ethyl]carbamoyl}methyl)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-8- yl]oxy}azetidine-1-carboxylate
(Intermediate 72)
Figure imgf000193_0001
A suspension of 2-bromo-N-[(1S)-1-(4-chloro-3- fluorophenyl)ethyl]acetamide (Intermediate 3) (50 mg, 0.17 mmol), tert-butyl 3-({3- oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-8-yl}oxy)azetidine-1-carboxylate (57 mg, 0.19 mmol) (Intermediate 71) and K2CO3 (70 mg, 0.51 mmol) in acetonitrile (5 mL) was stirred at 60 °C for 40 min. The reaction was allowed to cool to room temperature and was diluted with water (5 mL). The reaction was extracted with EtOAc (3 x 7 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-3% MeOH in DCM) to give 69 mg (71% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.67 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 4.9 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.37 (dd, J = 10.7, 2.0 Hz, 1H), 7.20 (dd, J = 8.3, 1.9 Hz, 1H), 7.09 (d, J = 4.9 Hz, 1H), 5.44 (ddd, J = 10.5, 6.6, 3.9 Hz, 1H), 4.94 (p, J = 7.1 Hz, 1H), 4.71 (d, J = 16.6 Hz, 1H), 4.64 (d, J = 16.6 Hz, 1H), 4.34– 4.22 (m, 2H), 3.99– 3.84 (m, 2H), 1.39 (s, 9H). LCMS (Analytical Method D) Rt = 4.28 min, MS (ESIpos): m/z= 421.05, 423.05 [M+H]+. Purity = 100%. Synthesis of 8‐(methylamino)‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrazin‐3‐one
(Intermediate 73)
Figure imgf000194_0001
A pressure vial was charged with 8-chloro-2H,3H-[1,2,4]triazolo[4,3- a]pyrazin-3-one (60 mg, 0.35 mmol) (Intermediate 60) and 2M methylamine in THF (1.76 mL). The reaction was heated at 80 oC for 18 h. The reaction was allowed to cool to room temperature and additional 2M methylamine in THF (1.76 mL) was added and the reaction was stirred at 80 oC for 45 min. The reaction was concentrated and the residue was diluted with water (1 mL) and EtOAc (2 mL). The resulting suspension was sonicated. The precipitate was collected by filtration affording the title compound as a beige solid (12 mg, 19% yield).1H NMR (250 MHz, DMSO-d6) d 7.70 (d, J = 4.5 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 6.99 (d, J = 4.8 Hz, 1H), 2.90 (d, J = 4.7 Hz, 3H). LCMS (Analytical Method D) Rt= 0.17 min, MS (ESIpos): m/z= 165.85 [M+H]+. Synthesis of 2H,3H‐[1,2,4]triazolo[4,3‐a]pyrimidin‐3‐one
(Intermediate 74)
Figure imgf000194_0002
A mixture of 2-hydrazinopyrimidine (100 mg, 0.91 mmol) and CDI (295 mg, 1.82 mmol) in THF (2 mL) was stirred at room temperature for 18 h. The solid material was removed by filtration, washing with ethyl acetate. The solid residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM) to give 20 mg (16% yield) of the title compound as a yellow solid.1H NMR (250 MHz, DMSO-d6) d 12.59 (s, 1H), 8.50 (dd, J = 2.0, 3.8 Hz, 1H), 8.28 (dd, J = 2.0, 7.0 Hz, 1H), 6.66 (dd, J = 3.8, 7.0 Hz, 1H). LCMS (Analytical Method E) Rt= 0.30 min, MS (ESIpos): m/z= 137.1 [M+H]+. Synthesis of 2‐[2‐(diphenylmethylidene)hydrazin‐1‐yl]‐5‐methylpyrimidine
(Intermediate 75)
Figure imgf000195_0001
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 N2 and sealed. The reaction was heated at 90 oC 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). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (40 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-30% EtOAc in heptane, to give 748 mg (67% yield) of the title compound as a yellow solid.1H NMR (500 MHz, Chloroform-d) d 8.32 (s, 1H), 8.29 (s, 2H), 7.68– 7.61 (m, 2H), 7.59– 7.54 (m, 2H), 7.54– 7.48 (m, 1H), 7.36– 7.34 (m, 1H), 7.34– 7.32 (m, 1H), 7.32– 7.29 (m, 3H), 2.19 (s, 3H). LCMS (Analytical Method D) Rt= 1.15, MS (ESIpos): m/z= 288.90 [M+H]+. Synthesis of 2‐hydrazinyl‐5‐methylpyrimidine dihydrochloride
(Intermediate 76)
Figure imgf000196_0001
A suspension of 2-[2-(diphenylmethylidene)hydrazin-1-yl]-5- methylpyrimidine (748 mg, 2.6 mmol) (Intermediate 75) in concentrated HCl (10 mL) was heated to 65 °C for 6 h. The reaction was allowed to cool to room temperature, filtered and washed with DCM (3 x 10 mL). The aqueous layer was concentrated to give 416 mg (81% yield) of the title compound as a yellow solid.1H NMR (500 MHz, DMSO-d6) d 10.24 (s, 2H), 9.59 (s, 1H), 8.43 (s, 2H), 2.18 (s, 3H). LCMS (Analytical Method D) Rt= solvent front, MS (ESIpos): m/z= 124.85 [M+H]+. Synthesis of 6‐methyl‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrimidin‐3‐one
(Intermediate 77)
Figure imgf000196_0002
To a suspension of 2‐hydrazinyl‐5‐methylpyrimidine dihydrochloride (150 mg, 0.76 mmol) (Intermediate 76) in MeCN (1.8 mL) was added CDI (148 mg, 0.91 mmol). The reaction was stirred at 80 oC for 1.5 h. The reaction was cooled to 0 oC and the precipitate collected by filtration. The solid was triturated in a mixture of water (0.5 mL) and EtOAc (0.5 mL). The resulting solid was triturated in MeOH to give 36 mg (32% yield) of the title compound as a yellow solid.1H NMR (250 MHz, DMSO- d6) d 12.50 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.12 (dd, J = 2.4, 1.3 Hz, 1H), 2.17 (d, J = 1.3 Hz, 3H). LCMS (Analytical Method B) Rt= 0.44, MS (ESIpos): m/z= 150.5 [M+H]+. Synthesis of 6‐chloro‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrimidin‐3‐one
(Intermediate 78)
Figure imgf000197_0001
A mixture of 5-chloro2-hydrazinopyrimidine (250 mg, 1.7 mmol) and CDI (337 mg, 2.1 mmol) in acetonitrile (5 mL) was stirred at 80 oC for 1 h. The reaction mixture was allowed to cool to room temperature. The solid formed as collected by filtration to give 120 mg (8% yield) of the title compound as an orange solid.1H NMR (500 MHz, DMSO-d6) d 12.72 (s, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H). LCMS (Analytical Method D) Rt= 0.35 min, MS (ESIpos): m/z= 170.90 [M+H]+. Synthesis of 5‐fluoro‐2‐hydrazinylpyrimidine
(Intermediate 79)
Figure imgf000197_0002
A solution of 2-chloro-5-fluoropyrimidine (1.04 mL, 11.3 mmol) and hydrazine hydrate (1:1) (5.66 mL, 116.0 mmol) in EtOH (10 mL) was heated at 60 oC for 6 h. The reaction was cooled to 0 oC and then sonicated. The precipitate was collected by filtration and rinsed with water affording 1.11 g (76% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.43– 8.36 (m, 2H), 8.18 (s, 1H), 4.16 (s, 2H). Synthesis of 6‐fluoro‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrimidin‐3‐one
(Intermediate 80)
Figure imgf000198_0001
To a solution of 5-fluoro-2-hydrazinylpyrimidine (250 mg, 2.0 mmol) (Intermediate 79) and Et3N (299 µL, 2.2 mmol) in dry THF (12 mL), under N2 at 0 oC, was added dropwise a solution of 4-nitrophenyl chloroformate (393 mg, 2.0 mmol) in dry THF (2 mL). The reaction was stirred at 0 oC for 1 h and then at room temperature for 18 h. The reaction was filtered. The precipitate was discarded. The filtrate was concentrated. The residue was triturated in DCM (x 2) and then in MeOH to afford 106 mg (32% yield) of the title compound as a yellow solid.1H NMR (250 MHz, DMSO- d6) d 12.72 (s, 1H), 8.72 (dd, J = 2.9, 0.6 Hz, 1H), 8.59 (t, J = 3.0 Hz, 1H). LCMS (Analytical Method D) Rt= 0.23 min, MS (ESIpos): m/z= 154.80 [M+H]+. Synthesis of 2‐hydrazinyl‐5‐methoxypyrimidine
(Intermediate 81)
Figure imgf000198_0002
A suspension of 2-chloro-5-methoxypyrimidine (1.5 g, 10.4 mmol) and hydrazine hydrate (1:1) (5.2 mL, 106.4 mmol) in EtOH (10 mL) was heated at 60 oC for 24 h. The reaction was cooled to 0 oC and then sonicated. The precipitate was collected by filtration and rinsed with water affording 1.39 g (96% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.16 (s, 2H), 7.70 (s, 1H), 4.03 (s, 2H), 3.76 (s, 3H). LCMS (Analytical Method E) Rt= 0.92, MS (ESIpos): m/z= 141.2
[M+H]+. Synthesis of 6‐methoxy‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrimidin‐3‐one
(Intermediate 82)
Figure imgf000199_0001
To a solution of 2-hydrazinyl-5-methoxypyrimidine (390 mg, 2.8 mmol) (Intermediate 81) and Et3N (427 µL, 3.1 mmol) in dry THF (20 mL), under N2 at 0 oC, was added dropwise a solution of 4-nitrophenyl chloroformate (561 mg, 2.8 mmol) in dry THF (3 mL). The reaction was stirred at 0 oC for 1 h and then at room temperature for 18 h. DMAP (10.2 mg, 0.1 mmol) was added to the reaction and the reaction was heated at 50 oC for 1 h. The reaction was allowed to cooled to room temperature and the resulting precipitate was collected by filtration. The precipitate was triturated in the minimum volume of a mixture of EtOAc/H2O to give 241 mg (47% yield) of the title compound as a yellow solid.1H NMR (250 MHz, DMSO-d6) d 12.55 (s, 1H), 8.44 (d, J = 3.0 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 3.80 (s, 3H). LCMS (Analytical Method D) Rt= 0.40, MS (ESIpos): m/z= 166.80 [M+H]+. Synthesis of 2‐[2‐(diphenylmethylidene)hydrazin‐1‐yl]‐4‐methoxypyrimidine
(Intermediate 83)
Figure imgf000199_0002
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 N2 and sealed. The reaction was heated at 90 oC 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). The combined organic extracts were washed with brine (60 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0- 25% EtOAc in heptane) to give 1.08 g (57% yield) of the title compound as a yellow solid.1H NMR (500 MHz, Chloroform-d) d 8.28 (s, 1H), 8.17 (d, J = 5.7 Hz, 1H), 7.69 – 7.62 (m, 2H), 7.62– 7.56 (m, 2H), 7.56– 7.51 (m, 1H), 7.37– 7.35 (m, 1H), 7.35– 7.34 (m, 1H), 7.34– 7.30 (m, 3H), 6.21 (d, J = 5.7 Hz, 1H), 3.97 (s, 3H). LCMS (Analytical Method D) Rt= 1.04 min, MS (ESIpos): m/z= 304.90 [M+H]+. Synthesis of 2-hydrazinyl-4-methoxypyrimidine dihydrochloride
(Intermediate 84)
Figure imgf000200_0001
A suspension of 2-[2-(diphenylmethylidene)hydrazin-1-yl]-4- methoxypyrimidine (1.08 g, 3.6 mmol) (Intermediate 83) in conc HCl (14 mL) was heated to 65 °C for 6 h. The reaction was allowed to cool to room temperature, filtered and washed with DCM (3 x 10 mL). The aqueous layer was concentrated to give 674 mg (89% yield) of the title compound as a yellow solid.1H NMR (500 MHz, DMSO- d6) d 8.19 (d, J = 6.2 Hz, 1H), 6.44 (d, J = 6.2 Hz, 1H), 3.94 (s, 3H). LCMS
(Analytical Method E) Rt= 1.06 min, MS (ESIpos): m/z= 141.1 [M+H]+. Synthesis of 7‐methoxy‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrimidin‐3‐one
(Intermediate 85)
Figure imgf000201_0002
To a suspension of 2-hydrazinyl-4-methoxypyrimidine-1,3-diium dichloride (150 mg, 0.7 mmol) (Intermediate 84) and Et3N (196 µL, 1.4 mmol) in MeCN (1.7 mL) was added CDI (137 mg, 0.8 mmol). The reaction was stirred at 80 oC for 2 h. The reaction was cooled to 0 oC and the resulting precipitate collected by filtration. The solid was triturated in a mixture of water (2 mL) and EtOAc (2 mL) to give 68 mg (58% yield) of the title compound as a white solid.1H NMR (250 MHz, DMSO-d6) d 12.05 (s, 1H), 8.15 (d, J = 7.4 Hz, 1H), 6.29 (d, J = 7.4 Hz, 1H), 3.92 (s, 3H). LCMS (Analytical Method B) Rt= 1.07 min, MS (ESIpos): m/z= 166.6 [M+H]+. Synthesis of 5,7‐dimethyl‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrimidin‐3‐one
(Intermediate 86)
Figure imgf000201_0001
A mixture of 2-hydrazinyl-4,6-dimethylpyrimidine (200 mg, 1.5 mmol) and CDI (0.28 g, 1.7 mmol) in acetonitrile (5 mL) was stirred at 60 oC for 20 min. The resulting solid was collected by filtration and washed with acetonitrile, to give 165 mg (70% yield) of the title compound as a pale yellow solid.1H NMR (250 MHz, DMSO- d6) d 12.19 (s, 1H), 6.30 (d, J = 1.1 Hz, 1H), 2.65 (d, J = 1.1 Hz, 3H), 2.32 (s, 3H). LCMS (Analytical Method D) Rt= 0.61 min, MS (ESIpos): m/z= 165 [M+H]+. Synthesis of 2‐chloro‐4‐methoxy‐5‐methylpyrimidine
(Intermediate 87)
Figure imgf000202_0001
5.4M Sodium methoxide in MeOH (1.14 mL) was added to a suspension of 2,4-dichloro-5-methylpyrimidine (1.0 g, 6.1 mmol) in MeOH (20 mL) and the reaction stirred for 20 h. The mixture was concentrated and the residue partitioned between EtOAc and water. The aqueous layer was extracted into EtOAc (x3), the combined organics washed with brine, dried (MgSO4) and concentrated. The residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-50% EtOAc in heptane to yield 600 mg (62% yield) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3) d 8.10 (s, 1H), 4.03 (s, 3H), 2.12 (d, J = 0.7 Hz, 3H). LCMS (Analytical Method D) Rt= 1.00, MS (ESIpos): m/z= 158.9 [M+H]+. Synthesis of 2‐hydrazinyl‐4‐methoxy‐5‐methylpyrimidine
(Intermediate 88)
Figure imgf000202_0002
Hydrazine hydrate (768 µL, 15.8 mmol) was added to a solution of 2‐ chloro‐4‐methoxy‐5‐methylpyrimidine (250 mg, 1.6 mmol) (Intermediate 87) in EtOH (4 mL) and the reaction heated to 60 °C for 4 h. The reaction was cooled and allowed to stand at room temperature for 18 h. The solid material was collected by filtration, washed with EtOH and dried affording 110 mg (34% yield) of the title compound as a white solid. LCMS (Analytical Method D) Rt= solvent front, MS (ESIpos): m/z= 154.90 [M+H]+. Synthesis of 7‐methoxy‐6‐methyl‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrimidin‐3‐one
(Intermediate 89)
Figure imgf000203_0001
A mixture of 2‐hydrazinyl‐4‐methoxy‐5‐methylpyrimidine (75 mg, 0.5 mmol) (Intermediate 88) and CDI (95 mg, 0.6 mmol) in acetonitrile (3 mL) was heated to 80 °C for 3 h. The mixture was cooled and the solid collected by filtration, washed with acetonitrile and dried. The solid was triturated with EtOAc and then purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-10% MeOH in DCM) to give 9 mg (10% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 11.97 (s, 1H), 8.04 (d, J = 1.3 Hz, 1H), 3.94 (s, 3H), 2.00 (d, J = 1.3 Hz, 3H). LCMS (Analytical Method D) Rt= 0.72, MS (ESIpos): m/z= 180.8 [M+H]+. Synthesis of 2-chloro-5-cyclopropylpyrimidine
(Intermediate 90)
Figure imgf000203_0002
5-Bromo-2-chloropyrimidine (600 mg, 3.1 mmol), cyclopropylboronic acid (300 mg, 3.49 mmol) and cesium carbonate (1.04 g, 10.82 mmol) were suspended in toluene/water (9:1, 10 ml) and the mixture was de-gassed with nitrogen for 10 min. Bis(cyclopentyldiphenylphosphane) dichloromethane dichloropalladium iron (130 mg, 0.16 mmol) was added and the mixture was stirred at 110 °C for 45 min, then cooled to room temperature. The mixture was diluted with EtOAc and filtered. The filtrate was partitioned with water. The organic phase was separated and concentrated in vacuo. The crude product was purified by Biotage Isolera™ chromatography (silica gel, 0-30% EtOAc in heptane) to afford the title compound (221 mg, 46% yield).1H NMR (500 MHz, Chloroform-d) d 8.34 (s, 2H), 1.89 - 1.81 (m, 1H), 1.14 - 1.08 (m, 2H), 0.79 - 0.74 (m, 2H). LCMS (Analytical Method D) Rt= 0.92 min (solvent front), MS
(ESIpos): m/z= 155.0, 157.0 [M+H]+. Synthesis of 5-cyclopropyl-2-hydrazinylpyrimidine
(Intermediate 91)
Figure imgf000204_0001
2-Chloro-5-cyclopropylpyrimidine (211 mg, 1.36 mmol) (Intermediate 90) was dissolved in ethanol (4 ml), then hydrazine hydrate (665 µl, 13.64 mmol) was added. The mixture was sealed under nitrogen and stirred at 60 °C for 2 hr. The reaction was concentrated in vacuo. The crude product was triturated with water and the precipitate filtered off. The filtrate was concentrated in vacuo to afford a residue, which was then triturated with acetonitrile. The precipitate was filtered off and the filtrate was collected and concentrated in vacuo to give the title compound.1H NMR (500 MHz, Chloroform-d) d 8.13 (s, 2H), 6.71 (s, 1H), 4.18 - 3.74 (m, 2H), 1.75 - 1.65 (m, 1H), 0.93 - 0.87 (m, 2H), 0.63 - 0.55 (m, 2H). LCMS (Analytical Method D) Rt= 0.31 min (solvent front), MS (ESIpos): m/z= 151.0 [M+H]+. Synthesis of 6-cyclopropyl-2H,3H-[1,2,4]triazolo[4,3-a]pyrimidin-3-one
(Intermediate 92)
Figure imgf000204_0002
5-Cyclopropyl-2-hydrazinylpyrimidine (125 mg, 0.75 mmol)
(Intermediate 91) was suspended in acetonitrile (4 ml).1-(1H-imidazole-1-carbonyl)- 1H-imidazole (135 mg, 0.83 mmol) was added and the solution was stirred at room temperature for 1 hr. The reaction mixture was left standing at room temperature overnight, then cooled to 0 °C and filtered. The precipitate was washed with acetonitrile and collected to afford the title compound (83 mg, 63% yield).1H NMR (500 MHz, DMSO-d6) d 12.49 (s, 1H), 8.39 (s, 1H), 7.97 (s, 1H), 1.94 - 1.86 (m, 1H), 0.95 - 0.86 (m, 2H), 0.84 - 0.75 (m, 2H). LCMS (Analytical Method D) Rt= 0.72 min (solvent front), MS (ESIpos): m/z= 177.0 [M+H]+. Synthesis of 7‐methyl‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrimidin‐3‐one (Intermediate 93-1) and 5‐methyl‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyrimidin‐3‐one (Intermediate 93-2)
Figure imgf000205_0001
A mixture of 2-hydrazinopyrimidine (250 mg, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in MeCN (5 mL) was stirred at 80 oC for 1.5 h. The reaction was allowed to cool to room temperature. The resulting solid was collected by filtration and washed with acetonitrile, to give 200 mg (2:1 mixutre of regioisomers, 66% yield) of the title compounds as a brown solid.
Major regioisomer: 1H NMR (250 MHz, DMSO-d6) d 12.36 (s, 1H), 8.17 (d, J = 7.1 Hz, 1H), 6.59 (d, J = 7.1 Hz, 1H), 2.42 (s, 3H).
Minor regioisomer: 1H NMR (250 MHz, DMSO-d6) d 12.36 (s, 1H), 8.27 (d, J = 4.0 Hz, 1H), 6.37 (dd, J = 4.0, 1.1 Hz, 1H), 2.70 (d, J = 1.0 Hz, 3H).
2:1 mixture of regioisomers: LCMS (Analytical Method D) Rt= solvent front, MS (ESIpos): m/z= 151 [M+H]+. Synthesis of 2-bromo-N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]propanamide
(Intermediate 94)
Figure imgf000205_0002
To a mixture of (1S)-1-(4-Chloro-3-fluorophenyl)ethan-1-amine hydrochloride (100 mg, 0.48 mmol) and triethylamine (200 µl, 1.43 mmol) in THF (2 ml) at 0 °C was added 2-bromopropanoyl chloride (50 µl, 0.49 mmol. The mixture was stirred under nitrogen for 3 h. The reaction was quenched with water and extracted with EtOAc. The organics were combined, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (148 mg, 96% yield) as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.73 (dd, J = 16.9, 7.6 Hz, 1H), 7.54 (q, J = 8.2 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.21 - 7.16 (m, 1H), 4.94 - 4.82 (m, 1H), 4.60 - 4.50 (m, 1H), 1.65 (dd, J = 10.0, 6.8 Hz, 3H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z 307.9, 309.9 [M+H]+. Synthesis of (R)‐N‐[(1E)‐[4‐(difluoromethoxy)phenyl]methylidene]‐2‐methylpropane‐
2‐sulfinamide (Intermediate 95)
Figure imgf000206_0001
Titanium tetraethoxide (647 µL, 2.63 mmol) was added to a solution of 4-(difluoromethoxy)-3-fluorobenzaldehyde (250 mg, 1.31 mmol) and (R)- tertbutylsulfinamide (175 mg, 1.45 mmol) in dichloromethane (10 mL) and the reaction stirred for 20 hours. Saturated NaHCO3 (aq, 5 mL) was added and the mixture stirred for 30 minutes. The precipitate was removed by filtration, washing with
dichloromethane. The filtrate was partitioned between water and dichloromethane. The aqueous layer was extracted into dichloromethane three times, the combined organics washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography eluting with 0-70% ethyl acetate/heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a colourless oil (327 mg, 85% yield).1H NMR (500 MHz, CDCl3) d 8.52 (d, J = 1.3 Hz, 1H), 7.72 (dd, J = 1.9, 10.7 Hz, 1H), 7.59 (dt, J = 1.4, 8.4 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 6.63 (t, J = 72.8 Hz, 1H), 1.27 (s, 9H). LCMS (Analytical Method D) Rt= 1.25 min, MS (ESIpos): m/z 294.0 [M+H]+. Synthesis of (R)‐N‐[(1S)‐1‐[4‐(difluoromethoxy)‐3‐fluorophenyl]ethyl]‐2‐
methylpropane‐2‐sulfinamide (Intermediate 96)
Figure imgf000207_0001
3M Methyl magnesium bromide in ether (557 µL) was added to a dry ice/acetone cooled solution of (R)‐N‐[(1E)‐[4‐(difluoromethoxy)phenyl]methylidene]‐2‐ methylpropane‐2‐sulfinamide (327 mg, 1.11 mmol) (Intermediate 17) in
tetrahydrofuran (7 mL). The reaction was stirred for 2 hours. The mixture was warmed in an ice/water bath and stirring continued for a further 18 hours. The reaction was cooled in ice/water and additional 3M methyl magnesium bromide in ether (557 µl) was added. The reaction was stirred for 1 hour then quenched by addition of water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography eluting with 0-5% methanol/dichloromethane. The relevant fractions were combined and concentrated in vacuo to yield The residue was repurified by chromatography eluting with 50-100% ethyl acetate/heptane then ethyl acetate. The relevant fractions were combined and concentrated in vacuo to yield the title compound as a colourless oil (180 mg, 52% yield).1H NMR (500 MHz, CDCl3) d 7.20 (t, J = 8.1 Hz, 1H), 7.16 (dd, J = 2.0, 11.3 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.54 (t, J = 73.5 Hz, 1H), 4.56 (qd, J = 2.8, 6.7 Hz, 1H), 3.30 (s, 1H), 1.51 (d, J = 6.7 Hz, 3H), 1.21 (s, 9H). LCMS (Analytical Method D) Rt= 1.09 min, MS (ESIpos): m/z 310.1 [M+H]+. Synthesis of (1S)‐1‐[4‐(difluoromethoxy)‐3‐fluorophenyl]ethan‐1‐amine hydrochloride
(Intermediate 97)
Figure imgf000208_0001
4M HCl in dioxane (872 µL) was added to a solution of (R)‐N‐[(1S)‐1‐ [4‐(difluoromethoxy)‐3‐fluorophenyl]ethyl]‐2‐methylpropane‐2‐sulfinamide (180 mg, 0.58 mmol) (Intermediate 18) in 1,4-dioxane (5 mL). The reaction was stirred for 1 hour then concentrated in vacuo to yield the title compound as a white solid (140 mg). 1H NMR (500 MHz, DMSO-d6) d 8.50 (s, 3H), 7.62 (d, J = 11.8 Hz, 1H), 7.45 (t, J = 8.3 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.27 (t, J = 73.0 Hz, 1H), 4.44 (q, J = 6.8 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H). LCMS (Analytical Method E) Rt= 1.73 min, MS
(ESIpos): m/z 206.2 [M+H]+. Synthesis of 2-bromo-N-[(1S)-1-(2,4,6-trimethylphenyl)ethyl]acetamide
(Intermediate 98)
Figure imgf000208_0002
(1S)-1-(2,4,6-trimethylphenyl)ethanamine (200 mg, 1.23 mmol) and triethylamine (0.38 ml, 2.7 mmol) were suspended in THF (15 ml), under a nitrogen atmosphere, and to the resulting solution was added bromoacetyl chloride (107 µl, 1.29 mmol). The solution immediately turned a dark brown and was left to stir at room temperature for 10 minutes. After this time, the reaction was concentrated in vacuo. The crude material (a brown residue) was purified by chromatography(100% heptane to 50% TBME) to afford the title compound (285 mg, 82% yield).1H NMR (500 MHz, DMSO-d6) d 8.62 (d, J = 6.2 Hz, 1H), 6.74 (s, 2H), 5.19– 5.04 (m, 1H), 3.97– 3.73 (m, 2H), 2.33 (s, 6H), 2.16 (s, 3H), 1.36 (d, J = 7.3 Hz, 3H). LCMS (Analytical Method D) Rt= 1.10 min, MS (ESIpos): m/z 284.1 / 286.2 [M+H]+. Synthesis of 2-bromo-N-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]acetamide
(Intermediate 99)
Figure imgf000209_0001
