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WO2022031998A2 - Process for the preparation of intermediates useful in the preparation of compounds that modulate splicing - Google Patents

Process for the preparation of intermediates useful in the preparation of compounds that modulate splicing Download PDF

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Publication number
WO2022031998A2
WO2022031998A2 PCT/US2021/044794 US2021044794W WO2022031998A2 WO 2022031998 A2 WO2022031998 A2 WO 2022031998A2 US 2021044794 W US2021044794 W US 2021044794W WO 2022031998 A2 WO2022031998 A2 WO 2022031998A2
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substituted
unsubstituted
formula
compound
heteroaryl
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WO2022031998A3 (en
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Michael Luzzio
Tiansheng Wang
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Skyhawk Therapeutics Inc
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Skyhawk Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen

Definitions

  • SMSMs are also useful in treating diseases in which modulation of pre-mRNA splicing affects the level of a protein, which in turn can be used to treat the diseases by either increasing, or decreasing the level of the particular protein. SMSMs useful in these types of methods are disclosed by, for example, in PCT publications WO 2019/028440 and WO 2020/163405. [0003] There, exists, therefore, a need to develop new processes and intermediates for the synthesis of these SMSMs.
  • Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
  • X is absent, -O-, -S-, - hydrogen, –CN, substituted or unsubstituted C 1 –C 6 alkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 6 heterocycloalkyl, substituted or unsubstituted C 1 –C 6 haloalkyl, substituted or unsubstituted C 1 –C 6 heteroalkyl, or -C 1 -C 4 alkylene
  • Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
  • X is absent, -O-, -S-, - hydrogen, –CN, substituted or unsubstituted C 1 –C 6 alkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 6 heterocycloalkyl, substituted or unsubstituted C 1 –C 6 haloalkyl, substituted or unsubstituted C 1 –C 6 heteroalkyl, or -C 1 -C 4 alkylene-OR 31
  • the compound of Formula (II) is reacted with the compound of Formula (III) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid.
  • a compound of Formula (II) is reacting with a compound of Formula (IV) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I).
  • a compound of Formula (II) is reacting with a compound of Formula (IVa) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I).
  • a compound of Formula (II) is reacting with a compound of Formula (V) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I).
  • a compound of Formula (II) is reacting with a compound of Formula (VI) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3- methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I).
  • a compound of Formula (II) is reacting with the compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid.
  • a compound of Formula (II) has a structure of Formula (IIa) or Formula (IIb): Formula (IIa) Formula (IIb).
  • a compound of Formula (II) has a structure of Formula (IIa): Formula (IIa).
  • a compound of Formula (II) has a structure of Formula (IIb): Formula (IIb).
  • a compound of Formula (VII) has a structure of Formula (VIIa): Formula (VIIa); and a compound of Formula (VIII) has a structure of Formula (VIIIa): Formula (VIIIa).
  • SMSM small molecule splicing modulator
  • a cell component e.g., DNA, RNA, pre-mRNA, protein, RNP, snRNA, carbohydrates, lipids, co-factors, nutrients and/or metabolites
  • a target polynucleotide e.g., a pre-mRNA
  • an SMSM can bind directly or indirectly to a target polynucleotide, e.g., RNA (e.g., a pre-mRNA) with a mutated, non-mutated, bulged and/or aberrant splice site, resulting in modulation of splicing of the target polynucleotide.
  • a target polynucleotide e.g., RNA (e.g., a pre-mRNA) with a mutated, non-mutated, bulged and/or aberrant splice site
  • an SMSM can bind directly or indirectly to a protein, e.g., a spliceosome protein or a ribonuclear protein, resulting in steric modulation of the protein and modulation of splicing of a target RNA.
  • an SMSM can bind directly or indirectly to a spliceosome component, e.g., a spliceosome protein or snRNA resulting in steric modulation of the spliceosome protein or snRNA and modulation of splicing of target polynucleotide.
  • a spliceosome component e.g., a spliceosome protein or snRNA resulting in steric modulation of the spliceosome protein or snRNA and modulation of splicing of target polynucleotide.
  • a spliceosome component e.g., a spliceosome protein or snRNA resulting in steric modulation of the spliceosome protein or snRNA and modulation of splicing of target polynucleotide.
  • These terms specifically exclude compounds consisting of oligonucleotides.
  • small molecule compounds that may bind to one or
  • Steps in alteration refers to changes in the spatial orientation of chemical moieties with respect to each other.
  • steric mechanisms include, but are not limited to, steric hindrance, steric shielding, steric attraction, chain crossing, steric repulsions, steric inhibition of resonance, and steric inhibition of protonation.
  • Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of hydrogen, unless indicated otherwise.
  • the definitions described herein apply irrespective of whether the terms in question appear alone or in combination.
  • heterocycloalkylaryl haloalkylheteroaryl
  • arylalkylheterocycloalkyl or “alkoxyalkyl”.
  • the last member of the combination is the radical which is binding to the rest of the molecule.
  • the other members of the combination are attached to the binding radical in reversed order in respect of the literal sequence, e.g. the combination arylalkylheterocycloalkyl refers to a heterocycloalkyl-radical which is substituted by an alkyl which is substituted by an aryl.
  • substituent denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule.
  • substituted denotes that a specified group bears one or more substituents. Where any group can carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same.
  • unsubstituted means that the specified group bears no substituents.
  • acetic acid AcOH
  • ethyl acetate EtOAc
  • butyl alcohol n-BuOH
  • 1,2-dichloroethane DCE
  • dichloromethane CH2Cl2, DCM
  • diisopropylethylamine Diiipea
  • dimethylformamide DMF
  • hydrogen chloride HCl
  • NMP N-methyl-2-pyrrolidone
  • MeI methyl Iodide
  • n-propanol n-PrOH
  • p-methoxybenzyl PMB
  • triethylamine Et3N
  • C 1 -C x includes C 1 -C 2 , C 1 -C 3 ... C 1 -C x .
  • a group designated as “C 1 -C 4 ” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t- butyl.
  • alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t- butyl.
  • halo halogen
  • halide are used interchangeably herein and denote fluoro, chloro, bromo, or iodo.
  • alkyl refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • An alkyl comprising up to 10 carbon atoms is referred to as a C 1 -C 10 alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a C 1 –C 6 alkyl.
  • Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly.
  • Alkyl groups include, but are not limited to, C 1 -C 10 alkyl, C 1 -C 9 alkyl, C 1 -C 8 alkyl, C 1 -C 7 alkyl, C 1 –C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl, C 2 -C 8 alkyl, C 3 -C 8 alkyl and C 4 -C 8 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n- pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like.
  • the alkyl is methyl or ethyl.
  • the alkyl is -CH(CH 3 ) 2 or - C(CH 3 ) 3 . Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below.
  • Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group.
  • the alkylene is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • the alkylene is -CH 2 -.
  • the alkylene is -CH 2 CH 2 -.
  • the alkylene is -CH 2 CH 2 CH 2 -.
  • alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined.
  • alkoxy group may be optionally substituted as described below.
  • Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy.
  • alkylamino refers to a radical of the formula -NHR a or -NR a R a where each R a is, independently, an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R a is H or an alkyl.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkenyl group has the formula -C ⁇ C-R a , wherein R a refers to the remaining portions of the alkynyl group. In some embodiments, R a is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Non-limiting examples of an alkynyl group include -C ⁇ CH, -C ⁇ CCH 3 -C ⁇ CCH 2 CH 3 , -CH 2 C ⁇ CH.
  • aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer. Aromatics can be optionally substituted.
  • aromatic includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
  • aryl refers to a radical comprising at least one aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl.
  • an aryl group can be a monoradical or a diradical (i.e., an arylene group).
  • an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2- dihydronaphthalene). In some embodiments, an aryl group comprises a fully reduced cycloalkyl group defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When aryl comprises a cycloalkyl group, the aryl is bonded to the rest of the molecule through an aromatic ring carbon atom.
  • An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems.
  • haloalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms.
  • haloalkyl examples include monofluoro-, difluoro-or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3- trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.
  • perhaloalkyl denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms.
  • haloalkoxy denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by same or different halogen atoms, particularly fluoro atoms.
  • haloalkoxyl include monofluoro-, difluoro-or trifluoro-methoxy, -ethoxy or -propoxy, for example 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy.
  • bicyclic ring system denotes two rings which are fused to each other via a common single or double bond (annelated bicyclic ring system), via a sequence of three or more common atoms (bridged bicyclic ring system) or via a common single atom (spiro bicyclic ring system).
  • Bicyclic ring systems can be saturated, partially unsaturated, unsaturated or aromatic.
  • Bicyclic ring systems can comprise heteroatoms selected from N, O and S.
  • Carbocyclic or “carbocycle” refer to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are saturated or partially unsaturated.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom).
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms.
  • Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl.
  • Polycyclic radicals include, for example, adamantyl, 1,2- dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)- one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.
  • bridged refers to any ring structure with two or more rings that contains a bridge connecting two bridgehead atoms.
  • the bridgehead atoms are defined as atoms that are the part of the skeletal framework of the molecule and which are bonded to three or more other skeletal atoms.
  • the bridgehead atoms are C, N, or P.
  • the bridge is a single atom or a chain of atoms that connects two bridgehead atoms.
  • the bridge is a valence bond that connects two bridgehead atoms.
  • the bridged ring system is cycloalkyl. In some embodiments, the bridged ring system is heterocycloalkyl.
  • fused refers to any ring structure described herein which is fused to an existing ring structure.
  • fused ring is a heterocyclyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with one or more N, S, and O atoms.
  • fused heterocyclyl or heteroaryl ring structures include 6-5 fused heterocycle, 6-6 fused heterocycle, 5-6 fused heterocycle, 5-5 fused heterocycle, 7-5 fused heterocycle, and 5-7 fused heterocycle.
  • haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
  • haloalkoxy refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2- dibromoethoxy, and the like. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a C 1 -C 6 fluoroalkyl.
  • a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2- fluoroethyl, and the like.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, or - N(aryl)-), sulfur (e.g.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C 1 –C 6 heteroalkyl. Representative heteroalkyl groups include, but are not limited to -OCH 2 OMe, -OCH 2 CH 2 OH, -OCH 2 CH 2 OMe, or -OCH 2 CH 2 OCH 2 CH 2 NH 2 .
  • heteroalkylene refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N or S atom.
  • “Heteroalkylene” or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below.
  • Representative heteroalkylene groups include, but are not limited to -OCH 2 CH 2 O-, -OCH 2 CH 2 OCH 2 CH 2 O-, or - OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 O-.
  • heterocycloalkyl refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized.
  • the nitrogen atom may be optionally quaternized.
  • the heterocycloalkyl radical is partially or fully saturated.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, t
  • heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms.
  • heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) that includes at least one heteroatom selected from nitrogen, oxygen and sulfur, wherein each heterocyclic group has from 3 to 12 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds.
  • Non-aromatic heterocyclic groups include rings having 3 to 12 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 12 atoms in its ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo- fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl is monocyclic or bicyclic.
  • monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl.
  • a heteroaryl contains 0-6 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C 1 -C 9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C 1 -C 5 heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • a bicyclic heteroaryl is a C 6 -C 9 heteroaryl.
  • a heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline).
  • a heteroaryl group comprises a fully reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 5,6,7,8-tetrahydroquinoline).
  • heteroaryl comprises a cycloalkyl or heterocycloalkyl group
  • the heteroaryl is bonded to the rest of the molecule through a heteroaromatic ring carbon or hetero atom.
  • a heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems.
  • the term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • optional substituents are independently selected from D, halogen, - CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , - NH(cyclopropyl), -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • tautomer refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond.
  • tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include: .
  • a “small molecular weight compound” can be used interchangeably with “small molecule” or “small organic molecule”. Small molecules refer to compounds other than peptides or oligonucleotides; and typically have molecular weights of less than about 2000 Daltons, e.g., less than about 900 Daltons.
  • Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
  • X is absent, -O-, -S-, - hydrogen, –CN, substituted or unsubstituted C 1 –C 6 alkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 6 heterocycloalkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, or -C 1 -C 4 alkylene-OR 31 ;
  • a compound of Formula (II) is reacted with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), in the presence of a transition metal catalyst such as palladium catalyst.
  • a compound of Formula (II) is reacted with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), in the presence of a solvent such as tetrahydrofuran or dimethylformamide.
  • a compound of Formula (II) is reacted with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), in the presence of a copper salt such as copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid.
  • a coupling reagent is a boronic acid or a boronic acid derivative such as boronic ester (e.g., pinacolyl or MIDA (N-methyliminodiacetate) ester).
  • the boronic acid derivative is potassium trifluoroborate.
  • the boronic acid derivative is sodium trihydroxyborate.
  • a process for preparing a compound of Formula (I) comprising the step of reacting the compound of Formula (II) with the compound of Formula (III) Formula (III).
  • the process comprising the step of reacting the compound of Formula (II) with the compound of Formula (IV) Formula (IV).
  • the process comprising the step of reacting the compound of Formula (II) with the compound of Formula (IVa) Formula (IVa).
  • a process for preparing a compound of Formula (I) comprising the step of reacting a compound of Formula (II) with the compound of Formula (V) Formula (V).
  • the process comprising the step of reacting the compound of Formula (II) with the compound of Formula (VI) Formula (VI).
  • ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
  • X is absent, -O-, -S-, - hydrogen, –CN, substituted or unsubstituted C 1 –C 6 alkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 6 heterocycloalkyl, substituted or unsubstituted C 1 –C 6 haloalkyl, substituted or unsubstituted C 1 –C 6 heteroalkyl, or -C 1 -C 4 alkylene-OR 31
  • a compound of Formula (II) is reacted with a compound of Formula (III) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I).
  • a compound of Formula (II) is reacted with a compound of Formula (IV) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I).
  • a compound of Formula (II) is reacted with a compound of Formula (IVa) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I).
  • a compound of Formula (II) is reacted with a compound of Formula (V) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I).
  • Formula (VI) wherein each variable within Formula (I) and Formula (III) is as described above for Formula (I).
  • a compound of Formula (II) is reacted with a compound of Formula (VI) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I).
  • Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
  • X is absent, -O-, -S-, - hydrogen, –CN, substituted or unsubstituted C 1 –C 6 alkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 6 heterocycloalkyl, substituted or unsubstituted C 1 –C 6 haloalkyl, substituted or unsubstituted C 1 –C 6 heteroalkyl, or -C 1 -C 4 alkylene-OR 31
  • HAL is Cl. In some embodimetns, HAL is F. In some embodimetns, HAL is Br. In some embodimetns, HAL is I. [0077] In one aspect, described herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof: Formula (I) wherein, Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; X is absent, -O-, -S-, - hydrogen, –CN, substituted or unsubstituted C 1 –C 6 alkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 6 heterocycloalkyl, substituted
  • Boc a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3, comprising the step of reacting a compound of Formula (II) Formula (IIa) with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI) Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I).
  • Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
  • X is absent, -O-, -S-, - hydrogen, –CN, substituted or unsubstituted C 1 –C 6 alkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 6 heterocycloalkyl, substituted or unsubstituted C 1 –C 6 haloalkyl, substituted or unsubstituted C 1 –C 6 heteroalkyl, or -C 1 -C 4 alkylene-OR 31
  • Boc a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3, comprising the step of reacting a compound of Formula (II*) Formula (II*) wherein HAL represents a halogen; with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI) Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I).
  • R is a protecting group, e.g. tert-butyloxycarbonyl (Boc).
  • the compound of Formula (II), Formula (II*), or Formula (IIa) is used in a process to produce a compound of Formula (I) comprising a step of stereoselectivity.
  • the step of stereoselectivity comprises asymmetric synthesis.
  • the step of stereoselectivity comprises asymmetric synthesis and chiral resolution.
  • the step of stereoselectivity comprises the use of one or more chiral centers in a compound of Formula (II), Formula (II*), or Formula (IIa).
  • the one or more chiral centers is a chiral auxiliary.
  • a compound of Formula (VII) has a structure of Formula (VIIa): Formula (VIIa); and a compound of Formula (VIII) has a structure of Formula (VIIIa): Formula (VIIIa).
  • a compound of Formula (I) is a compound of Formula (Ia) Formula (Ia).
  • the nitrogen atom bearing R group and the X group are on the same side of a plane. In some embodiments, the nitrogen atom bearing R group and the X group are on the opposite side of a plane.
  • a compound of Formula (I) is a compound of Formula (Ib) Formula (Ib).
  • a compound of Formula (I) is a compound of Formula (Ic) Formula (Ic).
  • a compound of Formula (I) is a compound of Formula (Id) Formula (Id).
  • a compound of Formula (Ie) is a compound of Formula (If) Formula (If).
  • R is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl. In some embodiments, R is hydrogen, -CH 3 , -CH 2 CH 3 , or -CH 2 CH 2 CH3.
  • R is hydrogen. In some embodiments, R is -CH 3 . In some embodiments, R is -CH 2 CH 3 . In some embodiments, R is -CH 2 CH 2 CH 3 . In some embodiments, each R 15 and R 18 is independently hydrogen or substituted or unsubstituted C 1 -C 4 alkyl. In some embodiments, each R 15 and R 18 is independently hydrogen, -CH 3 , or -CH 2 CH 3 . In some embodiments, each R 15 and R 18 is hydrogen. In some embodiments, each R 15 and R 18 is -CH 3 . In some embodiments, R 15 is hydrogen and R 18 is -CH 3 . In some embodiments, R 15 is -CH 3 and R 18 is hydrogen.
  • each R 16 and R 17 is independently hydrogen, F, –or substituted or unsubstituted C 1 -C 4 alkyl. In some embodiments, each R 16 and R 17 is independently hydrogen, F, -CH 3 , or -CH 2 CH 3 . In some embodiments, each R 16 and R 17 is independently hydrogen or F. In some embodiments, R 16 is hydrogen and R 17 is F. In some embodiments, R 16 is F and R 17 is hydrogen. In some embodiments, W is substituted or unsubstituted C 1 -C 3 alkylene. In some embodiments, W is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -. In some embodiments, W is -CH 2 CH 2 -.
  • W is -CH 2 CH 2 CH 2 -.
  • X is -NR X1 -.
  • R X1 is hydrogen, –CN, substituted or unsubstituted C 1 –C 6 alkyl, or substituted or unsubstituted C 3 –C 6 cycloalkyl.
  • R X1 is hydrogen, –CN, -CH 3 , -CH 2 CH 3 , - CH 2 CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , cyclopropyl, or cyclobutyl.
  • R X1 is hydrogen.
  • R X1 is –CN. In some embodiments, R X1 is - CH3. In some embodiments, R X1 is -CH 2 CH 3 . In some embodiments, R X1 is -CH 2 CH 2 CH3. In some embodiments, R X1 is -OCH 3 . In some embodiments, R X1 is -OCH 2 CH 3 . In some embodiments, R X1 is -OCH 2 CH 2 CH3. In some embodiments, R X1 is cyclopropyl. In some embodiments, R X1 is cyclobutyl. In some embodiments, ring Q is substituted or unsubstituted aryl. In some embodiments, ring Q is substituted aryl.
  • ring Q is aryl substituted with -OH and substituted or unsubstituted heteroaryl. In some embodiments, ring Q is 2-hydroxyphenyl substituted with substituted or unsubstituted heteroaryl. In some embodiments, ring Q is 2-hydroxyphenyl substituted with substituted or unsubstituted monocyclic heteroaryl. In some embodiments, ring Q is 2- hydroxyphenyl substituted with substituted or unsubstituted 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl comprises 0-1 O, 0-1 S, and 0-4 N heteroatoms.
  • the 5-membered heteroaryl is optionally substituted by one or more substituents each independently selected from oxo, C 1 -C 3 alkyl, and halogen.
  • ring Q is 2- hydroxyphenyl substituted with substituted or unsubstituted pyrazole or substituted or unsubstituted oxadiazole.
  • ring Q is 2-hydroxyphenyl substituted with pyrazole substituted with -CH 3 .
  • ring Q is 2-hydroxyphenyl substituted with oxadiazole substituted with -CH 3 .
  • ring Q is 2-hydroxyphenyl substituted with substituted or unsubstituted 6-membered heteroaryl.
  • the 6-membered heteroaryl comprises 1-4 N heteroatoms.
  • the 6-membered heteroaryl is optionally substituted by one or more substituents each independently selected from oxo, C 1 -C 3 alkyl, and halogen.
  • the 6-membered heteroaryl is 1-methylpyridin-2(1H)-one.
  • ring Q is substituted or unsubstituted 6/6 fused heteroaryl.
  • the 6/6 fused heteroaryl comprises 1-4 N heteroatoms.
  • the 6/6 fused heteroaryl comprises 1-2 N heteroatoms. In some embodiments, the 6/6 fused heteroaryl is optionally substituted by one or more substituents each independently selected from oxo, C 1 -C 3 alkyl, and halogen. In some embodiments, the 6/6 fused heteroaryl is optionally substituted by one or more substituents each independently selected from oxo and C 1 -C 3 alkyl. In some embodiments, the 6/6 fused heteroaryl is selected from 7-hydroxy-2-methylphthalazin-1-one, 6-hydroxy-3-methylquinazolin-4-one, and 7-hydroxy-2- methylisoquinolin-1-one.
  • the 6/6 fused heteroaryl is 7-hydroxy-N- methylquinoline-2-carboxamide.
  • ring Q is substituted or unsubstituted 6/5 fused heteroaryl.
  • the 6/5 fused heteroaryl comprises 0-1 O, 0-1 S and 0-3 N heteroatoms.
  • the 6/6 fused heteroaryl comprises 0-1 O and 1-2 N heteroatoms.
  • the 6/5 fused heteroaryl is optionally substituted by one or more substituents each independently selected from oxo, C 1 -C 3 alkyl, and halogen.
  • the 6/5 fused heteroaryl is optionally substituted by one or more substituents each independently selected from oxo and C 1 -C 3 alkyl. In some embodiments, the 6/5 fused heteroaryl is selected from 2-methylbenzo[d]oxazol-5-ol and 3-methylbenzo[d]oxazol-2(3H)-one.
  • a compound of Formula (I) is a compound of Formula (Iaa) Formula (Iaa).
  • a compound of Formula (I) is a compound of Formula (Ibb) Formula (Ibb).
  • a compound of Formula (I) is a compound of Formula (Icc) Formula (Icc).
  • a compound of Formula (II) is a compound of Formula (IIa) or Formula (IIb) Formula (IIa) Formula (IIb).
  • a compound of Formula (II) is a compound of Formula (IIc) or Formula (IId): Formula (IIc) Formula (IId).
  • a compound of Formula (II) is a compound of Formula (IIe) or Formula (IIf): Formula (IIe) Formula (IIf).
  • a compound of Formula (II) is a compound of Formula (IIg) or Formula (IIh): Formula (IIg) Formula (IIh).
  • a compound of Formula (II) is a compound of Formula (IIi) or Formula (IIj): Formula (IIi) Formula (IIj).
  • a compound of Formula (II) is a compound of Formula (IIk) or Formula (IIl): Formula (IIk) Formula (IIl).
  • R is hydrogen, substituted or unsubstituted C 1 –C 4 alkyl, or substituted or unsubstituted C 1 -C 4 heteroalkyl. In some embodiments, R is substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted C 1 -C 4 heteroalkyl. In some embodiments, R is substituted or unsubstituted C 1 –C 4 alkyl. In some embodiments, R is substituted or unsubstituted C 1 –C 4 heteroalkyl. In some embodiments, R is C 1 –C 4 heteroalkyl substituted with oxo and -CH 3 .
  • R is tert-butyloxycarbonyl.
  • each R 15 and R 18 is independently hydrogen or substituted or unsubstituted C 1 -C 4 alkyl.
  • each R 15 and R 18 is independently hydrogen, -CH 3 , or -CH 2 CH 3 .
  • each R 15 and R 18 is hydrogen.
  • each R 15 and R 18 is -CH 3 .
  • R 15 is hydrogen and R 18 is -CH 3 .
  • R 15 is -CH 3 and R 18 is hydrogen.
  • each R 16 and R 17 is independently hydrogen, F, –or substituted or unsubstituted C 1 –C 4 alkyl.
  • each R 16 and R 17 is independently hydrogen, F, -CH 3 , or -CH 2 CH 3 . In some embodiments, each R 16 and R 17 is independently hydrogen or F. In some embodiments, R 16 is hydrogen and R 17 is F. In some embodiments, R 16 is F and R 17 is hydrogen. In some embodiments, W is substituted or unsubstituted C 1 -C 3 alkylene. In some embodiments, W is -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -. In some embodiments, W is -CH 2 CH 2 -. In some embodiments, W is -CH 2 CH 2 CH 2 -. In some embodiments, X is -NR X1 -.
  • R X1 is hydrogen, –CN, substituted or unsubstituted C 1 –C 6 alkyl, or substituted or unsubstituted C 3 –C 6 cycloalkyl. In some embodiments, R X1 is hydrogen, –CN, -CH 3 , -CH 2 CH 3 , - CH 2 CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , cyclopropyl, or cyclobutyl. In some embodiments, R X1 is hydrogen. In some embodiments, R X1 is –CN. In some embodiments, R X1 is -CH 3 .
  • R X1 is -CH 2 CH 3 . In some embodiments, R X1 is -CH 2 CH 2 CH 3 . In some embodiments, R X1 is -OCH 3 . In some embodiments, R X1 is -OCH2CH3. In some embodiments, R X1 is -OCH 2 CH 2 CH 3 . In some embodiments, R X1 is cyclopropyl. In some embodiments, R X1 is cyclobutyl. [0101] In some embodiments, a compound of Formula (II) is a compound of Formula (IIaa) Formula (IIaa).