To a stirred solution of (1S)-1-[4-(trifluoromethyl)phenyl]ethanamine (292 µl, 1.59 mmol) and triethylamine (0.46 ml, 3.33 mmol) in THF (13 ml), at 0 oC under nitrogen, was added bromoacetyl chloride (132 µl, 1.59 mmol) dropwise. The reaction was stirred at 0 oC for 1 h. The reaction was quenched with water (15 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by Isolera™ chromatography (silica gel, eluting with 0-70% TBME in heptane) to give the title compound (231 mg, 45% yield).1H NMR (250 MHz, DMSO-d6) d 8.84 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 4.95 (p, J = 7.1 Hz, 1H), 3.88 (s, 2H), 1.38 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.05 min, MS (ESIpos): m/z 309.9, 311.9 [M+H]+. Synthesis of 6-chloro-5-fluoropyridine-3-carbaldehyde
(Intermediate 98)
Figure imgf000209_0002
A solution of 5-bromo-2-chloro-3-fluoropyridine (10 g, 47.5 mmol) in diethyl ether (150 mL) was cooled in a dry ice/acetone bath.2.5M Butyllithium in hexane (26.6 mL) was added over 20 minutes and the reaction stirred for 30 minutes. N,N-Dimethylformamide (18.4 mL, 237.6 mmol) was added over 10 minutes and stirring continued for 30 minutes. The reaction was quenched by addition of water and warmed to room temperature. The mixture was partitioned between ethyl acetate and water and the aqueous layer extracted into ethyl acetate three times. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallised from ethyl acetate/heptane (1:10) to give a portion of the title compound as an orange solid (120 mg). The filtrate was purified by chromatography (100 g, silica), eluting with 0-40% ethyl acetate/heptane to give a yellow solid (3.34 g, 36% yield).1H NMR (250 MHz, CDCl3) d 10.11 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 1.8 Hz, 1H), 7.92 (dd, J = 1.9, 7.6 Hz, 1H). LCMS (Analytical Method D) Rt= 0.88 min, MS (ESIpos): m/z 177.9, 180.1 [hydrate M+H]+. Synthesis of 5-fluoro-6-methylpyridine-3-carbaldehyde
(Intermediate 99)
Figure imgf000210_0001
A mixture of 6-chloro-5-fluoropyridine-3-carbaldehyde (3.3 g, 17.0 mmol) (Intermediate 13), 3.5M trimethylboroxine in THF (2.91 ml), potassium carbonate (4.69 g, 33.9 mmol) and Pd(PPh3)4 (0.98 g, 0.85 mmol) in 1,4-dioxane (30 mL) was degassed by sparging with nitrogen. The mixture was heated to 80 °C for 24 hours then cooled and filtered through a short pad of celite. The filtrate was
concentrated in vacuo to yield a residue. The residue was purified by chromatography (100 g, silica), eluting with 0-40% ethyl acetate/heptane. The relevant fractions were combined and concentrated in vacuo to yield the title compound (640 mg, 27% yield). 1H NMR (250 MHz, CDCl3) d 10.08 (d, J = 2.3 Hz, 1H), 8.77 (s, 1H), 7.77 (dd, J = 1.7, 8.9 Hz, 1H), 2.64 (d, J = 3.0 Hz, 3H). LCMS (Analytical Method D) Rt= 0.80 min, MS (ESIpos): m/z 139.9 [M+H]+. Synthesis of (R)-N-[(1E)-(5-fluoro-6-methylpyridin-3-yl)methylidene]-2- methylpropane-2-sulfinamide (Intermediate 100)
Figure imgf000211_0001
To a solution of 5-fluoro-6-methylpyridine-3-carbaldehyde (889 mg, 6.39 mmol) (Intermediate 99) in dichloromethane (60 mL) was added R-tert- Butylsulfinamide (852 mg, 7.03 mmol) followed by titanium tetraethoxide (3.15 ml, 12.8 mmol). The reaction was stirred for 24 hours then saturated NaHCO3 (aq, 30 mL) was added. The mixture was stirred vigorously for 1 hour then filtered through a pad of celite. The filtrate was extracted into dichloromethane three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo to yield the title compound as a yellow oil (1.38 g, 89% yield).1H NMR (250 MHz, CDCl3) d 8.66 (s, 1H), 8.62 (d, J = 1.8 Hz, 1H), 7.81 (dd, J = 1.6, 9.5 Hz, 1H), 2.60 (d, J = 3.0 Hz, 3H), 1.26 (s, 9H). LCMS (Analytical Method D) Rt= 1.08 min, MS (ESIpos): m/z 243.0 [M+H]+. Synthesis of (R)-N-[(1S)-1-(5-fluoro-6-methylpyridin-3-yl)ethyl]-2-methylpropane-2- sulfinamide (Intermediate 101)
Figure imgf000211_0002
3M Methyl magnesium bromide in ether (2.84 ml) was added slowly to a solution cooled (-60°C) of (R)-N-[(1E)-(5-fluoro-6-methylpyridin-3-yl)methylidene]-2- methylpropane-2-sulfinamide (1.38 g, 5.68 mmol) (Intermediate 100) in
tetrahydrofuran (40 mL). The reaction was warmed to -40 °C and stirred for 5 hours. The reaction was quenched by slow addition of water and warmed to room temperature. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo to give a residue. The residue was triturated with toluene, the solid material collected by filtration and dried in vacuo to yield the title compound as a white solid (460 mg, 31% yield).1H NMR (500 MHz, Chloroform-d) d 8.28 (s, 1H), 7.29 (dd, J = 10.1, 1.8 Hz, 1H), 4.61 (qd, J = 6.7, 3.3 Hz, 1H), 3.33 (d, J = 2.7 Hz, 1H), 2.52 (d, J = 2.9 Hz, 3H), 1.55 (d, J = 6.7 Hz, 3H), 1.21 (s, 9H). LCMS (Analytical Method D) Rt= 0.93 min, MS (ESIpos): m/z 259.0 [M+H]+. Synthesis of (1S)-1-(5-fluoro-6-methylpyridin-3-yl)ethan-1-amine dihydrochloride
(Intermediate 102)
Figure imgf000212_0001
4M HCl in dioxane (2.67 ml) was added to a solution of (R)-N-[(1S)-1- (5-fluoro-6-methylpyridin-3-yl)ethyl]-2-methylpropane-2-sulfinamide (460 mg, 1.78 mmol) (Intermediate 101). A thick white precipitate rapidly formed. The reaction was stirred for 45 minutes. The mixture was concentrated in vacuo to yield the title compound as a colourless oil (404 mg, quantitative yield). The material was used in the next step without characterization. Synthesis of 2‐[2‐(diphenylmethylidene)hydrazin‐1‐yl]‐4‐methoxypyridine
(Intermediate 103)
Figure imgf000212_0002
A mixture of 2-chloro-4-methoxypyridine (0.500 g, 3.48 mmol), benzophenone hydrazone (0.683 g, 3.5 mmol), palladium acetate (19.6 mg, 0.09 mmol), BINAP (54.2 mg, 0.09 mmol), phenyl boronic acid (21.2 mg, 0.17 mmol) and sodium tertbutoxide (2M in THF, 2.09 mL) in toluene (10 mL) was degassed with nitrogen. The reaction was heated to 90 °C for 18 h. The reaction was cooled and quenched into water. The aqueous layer was extracted with EtOAc (x3), the combined organics washed with brine, dried (MgSO4) and concentrated. The residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% EtOAc in heptane) to give 720 mg (55% yield) of the title compound as a brown oil.1H NMR (250 MHz, CDCl3) d 8.13 (s, 1H), 7.88 (d, J = 5.8 Hz, 1H), 7.63 - 7.54 (m, 3H), 7.54 - 7.48 (m, 2H), 7.37 - 7.28 (m, 5H), 7.00 (d, J = 2.3 Hz, 1H), 6.35 (dd, J = 2.4, 5.8 Hz, 1H), 3.92 (s, 3H). LCMS (Analytical Method D) Rt= 1.04, MS (ESIpos): m/z= 304.1 [M+H]+. Synthesis of 2‐hydrazinyl‐4‐methoxypyridine dihydrochloride
(Intermediate )104
Figure imgf000213_0001
A suspension of 2‐[2‐(diphenylmethylidene)hydrazin‐1‐yl]‐4‐ methoxypyridine (80%, 0.720 g, 1.9 mmol) (Inermediate 103) in concentrated HCl (10 mL) was heated to 65 °C for 18 h. The reaction was cooled and washed three times with DCM. The aqueous fraction was concentrated to yield 489 mg (91% yield) of the title compound as a pale yellow solid.1H NMR (500 MHz, DMSO-d6) d 7.79 (d, J = 7.0 Hz, 1H), 6.50 (dd, J = 2.5, 7.0 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H). Synthesis of 7‐methoxy‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐3‐one
(Intermediate 105)
Figure imgf000214_0001
CDI (336 mg, 2.1 mmol) was added to a suspension of 2‐hydrazinyl‐4‐ methoxypyridine dihydrochloride (75%, 489 mg, 1.7 mmol) (Intermediate 104) in acetonitrile (10 mL). The reaction was heated at 80 °C for 2 h. The reaction was allowed to cool to room temperature. The precipitate was collected by filtration and washed with acetonitrile. The resulting solid was triturated in MeOH/DCM to give 21 mg (7% yield) of the title compound as a tan solid.1H NMR (500 MHz, DMSO-d6) d 12.07 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.28 (dd, J = 2.3, 7.6 Hz, 1H), 3.80 (s, 3H). Synthesis of 6-methoxy-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one
(Intermediate 106)
Figure imgf000214_0002
To a solution of 2-hydrazinyl-5-methoxypyridine (255 mg, 1.8 mmol) in DCM (3.4 mL) was added CDI (891 mg, 5.5 mmol). The reaction was stirred at room temperature for 18 h. The suspension was cooled to 0 oC and filtered rinsing with cold DCM. The resulting solid was triturated in IPA to give 141 mg (47% yield) of the title compound as a beige solid.1H NMR (500 MHz, DMSO-d6) d 12.44 (s, 1H), 7.29– 7.24 (m, 1H), 7.21 (dd, J = 10.0, 0.8 Hz, 1H), 7.02 (dd, J = 10.0, 2.3 Hz, 1H), 3.75 (s, 3H). LCMS (Analytical Method D) Rt= 0.62 min, MS (ESIpos): m/z= 166.00 [M+H]+. Synthesis of 5‐methoxy‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐3‐one
(Intermediate 107)
Figure imgf000215_0001
To a solution of 2-hydrazinyl-6-methoxypyridine (573 mg, 4.1 mmol) in MeCN (9.2 mL) was added CDI (801 mg, 4.9 mmol). The reaction was stirred at 80 oC for 2 h. The reaction was cooled to 0 oC. The resulting precipitate was collected by filtration and then triturated in the minimum volume of MeCN to afford 357 mg (53% yield) of the title compound as a grey solid.1H NMR (500 MHz, DMSO-d6) d 12.10 (s, 1H), 7.02 (dd, J = 9.4, 7.2 Hz, 1H), 6.62 (d, J = 9.3 Hz, 1H), 5.68 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H). LCMS (Analytical Method E) Rt= 0.41 min, MS (ESIpos): m/z= 166.2 [M+H]+. Synthesis of 8-fluoro-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one
(Intermediate 108)
Figure imgf000215_0002
To a solution of 3-fluoro-2-hydrazinylpyridine (0.300 g, 2.4 mmol) in DCM (4 mL) was added CDI (1.148 g, 7.1 mmol). The reaction was stirred at room temperature for 18 h. The suspension was cooled to 0 oC and filtered rinsing with cold DCM to give 200 mg (54% yield) the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 12.76 (s, 1H), 7.71 (dd, J = 7.0, 0.7 Hz, 1H), 7.11 (ddd, J = 11.8, 7.3, 0.6 Hz, 1H), 6.54 (td, J = 7.2, 4.3 Hz, 1H). LCMS (Analytical Method D) Rt= 0.44 min, MS (ESIpos): m/z= 153.90 [M+H]+. Synthesis of 6‐fluoro‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐3‐one
(Intermediate 109)
Figure imgf000216_0001
To a solution of 5-fluoro-2-hydrazinylpyridine (250 mg, 2.0 mmol) in DCM (3.4 mL) was added CDI (957 mg, 5.9 mmol). The reaction was stirred at room temperature for 18 h. The suspension was cooled to 0 oC and filtered rinsing with cold DCM. The resulting solid was triturated in IPA and then in MeCN to afford 82 mg (25% yield) of the title compound as a beige solid.1H NMR (250 MHz, DMSO-d6) d 12.63 (s, 1H), 8.00 (ddd, J = 3.4, 2.0, 1.3 Hz, 1H), 7.35– 7.33 (m, 1H), 7.33– 7.29 (m, 1H). LCMS (Analytical Method D) Rt= 0.39 min, MS (ESIpos): m/z= 153.90 [M+H]+. Synthesis of 5‐fluoro‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐3‐one
(Intermediate 110)
Figure imgf000216_0002
To a solution of 2-fluoro-6-hydrazinylpyridine (100 mg, 0.79 mmol) and Et3N (121 µL, 0.87 mmol) in dry THF (2.6 mL), under N2 at 0 oC, was added dropwise a solution of 4-nitrophenyl chloroformate (159 mg, 0.79 mmol) in dry THF (0.5 mL). The reaction was stirred at 0 oC for 1 h. The reaction was stirred at room temperature for 18 h. The reaction was filtered. The precipitate was discarded. The filtrate was concentrated. The residue was diluted with the minimum volume of MeOH and sonicated. The precipitate was removed by filtration. The filtrate was dry loaded onto silica and purified by Biotage Isolera™ chromatography (silica gel, using 0-3% MeOH in DCM as eluent) to give 37 mg (27% yield) of the title compound as a beige solid.1H NMR (250 MHz, DMSO-d6) d 12.44 (s, 1H), 7.09 (ddd, J = 9.5, 7.0, 5.9 Hz, 1H), 6.95 (d, J = 9.4 Hz, 1H), 6.24– 6.13 (m, 1H). LCMS (Analytical Method D) Rt= 0.31 min, MS (ESIpos): m/z= 153.90 [M+H]+. Synthesis of 7‐methyl‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐3‐one
(Intermediate 111)
Figure imgf000217_0001
To a solution of 2-hydrazinyl-4-methylpyridine (500 mg, 4.1 mmol) in MeCN (9.5 mL) was added CDI (790 mg, 4.87 mmol). The reaction was stirred at 80 oC for 2 h. The reaction was concentrated and the residue was triturated in MeCN and then DCM to give 122 mg (19% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 12.27 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 6.96 (q, J = 1.1 Hz, 1H), 6.42 (dd, J = 7.2, 1.4 Hz, 1H), 2.23 (d, J = 1.1 Hz, 3H). LCMS (Analytical Method D) Rt= 0.68 min, MS (ESIpos): m/z= 149.95 [M+H]+. Synthesis of 7-iodo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one
(Intermediate 112)
Figure imgf000217_0002
To a mixture of 2-hydrazinyl-4-iodopyridine (4.42 g, 18.81 mmol) and CDI (3.35 g, 20.69 mmol) was added acetonitrile (60 ml). The mixture was stirred at 60 °C for 1 hr then cooled to room temperature. A white precipitate was collected by suction filtration and washed with acetonitrile to afford the title compound (4.2 g, 75% yield).1H NMR (500 MHz, DMSO-d6) d 12.47 (s, 1H), 7.76 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 6.79 - 6.73 (m, 1H). LCMS (Analytical Method D) Rt= 0.85 min, MS
(ESIpos): m/z= 261.8 [M+H]+. Synthesis of 3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile
(Intermediate 113)
Figure imgf000218_0001
A suspension of 6-hydrazinylpyridine-3-carbonitrile (500 mg, 3.73 mmol) and 1-(1H-imidazole-1-carbonyl)-1H-imidazole (630 mg, 3.89 mmol) in acetonitrile (20 ml) was stirred at 60 °C for 16 h.The reaction was cooled to room temperature. A beige precipitate was collected by suction filtration and washed with acetonitrile to afford the title compound (218 mg, 33% yield). The filtrate was concentrated in vacuo and the resultant residue purified by Isolera™ chromatography (silica gel, eluting with 0-20% MeOH in DCM) to afford the title compound (152 mg, 25% yield).1H NMR (500 MHz, DMSO-d6) d 12.75 (s, 1H), 8.71 (s, 1H), 7.39 - 7.22 (m, 2H). LCMS (Analytical Method D) Rt= 0.42 min, MS (ESIpos): m/z 161.20
[M+H]+. Synthesis of 3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile
(Intermediate 114)
Figure imgf000218_0002
A suspension mixture of 7-chloro-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3- one (105 mg, 0.62 mmol), potassium ferrocyanide (115.5 mg, 0.31 mmol), tBuXPhos Pd G3 pre-catalyst (48 mg, 0.06 mmol), tBuXPhos (27 mg, 0.06 mmol) and potassium acetate (10 mg, 0.1 mmol) in dioxane/water (1:1, 2 ml) was de-gassed with nitrogen for 5 min, then sealed and stirred at 100 °C for 1 hour. The reaction was quenched with water and acidified to pH ~3 with 1M HCl, then extracted with EtOAc three times. The organics were combined, filtered and the filtrate was concentrated in vacuo. The crude product was purified by chromarography (silica, gradient of 0-5% MeOH in DCM) to afford the title compound (45 mg, 43% yield).1H NMR (500 MHz, DMSO-d6) d 13.01 (s, 1H), 8.13 - 8.09 (m, 1H), 7.97 - 7.92 (m, 1H), 6.72 (dd, J = 7.3, 1.3 Hz, 1H). LCMS (Analytical Method D) Rt = 0.43 min, MS (ESIpos): m/z= 161.0 [M+H]+. Synthesis of 2-{5-bromo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- [4-(trifluoromethoxy)phenyl]ethyl]acetamide (Intermediate 115)
Figure imgf000219_0001
A mixture of 2-bromo-N-[(1S)-1-[4- (trifluoromethoxy)phenyl]ethyl]acetamide (Intermediate 2) (300 mg, 0.92 mmol), 5- bromo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (197 mg, 0.92 mmol) and potassium carbonate (378 mg, 2.73 mmol) in dry acetonitrile was stirred at 60 °C for 1 hour under nitrogen. The reaction was diluted with EtOAc (25 mL) and washed with brine. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic phases was dried over MgSO4, filtered and concentrated to yield the title compound (331 mg, 76% yield).1H NMR (500 MHz, DMSO-d6) d 8.64 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.18 (dd, J = 9.4, 0.7 Hz, 1H), 7.00 (dd, J = 9.4, 6.9 Hz, 1H), 6.80 (dd, J = 6.8, 0.6 Hz, 1H), 4.97 (p, J = 6.9 Hz, 1H), 4.55 (s, 2H), 1.39 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z= 458.9 [M+H]+. Synthesis of 2-{5-bromo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- (4-chloro-3-fluorophenyl)ethyl]acetamide (Intermediate 116)
Figure imgf000220_0001
The title compound was prepared in analogy to the procedure described for Intermediate 115, starting from 5-bromo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one and Intermediate 3 (68% yield).1H NMR (500 MHz, DMSO-d6) d 8.63 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.37 (dd, J = 10.8, 1.9 Hz, 1H), 7.20 (dd, J = 8.3, 1.9 Hz, 1H), 7.18 (dd, J = 9.4, 0.6 Hz, 1H), 7.01 (dd, J = 9.4, 6.9 Hz, 1H), 6.84 - 6.72 (m, 1H), 4.94 (m, 1H), 4.61 - 4.49 (m, 2H), 1.37 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method D) Rt= 1.11 min, MS (ESIpos): m/z= 428.9 [M+H]+. Synthesis of 2-{8-bromo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- (4-chloro-3-fluorophenyl)ethyl]acetamide (Intermediate 117)
Figure imgf000220_0002
The title compound was prepared in analogy to the procedure described for Intermediate 30, starting from 8-bromo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one and Intermediate 3 (45% yield).1H NMR (500 MHz, DMSO-d6) d 8.65 (d, J = 7.7 Hz, 1H), 7.95 (dd, J = 0.7, 7.0 Hz, 1H), 7.64 (dd, J = 0.7, 7.0 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.37 (dd, J = 1.9, 10.7 Hz, 1H), 7.22 (dd, J = 1.9, 8.3 Hz, 1H), 6.57 (t, J = 7.0 Hz, 1H), 4.94 (p, J = 7.0 Hz, 1H), 4.69 (d, J = 16.6 Hz, 1H), 4.61 (d, J = 16.6 Hz, 1H), 1.37 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.12 min, MS (ESIpos): m/z= 426.9, 428.9, 430.9 [M+H]+. Synthesis of tert-butyl 2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}acetate
(Intermediate 118)
Figure imgf000221_0001
To as stirred solution of [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1 g, 7.4 mmol) and tert-butyl bromoacetate (1.09 ml, 7.4 mmol) in MeCN (30 ml) was added K2CO3 (3.07 g, 22.2 mmol). The reaction was heated at 60 oC for 90 min. The reaction was allowed to cool to room temperature and filtered, rinsing with MeCN. The filtrate was concentrated in vacuo. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with, using 0-50% EtOAc in heptane), to give the title compound as a white solid (1.30 g, 70% yield).1H NMR (250 MHz, Chloroform-d) d 7.81 - 7.70 (m, 1H), 7.15 - 7.01 (m, 2H), 6.57 - 6.41 (m, 1H), 4.67 (s, 2H), 1.49 (s, 9H). LCMS (Analytical Method D) Rt = 0.96 min, MS (ESIpos): m/z= 194 [M+H- tBu]+. Synthesis of 2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}acetic acid
(Intermediate 119)
Figure imgf000221_0002
A solution of tert-butyl 2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetate (1.3 g, 5.22 mmol) (Intermediate 118) in 25% TFA in DCM (13 ml) was stirred at room temperature for 24 h. The reaction was concentrated. The crude product was triturated in DCM and the resulting solid was collected by filtration to give the title compound as a white solid (881 mg, 87% yield).1H NMR (250 MHz, DMSO-d6) d 13.22 (s, 1H), 7.88 (dt, J = 7.1, 1.2 Hz, 1H), 7.35– 7.14 (m, 2H), 6.64 (ddd, J = 7.3, 4.9, 2.5 Hz, 1H), 4.69 (s, 2H). LCMS (Analytical Method D) Rt = 0.28 min, MS (ESIpos): m/z= 194 [M+H]+. Synthesis of tert-butyl 2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}propanoate
(Intermediate 120)
Figure imgf000222_0001
To a stirred suspension of [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.15 g, 1.1 mmol) in MeCN (4.5 mL) was added tert-butyl 2-bromopropanoate (184.2 µL, 1.11 mmol) and K2CO3 (0.46 g, 3.33 mmol). The reaction was stirred at 60 oC for 20 h. The reaction was allowed to cool to room temperature and filtered, rinsing with MeCN. The filtrate was concentrated. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-36% EtOAc in heptane) to give 173 mg (58% yield) the title compound as a white solid.1H NMR (500 MHz, Chloroform-d) d 7.75 (dt, J = 7.1, 1.2 Hz, 1H), 7.12 (dt, J = 9.5, 1.1 Hz, 1H), 7.07 (ddd, J = 9.5, 6.2, 1.2 Hz, 1H), 6.47 (td, J = 6.8, 6.3, 1.1 Hz, 1H), 1.75 (d, J = 7.4 Hz, 3H), 1.45 (s, 10H). LCMS (Analytical Method D) Rt = 0.99 min, MS (ESIpos): m/z= 208.30 [M-tBu+H]+.
[98%]. Synthesis of 2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}propanoic acid
(Intermediate 121)
Figure imgf000222_0002
A solution of tert-butyl 2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetate (7.3 g, 29.3 mmol) (Intermediate 120) in 25% TFA in DCM (2 mL) was stirred at room temperature for 18 h. The reaction was concentrated and azeotroped with toluene and then DCM to give 127 mg (92% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 13.11 (s, 1H), 7.87 (dt, J = 7.1, 1.1 Hz, 1H), 7.33– 7.17 (m, 2H), 6.63 (ddd, J = 7.2, 4.9, 2.5 Hz, 1H), 5.04 (q, J = 7.3 Hz, 1H), 1.61 (d, J = 7.3 Hz, 3H). LCMS (Analytical Method D) Rt = 0.68 min, MS (ESIpos): m/z= 207.95 [M+H]+. Synthesis of tert-butyl 2-{6-bromo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetate
(Intermediate 122)
Figure imgf000223_0002
By analogy of method described for Intermediate 120, the title compound was prepared from 6-bromo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one and tert-butylbromoacetate.1H NMR (500 MHz, CDCl3) d 7.92 (dd, J = 1.0, 1.7 Hz, 1H), 7.11 (dd, J = 1.8, 9.9 Hz, 1H), 7.02 (dd, J = 1.0, 9.9 Hz, 1H), 4.65 (s, 2H), 1.48 (s, 9H). LCMS (Analytical Method D) Rt = 1.05 min, MS (ESIpos): m/z= 271.9 (M-tBu+H)+. Synthesis of 2-{6-bromo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}acetic acid
(Intermediate 123)
Figure imgf000223_0001
By analogy of method described for Intermediate 36, the title compound was prepared from Intermediate 122.1H NMR (500 MHz, DMSO-d6) d 8.20 - 8.15 (m, 1H), 7.33 (dd, J = 1.8, 9.9 Hz, 1H), 7.25 (dd, J = 0.9, 9.9 Hz, 1H), 4.69 (s, 2H). LCMS (Analytical Method D) Rt = 0.72 min, MS (ESIpos): m/z= 273.9 (M+H)+. Synthesis of tert-butyl 2-{5-bromo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetate
(Intermediate 124)
Figure imgf000224_0002
By analogy of method described for Intermediate 120, the title compound was prepared from 5-bromo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one and tert-butylbromoacetate.1H NMR (250 MHz, CDCl3) d 7.05 - 6.97 (m, 1H), 6.83 (dd, J = 6.8, 9.4 Hz, 1H), 6.61 - 6.55 (m, 1H), 4.62 (s, 2H), 1.49 (s, 9H). LCMS (Analytical Method D) Rt = 1.05 min, MS (ESIpos): m/z= 271.9 (M-tBu+H)+. Synthesis of 2-{5-bromo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}acetic acid
(Intermediate 125)
Figure imgf000224_0001
By analogy of method described for Intermediate 121, the title compound was prepared from Intermediate 39.1H NMR (500 MHz, DMSO-d6) d 7.19 (dd, J = 0.7, 9.4 Hz, 1H), 7.01 (dd, J = 6.9, 9.4 Hz, 1H), 6.81 (dd, J = 0.7, 6.9 Hz, 1H), 4.64 (s, 2H). LCMS (Analytical Method D) Rt = 0.68 min, MS (ESIpos): m/z= 271.9 (M+H)+. Synthesis of tert-butyl 2-{7-chloro-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetate
(Intermediate 126)
Figure imgf000225_0002
By analogy of method described for Intermediate 120, the title compound was prepared from 7-chloro-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one and tert-butylbromoacetate.1H NMR (500 MHz, CDCl3) d 7.70 (dd, J = 0.8, 7.4 Hz, 1H), 7.10 (dd, J = 0.8, 1.6 Hz, 1H), 6.45 (dd, J = 1.8, 7.4 Hz, 1H), 4.63 (s, 2H), 1.48 (s, 9H). LCMS (Analytical Method D) Rt = 1.04 min, MS (ESIpos): m/z= 305.95 (M+Na)+. Synthesis of 2-{7-chloro-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}acetic acid
(Intermediate 127)
Figure imgf000225_0001
By analogy of method described for Intermediate 121, the title compound was prepared from Intermediate 41.1H NMR (250 MHz, DMSO-d6) d 7.93 (dd, J = 0.9, 7.4 Hz, 1H), 7.51 (dd, J = 0.9, 1.9 Hz, 1H), 6.66 (dd, J = 1.9, 7.4 Hz, 1H), 4.67 (s, 2H). LCMS (Analytical Method D) Rt = 0.74 min, MS (ESIpos): m/z= 227.9 (M+H)+. Synthesis of tert-butyl 2-{7-iodo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetate
(Intermediate 128)
Figure imgf000226_0002
By analogy of method described for Intermediate 120, the title compound was prepared from 7-iodo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one and tert-butylbromoacetate.1H NMR (500 MHz, DMSO-d6) d 7.84 - 7.82 (m, 1H), 7.67 (dd, J = 7.3, 0.9 Hz, 1H), 6.83 (dd, J = 7.3, 1.4 Hz, 1H), 4.65 (s, 2H), 1.41 (s, 9H). LCMS (Analytical Method E) Rt = 1.66 min, MS (ESIpos): m/z= 376 (M+H)+. Synthesis of tert-butyl 2-{7-[(1-methylazetidin-3-yl)oxy]-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-2-yl}acetate (Intermediate 129)
Figure imgf000226_0001
tert-Butyl 2-{7-iodo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetate (250 mg, 0.67 mmol) (Intermediate 128), 1-methylazetidin-3-ol (60 µl, 0.76 mmol), Pd(OAc)2 (15 mg, 0.07 mmol), cesium carbonate (450 mg, 1.38 mmol) and JohnPhos (40 mg, 0.13 mmol) were suspended in toluene (5 ml) and de-gassed with nitrogen for 5 min. The mixture was sealed and stirred at 90 °C for 16 hrs. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo purified by Biotage Isolera™ chromatography (silica gel, eluting with 100% EtOAc in heptanes followed by 0-100% 7N ammonia MeOH affording the titled compound (49 mg, 20% yield).1H NMR (500 MHz, Methanol-d4) d 7.75 (dd, J = 7.6, 0.6 Hz), 6.42 (dd, J = 7.6, 2.2 Hz, 1H), 6.18 (d, J = 1.9 Hz, 1H), 4.92 - 4.87 (m, 1H), 4.61 (s, 2H), 3.85 - 3.80 (m, 2H), 3.31 - 3.29 (m, 2H), 2.42 (s, 3H), 1.48 (s, 9H). LCMS (Analytical Method D) Rt = 0.80 min, MS (ESIpos): m/z= 335 (M+H)+. Synthesis of 2-{7-[(1-methylazetidin-3-yl)oxy]-3-oxo-2H,3H-[1,2,4]triazolo[4,3- a]pyridin-2-yl}acetic acid; trifluoroacetic acid (Intermediate 130)
Figure imgf000227_0001
tert-Butyl 2-{7-[(1-methylazetidin-3-yl)oxy]-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-2-yl}acetate (49 mg, 0.13 mmol) (Intermediate 129) was dissolved in 20% TFA in DCM (2 mL) and the mixture was stirred under nitrogen for 16 hours. The reaction was concentrated in vacuo to give the title compound. Yield, assume quantitative. The compound was used in the next step without further purification. LCMS (Analytical Method D) Rt = 0.81 min, MS (ESIpos): m/z= 279 (M+H)+. Synthesis of tert-butyl 2-{3-oxo-7-phenyl-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetate
(Intermediate 131)
Figure imgf000227_0002
tert-Butyl 2-{7-iodo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetate (94%, 115 mg, 0.29 mmol) (Intermediate 128), phenylboronic acid (75 mg, 0.62 mmol), Pd(dppf)Cl2 (21 mg, 0.03 mmol) and potassium carbonate (85 mg, 0.62 mmol) were suspended in THF/ water mixture (9:1, 2 ml) and the mixture was de- gassed with nitrogen whilst sonicating for 5 min. The reaction mixture was sealed and stirred at 90 °C for 2 h. The reaction mixture was allowed to cool to room temperature and quenched with water. The aqueous phase was extracted with EtOAc (2 x 10 ml) and the organics were combined and concentrated in vacuo. The resultant residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-100% EtOAc in heptane) followed by preparative HPLC (Method A2) to afford the title compound (72 mg, 75% yield).1H NMR (500 MHz, Chloroform-d) d 7.81 (dd, J = 7.4, 1.0 Hz, 1H), 7.59 - 7.56 (m, 2H), 7.50 - 7.41 (m, 3H), 7.25 - 7.22 (m, 1H), 6.78 (dd, J = 7.4, 1.6 Hz), 4.83 - 4.53 (m, 2H), 1.49 (s, 9H). LCMS (Analytical Method D) Rt = 1.16 min, MS (ESIpos): m/z= 326.0 (M+H)+. Synthesis of 2-{3-oxo-7-phenyl-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}acetic acid
(Intermediate 132)
Figure imgf000228_0001
Tert-butyl 2-{3-oxo-7-phenyl-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetate (98%, 55 mg, 0.17 mmol) (Intermediate 131) was taken up in DCM (2 ml) and trifluoroacetic acid (500 µl, 6.53 mmol) was added. The mixture was stirred at room temperature for 1 h, then concentrated in vacuo to give the title compound. Yield, assume quantitative. LCMS (Analytical Method D) Rt = 0.93 min, MS (ESIpos): m/z= 270.0 (M+H)+. Synthesis of tert‐butyl 3‐{3‐oxo‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐8‐yl}‐2,5‐dihydro‐ 1H‐pyrrole‐1‐carboxylate (Intermediate 133)
Figure imgf000229_0001
A mixure of 8-chloro-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (400 mg, 2.36 mmol),tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H-pyrrole-1-carboxylate (696 mg, 2.36 mmol), Cs2CO3 (1.54 g, 4.72 mmol),
Pd(dppf)Cl2 (345 mg, 0.47 mmol) and degassed dioxane/water (2:1, 6 mL) was degassed for 5 min and then stirred at 90 °C for 5 h. The mixture was cooled and diluted with water/ethyl acetate (60 mL, 1:1). The solid material was collected by filtration and dried in vacuo to yield the title compound as a beige solid (240 mg, 34% yield).1H NMR (250 MHz, Chloroform-d) d 9.73 (s, 1H), 7.75 (d, J = 6.8 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 6.89 (d, J = 6.6 Hz, 1H), 6.56 (t, J = 7.0 Hz, 1H), 4.63– 4.46 (m, 2H), 4.45– 4.31 (m, 2H), 1.51 (s, 9H). LCMS (Analytical Method D) Rt= 1.03 min, MS (ESIpos): m/z 302.9 [M+H]+.
Synthesis of tert‐butyl 3‐[2‐({[(1S)‐1‐(4‐methylphenyl)ethyl]carbamoyl}methyl)‐3‐oxo‐ 2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐8‐yl]‐2,5‐dihydro‐1H‐pyrrole‐1‐carboxylate
(Intermediate 134)
Figure imgf000230_0001
A suspension of tert-butyl 3-{3-oxo-2H,3H-[1,2,4]triazolo[4,3- a]pyridin-8-yl}-2,5-dihydro-1H-pyrrole-1-carboxylate (300 mg, 0.99 mmol)
(Intermediate 133), 2-bromo-N-[(1S)-1-(4-methylphenyl)ethyl]acetamide (254 mg, 0.99 mmol) (Intermediate 1) and K2CO3 (411 mg, 2.98 mmol) in acetonitrile (20 mL) was stirred at 60 °C for 3 h. The mixture was cooled, diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography, eluting with 0- 2.5% MeOH in DCM to yield the title compound as a white solid (350 mg, 72% yield). 1H NMR (250 MHz, DMSO-d6) d 8.57 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 6.9 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.9 Hz, 4H), 6.97 (d, J = 13.1 Hz, 1H), 6.69 (t, J = 7.0 Hz, 1H), 5.03 - 4.81 (m, 1H), 4.62 (s, 2H), 4.54 - 4.37 (m, 2H), 4.37 - 4.19 (m, 2H), 2.28 (s, 3H), 1.46 (s, 9H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method D) Rt= 1.20 min, MS (ESIpos): m/z 478.05 [M+H]+. Synthesis of tert‐butyl 3‐[2‐({[(1S)‐1‐(4‐methylphenyl)ethyl]carbamoyl}methyl)‐3‐oxo‐ 2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐8‐yl]pyrrolidine‐1‐carboxylate
(Intermediate 135)
Figure imgf000231_0001
A mixture of tert‐butyl 3‐[2‐({[(1S)‐1‐(4‐
methylphenyl)ethyl]carbamoyl}methyl)‐3‐oxo‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐8‐ yl]‐2,5‐dihydro‐1H‐pyrrole‐1‐carboxylate (250 mg, 0.52 mmol) (Intermediate 134) and 10% palladium on charcoal (19 mg) in ethanol (7.5 mL) and dichloromethane (0.75 mL) was stirred under an atmosphere of hydrogen for 3.5 hours. The mixture was filtered through a pad of celite, washed with methanol and concentrated in vacuo. The residue was purified by chromatography, eluting with 0-10%
methanol/dichloromethane. Fractions containing product were combined and concentrated in vacuo. The residue was further purified by HPLC (Method B2). The relevant fractions were combined and concentrated in vacuo to yield the title compound as a mixture of diastereoisomers as a colourless sticky oil (101 mg, 30% yield). LCMS (Analytical Method B) Rt= 3.46 min, MS (ESIpos): m/z 480.3 [M+H]+. Synthesis of tert-butyl 1-[2-({[(1S)-1-(4-chloro-3- fluorophenyl)ethyl]carbamoyl}methyl)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8- yl]-1,6-diazaspiro[3.3]heptane-6-carboxylate
(Intermediate 136)
Figure imgf000232_0001
A mixture of 2-{8-bromo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}-N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]acetamide (50 mg, 0.12 mmol)
(Intermediate ), 1176-boc-1,6-diazaspiro[3.3]heptane hemioxalate (28.44 mg, 0.06 mmol), Pd2dba3 (5.35 mg, 0.01 mmol), Xantphos (6.77 mg, 0.01 mmol) and sodium tert-butoxide (33.71 mg, 0.35 mmol) in toluene (1 mL) was degassed by sparging with nitrogen. The mixture was heated to 100 °C for 2 hours then cooled and quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by Biotage Isolera™ chromatography (10 g, silica), eluting with 40-100% ethyl acetate/heptane to yield the title compound (32 mg, 50% yield).LCMS (Analytical Method B) Rt= 3.13 min, MS (ESIpos): m/z 545 [M+H]+ Synthesis of 2-{7-iodo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- (2,4,6-trimethylphenyl)ethyl]acetamide
(Intermediate 137)
Figure imgf000233_0001
7-Iodo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (147 mg, 0.56 mmol) (Intermediate 112) and potassium carbonate (233 mg, 1.69 mmol) were suspended in a mixture of acetonitrile (2 mL) and DMF (1 mL) and stirred at room temperature, under a nitrogen atmosphere, for 30 minutes. After this time, 2-bromo-N-[(1S)-1-(2,4,6- trimethylphenyl)ethyl]acetamide (160 mg, 0.56 mmol) (Intermediate 4) was added and the resulting mixture heated to 60 °C for 3 hours. The reaction mixture was partitioned between EtOAc (20 mL) and water (15 mL). The organic phase was separated and concentrated in vacuo to afford the crude product. The crude product was purified by Biotage Isolera™ chromatography (silica, eluent 100% Heptane to 50% EtOAc) to afford the title compound (102 mg, 38% yield).1H NMR (250 MHz, DMSO-d6) d 8.53 (d, J = 6.1 Hz, 1H), 7.80– 7.73 (m, 1H), 7.68– 7.60 (m, 1H), 6.86– 6.76 (m, 1H), 6.73 (s, 2H), 5.22– 5.04 (m, 1H), 4.51 (s, 2H), 2.32 (s, 6H), 2.15 (s, 3H), 1.37 (d, J = 7.3 Hz, 3H). LCMS (Analytical Method D) Rt= 1.17 min, MS (ESIpos): m/z 465, 467 [M+H]+. Synthesis of 2-{7-iodo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1-[4- (trifluoromethoxy)phenyl]ethyl]acetamide
(Intermediate 138)
Figure imgf000233_0002
7-Iodo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3-one (100 mg, 0.38 mmol) (Intermediate 27), 2-bromo-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (130 mg, 0.38 mmol) (Intermediate 2) and potassium carbonate (159 mg, 1.15 mmol) were suspended in DMF (1 ml) and the mixture was stirred at 60 °C for 2 h.The reaction mixture was allowed to cool to room temperature. Water was added, resulting in formation of a precipitate. The solid was collected by suction filtration, then triturated with water/MeOH (5:1) and was thoroughly dried in the vacuum oven to afford the title compound (177 mg, 89% yield).1H NMR (500 MHz, DMSO-d6) d 8.62 (d, J = 6.9 Hz, 1H), 7.81 (s, 1H), 7.66 (d, J = 7.0 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.37 - 7.27 (m, 2H), 6.82 (d, J = 7.0 Hz, 1H), 5.00 - 4.92 (m, 1H), 4.61 - 4.49 (m, 2H), 1.37 (d, J = 6.7 Hz, 3H). LCMS (Analytical Method D) Rt= 1.15 min, MS (ESIpos): m/z 506.9[M+H]+. EXAMPLE 1 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-b]pyridazin-2-yl}acetamide
(Compound I-1-1)
Figure imgf000234_0001
A mixture of 2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one (Intermediate 33) (30 mg, 0.22 mmol), 2-bromo-N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]acetamide (Intermediate 3) (65 mg, 0.22 mmol) and potassium carbonate (91 mg, 0.66 mmol) in acetonitrile (3 mL) was heated to 60 °C for 90 minutes. The reaction was cooled and quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC, Method B2 to yield the title compound (39 mg, 51% yield).1H NMR (500 MHz, DMSO-d6) d 8.64 (d, J = 7.6 Hz, 1H), 8.28 (dd, J = 1.4, 4.0 Hz, 1H), 7.80 (dd, J = 1.4, 9.7 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.36 (dd, J = 1.9, 10.7 Hz, 1H), 7.20 (dd, J 1.8, 8.3 Hz, 1H), 7.14 (dd, J = 4.0, 9.7 Hz, 1H), 4.94 (p, J = 7.0 Hz, 1H), 4.65 (d, J = 16.5 Hz, 1H), 4.61 (d, J = 16.5 Hz, 1H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt= 2.30 min, MS (ESIpos): m/z 350 [M+H]+, purity = 99%.
EXAMPLES 1-2 THROUGH 1-36
Synthesis of Compounds 1-1-2 through Compound 1-1-36
Each of Compounds 1-1-2 through 1-1-36 as listed in Table 5 were prepared according to the method of Example 1, using the intermediates listed in the "Synthesis" column for such compounds. The final compounds were purified by preparative HPLC Methods, A1, A2, B1 or B2.
Table 5
Representative Compounds
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0002
EXAMPLE 2 Synthesis of 2-{6-cyclopropyl-3-oxo-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-2-yl}-N- [(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide
(Compound I-2)
Figure imgf000270_0001
A pressure tube was charged with 2-{6-chloro-3-oxo-2H,3H- [1,2,4]triazolo[4,3-b]pyridazin-2-yl}-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]- acetamide (100 mg, 0.24 mmol) (Compound I-1-14), cyclopropylboronic acid (25 mg, 0.29 mmol), K3PO4 (102 mg, 0.48 mmol) and THF/H2O (15 mL) and degassed with N2 for 5 min. Pd(dppf)Cl2 (35.2 mg, 0.05 mmol) was added. The tube was flushed with N2 and sealed. The reaction was stirred at 80 oC for 4 h. The diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-3% MeOH in DCM). Further purification by preparative HPLC (Method D) to was performed affording 9 mg (9% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) d 8.63 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 9.8 Hz, 1H), 7.49– 7.40 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 9.8 Hz, 1H), 4.96 (p, J = 7.1 Hz, 1H), 4.59 (s, 2H), 2.19– 2.05 (m, 1H), 1.38 (d, J = 7.0 Hz, 3H), 1.10– 1.02 (m, 2H), 1.02– 0.94 (m, 2H). LCMS (Analytical Method A) Rt = 2.95 min, MS (ESIpos): m/z= 422 [M+H]+, Purity = 100%. EXAMPLE 3 Synthesis of 2-[3-oxo-6-(piperidin-1-yl)-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-2-yl]-N- [(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide
(Compound I-3-1)
Figure imgf000271_0001
A mixture of 2-{6-chloro-3-oxo-2H,3H-[1,2,4]triazolo[4,3-b]pyridazin- 2-yl}-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide (Compound I-1-14) (56 mg, 0.13 mmol) and piperidine (133 µl, 1.35 mmol) in N-methyl-pyrrolidone (0.5 mL) was heated to 120 °C under microwave irradiation for 10 minutes. The mixture was partitioned between water and ethyl acetate and extracted into ethyl acetate three times. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC, Method B2 to yield the title compound as a white solid (27 mg, 43% yield). 1H NMR (500 MHz, DMSO-d6) d 8.61 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 10.3 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.34 - 7.29 (m, 3H), 4.95 (p, J = 7.1 Hz, 1H), 4.54 (s, 2H), 3.48 - 3.45 (m, 4H), 1.58 (dd, J = 5.1, 11.6 Hz, 6H), 1.37 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 3.24 min, MS (ESIpos): m/z 465 [M+H]+, Purity = 100%. EXAMPLES 3-2 THROUGH 3-8 Synthesis of Compounds I-3-2 through Compound I-3-8 Each of Compounds I-3-2 through I-3-8 as listed in Table 6 were prepared according to the method of Example 3, using the intermediates listed in the "Synthesis" column for such compounds .
Table 6
Representative Compounds
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
EXAMPLE 4 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{6-cyclopropyl-3-oxo- 2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-2-yl}acetamide
(Compound I-4-1)
Figure imgf000280_0001
To a stirred suspension of 2-{6-cyclopropyl-3-oxo-2H,3H- [1,2,4]triazolo[4,3-b]pyridazin-2-yl}acetic acid (Intermediate 57) (105 mg, 0.33 mmol) and diisopropylethylamine (213 µl, 1.19 mmol) in DCM (5 ml) was added HATU (139 mg, 0.36 mmol). After 20 min(1S)-1-(4-chloro-3-fluorophenyl)ethan-1-amine hydrochloride (70 mg, 0.33 mmol) was added. The reaction was stirred at room temperature for 90 min. DMF (3 ml) was then added to the reaction. Another portion of (1S)-1-(4-chloro-3-fluorophenyl)ethan-1-amine hydrochloride (70 mg, 0.33 mmol) was added and the reaction was stirred at room temperature for 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 Biotage Isolera™
chromatography (silica gel, eluting with 0-3% MeOH in DCM). Further purification by preparative HPLC, Method B1 gave the title compound (36 mg, 28% yield). 1H NMR (500 MHz, DMSO-d6) d 8.61 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 9.8 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.36 (dd, J = 10.7, 2.0 Hz, 1H), 7.19 (dd, J = 8.3, 2.0 Hz, 1H), 7.04 (d, J = 9.8 Hz, 1H), 4.93 (p, J = 7.1 Hz, 1H), 4.62 (d, J = 16.6 Hz, 1H), 4.57 (d, J = 16.6 Hz, 1H), 2.17– 2.03 (m, 1H), 1.10– 1.03 (m, 2H), 1.00– 0.93 (m, 2H). LCMS (Analytical Method C) Rt = 3.61 min, MS (ESIpos): m/z 389.95, 392.00 [M+H]+, Purity = 100%. EXAMPLE 5 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{8-cyclopropyl-3-oxo- 2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-2-yl}acetamide
(Compound I-5-1)
Figure imgf000281_0001
A pressure tube was charged with cyclopropylboronic acid (13 mg, 0.15 mmol), N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{8-iodo-3-oxo-2H,3H- [1,2,4]triazolo-[4,3-b]pyridazin-2-yl}acetamide (Compound I-1-27) (60 mg, 0.13 mmol), K3PO4 (53.55 mg, 0.25 mmol) and THF / H2O (5:1, 7.5 ml) and degassed with N2 for 5 min. Pd(dppf)Cl2 (18.5 mg, 0.03 mmol) was added. The tube was flushed with N2 and sealed. The reaction was stirred at 75 oC for 5.5 h. The crude product was purified by purified Biotage Isolera™ chromatography (silica gel, eluting with 0-2.5% MeOH in DCM). The resulting solid was triturated in MeOH to give the title compound (17 mg, 35% yield). 1H NMR (500 MHz, DMSO-d6) d 8.64 (d, J = 7.7 Hz, 1H), 8.14 (d, J = 4.5 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.37 (dd, J = 10.7, 2.0 Hz, 1H), 7.20 (dd, J = 8.3, 2.0 Hz, 1H), 6.76 (d, J = 4.5 Hz, 1H), 4.95 (p, J = 7.1 Hz, 1H), 4.68 (d, J = 16.5 Hz, 1H), 4.61 (d, J = 16.5 Hz, 1H), 2.13 (tt, J = 8.0, 5.4 Hz, 1H), 1.37 (d, J = 7.0 Hz, 3H), 1.18– 1.11 (m, 4H). LCMS (Analytical Method C) Rt = 3.67 min, MS (ESIpos): m/z 390.0, 392.00 [M+H]+, Purity = 100%. EXAMPLE 6 Synthesis of (2R/S*)-N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-b]pyridazin-2-yl}propanamide
(Compounds I-6-1 and I-6-2)
Figure imgf000282_0001
A mixture of 2H,3H-[1,2,4]triazolo[4,3-b]pyridazin-3-one (Intermediate 33) (60 mg, 0.44 mmol), 2-bromo-N-[(1S)-1-(4-chloro-3- fluorophenyl)ethyl]propanamide (Intermediate 13) (148 mg, 0.46 mmol) and potassium carbonate (90 mg, 0.65 mmol) was suspended in acetonitrile (2 ml) and the mixture was stirred at 60 °C under a nitrogen atmosphere for 18 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The crude product was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-10% MeOH in DCM) to give the mixture of diastereomers (144 mg), which was separated using the following conditions: Chiralpak IC 5mm, 250 x 20mm, mobile phase of CO2 / (Methanol + 0.5% isopropylamine) 70/30, flow rate 50 ml/min, 40 °C, 150 bar to give Compound I-6-1 and Compound I-6-2. Diastereoisomer 1 (Compound I-6-1):
Yield: 53 mg, 29%. 1H NMR (500 MHz, DMSO-d6) d 8.45 (d, J = 7.8 Hz, 1H), 8.29 (dd, J = 4.0, 1.4 Hz, 1H), 7.83 (dd, J = 9.6, 1.4 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.33 (dd, J = 10.9, 1.9 Hz, 1H), 7.18 (dd, J = 8.3, 1.9 Hz, 1H), 7.15 (dd, J = 9.6, 4.0 Hz, 1H), 5.02 (q, J = 7.1 Hz, 1H), 4.94 (p, J = 7.1 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H), 1.35 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method B) Rt = 2.49 min, MS (ESIpos): m/z 364.1, 366.1 [M+H]+, Purity = 89%. Diastereoisomer 2 (Compound I-6-2):
Yield: 50 mg, 28%. 1H NMR (500 MHz, DMSO-d6) d 8.43 (d, J = 7.6 Hz, 1H), 8.27 (dd, J = 4.0, 1.5 Hz, 1H), 7.83 (dd, J = 9.6, 1.4 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.32 (dd, J = 10.7, 1.9 Hz, 1H), 7.16 (dd, J = 8.3, 2.0 Hz, 1H), 7.13 (dd, J = 9.7, 4.0 Hz, 1H), 4.98 (q, J = 7.2 Hz, 1H), 4.91 (p, J = 7.1 Hz, 1H), 1.59 (d, J = 7.2 Hz, 3H), 1.34 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method B) Rt = 2.49 min, MS (ESIpos): m/z 364.1, 366.1 [M+H]+, Purity = 90%. EXAMPLE 7
Synthesis of Compounds 1-7-1 to 1-7-16
Each of Compounds 1-7-1 through 1-7-16 as listed in Table 7 could be prepared according to the methods above, using the intermediates listed in the "Synthesis" column for such compounds.
Table 7
Representative Compounds
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0002
EXAMPLE 8 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyrazin-2-yl}acetamide
(Compound II-1-1)
Figure imgf000288_0001
A mixture of 2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-3-one (22 mg, 0.16 mmol), 2-bromo-N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]acetamide (48 mg, 0.16 mmol) (Intermediate 3) and potassium carbonate (67.57 mg, 0.49 mmol) in acetonitrile (2 mL) was heated to 60 °C for 4 hours. The reaction was cooled and quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated with ethyl acetate to yield the title compound (17 mg, 30% yield).1H NMR (500 MHz, DMSO-d6) d 8.91 (d, J = 1.4 Hz, 1H), 8.67 (d, J = 7.6 Hz, 1H), 7.92 (dd, J = 1.6, 4.9 Hz, 1H), 7.55 (dd, J = 6.4, 10.1 Hz, 2H), 7.36 (dd, J = 1.6, 10.7 Hz, 1H), 7.22 - 7.17 (m, 1H), 4.94 (p, J = 7.1 Hz, 1H), 4.71 (d, J = 16.6 Hz, 1H), 4.66 (d, J = 16.6 Hz, 1H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 2.44min, MS (ESIpos): m/z= 350 [M+H]+, Purity = 96%.
EXAMPLES 8-2 THROUGH 8-10
Synthesis of Compounds II- 1-2 through Compound II- 1-10
Each of Compounds II- 1-2 through II-1-10 as listed in Table 8 were prepared according to the method of Example 8, using the intermediates listed in the "Synthesis" column for such compounds. The final compounds were purified by preparative HPLC Methods, A1, A2, B1 or B2.
Table 8
Representative Compounds
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
EXAMPLE 9 Synthesis of N-[(1S)-1-(4-methylphenyl)ethyl]-2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3- c]pyrimidin-2-yl}acetamide
(Compound II-2-1)
Figure imgf000295_0001
A mixture of 2H,3H‐[1,2,4]triazolo[4,3‐c]pyrimidin‐3‐one (85%, 20 mg, 0.12 mmol) (Intermediate 4), 2‐bromo‐N‐[(1S)‐1‐(4‐methylphenyl)ethyl]acetamide (34 mg, 0.13 mmol) (Intermediate 1) and potassium carbonate (52 mg, 0.37 mmol) in acetonitrile (2 mL) was heated to 60 °C for 2 h. The reaction was quenched into water and extracted into ethyl acetate. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by Biotage Isolera™ chromatography (silica gel, eluting with 0-10% MeOH in DCM) to yield 17 mg (39% yield) of the title compound as a beige solid.1H NMR (500 MHz, DMSO-d6) d 8.81 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.0 Hz, 1H), 7.23 - 7.18 (m, 3H), 7.13 (d, J = 7.9 Hz, 2H), 4.90 (p, J = 7.2 Hz, 1H), 4.54 (s, 2H), 2.27 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method B) Rt = 2.42min, MS (ESIpos): m/z= 312 [M+H]+, Purity = 87%. EXAMPLE 10 Synthesis of 2-{5,7-dimethyl-3-oxo-2H,3H-[1,2,4]triazolo[4,3-c]pyrimidin-2-yl}-N- [(1S)-1-(4-methylphenyl)ethyl]acetamide