  • a compound of Formula (IV) is a compound of Formula (IVaa) Formula (IVaa).
  • a compound of Formula (IV) is a compound of Formula (IVb) Formula (IVb).
  • a compound of Formula (V) is a compound of Formula (Va) Formula (Va).
  • a process of preparing a compound of Formula (IIaa) comprises the step of reacting a compound of Formula (X): Formula (X) with a base, such as sodium hydride in a solvent, such as dimethylformamide and a methylation agent, such as methyl iodide.
  • the process comprises the step of reacting a compound of Formula (XI): Formula (XI) with a compound of Formula (XII): Formula (XII) in the presence of a base such as N,N-Diisopropylethylamine and a solvent such as 1-butanol.
  • a base such as N,N-Diisopropylethylamine
  • a solvent such as 1-butanol.
  • the process comprises the step of reacting a compound of Formula (XIII): Formula (XIII) in a solvent, such as ethanol in the presence of a palladium catalyst under a hydrogen atmosphere.
  • the process comprises the step of reacting a racemic mixture of a compound of Formula (XIII) with a chiral resolving agent, such as (R)-(-)-mandelic acid in the presence of a solvent, such as methyl ethyl ketone.
  • a chiral resolving agent such as (R)-(-)-mandelic acid
  • a solvent such as methyl ethyl ketone
  • the process comprises further steps of neutralizing a precipitated salt with sodium bicarbonate and extraction with ethyl acetate.
  • the process comprises repeating steps until the desired chiral purity is achieved.
  • the chiral purity of a compound of Formula (XIII) is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100%.
  • the process comprises the step of reacting a compound of Formula (XIV): Formula (XIV) with a nitration agent, such as tert-Butyl nitrite and a sulfiding agent, such as 1,2-dimethyldisulfide.
  • the process comprises the step of reacting a compound of Formula (XV): Formula (XV) with a bromination agent, such as N-Bromosuccinimide and a solvent, such as acetonitrile.
  • a bromination agent such as N-Bromosuccinimide
  • a solvent such as acetonitrile
  • X is absent, hydrogen, –CN, substituted or unsubstituted C 1 –C 6 alkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 6 heterocycloalkyl, substituted or unsubstituted C 1 –C 6 haloalkyl, substituted or un
  • described herein is a compound of Formula (III), Formula (III) wherein ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
  • ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
  • ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
  • ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
  • ring Q is substituted or unsubstituted aryl. In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted heteroaryl. In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted cycloalkyl.
  • ring Q is substituted or unsubstituted heterocycloalkyl.
  • ring Q is a fused ring.
  • ring Q is monocyclic.
  • ring Q is polycyclic.
  • ring Q is bicyclic.
  • ring Q is unsubstituted.
  • ring Q is substituted.
  • ring Q is substituted or unsubstituted cycloalkyl. In some embodiments, ring Q is substituted or unsubstituted C 3 –C 8 cycloalkyl. In some embodiments, ring Q is substituted or unsubstituted C 3 -C 6 cycloalkyl. [0120] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted heterocycloalkyl.
  • ring Q is substituted or unsubstituted C 2 -C 8 heterocycloalkyl. In some embodiments, ring Q is substituted or unsubstituted C 2 -C 5 heterocycloalkyl. [0121] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted phenyl.
  • each R 31 is independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [0125] In some embodiments, ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted aryl.
  • each R 31 is independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 1 –C 4 heteroalkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted heteroaryl.
  • each R 31 is independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 alkyl, -CD 3 , substituted or unsubstituted C 1 –C 4 haloalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • each R Q is independently selected from hydrogen, deuterium, –F, –Cl, -CN, –OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , –CF 3, –OCH 3 , -OCH 2 CH 3 , -CH 2 OCH 3 , - OCH 2 CH 2 CH3, and -OCH(CH3)2.
  • ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • ring Q is substituted or unsubstituted heteroaryl.
  • ring Q is substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl.
  • ring Q is substituted or unsubstituted 6-membered monocyclic heteroaryl.
  • ring Q is 6-membered monocyclic heteroaryl selected from: [0135]
  • each R Q is independently selected from hydrogen, deuterium, –F, –Cl, -CN, –OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , –CF 3 , –OCH 3 , -OCH 2 CH 3 , -CH 2 OCH 3 , - OCH 2 CH 2 CH 3 , and -OCH(CH 3 ) 2.
  • ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • each R Q is independently hydrogen,–F, –Cl, -CN, –OH, -CH 3 ,–CF 3 , or –OCH 3. [0137] In some embodiments, each R Q is independently hydrogen or –F. [0138] In some embodiments, each R Q is hydrogen. [0139] In some embodiments, ring P is substituted or unsubstituted heteroaryl. [0140] In some embodiments, ring P is heteroaryl selected from the group consisting of: .
  • each R B is independently selected from H, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 alkyl, -CD 3 , substituted or unsubstituted C 1 –C 6 fluoroalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 –C 6 alkoxy, deuterium substituted C 1 –C 6 alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 cycloalkyl, substituted or unsubstituted C 2 –C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl, -CD 3 , substituted or unsubstituted C 1 –C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3–7 cycloalkyl, and substituted or unsubstituted C 2 –C 7 heterocycloalkyl.
  • m is 0, 1, 2, or 3.
  • ring P is heteroaryl selected from the group consisting of: [0144]
  • each R B is independently selected from H, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 alkyl, -CD 3 , substituted or unsubstituted C 1 –C 6 fluoroalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 –C 6 alkoxy, deuterium substituted C 1 –C 6 alkoxy, -OCD 3 , substituted or unsubstituted C 3–7 cycloalkyl, substituted or unsubstituted C 2 –C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C 1 –C 6 alkyl, -CD 3 , substituted or unsubstituted C 1 –C 6 fluoroalkyl, substituted or unsubstituted C 1 –C 6 heteroalkyl, substituted or unsubstituted C 3–7 cycloalkyl, and substituted or unsubstituted C 2 –C 7 heterocycloalkyl.
  • each R B is independently H, deuterium, –F, –Cl, –CN, –CH 3 , –CF 3 , – OH, or –OCH 3 .
  • each R B is independently –F or –OCH 3 .
  • R B1 is hydrogen, deuterium, –CH 3 , –CF 3 , or –CD 3 .
  • m is 0 or 1.
  • each R 31 is independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, -CD 3 , substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 1 –C 4 heteroalkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, substituted or unsubstituted C 2 –C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • ring Q is selected from the group consisting of: [0153] In some embodiments, ring Q is selected from the group consisting of: , , [0154] In some embodiments, ring Q is selected from the group consisting of: [0155] In some embodiments, ring Q is selected from the group consisting of: [0156] In some embodiments, R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C 1 –C 6 alkyl, -CD 3 , substituted or unsubstituted C 1 –C 6 fluoroalkyl, substituted or unsubstituted C 1 –C 6 heteroalkyl, substituted or unsubstituted C 3–7 cycloalkyl, and substituted or unsubstituted C 2 –C 7 heterocycloalkyl.
  • each R A1 is H.
  • each R Y1 is H.
  • ring Q is
  • a 2 is CH, CH 2 , C(CH 3 ), N, N(CH 3 ), or C(CH 3 ). In some embodiments, A 2 is CH, C(CH 3 ), N, N(CH 3 ), or C(CH 3 ). In some embodiments, A 2 is CH, C(CH 3 ), N, or C(CH 3 ). In some embodiments, A 2 is CH. In some embodiments, A 2 is C(CH3). In some embodiments, A 2 is N. In some embodiments, A 2 is C(CH 3 ). In some embodiments, A 3 is CH, CH 2 , C(CH 3 ), N, N(CH 3 ), or C(CH 3 ).
  • R is tert- butyloxycarbonyl (BOC).
  • ring Q is optionally substituted phenyl. In some embodiments, ring Q is optionally substituted naphthyl.
  • ring Q is substituted or unsubstituted fused heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 6-6 fused heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 6-5 fused heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 5-6 fused heteroaryl.
  • ring Q is substituted or unsubstituted 7-5 fused heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 5-7 fused heteroaryl. [0162] In some embodiments, ring Q is fully aromatic. In some embodiments, ring Q is partially unsaturated. [0163] In some embodiments, ring Q is 2-OH phenyl substituted by a halogen, such as Cl. [0164] In some embodiments, ring Q is optionally substituted heteroaryl. In some embodiments, ring Q is optionally substituted monocyclic heteroaryl. In some embodiments, ring Q is optionally substituted bicyclic heteroaryl.
  • ring Q is optionally substituted, fused 5-7, 5-6, 6-6, 6-5 or 7-5 heteroaryl. In some embodiments, ring Q is optionally substituted, fused 6-6 heteroaryl. [0165] In some embodiments, ring Q is . In some embodiments, ring Q is .
  • a 1 is CR A1 and R A1 is substituted or unsubstituted C 1 –C 6 alkyl.
  • R A1 is C 1 –C 6 alkyl that is optionally substituted with one or more halogen (such as F).
  • R A1 is optionally substituted C 1 –C 3 alkyl.
  • R A1 is C 1 –C 3 alkyl that is optionally substituted with one or more F.
  • one or more hydrogens in R A1 are replaced by deuterium.
  • R A1 is H.
  • R A1 is methyl.
  • R A1 is methyl, ethyl, CF 3 , CHF 2 , or CH 2 CF 3 . In some embodiments, R A1 is CD 3 or CD 2 CD 3. In some embodiments, R A1 is halogen. In some embodiments, R A1 is F. In some embodiments, A 1 is NR Y1 . In some embodiments, A 1 is NR Y1 and R Y1 is H. In some embodiments, A 1 is NR Y1 and R Y1 is substituted or unsubstituted C 1 –C 6 alkyl. In some embodiments, R Y1 is C 1 –C 6 alkyl that is optionally substituted with one or more halogen (such as F).
  • R Y1 is optionally substituted C 1 –C 3 alkyl. In some embodiments, R Y1 is C 1 –C 3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in R Y1 are replaced by deuterium. In some embodiments, R Y1 is H. In some embodiments, R Y1 is methyl. In some embodiments, R Y1 is methyl, ethyl, CF 3 , CHF 2 , or CH 2 CF 3 . In some embodiments, R Y1 is CD 3 or CD 2 CD 3 . [0168] In some embodiments, A 2 is CH, CH 2, C(CH 3 ), N, or C(CH 3 ).
  • R A1 is C 1 –C 6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, R A1 is optionally substituted C 1 –C 3 alkyl. In some embodiments, R A1 is C 1 –C 3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in R A1 are replaced by deuterium. In some embodiments, R A1 is H. In some embodiments, R A1 is methyl. In some embodiments, R A1 is methyl, ethyl, CF 3 , CHF 2 , or CH 2 CF 3 . In some embodiments, R A1 is CD 3 or CD 2 CD 3.
  • R A1 is halogen. In some embodiments, R A1 is F. In some embodiments, A 2 is NR Y1 . In some embodiments, A 2 is NR Y1 and R Y1 is H. In some embodiments, A 2 is NR Y1 and R Y1 is substituted or unsubstituted C 1 –C 6 alkyl. In some embodiments, R Y1 is C 1 –C 6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, R Y1 is optionally substituted C 1 –C 3 alkyl. In some embodiments, R Y1 is C 1 –C 3 alkyl that is optionally substituted with one or more F.
  • a 3 is N. In some embodiments, A 3 is C(CH 3 ). In some embodiments, A 3 is S. In some embodiments, A 3 is CR A1 . In some embodiments, A 3 is CR A1 and R A1 is H. In some embodiments, A 3 is CR A1 and R A1 is substituted or unsubstituted C 1 –C 6 alkyl. In some embodiments, R A1 is C 1 –C 6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, R A1 is optionally substituted C 1 –C 3 alkyl. In some embodiments, R A1 is C 1 –C 3 alkyl that is optionally substituted with one or more F.
  • R A1 is H. In some embodiments, R A1 is methyl. In some embodiments, R A1 is methyl, ethyl, CF 3 , CHF 2 , or CH 2 CF 3 . In some embodiments, R A1 is CD 3 or CD 2 CD 3 . In some embodiments, R A1 is halogen. In some embodiments, R A1 is F. In some embodiments, A 3 is NR Y1 . In some embodiments, A 3 is NR Y1 and R Y1 is H.
  • a 3 is NR Y1 and R Y1 is substituted or unsubstituted C 1 –C 6 alkyl.
  • R Y1 is C 1 –C 6 alkyl that is optionally substituted with one or more halogen (such as F).
  • R Y1 is optionally substituted C 1 –C 3 alkyl.
  • R Y1 is C 1 –C 3 alkyl that is optionally substituted with one or more F.
  • one or more hydrogens in R Y1 are replaced by deuterium.
  • R Y1 is H.
  • R Y1 is methyl.
  • a 4 is S. In some embodiments, A 4 is CR A1 . In some embodiments, A 4 is CR A1 and R A1 is H. In some embodiments, A 4 is CR A1 and R A1 is substituted or unsubstituted C 1 –C 6 alkyl. In some embodiments, R A1 is C 1 –C 6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, R A1 is optionally substituted C 1 –C 3 alkyl. In some embodiments, R A1 is C 1 –C 3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in R A1 are replaced by deuterium.
  • R A1 is H. In some embodiments, R A1 is methyl. In some embodiments, R A1 is methyl, ethyl, CF 3 , CHF 2 , or CH 2 CF 3 . In some embodiments, R A1 is CD 3 or CD 2 CD 3 . In some embodiments, R A1 is halogen. In some embodiments, R A1 is F. In some embodiments, A 4 is NR Y1 . In some embodiments, A 4 is NR Y1 and R Y1 is H. In some embodiments, A 4 is NR Y1 and R Y1 is substituted or unsubstituted C 1 –C 6 alkyl.
  • R Y1 is C 1 –C 6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, R Y1 is optionally substituted C 1 –C 3 alkyl. In some embodiments, R Y1 is C 1 –C 3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in R Y1 are replaced by deuterium. In some embodiments, R Y1 is H. In some embodiments, R Y1 is methyl. In some embodiments, R Y1 is methyl, ethyl, CF3, CHF 2 , or CH 2 CF 3 .
  • R Y1 is CD 3 or CD 2 CD 3 .
  • W is substituted or unsubstituted C 1 -C 3 alkylene.
  • W is –CH 2 –.
  • W is –CH 2 CH 2 –.
  • W is –CH 2 CH 2 CH 2 –.
  • W is substituted or unsubstituted C 1 -C 2 heteroalkylene.
  • W is –CH 2 OCH 2 –.
  • W is –CH 2 O–, wherein oxygen atom in W is attached to a carbon atom having R 18 group.
  • W is substituted or unsubstituted C 3 –C 8 cycloalkylene or substituted or unsubstituted C 2 -C 3 alkenylene.
  • W is substituted or unsubstituted C 3 –C 8 cycloalkylene.
  • W is substituted or unsubstituted cyclopropylene.
  • W is substituted or unsubstituted C 2 -C 3 alkenylene.
  • R is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 –C 5 cycloalkyl, or substituted or unsubstituted C 2 –C 4 heterocycloalkyl.
  • R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , cyclopropyl, or oxetanyl.
  • R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH2OH, - CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , cyclopropyl, or oxetanyl.
  • R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, cyclopropyl, or oxetanyl.
  • R is hydrogen, -CH 3 , -CH 2 OH, -CH 2 CN, -CHF 2 , -CF 3 , or cyclopropyl.
  • R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , cyclopropyl, or oxetanyl. In some embodiments, R is -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , or -CF 3 . In some embodiments, R is hydrogen.
  • R 15 and R 18 are selected from hydrogen, deuterium, F, –OR 31 , substituted or unsubstituted C 1 –C 3 alkyl, substituted or unsubstituted C 1 –C 3 fluoroalkyl, and substituted or unsubstituted C 1 –C 3 heteroalkyl.
  • R 15 and R 18 are selected from hydrogen, deuterium, F, -CH 3 , -CH 2 CH 3 , - CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -OH, -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 .
  • R 15 and R 18 are selected from hydrogen, deuterium, F, -CH 3 , -CH 2 OH, -OCH 2 CN, -OH, -OCH 3 , -OCH 2 CN, - OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 . In some embodiments, R 15 and R 18 are selected from hydrogen, deuterium, F, -CH 3 , -OCH 3 , -OCF 3 , -CH 2 F, -CHF 2 , and -CF 3 . In some embodiments, R 15 and R 18 are selected from hydrogen, deuterium, F, -CH 3 , and -OCH 3 .
  • R 15 is F and R 18 is hydrogen. In some embodiments, R 15 is hydrogen and R 18 is F. In some embodiments, R 15 is hydrogen and R 18 is CH 3 . In some embodiments, R 15 is CH 3 and R 18 is hydrogen. In some embodiments, R 15 and R 18 are the same. In some embodiments, R 15 and R 18 are different. [0174] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, at least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 is F.
  • one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 is F. In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 are F. In some embodiments, at least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 is F. In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 is F.
  • R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are F.
  • R 11 is H, D, or F.
  • R 11 is D.
  • R 11 is H.
  • R 11 is F.
  • R 12 is H, D, or F.
  • R 12 is D. In some embodiments, R 12 is H. In some embodiments, R 12 is F. [0177] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 13 is H, D, or F. In some embodiments, R 13 is D. In some embodiments, R 13 is H. In some embodiments, R 13 is F. [0178] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 14 is H, D, or F. In some embodiments, R 14 is D.
  • R 14 is H. In some embodiments, R 14 is F. [0179] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 15 is H, D, F, CH 2 F, CHF 2 , CF 3 , or CH 3 . In some embodiments, R 15 is H or D. In some embodiments, R 15 is F, CH 2 F, CHF 2 , CF 3 , or CH 3 . In some embodiments, R 15 is F, CF 3 , CHF 2 , or CH 2 F. In some embodiments, R 15 is F.
  • R 16 is H, D, or F. In some embodiments, R 16 is D. In some embodiments, R 16 is H. some embodiments, R 16 is F. [0181] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 17 is H, D, or F. In some embodiments, R 17 is D. In some embodiments, R 17 is H. In some embodiments, R 17 is F.
  • R 18 is H, D, F, CH 2 F, CHF 2 , CF 3 , or CH 3 . In some embodiments, R 18 is H or D. In some embodiments, R 18 is F, CH 2 F, CHF 2 , CF 3 , or CH 3 . In some embodiments, R 18 is F, CF 3 , CHF 2 , or CH 2 F. In some embodiments, R 18 is F.
  • R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 comprises a fluorine, e.g., F or C 1 -C 4 fluoroalkyl such as CH 2 F, CF 3 , CHF 2 , and CH 3 CH 2 F.
  • at least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 is F or C 1 –C 4 fluoroalkyl.
  • one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 comprises a fluorine. In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 comprise a fluorine. In some embodiments, at least one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 comprises a fluorine. In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 comprises a fluorine.
  • At least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 comprise a fluorine.
  • at least one of W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 comprises a fluorine, e.g., F or C 1 -C 4 fluoroalkyl such as CH 2 F, CF 3 , CHF 2 , and CH 3 CH 2 F.
  • one of W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 comprises a fluorine. In some embodiments, W comprises a fluorine.
  • R 11 , R 12 , R 19 , R 20 and R 16 are hydrogen.
  • R 19 is hydrogen.
  • R 19 is H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, - OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, - CH 2 CHF 2 , and -CH 2 CF 3 .
  • R 19 is H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, - CH 2 F, -CHF 2 , and -CF 3 . In some embodiments, R 19 is F or -OCH 3 .
  • R 20 is hydrogen.
  • R 20 is H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, - OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, - CH 2 CHF 2 , and -CH 2 CF 3 .
  • R 20 is H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, - CH 2 F, -CHF 2 , and -CF 3 . In some embodiments, R 20 is F or -OCH 3 .
  • R 20 is H, D, or F. In some embodiments, R 20 is D. In some embodiments, R 20 is H. In some embodiments, R 20 is F.
  • R 16 and R 19 are H. In some embodiments, R 16 and R 19 are D. In some embodiments, R 16 and R 19 are F. [0190] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 19 and R 20 are H. In some embodiments, R 19 and R 20 are D. In some embodiments, R 19 and R 20 are F.
  • R 17 and R 20 are H. In some embodiments, R 17 and R 20 are D. In some embodiments, R 17 and R 20 are F. [0192] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R 11 , R 12 , R 19 , R 20 and R 16 are hydrogen.
  • R 19 is hydrogen.
  • R 19 is H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, - OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH2F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, - CH 2 CHF 2 , and -CH 2 CF 3 .
  • R 19 is H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, - CH 2 F, -CHF 2 , and -CF 3 . In some embodiments, R 19 is F or -OCH 3 .
  • R 20 is hydrogen.
  • R 20 is H, F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OH, -OCH 2 CN, - OCF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, - CH 2 CHF 2 , and -CH 2 CF 3 .
  • R 20 is H, F, -OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, - CH 2 F, -CHF 2 , and -CF 3 . In some embodiments, R 20 is F or -OCH 3 .
  • at least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 is F.
  • one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 is F. In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 are F. In some embodiments, at least one of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 is F. In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 is F.
  • R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 are F.
  • at least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 comprises a fluorine, e.g., F or C 1 –C 4 fluoroalkyl such as CH2F, CF3, CHF2, and CH3CH2F.
  • At least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 is F or C 1 -C 4 fluoroalkyl. In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 comprises a fluorine. In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 comprise a fluorine.
  • At least one of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 comprises a fluorine. In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 comprises a fluorine. In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 comprise a fluorine.
  • At least one of W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 comprises a fluorine, e.g., F or C 1 –C 4 fluoroalkyl such as CH2F, CF3, CHF2, and CH3CH2F.
  • one of W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 comprises a fluorine. In some embodiments, W comprises a fluorine.
  • X is absent.
  • X is -O-.
  • X is -S-.
  • X is -NR X1 -. In some embodiments, X is N-C 1 -C 6 alkyl. In some embodiments, X is N-methyl. In some embodiments, X is N-C 1- C 6 cycloalkyl. In some embodiments, X is N-cyclopropyl. [0206] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), X is -CR X2 R X3 -.
  • Z is CR 5 .
  • Z is CH.
  • each R 31 is independently hydrogen, deuterium, substituted or unsubstituted C 1 –C 4 alkyl, -CD 3 , or substituted or unsubstituted C 1 –C 4 haloalkyl.
  • each R 31 is independently hydrogen, deuterium, or C 1 -C 4 alkyl.
  • each R 31 is independently hydrogen, deuterium, or methyl.
  • R 31 is H.
  • R 31 is methyl.
  • R1 is H. In some embodiments, R1 is halogen. In some embodiments, R1 is OH. In some embodiments, R1 is –OR 31 . In some embodiments, R1 is CN. In some embodiments, R1 is substituted or unsubstituted alkyl. In some embodiments, R1 is substituted or unsubstituted haloalkyl. In some embodiments, R1 is substituted or unsubstituted heteroalkyl.
  • R1 is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic cycloalkyl, or substituted or unsubstituted monocyclic heteroaryl.
  • R1 is substituted or unsubstituted polycyclic aryl, substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic cycloalkyl, or substituted or unsubstituted polycyclic heteroaryl.
  • R1 is a fused ring.
  • R1 is a bridged ring.
  • R1 is a spiro ring.
  • R2 is H.
  • R2 is halogen.
  • R2 is OH.
  • R2 is –OR 31 .
  • R2 is CN.
  • R2 is substituted or unsubstituted alkyl.
  • R2 is substituted or unsubstituted haloalkyl.
  • R2 is substituted or unsubstituted heteroalkyl.
  • R2 is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic cycloalkyl, or substituted or unsubstituted monocyclic heteroaryl.
  • R2 is substituted or unsubstituted polycyclic aryl, substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic cycloalkyl, or substituted or unsubstituted polycyclic heteroaryl.
  • R2 is a fused ring.
  • R2 is a bridged ring.
  • R2 is a spiro ring.
  • a compound described herein possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • isomers as well as the appropriate mixtures thereof.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • Compounds can be prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc.
  • Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.
  • the starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.
  • the starting materials can be available from commercial sources or can be readily prepared. By way of example only, provided are schemes for preparing the Examples described herein.
  • Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • ( ⁇ ) (1S,2S,3R,5R) or racemic (1S,2S,3R,5R) indicates that the relative product stereochemistry shown is based on known stereochemistry of similar compounds and or reactions and the product is a racemic mixture of enantiomers of both (1S,2S,3R,5R) and (1R,2R,3S,5S) stereoisomers.
  • a compound in which the absolute stereochemistry of separated enantiomers is undetermined is represented as being either of the single enantiomers, for example (1S,2S,3R,5R) or (1R,2R,3S,5S) or drawn as being either possible single enantiomer.
  • Example 1 Preparation of 7-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)-6-hydroxy-2-methyl-4H-chromen-4-one and 7-(6- (((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-6- hydroxy-2-methyl-4H-chromen-4-one (Compound 5A and 5B).
  • Step 1 Preparation of racemic tert-butyl (1S,2R,3R,5R)-2-fluoro-3-((3-(methylthio)- 1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate, and tert-butyl (1R,2S,3S,5S)- 2-fluoro-3-((3-(methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • the resulting solution was placed in a preheated oil bath stirred at 120°C for 2 hours under nitrogen.
  • the reaction mixture was removed from heat and cooled to room temperature and diluted with water (700 mL) and then extracted with ethyl acetate (3 x 250 mL). The organic layers were combined, washed with brine (250 mL), and dried over anhydrous Na 2 SO 4 . The mixture was filtered and then concentrated under reduced pressure.
  • Step 2 Preparation of racemic mixture of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-(methyl(3- (methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate, tert-butyl (1R,2S,3S,5S)-2-fluoro-3-(methyl(3-(methylthio)-1,2,4-triazin-6-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate.
  • the resultant mixture was cooled to 0°C followed by portion wise addition of sodium hydride (4.54 g, 113.51 mmol) with the internal temperature maintained at 0°C under nitrogen. The cooling bath was removed, and the mixture was stirred for additional 0.5 h and allowed to come to room temperature under nitrogen. Methyl iodide (7.20 mL, 115.66 mmol) was added dropwise at room temperature with stirring. The resulting mixture was stirred for additional 1 h at room temperature. The reaction mixture was then cooled to 0°C and quenched with water (1 L). The resulting mixture was extracted with ethyl acetate (3 x 250 mL).
  • Step 3 Chiral Separation of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-(methyl(3-(methylthio)- 1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,2S,3S,5S)- 2-fluoro-3-(methyl(3-(methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate.
  • Step 4 Preparation of 1-(3-bromo-4-methoxyphenyl)-N-(2,2- dimethoxyethyl)methanimine.
  • Step 5 Preparation of 7-bromo-6-methoxyisoquinoline.
  • Step 6 Preparation of 6-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoquinoline.
  • the resulting mixture was placed in a preheated oil bath and was stirred for 4 hours at 100°C then removed from heat, allowed to cool.
  • the resulting mixture was diluted with ethyl acetate (200 mL), filtered through a celite pad and concentrated under reduced pressure.
  • Step 7 Preparation of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-((3-(6-methoxyisoquinolin-7- yl)-1,2,4-triazin-6-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,2S,3S,5S)-2-fluoro-3-((3-(6-methoxyisoquinolin-7-yl)-1,2,4-triazin-6-yl)(methyl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 8 Preparation of 7-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)isoquinolin-6-ol and 7-(6-(((1R,2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)isoquinolin-6-ol (Compound 5A and 5B).
  • Example 2 Synthesis of (1R,2S,3S,5S)-tert-Butyl 3-amino-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 1 tert-Butyl 3-((triethylsilyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2-2).
  • Step 2 tert-Butyl 2-fluoro-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (Rac-2-3).
  • reaction mixture was quenched by adding of 1N sodium hydroxide solution (16.9 L), diluted with toluene (13.0 L) and stirred vigorously for 30 minutes.
  • the reaction mass was filtered through a celite pad and washed with toluene (6.5 L). Phases were separated and the aqueous layer was extracted with toluene (2 x 3.25 L). The combined organic extracts were washed with brine (6.5 L), dried over sodium sulphate, filtered and concentrated in vacuum to obtain Rac-2-4 (1.7 Kg, 95%) as an off white solid.
  • Example 3 Preparation of (1R,2S,3S,5S)-tert-Butyl 2-fluoro-3-(methyl(3-(methylthio)- 1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate Formula (IIaa).
  • Step 1 6-Bromo-1,2,4-triazin-3-amine (3-2): NBS (556 g, 3.122 mol, 1.2 eq) was added portion wise to a solution of 3-1 (250 g, 2.601 mol, 1.0 eq) in MeCN (1.8 L) and water (3.7 L) at 0 °C.
  • Step 2 6-Bromo-3-(methylthio)-1,2,4-triazine (3-3): tert-Butyl nitrite (442 g, 4.286 mol, 5.0 eq) was added drop wise to a solution of 3-2 (150 g, 0.857 mol) and 1,2-dimethyldisulfide (121 g, 1.286 mol, 1.5 eq) in MeCN (2.3 L) at 0 °C, then allowed to warm to RT and stirred for 4 h. After completion of the reaction (by TLC), the reaction mixture was cooled to 0 °C.
  • Step 3 (1R,2S,3S,5S)-tert-Butyl 2-fluoro-3-((3-(methylthio)-1,2,4-triazin-6-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (3-5): To a 1000 mL 3-necked round-bottom flask were added 3-3 (24.0 g, 0.116 mol, 1.00 eq), 3-4 (43.0 g, 0.176 mol, 1.51 eq), DIEA (60.0 mL, 0.344 mol, 2.96 eq) and n-BuOH (360 mL). The resulting mixture was stirred for 2 h at 120 °C.
  • the reaction mixture was diluted with water (700 mL) and extracted with EtOAc (3 x 250 mL). The combined organic extracts were washed with brine (250 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with pet ether / EtOAc (4:1) to afford 3-5 (24 g, 55.77%) as a yellow solid.
  • Step 4 (1R,2S,3S,5S)-tert-Butyl 2-fluoro-3-(methyl(3-(methylthio)-1,2,4-triazin-6- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (3-6): To a 1000 mL 3-necked round-bottom flask, 3-5 (21.00 g, 0.056 mol, 1.0 eq) and DMF (250 mL) were added. To the above mixture was added NaH (4.54 g, 0.113 mol, 2.0 eq, 60%) in portions at 0 °C. The resulting mixture was stirred for an additional 0.5 h at room temperature.
  • Example 4 Synthesis of 6-(6-[[(1R,2R,3S,5S)-2-Fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino]-1,2,4-triazin-3-yl)-7-hydroxy-2-methylphthalazin-1-one.
  • Step 1 4-Bromo-3-methoxy-N-methylbenzohydrazide.
  • Step 2 4-Bromo-3-methoxy-N-methyl-N'-methylidenebenzohydrazide.
  • 4-bromo-3-methoxy-N-methylbenzohydrazide 52.0 g, 200.69 mmol, 1.00 equiv
  • paraformaldehyde 7.23 g, 240.83 mmol, 1.20 equiv
  • Toluene 1.0 L
  • the resulting solution was stirred for 16 h at 120 degrees C in an oil bath.
  • the reaction mixture was cooled to room temperature and concentrated.
  • Step 3 6-Bromo-7-methoxy-2-methylphthalazin-1-one.
  • Step 5 tert-Butyl (1R,2S,3S,5S)-2-fluoro-3-[[3-(7-methoxy-2-methyl-1-oxophthalazin-6- yl)-1,2,4-triazin-6-yl](methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 6 tert-Butyl (1R,2S,3S,5S)-2-fluoro-3-((3-(7-hydroxy-2-methyl-1-oxo-1,2- dihydrophthalazin-6-yl)-1,2,4-triazin-6-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate.
  • the resulting solution was stirred for 2 h at 100°C.
  • the reaction was then quenched by the addition of 400 mL of NH4Cl aq.
  • the pH value of the solution was adjusted to 6 with 1N HCl.
  • the resulting solution was extracted with 20% MeCN/EtOAc (6 x 500 mL), dried over anhydrous sodium sulfate and concentrated.
  • Step 7 6-(6-[[(1R,2R,3S,5S)-2-Fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino]- 1,2,4-triazin-3-yl)-7-hydroxy-2-methylphthalazin-1-one.
  • the reaction was then quenched by the addition of saturated aqueous of NaHCO 3 (200 mL).
  • the resulting solution was extracted with 20% MeCN/EtOAc (5 x 200 mL), dried over anhydrous sodium sulfate and concentrated.
  • the eluant was concentrated under vacuum. The residue was was dissolved in 2N HCl (200 mL), and extracted with 20% MeCN/EtOAc (5*200 mL).
  • the aqueous layer was basified to pH ⁇ 8 with saturated aqueous of NaHCO 3 .
  • the resulting mixture was extracted with 20% MeCN/EtOAc (5*200 mL).
  • the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the precipitated solids were collected by filtration and washed with EtOAc. The solid was dried in an oven under reduced pressure.
  • Example 5 Synthesis of 7-(6- ⁇ [(2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino ⁇ -1,2,4-triazin-3-yl)-6-hydroxy-3-methylquinazolin-4-one.
  • Step 1 Methyl 4-bromo-5-methoxy-2-nitrobenzoate.
  • methyl 4-bromo-5-fluoro-2- nitrobenzoate (200.00 g, 719 mmol, 1.00 equiv)
  • MeOH (2 L) MeONa (46.62 g, 863 mmol, 1.20 equiv).
  • the resulting solution was stirred for 3 hr at room temperature.
  • the resulting mixture was concentrated.
  • the resulting mixture was dissolved in 2 L of EA, washed with 2x1 L of H20. The organic layers were concentrated.
  • Step 6 6-Methoxy-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin- 4-one.
  • Step 7 tert-Butyl (2S,3S,5S)-2-fluoro-3-[[3-(6-methoxy-3-methyl-4-oxoquinazolin-7-yl)- 1,2,4-triazin-6-yl] (methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 8 tert-Butyl (2S,3S,5S)-2-fluoro-3- ⁇ [3-(6-hydroxy-3-methyl-4-oxoquinazolin-7-yl)- 1,2,4-triazin-6-yl](methyl)amino ⁇ -8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 9 7-(6- ⁇ [(2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino ⁇ -1,2,4- triazin-3-yl)-6-hydroxy-3-methylquinazolin-4-one.
  • Example 6 Synthesis of 6-(6- ⁇ [(2R,3S,5S)-2-Fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino ⁇ -1,2,4-triazin-3-yl)-7-hydroxy-2-methylisoquinolin-1-one.
  • Step 1a (tert-Butoxycarbonyl)amino 2,2-dimethylpropanoate.
  • Step 2a [(2,2-Dimethylpropanoyl)oxy]azanium triflate.
  • Step 1 4-Bromo-3-methoxybenzoyl chloride.
  • 4-bromo-3-methoxybenzoic acid (120.00 g, 519.379 mmol, 1.00 equiv)
  • DCM (1.20 L
  • DMF (12 mL).
  • Step 2 (4-Bromo-3-methoxyphenyl)formamido 2,2-dimethylpropanoate.
  • Step 5 7-Methoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin- 1(2H)-one.
  • Step 6 tert-Butyl (2S,3S,5S)-2-fluoro-3-[[3-(7-methoxy-2-methyl-1-oxoisoquinolin-6-yl)- 1,2,4-triazin-6-yl](methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 7 tert-Butyl (2S,3S,5S)-2-fluoro-3- ⁇ [3-(7-hydroxy-2-methyl-1-oxoisoquinolin-6-yl)- 1,2,4-triazin-6-yl](methyl)amino ⁇ -8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 9 6-(6- ⁇ [(2R,3S,5S)-2-Fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino ⁇ -1,2,4- triazin-3-yl)-7-hydroxy-2-methylisoquinolin-1-one.
  • Example 7 Synthesis of 2-(6- ⁇ [(2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino ⁇ -1,2,4-triazin-3-yl)-5-(4-methyl-1H-pyrazol-1-yl)phenol and 2-(6- ⁇ [(1S,2S,3R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino ⁇ -1,2,4-triazin-3-yl)-5-(4- methyl-1H-pyrazol-1-yl)phenol (Compounds 10A & 10B).
  • Step 1 Synthesis of 1-bromo-4-iodo-2-(methoxymethoxy)benzene.
  • 2-bromo-5-iodophenol (25.00 g, 83.639 mmol, 1.00 equiv)
  • tetrahydrofuran (300.00 mL).
  • NaH 4.01 g, 167.277 mmol, 2.00 equiv
  • Step 3 Synthesis of 1-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]-4-methylpyrazole.
  • 1-[4-bromo-3- (methoxymethoxy)phenyl]-4-methylpyrazole 2.4 g, 8.077 mmol, 1.00 equiv
  • THF 70.00 mL
  • Step 4 Synthesis of tert-butyl (1S,2R,3R)-2-fluoro-3-([3-[2-(methoxymethoxy)-4-(4- methylpyrazol-1-yl)phenyl]-1,2,4-triazin-6-yl](methyl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate and tert-butyl (2S,3S,5S)-2-fluoro-3-([3-[2-(methoxymethoxy)-4-(4-methylpyrazol- 1-yl)phenyl]-1,2,4-triazin-6-yl](methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (INT 4A & INT 4B).
  • Step 5 Synthesis of 2-(6-[[(1S,2S,3R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino]-1,2,4-triazin-3-yl)-5-(4-methylpyrazol-1-yl)phenol and 2-(6-[[(2R,3S,5S)-2- fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino]-1,2,4-triazin-3-yl)-5-(4-methylpyrazol-1- yl)phenol (Compounds 10A & 10B).
  • Example 8 Synthesis of 2-(6- ⁇ [(1S,2S,3R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino ⁇ -1,2,4-triazin-3-yl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenol and 2-(6- ⁇ [(2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino ⁇ -1,2,4-triazin-3-yl)-5-(5- methyl-1,2,4-oxadiazol-3-yl)phenol (Compounds 11A & 11B).
  • Step 1 Synthesis of 4-bromo-N-hydroxy-3-(methoxymethoxy)benzenecarboximidamide.
  • 4-bromo-3- (methoxymethoxy)benzonitrile (4.00 g, 16.524 mmol, 1.00 equiv)
  • NH 2 OH.HCl (2.30 g, 33.048 mmol, 2 equiv)
  • Et 3 N (3.34 g, 33.048 mmol, 2.00 equiv
  • EtOH 50.00 mL
  • the resulting solution was stirred for 2 hr at 80 degrees C.
  • the reaction solvent was removed and diluted with 100 mL of water.
  • Step 2 Synthesis of 3-[4-bromo-3-(methoxymethoxy)phenyl]-5-methyl-1,2,4-oxadiazole.
  • Step 3 Synthesis of 3-[3-(methoxymethoxy)-4-(tributylstannyl)phenyl]-5-methyl-1,2,4- oxadiazole.
  • reaction solvent was removed under vacuum to leave the residue.
  • the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (10%) as the eluent. This resulted in 2 g (46.99%) of 3-[3-(methoxymethoxy)-4-(tributylstannyl)phenyl]-5-methyl-1,2,4-oxadiazole as light brown oil.
  • Step 4 Synthesis of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-([3-[2-(methoxymethoxy)-4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,4-triazin-6-yl](methyl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,2S,3S,5S)-2-fluoro-3-([3-[2- (methoxymethoxy)-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,4-triazin-6-yl](methyl)amino)- 8-azabicyclo[3.2.1]octane-8-carboxylate (INT 11A & INT 11B).
  • Step 5 Synthesis of 2-(6-[[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino]- 1,2,4- triazin-3-yl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenol and 2-(6- [[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino]-1,2,4-triazin-3-yl)-5-(5- methyl-1,2,4-oxadiazol-3-yl)phenol (Compound 11A & Compound 11B).

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Abstract

Described herein are processes for preparing compounds useful in the preparation of small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, and compounds used in such processes.

Description

PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL IN THE PREPARATION OF COMPOUNDS THAT MODULATE SPLICING CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 63/061,744 filed on August 5, 2020, and U.S. Provisional Application No. 63/161,233 filed on March 15, 2021, the disclosures of which is hereby incorporated by reference in their entirety. BACKGROUND [0002] Compounds that modulate splicing of pre-mRNA, sometimes referred to as small molecule splicing modulators (SMSMs), are useful in treating many diseases which are caused by aberrant pre- mRNA splicing. These SMSMs are also useful in treating diseases in which modulation of pre-mRNA splicing affects the level of a protein, which in turn can be used to treat the diseases by either increasing, or decreasing the level of the particular protein. SMSMs useful in these types of methods are disclosed by, for example, in PCT publications WO 2019/028440 and WO 2020/163405. [0003] There, exists, therefore, a need to develop new processes and intermediates for the synthesis of these SMSMs. SUMMARY [0004] In one aspect, described herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
Figure imgf000002_0001
Formula (I) wherein, Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; X is absent, -O-, -S-, -
Figure imgf000002_0002
hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C6 heterocycloalkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, or -C1-C4 alkylene-OR31; each RX2 and RX3 is independently hydrogen, –OR31, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; each
Figure imgf000003_0004
is independently a single or a double bond; Z is N, C or CR5; R5 is hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1– C4 haloalkyl; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3–C8 cycloalkylene, or substituted or unsubstituted C2–C7 heterocycloalkylene; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; each R31 is independently hydrogen, halogen, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3, comprising the step of reacting a compound of Formula (II)
Figure imgf000003_0001
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI)
Figure imgf000003_0002
Formula (III)
Figure imgf000003_0003
Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I); wherein each variable within Formula (III), Formula (IV), Formula (IVa), Formula (V), and Formula (VI) is as described above for Formula (I). [0005] In one aspect, described herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
Figure imgf000004_0001
Formula (I) wherein, Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; X is absent, -O-, -S-, -
Figure imgf000004_0002
hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C6 heterocycloalkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, or -C1-C4 alkylene-OR31; each RX2 and RX3 is independently hydrogen, –OR31, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, or substituted or unsubstituted C1–C4 heteroalkyl; each
Figure imgf000004_0003
is independently a single or a double bond; Z is N, C or CR5; R5 is hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1– C4 haloalkyl; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3–C8 cycloalkylene, or substituted or unsubstituted C2–C7 heterocycloalkylene; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; each R31 is independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; R is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3, comprising the step of reacting a compound of Formula (II)
Figure imgf000005_0001
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (III)
Figure imgf000005_0002
Formula (III) to produce a compound of Formula (I), wherein each variable within Formula (III) is as described above for Formula (I). In some embodiments, the compound of Formula (II) is reacted with the compound of Formula (III) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid. [0006] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000005_0003
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000006_0001
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (IV)
Figure imgf000006_0002
Formula (IV) to produce a compound of Formula (I), wherein each variable within Formula (I), Formula (II) and Formula (IV) is as described above for Formula (I). In some embodiments of a process for preparing a compound of Formula (I), a compound of Formula (II) is reacting with a compound of Formula (IV) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I). [0007] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000006_0003
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000006_0004
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (IVa)
Figure imgf000007_0001
Formula (IVa) to produce a compound of Formula (I), wherein each variable within Formula (I), Formula (II) and Formula (IVa) is as described above for Formula (I). In some embodiments of a process for preparing a compound of Formula (I), a compound of Formula (II) is reacting with a compound of Formula (IVa) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I). [0008] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000007_0002
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000007_0003
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (V)
Figure imgf000008_0001
Formula (V) to produce a compound of Formula (I), wherein each variable within Formula (I), Formula (II) and Formula (V) is as described above for Formula (I). In some embodiments of a process for preparing a compound of Formula (I), a compound of Formula (II) is reacting with a compound of Formula (V) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I). [0009] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000008_0002
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000008_0003
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (VI)
Figure imgf000008_0004
Formula (VI) to produce a compound of Formula (I), wherein each variable within Formula (I) and Formula (VI) is as described above for Formula (I). In some embodiments of a process for preparing a compound of Formula (I), a compound of Formula (II) is reacting with a compound of Formula (VI) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3- methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I). [0010] In some embodiments of a process for preparing a compound of Formula (I), a compound of Formula (II) is reacting with the compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid. [0011] In another aspect described herein, is a process for preparing a compound of Formula (VII)
Figure imgf000009_0001
Formula (VII) comprising reacting a compound of Formula (VIII)
Figure imgf000009_0002
Formula (VIII) wherein R3 is a halogen, such as Cl, Br, or I; or O-CH2CF3 with a compound of Formula (IX)
Figure imgf000009_0003
Formula (IX) to produce a compound of Formula (VII), wherein each R1 and R2 is independently hydrogen, halogen, -OH, –OR31, –CN,–SR31, -S(=O)R31, -SO2R31, -NR31R32, -NR31S(=O)(=NR31)R32, - NR31S(=O)2R31R32, -SO2NR31R32, -C(=O)R31, -OC(=O)R31, -C(=O)OR31, -OC(=O)OR31, - C(=O)NR31R32, -OC(=O)NR31R32, -NR31C(=O)R32, -P(=O)R31R32, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R31 and R32 is independently hydrogen, halogen, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0012] In some embodiments, a compound of Formula (II) has a structure of Formula (IIa) or Formula (IIb):
Figure imgf000010_0001
Formula (IIa) Formula (IIb). [0013] In some embodiments, a compound of Formula (II) has a structure of Formula (IIa):
Figure imgf000010_0002
Formula (IIa). [0014] In some embodiments, a compound of Formula (II) has a structure of Formula (IIb):
Figure imgf000010_0003
Formula (IIb). [0015] In some embodiments, a compound of Formula (VII) has a structure of Formula (VIIa):
Figure imgf000010_0004
Formula (VIIa); and a compound of Formula (VIII) has a structure of Formula (VIIIa):
Figure imgf000010_0005
Formula (VIIIa). [0016] Also provided herein are uses of a compound disclosed herein, in the manufacture of a SMSM for the treatment of a condition or disease. INCORPORATION BY REFERENCE [0017] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION [0018] Certain specific details of this description are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. [0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. Definitions [0020] The terms “small molecule splicing modulator” or “SMSM” denote a small molecule compound that binds to a cell component (e.g., DNA, RNA, pre-mRNA, protein, RNP, snRNA, carbohydrates, lipids, co-factors, nutrients and/or metabolites) and modulates splicing of a target polynucleotide, e.g., a pre-mRNA. For example, an SMSM can bind directly or indirectly to a target polynucleotide, e.g., RNA (e.g., a pre-mRNA) with a mutated, non-mutated, bulged and/or aberrant splice site, resulting in modulation of splicing of the target polynucleotide. For example, an SMSM can bind directly or indirectly to a protein, e.g., a spliceosome protein or a ribonuclear protein, resulting in steric modulation of the protein and modulation of splicing of a target RNA. For example, an SMSM can bind directly or indirectly to a spliceosome component, e.g., a spliceosome protein or snRNA resulting in steric modulation of the spliceosome protein or snRNA and modulation of splicing of target polynucleotide. These terms specifically exclude compounds consisting of oligonucleotides. These terms include small molecule compounds that may bind to one or more secondary or tertiary structure elements of a target RNA. These sites include RNA triplexes, 3WJs, 4WJs, parallel-Y junctions, hairpins, bulge loops, pseudoknots, internal loops, and other higher-order RNA structural motifs. [0021] “Steric alteration”, “steric modification” or “steric modulation” herein refers to changes in the spatial orientation of chemical moieties with respect to each other. A person of ordinary skill in the art would recognize steric mechanisms include, but are not limited to, steric hindrance, steric shielding, steric attraction, chain crossing, steric repulsions, steric inhibition of resonance, and steric inhibition of protonation. [0022] Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of hydrogen, unless indicated otherwise. [0023] The definitions described herein apply irrespective of whether the terms in question appear alone or in combination. It is contemplated that the definitions described herein can be appended to form chemically-relevant combinations, such as e.g. “heterocycloalkylaryl”, “haloalkylheteroaryl”, “arylalkylheterocycloalkyl”, or “alkoxyalkyl”. The last member of the combination is the radical which is binding to the rest of the molecule. The other members of the combination are attached to the binding radical in reversed order in respect of the literal sequence, e.g. the combination arylalkylheterocycloalkyl refers to a heterocycloalkyl-radical which is substituted by an alkyl which is substituted by an aryl. [0024] When indicating the number of substituents, the term “one or more” refers to the range from one substituent to the highest possible number of substitutions, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents. [0025] The term “substituent” denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. [0026] The term “substituted” denotes that a specified group bears one or more substituents. Where any group can carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same. The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. [0027] The following abbreviations are used throughout the specification: acetic acid (AcOH); ethyl acetate (EtOAc); butyl alcohol (n-BuOH); 1,2-dichloroethane (DCE); dichloromethane (CH2Cl2, DCM); diisopropylethylamine (Diipea); dimethylformamide (DMF); hydrogen chloride (HCl); methanol (MeOH); methoxymethyl bromide (MOMBr); N-methyl-2-pyrrolidone (NMP); methyl Iodide (MeI); n-propanol (n-PrOH); p-methoxybenzyl (PMB); triethylamine (Et3N); [1,1’- Bis(diphenylphosphino)ferrocene] dichloropalladium(II); (Pd(dppf)Cl2); sodium ethane thiolate (EtSNa); sodium acetate (NaOAc); sodium hydride (NaH); sodium hydroxide (NaOH); tetrahydropyran (THP); tetrahydrofuran (THF). [0028] As used herein, C1-Cx includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t- butyl. [0029] The term “oxo” refers to the =O substituent. [0030] The term “thioxo” refers to the =S substituent. [0031] The term “halo”, “halogen”, and “halide” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. [0032] The term “alkyl” refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An alkyl comprising up to 10 carbon atoms is referred to as a C1-C10 alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a C1–C6 alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, C1-C10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1–C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n- pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, the alkyl is -CH(CH3)2 or - C(CH3)3. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below. “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group. In some embodiments, the alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-. [0033] The term “alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy. [0034] The term “alkylamino” refers to a radical of the formula -NHRa or -NRaRa where each Ra is, independently, an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below. [0035] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(Ra)=CRa 2, wherein Ra refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, Ra is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2. [0036] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡C-Ra, wherein Ra refers to the remaining portions of the alkynyl group. In some embodiments, Ra is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH3 -C≡CCH2CH3, -CH2C≡CH. [0037] The term “aromatic” refers to a planar ring having a delocalized ^-electron system containing 4n+2 ^ electrons, where n is an integer. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl). [0038] The term “aryl” refers to a radical comprising at least one aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2- dihydronaphthalene). In some embodiments, an aryl group comprises a fully reduced cycloalkyl group defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When aryl comprises a cycloalkyl group, the aryl is bonded to the rest of the molecule through an aromatic ring carbon atom. An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. [0039] The term “haloalkyl” denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro-or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3- trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl. The term “perhaloalkyl” denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. [0040] The term “haloalkoxy” denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloalkoxyl include monofluoro-, difluoro-or trifluoro-methoxy, -ethoxy or -propoxy, for example 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy. The term “perhaloalkoxy” denotes an alkoxy group where all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. [0041] The term “bicyclic ring system” denotes two rings which are fused to each other via a common single or double bond (annelated bicyclic ring system), via a sequence of three or more common atoms (bridged bicyclic ring system) or via a common single atom (spiro bicyclic ring system). Bicyclic ring systems can be saturated, partially unsaturated, unsaturated or aromatic. Bicyclic ring systems can comprise heteroatoms selected from N, O and S. [0042] The terms “carbocyclic” or “carbocycle” refer to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl. [0043] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2- dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)- one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. [0044] The term “bridged” refers to any ring structure with two or more rings that contains a bridge connecting two bridgehead atoms. The bridgehead atoms are defined as atoms that are the part of the skeletal framework of the molecule and which are bonded to three or more other skeletal atoms. In some embodiments, the bridgehead atoms are C, N, or P. In some embodiments, the bridge is a single atom or a chain of atoms that connects two bridgehead atoms. In some embodiments, the bridge is a valence bond that connects two bridgehead atoms. In some embodiments, the bridged ring system is cycloalkyl. In some embodiments, the bridged ring system is heterocycloalkyl. [0045] The term “fused” refers to any ring structure described herein which is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with one or more N, S, and O atoms. The non-limiting examples of fused heterocyclyl or heteroaryl ring structures include 6-5 fused heterocycle, 6-6 fused heterocycle, 5-6 fused heterocycle, 5-5 fused heterocycle, 7-5 fused heterocycle, and 5-7 fused heterocycle. [0046] The term “haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted. [0047] The term “haloalkoxy” refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2- dibromoethoxy, and the like. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted. [0048] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6 fluoroalkyl. In some embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2- fluoroethyl, and the like. [0049] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, or - N(aryl)-), sulfur (e.g. -S-, -S(=O)-, or -S(=O)2-), or combinations thereof. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C1–C6 heteroalkyl. Representative heteroalkyl groups include, but are not limited to -OCH2OMe, -OCH2CH2OH, -OCH2CH2OMe, or -OCH2CH2OCH2CH2NH2. [0050] The term “heteroalkylene” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N or S atom. “Heteroalkylene” or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkylene groups include, but are not limited to -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or - OCH2CH2OCH2CH2OCH2CH2O-. [0051] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted. [0052] The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) that includes at least one heteroatom selected from nitrogen, oxygen and sulfur, wherein each heterocyclic group has from 3 to 12 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 12 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 12 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3 h-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)- onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo- fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic. [0053] The term “heteroaryl” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, heteroaryl is monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl. In some embodiments, a heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, a heteroaryl group comprises a fully reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl comprises a cycloalkyl or heterocycloalkyl group, the heteroaryl is bonded to the rest of the molecule through a heteroaromatic ring carbon or hetero atom. A heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. [0054] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, - CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1- C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl, and -S(=O)2(C1- C4 alkyl). In some embodiments, optional substituents are independently selected from D, halogen, - CN, -NH2, -OH, -NH(CH3), -N(CH3)2, - NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent includes oxo (=O). In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, =O, -NH(CH3), -N(CH3)2, - NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. [0055] The term “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:
Figure imgf000020_0001
. [0056] As used herein, a “small molecular weight compound” can be used interchangeably with “small molecule” or “small organic molecule”. Small molecules refer to compounds other than peptides or oligonucleotides; and typically have molecular weights of less than about 2000 Daltons, e.g., less than about 900 Daltons. [0057] In one aspect, described herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
Figure imgf000020_0002
Formula (I) wherein, Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; X is absent, -O-, -S-, -
Figure imgf000020_0003
hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C6 heterocycloalkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, or -C1-C4 alkylene-OR31; each RX2 and RX3 is independently hydrogen, –OR31, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; each is independently a single or a double bond; Z is N, C or CR5; R5 is hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1–C4 haloalkyl; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3–C8 cycloalkylene, or substituted or unsubstituted C2–C7 heterocycloalkylene; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, – OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; each R31 is independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, substituted or unsubstituted C3–C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3, comprising the step of reacting a compound of Formula (II)
Figure imgf000021_0001
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a coupling reagent, such as a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI)
Figure imgf000021_0002
Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I). [0058] In some embodiments, a compound of Formula (II) is reacted with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), in the presence of a transition metal catalyst such as palladium catalyst. In some embodiments, a compound of Formula (II) is reacted with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), in the presence of a solvent such as tetrahydrofuran or dimethylformamide. In some embodiments, a compound of Formula (II) is reacted with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), in the presence of a copper salt such as copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid. [0059] In some embodiments, a coupling reagent is a boronic acid or a boronic acid derivative such as boronic ester (e.g., pinacolyl or MIDA (N-methyliminodiacetate) ester). In some embodiments, the boronic acid derivative is potassium trifluoroborate. In some embodiments, the boronic acid derivative is sodium trihydroxyborate. [0060] In some embodiments of a process for preparing a compound of Formula (I), the process comprising the step of reacting the compound of Formula (II) with the compound of Formula (III)
Figure imgf000022_0001
Formula (III). [0061] In some embodiments of a process for preparing a compound of Formula (I), the process comprising the step of reacting the compound of Formula (II) with the compound of Formula (IV)
Figure imgf000022_0002
Formula (IV). [0062] In some embodiments of a process for preparing a compound of Formula (I), the process comprising the step of reacting the compound of Formula (II) with the compound of Formula (IVa)
Figure imgf000022_0003
Formula (IVa). [0063] In some embodiments of a process for preparing a compound of Formula (I), the process comprising the step of reacting a compound of Formula (II) with the compound of Formula (V)
Figure imgf000023_0001
Formula (V). [0064] In some embodiments of a process for preparing a compound of Formula (I), the process comprising the step of reacting the compound of Formula (II) with the compound of Formula (VI)
Figure imgf000023_0002
Formula (VI). [0065] In one aspect, described herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
Figure imgf000023_0003
Formula (I) wherein, ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; X is absent, -O-, -S-, -
Figure imgf000023_0004
hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C6 heterocycloalkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, or -C1-C4 alkylene-OR31; each RX2 and RX3 is independently hydrogen, –OR31, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, or substituted or unsubstituted C1–C4 heteroalkyl; each is independently a single or a double bond; Z is N, C or CR5; R5 is hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1– C4 haloalkyl; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3–C8 cycloalkylene, or substituted or unsubstituted C2–C7 heterocycloalkylene; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; each R31 is independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, substituted or unsubstituted C3–C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl;a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3, comprising the step of reacting a compound of Formula (II)
Figure imgf000024_0001
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (III),
Figure imgf000024_0002
Formula (III) wherein each variable within Formula (I) and Formula (III) is as described above for Formula (I). [0066] In some embodiments, a compound of Formula (II) is reacted with a compound of Formula (III) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I). [0067] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000025_0001
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000025_0002
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (IV),
Figure imgf000025_0003
Formula (IV) wherein each variable within Formula (I) and Formula (IV) is as described above for Formula (I). [0068] In some embodiments, a compound of Formula (II) is reacted with a compound of Formula (IV) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I). [0069] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000025_0004
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000026_0001
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (IVa),
Figure imgf000026_0002
Formula (IVa) wherein each variable within Formula (I) and Formula (IVa) is as described above for Formula (I). [0070] In some embodiments, a compound of Formula (II) is reacted with a compound of Formula (IVa) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I). [0071] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000026_0003
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000026_0004
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (V),
Figure imgf000027_0001
Formula (V) wherein each variable within Formula (I) and Formula (III) is as described above for Formula (I). [0072] In some embodiments, a compound of Formula (II) is reacted with a compound of Formula (V) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I). [0073] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000027_0002
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000027_0003
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (VI).