(Compound II-3-1)
Figure imgf000296_0001
A mixture of 5,7‐dimethyl‐2H,3H‐[1,2,4]triazolo[4,3‐c]pyrimidin‐3‐one (20 mg, 0.12 mmol) (Intermediate 5), 2‐bromo‐N‐[(1S)‐1‐(4‐
methylphenyl)ethyl]acetamide (31 mg, 0.12 mmol) (Intermediate 1) and potassium carbonate (51 mg, 0.37 mmol) in acetonitrile (2 mL) was heated to 60 °C for 2 h. The reaction was cooled and quenched into water. The aqueous layer was extracted into ethyl acetate (x3). The combined organic extracts was washed with brine, dried (MgSO4), filtered and concentrated. The residue was triturated with ethyl acetate, the solid material collected by filtration, washed with ethyl acetate and dried to yield 21 mg (48% yield) of the title compound as a beige solid.1H NMR (500 MHz, DMSO-d6) d 8.46 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.80 (s, 1H), 4.89 (p, J = 7.1 Hz, 1H), 4.45 (s, 2H), 2.74 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 2.48min, MS (ESIpos): m/z= 340 [M+H]+, Purity = 94%.
Synthesis of N-[(1S)-1-(4-chlorophenyl)ethyl]-2-{5,7-dimethyl-3-oxo-2H,3H- [1,2,4]triazolo[4,3-c]pyrimidin-2-yl}acetamide
(Compound II-3-2)
Figure imgf000296_0002
By analogy of the procedure described for Compound II-3-1 using Intermediate 8 and Intermediate 59, the title compound was prepared.1H NMR (500 MHz, DMSO-d6) d 8.81 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.0 Hz, 1H), 7.23– 7.18 (m, 3H), 7.13 (d, J = 7.9 Hz, 2H), 4.90 (p, J = 7.2 Hz, 1H), 4.54 (s, 2H), 2.27 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 2.57min, MS (ESIpos): m/z= 360 [M+H]+, Purity = 95%. EXAMPLE 11 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-[3-oxo-8-(piperazin-1-yl)- 2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-2-yl]acetamide
(Compound II-4-1)
Figure imgf000297_0001
tert-Butyl 4-[2-({[(1S)-1-(4-chloro-3- fluorophenyl)ethyl]carbamoyl}methyl) -3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-8- yl]piperazine-1-carboxylate (81 mg, 0.15 mmol) (Intermediate 15) was dissolved in 25% TFA in DCM (1 mL). The reaction was stirred at room temperature for 30 min. The reaction was concentrated. The crude product was loaded onto an SCX cartridge (1 g) in MeOH and washed with DCM (2 mL), MeOH (2 mL), DCM (2 mL), MeOH (2 mL) and DCM (2 mL). The product was eluted with 2M NH3 in MeOH (10 mL) and concentrated to give 55 mg (75% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.62 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.34 (dd, J = 10.7, 1.8 Hz, 1H), 7.23– 7.15 (m, 2H), 7.09 (d, J = 4.7 Hz, 1H), 4.94 (p, J = 7.1 Hz, 1H), 4.67 (d, J = 16.7 Hz, 1H), 4.61 (d, J = 16.7 Hz, 1H), 4.00– 3.79 (m, 4H), 2.85– 2.69 (m, 4H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 2.75min, MS (ESIpos): m/z= 434.10, 436.05 [M+H]+, Purity = 99%. EXAMPLE 12 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-[8-(4-methylpiperazin-1-yl)- 3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-2-yl]acetamide
(Compound II-5-1)
Figure imgf000298_0001
To a solution of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-[3-oxo-8- (piperazin-1-yl)-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-2-yl]acetamide (30 mg, 0.07 mmol) (Compound 4) in DCM (3 mL) was added formaldehyde (37% in water, 51 µL, 0.69 mmol) and then STAB (73 mg, 0.35 mmol). The reaction was stirred for 30 min. The reaction was diluted with sat NaHCO3 (aq) (1 mL) and then the pH was adjusted to pH 10 with 2M K2CO3(aq). The layers were separated and the aqueous phase was extracted with DCM (2 x 3 mL). The combined organic extracts were dried
(hydrophobic frit) and concentrated. The crude product was loaded onto an SCX cartridge (1 g) in MeOH and washed with DCM (2 mL), MeOH (2 mL), DCM (2 mL), MeOH (2 mL) and DCM (2 mL). The product was eluted with 2M NH3 in MeOH (6 mL) and concentrated to give 20 mg (59% yield) of the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) d 8.62 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.34(dd, J = 10.7, 1.9 Hz, 1H), 7.23 (d, J = 4.7 Hz, 1H), 7.19 (dd, J = 8.3, 1.8 Hz, 1H), 7.09 (d, J = 4.7 Hz, 1H), 4.95 (p, J = 7.1 Hz, 1H), 4.68 (d, J = 16.7 Hz, 1H), 4.62 (d, J = 16.7 Hz, 1H), 4.03– 3.88 (m, 4H), 2.44– 2.36 (m, 4H), 2.20 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 2.77min, MS (ESIpos): m/z= 448.10, 450.10 [M+H]+, Purity = 100%. EXAMPLE 13 Synthesis of 2-[8-(azetidin-3-yloxy)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-2-yl]- N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]acetamide
(Compound II-6-1)
Figure imgf000299_0001
A solution of tert-butyl 3-{[2-({[(1S)-1-(4-chloro-3- fluorophenyl)ethyl]carbamoyl}methyl)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-8- yl]oxy}azetidine-1-carboxylate (68 mg, 0.13 mmol) (81 mg, 0.15 mmol) (Intermediate 18) in 25% TFA in DCM (1 mL) was stirred at room temperature for 40 min. The reaction was concentrated. The crude product was purified by preparative HPLC (Method A) to give 15 mg (25% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.72 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 4.9 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.43 (dd, J = 10.7, 1.9 Hz, 1H), 7.27 (dd, J = 8.3, 1.9 Hz, 1H), 7.14 (d, J = 4.9 Hz, 1H), 5.54 (p, J = 6.2 Hz, 1H), 5.00 (p, J = 7.0 Hz, 1H), 4.76 (d, J = 16.6 Hz, 1H), 4.70 (d, J = 16.6 Hz, 1H), 3.90– 3.76 (m, 2H), 3.71– 3.56 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 2.73min, MS (ESIpos): m/z= 421.05, 423.00 [M+H]+, Purity = 99%.
EXAMPLE 14 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{8-[(1-methylazetidin-3- yl)oxy]-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrazin-2-yl}acetamide
(Compound II-7-1)
Figure imgf000300_0001
To a solution of 2-[8-(azetidin-3-yloxy)-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyrazin-2-yl]-N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]acetamide (10 mg, 0.02 mmol) (Compound 6) in DCM (2 mL) was added formaldehyde (18 µL, 0.24 mmol) in water and then STAB (25 mg, 0.12 mmol). The reaction was stirred for 30 min. The reaction was diluted with saturated NaHCO3(aq) (1 mL) and then the pH was adjusted to pH 9 with 2M K2CO3(aq). The layers were separated and the aqueous phase was extracted with DCM (2 x 3 mL). The combined organic extracts were dried (hydrophobic frit) and concentrated to give 6 mg (52% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.67 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 4.9 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.37 (dd, J = 10.7, 2.0 Hz, 1H), 7.21 (dd, J = 8.3, 2.0 Hz, 1H), 7.08 (d, J = 4.9 Hz, 1H), 5.26 (p, J = 5.7 Hz, 1H), 4.94 (p, J = 7.0 Hz, 1H), 4.70 (d, J = 16.6 Hz, 1H), 4.63 (d, J = 16.6 Hz, 1H), 3.69 (td, J = 6.4, 2.5 Hz, 2H), 3.09 (dd, J = 8.4, 5.3 Hz, 2H), 2.29 (s, 3H), 1.37 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 2.9min, MS (ESIpos): m/z= 434.90, 436.90 [M+H]+, Purity = 99%. EXAMPLE 15 Synthesis of Compounds II-8-1 to II-8-42 Each of Compounds 8-1 through 8-42 as listed in Table 9 could be prepared according to the methods above, using the intermediates listed in the "Synthesis" column for such compounds .
Table 9
Representative Compounds
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0002
EXAMPLE 16 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyrimidin-2-yl}acetamide
(Compound III-1-1)
Figure imgf000314_0001
A mixture of 2H,3H-[1,2,4]triazolo[4,3-a]pyrimidin-3-one (20 mg, 0.15 mmol) (Intermediate 22) , 2-bromo-N-[(1S)-1-(4-chloro-3- fluorophenyl)ethyl]acetamide (43 mg, 0.15 mmol) (Intermediate 3) and potassium carbonate (61 mg, 0.44 mmol) in acetonitrile (2 mL) was heated to 60 °C for 3 hours. The reaction was cooled and quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated with ethyl acetate and the solid material dried in vacuo to yield the title compound (22 mg, 43% yield).1H NMR (500 MHz, DMSO-d6) d 8.62 (d, J = 7.7 Hz, 1H), 8.55 (dd, J = 2.0, 3.8 Hz, 1H), 8.37 (dd, J = 2.0, 7.0 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.36 (dd, J = 1.9, 10.7 Hz, 1H), 7.20 (dd, J = 1.9, 8.3 Hz, 1H), 6.73 (dd, J = 3.8, 7.0 Hz, 1H), 4.94 (p, J = 7.0 Hz, 1H), 4.64 (d, J = 16.6 Hz, 1H), 4.59 (d, J = 16.6 Hz, 1H), 1.37 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 2.31min, MS (ESIpos): m/z= 350 [M+H]+, Purity = 98%. EXAMPLES 16-2 THROUGH 16-29 Synthesis of Compounds III-1-2 through Compound III-1-29 Each of Compounds III-1-2 through III-1-29 as listed in Table 10 were prepared according to the method of Example 16, using the intermedieates listed in the “Synthesis” column for such compounds.
Table 10
Representative Compounds
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000341_0001
Figure imgf000342_0001
Figure imgf000343_0001
EXAMPLE 17 Synthesis of 2-{7-methyl-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl}-N-[(1S)- 1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide
(Compound III-2-1) and 2-{5-methyl-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl}-N-[(1S)-1-[4- (trifluoromethoxy)phenyl]ethyl]acetamide
(Compound III-2-2)
Figure imgf000344_0001
A mixture of Intermediate 93-1 and Intermediate 93-2 (21 mg, 0.14 mmol), Intermediate 2 (46 mg, 0.14 mmol) and potassium carbonate (58 mg, 0.42 mmol) in acetonitrile (2 mL) was heated to 60 °C for 3 hours. The reaction was cooled and quenched into water. The aqueous layer was extracted into ethyl acetate three times, the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude title product (50 mg) as a mixture of 2 isomers. Analytical Method F shows ratio of 3:2 of the isomeric mixture. The mixture was separated Preparative HPLC, Method F to afford Compound III-2-1 (9 mg, 14% yield, 89% purity) and Compound III-2-2 (16 mg, 27% yield, 95% purity).
Compound III-2-1:
1H NMR (500 MHz, DMSO-d6) d 8.60 (d, J = 7.7 Hz, 1H), 8.25 (d, J = 7.1 Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.65 (d, J = 7.1 Hz, 1H), 4.97 (p, J = 7.0 Hz, 1H), 4.56 (s, 2H), 2.45 (s, 3H), 1.39 (d, J = 7.0 Hz, 3H).
LCMS (Analytical Method B) Rt = 2.71min, MS (ESIpos): m/z= 396 [M+H]+, Purity = 95%. Compound III-2-2:
1H NMR (500 MHz, DMSO-d6) d 8.62 (d, J = 7.7 Hz, 1H), 8.32 (d, J = 4.0 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.45 (dd, J = 4.0, 1.1 Hz, 1H), 4.97 (p, J = 7.2 Hz, 1H), 4.54 (s, 2H), 2.74 - 2.69 (m, 3H), 1.39 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method B) Rt = 2.74min, MS (ESIpos): m/z= 396 [M+H]+, Purity = 89%. Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{7-methyl-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyrimidin-2-yl}acetamide
(Compound III-2-3) and N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{5-methyl-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyrimidin-2-yl}acetamide
(Compound III-2-4)
Figure imgf000345_0001
Figure imgf000346_0001
By analogy of the method described in Example 17 for the synthesis of Compound III-2-1 and Compound III-2-2, the title compounds were prepared.
Compound III-2-3:
1H NMR (500 MHz, DMSO-d6) d 8.59 (d, J = 7.7 Hz, 1H), 8.24 (d, J = 7.1 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.36 (dd, J = 10.6, 1.9 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.65 (d, J = 7.1 Hz, 1H), 4.93 (q, J = 7.2 Hz, 1H), 4.66 - 4.51 (m, 2H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 3.43 min, MS (ESIpos): m/z= 363.9 ,365.9 [M+H]+. Purity = 100%.
Compound III-2-4:
1H NMR (500 MHz, DMSO-d6) d 8.61 (d, J = 7.7 Hz, 1H), 8.33 (d, J = 4.0 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.37 (dd, J = 10.7, 1.9 Hz, 1H), 7.21 (dd, J = 8.3, 1.8 Hz, 1H), 6.46 (dd, J = 4.0, 1.0 Hz, 1H), 4.95 (p, J = 7.1 Hz, 1H), 4.64 - 4.48 (m, 2H), 2.75 - 2.70 (m, 3H), 1.38 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 3.49min, MS (ESIpos): m/z= 363.9, 365.9 [M+H]+. Purity = 100%.
EXAMPLE 18 Synthesis of (2S*)-N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyrimidin-2-yl}propanamide
(Compound III-3-1) and (2R*)-N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3- a]pyrimidin-2-yl}propanamide
(Compound III-3-2)
Figure imgf000347_0001
The mixture of diastereomers Compound III-1-29 was separated using the following conditions: Stationary Phase: Chiralpak IG 5µm, 250 x 30mm; Mobile phase: CO2 / Isopropanol 70/30; Flowrate: 70mL/min UV detection: l=220 nm;
Temperature: 40 °C; Pressure: 126 bars to give Compound III-3-1 and Compound III-3- 2.
Diastereomer 1: Compound III-3-1 (yield: 6 mg (5%))
1H NMR (500 MHz, DMSO-d6) d 8.55 (dd, J = 3.8, 2.0 Hz, 1H), 8.40– 8.31 (m, 2H), 7.53 (t, J = 8.1 Hz, 1H), 7.32 (dd, J = 10.7, 2.0 Hz, 1H), 7.16 (dd, J = 8.3, 2.0 Hz, 1H), 6.73 (dd, J = 7.0, 3.8 Hz, 1H), 5.00– 4.88 (m, 2H), 1.59 (d, J = 7.2 Hz, 3H), 1.34 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method A) Rt = 2.46 min, MS (ESIpos): m/z 264.2 [M+H]+, Purity = 97%.
Diastereomer 2: Compound III-3-2 (yield: 7 mg (6%))
1H NMR (500 MHz, DMSO-d6) d 8.56 (dd, J = 3.8, 2.0 Hz, 1H), 8.39– 8.34 (m, 2H), 7.50 (t, J = 8.1 Hz, 1H), 7.33 (dd, J = 10.8, 1.9 Hz, 1H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 6.73 (dd, J = 7.0, 3.8 Hz, 1H), 5.02– 4.91 (m, 2H), 1.57 (d, J = 7.2 Hz, 3H), 1.34 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method A) Rt = 2.46 min, MS (ESIpos): m/z 264.2 [M+H]+, Purity = 100%. EXAMPLE 19
Synthesis of Compounds III-4-1 to III-4-23
Each of Compounds III-4-1 through III-4-23 as listed in Table 11 could be prepared according to the methods above, using the intermediates listed in the "Synthesis" column for such compounds.
Table 11
Representative Compounds
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
EXAMPLE 20 Synthesis of N-[(1S)-1-(4-methylphenyl)ethyl]-2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3- a]pyridin-2-yl}acetamide
(Compound IV-1-1)
Figure imgf000356_0001
To a stirred solution of 2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}acetic acid (200 mg, 1.04 mmol) (Intermediate 119) and diisopropylethylamine (277 µL, 1.55 mmol) in DCM (5 mL) was added HATU (433 mg, 1.14 mmol). The reaction was stirred for 10 min before the addition of (1S)-1-(4-methylphenyl)ethan-1-amine (168 µL, 1.14 mmol). The reaction was stirred overnight. The reaction was washed with saturated NaHCO3 (aq) (5 mL). The aqueous phase was extracted with DCM (2 x 5 mL). The combined organic extracts were dried (hydrophobic frit) and concentrated. The crude product was purified by preparative HPLC (Method B1) to give 145 mg (45% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.54 (d, J = 7.9 Hz, 1H), 7.85 (dt, J = 7.1, 1.1 Hz, 1H), 7.25– 7.17 (m, 4H), 7.13 (d, J = 7.9 Hz, 2H), 6.61 (ddd, J = 7.2, 5.6, 1.7 Hz, 1H), 4.89 (p, J = 7.1 Hz, 1H), 4.55 (s, 2H), 2.27 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 3.28 min, MS (ESIpos): m/z= 311.05 [M+H]+. EXAMPLES 20-2 THROUGH 20-27 Synthesis of Compounds IV-1-2 through Compound IV-1-27 Each of Compounds IV-1-2 through IV-1-27 as listed in Table 12 were prepared according to the method of Example 20, using the intermediates listed in the “Synthesis” column for such compounds. Table 12
Representative Compounds
Figure imgf000357_0001
Figure imgf000358_0001
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
Figure imgf000362_0001
Figure imgf000363_0001
Figure imgf000364_0001
Figure imgf000365_0001
Figure imgf000366_0001
Figure imgf000367_0001
Figure imgf000368_0001
Figure imgf000369_0001
Figure imgf000370_0001
Figure imgf000371_0001
Figure imgf000372_0001
Figure imgf000373_0001
Figure imgf000374_0001
Figure imgf000375_0001
Figure imgf000376_0001
Figure imgf000377_0001
Figure imgf000378_0001
Figure imgf000379_0001
Figure imgf000380_0002
EXAMPLE 21 Syntesis of 2-{6-methoxy-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- (4-methylphenyl)ethyl]acetamide
(Compound IV-2-1)
Figure imgf000380_0001
A suspension of 2-bromo-N-[(1S)-1-(4-methylphenyl)ethyl]acetamide (78 mg, 0.3 mmol) (Intermediate 1), 6-methoxy-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-3- one (50 mg, 0.3 mmol) (Intermediate 106) and K2CO3 (126 mg, 0.91 mmol) in MeCN (2 mL) was stirred at 60 °C for 2 h. The reaction was allowed to cool to room temperature and was diluted with water (1 mL). The reaction was extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by preparative HPLC (Method B1) to give 54 mg (52% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.53 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 1.7 Hz, 1H), 7.21 (dd, J = 8.9, 5.9 Hz, 3H), 7.12 (d, J = 7.9 Hz, 2H), 7.06 (dd, J = 10.0, 2.2 Hz, 1H), 4.88 (p, J = 7.0 Hz, 1H), 4.55 (s, 2H), 3.76 (s, 3H), 2.27 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H). LCMS
(Analytical Method C) Rt = 3.57 min, MS (ESIpos): m/z= 341.15 [M+H]+, Purity = 100%. EXAMPLES 21-2 THROUGH 21-29 Synthesis of Compounds IV-2-2 through Compound IV-2-29 Each of Compounds IV-2-2 through IV-2-29 as listed in Table 13 were prepared according to the method of Example 21, using the intermediates listed in the “Synthesis” column for such compounds.
Table 13
Representative Compounds
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000390_0001
Figure imgf000391_0001
Figure imgf000392_0001
Figure imgf000393_0001
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Figure imgf000401_0001
Figure imgf000402_0002
EXAMPLE 22 Syntesis of 2-[5-(3-hydroxyazetidin-1-yl)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl]-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide
(Compound IV-3-1)
Figure imgf000402_0001
A mixture of 2‐{5‐bromo‐3‐oxo‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐2‐ yl}‐N‐[(1S)‐1‐[4‐(trifluoromethoxy)phenyl]ethyl]acetamide (50 mg, 0.10 mmol) (Intermediate 115), DIPEA (0.18 mL, 1.0 mmol), and azetidin-3-ol hydrochloride (57 mg, 0.52 mmol) in NMP (0.2 mL) was heated in the microwave at 120 oC for 10 min. The reaction mixture was diluted with EtOAc and washed with water, then brine. The organic layer was concentrated. The crude product was purified by preparative HPLC (Method B1) to give 20 mg (40% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.60 (d, J = 7.8 Hz, 1H), 7.55 - 7.38 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.99 (dd, J = 9.2, 7.2 Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H), 5.64 (d, J = 6.0 Hz, 1H), 5.32 (d, J = 7.1 Hz, 1H), 4.96 (p, J = 7.2 Hz, 1H), 4.49 (dd, J = 11.5, 6.2 Hz, 1H), 4.45 (s, 2H), 4.36 - 4.24 (m, 2H), 3.77 (dd, J = 8.8, 5.1 Hz, 2H), 1.38 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 3.63 min, MS (ESIpos): m/z= 451.9 [M+H]+, Purity = 100%. EXAMPLES 22-2 THROUGH 22-8 Synthesis of Compounds IV-3-2 through Compound IV-3-8 Each of Compounds IV-3-2 through IV-3-8 as listed in Table 14 were prepared according to the method of Example 22, using the intermediates listed in the “Synthesis” column for such compounds.
Table 14
Representative Compounds
Figure imgf000404_0001
Figure imgf000405_0001
Figure imgf000406_0001
Figure imgf000407_0001
EXAMPLE 23 Syntesis of 2-[7-(4-methylpiperazin-1-yl)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl]-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide
(Compound IV-4-1)
Figure imgf000408_0001
2-{7-Chloro-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- [4-(trifluoromethoxy)phenyl]ethyl]acetamide (50 mg, 0.12 mmol) (Compound IV-2-10) and 1-methylpiperazine (70 µL, 0.63 mmol) were dissolved in NMP (0.5 mL) and the solution was sealed under a nitrogen atmosphere and stirred at 120 °C for 1 h.
Additional 1-methylpiperazine (400 µL, 3.59 mmol) was added and the reaction was stirred at 120 °C for 16 h. The reaction was cooled to room temperature then partitioned between water and EtOAc. The organic phase was separated and the aqueous extracted with EtOAc (x3). The combined organics were concentrated. The crude product was purification by preparative HPLC (Method B1) to give 23 mg (39% yield) as a beige solid.1H NMR (500 MHz, DMSO-d6) d 8.57 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.35 - 7.29 (m, 2H), 6.65 (dd, J = 7.9, 2.2 Hz, 1H), 6.07 (d, J = 1.9 Hz, 1H), 4.95 (p, J = 7.1 Hz, 1H), 4.44 (s, 2H), 3.26 - 3.22 (m, 4H), 2.43 - 2.38 (m, 4H), 2.21 (s, 3H), 1.37 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 1.75min, MS (ESIpos): m/z= 479 [M+H]+, Purity = 98%. EXAMPLES 23-2 THROUGH 23-7
Synthesis of Compounds IV-4-2 through Compound IV-4-7
Each of Compounds IV-4-2 through IV-4-7 as listed in Table 15 were prepared according to the method of Example 23, using the intermediates listed in the 5 “Synthesis” column for such compounds.
Table 15
Representative Compounds
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
EXAMPLE 24 Synthesis of (2R/S*)-N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-2-yl}propanamide
(Compounds IV-5-1 and IV-5-2)
Figure imgf000415_0001
To a stirred mixture of 2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2- yl}propanoic acid (Intermediate 121) (64 mg, 0.31 mmol), (1S)-1-(4-chloro-3- fluorophenyl)ethan-1-amine hydrochloride (71.38 mg, 0.34 mmol) and
diisopropylethylamine (198.51 µl, 1.11 mmol) in DCM (1.5 ml) was added HATU (129 mg, 0.34 mmol). The reaction was at room temperature for 90 min. The reaction was washed with sat NaHCO3(aq) (3 ml). The aqueous phase was extracted with DCM (2 x 3 ml). The combined organic extracts were dried (hydrophobic frit) and concentrated. The crude product was purified by preparative HPLC, (Method B1) to give the compound as a mixture of diastereoisomers. (69 mg, 62% yield). The mixture of diastereoisomers were separated by SFC Chiral Purification (Column: Chiralpak A1 (20 mm x 250 mm, 5 µm); eluent A: MeOH + 0.5% isopropylamine, eluent B: CO2, gradient: isocratic 80%; flow 50 mL/min; UV: 220 nm). SFC Chiral Analysis (Column: Chiralpak A1 (4.6 mm x 250 mm, 5 µm); eluent A: MeOH + 0.5% isopropylamine, eluent B: CO2; gradient: isocratic 80% B; flow 2.4 mL/min; UV: 220 nm). Diastereoisomer 1 (Compound IV-5-1): 25 mg (42% yield) 1H NMR (500 MHz, DMSO-d6) d 8.41 (d, J = 7.6 Hz, 1H), 7.92– 7.81 (m, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.33 (dd, J = 10.7, 1.9 Hz, 1H), 7.26– 7.19 (m, 2H), 7.16 (dd, J = 8.3, 1.9 Hz, 1H), 6.61 (ddd, J = 7.2, 5.9, 1.5 Hz, 1H), 5.00– 4.81 (m, 2H), 1.58 (d, J = 7.2 Hz, 3H), 1.34 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method C) Rt = 3.75 min, MS (ESIpos): m/z= 363.05, 365.00 [M+H]+, Purity = 100%. Chiral analysis Rt = 5.33 min, ee: 100%. Diastereosiomer 2 (Compound IV-5-2): 26 mg (44% yield) 1H NMR (500 MHz, DMSO-d6) d 8.41 (d, J = 7.9 Hz, 1H), 7.93– 7.82 (m, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.34 (dd, J = 10.9, 1.9 Hz, 1H), 7.26– 7.20 (m, 2H), 7.18 (dd, J = 8.3, 1.9 Hz, 1H), 6.62 (ddd, J = 7.2, 4.2, 3.1 Hz, 1H), 5.02– 4.89 (m, 2H), 1.55 (d, J = 7.1 Hz, 3H), 1.34 (d, J = 7.1 Hz, 3H). LCMS (Analytical Method C) Rt = 3.78 min, MS (ESIpos): m/z= 363.05, 365 [M+H]+, Purity = 100%. Chiral analysis Rt = 6.31 min, ee: 100%.
Synthesis of (2R/S*)- N-[(1S)-1-(4-methylphenyl)ethyl]-2-{3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-2-yl}propanamide (Compounds IV-5-3 and IV-5-4)
Figure imgf000416_0001
Diastereoisomeric mixture Compound IV-1-25 (61 mg) was separated by SFC Chiral Purification (Column: Chiralpak A1 (20 mm x 250 mm, 5 µm); eluent A: MeOH + 0.5% isopropylamine, eluent B: CO2, gradient: isocratic 90%; flow 50 mL/min; UV: 220 nm). SFC Chiral Analysis (Column: Chiralpak A1 (4.6 mm x 250 mm, 5 µm); eluent A: MeOH + 0.5% isopropylamine, eluent B: CO2; gradient: isocratic 80% B; flow 2.4 mL/min; UV: 220 nm). Diastereosiomer 1 (Compound IV-5-3): 24 mg (39% yield) 1H NMR (500 MHz, DMSO-d6) d 8.33 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 7.1 Hz, 1H), 7.26– 7.22 (m, 1H), 7.22– 7.18 (m, 1H), 7.17 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.65– 6.54 (m, 1H), 4.92 (q, J = 7.2 Hz, 1H), 4.89– 4.81 (m, 1H), 2.26 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H), 1.32 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 3.59 min, MS (ESIpos): m/z= 325 [M+H]+, Purity = 100%. Chiral analysis Rt = 4.65 min, ee: 99.8%. Diastereoisomer 2 (Compound IV-5-4): 27 mg (44% yield) 1H NMR (500 MHz, DMSO-d6) d 8.29 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.1 Hz, 1H), 7.27– 7.23 (m, 1H), 7.23– 7.19 (m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 6.63– 6.57 (m, 1H), 4.94 (q, J = 7.1 Hz, 1H), 4.91– 4.85 (m, 1H), 2.26 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H), 1.32 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 3.62 min, MS (ESIpos): m/z= 325 [M+H]+, Purity = 100%. Chiral analysis Rt = 5.31 min, ee: 100%. Synthesis of N‐[(1R/S*)‐1‐[4‐(difluoromethoxy)phenyl]ethyl]‐2‐{3‐oxo‐2H,3H‐ [1,2,4]triazolo[4,3‐a]pyridin‐2‐yl}acetamide (Compounds IV-5-5 and IV-5-6)
Figure imgf000417_0001
A solution of 2‐{3‐oxo‐2H,3H‐[1,2,4]triazolo[4,3‐a]pyridin‐2‐yl}acetic acid (50 mg, 0.26 mmol) (Intermediate 119), HATU (108 mg, 0.28 mmol) and diisopropylethylamine (138 µl, 0.78 mmol) in N,N-dimethylformamide (3 mL) was stirred for 10 minutes.1-[4-(Difluoromethoxy)phenyl]ethanamine (48 mg, 0.26 mmol) was added and stirring continued for 1 hour. The reaction was quenched into water and extracted into ethyl acetate three times. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC (Method B1). The relevant fractions were combined and concentrated in vacuo to yield the title compounds as a racemic mixture as a white solid (40 mg, 43% yield). 1H NMR (500 MHz, DMSO-d6) d 8.62 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.1 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.25 - 7.19 (m, 2H), 7.13 (d, J = 8.6 Hz, 2H), 7.11 (t, J = 74.3 Hz, 1H), 6.62 (ddd, J = 1.6, 5.7, 7.2 Hz, 1H), 4.92 (p, J = 7.3 Hz, 1H), 4.56 (s, 2H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt= 2.51 min, MS (ESIpos): m/z 363.2 [M+H]+.
The racemic mixture (35 mg) was separated by Preparative chiral SFC, Method A. The relevant fractions were combined and concentrated in vacuo to yield the title compounds as white solids (10 mg of each enantiomer). Analytical data of (Compound IV-5-5) and (Compound IV-5-6) are consistent with the racemate. EXAMPLE 25 Synthesis of 2-[8-(methylamino)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl]-N- [(1S)-1-(4-methylphenyl)ethyl]acetamide
(Compound IV-6-1)
Figure imgf000418_0001
A pressure tube was charged with 2-{8-chloro-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1-(4-methylphenyl)ethyl]acetamide (50 mg, 0.15 mmol) (Compound IV-2-2), tBuBrettPhos Pd G3 (14.87 mg, 0.02 mmol), Cs2CO3 (141.74 mg, 0.44 mmol), NMP (2 mL) and water (0.08 mL). The suspension was degassed with N2 for 5 min.2M Methylamine in THF (73 µL) was added and the pressure tube was flushed with N2 and sealed. The reaction was heated at 100 oC for 18 h. The reaction mixture was loaded directly onto an SCX cartridge (2 g) and washed with DCM (2 mL), MeOH (2 mL), DCM (2 mL), MeOH (2 mL) and DCM (2 mL). The washings were concentrated. The resulting residue was diluted with EtOAc (6 mL) and washed with water (4 x 6 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by preparative HPLC (Method B1) affording 14 mg (29% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.54 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 6.3 Hz, 1H), 7.13 (d, J = 7.9 Hz, 2H), 6.51 (t, J = 7.0 Hz, 1H), 6.18 (q, J = 4.8 Hz, 1H), 5.89 (d, J = 7.2 Hz, 1H), 4.88 (p, J = 7.1 Hz, 1H), 4.56 (s, 1H), 4.55 (s, 1H), 2.75 (d, J = 4.9 Hz, 3H), 2.27 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 3.67 min, MS (ESIpos): m/z= 340 [M+H]+, Purity = 100%. EXAMPLE 26 Synthesis of 2-{8-amino-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1-(4- methylphenyl)ethyl]acetamide
(Compound IV-7-1) and tert-butyl N-[2-({[(1S)-1-(4-methylphenyl)ethyl]carbamoyl}methyl)-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-8-yl]carbamate (Compound IV-7-2)
Figure imgf000419_0001
Figure imgf000420_0001
A pressure tube was charged with 2-{8-chloro-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1-(4-methylphenyl)ethyl]acetamide (100 mg, 0.3 mmol) (Compound IV-2-2), tert-butyl carbamate (316 mg, 2.7 mmol), Cs2CO3 (208 mg, 0.6 mmol), tBuBrettPhos Pd G3 (30 mg, 0.03 mmol), NMP (1.5 mL) and water (0.15 mL). The suspension was degassed with N2 for 5 min and sealed. The reaction was heated at 100 oC for 18 h. The reaction was filtered, rinsing with EtOAc (5 mL). The resulting filtrate was washed with water (4 x 5 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by preparative HPLC (Method A1) affording 9 mg (10% yield) of Compound 7-1 as a white solid and 11 mg (9% yield) of Compound 7-2 as an off-white solid. Compound IV-7-1:
1H NMR (500 MHz, DMSO-d6) d 8.54 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 6.8 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.44 (t, J = 7.0 Hz, 1H), 6.13 (d, J = 7.1 Hz, 1H), 5.71 (s, 2H), 4.89 (p, J = 7.0 Hz, 1H), 4.56 (s, 2H), 2.27 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 3.35 min, MS (ESIpos): m/z= 326 [M+H]+, Purity = 100%. Compound IV-7-2:
1H NMR (250 MHz, Chloroform-d) d 7.71 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.15 (q, J = 8.2 Hz, 4H), 7.05 (s, 1H), 6.54 (t, J = 7.2 Hz, 1H), 6.36 (d, J = 7.3 Hz, 1H), 5.12 (p, J = 7.1 Hz, 1H), 4.70 (d, J = 16.3 Hz, 1H), 4.61 (d, J = 16.4 Hz, 1H), 2.32 (s, 3H), 1.54 (s, 9H), 1.48 (d, J = 6.9 Hz, 3H). LCMS (Analytical Method C) Rt = 4.22 min, MS (ESIpos): m/z= 426 [M+H]+, Purity = 100%. EXAMPLE 27 Synthesis of 2-{8-methoxy-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- (4-methylphenyl)ethyl]acetamide
(Compound IV-8-1)
Figure imgf000421_0001
A pressure tube was charged with 2-{8-chloro-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1-(4-methylphenyl)ethyl]acetamide (100 mg, 0.29 mmol) (Compound IV-2-2), Ad-BippyPhos (3.8 mg, 6 µmol), Pd(OAc)2 (0.7 mg, 3 µmol), Cs2CO3 (141.74 mg, 0.44 mmol), dry toluene (2.5 mL) and dry MeOH (2.5 mL). The suspension was degassed with N2 for 5 min and sealed. The reaction was heated at 80 oC for 18 h. The reaction was filtered, diluted with water (5 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were dried
(hydrophobic frit) and concentrated. The crude product was dissolved in DMSO/MeOH (2:1, 3 mL), sonicated and filtered. The filtrate was purified by preparative HPLC (Method A) to give 13 mg (13% yield) of the title compound as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.54 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 6.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.59 (d, J = 6.7 Hz, 1H), 6.58– 6.53 (m, 1H), 4.88 (p, J = 7.1 Hz, 1H), 4.55 (s, 2H), 3.88 (s, 3H), 2.27 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method C) Rt = 3.59 min, MS (ESIpos): m/z= 341 [M+H]+, Purity = 100%. EXAMPLE 28 Synthesis of 2-{8-[(2,2-difluoroethyl)amino]-3-oxo-2H,3H-[1,2,4]triazolo[4,3- a]pyridin-2-yl}-N-[(1S)-1-(4-methylphenyl)ethyl]acetamide
(Compound IV-9-1)
Figure imgf000422_0001
A pressure tube was charged with 2-{8-chloro-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1-(4-methylphenyl)ethyl]acetamide (100 mg, 0.29 mmol) (Compound IV-2-2), tBuBrettPhos Pd G3 (30 mg, 0.03 mmol), Cs2CO3 (283 mg, 0.87 mmol), 2,2-difluoroethanamine (181 µL, 2.61 mmol), and degassed NMP/water (10:1, 1.65 mL). The reaction was degassed with N2 for 1 min and sealed. The reaction was heated at 100 oC for 18 h. The reaction was diluted with EtOAc (6 mL) and washed with water (4 x 6 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by preparative HPLC (Method B1) affording 11 mg (10% yield) of the title compound.1H NMR (500 MHz, DMSO-d6) d 8.55 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 6.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.51 (t, J = 7.1 Hz, 1H), 6.30 (t, J = 6.4 Hz, 1H), 6.22 (d, J = 7.3 Hz, 1H), 6.15 (tt, J = 55.8, 4.0 Hz, 1H), 4.90 (p, J = 7.1 Hz, 1H), 4.58 (s, 2H), 3.62 (tdd, J = 15.3, 6.2, 4.1 Hz, 2H), 2.28 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt =
2.87min, MS (ESIpos): m/z= 390 [M+H]+, Purity = 99%. EXAMPLE 29 Synthesis of N-[(1S)-1-(4-methylphenyl)ethyl]-2-[3-oxo-8-(pyrrolidin-3-yl)-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-2-yl]acetamide
(Compound IV-10-1)
Figure imgf000423_0001
4M HCl in dioxane (58.64 µl) was added to a solution of tert‐butyl 3‐[2‐ ({[(1S)‐1‐(4‐methylphenyl)ethyl]carbamoyl}methyl)‐3‐oxo‐2H,3H‐[1,2,4]triazolo[4,3‐ a]pyridin‐8‐yl]pyrrolidine‐1‐carboxylate (Intermediate 135) (75% purity, 25 mg, 0.04 mmol) in 1,4-dioxane (2 mL). The reaction was stirred for 3 hours then additional 4M HCl in dioxane (58 µl) was added and stirring continued for 18 hours. The reaction was heated to 45 °C for 4 hours then concentrated in vacuo. The residue was taken up in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added and the reaction was stirred for 20 hours. The reaction was concentrated in vacuo and the residue taken up in toluene and concentrated in vacuo three times. The residue was purified by preparative HPLC (Method A1). The relevant fractions were combined, the solvent volume reduced in vacuo and freeze dried to yield the title compound as a mixture of diastereoisomers as a white solid (9 mg, 61% yield). 1H NMR (500 MHz, DMSO-d6) d 8.50 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 6.9 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 6.7 Hz, 1H), 6.58 (t, J = 6.8 Hz, 1H), 4.90 (p, J = 7.1 Hz, 1H), 4.57 (s, 2H), 3.14 (ddd, J = 3.1, 7.5, 10.8 Hz, 1H), 2.99 - 2.93 (m, 1H), 2.90 - 2.83 (m, 1H), 2.75 (dd, J = 7.2, 10.5 Hz, 1H), 2.27 (s, 3H), 2.10 - 2.02 (m, 1H), 1.86 - 1.78 (m, 1H), 1.35 (d, J = 7.0 Hz, 3H). One proton obscured by water peak. LCMS (Analytical Method A) Rt= 1.44 min, MS (ESIpos): m/z 380.2 [M+H]+. EXAMPLE 30 Synthesis of N-[(1S)-1-(4-methylphenyl)ethyl]-2-[8-(1-methylpyrrolidin-3-yl)-3-oxo- 2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl]acetamide
(Compound IV-11-1)
Figure imgf000424_0001
Formaldehyde (37% in water, 58 µL, 0.78 mmol) was added to a solution of N‐[(1S)‐1‐(4‐methylphenyl)ethyl]‐2‐[3‐oxo‐8‐(pyrrolidin‐3‐yl)‐2H,3H‐ [1,2,4]triazolo[4,3‐a]pyridin‐2‐yl]acetamide trifluoroacetic acid salt (Compound IV-10) (88% purity, 44 mg, 0.08 mmol) in dichloromethane (2 mL) and methanol (0.5 mL). The reaction was stirred for 30 minutes then sodium triacetoxyborohydride (66 mg, 0.31 mmol) was added and stirring continued for a further 3 hours. The reaction was quenched into water and extracted into ethyl acetate three times. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC (Method B1). The relevant fractions were combined, the solvent volume reduced in vacuo and freeze dried. The residue was further purified by preparative HPLC (Method C). The relevant fractions were combined and concentrated in vacuo to yield the title compound as a white solid (6 mg, 17% yield).1H NMR (500 MHz, DMSO-d6) d 8.50 (dd, J = 4.4, 7.7 Hz, 1H), 8.25 (s, 1H), 7.73 (d, J = 7.0 Hz, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.15 - 7.10 (m, 3H), 6.60 (t, J = 6.8 Hz, 1H), 4.90 (p, J = 7.0 Hz, 1H), 4.57 (s, 2H), 3.54 - 3.46 (m, 1H), 2.83 (t, J = 8.3 Hz, 1H), 2.68 - 2.58 (m, 3H), 2.30 (s, 3H), 2.27 (s, 3H), 2.23 - 2.17 (m, 1H), 1.92 - 1.84 (m, 1H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt= 1.45 min, MS (ESIpos): m/z 394.2 [M+H]+. EXAMPLE 31 Synthesis of 2-[7-(oxetan-3-yloxy)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl]-N- [(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide
(Compound IV-12-1)
Figure imgf000425_0001
2-{7-Chloro-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- [4-(trifluoromethoxy)phenyl]ethyl]acetamide (40 mg, 0.09 mmol) (Compound IV-2- 10), oxetan-3-ol (12 µl, 0.19 mmol), Pd(OAc)2 (3 mg, 0.01 mmol), JohnPhos (8 mg, 0.03 mmol) and cesium carbonate (60 mg, 0.18 mmol) were suspended in toluene (1 ml) and the mixture was de-gassed with nitrogen for 5 min, then sealed and stirred at 90 °C for 18 hrs. The reaction was cooled to room temperature, filtered through celite, washing with EtOAc. The filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC (Method B1) followed by chiral preparative HPLC using 10% Methanol: 90% CO2 with Synergi 4u Polar-RP, 4.6 x 250mm at 15ml/min to afford the title compound (10.9 mg, 26% yield) as a white solid.1H NMR (500 MHz, DMSO-d6) d 8.61 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.47 - 7.41 (m, 2H, H18), 7.34 - 7.30 (m, 2H), 6.38 (dd, J = 7.6, 2.2 Hz), 6.21 (d, J = 2.0 Hz, 1H), 5.33 (p, J = 5.5 Hz, 1H), 4.99 - 4.91 (m, 3H), 4.57 - 4.52 (m, 2H), 4.51 - 4.47 (m, 2H), 1.37 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 2.75 min, MS (ESIpos): m/z 453.2 [M+H]+, Purity = 97%. EXAMPLE 32 Synthesis of 2-[7-(4-hydroxypiperidin-1-yl)-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin- 2-yl]-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide
(Compound IV-13-1)
Figure imgf000426_0001
2-{7-iodo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- [4-(trifluoromethoxy)phenyl]ethyl]acetamide (50 mg, 0.1 mmol) (Intermediate 138), piperidin-4-ol (22 mg, 0.22 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), cesium carbonate (96 mg, 0.29 mmol), JohnPhos (13 mg, 0.04 mmol) were suspended in toluene (1 ml) and the mixture was de-gassed with nitrogen for 5 min, then sealed and stirred at 100 °C for 16 h. The reaction was re-treated with piperidin-4-ol (22 mg, 0.22 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), cesium carbonate (96 mg, 0.29 mmol), JohnPhos (13 mg, 0.04 mmol) and stirred at 100 °C for another 2 h. The mixture was cooled to room temperature then partitioned between water and EtOAc. The organics combined and concentrated in vacuo. The crude product was purified by preparative HPLC Method B1 to afford the title compound (8 mg, 16% yield).1H NMR (500 MHz, DMSO-d6) d 8.58 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 6.63 (dd, J = 7.9, 2.2 Hz, 1H), 6.06 (d, J = 1.8 Hz, 1H), 4.95 (p, J = 7.1 Hz, 1H), 4.72 (s, 1H), 4.46 - 4.41 (m, 2H), 3.69 (s, 1H), 3.64 - 3.56 (m, 2H), 3.04 - 2.96 (m, 2H), 1.82 - 1.75 (m, 2H), 1.46 - 1.39 (m, 2H), 1.37 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 2.57 min, MS (ESIpos): m/z 480.2 [M+H]+, Purity = 95%. EXAMPLE 33 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-[8-(morpholin-4-yl)-3-oxo- 2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl]acetamide
(Compound IV-14-1)
Figure imgf000427_0001
2-{8-bromo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- (4-chloro-3-fluorophenyl)ethyl]acetamide (20 mg, 0.05 mmol) (Intermediate 117), morpholine (8.18 µl, 0.09 mmol), Pd2dba3 (2.14 mg, 0.002 mmol), Xantphos (2.71 mg, 0.005 mmol) and sodium tertbutoxide (13.48 mg, 0.14 mmol) in toluene (0.5 mL) was degassed by sparging with nitrogen. The mixture was heated to 100 °C for 3 hours then cooled and diluted with ethyl acetate. The mixture was filtered through a pad of celite, washing with ethyl acetate and the residue was concentrated in vacuo. The residue was purified by preparative HPLC (Method B2) to yield the title compound as a white solid (2 mg, 10% yield).1H NMR (500 MHz, DMSO-d6) d 8.63 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 6.9 Hz, 1H), 7.34 (d, J = 10.7 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 6.57 (t, J = 7.0 Hz, 1H), 6.42 (d, J = 7.3 Hz, 1H), 4.94 (p, J = 7.1 Hz, 1H), 4.64 (d, J = 16.7 Hz, 1H), 4.58 (d, J = 16.5 Hz, 1H), 3.77 - 3.71 (m, 4H), 1.36 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 2.79 min, MS (ESIpos): m/z 434
[M+H]+, Purity = 96%. EXAMPLE 34 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-(8-{1,6- diazaspiro[3.3]heptan-1-yl}-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl)acetamide
(Compound IV-15-1)
Figure imgf000428_0001
Trifluoroacetic acid (250 µl, 3.27 mmol) was added to a solution of tert- butyl 1-[2-({[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]carbamoyl}methyl)-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-1,6-diazaspiro[3.3]heptane-6-carboxylate (51 mg, 0.07 mmol) (Intermediate 136) in dichloromethane (1 mL). The reaction was stirred for 1 hour then concentrated in vacuo. The residue was repeatedly taken up in toluene and concentrated in vacuo. The residue was purified by preparative HPLC Method A2 to yield the title compound as a white solid (17 mg, 51% yield).1H NMR (500 MHz, DMSO-d6) d 8.56 (d, J = 7.7 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.27 (dd, J = 1.8, 10.7 Hz, 1H), 7.19 (d, J = 6.6 Hz, 1H), 7.12 (dd, J = 1.8, 8.3 Hz, 1H), 6.46 (t, J = 7.0 Hz, 1H), 6.31 (d, J = 7.3 Hz, 1H), 4.87 (p, J = 7.3 Hz, 1H), 4.59 - 4.50 (m, 2H), 4.09 (dd, J = 3.8, 9.0 Hz, 2H), 3.88 (t, J = 7.5 Hz, 2H), 3.46 (d, J = 9.2 Hz, 2H), 2.40 - 2.37 (m, 2H), 1.29 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 1.83 min, MS (ESIpos): m/z 445.2, 447.2 [M+H]+, Purity = 98%. EXAMPLE 35 Synthesis of N-[(1S)-1-(4-chloro-3-fluorophenyl)ethyl]-2-(8-{1,6- diazaspiro[3.3]heptan-1-yl}-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl)acetamide
(Compound IV-16-1)
Figure imgf000429_0001
Formaldehyde (30.3 µl, 0.41 mmol) was added to a solution of N-[(1S)- 1-(4-chloro-3-fluorophenyl)ethyl]-2-(8-{1,6-diazaspiro[3.3]heptan-1-yl}-3-oxo-2H,3H- [1,2,4]triazolo[4,3-a]pyridin-2-yl)acetamide (33 mg, 0.04 mmol) (Compound IV-15) in dichloromethane (1 mL) and methanol (0.3 ml). The reaction was stirred for 30 minutes then sodium triacetoxyborohydride (35 mg, 0.16 mmol) was added and the reaction stirred for 2 hours. The reaction was quenched into saturated NaHCO3 (aq). The aqueous layer was extracted into ethyl acetate three times, the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC (Method A2) to yield the title compound as a white solid (9 mg, 48% yield).1H NMR (500 MHz, DMSO-d6) d 8.62 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.34 (dd, J = 2.0, 10.7 Hz, 1H), 7.25 (dd, J = 1.1, 6.4 Hz, 1H), 7.19 (dd, J = 1.9, 8.3 Hz, 1H), 6.55 - 6.49 (m, 2H), 4.94 (p, J = 6.9 Hz, 1H), 4.61 (d, J = 16.6 Hz, 1H), 4.57 (d, J = 16.6 Hz, 1H), 3.97 (t, J = 7.4 Hz, 2H), 3.92 (d, J = 7.6 Hz, 2H), 3.26 (d, J = 8.5 Hz, 2H), 2.46 - 2.43 (m, 2H), 2.25 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H). LCMS (Analytical Method A) Rt = 1.89 min, MS (ESIpos): m/z 459 [M+H]+, Purity = 97%. EXAMPLE 38 Synthesis of 2-{7-methoxy-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- (2,4,6-trimethylphenyl)ethyl]acetamide
(Compound IV-17-1)
Figure imgf000430_0001
2-{7-iodo-3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}-N-[(1S)-1- (2,4,6-trimethylphenyl)ethyl]acetamide (50 mg, 0.1 mmol) (Intermediate 137), methanol (0.25 ml, 6.17 mmol), Pd(OAc)2 (2.3 mg, 0.01 mmol), cesium carbonate (70 mg, 0.21 mmol) and JohnPhos (6.11 mg, 0.02 mmol) were suspended in toluene (1 mL) and the mixture was de-gassed with nitrogen for 20 minutes, before being sealed and stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated in vacuo and purified by preparative HPLC (Method A2) to afford the title compound 24 mg (62% yield).1H NMR (500 MHz, DMSO-d6) d 8.51 (d, J = 6.2 Hz, 1H), 7.78– 7.71 (m, 1H), 6.73 (s, 2H), 6.45– 6.40 (m, 1H), 6.34– 6.29 (m, 1H), 5.14 (p, J = 7.2 Hz, 1H), 4.51– 4.38 (m, 2H), 3.79 (s, 3H), 2.33 (s, 6H), 2.15 (s, 3H), 1.37 (d, J = 7.3 Hz, 3H). LCMS
(Analytical Method F) Rt = 4.23 min, MS (ESIpos): m/z 369 [M+H]+, Purity = 100%. EXAMPLE 37 Synthesis of Compounds IV-18-1 to IV-18-24 Each of Compounds IV-18-1 through IV-18-24 as listed in Table 16 could be prepared according to the methods above, using the intermediates listed in the "Synthesis" column for such compounds. Table 16
Representative Compounds
Figure imgf000431_0001
Figure imgf000432_0001
Figure imgf000433_0001
Figure imgf000434_0001
Figure imgf000435_0001
Figure imgf000436_0001
Figure imgf000437_0001
EXAMPLE 38 Human GPR139 FLIPRTM Assay FLIPRTM technology was used to test compounds on a CHO-K1 cell line (Chinese Hamster (Cricetulus griseus) Ovary cells, initiated from a biopsy of an adult Chinese hamster by T. T. Puck in 1957) stably expressing human GPR139
(PathHunter® CHO-K1 human GPR139 b-Arrestin cell line; DiscoverX, Fremont, CA; cat.93-0954C2), by measuring the intracellular calcium fluxes induced by increasing concentrations of test and reference compounds in the Fluorometric Imaging Plate Reader Tetra (FLIPRTETRA®, Molecular Devices, CA). Cells were cultured at 37 °C, 5% CO2 in Cell Culture Kit-107 (DiscoverX, #92-3107G) for no more than 20 passages. All assays were run with cells previously frozen at a low passage number (< 20), thawed, plated in assay media without selection antibiotics at 20000 cells/ 50 µl/ well in a 384 well plate (Corning 384-Well CellBIND black, clear bottom, polystyrene barcoded plates) and incubated at 37 °C, 5% CO2 overnight. The Calcium 5 dye solution (FLIPRTM Calcium 5 Assay Kit, Molecular Devices, San Jose CA, #R8187) was prepared according to the manufacturer guidelines (in HBSS Buffer, Hanks' Balanced Salt Solution, 20 mM HEPES, hydroxyethyl piperazineethanesulfonic acid; pH 7.4). Cells were equilibrated at room temperature for 30 minutes, and then loaded with 50 µl/well of Calcium 5 dye solution supplemented with 2.5 mM Probenecid for 60 minutes at room temperature in the dark. Cell and compound plates were transferred into the FLIPRTETRA® and 10 µl/well of the test compound solutions (6X) were automatically dispensed into the cell plates. The fluorescence intensity reflecting intracellular calcium changes was recorded before and after compound addition with an excitation and emission wavelengths of 470-495 nm and 515-575 nm, respectively. Fluorescence intensity raw data were fitted to the four-parameter logistic equation:
Figure imgf000438_0001
The efficacy of saturating concentrations of the agonist JNJ63533054 (Sigma Aldrich, St Louis, MO, 20 mM) was set as maximal response (100% Emax) and the bottom defined by the signal achieved with 0.1 % DMSO.
Activity expressed as EC50 of representative compounds against the GPR139 receptor is provided in Table 17 below. With respect to GPR139 activity: "++++" denotes an EC50 of less than 1 nM; "+++" denotes an EC50 of from 1 nM to less than 10 nM; "++" denotes an EC50 of from 10 nM to less than 100 nM; and "+" denotes an EC50 of 100 nM or more. Efficacy of representative compounds with respect to the agonist JNJ63533054: "++++" denotes a %Emax of more than 80%; "+++" denotes a %Emax from 50% to less than 80%; "++" denotes a %Emax from 25% to less than 50%; and "+" denotes a %Emax less than 25%.
Table 17
Human GPR139 EC50 and % Emax FLIPR Assay Results
Figure imgf000438_0002
Figure imgf000439_0001
Figure imgf000440_0001
Figure imgf000441_0001
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
EXAMPLE 39 Rat GPR139 FLIPRTM Assay For the rat GPR139 FLIPRTM assay, a stably expressing CHO-K1 rat GPR139 cell line was generated de novo by transfecting rGPR139 into parental CHO- K1 cells. Compounds were tested by measuring the intracellular calcium fluxes induced by increasing concentrations of test and reference compounds in the
Fluorometric Imaging Plate Reader Tetra (FLIPRTETRA®, Molecular Devices, CA). Cells were cultured at 37 °C, 5% CO2 in Nutrient Mixture F-12 Ham, 5% FBS (fetal bovine serum), 2 mM L-Glutamine, 1 mg/ml G-418 for no more than 20 passages. All assays were run with cells frozen at a low passage number (< 20), thawed, plated in assay media without selection antibiotics at 20000 cells/ 50 µl/ well in a 384 well plate (Corning 384-Well CellBIND black, clear bottom, polystyrene barcoded plates) and incubated at 37 °C, 5% CO2 overnight. The Calcium 5 dye solution (FLIPRTM Calcium 5 Assay Kit, Molecular Devices #R8187) was prepared according to the manufacturer guidelines (in HBSS Buffer, 20 mM HEPES pH 7.4). Cells were equilibrated at room temperature for 30 minutes, and then loaded with 50 µl/well of Calcium 5 dye solution supplemented with 2.5 mM Probenecid for 60 minutes at room temperature in the dark. Cell and compound plates were transferred into the FLIPRTETRA® and 10 µl/well of the test compound solutions (6X) were automatically dispensed into the cell plates. The fluorescence intensity reflecting intracellular calcium changes was recorded before and after compound addition with an excitation and emission wavelengths of 470-495 nm and 515-575 nm respectively. Fluorescence intensity raw data were fitted to the four- parameter logistic equation:
Figure imgf000445_0001
The efficacy of saturating concentrations of the agonist JNJ63533054 (Sigma Aldrich, St Louis, MO, 20 mM) was set as maximal response (100% Emax) and the bottom defined by the signal achieved with 0.1 % DMSO.
Activity expressed as EC50 of representative compounds against the GPR139 receptor is provided in Table 18 below. With respect to GPR139 activity: "++++" denotes an EC50 of less than 1 nM; "+++" denotes an EC50 of from 1 nM to less than 10 nM; "++" denotes an EC50 of from 10 nM to less than 100 nM; and "+" denotes an EC50 of 100 nM or more. Efficacy of representative compounds with respect to the agonist JNJ63533054: "++++" denotes a %Emax of more than 80%; "+++" denotes a %Emax from 50% to less than 80%; "++" denotes a %Emax from 25% to less than 50%; and "+" denotes a %Emax less than 25%.
Table 18
Rat GPR139 EC50 and % Emax FLIPR Assay Results
Figure imgf000445_0002
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
EXAMPLE 40 Human GPR139 PathHunterTM ß-Arrestin Assay PathHunterTM ß-Arrestin assay technology was used to test compounds on a CHO-K1 cell line stably expressing GPR139 (PathHunter® CHO-K1 human GPR139 b-Arrestin cell line; DiscoverX, Fremont, CA; # 93-0954C2). Cells were treated with compounds and a ß-galactosidase fragment, which complements a second ß-galactosidase fragment tagged to GPR139. The chemiluminescence signal achieved by ß-galactosidase fragment complementation was measured on an Envision plate reader (Perkin Elmer, Waltham, MA). The GPR139 profile was evaluated by testing increasing concentrations of the test compounds, comparing the response to the maximum activation achieved with reference agonist JNJ63533054 (Sigma Aldrich, St Louis, MO, 20 mM). EC50 (the concentration of a compound that causes half-maximal response in a functional assay), Emax (the maximum possible effect for an agonist in a concentration-response curve) and Hill slope were calculated from raw luminescence intensity data using a four-parameter logistic equation. Cells were maintained in Cell culture kit 107 (DiscoverX, Fremont, CA) and subcultured at 80-90 % confluency. All assays were run with cells frozen at a low passage number (< 12), thawed and plated in Cell plating reagent 2 (DiscoverX, Fremont, CA) at 10000 cells/ 20 µl/ well in a 384 well plate and incubated at 37 °C, 5% CO2 overnight. Cell plates were equilibrated for 30 min at RT (room temperature) before treatment with compounds (5 µl/well of 5x final concentrations) for 90 min at RT. Plates were then incubated for 3 h at RT with detection solution (DiscoverX, Fremont, CA), and the chemiluminescence signal was detected using an Envision plate reader (Perkin Elmer, Waltham, MA) in luminscence mode (measurement time 0.1 s). For data analysis, concentration-response data of test and reference agonists were fitted to the four-parameter logistic equation:
Figure imgf000452_0001
The efficacy of saturating concentrations of the agonist JNJ63533054 (20 mM) was set as maximal response (100% Emax) and the bottom defined by the signal achieved with 0.1 % DMSO.
Activity expressed as EC50 of representative compounds against the GPR139 receptor is provided in Table 19 below. With respect to GPR139 activity: "++++" denotes an EC50 of less than 1 nM; "+++" denotes an EC50 of from 1 nM to less than 10 nM; "++" denotes an EC50 of from 10 nM to less than 100 nM; and "+" denotes an EC50 of 100 nM or more. Efficacy of representative compounds with respect to the agonist JNJ63533054: "++++" denotes a %Emax of more than 80%; "+++" denotes a %Emax from 50% to less than 80%; "++" denotes a %Emax from 25% to less than 50%; and "+" denotes a %Emax less than 25%. Table 19
Human GPR139 EC50 and % Emax b-arrestin Assay Results
Figure imgf000453_0001
Figure imgf000454_0001
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0001
Figure imgf000458_0001
The various embodiments described above can be combined to provide further embodiments. All of the U S. patents, U S. patent application publications, U S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, including U S. Provisional Patent Application No. 62/758,445, filed November 9, 2018, U S. Provisional Patent Application No. 62/760,839, filed November 13, 2018, U S. Provisional Patent Application No. 62/758,451, filed November 9, 2018, U S.
Provisional Patent Application No. 62/760,841, filed November 13, 2018, U S.
Provisional Patent Application No. 62/760,847, filed November 13, 2018, and U S. Provisional Patent Application No. 62/760,849, filed November 13, 2018, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.
These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible
embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS 1. A compound having the structure of Formula (I):
Figure imgf000460_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R101 is H or lower alkyl;
R102 is H, lower alkyl, or carbocyclyl;
R103 is H or lower alkyl;
or R102 and R103, together with the atom to which they are attached, form a C3-C6 cycloalkyl;
R104, R109, R110, R111, and R112 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;
R106, R107, and R108 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 R104, R106, R107, R108, R109, R110, R111, and R112 are each, independently, optionally substituted by one or more R'; and
each R' is, independently, halo, -OH, lower alkyl, lower haloaklyl, or lower alkoxy.
2. The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R102 is lower alkyl.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R102 is methyl, ethyl, or isopropyl.
4. The compound of any one of claims 1–3, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R102 is methyl.
5. The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R102 is carbocycle.
6. The compound of any one of claims 1 or 5, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R102 is C3-C6 cycloalkyl.
7. The compound of any one of claims 1, 5, or 6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R102 is cyclopropyl.
8. The compound of any one of claims 1–7, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R103 is H.
9. The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R102 and R103, together with the atom to which they are attached, form a C3-C6 cycloalkyl.
10. The compound of any one of claims 1 or 9, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R102 and R103, together with the atom to which they are attached, form cyclopropyl.
11. The compound of any one of claims 1–10, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R109, R111, and R112, are H.
12. The compound of any one of claims 1–11, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R104 is H, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, or C3-C6 cycloalkyl.
13. The compound of any one of claims 1–12, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R104 is methyl.
14. The compound of any one of claims 1–12, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R104 is F or Cl.
15. The compound of any one of claims 1–12, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R104 is lower haloalkoxy.
16. The compound of any one of claims 1–12, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R104 is -OCF3.
17. The compound of any one of claims 1–12, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R104 is cyclopropyl.
18. The compound of any one of claims 1–17, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R110 is H, halo, or lower alkyl.
19. The compound of any one of claims 1–18, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R110 is H.
20. The compound of any one of claims 1–18, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R110 is F or Cl.
21. The compound of any one of claims 1–18, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R110 is methyl.
22. The compound of any one of claims 1–21, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is H, halo, lower alkyl, lower alkoxy, carbocycle, or heterocycle.
23. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is H.
24. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is halo.
25. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is F or Cl.
26. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is lower alkyl.
27. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is methyl.
28. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is lower alkoxy.
29. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is methoxy.
30. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is carbocycle.
31. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is C3- C6 cycloalkyl.
32. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is cyclopropyl.
33. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is heterocycle.
34. The compound of any one of claims 1–22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R106 is
Figure imgf000464_0001
.
35. The compound of any one of claims 1–34, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is H, halo, lower alkyl, lower alkoxy, carbocycle, or heterocycle.
36. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is H.
37. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is halo.
38. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is F or Cl.
39. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is lower alkyl.
40. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is methyl.
41. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is lower alkoxy.
42. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is methoxy.
43. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is carbocycle.
44. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is C3- C6 cycloalkyl.
45. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is cyclopropyl.
46. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is heterocycle.
47. The compound of any one of claims 1–35, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R107 is morpholino.
48. The compound of any one of claims 1–47, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is H, halo, lower alkyl, lower haloalkyl, lower alkoxy, -NR2, carbocycle, heterocycle, or
-NR-heterocyclyl.
49. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is H.
50. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is halo.
51. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is I.
52. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is lower alkyl.
53. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is methyl.
54. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is lower haloaklyl.
55. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is–CF3.
56. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is lower alkoxy.
57. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is methoxy.
58. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is -NR2.
59. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is -NHCH3 or -NHCH2CHF2.
60. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is carbocycle.
61. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is C3- C6 cycloalkyl.
62. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is cyclopropyl.
63. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is heterocycle.
64. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is morpholino.
65. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is -NR-heterocyclyl.
66. The compound of any one of claims 1–48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R108 is
Figure imgf000468_0001
.
67. The compound of any one of claims 1–66, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R111 is H or lower alkyl.
68. The compound of any one of claims 1–67, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R111 is methyl.
69. The compound of any one of claims 1–68, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R112 is H or halo.
70. The compound of any one of claims 1–69, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R112 is F or Cl.
71. The compound of any one of claims 1–70, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R101 is H.
72. The compound of any one of claims 1–70, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R101 is methyl.
73. The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the compounds has the structure of any one of the compounds listed in Table 1.
74. A compound having the structure of Formula (II):
Figure imgf000469_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R201 is H;
R202 is lower alkyl;
R203 is H; R204, R209, R210, R211, and R212 are each, independently, H, halo, lower alkyl, lower alkoxy, or lower haloalkoxy;
Q206 is N and Q207 is CR207, or Q206 is CR206 and Q207 is N;
R205, R206, R207, and R208 are each, independently, H, halo, -NR2, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, carbocyclyl, heterocyclyl, -O-heterocyclyl, -NR-carbocyclyl, or -NR-heterocyclyl;
wherein R204, R205, R206, R207, R208, R209, R210, R211, and R212 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 Q207 is CR207, then R207 is not phenyl.
75. The compound of claim 74, having the structure of Formula (II-A):
Figure imgf000470_0002
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.
76. The compound of claim 74, having the structure of Formula (II-B):
Figure imgf000470_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.
77. The compound of any one of claims 74–76, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R202 is methyl, ethyl, or isopropyl.
78. The compound of any one of claims 74–77, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R202 is methyl.
79. The compound of any one of claims 74–78, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R203 is H.
80. The compound of any one of claims 74–79, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R209 is H.
81. The compound of any one of claims 74–80, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R211 is H.
82. The compound of any one of claims 74–81, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is halo, lower alkyl, or lower haloalkoxy.
83. The compound of any one of claims 74–81, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is H.
84. The compound of any one of claims 74–82, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is halo.
85. The compound of any one of claims 74–82, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is F or Cl.
86. The compound of any one of claims 74–82, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is lower alkyl.
87. The compound of any one of claims 74–82, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is methyl.
88. The compound of any one of claims 74–82, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is lower haloalkoxy.
89. The compound of any one of claims 74–82, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R204 is–OCF3.
90. The compound of any one of claims 74–89, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R210 is H or halo.
91. The compound of any one of claims 74–90, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R210 is H.
92. The compound of any one of claims 74–90, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R210 is halo.
93. The compound of any one of claims 74–90, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R210 is F or Cl.
94. The compound of any one of claims 74–93, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R212 is H or halo.
95. The compound of any one of claims 74–94, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R212 is H.
96. The compound of any one of claims 74–94, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R212 is halo.
97. The compound of any one of claims 74–94, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R212 is F or Cl.
98. The compound of any one of claims 74–97, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R205 is H, lower alkyl, carbocycle, or heterocycle.
99. The compound of any one of claims 74–98, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R205 is H.
100. The compound of any one of claims 74–98, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R205 is lower alkyl.
101. The compound of any one of claims 74–98, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R205 is methyl.
102. The compound of any one of claims 74–98, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R205 is carbocycle.
103. The compound of any one of claims 74–98, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R205 is C3- C6 cycloalkyl.
104. The compound of any one of claims 74–98, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R205 is cyclopropyl.
105. The compound of any one of claims 74–98, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R205 is heterocycle.
106. The compound of any one of claims 74–98, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R205 is
Figure imgf000474_0001
.
107. The compound of any one of claims 74 or 76–106, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
108. The compound of any one of claims 74 or 76–107, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is H.
109. The compound of any one of claims 74 or 76–107, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is halo.
110. The compound of any one of claims 74 or 76–107, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is Cl.
111. The compound of any one of claims 74 or 76–107, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is lower alkyl.
112. The compound of any one of claims 74 or 76–107, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is methyl.
113. The compound of any one of claims 74 or 76–107, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is lower alkoxy.
114. The compound of any one of claims 74 or 76–107, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is methoxy.
115. The compound of any one of claims 74 or 76–107, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is carbocycle.
116. The compound of any one of claims 74 or 76–107, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is C3-C6 cycloalkyl.
117. The compound of any one of claims 74 or 76–107, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R206 is cyclopropyl.
118. The compound of any one of claims 74–75 or 77–106, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
119. The compound of any one of claims 74–75, 77–106, or 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is H.
120. The compound of any one of claims 74–75, 77–106, or 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is halo.
121. The compound of any one of claims 74–75, 77–106, or 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is Cl.
122. The compound of any one of claims 74–75, 77–106, or 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is lower alkyl.
123. The compound of any one of claims 74–75, 77–106, or 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is methyl.
124. The compound of any one of claims 74–75, 77–106, or 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is lower alkoxy.
125. The compound of any one of claims 74–75, 77–106, or 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is methoxy.
126. The compound of any one of claims 74–75, 77–106, or 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is carbocycle.
127. The compound of any one of claims 74–75, 77–106, or 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is C3-C6 cycloalkyl.
128. The compound of any one of claims 74–75, 77–106, or 118, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R207 is cyclopropyl.