Figure imgf000028_0001
Formula (VI) wherein each variable within Formula (I) and Formula (III) is as described above for Formula (I). [0074] In some embodiments, a compound of Formula (II) is reacted with a compound of Formula (VI) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid to produce a compound of Formula (I). [0075] In one aspect, described herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
Figure imgf000028_0002
Formula (I) wherein, Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; X is absent, -O-, -S-, -
Figure imgf000028_0003
hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C6 heterocycloalkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, or -C1-C4 alkylene-OR31; each RX2 and RX3 is independently hydrogen, –OR31, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; each is independently a single or a double bond; Z is N, C or CR5; R5 is hydrogen, substituted or unsubstituted C1–C4 alkyl, or substituted or unsubstituted C1–C4 haloalkyl; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3–C8 cycloalkylene, or substituted or unsubstituted C2–C7 heterocycloalkylene; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; each R31 is independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1– C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3, comprising the step of reacting a compound of Formula (II*)
Figure imgf000029_0001
Formula (II*) wherein HAL represents a halogen; with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI)
Figure imgf000029_0002
Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I). [0076] In some embodimetns, HAL is Cl. In some embodimetns, HAL is F. In some embodimetns, HAL is Br. In some embodimetns, HAL is I. [0077] In one aspect, described herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
Figure imgf000029_0003
Formula (I) wherein, Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; X is absent, -O-, -S-, -
Figure imgf000030_0001
hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C6 heterocycloalkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, or -C1-C4 alkylene-OR31; each RX2 and RX3 is independently hydrogen, –OR31, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; each is independently a single or a double bond; Z is N, C or CR5; R5 is hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1– C4 haloalkyl; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3–C8 cycloalkylene, or substituted or unsubstituted C2–C7 heterocycloalkylene; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; each R31 is independently hydrogen, halogen, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; R is hydrogen, substituted or unsubstituted C1-C4 alkyl, or a protecting group (e.g. Boc); a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3, comprising the step of reacting a compound of Formula (II)
Figure imgf000030_0002
Formula (IIa) with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI)
Figure imgf000031_0001
Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I). [0078] In one aspect, described herein is a process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
Figure imgf000031_0002
Formula (I) wherein, Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; X is absent, -O-, -S-, -
Figure imgf000031_0003
hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C6 heterocycloalkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, or -C1-C4 alkylene-OR31; each RX2 and RX3 is independently hydrogen, –OR31, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, or substituted or unsubstituted C1–C4 heteroalkyl; each is independently a single or a double bond; Z is N, C or CR5; R5 is hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1– C4 haloalkyl; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3–C8 cycloalkylene, or substituted or unsubstituted C2–C7 heterocycloalkylene; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; each R31 is independently hydrogen, halogen, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1-C4 heteroalkyl; R is hydrogen, substituted or unsubstituted C1–C4 alkyl, or a protecting group (e.g. Boc); a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3, comprising the step of reacting a compound of Formula (II*)
Figure imgf000032_0001
Formula (II*) wherein HAL represents a halogen; with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI)
Figure imgf000032_0002
Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I). [0079] In some embodiments, R is a protecting group, e.g. tert-butyloxycarbonyl (Boc). [0080] In some embodiments, the compound of Formula (II), Formula (II*), or Formula (IIa) is used in a process to produce a compound of Formula (I) comprising a step of stereoselectivity. In some embodiments, the step of stereoselectivity comprises asymmetric synthesis. In some embodiments, the step of stereoselectivity comprises asymmetric synthesis and chiral resolution. In some embodiments, the step of stereoselectivity comprises the use of one or more chiral centers in a compound of Formula (II), Formula (II*), or Formula (IIa). In some embodiments, the one or more chiral centers is a chiral auxiliary. In some embodiments, the chiral auxiliary is -S(=O)(=NRL1)RL1. [0081] In another aspect described herein, is a process for preparing a compound of Formula (VII)
Figure imgf000032_0003
Formula (VII) comprising reacting a compound of Formula (VIII)
Figure imgf000033_0001
Formula (VIII) wherein R3 is a halogen, such as Cl, Br, or I; or O-CH2CF3; RL is halogen, -O(C=O)RL1, -SRL1, - S(=O)RL1, or -S(=O)2RL1; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; with a compound of Formula (IX)
Figure imgf000033_0002
Formula (IX) to produce a compound of Formula (VII), wherein each R1 and R2 is independently hydrogen, halogen, -OH, –OR31, –CN,–SR31, -S(=O)R31, -SO2R31, -NR31R32, -NR31S(=O)(=NR31)R32, - NR31S(=O)2R31R32, -SO2NR31R32, -C(=O)R31, -OC(=O)R31, -C(=O)OR31, -OC(=O)OR31, - C(=O)NR31R32, -OC(=O)NR31R32, -NR31C(=O)R32, -P(=O)R31R32, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R31 and R32 is independently hydrogen, halogen, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0082] In some embodiments, a compound of Formula (VII) has a structure of Formula (VIIa):
Figure imgf000033_0003
Formula (VIIa); and a compound of Formula (VIII) has a structure of Formula (VIIIa):
Figure imgf000033_0004
Formula (VIIIa). [0083] In some embodiments, a compound of Formula (I) is a compound of Formula (Ia)
Figure imgf000034_0005
Formula (Ia). [0084] In some embodiments, the nitrogen atom bearing R group and the X group are on the same side of a plane. In some embodiments, the nitrogen atom bearing R group and the X group are on the opposite side of a plane. [0085] In some embodiments, a compound of Formula (I) is a compound of Formula (Ib)
Figure imgf000034_0001
Formula (Ib). [0086] In some embodiments, a compound of Formula (I) is a compound of Formula (Ic)
Figure imgf000034_0002
Formula (Ic). [0087] In some embodiments, a compound of Formula (I) is a compound of Formula (Id)
Figure imgf000034_0003
Formula (Id). [0088] In some embodiments, a compound of Formula (I) is a compound of Formula (Ie)
Figure imgf000034_0004
[0089] In some embodiments, a compound of Formula (I) is a compound of Formula (If)
Figure imgf000035_0001
Formula (If). [0090] In some embodiments, R is hydrogen or substituted or unsubstituted C1-C4 alkyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, or -CH2CH2CH3. In some embodiments, R is hydrogen. In some embodiments, R is -CH3. In some embodiments, R is -CH2CH3. In some embodiments, R is -CH2CH2CH3. In some embodiments, each R15 and R18 is independently hydrogen or substituted or unsubstituted C1-C4 alkyl. In some embodiments, each R15 and R18 is independently hydrogen, -CH3, or -CH2CH3. In some embodiments, each R15 and R18 is hydrogen. In some embodiments, each R15 and R18 is -CH3. In some embodiments, R15 is hydrogen and R18 is -CH3. In some embodiments, R15 is -CH3 and R18 is hydrogen. In some embodiments, each R16 and R17 is independently hydrogen, F, –or substituted or unsubstituted C1-C4 alkyl. In some embodiments, each R16 and R17 is independently hydrogen, F, -CH3, or -CH2CH3. In some embodiments, each R16 and R17 is independently hydrogen or F. In some embodiments, R16 is hydrogen and R17 is F. In some embodiments, R16 is F and R17 is hydrogen. In some embodiments, W is substituted or unsubstituted C1-C3 alkylene. In some embodiments, W is -CH2CH2- or -CH2CH2CH2-. In some embodiments, W is -CH2CH2-. In some embodiments, W is -CH2CH2CH2-. In some embodiments, X is -NRX1-. In some embodiments, RX1 is hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, or substituted or unsubstituted C3–C6 cycloalkyl. In some embodiments, RX1 is hydrogen, –CN, -CH3, -CH2CH3, - CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, cyclopropyl, or cyclobutyl. In some embodiments, RX1 is hydrogen. In some embodiments, RX1 is –CN. In some embodiments, RX1 is - CH3. In some embodiments, RX1 is -CH2CH3. In some embodiments, RX1 is -CH2CH2CH3. In some embodiments, RX1 is -OCH3. In some embodiments, RX1 is -OCH2CH3. In some embodiments, RX1 is -OCH2CH2CH3. In some embodiments, RX1 is cyclopropyl. In some embodiments, RX1 is cyclobutyl. In some embodiments, ring Q is substituted or unsubstituted aryl. In some embodiments, ring Q is substituted aryl. In some embodiments, ring Q is aryl substituted with -OH and substituted or unsubstituted heteroaryl. In some embodiments, ring Q is 2-hydroxyphenyl substituted with substituted or unsubstituted heteroaryl. In some embodiments, ring Q is 2-hydroxyphenyl substituted with substituted or unsubstituted monocyclic heteroaryl. In some embodiments, ring Q is 2- hydroxyphenyl substituted with substituted or unsubstituted 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl comprises 0-1 O, 0-1 S, and 0-4 N heteroatoms. In some embodiments, the 5-membered heteroaryl is optionally substituted by one or more substituents each independently selected from oxo, C1-C3 alkyl, and halogen. In some embodiments, ring Q is 2- hydroxyphenyl substituted with substituted or unsubstituted pyrazole or substituted or unsubstituted oxadiazole. In some embodiments, ring Q is 2-hydroxyphenyl substituted with pyrazole substituted with -CH3. In some embodiments, ring Q is 2-hydroxyphenyl substituted with oxadiazole substituted with -CH3. In some embodiments, ring Q is 2-hydroxyphenyl substituted with substituted or unsubstituted 6-membered heteroaryl. In some embodiments, the 6-membered heteroaryl comprises 1-4 N heteroatoms. In some embodiments, the 6-membered heteroaryl is optionally substituted by one or more substituents each independently selected from oxo, C1-C3 alkyl, and halogen. In some embodiments, the 6-membered heteroaryl is 1-methylpyridin-2(1H)-one. In some embodiments, ring Q is substituted or unsubstituted 6/6 fused heteroaryl. In some embodiments, the 6/6 fused heteroaryl comprises 1-4 N heteroatoms. In some embodiments, the 6/6 fused heteroaryl comprises 1-2 N heteroatoms. In some embodiments, the 6/6 fused heteroaryl is optionally substituted by one or more substituents each independently selected from oxo, C1-C3 alkyl, and halogen. In some embodiments, the 6/6 fused heteroaryl is optionally substituted by one or more substituents each independently selected from oxo and C1-C3 alkyl. In some embodiments, the 6/6 fused heteroaryl is selected from 7-hydroxy-2-methylphthalazin-1-one, 6-hydroxy-3-methylquinazolin-4-one, and 7-hydroxy-2- methylisoquinolin-1-one. In some embodiments, the 6/6 fused heteroaryl is 7-hydroxy-N- methylquinoline-2-carboxamide. In some embodiments, ring Q is substituted or unsubstituted 6/5 fused heteroaryl. In some embodiments, the 6/5 fused heteroaryl comprises 0-1 O, 0-1 S and 0-3 N heteroatoms. In some embodiments, the 6/6 fused heteroaryl comprises 0-1 O and 1-2 N heteroatoms. In some embodiments, the 6/5 fused heteroaryl is optionally substituted by one or more substituents each independently selected from oxo, C1-C3 alkyl, and halogen. In some embodiments, the 6/5 fused heteroaryl is optionally substituted by one or more substituents each independently selected from oxo and C1-C3 alkyl. In some embodiments, the 6/5 fused heteroaryl is selected from 2-methylbenzo[d]oxazol-5-ol and 3-methylbenzo[d]oxazol-2(3H)-one. [0091] In some embodiments, a compound of Formula (I) is a compound of Formula (Iaa)
Figure imgf000036_0001
Formula (Iaa). [0092] In some embodiments, a compound of Formula (I) is a compound of Formula (Ibb)
Figure imgf000037_0001
Formula (Ibb). [0093] In some embodiments, a compound of Formula (I) is a compound of Formula (Icc)
Figure imgf000037_0002
Formula (Icc). [0094] In some embodiments, a compound of Formula (II) is a compound of Formula (IIa) or Formula (IIb)
Figure imgf000037_0003
Formula (IIa) Formula (IIb). [0095] In some embodiments, a compound of Formula (II) is a compound of Formula (IIc) or Formula (IId):
Figure imgf000037_0004
Formula (IIc) Formula (IId). [0096] In some embodiments, a compound of Formula (II) is a compound of Formula (IIe) or Formula (IIf):
Figure imgf000038_0001
Formula (IIe) Formula (IIf). [0097] In some embodiments, a compound of Formula (II) is a compound of Formula (IIg) or Formula (IIh):
Figure imgf000038_0002
Formula (IIg) Formula (IIh). [0098] In some embodiments, a compound of Formula (II) is a compound of Formula (IIi) or Formula (IIj):
Figure imgf000038_0003
Formula (IIi) Formula (IIj). [0099] In some embodiments, a compound of Formula (II) is a compound of Formula (IIk) or Formula (IIl):
Figure imgf000038_0004
Formula (IIk) Formula (IIl). [0100] In some embodiments, R is hydrogen, substituted or unsubstituted C1–C4 alkyl, or substituted or unsubstituted C1-C4heteroalkyl. In some embodiments, R is substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1-C4heteroalkyl. In some embodiments, R is substituted or unsubstituted C1–C4 alkyl. In some embodiments, R is substituted or unsubstituted C1–C4heteroalkyl. In some embodiments, R is C1–C4heteroalkyl substituted with oxo and -CH3. In some embodiments, R is tert-butyloxycarbonyl. In some embodiments, each R15 and R18 is independently hydrogen or substituted or unsubstituted C1-C4 alkyl. In some embodiments, each R15 and R18 is independently hydrogen, -CH3, or -CH2CH3. In some embodiments, each R15 and R18 is hydrogen. In some embodiments, each R15 and R18 is -CH3. In some embodiments, R15 is hydrogen and R18 is -CH3. In some embodiments, R15 is -CH3 and R18 is hydrogen. In some embodiments, each R16 and R17 is independently hydrogen, F, –or substituted or unsubstituted C1–C4 alkyl. In some embodiments, each R16 and R17 is independently hydrogen, F, -CH3, or -CH2CH3. In some embodiments, each R16 and R17 is independently hydrogen or F. In some embodiments, R16 is hydrogen and R17 is F. In some embodiments, R16 is F and R17 is hydrogen. In some embodiments, W is substituted or unsubstituted C1-C3 alkylene. In some embodiments, W is -CH2CH2- or -CH2CH2CH2-. In some embodiments, W is -CH2CH2-. In some embodiments, W is -CH2CH2CH2-. In some embodiments, X is -NRX1-. In some embodiments, RX1 is hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, or substituted or unsubstituted C3–C6 cycloalkyl. In some embodiments, RX1 is hydrogen, –CN, -CH3, -CH2CH3, - CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, cyclopropyl, or cyclobutyl. In some embodiments, RX1 is hydrogen. In some embodiments, RX1 is –CN. In some embodiments, RX1 is -CH3. In some embodiments, RX1 is -CH2CH3. In some embodiments, RX1 is -CH2CH2CH3. In some embodiments, RX1 is -OCH3. In some embodiments, RX1 is -OCH2CH3. In some embodiments, RX1 is -OCH2CH2CH3. In some embodiments, RX1 is cyclopropyl. In some embodiments, RX1 is cyclobutyl. [0101] In some embodiments, a compound of Formula (II) is a compound of Formula (IIaa)
Figure imgf000039_0001
Formula (IIaa). [0102] In some embodiments, a compound of Formula (IV) is a compound of Formula (IVaa)
Figure imgf000039_0002
Formula (IVaa). [0103] In some embodiments, a compound of Formula (IV) is a compound of Formula (IVb)
Figure imgf000039_0003
Formula (IVb). [0104] In some embodiments, a compound of Formula (V) is a compound of Formula (Va)
Figure imgf000040_0001
Formula (Va). [0105] In some embodiments, a process of preparing a compound of Formula (IIaa) comprises the step of reacting a compound of Formula (X):
Figure imgf000040_0002
Formula (X) with a base, such as sodium hydride in a solvent, such as dimethylformamide and a methylation agent, such as methyl iodide. [0106] In some embodiments of a process for preparing a compound of Formula (X), the process comprises the step of reacting a compound of Formula (XI):
Figure imgf000040_0003
Formula (XI) with a compound of Formula (XII):
Figure imgf000040_0004
Formula (XII) in the presence of a base such as N,N-Diisopropylethylamine and a solvent such as 1-butanol. [0107] In some embodiments of a process for preparing a compound of Formula (XI), the process comprises the step of reacting a compound of Formula (XIII):
Figure imgf000040_0005
Formula (XIII) in a solvent, such as ethanol in the presence of a palladium catalyst under a hydrogen atmosphere. [0108] In some embodiments of a process for preparing a chirally pure compound of Formula (XIII), the process comprises the step of reacting a racemic mixture of a compound of Formula (XIII) with a chiral resolving agent, such as (R)-(-)-mandelic acid in the presence of a solvent, such as methyl ethyl ketone. In some embodiments of a process for preparing a chirally pure compound of Formula (XIII), the process comprises further steps of neutralizing a precipitated salt with sodium bicarbonate and extraction with ethyl acetate. In some embodiments of a process for preparing a chirally pure compound of Formula (XIII), the process comprises repeating steps until the desired chiral purity is achieved. In some embodiments, the chiral purity of a compound of Formula (XIII) is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100%. [0109] In some embodiments of a process for preparing a compound of Formula (XII), the process comprises the step of reacting a compound of Formula (XIV):
Figure imgf000041_0001
Formula (XIV) with a nitration agent, such as tert-Butyl nitrite and a sulfiding agent, such as 1,2-dimethyldisulfide. [0110] In some embodiments of a process for preparing a compound of Formula (XIV), the process comprises the step of reacting a compound of Formula (XV):
Figure imgf000041_0002
Formula (XV) with a bromination agent, such as N-Bromosuccinimide and a solvent, such as acetonitrile. [0111] In one aspect, described herein is a compound of Formula (II),
Figure imgf000041_0003
Formula (II) wherein, RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, or -S(=O)2RL1; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X is absent,
Figure imgf000041_0004
hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C6 heterocycloalkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, or -C1-C4 alkylene-OR31; each RX2 and RX3 is independently hydrogen, –OR31, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1–C4 heteroalkyl; each is independently a single or a double bond; Z is N, C or CR5; R5 is hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1-C4 haloalkyl; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3–C8 cycloalkylene, or substituted or unsubstituted C2–C7 heterocycloalkylene; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; each R31 is independently hydrogen, halogen, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, substituted or unsubstituted C3–C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; R is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3. [0112] In one aspect, described herein is a compound of Formula (III),
Figure imgf000042_0001
Formula (III) wherein ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. [0113] In one aspect, described herein is a compound of Formula (IV),
Figure imgf000043_0001
Formula (IV) wherein ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. [0114] In one aspect, described herein is a compound of Formula (IVa),
Figure imgf000043_0002
Formula (IVa) wherein ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. [0115] In one aspect, described herein is a compound of Formula (V),
Figure imgf000043_0003
Formula (V) wherein ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. [0116] In one aspect, described herein is a compound of Formula (VI)
Figure imgf000043_0004
Formula (VI) wherein ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. [0117] In one aspect, described herein is a compound of Formula (VII),
Figure imgf000044_0001
Formula (VII) wherein each R1 and R2 is independently hydrogen, halogen, -OH, –OR31, –CN,–SR31, -S(=O)R31, - SO2R31, -NR31R32, -NR31S(=O)(=NR31)R32, -NR31S(=O)2R31R32, -SO2NR31R32, -C(=O)R31, - OC(=O)R31, -C(=O)OR31, -OC(=O)OR31, -C(=O)NR31R32, -OC(=O)NR31R32, -NR31C(=O)R32, - P(=O)R31R32, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R31 and R32 is independently hydrogen, halogen, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0118] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted aryl. In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted heteroaryl. In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted cycloalkyl. In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted heterocycloalkyl. In some embodiments, ring Q is a fused ring. In some embodiments, ring Q is monocyclic. In some embodiments, ring Q is polycyclic. In some embodiments, ring Q is bicyclic. In some embodiments, ring Q is unsubstituted. In some embodiments, ring Q is substituted. [0119] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted cycloalkyl. In some embodiments, ring Q is substituted or unsubstituted C3–C8 cycloalkyl. In some embodiments, ring Q is substituted or unsubstituted C3-C6 cycloalkyl. [0120] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted heterocycloalkyl. In some embodiments, ring Q is substituted or unsubstituted C2-C8 heterocycloalkyl. In some embodiments, ring Q is substituted or unsubstituted C2-C5 heterocycloalkyl. [0121] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted phenyl. [0122] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is 2–hydroxy–phenyl substituted with 1, 2, or 3 substituents independently selected from: deuterium, halogen, -OH, -NO2, -CN, -SR31, -S(=O)R31, - S(=O)2R31, -N(R31)2, -C(=O)R31, -OC(=O)R31, -C(=O)OR31, -C(=O)N(R31)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2- C6 alkynyl, substituted or unsubstituted C1–C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0123] In some embodiments, each R31 is independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0124] In some embodiments, ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [0125] In some embodiments, ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted aryl. In some embodiments, if aryl is substituted then it is substituted with 1 or 2 substituents independently selected from: deuterium, halogen, -OH, -NO2, -CN, –SR31, –S(=O)R31, – S(=O)2R31, –N(R31)2, –C(=O)R31, –OC(=O)R31, –C(=O)OR31, –C(=O)N(R31)2, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2- C6 alkynyl, substituted or unsubstituted C1–C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl. [0126] In some embodiments, each R31 is independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0127] In some embodiments, ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted heteroaryl. In some embodiments, if heteroaryl is substituted then it is substituted with 1 or 2 substituents independently selected from: deuterium, halogen, -OH, -NO2, -CN, –SR31, – S(=O)R31, –S(=O)2R31, –N(R31)2, –C(=O)R31, –OC(=O)R31, –C(=O)OR31, –C(=O)N(R31)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl. [0128] In some embodiments, each R31 is independently hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, -CD3, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Figure imgf000046_0001
[0130] In some embodiments, each RQ is independently selected from hydrogen, deuterium, –F, –Cl, -CN, –OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, –CF3, –OCH3, -OCH2CH3, -CH2OCH3, - OCH2CH2CH3, and -OCH(CH3)2. In some embodiments, ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [0131] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted heteroaryl. [0132] In some embodiments, ring Q is substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl. [0133] In some embodiments, ring Q is substituted or unsubstituted 6-membered monocyclic heteroaryl. [0134] In some embodiments, ring Q is 6-membered monocyclic heteroaryl selected from:
Figure imgf000046_0002
[0135] In some embodiments, each RQ is independently selected from hydrogen, deuterium, –F, –Cl, -CN, –OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, –CF3, –OCH3, -OCH2CH3, -CH2OCH3, - OCH2CH2CH3, and -OCH(CH3)2. In some embodiments, ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [0136] In some embodiments, each RQ is independently hydrogen,–F, –Cl, -CN, –OH, -CH3,–CF3, or –OCH3. [0137] In some embodiments, each RQ is independently hydrogen or –F. [0138] In some embodiments, each RQ is hydrogen. [0139] In some embodiments, ring P is substituted or unsubstituted heteroaryl. [0140] In some embodiments, ring P is heteroaryl selected from the group consisting of:
Figure imgf000047_0001
. [0141] In some embodiments, each RB is independently selected from H, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1–C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1–C6 alkoxy, deuterium substituted C1–C6 alkoxy, -OCD3, substituted or unsubstituted C3–7 cycloalkyl, substituted or unsubstituted C2–C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0142] In some embodiments, RB1 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1–C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3–7 cycloalkyl, and substituted or unsubstituted C2–C7 heterocycloalkyl. In some embodiments, m is 0, 1, 2, or 3. [0143] In some embodiments, ring P is heteroaryl selected from the group consisting of:
Figure imgf000048_0001
[0144] In some embodiments, each RB is independently selected from H, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C1-C6 alkyl, -CD3, substituted or unsubstituted C1–C6 fluoroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1–C6 alkoxy, deuterium substituted C1–C6 alkoxy, -OCD3, substituted or unsubstituted C3–7 cycloalkyl, substituted or unsubstituted C2–C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0145] In some embodiments, RB1 is selected from hydrogen, deuterium, substituted or unsubstituted C1–C6 alkyl, -CD3, substituted or unsubstituted C1–C6 fluoroalkyl, substituted or unsubstituted C1–C6 heteroalkyl, substituted or unsubstituted C3–7 cycloalkyl, and substituted or unsubstituted C2–C7 heterocycloalkyl. In some embodiments, m is 0, 1, 2, or 3 [0146] In some embodiments, each RB is independently H, deuterium, –F, –Cl, –CN, –CH3, –CF3, – OH, or –OCH3. [0147] In some embodiments, each RB is independently –F or –OCH3. [0148] In some embodiments, RB1 is hydrogen, deuterium, –CH3, –CF3, or –CD3. [0149] In some embodiments, m is 0 or 1. [0150] In some embodiments, ring Q is 2–naphthyl substituted at the 3 position with 0, 1, and 2 substituents independently selected from: deuterium, halogen, -OH, -NO2, -CN, –SR31, –S(=O)R31, – S(=O)2R31, –N(R31)2, –C(=O)R31, –OC(=O)R31, –C(=O)OR31, –C(=O)N(R31)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2- C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0151] In some embodiments, each R31 is independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0152] In some embodiments, ring Q is selected from the group consisting of:
Figure imgf000049_0001
[0153] In some embodiments, ring Q is selected from the group consisting of:
Figure imgf000049_0002
, , [0154] In some embodiments, ring Q is selected from the group consisting of:
Figure imgf000049_0003
Figure imgf000050_0001
[0155] In some embodiments, ring Q is selected from the group consisting of:
Figure imgf000050_0002
Figure imgf000051_0001
[0156] In some embodiments, RB1 is selected from hydrogen, deuterium, substituted or unsubstituted C1–C6 alkyl, -CD3, substituted or unsubstituted C1–C6 fluoroalkyl, substituted or unsubstituted C1–C6 heteroalkyl, substituted or unsubstituted C3–7 cycloalkyl, and substituted or unsubstituted C2–C7 heterocycloalkyl. [0157] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is:
Figure imgf000051_0002
, wherein each A1, A2, A3, and A4 is independently N, -NRY1-, -O-, -S-, or CRA1; each RA1 is independently hydrogen, halogen =O, or substituted or unsubstituted C1-C6 alkyl; and each RY1 is independently hydrogen or substituted or unsubstituted C1–C6 alkyl. In some embodiments, each RA1 is H. In some embodiments, each RY1 is H. In some embodiments, ring Q is
Figure imgf000051_0003
Figure imgf000052_0001
Figure imgf000053_0003
Figure imgf000053_0001
Figure imgf000053_0002
[0158] In some embodiments, A1 is CH, CH2, CF, CF2, C(CH3), N, N(CH3), O, or C(=O). In some embodiments, A1 is CH, CF, C(CH3), N, N(CH3), O, or C(=O). In some embodiments, A1 is CH, CF, C(CH3), N, O, or C(=O). In some embodiments, A1 is CH. In some embodiments, A1 is CF. In some embodiments, A1 is C(CH3). In some embodiments, A1 is N. In some embodiments, A1 is O. In some embodiments, A1 is C(=O). In some embodiments, A2 is CH, CH2, C(CH3), N, N(CH3), or C(CH3). In some embodiments, A2 is CH, C(CH3), N, N(CH3), or C(CH3). In some embodiments, A2 is CH, C(CH3), N, or C(CH3). In some embodiments, A2 is CH. In some embodiments, A2 is C(CH3). In some embodiments, A2 is N. In some embodiments, A2 is C(CH3). In some embodiments, A3 is CH, CH2, C(CH3), N, N(CH3), or C(CH3). In some embodiments, A3 is CH, C(CH3), N, N(CH3), or C(CH3). In some embodiments, A3 is CH, C(CH3), N, or C(CH3). In some embodiments, A3 is CH. In some embodiments, A3 is C(CH3). In some embodiments, A3 is N. In some embodiments, A3 is C(CH3). In some embodiments, A4 is CH, CH2, C(CH3), N, N(CH3), O, or C(=O). In some embodiments, A4 is CH, C(CH3), N, N(CH3), O, or C(=O). In some embodiments, A4 is CH, C(CH3), N, O, or C(=O). In some embodiments, A4 is CH. In some embodiments, A4 is C(CH3). In some embodiments, A4 is N. In some embodiments, A4 is O. In some embodiments, A4 is C(=O). In some embodiments, one of A1 , A2, A3, and A4 is C(=O). [0159] In some embodiments, R is substituted or unsubstituted C1-C4 heteroalkyl. In some embodiments, R is C1-C4 heteroalkyl substituted by a t-butyl group. In some embodiments, R is tert- butyloxycarbonyl (BOC). [0160] In some embodiments, ring Q is optionally substituted phenyl. In some embodiments, ring Q is optionally substituted naphthyl. [0161] In some embodiments, ring Q is substituted or unsubstituted fused heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 6-6 fused heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 6-5 fused heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 5-6 fused heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 7-5 fused heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 5-7 fused heteroaryl. [0162] In some embodiments, ring Q is fully aromatic. In some embodiments, ring Q is partially unsaturated. [0163] In some embodiments, ring Q is 2-OH phenyl substituted by a halogen, such as Cl. [0164] In some embodiments, ring Q is optionally substituted heteroaryl. In some embodiments, ring Q is optionally substituted monocyclic heteroaryl. In some embodiments, ring Q is optionally substituted bicyclic heteroaryl. In some embodiments, ring Q is optionally substituted, fused 5-7, 5-6, 6-6, 6-5 or 7-5 heteroaryl. In some embodiments, ring Q is optionally substituted, fused 6-6 heteroaryl. [0165] In some embodiments, ring Q is
Figure imgf000054_0001
. In some embodiments, ring Q is
Figure imgf000054_0002
. [0166] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is:
Figure imgf000055_0001
, wherein each A1, A2, A3, and A4 is independently N, -NRY1-, -O-, -S-, - S(=O)2-, C(RA1)2 or CRA1; each RA1 is independently hydrogen, halogen =O, or substituted or unsubstituted C1-C6 alkyl; and each RY1 is independently hydrogen or substituted or unsubstituted C1– C6 alkyl. [0167] In some embodiments, A1 is CH, CH2, CF, C(CH3), N, O, or C(=O). In some embodiments, A1 is CH. In some embodiments, A1 is CH2. In some embodiments, A1 is -S(=O)2-. In some embodiments, A1 is CF. In some embodiments, A1 is C(CH3). In some embodiments, A1 is N. In some embodiments, A1 is O. In some embodiments, A1 is C(=O). In some embodiments, A1 is S. In some embodiments, A1 is CRA1. In some embodiments, A1 is CRA1 and RA1 is H. In some embodiments, A1 is CRA1 and RA1 is substituted or unsubstituted C1–C6 alkyl. In some embodiments, RA1 is C1–C6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, RA1 is optionally substituted C1–C3 alkyl. In some embodiments, RA1 is C1–C3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in RA1 are replaced by deuterium. In some embodiments, RA1 is H. In some embodiments, RA1 is methyl. In some embodiments, RA1 is methyl, ethyl, CF3, CHF2, or CH2CF3. In some embodiments, RA1 is CD3 or CD2CD3. In some embodiments, RA1 is halogen. In some embodiments, RA1 is F. In some embodiments, A1 is NRY1. In some embodiments, A1 is NRY1 and RY1 is H. In some embodiments, A1 is NRY1 and RY1 is substituted or unsubstituted C1–C6 alkyl. In some embodiments, RY1 is C1–C6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, RY1 is optionally substituted C1–C3 alkyl. In some embodiments, RY1 is C1–C3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in RY1 are replaced by deuterium. In some embodiments, RY1 is H. In some embodiments, RY1 is methyl. In some embodiments, RY1 is methyl, ethyl, CF3, CHF2, or CH2CF3. In some embodiments, RY1 is CD3 or CD2CD3. [0168] In some embodiments, A2 is CH, CH2, C(CH3), N, or C(CH3). In some embodiments, A2 is CH. In some embodiments, A2 is CH2. In some embodiments, A2 is C(CH3). In some embodiments, A2 is -S(=O)2-. In some embodiments, A2 is N. In some embodiments, A2 is C(CH3). In some embodiments, A2 is S. In some embodiments, A2 is CRA1. In some embodiments, A2 is CRA1 and RA1 is H. In some embodiments, A2 is CRA1 and RA1 is substituted or unsubstituted C1–C6 alkyl. In some embodiments, RA1 is C1–C6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, RA1 is optionally substituted C1–C3 alkyl. In some embodiments, RA1 is C1–C3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in RA1 are replaced by deuterium. In some embodiments, RA1 is H. In some embodiments, RA1 is methyl. In some embodiments, RA1 is methyl, ethyl, CF3, CHF2, or CH2CF3. In some embodiments, RA1 is CD3 or CD2CD3. In some embodiments, RA1 is halogen. In some embodiments, RA1 is F. In some embodiments, A2 is NRY1. In some embodiments, A2 is NRY1 and RY1 is H. In some embodiments, A2 is NRY1 and RY1 is substituted or unsubstituted C1–C6 alkyl. In some embodiments, RY1 is C1–C6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, RY1 is optionally substituted C1–C3 alkyl. In some embodiments, RY1 is C1–C3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in RY1 are replaced by deuterium. In some embodiments, RY1 is H. In some embodiments, RY1 is methyl. In some embodiments, RY1 is methyl, ethyl, CF3, CHF2, or CH2CF3. In some embodiments, RY1 is CD3 or CD2CD3. [0169] In some embodiments, A3 is CH, CH2, C(CH3), N, or C(CH3). In some embodiments, A3 is CH. In some embodiments, A3 is CH2. In some embodiments, A3 is C(CH3). In some embodiments, A3 is -S(=O)2-. In some embodiments, A3 is N. In some embodiments, A3 is C(CH3). In some embodiments, A3 is S. In some embodiments, A3 is CRA1. In some embodiments, A3 is CRA1 and RA1 is H. In some embodiments, A3 is CRA1 and RA1 is substituted or unsubstituted C1–C6 alkyl. In some embodiments, RA1 is C1–C6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, RA1 is optionally substituted C1–C3 alkyl. In some embodiments, RA1 is C1–C3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in RA1 are replaced by deuterium. In some embodiments, RA1 is H. In some embodiments, RA1 is methyl. In some embodiments, RA1 is methyl, ethyl, CF3, CHF2, or CH2CF3. In some embodiments, RA1 is CD3 or CD2CD3. In some embodiments, RA1 is halogen. In some embodiments, RA1 is F. In some embodiments, A3 is NRY1 . In some embodiments, A3 is NRY1 and RY1 is H. In some embodiments, A3 is NRY1 and RY1 is substituted or unsubstituted C1–C6 alkyl. In some embodiments, RY1 is C1–C6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, RY1 is optionally substituted C1–C3 alkyl. In some embodiments, RY1 is C1–C3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in RY1 are replaced by deuterium. In some embodiments, RY1 is H. In some embodiments, RY1 is methyl. In some embodiments, RY1 is methyl, ethyl, CF3, CHF2, or CH2CF3. In some embodiments, RY1 is CD3 or CD2CD3. In some embodiments, A3 is N(CH3). [0170] In some embodiments, A4 is CH, CH2, C(CH3), N, O, or C(=O). In some embodiments, A4 is CH. In some embodiments, A4 is CH2. In some embodiments, A4 is C(CH3). In some embodiments, A4 is -S(=O)2-. In some embodiments, A4 is N. In some embodiments, A4 is O. In some embodiments, A4 is C(=O). In some embodiments, A4 is S. In some embodiments, A4 is CRA1. In some embodiments, A4 is CRA1 and RA1 is H. In some embodiments, A4 is CRA1 and RA1 is substituted or unsubstituted C1–C6 alkyl. In some embodiments, RA1 is C1–C6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, RA1 is optionally substituted C1–C3 alkyl. In some embodiments, RA1 is C1–C3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in RA1 are replaced by deuterium. In some embodiments, RA1 is H. In some embodiments, RA1 is methyl. In some embodiments, RA1 is methyl, ethyl, CF3, CHF2, or CH2CF3. In some embodiments, RA1 is CD3 or CD2CD3. In some embodiments, RA1 is halogen. In some embodiments, RA1 is F. In some embodiments, A4 is NRY1. In some embodiments, A4 is NRY1 and RY1 is H. In some embodiments, A4 is NRY1 and RY1 is substituted or unsubstituted C1–C6 alkyl. In some embodiments, RY1 is C1–C6 alkyl that is optionally substituted with one or more halogen (such as F). In some embodiments, RY1 is optionally substituted C1–C3 alkyl. In some embodiments, RY1 is C1–C3 alkyl that is optionally substituted with one or more F. In some embodiments, one or more hydrogens in RY1 are replaced by deuterium. In some embodiments, RY1 is H. In some embodiments, RY1 is methyl. In some embodiments, RY1 is methyl, ethyl, CF3, CHF2, or CH2CF3. In some embodiments, RY1 is CD3 or CD2CD3. [0171] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), W is substituted or unsubstituted C1-C3 alkylene. In some embodiments, W is –CH2–. In some embodiments, W is –CH2CH2–. In some embodiments, W is –CH2CH2CH2–. In some embodiments, W is substituted or unsubstituted C1-C2 heteroalkylene. In some embodiments, W is –CH2OCH2–. In some embodiments, W is –CH2O–, wherein oxygen atom in W is attached to a carbon atom having R18 group. In some embodiments, W is substituted or unsubstituted C3–C8 cycloalkylene or substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is substituted or unsubstituted C3–C8 cycloalkylene. In some embodiments, W is substituted or unsubstituted cyclopropylene. In some embodiments, W is substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is -CH=CH-. [0172] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), , R is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3–C5 cycloalkyl, or substituted or unsubstituted C2–C4 heterocycloalkyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - C(OH)(CH3)2, -CH2CN, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NHCH3, - CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, or azetidinyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2OH, - CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, cyclopropyl, or oxetanyl. In some embodiments, R is hydrogen, -CH3, -CH2OH, -CH2CN, -CHF2, -CF3, or cyclopropyl. In some embodiments, R is hydrogen, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, cyclopropyl, or oxetanyl. In some embodiments, R is -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R is hydrogen. [0173] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R15 and R18 are selected from hydrogen, deuterium, F, –OR31, substituted or unsubstituted C1–C3 alkyl, substituted or unsubstituted C1–C3 fluoroalkyl, and substituted or unsubstituted C1–C3 heteroalkyl. In some embodiments, R15 and R18 are selected from hydrogen, deuterium, F, -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, -CH2OH, -CH2CH2OH, -CH2NHCH3, -CH2N(CH3)2, -OH, -OCH3, - OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -CH2F, -CHF2, and -CF3. In one embodiment, R15 and R18 are selected from hydrogen, deuterium, F, -CH3, -CH2OH, -OCH2CN, -OH, -OCH3, -OCH2CN, - OCF3, -CH2F, -CHF2, and -CF3. In some embodiments, R15 and R18 are selected from hydrogen, deuterium, F, -CH3, -OCH3, -OCF3, -CH2F, -CHF2, and -CF3. In some embodiments, R15 and R18 are selected from hydrogen, deuterium, F, -CH3, and -OCH3. In some embodiments, R15 is F and R18 is hydrogen. In some embodiments, R15 is hydrogen and R18 is F. In some embodiments, R15 is hydrogen and R18 is CH3. In some embodiments, R15 is CH3 and R18 is hydrogen. In some embodiments, R15 and R18 are the same. In some embodiments, R15 and R18 are different. [0174] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, at least one of R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 is F. In some embodiments, one of R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 is F. In some embodiments, at least two of R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 are F. In some embodiments, at least one of R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 is F. In some embodiments, one of R11, R12, R13, R14, R16, and R17 is F. In some embodiments, at least two of R11, R12, R13, R14, R16, and R17 are F. [0175] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), , or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R11 is H, D, or F. In some embodiments, R11 is D. In some embodiments, R11 is H. In some embodiments, R11 is F. [0176] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R12 is H, D, or F. In some embodiments, R12 is D. In some embodiments, R12 is H. In some embodiments, R12 is F. [0177] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R13 is H, D, or F. In some embodiments, R13 is D. In some embodiments, R13 is H. In some embodiments, R13 is F. [0178] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R14 is H, D, or F. In some embodiments, R14 is D. In some embodiments, R14 is H. In some embodiments, R14 is F. [0179] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R15 is H, D, F, CH2F, CHF2, CF3, or CH3. In some embodiments, R15 is H or D. In some embodiments, R15 is F, CH2F, CHF2, CF3, or CH3. In some embodiments, R15 is F, CF3, CHF2, or CH2F. In some embodiments, R15 is F. [0180] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R16 is H, D, or F. In some embodiments, R16 is D. In In some embodiments, R16 is H. some embodiments, R16 is F. [0181] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R17 is H, D, or F. In some embodiments, R17 is D. In some embodiments, R17 is H. In some embodiments, R17 is F. [0182] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R18 is H, D, F, CH2F, CHF2, CF3, or CH3. In some embodiments, R18 is H or D. In some embodiments, R18 is F, CH2F, CHF2, CF3, or CH3. In some embodiments, R18 is F, CF3, CHF2, or CH2F. In some embodiments, R18 is F. [0183] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, at least one of R11, R12, R13, R14, R15, R16, R17, and R18 comprises a fluorine, e.g., F or C1-C4 fluoroalkyl such as CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, at least one of R11, R12, R13, R14, R15, R16, R17, and R18 is F or C1–C4 fluoroalkyl. In some embodiments, one of R11, R12, R13, R14, R15, R16, R17, and R18 comprises a fluorine. In some embodiments, at least two of R11, R12, R13, R14, R15, R16, R17, and R18 comprise a fluorine. In some embodiments, at least one of R11, R12, R13, R14, R16, and R17 comprises a fluorine. In some embodiments, one of R11, R12, R13, R14, R16, and R17 comprises a fluorine. In some embodiments, at least two of R11, R12, R13, R14, R16, and R17 comprise a fluorine. [0184] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, at least one of W, R11, R12, R13, R14, R15, R16, R17, and R18 comprises a fluorine, e.g., F or C1-C4 fluoroalkyl such as CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, one of W, R11, R12, R13, R14, R15, R16, R17, and R18 comprises a fluorine. In some embodiments, W comprises a fluorine. [0185] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R11, R12, R19, R20 and R16 are hydrogen. [0186] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R19 is hydrogen. In some embodiments, R19 is H, F, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, - OCF3, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, and -CH2CF3. In some embodiments, R19 is H, F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, - CH2F, -CHF2, and -CF3. In some embodiments, R19 is F or -OCH3. [0187] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R20 is hydrogen. In some embodiments, R20 is H, F, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, - OCF3, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, and -CH2CF3. In some embodiments, R20 is H, F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, - CH2F, -CHF2, and -CF3. In some embodiments, R20 is F or -OCH3. [0188] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R20 is H, D, or F. In some embodiments, R20 is D. In some embodiments, R20 is H. In some embodiments, R20 is F. [0189] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R16 and R19 are H. In some embodiments, R16 and R19 are D. In some embodiments, R16 and R19 are F. [0190] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R19 and R20 are H. In some embodiments, R19 and R20 are D. In some embodiments, R19 and R20 are F. [0191] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R17 and R20 are H. In some embodiments, R17 and R20 are D. In some embodiments, R17 and R20 are F. [0192] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R11, R12, R19, R20 and R16 are hydrogen. [0193] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R19 is hydrogen. In some embodiments, R19 is H, F, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, - OCF3, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, and -CH2CF3. In some embodiments, R19 is H, F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, - CH2F, -CHF2, and -CF3. In some embodiments, R19 is F or -OCH3. [0194] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R20 is hydrogen. In some embodiments, R20 is H, F, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, - OCF3, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, and -CH2CF3. In some embodiments, R20 is H, F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, - CH2F, -CHF2, and -CF3. In some embodiments, R20 is F or -OCH3. [0195] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, at least one of R11, R12, R13, R14, R15, R16, R17, R19, R20, and R18 is F. In some embodiments, one of R11, R12, R13, R14, R15, R16, R17, R19, R20, and R18 is F. In some embodiments, at least two of R11, R12, R13, R14, R15, R16, R17, R19, R20, and R18 are F. In some embodiments, at least one of R11, R12, R13, R14, R16, R19, R20, and R17 is F. In some embodiments, one of R11, R12, R13, R14, R16, R19, R20, and R17 is F. In some embodiments, at least two of R11, R12, R13, R14, R16, R19, R20, and R17 are F. [0196] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, at least one of R11, R12, R13, R14, R15, R16, R17, R19, R20, and R18 comprises a fluorine, e.g., F or C1–C4 fluoroalkyl such as CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, at least one of R11, R12, R13, R14, R15, R16, R17, R19, R20, and R18 is F or C1-C4 fluoroalkyl. In some embodiments, one of R11, R12, R13, R14, R15, R16, R17, R19, R20, and R18 comprises a fluorine. In some embodiments, at least two of R11, R12, R13, R14, R15, R16, R17, R19, R20, and R18 comprise a fluorine. In some embodiments, at least one of R11, R12, R13, R14, R16, R19, R20, and R17 comprises a fluorine. In some embodiments, one of R11, R12, R13, R14, R16, R19, R20, and R17 comprises a fluorine. In some embodiments, at least two of R11, R12, R13, R14, R16, and R17 comprise a fluorine. [0197] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, at least one of W, R11, R12, R13, R14, R15, R16, R17, R19, R20, and R18 comprises a fluorine, e.g., F or C1–C4 fluoroalkyl such as CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, one of W, R11, R12, R13, R14, R15, R16, R17, R19, R20, and R18 comprises a fluorine. In some embodiments, W comprises a fluorine.