129. The compound of any one of claims 74–128, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is H, lower alkyl, lower haloalkyl, lower alkoxy, -NR2, carbocycle, heterocycle, substituted heterocycle, -O-heterocyclyl, substituted -O-heterocyclyl, or -NR-heterocyclyl.
130. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is H.
131. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is lower alkyl.
132. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is methyl.
133. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is lower haloalkyl.
134. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is -CHF2.
135. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is lower alkoxy.
136. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is methoxy.
137. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is -NR2.
138. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is -NHCH3.
139. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is carbocycle.
140. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is C3- C6 cycloalkyl.
141. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is cyclopropyl.
142. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is heterocycle.
143. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is
Figure imgf000479_0001
144. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is substituted heterocycle.
145. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is
Figure imgf000479_0002
.
146. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is -O-heterocyclyl.
147. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is
Figure imgf000479_0003
.
148. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is substituted -O-heterocyclyl.
149. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is
Figure imgf000480_0001
.
150. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is -NR-heterocyclyl.
151. The compound of any one of claims 74–129, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R208 is
Figure imgf000480_0002
.
152. The compound of any one of claims 74–151, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R201 is H.
153. The compound of claim 74, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the compounds has the structure of any one of the compounds listed in Table 2.
154. A compound having the structure of Formula (III):
Figure imgf000481_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
R301 is H or lower alkyl;
R302 is methyl and R303 is H;
R304, R309, R310, R311, and R312 are each, independently, H, halo, lower alkyl, lower alkoxy, lower haloalkoxy, or carbocyclyl;
R305, R306, and R307 are each, independently, H, halo, lower alkyl, lower alkoxy, or carbocyclyl; and
and wherein R304, R305, R306, R307, R309, R310, R311, and R312 are each, independently, optionally substituted by one or more R'; and
each R' is, independently, halo.
155. The compound of claim 154, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R309 is H.
156. The compound of claim 154, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R309 is halo.
157. The compound of claim 154, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R309 is lower alkyl or lower alkoxy.
158. The compound of claim 154, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R309 is carbocyclyl.
159. The compound of any one of claims 154–158, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R311 is H or lower alkyl.
160. The compound of any one of claims 154–159, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R311 is H.
161. The compound of any one of claims 154–159, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R311 is lower alkyl.
162. The compound of any one of claims 154–159, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R311 is methyl.
163. The compound of any one of claims 154–162, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R304 is halo, lower alkyl, lower haloalkoxy, or carbocycle.
164. The compound of any one of claims 154–163, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R304 is halo.
165. The compound of any one of claims 154–163, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R304 is F or Cl.
166. The compound of any one of claims 154–163, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R304 is lower alkyl.
167. The compound of any one of claims 154–163, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R304 is methyl.
168. The compound of any one of claims 154–163, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R304 is lower haloalkoxy.
169. The compound of any one of claims 154–163, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R304 is–OCF3, or–OCHF2.
170. The compound of any one of claims 154–163, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R304 is carbocycle.
171. The compound of any one of claims 154–163, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R304 is C3- C6 cycloalkyl.
172. The compound of any one of claims 154–163, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R304 is cyclopropyl.
173. The compound of any one of claims 154–172, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R310 is H or halo.
174. The compound of any one of claims 154–173, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R310 is H.
175. The compound of any one of claims 154–173, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R310 is halo.
176. The compound of any one of claims 154–173, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R310 is F or Cl.
177. The compound of any one of claims 154–176, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R312 is H or halo.
178. The compound of any one of claims 154–177, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R312 is H.
179. The compound of any one of claims 154–177, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R312 is halo.
180. The compound of any one of claims 154–177, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R312 is F or Cl.
181. The compound of any one of claims 154–180, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R305 is H, lower alkyl, or carbocycle.
182. The compound of any one of claims 154–181, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R305 is H.
183. The compound of any one of claims 154–181, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R305 is lower alkyl.
184. The compound of any one of claims 154–181, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R305 is methyl.
185. The compound of any one of claims 154–181, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R305 is carbocycle.
186. The compound of any one of claims 154–181, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R305 is C3- C6 cycloalkyl.
187. The compound of any one of claims 154–181, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R305 is cyclopropyl.
188. The compound of any one of claims 154-187, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
189. The compound of any one of claims 154-188, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is H.
190. The compound of any one of claims 154-188, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is halo.
191. The compound of any one of claims 154-188, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is For Cl.
192. The compound of any one of claims 154-188, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is lower alkyl.
193. The compound of any one of claims 154-188, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is methyl.
194. The compound of any one of claims 154-188, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is lower alkoxy.
195. The compound of any one of claims 154-188, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is methoxy.
196. The compound of any one of claims 154-188, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is carbocycle.
197. The compound of any one of claims 154-188, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is C3- C6 cycloalkyl.
198. The compound of any one of claims 154-188, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R306 is cyclopropyl.
199. The compound of any one of claims 154-198, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is H, halo, lower alkyl, lower alkoxy, or carbocycle.
200. The compound of any one of claims 154-199, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is H.
201. The compound of any one of claims 154-199, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is halo.
202. The compound of any one of claims 154-199, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is Cl.
203. The compound of any one of claims 154-199, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is lower alkyl.
204. The compound of any one of claims 154-199, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is methyl.
205. The compound of any one of claims 154-199, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is lower alkoxy.
206. The compound of any one of claims 154-199, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is methoxy.
207. The compound of any one of claims 154-199, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is carbocycle.
208. The compound of any one of claims 154-199, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is C3- C6 cycloalkyl.
209. The compound of any one of claims 154-199, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R307 is cyclopropyl.
210. The compound of any one of claims 154–209, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R301 is H or lower alkyl.
211. The compound of any one of claims 154–210, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R301 is H.
212. The compound of any one of claims 154–210, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R301 is lower alkyl.
213. The compound of any one of claims 154–210, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R301 is methyl.
214. The compound of claim 154, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the compounds has the structure of any one of the compounds listed in Table 3.
215. A compound having the structure of Formula (IV):
Figure imgf000489_0001
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R401 is H or lower alkyl;
R402 is H, lower alkyl, or carbocyclyl;
R403 is H or lower alkyl;
or R402 and R403, together with the atom to which they are attached, form a C3-C6 cycloalkyl;
R404, R409, R410, R411, and R412 are each, independently, H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or aryl;
Q409, Q410, and Q412 are each independently C or N;
R405, R406, R407, and R408 are each, independently, H, halo, -CN, -NR2, -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;
and wherein R404, R405, R406, R407, R408, R409, R410, R411, and R412 are each, independently, optionally substituted by one or more R'; and
each R' is, independently, halo, -OH, lower alkyl, lower haloaklyl, or lower alkoxy.
216. The compound of claim 215, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R402 is lower alkyl.
217. The compound of claim 215 or 216, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R402 is methyl.
218. The compound of claim 215, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R402 is carbocycle.
219. The compound of any one of claims 215 or 218, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R402 is C3-C6 cycloalkyl.
220. The compound of any one of claims 215, 218, or 219, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R402 is cyclopropyl.
221. The compound of any one of claims 215–220, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R403 is H.
222. The compound of claim 215, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R402 and R403, together with the atom to which they are attached, form a C3-C6 cycloalkyl.
223. The compound of any one of claims 215 or 222, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R402 and R403, together with the atom to which they are attached, form cyclopropyl.
224. The compound of any one of claims 215–223, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R409 is H or lower alkyl.
225. The compound of any one of claims 215–224, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R409 is H.
226. The compound of any one of claims 215–224, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R409 is lower alkyl.
227. The compound of any one of claims 215–224, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R409 is methyl.
228. The compound of any one of claims 215–227, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R411 is H, halo, or lower alkyl.
229. The compound of any one of claims 215–228, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R411 is H.
230. The compound of any one of claims 215–228, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R411 is halo.
231. The compound of any one of claims 215–228, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R411 is F.
232. The compound of any one of claims 215–228, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R411 is lower alkyl.
233. The compound of any one of claims 215–228, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R411 is methyl.
234. The compound of any one of claims 215–233, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is H, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or aryl.
235. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is H.
236. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is halo.
237. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is F or Cl.
238. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is lower alkyl.
239. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is methyl.
240. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is lower alkoxy.
241. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is -OCH(CH3)2.
242. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is lower haloalkyl.
243. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is -CF3.
244. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is lower haloalkoxy.
245. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is -OCF3 or -OCHF2.
246. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is aryl.
247. The compound of any one of claims 215–234, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R404 is phenyl.
248. The compound of any one of claims 215–247, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R410 is H, halo, or lower alkyl.
249. The compound of any one of claims 215–248, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R410 is H.
250. The compound of any one of claims 215–248, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R410 is halo.
251. The compound of any one of claims 215–248, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R410 is F or Cl.
252. The compound of any one of claims 215–248, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R410 is lower alkyl.
253. The compound of any one of claims 215–248, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R410 is methyl.
254. The compound of any one of claims 215–253, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R412 is H or halo.
255. The compound of any one of claims 215–254, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R412 is H.
256. The compound of any one of claims 215–254, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R412 is halo.
257. The compound of any one of claims 215–254, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R412 is F.
258. The compound of any one of claims 215–257, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R405 is H, halo, lower alkoxy, heterocycle, or substituted heterocycle.
259. The compound of any one of claims 215–258, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R405 is H.
260. The compound of any one of claims 215–258, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R405 is halo.
261. The compound of any one of claims 215–258, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R405 is F or Br.
262. The compound of any one of claims 215–258, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R405 is lower alkoxy.
263. The compound of any one of claims 215–258, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R405 is methoxy.
264. The compound of any one of claims 215–258, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R405 is heterocycle.
265. The compound of any one of claims 215–258, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R405 is
Figure imgf000495_0001
266. The compound of any one of claims 215–258, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R405 is substituted heterocycle.
267. The compound of any one of claims 215–258, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R405 is
Figure imgf000495_0002
268. The compound of any one of claims 215–267, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is H, halo, -CN, lower alkyl, lower alkoxy, or carbocycle.
269. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is H.
270. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is halo.
271. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is F, Cl, or Br.
272. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is -CN.
273. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is lower alkyl.
274. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is methyl.
275. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is lower alkoxy.
276. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is methoxy.
277. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is carbocycle.
278. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is C3-C6 cycloalkyl.
279. The compound of any one of claims 215–268, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R406 is cyclopropyl.
280. The compound of any one of claims 215–279, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is H, halo, -CN, lower alkyl, lower alkoxy, carbocycle, substituted carbocycle, aryl, heterocycle, substituted heterocycle, -O-heterocyclyl, or -NR-heterocyclyl.
281. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is H.
282. The compound of any one of claims 215–281, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is halo.
283. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is F, Cl, or I.
284. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is -CN.
285. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is lower alkyl.
286. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is methyl.
287. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is lower alkoxy.
288. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is methoxy.
289. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is carbocycle.
290. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is C3-C6 cycloalkyl.
291. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is cyclopropyl or cyclobutyl.
292. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is substituted carbocycle.
293. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is
Figure imgf000499_0001
.
294. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is aryl.
295. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is phenyl.
296. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is heterocycle.
297. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is
Figure imgf000499_0002
.
298. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is substituted heterocycle.
299. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is
Figure imgf000500_0001
300. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is -O-heterocyclyl.
301. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is
Figure imgf000500_0002
.
302. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is -NR-heterocyclyl.
303. The compound of any one of claims 215–280, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R407 is
Figure imgf000500_0003
.
304. The compound of any one of claims 215–303, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is H, halo, -NR2, -NRC(O)OR, lower alkoxy, heterocycle, or substituted heterocycle.
305. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is H.
306. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is halo.
307. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is F or Cl.
308. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is -NR2.
309. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is -NH2, -NHCH3, or
Figure imgf000501_0001
310. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is -NRC(O)OR.
311. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is -NHC(O)OC(CH3)3.
312. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is heterocycle.
313. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is
Figure imgf000502_0001
314. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is substituted heterocycle.
315. The compound of any one of claims 215–304, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R408 is
Figure imgf000502_0002
.
316. The compound of any one of claims 215–315, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R401 is H or lower alkyl.
317. The compound of any one of claims 215–316, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R401 is H.
318. The compound of any one of claims 215–316, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R401 is lower alkyl.
319. The compound of any one of claims 215–316, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R401 is methyl.
320. The compound of claim 215, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the compounds has the structure of any one of the compounds listed in Table 4.
321. A pharmaceutical composition comprising a compound of any one of claims 1-320, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
322. A method for modulating the GPR139 receptor, comprising contacting the GPR139 receptor with an effective amount of a compound of any one of claims 1-320, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a composition comprising the same.
323. A method for treating a GPR139 dependent condition, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-320, 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.
324. A method for treating a neurobehavioral disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-320, 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.
325. The method of claim 324, wherein the neurobehavioral disease or disorder is schizophrenia, ADHD, autism, compulsive-like alcohol drinking, or an affective disorder.
326. A method for treating an eating disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-320, 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.
327. The method of claim 326, wherein the eating disorder is binge-eating disorder.
328. A method of treating an opioid-use disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-320, 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.
PCT/US2019/060788 2018-11-09 2019-11-11 Gpr139 receptor modulators WO2020097609A1 (en)