Figure imgf000062_0001
Figure imgf000063_0001
[0199] In some embodiments,
Figure imgf000063_0002
selected from the group consisting of
Figure imgf000063_0003
Figure imgf000064_0001
. In some embodiments,
Figure imgf000064_0002
is selected from the group consisting of
Figure imgf000065_0001
[0201] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), X is absent. [0202] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), X is -O-. [0203] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), X is -S-. [0204] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), X is -C(=O)-. [0205] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), X is -NRX1-. In some embodiments, X is N-C1-C6 alkyl. In some embodiments, X is N-methyl. In some embodiments, X is N-C1-C6 cycloalkyl. In some embodiments, X is N-cyclopropyl. [0206] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), X is -CRX2RX3-. [0207] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula
Figure imgf000065_0002
. [0208] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), X is or =CRX1-. [0209] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), Z is N. [0210] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), Z is C. [0211] In some embodiments of a compound of Formula (I), Formula (II), Formula (II*), or Formula (IIa), Z is CR5. In some embodiments, Z is CH. [0212] In some embodiments, each R31 is independently hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, -CD3, or substituted or unsubstituted C1–C4 haloalkyl. In some embodiments, each R31 is independently hydrogen, deuterium, or C1-C4 alkyl. In some embodiments, each R31 is independently hydrogen, deuterium, or methyl. In some embodiments, R31 is H. In some embodiments, R31 is methyl. [0213] In some embodiments, R1 is H. In some embodiments, R1 is halogen. In some embodiments, R1 is OH. In some embodiments, R1 is –OR31. In some embodiments, R1 is CN. In some embodiments, R1 is substituted or unsubstituted alkyl. In some embodiments, R1 is substituted or unsubstituted haloalkyl. In some embodiments, R1 is substituted or unsubstituted heteroalkyl. In some embodiments, R1 is –SR31, -S(=O)R31, -SO2R31, -NR31R32, -NR31S(=O)(=NR31)R32, - NR31S(=O)2R31R32, -SO2NR31R32, -C(=O)R31, -OC(=O)R31, -C(=O)OR31, -OC(=O)OR31, - C(=O)NR31R32, -OC(=O)NR31R32, -NR31C(=O)R32, or -P(=O)R31R32. [0214] In some embodiments, R1 is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic cycloalkyl, or substituted or unsubstituted monocyclic heteroaryl. [0215] In some embodiments, R1 is substituted or unsubstituted polycyclic aryl, substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic cycloalkyl, or substituted or unsubstituted polycyclic heteroaryl. In some embodiments, R1 is a fused ring. In some embodiments, R1 is a bridged ring. In some embodiments, R1 is a spiro ring. [0216] In some embodiments, R2 is H. In some embodiments, R2 is halogen. In some embodiments, R2 is OH. In some embodiments, R2 is –OR31. In some embodiments, R2 is CN. In some embodiments, R2 is substituted or unsubstituted alkyl. In some embodiments, R2 is substituted or unsubstituted haloalkyl. In some embodiments, R2 is substituted or unsubstituted heteroalkyl. In some embodiments, R2 is –SR31, -S(=O)R31, -SO2R31, -NR31R32, -NR31S(=O)(=NR31)R32, - NR31S(=O)2R31R32, -SO2NR31R32, -C(=O)R31, -OC(=O)R31, -C(=O)OR31, -OC(=O)OR31, - C(=O)NR31R32, -OC(=O)NR31R32, -NR31C(=O)R32, or -P(=O)R31R32. [0217] In some embodiments, R2 is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic cycloalkyl, or substituted or unsubstituted monocyclic heteroaryl. [0218] In some embodiments, R2 is substituted or unsubstituted polycyclic aryl, substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic cycloalkyl, or substituted or unsubstituted polycyclic heteroaryl. In some embodiments, R2 is a fused ring. In some embodiments, R2 is a bridged ring. In some embodiments, R2 is a spiro ring. [0219] In some embodiments, a compound described herein, possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis. EXAMPLES [0220] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. Compounds described herein can be synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology can be employed. Compounds can be prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific. The starting materials can be available from commercial sources or can be readily prepared. By way of example only, provided are schemes for preparing the Examples described herein. [0221] The following abbreviations are used: DCM – dichloromethane; DIPEA – N,N- diisopropylethylamine; DMSO - dimethyl sulfoxide; DMF - N,N-dimethylformamide; EDCI - N-(3- Dimethylaminopropyl)-N′-ethylcarbodiimide; Et2O - diethyl ether; EtOAc - ethyl acetate; EtOH - ethyl alcohol; HOBt – 1-hydroxybenzotriazole; LCMS – liquid chromatography mass spectrometer; MeCN – acetonitrile; MeOH - methyl alcohol; Ms – mesylate; MTBE – methyl tert-butyl ether; Selectfluor - 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); SFC - supercritical fluid chromatography; THF - tetrahydrofuran; TMSCl – trimethylsilyl chloride; h – hour; min – minute; rt - room temperature (22-25 °C); g – grams; mL - milliliters; mg – milligrams; mmol – millimoles. [0222] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527–29074–5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0–19–509618–5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley–VCH, ISBN: 0–471–19031–4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0–471–60180–2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley–VCH, ISBN: 3–527–29871–1; Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0–471– 93022–9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0–471–19095–0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley– Interscience, ISBN: 0–471–57456–2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3–527–29645–X, in 8 volumes; “Organic Reactions” (1942–2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. [0223] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. A detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure). Stereochemistry: [0224] (±) or racemic indicates that the product is a racemic mixture of enantiomers. For example (±) (1S,2S,3R,5R) or racemic (1S,2S,3R,5R) indicates that the relative product stereochemistry shown is based on known stereochemistry of similar compounds and or reactions and the product is a racemic mixture of enantiomers of both (1S,2S,3R,5R) and (1R,2R,3S,5S) stereoisomers. A compound in which the absolute stereochemistry of separated enantiomers is undetermined is represented as being either of the single enantiomers, for example (1S,2S,3R,5R) or (1R,2R,3S,5S) or drawn as being either possible single enantiomer. In such cases, the product is pure and a single enantiomer, but absolute stereochemistry is not identified, but relative stereochemistry is known and indicated. [0225] Example 1: Preparation of 7-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)-6-hydroxy-2-methyl-4H-chromen-4-one and 7-(6- (((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)-6- hydroxy-2-methyl-4H-chromen-4-one (Compound 5A and 5B).
Figure imgf000070_0001
[0226] Step 1: Preparation of racemic tert-butyl (1S,2R,3R,5R)-2-fluoro-3-((3-(methylthio)- 1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate, and tert-butyl (1R,2S,3S,5S)- 2-fluoro-3-((3-(methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. [0227] To a 1000 mL 3-necked round-bottom flask was added 6-bromo-3-(methylsulfanyl)-1,2,4- triazine (24.00 g, 116.5 mmol), a racemic mixture of tert-butyl (1S,2R,3R,5R)-3-amino-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,2S,3S,5S)-3-amino-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate (43.0 g, 176 mmol), DIEA(60 mL, 344.5 mmol) and n-butanol (360 mL) under nitrogen. The resulting solution was placed in a preheated oil bath stirred at 120°C for 2 hours under nitrogen. The reaction mixture was removed from heat and cooled to room temperature and diluted with water (700 mL) and then extracted with ethyl acetate (3 x 250 mL). The organic layers were combined, washed with brine (250 mL), and dried over anhydrous Na2SO4. The mixture was filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/ EtOAc (4:1) which gave a racemic mixture of tert-butyl (1S,2R,3R,5R)-2- fluoro-3-((3-(methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate, and tert-butyl (1R,2S,3S,5S)-2-fluoro-3-((3-(methylthio)-1,2,4-triazin-6-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (24g, 55.8%) [M+H]+=370. [0228] Step 2: Preparation of racemic mixture of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-(methyl(3- (methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate, tert-butyl (1R,2S,3S,5S)-2-fluoro-3-(methyl(3-(methylthio)-1,2,4-triazin-6-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate. [0229] To a 1000 mL 3-necked round-bottom flask was added tert-butyl (1S,2R,3R,5R)-2-fluoro-3- ((3-(methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate, and tert-butyl (1R,2S,3S,5S)-2-fluoro-3-((3-(methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (21 g, 56.84 mmol) and dimethylformamide (420 mL) under nitrogen. The resultant mixture was cooled to 0°C followed by portion wise addition of sodium hydride (4.54 g, 113.51 mmol) with the internal temperature maintained at 0°C under nitrogen. The cooling bath was removed, and the mixture was stirred for additional 0.5 h and allowed to come to room temperature under nitrogen. Methyl iodide (7.20 mL, 115.66 mmol) was added dropwise at room temperature with stirring. The resulting mixture was stirred for additional 1 h at room temperature. The reaction mixture was then cooled to 0°C and quenched with water (1 L). The resulting mixture was extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with water (2x250 mL) and saturated brine (250 mL), and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (CH2Cl2/EtOAc (19:1)) which gave 17 g (78%) of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-(methyl(3-(methylthio)-1,2,4-triazin-6- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,2S,3S,5S)-2-fluoro-3- (methyl(3-(methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate as a racemic yellow solid, [M+H]+=384. [0230] Step 3: Chiral Separation of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-(methyl(3-(methylthio)- 1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,2S,3S,5S)- 2-fluoro-3-(methyl(3-(methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate. [0231] The racemic mixture of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-(methyl(3-(methylthio)-1,2,4- triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,2S,3S,5S)-2-fluoro-3- (methyl(3-(methylthio)-1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (11.00 g, 28.684 mmol) was purified into individual isomers by Prep-SFC. The following conditions were used (Column: CHIRALPAK IG, 2*25cm,5um; Mobile Phase A: CO2, Mobile Phase B: EtOH--HPLC; Flow rate: 40 mL/min; Gradient: 50% B; 250 nm; RT1: 3.99 min; RT2: 6.19 min; Injection volume: 4 ml; Number Of Runs: 80;) which gave isomer 1 (5.0 g) as a yellow solid and isomer 2 (5.2g) as a yellow solid. [0232] Step 4: Preparation of 1-(3-bromo-4-methoxyphenyl)-N-(2,2- dimethoxyethyl)methanimine. [0233] To a 500 mL 3-necked round-bottom flask was added 3-bromo-4-methoxybenzaldehyde (25 g, 116.000 mmol), toluene (250 mL) and 2,2-dimethoxyethan-1-amine (19 mL, 174.1 mmol, 1.50). The reaction flask was fitted with a Dean-Stark trap and the mixture was placed in a preheated oil bath at 120°C and was stirred for 6 hours, removed from heat, and allowed to cool. The resulting mixture was then concentrated under vacuum to a constant weight which gave after isolation 37g of 1-(3-bromo-4- methoxyphenyl)-N-(2,2-dimethoxyethyl)methanimine that was used directly in the next step m/z: 302(M+H+). [0234] Step 5: Preparation of 7-bromo-6-methoxyisoquinoline. [0235] To a 1000mL 1-necked round-bottom flask was added 1-(3-bromo-4-methoxyphenyl)-N-(2,2- dimethoxyethyl)methanimine (37 g, 122.45 mmol), and tetrahydrofuran (370 mL). The mixture was then cooled to 0oC and isopropyl chloroformate (15.01 g, 122.45 mmol) was added dropwise. After stirring for 5 min, triethyl phosphite (24.42 g, 146.970 mmol) was added and mixture was stirred for 20 min, then the cooling bath was removed. The resulting mixture was then stirred for 18 hours at room temperature. The solvent was then removed, and the remaining residue was azeotroped with 100ml of toluene. To the resultant mixture, titanium tetrachloride (94.16 g) and chloroform (375 mL) were added and the mixture was heated to reflux for 48 hr. The mixture was removed from heat and then poured on ice/water. The pH was then adjusted to 9 with ammonium hydroxide. The reaction mixture was extracted with ethyl acetate (4X200mL). The organics were combined and concentrated to dryness under reduced pressure which was purified by silica gel column(ethyl acetate:petroleum ether 3:7) which gave after isolation 6.1 g of 7-bromo-6-methoxyisoquinoline as a solid. m/z: 238(M+H+). [0236] Step 6: Preparation of 6-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoquinoline. [0237] To a 40 mL vial purged and maintained with an inert atmosphere of nitrogen was added 7- bromo-6-methoxyisoquinoline (1.50 g, 6.3 mmol), bis(pinacolato)diboron (1.92 g, 7.561 mmol), 1,1 - Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.51 g, 0.625 mmol), potassium acetate (1.24 g, 12.635 mmol) and dioxane (30 mL, 354.123 mmol). The resulting mixture was placed in a preheated oil bath and was stirred for 4 hours at 100°C then removed from heat, allowed to cool. The resulting mixture was diluted with ethyl acetate (200 mL), filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH 9:1) which gave a reddish brown solid which was further purified by Preparative-HPLC (C18; mobile phase: NH4HCO3 (aq) / MeCN; Gradient: 10% B to 50% B in 30 min; Detector: 254 nm) which gave after isolation 1.4 g of 6-methoxy-7-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)isoquinoline as a solid m/z: 286(M+H+). [0238] Step 7: Preparation of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-((3-(6-methoxyisoquinolin-7- yl)-1,2,4-triazin-6-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,2S,3S,5S)-2-fluoro-3-((3-(6-methoxyisoquinolin-7-yl)-1,2,4-triazin-6-yl)(methyl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate. [0239] To a 40 mL vial purged and maintained with an inert atmosphere of nitrogen was added Isomer 1 (300 mg, 0.782 mmol), 6-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (670 mg, 2.35 mmol), tetrakis(triphenylphosphine) palladium(0) (135 mg, 0.117 mmol, 0.15), copper(I)-3-methylsalicylate (504 mg, 2.348 mmol) and tetrahydrofuran (7.50 mL). The resulting mixture was placed in a preheated oil bath at 70°C and was stirred for 12 hours then removed from heat, allowed to cool. The resulting mixture was diluted with CH2Cl2 (100mL). The resulting mixture was washed with 3x25 mL of ammonium hydroxide (10%) and 50 mL of brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: 100%) which gave after isolation, 278 mg of INT 7A as a light yellow solid. m/z:495(M+H+). [0240] Following the procedure above, but starting with Isomer 2 (350 mg, 0.913 mmol) which after isolation gave 350 mg of INT 7B as a yellow solid, m/z:495(M+H+). [0241] Step 8: Preparation of 7-(6-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)-1,2,4-triazin-3-yl)isoquinolin-6-ol and 7-(6-(((1R,2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-1,2,4-triazin-3-yl)isoquinolin-6-ol (Compound 5A and 5B). [0242] To a 100-mL round-bottom flask, was placed INT 7A (150 mg, 0.303 mmol), dichloromethane (5 mL, 78.65 mmol), and boron tribromide (759.82 mg, 3.033 mmol). The resulting solution was stirred for 4 hours at room temperature followed by quenching with aqueous sodium bicarbonate to a final pH of 9. The mixture was extracted with dichloromethane (3x50 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC, (IntelFlash-1): Column: C18; mobile phase: NH4HCO3 (aq) / MeCN; Gradient: 10% B to 50% B in 30 min; Detector254 nm, which gave after isolation 30 mg of Compound 5A as a yellow solid (ES, m/z): [M+1]+ = 381.2.1H NMR (300 MHz, DMSO-d6) δ ppm 12.96 (s, 1H), 9.31 (d, J = 1.1 Hz, 1H), 8.99 (s, 1H), 8.87 (s, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 5.9 Hz, 1H), 7.38 (s, 1H), 4.94 (d, J = 24.8 Hz, 1H), 4.70 (d, J = 52.0 Hz, 1H), 3.55 (s, 2H), 3.18 (d, J = 1.7 Hz, 3H), 2.35 – 2.19 (m, 1H), 1.87 – 1.52 (m, 5H). [0243] Following the procedure above, but starting with INT 7B (150 mg, 0.303 mmol), gave 25 mg of Compound 5B as a yellow solid (ES, m/z): [M+1]+ = 381.2.1H NMR (300 MHz, DMSO-d6) δ ppm 12.96 (s, 1H), 9.31 (d, J = 1.1 Hz, 1H), 8.99 (s, 1H), 8.87 (s, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 5.9 Hz, 1H), 7.38 (s, 1H), 4.94 (d, J = 24.8 Hz, 1H), 4.70 (d, J = 52.0 Hz, 1H), 3.55 (s, 2H), 3.18 (d, J = 1.7 Hz, 3H), 2.35 – 2.19 (m, 1H), 1.87 – 1.52 (m, 5H). [0244] Example 2: Synthesis of (1R,2S,3S,5S)-tert-Butyl 3-amino-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate.
Figure imgf000074_0001
[0245] Step 1: tert-Butyl 3-((triethylsilyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2-2). [0246] To a stirred solution of lithium diisopropylamide (15.0 L, 29.83 moles) in THF (14.4 L) at – 78 °C was added 2-1 (4.20 Kg, 21.30 moles ) in THF (9.6 L) slowly over a period of 1 h keeping the temperature below -70 °C. The reaction mixture was stirred for 30 minutes at -78 °C (became deep yellow), triethylchlorosilane (3.53 Kg, 23.44 moles) was added for 15 minutes and the reaction mixture was stirred 10 minutes at -78 °C. The reaction mixture was allowed to warm to -15 °C to -10 °C and stirred for 2 h. After consumption of starting material by TLC, the reaction mass was quenched by adding 10% sodium bicarbonate solution (33.6 L) at 0 °C to 5 °C and extracted with MTBE (3 x 19.2 L) at room temperature. The combined organic extracts were washed with brine (26.4 L), dried over sodium sulphate, filtered and concentrated in vacuum to afford 2-2 (7.2 Kg, crude) as an orange oil which was used in the next step without further purification. [0247] Step 2: tert-Butyl 2-fluoro-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (Rac-2-3). [0248] To a solution of selectfluor (9.0 Kg, 25.44 moles) in acetonitrile (100 L) was added 2-2 (7.2 Kg, 21.20 moles) in acetonitrile (14.4 L) at -30 °C for 30 minutes under nitrogen. The reaction mixture was slowly warmed to 10 °C over a period of 1 h 30 minutes. After consumption of starting material by TLC, the reaction mixture was quenched by adding water (93.6 L) at 10 °C. The reaction mass was extracted with MTBE (3 x 28.8 L), and the combined organic extracts were washed with brine (2 x 36 L), dried over sodium sulphate and concentrated in vacuum to afford 4.5 Kg (crude) of 2-3. This crude product was dissolved in petroleum ether (50.4 L), heated to 60 °C and stirred for 10 min. Undissolved solids were removed by filtration and the filtrate was concentrated to 2 volumes and stirred for 30 minutes at room temperature. Solids were collected by filtration and dried to obtain 3.8 Kg of crude 2- 3. The crude 2-3 was dissolved in acetonitrile (7.6 L) and water (22.8 L) was slowly added over 30 minutes, the precipitated solid was aged for 2 h. This solid was filltered and dried to obtain Rac-2-3 (3.2 Kg, 62%) as an off white solid.1H NMR (400 MHz, CDCl3): δ 4.66 – 4.32 (m, 3H), 3.11 – 3.08 (m, 1H), 2.37-2.31 (m, 1H), 2.13 – 1.97 (m, 2H), 1.66 – 1.25 (m, 11H); Mass (m/z): 144 (M+H-Boc). [0249] Step 3: tert-Butyl 3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate (Rac-2-4). [0250] To a stirred solution of Rac-2-3 (1.3 Kg, 5.34 moles) in methanol (7.8 L) was added benzyl amine (0.63 Kg, 5.878 moles) at 0 °C for 30 minutes followed by titanium(IV) propan-2-olate (2.58 Kg, 9.080 moles) for 15 minutes. The reaction mixture was stirred at room temperature for 2 h, diluted with methanol (7.8 L), cooled to -15 °C and then sodiumborohydride (0.35 kg, 9.08 moles) was added portion wise. The reaction mixture was stirred for 30 minutes at 0 °C. After consumption of starting material by TLC, the reaction mixture was quenched by adding of 1N sodium hydroxide solution (16.9 L), diluted with toluene (13.0 L) and stirred vigorously for 30 minutes. The reaction mass was filtered through a celite pad and washed with toluene (6.5 L). Phases were separated and the aqueous layer was extracted with toluene (2 x 3.25 L). The combined organic extracts were washed with brine (6.5 L), dried over sodium sulphate, filtered and concentrated in vacuum to obtain Rac-2-4 (1.7 Kg, 95%) as an off white solid.1H NMR (400 MHz, CDCl3): δ 7.33 – 7.22 (m, 5H), 4.67 – 4.30 (m, 3H), 3.89 – 3.77 (m, 2H), 2.91-2.79 (m, 1H), 1.92 – 1.79 (m, 3H), 1.61 – 1.51 (m, 1H), 1.45 (s, 9H); Mass (m/z): 335 (M+H). [0251] Step 4: (1R,2S,3S,5S)-tert-Butyl-3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate(2-4). [0252] To a solution of Rac-2-4 (1.0 Kg, 2.990 moles, 50% ee) in methyl ethyl ketone (12.0 L) was added (R)-(-)-mandelic acid (0.227 Kg, 1.495 moles) in methyl ethyl ketone (3.0 L) slowly over a period of 1 h at room temperature. The reaction mixture was heated to 60 °C, stirred for 3 h, cooled to room temperature and stirred for 18 h. The precipitated solid was filtered, washed with methyl ethyl ketone (1.0 L) and dried to obtain 0.45 Kg of salt. The salt was neutralised with sat NaHCO3 solution and extracted with ethyl acetate (2 x 400 mL). The combined organic extracts were dried over sodium sulphate and concentrated under vacuum to obtain 2-4 (0.315 Kg, 88% chiral purity) as an off-white solid. The chiral resolution and free basing steps were repeated in an identical manner to provide the desired compound 2-4 as an off-white solid (0.225 kg, 98% chiral purity, 22.5%). [0253] Step 5: (1R,2S,3S,5S)-tert-Butyl 3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate (2-5). [0254] To a solution of 2-4 (225.0 g, 1.524 moles) in ethanol (675 mL) was added 10% Pd/C (45.0 g) and the reaction mixture was stirred for 18 h under hydrogen atmosphere. After consumption of starting material by TLC, the reaction mixture was purged with nitrogen and filtered over celite, washing the celite pad with ethanol (1.0 L). Concentration in vacuo afforded 2-5 (157.1 g, 95%) as an off white solid.1H NMR (500 MHz, DMSO-d6): δ 4.40 – 4.28 (m, 2H), 4.06 (bs, 1H), 2.94 – 2.85 (m, 1H), 1.78 – 1.76 (m, 2H), 1.56 – 1.44 (m, 6H), 1.43 (s, 9H); 19F NMR (500 MHz, DMSO-d6): δ 199.2; Mass (m/z): 245.2 (M+H); GC purity: 98.03%. [0255] Example 3: Preparation of (1R,2S,3S,5S)-tert-Butyl 2-fluoro-3-(methyl(3-(methylthio)- 1,2,4-triazin-6-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate Formula (IIaa).