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
US201862760847P 2018-11-13 2018-11-13
US201862760841P 2018-11-13 2018-11-13
US201862760839P 2018-11-13 2018-11-13
US201862760849P 2018-11-13 2018-11-13
US62/760,841 2018-11-13
US62/760,839 2018-11-13
US62/760,847 2018-11-13
US62/760,849 2018-11-13

Publications (1)

Publication Number Publication Date
WO2020097609A1 true WO2020097609A1 (en) 2020-05-14

Family

ID=68887110

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/060788 WO2020097609A1 (en) 2018-11-09 2019-11-11 Gpr139 receptor modulators

Country Status (1)

Country Link
WO (1) WO2020097609A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021234451A1 (en) * 2020-05-22 2021-11-25 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
WO2021234450A1 (en) * 2020-05-22 2021-11-25 Takeda Pharmaceutical Company Limited 1-((1h-pyrazol-4-yl)methyl)-3-(phenyl)-1,3-dihydro-2h-imidazol-2-one derivatives and related compounds as gpr139 antagonists for the treatment of e.g. depression
WO2023165262A1 (en) * 2022-03-01 2023-09-07 上海科技大学 Thieno-nitrogen-containing heterocyclic compound, pharmaceutical composition comprising same, preparation method therefor, and use thereof
WO2023165263A1 (en) * 2022-03-01 2023-09-07 上海科技大学 Pyrrolotriazinone compound, pharmaceutical composition comprising same, preparation method therefor, and use thereof
WO2023147336A3 (en) * 2022-01-26 2023-09-28 University Of Florida Research Foundation, Incorporated Small molecule modulators of gpr139 complex

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010105750A1 (en) * 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft Triazole derivatives as vasopressin-receptor inhibitors for treating cardiac insufficiency
US20160145218A1 (en) * 2014-11-20 2016-05-26 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazine modulators of gpr139

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010105750A1 (en) * 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft Triazole derivatives as vasopressin-receptor inhibitors for treating cardiac insufficiency
US20160145218A1 (en) * 2014-11-20 2016-05-26 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazine modulators of gpr139
WO2016081736A1 (en) 2014-11-20 2016-05-26 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazines as modulators of gpr139

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DVORAK ET AL., ACSMED CHEM LETT, vol. 6, no. 9, 2015, pages 1015 - 1018
HU ET AL., JBIOMOL SCREEN, vol. 14, 2009, pages 789 - 97
ISBERG ET AL., JCHEM INFMODEL, vol. 54, no. 6, 2014, pages 1552 - 1557
LIT ET AL.: "Salt Selection for Basic Drugs", INT. J. PHARM., vol. 33, 1986, pages 201 - 217
SHI ET AL., ACSMED CHEM LETT, vol. 2, 2011, pages 303 - 6
WANG ET AL., ACTA PHARMACOLOGICA SINICA, vol. 36, 2015, pages 874 - 878

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021234451A1 (en) * 2020-05-22 2021-11-25 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
WO2021234450A1 (en) * 2020-05-22 2021-11-25 Takeda Pharmaceutical Company Limited 1-((1h-pyrazol-4-yl)methyl)-3-(phenyl)-1,3-dihydro-2h-imidazol-2-one derivatives and related compounds as gpr139 antagonists for the treatment of e.g. depression
WO2023147336A3 (en) * 2022-01-26 2023-09-28 University Of Florida Research Foundation, Incorporated Small molecule modulators of gpr139 complex
WO2023165262A1 (en) * 2022-03-01 2023-09-07 上海科技大学 Thieno-nitrogen-containing heterocyclic compound, pharmaceutical composition comprising same, preparation method therefor, and use thereof
WO2023165263A1 (en) * 2022-03-01 2023-09-07 上海科技大学 Pyrrolotriazinone compound, pharmaceutical composition comprising same, preparation method therefor, and use thereof

Similar Documents

Publication Publication Date Title
WO2020097609A1 (en) Gpr139 receptor modulators
US10730880B2 (en) 4,6-substituted-pyrazolo[1,5-a]pyrazines as Janus kinase inhibitors
US9611269B2 (en) Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors
CA2818545C (en) Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as jak inhibitors
IL273079A (en) Heterocyclylamines as pi3k inhibitors
CA2957046C (en) Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
KR20190056435A (en) Substituted 1H-imidazo [4,5-b] pyridin-2 (3H) -one and its use as a GLUN2B receptor modulator
EP3715347A1 (en) Piperidin-4-yl azetidine derivatives as jak1 inhibitors
AU2013337824A1 (en) Tricyclic fused thiophene derivatives as JAK inhibitors
RU2764980C2 (en) Bicyclic amines as new inhibitors of jak kinase
CN112469715A (en) Pyrimidine compound and pharmaceutical composition for preventing or treating cancer comprising the same
EP3679043B1 (en) Vasopressin receptor antagonists and products and methods related thereto
CN113631557B (en) JAK kinase inhibitor, preparation method thereof and application thereof in medicine field
JP7462951B2 (en) JAK inhibitors
WO2018167690A1 (en) Heterocyclic derivatives for the treatment of cystic fibrosis
BR112019019157A2 (en) kappa-opioid receptor antagonists and related products and methods
JP2023522863A (en) Tricyclic compounds as EGFR inhibitors
US11858943B2 (en) Vasopressin receptor antagonists and products and methods related thereto
WO2022002097A1 (en) Pyrazolo[1,5-a]pyridine compound, preparation method therefor and use thereof
WO2021127459A1 (en) Gpr139 receptor modulators
EP3894414B1 (en) 1-(2,6-diazaspiro[3.3]heptan-6-yl)-5,6-dihydro-4h-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine derivatives as vasopressin antagonists for the treatment of neuro-psychological disorders
ES2964630T3 (en) Substituted xanthine derivatives
NZ717505B2 (en) Heterocyclylamines as pi3k inhibitors
NZ751428B2 (en) Heterocyclylamines as pi3k inhibitors

Legal Events

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

Ref document number: 19820917

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19820917

Country of ref document: EP

Kind code of ref document: A1