Figure imgf000076_0001
[0256] Step 1: 6-Bromo-1,2,4-triazin-3-amine (3-2): NBS (556 g, 3.122 mol, 1.2 eq) was added portion wise to a solution of 3-1 (250 g, 2.601 mol, 1.0 eq) in MeCN (1.8 L) and water (3.7 L) at 0 °C. The resulting solution was stirred at 0 °C for 10 minutes, then allowed to warm to RT and stirred for 4 h. After completion of the reaction (by TLC), the reaction mixture was cooled to 0 °C, 30% sodium carbonate solution was added to reaction mixture up to PH ~ 9 to 9.5 and stirred for 10 minutes at 25 °C. The aqueous layer was extracted with ethyl acetate (4 x 1.0 L), combined organic extrats were washed with brine (1.25 L), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give crude product which was purified by slurrying in acetonitrile: ethanol (2:0.1 vol) to obtain 3-2 (145 g, 33%) as pale yellow solid. [0257] Step 2: 6-Bromo-3-(methylthio)-1,2,4-triazine (3-3): tert-Butyl nitrite (442 g, 4.286 mol, 5.0 eq) was added drop wise to a solution of 3-2 (150 g, 0.857 mol) and 1,2-dimethyldisulfide (121 g, 1.286 mol, 1.5 eq) in MeCN (2.3 L) at 0 °C, then allowed to warm to RT and stirred for 4 h. After completion of the reaction (by TLC), the reaction mixture was cooled to 0 °C. MeOH (1.0 L) was added to reaction mixture and the resulting mixture was stirred for 10 min, then volatiles were evaporated under reduced pressure at 30 °C to give crude productwhich was purified by silica gel column chromatography using 10% EtOAc: pet ether to furnish 3-3 (65.0 g, 37%) as an off white solid. [0258] Step 3: (1R,2S,3S,5S)-tert-Butyl 2-fluoro-3-((3-(methylthio)-1,2,4-triazin-6-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (3-5): To a 1000 mL 3-necked round-bottom flask were added 3-3 (24.0 g, 0.116 mol, 1.00 eq), 3-4 (43.0 g, 0.176 mol, 1.51 eq), DIEA (60.0 mL, 0.344 mol, 2.96 eq) and n-BuOH (360 mL). The resulting mixture was stirred for 2 h at 120 °C. The reaction mixture was diluted with water (700 mL) and extracted with EtOAc (3 x 250 mL). The combined organic extracts were washed with brine (250 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with pet ether / EtOAc (4:1) to afford 3-5 (24 g, 55.77%) as a yellow solid. [0259] Step 4: (1R,2S,3S,5S)-tert-Butyl 2-fluoro-3-(methyl(3-(methylthio)-1,2,4-triazin-6- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (3-6): To a 1000 mL 3-necked round-bottom flask, 3-5 (21.00 g, 0.056 mol, 1.0 eq) and DMF (250 mL) were added. To the above mixture was added NaH (4.54 g, 0.113 mol, 2.0 eq, 60%) in portions at 0 °C. The resulting mixture was stirred for an additional 0.5 h at room temperature. To the above mixture was added methyl iodide (7.20 mL, 0.115 mmol, 2.03 eq) drop wise at room temperature. The resulting mixture was stirred for an additional 1 h at room temperature. The reaction was quenched by the addition of water (250 mL) at 0 °C and extracted with EtOAc (3 x 250 mL). The combined organic extracts were washed with water (2x250 mL) and brine (250 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with pet ether / EtOAc (4:1) to 3-6 (17 g, 77.99%) as a yellow solid. [0260] Example 4: Synthesis of 6-(6-[[(1R,2R,3S,5S)-2-Fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino]-1,2,4-triazin-3-yl)-7-hydroxy-2-methylphthalazin-1-one.
Figure imgf000077_0001
[0261] Step 1: 4-Bromo-3-methoxy-N-methylbenzohydrazide. [0262] To a 3 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-3-methoxybenzoic acid (80.0 g, 346.25 mmol, 1.00 equiv), methyl hydrazine (63.81 g, 1384.98 mmol, 4.00 equiv), DMF (1.0 L), EDCI (79.65 g, 415.50 mmol, 1.20 equiv) and HOBt (56.15 g, 415.50 mmol, 1.20 equiv) was added at 0℃. The resulting solution was stirred for 12 h at room temperature. The reaction was then quenched by the addition of 2.0 L of water. The resulting solution was extracted with 3x2 L of ethyl acetate. The organic extracts were washed with 3 x 3 L of saturated aqueous NaCl. The mixture was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Flash column chromatography with the following conditions: Column, C18; mobile phase, 0.1%NH4HCO3/H2O: ACN=20-80%; Detector, 254 nm. This resulted in 92 g (57.97%) of 4-bromo-3-methoxy-N-methylbenzohydrazide as light yellow oil. [0263] Step 2: 4-Bromo-3-methoxy-N-methyl-N'-methylidenebenzohydrazide. [0264] To a 2 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-3-methoxy-N-methylbenzohydrazide (52.0 g, 200.69 mmol, 1.00 equiv), paraformaldehyde (7.23 g, 240.83 mmol, 1.20 equiv), Toluene (1.0 L). The resulting solution was stirred for 16 h at 120 degrees C in an oil bath. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:3). This provided 45 g (82.71%) of 4-bromo-3-methoxy-N- methyl-N'-methylidenebenzohydrazide as a white solid. [0265] Step 3: 6-Bromo-7-methoxy-2-methylphthalazin-1-one. [0266] To a 2 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-3-methoxy-N-methyl-N'-methylenebenzohydrazide (45.0 g, 165.98 mmol, 1.00 equiv), quinone (26.91 g, 248.98 mmol, 1.50 equiv), Pd(OAc)2 (2.80 g, 12.45 mmol, 0.10 equiv), HOAc (900 mL). The resulting solution was stirred for 12 h at 120 degrees C in an oil bath. The reaction mixture was cooled with a water/ice bath. The resulting mixture was concentrated. The pH value of the solution was adjusted to 8 with saturated NaHCO3 aq. The resulting solution was extracted with 5x1.5L of ethyl acetate dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 36 g (80.59%) of 6-bromo-7-methoxy-2-methylphthalazin-1-one as a light yellow solid. [0267] Step 4: 7-methoxy-2-methyl-1-oxophthalazin-6-ylboronic acid. [0268] To a 2 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-7-methoxy-2-methylphthalazin-1-one (36 g, 133.78 mmol, 1.00 equiv), (PinB)2 (53.3 g, 200.67 mmol, 1.50 equiv), Pd(dppf)Cl2.CH2Cl2 (5.46 g, 6.69 mmol, 0.05 equiv), KOAc (26.26 g, 267.56 mmol, 2.00 equiv), dioxane (360 ml). The resulting solution was stirred for 4 h at 100 degrees C in an oil bath. The reaction mixture was cooled and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:2). The crude product was re-crystallized from PE/EA in the ratio of 4:1. This provided 30.0 g (70.92 %) of 7-methoxy-2-methyl-1-oxophthalazin-6-ylboronic acid as a white solid. [0269] Step 5: tert-Butyl (1R,2S,3S,5S)-2-fluoro-3-[[3-(7-methoxy-2-methyl-1-oxophthalazin-6- yl)-1,2,4-triazin-6-yl](methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate. [0270] To a 500 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (1R,2S,3S,5S)-2-fluoro-3-[methyl[3-(methylsulfanyl)-1,2,4-triazin-6-yl]amino]-8- azabicyclo [3.2.1]octane-8-carboxylate (18.13 g, 47.44 mmol, 1.00 equiv), 7-methoxy-2-methyl-1- oxophthalazin -6-ylboronic acid (30.0 g, 94.88 mmol, 2.00 equiv), Pd(PPh3)4 (2.74 g, 2.37 mmol, 0.05 equiv), copper(I)-3-methylsalicylate (20.37 g, 94.88 mmol, 2.0 equiv), THF (300 mL). The resulting solution was stirred for 3 h at 70 degrees C. The reaction mixture was cooled. The crude product was purified by HP-Flash with the following conditions: Column, XB-C18; mobile phase, 0.1%NH4HCO3/H2O: ACN=20-70%; Detector, 254 nm. This resulted in 15.0 g (60.17%) of tert- butyl (1R,2S,3S,5S)-2-fluoro-3-[[3-(7-methoxy-2-methyl-1-oxophthalazin-6-yl)-1,2,4-triazin-6- yl](methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. [0271] Step 6: tert-Butyl (1R,2S,3S,5S)-2-fluoro-3-((3-(7-hydroxy-2-methyl-1-oxo-1,2- dihydrophthalazin-6-yl)-1,2,4-triazin-6-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate. [0272] To a 500 mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl tert-butyl (1R,2S,3S,5S)-2-fluoro-3-[[3-(7-methoxy-2-methyl-1- oxophthalazin-6-yl)- 1,2,4-triazin- 6-yl](methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (15.0 g, 28.54 mmol, 1.00 equiv), DMF (150 ml ), and NaSEt (12.0 g, 142.70 mmol, 5.00 equiv). The resulting solution was stirred for 2 h at 100℃. The reaction was then quenched by the addition of 400 mL of NH4Cl aq. The pH value of the solution was adjusted to 6 with 1N HCl. The resulting solution was extracted with 20% MeCN/EtOAc (6 x 500 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by HP-Flash with the following conditions: Column, XB-C18; mobile phase, 0.1%NH4HCO3/H2O: ACN=10-60%; Detector, 254 nm. This resulted in 13 g (89.04%) of tert-butyl (1R,2S,3S,5S)-2-fluoro-3-((3-(7-hydroxy-2-methyl- 1-oxo-1,2-dihydrophthalazin-6-yl)-1,2,4-triazin-6-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate as a yellow solid. [0273] Step 7: 6-(6-[[(1R,2R,3S,5S)-2-Fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino]- 1,2,4-triazin-3-yl)-7-hydroxy-2-methylphthalazin-1-one. [0274] To a 500 mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (1R,2S,3S,5S)-2-fluoro-3-[[3-(7-methoxy-2-methyl-1- oxophthalazin-6-yl)-1,2,4-triazin -6-yl] (methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (13.0 g, 25.41 mmol, 1.00 equiv), HCl/EA (195 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated. The reaction was then quenched by the addition of saturated aqueous of NaHCO3 (200 mL). The resulting solution was extracted with 20% MeCN/EtOAc (5 x 200 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by HP-Flash with the following conditions: Column, XB-C18; mobile phase, 0.1%NH4HCO3/H2O: ACN=10-60%; Detector, 254 nm. The eluant was concentrated under vacuum. The residue was was dissolved in 2N HCl (200 mL), and extracted with 20% MeCN/EtOAc (5*200 mL). The aqueous layer was basified to pH ~8 with saturated aqueous of NaHCO3. The resulting mixture was extracted with 20% MeCN/EtOAc (5*200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with EtOAc. The solid was dried in an oven under reduced pressure. This resulted in 5.5 g (52.63 %) of 6-(6-[[(1R,2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl](methyl)amino]-1,2,4-triazin-3-yl)-7-hydroxy-2-methylphthalazin-1-one as a yellow solid. H-NMR- PH-SKY-RGX-0066062-0: (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.29 (s, 2H), 8.96 (s, 1H), 8.76 (s, 1H), 8.47 (s, 1H), 7.67 (s, 1H), 5.09 (t, J = 39.1 Hz, 2H), 4.23 (d, J = 39.0 Hz, 2H), 3.71 (s, 3H), 3.20 (d, J = 1.6 Hz, 3H), 2.69 – 2.58 (m, 1H), 2.13 – 2.05 (m, 4H), 1.94 (d, J = 13.6 Hz, 1H).; (ES, m/z) [M+H]+=412.05. [0275] Example 5: Synthesis of 7-(6-{[(2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino}-1,2,4-triazin-3-yl)-6-hydroxy-3-methylquinazolin-4-one.
Figure imgf000081_0001
[0276] Step 1: Methyl 4-bromo-5-methoxy-2-nitrobenzoate. [0277] To a 5000-mL 4-necked round-bottom flask, was placed methyl 4-bromo-5-fluoro-2- nitrobenzoate (200.00 g, 719 mmol, 1.00 equiv), MeOH (2 L), MeONa (46.62 g, 863 mmol, 1.20 equiv). The resulting solution was stirred for 3 hr at room temperature. The resulting mixture was concentrated. The resulting mixture was dissolved in 2 L of EA, washed with 2x1 L of H20. The organic layers were concentrated. This resulted in 200 g (96.1%) of methyl 4-bromo-5-methoxy-2- nitrobenzoate as a solid. (CDCl3, ppm): δ 8.28 (s, 1H), 7.08 (s, 1H), 4.04 (s, 3H), 3.95 (s, 3H). [0278] Step 2: 4-Bromo-5-methoxy-2-nitrobenzoic acid. [0279] Into a 5 L 4-necked round-bottom flask was placed methyl 4-bromo-5-methoxy-2- nitrobenzoate (200 g, 690 mmol, 1.00 equiv), MeOH (1 L), H2O (1 L), LiOH (33.12 g, 1.38 mol, 2.00 equiv). The resulting solution was stirred for 3 hr at 25 degrees C. The resulting mixture was concentrated to removed most of MeOH. The resulting mixture was diluted with 1L of water, washed with 500 mL of Et2O. The PH value of the aqueous phase was adjusted to 4 with HCl (2N), extracted with 2x1 L of dichloromethane and the organic layers combined. The organic layers were concentrated. This resulted in 170 g (89.4%) of 4-bromo-5-methoxy-2-nitrobenzoic acid as a solid. (CDCl3, ppm): δ 8.27 (s, 1H), 7.21 (s, 1H), 4.07 (s, 3H). [0280] Step 3: 4-Bromo-5-methoxy-N-methyl-2-nitrobenzamide. [0281] To a 5 L flask were added 4-bromo-5-methoxy-2-nitrobenzoic acid (170 g, 615.848 mmol, 1.00 equiv), HATU (281.00 g, 739.018 mmol, 1.2 equiv), DMF (2 L) and DIEA (318.38 g, 2463.392 mmol, 4 equiv). The mixture was stirred for 15 min then MeNH2.HCl (83.16 g, 1231.696 mmol, 2 equiv) was added. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was diluted with EA (10 L), washed with water (3x2 L). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 4-bromo-5- methoxy-N-methyl-2-nitrobenzamide (150 g, 84.25%) as a yellow solid. [0282] Step 4: 2-Amino-4-bromo-5-methoxy-N-methylbenzamide. [0283] To a stirred solution of 4-bromo-5-methoxy-N-methyl-2-nitrobenzamide (150 g, 518.879 mmol, 1.00 equiv) and NH4Cl (277.55 g, 5188.790 mmol, 10 equiv) in THF (1600 mL) and H2O (400 mL) was added Zn (339.39 g, 5188.790 mmol, 10 equiv) in portions at 20 - 30 degrees C. The resulting mixture was stirred for 4 h at room temperature. The resulting mixture was filtered, the filter cake was washed with THF (2 x 200 mL). To the filtrate was added 2L of EA and 1L of brine. The organic layer was separated and concentrated under reduced pressure. This resulted in 2-amino- 4-bromo-5-methoxy-N-methylbenzamide (110 g, 81.82%) as a yellow solid. [0284] Step 5: 7-Bromo-6-methoxy-3-methylquinazolin-4-one. [0285] To a 2 L flask were added 2-amino-4-bromo-5-methoxy-N-methylbenzamide (110 g, 424.542 mmol, 1.00 equiv), trimethyl orthoformate (135.16 g, 1273.626 mmol, 3 equiv), para-toluene sulfonate (3.66 g, 21.227 mmol, 0.05 equiv) and MeOH (1 L). The resulting mixture was stirred for 4 h at 75 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 7-bromo-6-methoxy-3- methylquinazolin-4-one (60 g, 52.52%) as a yellow solid. [0286] Step 6: 6-Methoxy-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin- 4-one. [0287] Into a 2 L flask purged and maintained with an inert atmosphere of nitrogen, was placed 7- bromo-6-methoxy-3-methylquinazolin-4-one (60 g, 223 mmol, 1.00 equiv), bis(pinacolato)diboron (68 g, 267 mmol, 1.2 equiv), Pd(dppf)Cl2 (8 g, 11.2 mmol, 0.05 equiv), KOAc (44 g, 446 mmol, 2 equiv), dioxane (600 mL). The resulting solution was stirred for 3 hr at 100 degrees C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 20 g (28.37%) of 6-methoxy-3-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-one as a yellow solid. [0288] Step 7: tert-Butyl (2S,3S,5S)-2-fluoro-3-[[3-(6-methoxy-3-methyl-4-oxoquinazolin-7-yl)- 1,2,4-triazin-6-yl] (methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate. [0289] To a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed tert- butyl (2S,3S,5S)-2-fluoro-3-[methyl[3-(methylsulfanyl)-1,2,4-triazin-6-yl]amino]-8- azabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 3.12 mmol, 1.00 equiv), lambda1-copper(1+) 2- hydroxy-3-methylbenzoate (1.68 g, 7.82 mmol, 2.50 equiv), 6-methoxy-3-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-one (1.98 g, 6.26 mmol, 2.00 equiv), Pd(PPh3)4 (180 mg, 0.16 mmol, 0.05 equiv), THF (12 mL). The resulting solution was stirred for 2 hr at 70 degrees C. This reaction was repeated for more than 17 times. The resulting mixture was combined and concentrated and purified by silica gel column, eluted with PE/EA (70%). The crude product was then purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/5MM NH4HCO3=20% increasing to ACN/5MM NH4HCO3=90% within 25 min; Detector, 254 nm. This resulted in 18 g (64.5 %) of tert-butyl (2S,3S,5S)-2-fluoro-3- [[3-(6-methoxy-3-methyl-4-oxoquinazolin-7-yl)-1,2,4-triazin-6-yl] (methyl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. [0290] Step 8: tert-Butyl (2S,3S,5S)-2-fluoro-3-{[3-(6-hydroxy-3-methyl-4-oxoquinazolin-7-yl)- 1,2,4-triazin-6-yl](methyl)amino}-8-azabicyclo[3.2.1]octane-8-carboxylate. [0291] To a 40 mL tube were added tert-butyl (2S,3S,5S)-2-fluoro-3-{[3-(6-methoxy-3-methyl-4- oxoquinazolin-7-yl)-1,2,4-triazin-6-yl](methyl)amino}-8-azabicyclo[3.2.1]octane-8-carboxylate (2 g, 3.805 mmol, 1.00 equiv), (methylsulfanyl)sodium (1.33 g, 19.025 mmol, 5 equiv) and DMF (20 mL). The resulting mixture was stirred for 2h at 100 degrees C. The mixture was allowed to cool down to RT then 50 mL of water was added. The reaction was repeated for 8 times. The mixture was combined and acidified to pH 5 with HCl (1N) then neutralized to PH 8 with saturated NaHCO3. The resulting mixture was extracted with EA/iPrOH (95/5, 6 x 800 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl (2S,3S,5S)-2-fluoro-3-{[3-(6-hydroxy-3-methyl-4- oxoquinazolin-7-yl)-1,2,4-triazin-6-yl](methyl)amino}-8-azabicyclo[3.2.1]octane-8-carboxylate (15 g, 85.6%, crude) as a yellow solid. [0292] Step 9: 7-(6-{[(2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino}-1,2,4- triazin-3-yl)-6-hydroxy-3-methylquinazolin-4-one. [0293] Into a 100 mL flask were added tert-butyl (2S,3S,5S)-2-fluoro-3-{[3-(6-hydroxy-3-methyl-4- oxoquinazolin-7-yl)-1,2,4-triazin-6-yl](methyl)amino}-8-azabicyclo[3.2.1]octane-8-carboxylate (15 g, 29.35 mmol, 1.00 equiv) and EA (450 mL). To the above mixture was added HCl (4N in EA, 150 mL) at 0 degrees C. The resulting mixture was stirred for additional 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was diluted with water (150 mL), basified to pH 9 with NaHCO3, stirred for 1h at RT. Then EA (5000 mL) and iPrOH (1000 mL) were added and the mixture was stirred for 1h at RT. The two layers were separated, the aqueous layer was extracted with EA/iPrOH (10/1, 1000 mL x 6). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford crude product. The residue was purified by HP-reverse flash chromatography with the following conditions: column, C 18; mobile phase, MeCN in water (0.05% NH4HCO3), 10% to 30% gradient in 10 min then 30% held; detector, UV 254 nm. This resulted in 7-(6-{[(2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl](methyl)amino}-1,2,4-triazin-3-yl)-6-hydroxy-3-methylquinazolin-4-one (7.98g, 66.5%) as a yellow solid. M/z (ESI) = 412.15 (M+H)+, 1H NMR (400 MHz, Chloroform-d) δ 12.57 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 7.91 (d, J = 12.5 Hz, 2H), 5.38 – 5.18 (m, 1H), 4.71 (dd, J = 51.9, 3.4 Hz, 1H), 3.75 (s, 2H), 3.59 (s, 3H), 3.21 (d, J = 1.7 Hz, 3H), 2.27 (td, J = 12.7, 3.2 Hz, 1H), 2.05 (d, J = 7.3 Hz, 2H), 1.91 – 1.77 (m, 2H), 1.68 – 1.64 (m, 1H)., M/z (ESI) = 412.15 (M+H)+. [0294] Example 6: Synthesis of 6-(6-{[(2R,3S,5S)-2-Fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino}-1,2,4-triazin-3-yl)-7-hydroxy-2-methylisoquinolin-1-one.
Figure imgf000084_0001
[0295] Step 1a: (tert-Butoxycarbonyl)amino 2,2-dimethylpropanoate. [0296] To a 3 L 4-necked round-bottom flask were added tert-butyl N-hydroxycarbamate (100 g, 751.880 mmol, 1.00 equiv) and ACN (1.00 L). Then pivalic anhydride (140 g, 751.880 mmol, 1.00 equiv) was added dropwise and the resulting mixture heated to reflux overnight. After 18 hours, the reaction mixture was allowed to cool to ambient temperature, then concentrated under vacuum. The residue was partitioned between EtOAc (2000mL) and saturated NaHCO3 aqueous solution (500 mL). The organic layers were separated and washed with saturated NaHCO3 aqueous solution (3 x 500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 150 g (92%) (tert-butoxycarbonyl)amino 2,2-dimethylpropanoate as an off-white solid. [0297] Step 2a: [(2,2-Dimethylpropanoyl)oxy]azanium triflate. [0298] To a 3 L 4-necked round-bottom flask were added (tert-butoxycarbonyl)amino 2,2- dimethylpropanoate (150.00 g, 690.401 mmol, 1.00 equiv) and diethyl ether (1.5 L).The resulting mixture was cooled down to 0 degrees C and then 2,2,2-trifluoroethanesulfonic acid (113.29 g, 690.401 mmol, 1.00 equiv) was added (vigorous evolution of gas noted). The reaction mixture was stirred at 0 degrees C for 5 min and then allowed to warm to rt. After 1 hour hexanes (150 mL) was added and the mixture stirred for 10 min. The resulting solid was filtered, washed with hexanes (3 x 100 ml) and then dried in the vacuum oven to afford 166 g (89.98%) [(2,2- dimethylpropanoyl)oxy]azanium triflate as an off-white solid. [0299] Step 1: 4-Bromo-3-methoxybenzoyl chloride. [0300] To a 2 L 4-necked round-bottom flask were added 4-bromo-3-methoxybenzoic acid (120.00 g, 519.379 mmol, 1.00 equiv), DCM (1.20 L) and DMF (12 mL). To this stirred suspension was added oxalyl chloride (79.11 g, 623.255 mmol, 1.20 equiv) dropwise at ambient temperature under nitrogen atmosphere. The resulting solution was stirred for 3h at ambient temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 4-bromo-3-methoxybenzoyl chloride (120 g, crude, calculated as 519.379 mmol) as an off-white solid, which was used directly in next step. [0301] Step 2: (4-Bromo-3-methoxyphenyl)formamido 2,2-dimethylpropanoate. [0302] To a 3 L 4-necked round-bottom flask were added [(2,2-dimethylpropanoyl)oxy]azanium triflate (152.00 g, 568.820 mmol, 1.18 equiv) and EA (500 mL), then a solution of NaHCO3 (88.00 g, 1047.537 mmol, 2.18 equiv) in H2O (500 mL) was added dropwise at 0 degrees C. After stirring for 30 min, the solution of 4-bromo-3-methoxybenzoyl chloride (120.00 g, 480.981 mmol, 1.00 equiv) in EA (1.20 L) was added dropwise at 0 degrees C. The resulting mixture was then stirred for 2h at ambient temperature. The organic phase was separated and the aqueous phase extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution (2x500 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified silica gel column chromatography with PE/EA (5/1) as the eluent to afford 126 g (79.6%) (4-bromo-3- methoxyphenyl)formamido 2,2-dimethylpropanoate as a white solid. [0303] Step 3: 6-Bromo-7-methoxy-2H-isoquinolin-1-one. [0304] Into a 3 L 4-necked round-bottom flask were added (4-bromo-3-methoxyphenyl)formamido 2,2-dimethylpropanoate (143.00 g, 433.100 mmol, 1.00 equiv) and vinyl acetate (55.93 g, 649.650 mmol, 1.50 equiv) and CsOAc (25.77 g, 134.261 mmol, 0.31 equiv) and Bis[(pentamethylcyclopentadienyl)dichloro-rhodium] (2.68 g, 4.331 mmol, 0.01 equiv) and MeOH (1.4 L) . The resulting mixture was stirred for 16 h at 40 degrees C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with cold diethyl ether (3x100 mL). This provided 6-bromo-7-methoxy-2H- isoquinolin-1-one (65 g, 60%) as an off-white solid. [0305] Step 4: 6-Bromo-7-methoxy-2-methylisoquinolin-1-one. [0306] To a 1 L 3-necked round-bottom flask were added 6-bromo-7-methoxy-2H-isoquinolin-1-one (65.00 g, 255.822 mmol, 1.00 equiv), THF (650.00 mL) and DMF (300.00 mL). To this stirred suspension was added NaH (9.33 g, 388.849 mmol, 1.52 equiv) in portions at 0 C under nitrogen atmosphere, and the resulting solution was stirred for 30 min at 0 C. Then iodomethane (40.31 g, 283.995 mmol, 1.11 equiv) was added dropwise at 0 C under nitrogen atmosphere. The resulting solution was warmed to ambient temperature and stirred for 1 h. The reaction mixture was poured into cold water (2L) and stirred for 15 min. The precipitated solids were collected by filtration and washed with cold water (3x100 mL). This provided 6-bromo-7-methoxy-2-methylisoquinolin-1-one (60 g, 87.5%) as an off-white solid. [0307] Step 5: 7-Methoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin- 1(2H)-one. [0308] To a 1 L 3-necked round-bottom flask were added 6-bromo-7-methoxy-2-methylisoquinolin- 1-one (60.00 g, 224.719 mmol, 1.00 equiv) and Pd(dppf)Cl2 (8.22 g, 11.236 mmol, 0.05 equiv) and KOAc (33.03 g, 337.08 mmol, 1.50 equiv) and bis(pinacolato)diboron (82.62 g, 337.08 mmol, 1.50 equiv) and Dioxane (1000.00 mL). The resulting mixture was stirred for 3h at 100 degrees C, then cooled down to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1). This provided 7- methoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one (45 g, 63.57%) as a light grey solid. [0309] Step 6: tert-Butyl (2S,3S,5S)-2-fluoro-3-[[3-(7-methoxy-2-methyl-1-oxoisoquinolin-6-yl)- 1,2,4-triazin-6-yl](methyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate. [0310] To a 40 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (1R,2S,3S,5S)-2-fluoro-3-[methyl[3-(methylsulfanyl)-1,2,4-triazin-6- yl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.608 mmol, 1.00 equiv), 7-methoxy-2- methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (2.05 g, 6.519 mmol, 2.5 equiv), copper(I)-3-methylsalicylate (1.40 g, 6.519 mmol, 2.5 equiv), Pd(PPh3)4 (0.30 g, 0.261 mmol, 0.1 equiv), THF (10.00 mL). The resulting solution was stirred for 2 h at 70 C. The reaction was quenched by the addition of 30 mL 10% wt NH3.H2O and the solids were filtered out. The resulting solution was extracted with 3x50 mL of dichloromethane. The combined organic phases were washed with 50 ml of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase: ACN in water (0.5% NH4HCO3), 25% to 85% gradient in 30 min; detector, UV 254 nm. This provided 0.80 g (58.6%) of tert-butyl (2S,3S,5S)-2- fluoro-3-[[3-(7-methoxy-2-methyl-1-oxoisoquinolin-6-yl)-1,2,4-triazin-6-yl](methyl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate as a light yellow solid. (ES, m/z): [M+H]+=525.3. [0311] Step 7: tert-Butyl (2S,3S,5S)-2-fluoro-3-{[3-(7-hydroxy-2-methyl-1-oxoisoquinolin-6-yl)- 1,2,4-triazin-6-yl](methyl)amino}-8-azabicyclo[3.2.1]octane-8-carboxylate. [0312] To a 3-necked round-bottom flask were added tert-butyl (2S,3S,5S)-2-fluoro-3-{[3-(7- methoxy-2-methyl-1-oxoisoquinolin-6-yl)-1,2,4-triazin-6-yl](methyl)amino}-8- azabicyclo[3.2.1]octane-8-carboxylate (16 g, 30.450 mmol, 1.00 equiv),sodium thiomethoxide (10.7 g, 152.490 mmol, 5.0 equiv) and DMF (160 mL) at room temperature. The resulting mixture was stirred for 2 h at 100 C under nitrogen atmosphere. The reaction mixture was cooled down to ambient temperature and quenched with 200 mL cold water. The resulting mixture was acidified to pH 6 with 2N HCl (aq.). The precipitated solid was filtered and collected. This provided tert-butyl (2S,3S,5S)-2-fluoro-3-{[3-(7-hydroxy-2-methyl-1-oxoisoquinolin-6-yl)-1,2,4-triazin-6- yl](methyl)amino}-8-azabicyclo[3.2.1]octane-8-carboxylate (18 g, crude,quantitative) as a yellow solid, which was directly used in the next step without further purification. (ES, m/z):[M+H]+=511.2 [0313] Step 9: 6-(6-{[(2R,3S,5S)-2-Fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino}-1,2,4- triazin-3-yl)-7-hydroxy-2-methylisoquinolin-1-one. [0314] To a round-bottom flask were added tert-butyl (2S,3S,5S)-2-fluoro-3-{[3-(7-hydroxy-2- methyl-1-oxoisoquinolin-6-yl)-1,2,4-triazin-6-yl](methyl)amino}-8-azabicyclo[3.2.1]octane-8- carboxylate (18 g, crude, calculated as 30.450 mmol, 1.00 equiv), EA (180 mL) and HCl in EA (180 mL) at room temperature. The resulting mixture was stirred for 1.5 h at 35 C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 8 with saturated NaHCO3 (aq.). The precipitated solids were collected by filtration. The crude product was purified by Prep-HPLC with the following conditions: column, C18 silica gel; mobile phase: ACN in water (0.5% NH4HCO3), 25% to 85% gradient in 30 min; detector, UV 254 nm. This provided 6-(6-{[(2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino}- 1,2,4-triazin-3-yl)-7-hydroxy-2-methylisoquinolin-1-one (5 g, 39.95%) as a light yellow solid. 1H NMR (300 MHz, Chloroform-d) δ 12.34 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.06 (s, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.53 (d, J = 7.3 Hz, 1H), 5.46 – 5.19 (m, 1H), 4.74 (dt, J = 52.1, 3.2 Hz, 1H), 3.77 (s, 2H), 3.62 (s, 3H), 3.22 (d, J = 1.7 Hz, 3H), 2.29 (td, J = 12.7, 3.0 Hz, 1H), 2.15 – 1.98 (m, 2H), 1.91 – 1.81 (m, 2H)., (ES, m/z):[M+H]+=411.2. [0315] Example 7: Synthesis of 2-(6-{[(2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino}-1,2,4-triazin-3-yl)-5-(4-methyl-1H-pyrazol-1-yl)phenol and 2-(6- {[(1S,2S,3R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino}-1,2,4-triazin-3-yl)-5-(4- methyl-1H-pyrazol-1-yl)phenol (Compounds 10A & 10B).
Figure imgf000088_0001
[0316] Step 1: Synthesis of 1-bromo-4-iodo-2-(methoxymethoxy)benzene. [0317] Into a 1-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-5-iodophenol (25.00 g, 83.639 mmol, 1.00 equiv), tetrahydrofuran (300.00 mL). This was followed by the addition of NaH (4.01 g, 167.277 mmol, 2.00 equiv) in several batches at 0 degrees C.. To this was added methane, bromomethoxy- (15.68 g, 125.475 mmol, 1.50 equiv) dropwise with stirring at 0 degrees C after 30 min. The resulting solution was stirred for 2 hr at room temperature. The reaction was then quenched by the addition of 200 mL of water/ice. The resulting solution was extracted with 3x300 mL of ethyl acetate dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 22 g (76.70%) of 1-bromo-4-iodo-2- (methoxymethoxy)benzene as brown oil. 1H NMR (300 MHz, Chloroform-d) δ 7.48 (d, J = 1.7 Hz, 1H), 7.27 – 7.20 (m, 2H), 5.25 (s, 2H), 3.54 (s, 3H). [0318] Step 2: Synthesis of 1-[4-bromo-3-(methoxymethoxy)phenyl]-4-methylpyrazole. [0319] Into a 100 mL 3-necked round-bottom flask were added 1-bromo-4-iodo-2- (methoxymethoxy)benzene(4.00 g, 11.663 mmol, 1.00 equiv), fomepizole(1.34 g, 16.320 mmol, 1.40 equiv), CuI(222.00 mg, 1.166 mmol, 0.10 equiv), N1,N2-dimethylcyclohexane-1,2-diamine(332.00 mg, 2.334 mmol, 0.20 equiv), Cs2CO3(7.60 g, 23.326 mmol, 2.00 equiv) and DMF(80.00 mL). The resulting mixture was stirred for 2 h at 110 degrees C under nitrogen atmosphere. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (9:1) to afford 1-[4-bromo-3- (methoxymethoxy)phenyl]-4-methylpyrazole (2.91g,83.96%) as a colorless oil. [0320] Step 3: Synthesis of 1-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]-4-methylpyrazole. [0321] Into a 250 mL 3-necked round-bottom flask were added 1-[4-bromo-3- (methoxymethoxy)phenyl]-4-methylpyrazole (2.4 g, 8.077 mmol, 1.00 equiv) and THF (70.00 mL). To the above mixture was added n-BuLi (4.20 mL, 10.500 mmol, 1.30 equiv) dropwise at -78 degrees C. The resulting mixture was stirred for additional 30 min at -78 degrees C. To the above mixture was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.55 g, 13.730 mmol, 1.70 equiv) dropwise at -78 degrees C. The resulting mixture was stirred for additional 1 h at room temperature.The resulting mixture was diluted with EtOAc (200 mL). The reaction was quenched by the addition of water (50 mL). The organic layers were washed with 50 mL of brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4- methylpyrazole (2.8g,65.46%) as a colorless oil. m/z:345(M+H+). [0322] Step 4: Synthesis of tert-butyl (1S,2R,3R)-2-fluoro-3-([3-[2-(methoxymethoxy)-4-(4- methylpyrazol-1-yl)phenyl]-1,2,4-triazin-6-yl](methyl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate and tert-butyl (2S,3S,5S)-2-fluoro-3-([3-[2-(methoxymethoxy)-4-(4-methylpyrazol- 1-yl)phenyl]-1,2,4-triazin-6-yl](methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (INT 4A & INT 4B). [0323] Into a 40 mL vial were added ISOMER 1 (300.00 mg, 0.782 mmol, 1.00 equiv), 1-[3- (methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methylpyrazole (1.24 g, 2.342 mmol, 2.99 equiv, 65%), CuMeSal (504.00 mg, 2.348 mmol, 3.00 equiv), Pd(PPh3)4 (135.00 mg, 0.117 mmol, 0.15 equiv) and THF (7.50 mL). The resulting mixture was stirred for 6 h at 70 degrees C under nitrogen atmosphere. The resulting mixture was diluted with DCM (100 mL). The combined organic layers were washed with 10% NH4OH (4x25 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford INT 4A (266 mg, 61.42%) as a yellow solid. m/z:554(M+H+). Following the procedure above, but starting with ISOMER 2 to afford INT 4B (308mg,71.11%) as a yellow solid. m/z:554(M+H+). [0324] Step 5: Synthesis of 2-(6-[[(1S,2S,3R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino]-1,2,4-triazin-3-yl)-5-(4-methylpyrazol-1-yl)phenol and 2-(6-[[(2R,3S,5S)-2- fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino]-1,2,4-triazin-3-yl)-5-(4-methylpyrazol-1- yl)phenol (Compounds 10A & 10B). [0325] Into a 100-mL 3-necked round-bottom flask, was placed INT 4A (100.00 mg, 0.181 mmol, 1.00 equiv), DCM (5.00 mL), HCl(gas)in 1,4-dioxane (5.00 mL, 87.587 mmol, 484.92 equiv). The resulting solution was stirred for 2 hr at room temperature. The pH value of the solution was adjusted to 9 with NaHCO3 (1 mol/L). The resulting solution was extracted with 2x30 mL of dichloromethane dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column: C18; mobile phase: NH4HCO3 (aq) / MeCN; Gradient: 10% B to 55% B in 30 min; Detector254 nm. This resulted in 30.4 mg (41.10%) of Compound 10A as a light yellow solid.1H NMR (300 MHz, Chloroform-d) δ ppm 12.57 (s, 1H), 8.38 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.81 – 7.70 (m, 1H), 7.57 (s, 1H), 7.40 – 7.32 (m, 2H), 5.40 – 5.13 (m, 1H), 4.73 (d, J = 52.0 Hz, 1H), 3.76 (s, 2H), 3.19 (d, J = 1.7 Hz, 3H), 2.27 (td, J = 12.8, 3.3 Hz, 1H), 2.19 (s, 3H), 2.06 (d, J = 6.9 Hz, 2H), 1.90 – 1.78 (m, 2H), 1.75 – 1.68 (m, 1H). [0326] Following the procedure above, but starting with INT 4B (100.00 mg, 0.181 mmol, 1.00 equiv) resulted in 30.2 mg (40.83%) of Compound 10B. 1H NMR (300 MHz, Chloroform-d) δ ppm 12.57 (s, 1H), 8.38 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.81 – 7.70 (m, 1H), 7.57 (s, 1H), 7.40 – 7.32 (m, 2H), 5.40 – 5.13 (m, 1H), 4.73 (d, J = 52.0 Hz, 1H), 3.76 (s, 2H), 3.19 (d, J = 1.7 Hz, 3H), 2.27 (td, J = 12.8, 3.3 Hz, 1H), 2.19 (s, 3H), 2.06 (d, J = 6.9 Hz, 2H), 1.90 – 1.78 (m, 2H), 1.75 – 1.68 (m, 1H). [0327] Example 8: Synthesis of 2-(6-{[(1S,2S,3R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino}-1,2,4-triazin-3-yl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenol and 2-(6- {[(2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino}-1,2,4-triazin-3-yl)-5-(5- methyl-1,2,4-oxadiazol-3-yl)phenol (Compounds 11A & 11B).
Figure imgf000091_0001
[0328] Step 1: Synthesis of 4-bromo-N-hydroxy-3-(methoxymethoxy)benzenecarboximidamide. [0329] Into a 100-mL 3-necked round-bottom flask, was placed 4-bromo-3- (methoxymethoxy)benzonitrile (4.00 g, 16.524 mmol, 1.00 equiv), NH2OH.HCl (2.30 g, 33.048 mmol, 2 equiv), Et3N (3.34 g, 33.048 mmol, 2.00 equiv), EtOH (50.00 mL). The resulting solution was stirred for 2 hr at 80 degrees C. The reaction solvent was removed and diluted with 100 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate, and the combined organic phase was concentrated. This resulted in 4 g (87.99%) of 4-bromo-N-hydroxy-3- (methoxymethoxy)benzenecarboximidamide as a light yellow solid, which was used directly in the next step. [0330] Step 2: Synthesis of 3-[4-bromo-3-(methoxymethoxy)phenyl]-5-methyl-1,2,4-oxadiazole. [0331] Into a 100-mL round-bottom flask, was placed 4-bromo-N-hydroxy-3- (methoxymethoxy)benzenecarboximidamide (4.00 g), Ac2O (20.00 mL). The resulting solution was stirred for 1 hr at 120 degrees C. The reaction mixture was cooled down to ambient temperature and poured into 100 mL water. The pH value of the resulting aqueous solution was adjusted to 8 with solid Na2CO3. The aqueous solution was then extracted with 3*100 mL of ethyl acetate, and the combined organic phase was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (10%) as the eluent. This resulted in 2.5 g (57.48%) of 3-[4-bromo-3- (methoxymethoxy)phenyl]-5-methyl-1,2,4-oxadiazole as an off-white solid. [0332] Step 3: Synthesis of 3-[3-(methoxymethoxy)-4-(tributylstannyl)phenyl]-5-methyl-1,2,4- oxadiazole. [0333] Into a 100-mL round-bottom flask, was placed 3-[4-bromo-3-(methoxymethoxy)phenyl]-5- methyl-1,2,4-oxadiazole (2.50 g, 8.358 mmol, 1.00 equiv), Pd2(dba)3 (0.77 g, 0.000 mmol, 0.10 equiv), PCy3 (0.47 g, 1.672 mmol, 0.20 equiv), Bu3SnSnBu3 (12.12 g, 20.895 mmol, 2.50 equiv), toluene (50.00 mL). The resulting solution was stirred for 16 hr at 100 degrees C under nitrogen atmosphere. The reaction solvent was removed under vacuum to leave the residue. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (10%) as the eluent. This resulted in 2 g (46.99%) of 3-[3-(methoxymethoxy)-4-(tributylstannyl)phenyl]-5-methyl-1,2,4-oxadiazole as light brown oil. [0334] Step 4: Synthesis of tert-butyl (1S,2R,3R,5R)-2-fluoro-3-([3-[2-(methoxymethoxy)-4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,4-triazin-6-yl](methyl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,2S,3S,5S)-2-fluoro-3-([3-[2- (methoxymethoxy)-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,4-triazin-6-yl](methyl)amino)- 8-azabicyclo[3.2.1]octane-8-carboxylate (INT 11A & INT 11B). [0335] Into a 100 mL 3-necked round-bottom flask were added tert-butyl ISOMER 1 (200.00 mg, 0.522 mmol, 1.00 equiv), 3-[3-(methoxymethoxy)-4-(tributylstannyl)phenyl]-5-methyl-1,2,4- oxadiazole (796.81 mg, 1.565 mmol, 3.00 equiv), Copper(I) 3-methylsalicylate (278.60 mg, 1.304 mmol, 2.5 equiv),THF (4.00 mL, 49.372 mmol, 94.67 equiv) and Pd(PPh3)4 (60.27 mg, 0.052 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred for 2 h at 70 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was quenched with NH3.H2O (15 mL) at room temperature and filtered off. The filtrate was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to leave the residue, which was purified on silica gel column chromatography with ethyl acetate/petroleum ether (10%~50%) as the eluent to afford INT 11A (200mg, 69.02%) as a light yellow solid. Following the above procedure, but beginning with ISOMER 2 (200.00 mg, 0.522 mmol, 1.00 equiv) to afford INT 11B (220 mg, 75.92%) as a light yellow solid. [0336] Step 5: Synthesis of 2-(6-[[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino]- 1,2,4- triazin-3-yl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenol and 2-(6- [[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino]-1,2,4-triazin-3-yl)-5-(5- methyl-1,2,4-oxadiazol-3-yl)phenol (Compound 11A & Compound 11B). [0337] Into a 100 mL 3-necked round-bottom flask were added methoxymethanol; INT 11A (200.00 mg, 0.359 mmol, 1.00 equiv) and DCM (6.00 mL, 94.380 mmol, 263.14 equiv) at room temperature. Then TFA (2.00 mL, 26.926 mmol, 75.07 equiv) was added and the resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford Compound 11A (33 mg, 21.94%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.83 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.3, 1.7 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 5.03 - 4.80 (m, 1H), 4.79 - 4.58 (m, 1H), 3.58 - 3.50 (m, 2H), 3.16 (d, J = 1.7 Hz, 3H), 2.69 (s, 3H), 2.33 - 2.21 (m, 1H), 1.86 - 1.53 (s, 5H). [0338] Following the above preocedure, but beginning with INT 11B to afford Compound 11B (58mg,38.22%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.83 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.3, 1.7 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 5.03 - 4.80 (m, 1H), 4.79 - 4.58 (m, 1H), 3.58 - 3.50 (m, 2H), 3.16 (d, J = 1.7 Hz, 3H), 2.69 (s, 3H), 2.33 - 2.21 (m, 1H), 1.86 - 1.53 (s, 5H).

Claims

CLAIMS What is claimed is: 1. A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
Figure imgf000094_0001
Formula (I) wherein, ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; X is absent, -O-, -S-, -
Figure imgf000094_0002
hydrogen, –CN, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C6 heterocycloalkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, or -C1-C4 alkylene-OR31; each RX2 and RX3 is independently hydrogen, –OR31, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C1–C4 heteroalkyl; each is independently a single or a double bond; Z is N, C or CR5; R5 is hydrogen, substituted or unsubstituted C1–C4 alkyl, or substituted or unsubstituted C1-C4 haloalkyl; W is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, substituted or unsubstituted C3–C8 cycloalkylene, or substituted or unsubstituted C2–C7 heterocycloalkylene; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; each R31 is independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1–C6 heteroalkyl, substituted or unsubstituted C3–C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR31, substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1– C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; R is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; a is 0, 1, 2, or 3; b is 0, 1, 2, or 3; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3, comprising the step of reacting a compound of Formula (II)
Figure imgf000095_0001
Formula (II) wherein RL is halogen, -O(C=O)RL1, -SRL1, -S(=O)RL1, -S(=O)2RL1, or -S(=O)(=NRL1)RL1 ; and each RL1 is independently substituted or unsubstituted C1–C8 alkyl, substituted or unsubstituted C1–C8 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein each other variable in Formula (II) is as described above for Formula (I); with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI)
Figure imgf000095_0002
Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce the compound of Formula (I).
2. The process of claim 1, wherein a compound of Formula (II) has a structure of Formula (IIa) or Formula (IIb):
Figure imgf000095_0003
Formula (IIa) Formula (IIb).
3. The process of claim 1 or claim 2, comprising the step of reacting the compound of Formula (II) with the compound of Formula (III)
Figure imgf000095_0004
Formula (III) to produce the compound of Formula (I).
4. The process of claim 1 or claim 2, comprising the step of reacting the compound of Formula (II) with the compound of Formula (IV)
Figure imgf000096_0001
to produce the compound of Formula (I).
5. The process of claim 1 or claim 2, comprising the step of reacting the compound of Formula (II) with the compound of Formula (V)
Figure imgf000096_0002
Formula (V) to produce the compound of Formula (I).
6. The process of claim 1 or claim 2, comprising the step of reacting the compound of Formula (II) with the compound of Formula (VI)
Figure imgf000096_0003
Formula (VI) to produce the compound of Formula (I).
7. A process for preparing a compound of Formula (VII)
Figure imgf000096_0004
Formula (VII) comprising reacting a compound of Formula (VIII)
Figure imgf000096_0005
Formula (VIII) wherein R3 is a halogen, such as Cl, Br, or I; or O-CH2CF3 with a compound of Formula (IX)
Figure imgf000097_0001
Formula (IX) to produce a compound of Formula (VII), wherein each R1 and R2 is independently hydrogen, halogen, -OH, –OR31, –CN,–SR31, -S(=O)R31, -SO2R31, -NR31R32, -NR31S(=O)(=NR31)R32, - NR31S(=O)2R31R32, -SO2NR31R32, -C(=O)R31, -OC(=O)R31, -C(=O)OR31, -OC(=O)OR31, - C(=O)NR31R32, -OC(=O)NR31R32, -NR31C(=O)R32, -P(=O)R31R32, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R31 and R32 is independently hydrogen, halogen, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
8. The process of claim 7, wherein a compound of Formula (VII) has a structure of Formula (VIIa):
Figure imgf000097_0002
Formula (VIIa); and wherein a compound of Formula (VIII) has a structure of Formula (VIIIa):
Figure imgf000097_0003
Formula (VIIIa).
9. The process of claim 7 or claim 8, wherein R1 is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic cycloalkyl, or substituted or unsubstituted monocyclic heteroaryl.
10. The process of claim 7 or claim 8, wherein R1 is substituted or unsubstituted polycyclic aryl, substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic cycloalkyl, or substituted or unsubstituted polycyclic heteroaryl.
11. The process of claim 7 or claim 8, wherein R2 is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic cycloalkyl, or substituted or unsubstituted monocyclic heteroaryl.
12. The process of claim 7 or claim 8, wherein R2 is substituted or unsubstituted polycyclic aryl, substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic cycloalkyl, or substituted or unsubstituted polycyclic heteroaryl.
13. The process of any one of claims 1-6, comprising the steps of reacting the compound of Formula (II) with the compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI) in the presence of a palladium catalyst, tetrahydrofuran or dimethylformamide, and a copper (I) salt of 3-methyl salicylic acid or 2-thienyl carboxylic acid.
14. The process of any one of claims 1-6, wherein Q is substituted or unsubstituted fused aryl, substituted or unsubstituted fused heteroaryl, substituted or unsubstituted fused cycloalkyl, or substituted or unsubstituted fused heterocycloalkyl.
15. A compound of Formula (III)
Figure imgf000098_0001
Formula (III) wherein Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
16. A compound of Formula (IV)
Figure imgf000098_0002
Formula (IV) wherein Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
17. A compound of Formula (IVa)
Figure imgf000098_0003
Formula (IVa) wherein Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
18. A compound of Formula (V)
Figure imgf000099_0001
Formula (V) wherein Ring Q substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
19. A compound of Formula (VI)
Figure imgf000099_0002
Formula (VI) wherein Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
20. The compound of any one of claims 15-19, wherein Q is substituted or unsubstituted fused aryl, substituted or unsubstituted fused heteroaryl, substituted or unsubstituted fused cycloalkyl, or substituted or unsubstituted fused heterocycloalkyl.
21. A compound of Formula (VII)
Figure imgf000099_0003
Formula (VII) wherein each R1 and R2 is independently hydrogen, halogen, -OH, –OR31, –CN,–SR31, - S(=O)R31, -SO2R31, -NR31R32, -NR31S(=O)(=NR31)R32, -NR31S(=O)2R31R32, -SO2NR31R32, - C(=O)R31, -OC(=O)R31, -C(=O)OR31, -OC(=O)OR31, -C(=O)NR31R32, -OC(=O)NR31R32, - NR31C(=O)R32, -P(=O)R31R32, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R31 and R32 is independently hydrogen, halogen, substituted or unsubstituted C1–C6 alkyl, substituted or unsubstituted C1–C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
22. The compound of claim 21, wherein R1 is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic cycloalkyl, or substituted or unsubstituted monocyclic heteroaryl.
23. The compound of claim 21, wherein R1 is substituted or unsubstituted polycyclic aryl, substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic cycloalkyl, or substituted or unsubstituted polycyclic heteroaryl.
24. The compound of claim 21, wherein R2 is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic cycloalkyl, or substituted or unsubstituted monocyclic heteroaryl.
25. The compound of claim 21, wherein R2 is substituted or unsubstituted polycyclic aryl, substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic cycloalkyl, or substituted or unsubstituted polycyclic heteroaryl.
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