WO2022032007A2 - 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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WO2022032007A2
WO2022032007A2 PCT/US2021/044804 US2021044804W WO2022032007A2 WO 2022032007 A2 WO2022032007 A2 WO 2022032007A2 US 2021044804 W US2021044804 W US 2021044804W WO 2022032007 A2 WO2022032007 A2 WO 2022032007A2
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substituted
unsubstituted
formula
compound
alkyl
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PCT/US2021/044804
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French (fr)
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WO2022032007A3 (en
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Michael Luzzio
Tiansheng Wang
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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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • 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 System
    • 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 System
    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen

Definitions

  • SMSMs small molecule splicing modulators
  • 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-, -
  • R X1 is 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 Ci-C 6 heteroalkyl, or -C 1 -C 4 alkyl ene-OR 31 ; each R X2 and R X3 is independently hydrogen, -OR 31 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 haloalkyl, or substituted or unsubstituted C 1 -C 4 heteroalkyl
  • 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-, -
  • R X1 is 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 alkyl ene-OR 31 ; each R X2 and R X3 is independently hydrogen, -OR 31 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 haloalkyl, or substituted or unsubstituted C 1 -C 4 heteroal
  • a compound of Formula (II) is reacting 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).
  • Formula (IV) wherein each variable within Formula (I) and Formula (IV) is as described above for 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)
  • Formula (IVa) wherein each variable within Formula (I) and Formula (IVa) is as described above for 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)
  • Formula (V) wherein each variable within Formula (I), and Formula (V) is as described above for 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).
  • Formula (VI) wherein each variable within Formula (I) and Formula (VI) is as described above for 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).
  • R 3 is a halogen, such as Cl, Br, or I; or O-CH 2 CF 3 ;
  • a compound of Formula (II) has a structure of Formula (Ila):
  • a compound of Formula (II) has a structure of Formula (lib):
  • a compound of Formula (VII) has a structure of Formula (Vila):
  • Formula (Vila); and a compound of Formula (VIII) has a structure of Formula (Villa):
  • small molecule splicing modulator 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.
  • a cell component e.g., DNA, RNA, pre-mRNA, protein, RNP, snRNA, carbohydrates, lipids, co-factors, nutrients and/or metabolites
  • 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.
  • the term “one or more” refers to the range from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents.
  • substituted 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.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents.
  • 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, zso-propyl, //-butyl, iso-butyl, secbutyl, and /-butyl.
  • halo halogen
  • halide halogen
  • 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 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, C1-C10 alkyl, C1-C9 alkyl, Ci-C 8 alkyl, C1-C7 alkyl, Ci-C 6 alkyl, C1-C5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C 3 -C 8 alkyl and C4-C8 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, //-propyl, 1 -methylethyl (z-propyl), zz-butyl, z-butyl, .s- butyl, //-pentyl, 1,1 -dimethyl ethyl (/-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. 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.
  • 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 (/'.c., 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.
  • R a is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • aromatic refers to a planar ring having a delocalized n-electron system containing 4n+2 n electrons, where n is an integer. Aromatics can be optionally substituted.
  • aromatic includes both aryl groups e.g., phenyl, naphthal enyl) 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. 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.
  • 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 include monofluoro-, difluoro-or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.
  • haloalkyl 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 examples include monofluoro-, difluoro-or trifluoro-methoxy, -ethoxy or -propoxy, for example 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy.
  • perhaloalkoxy denotes an alkoxy group where all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms.
  • 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-l(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[l.l.l]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, tri chloromethoxy, 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.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl.
  • 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, -OCIUClUOMe, or - OCH 2 CH 2 OCH 2 CH 2 NH2.
  • 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.
  • 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[l,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,
  • 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 0 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-l-yl ( N -attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-l-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, phthal
  • 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 0 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.
  • 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. 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:
  • 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;
  • R X1 is 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 alkyl ene-OR 31 ; each R X2 and R X3 is independently hydrogen,
  • Formula (III) Formula (IV) 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).
  • a compound of Formula (II) has a structure of Formula (Ila) or Formula (lib):
  • a coupling reagent is a boronic acid or a boronic acid derivative such as boronic ester (e.g., pinacolyl or MIDA (N-methyliminodiacetate) ester).
  • boronic acid derivative is potassium trifluoroborate.
  • the boronic acid derivative is sodium trihydroxyborate.
  • R X1 is 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 ; each R X2 and R X3 is independently hydrogen, -OR 31 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 haloalkyl, or substituted or unsubstituted C 1 -C 4 heteroalkyl; each is independently a single or a double bond; Z is N, C or CR 5 ; R 5 is hydrogen, substituted or unsubstituted C 1
  • Formula (III) Formula (IV) 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’).
  • R X1 is 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 ; each R X2 and R X3 is independently hydrogen, -OR 31 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 haloalkyl, or substituted or unsubstituted C 1 -C 4 heteroalkyl; each is independently a single or a double bond; Z is N, C or CR 5 ; R 5 is hydrogen, substituted or unsubstituted C 1
  • HAL is Cl. In some embodimetns, HAL is F. In some embodimetns, HAL is Br. In some embodimetns, HAL is I.
  • R X1 is 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 ; each R X2 and R X3 is independently hydrogen, -OR 31 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 haloalkyl, or substituted or unsubstituted C 1 -C 4 heteroalkyl; each is independently a single or a double bond; Z is N, C or CR 5 ; R 5 is hydrogen, substituted or unsubstituted C 1
  • R is a protecting group, e.g. /c/7-butyloxycarbonyl (Boc).
  • 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-, -
  • R X1 is 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 alkyl ene-OR 31 ; each R X2 and R X3 is independently hydrogen, -OR 31 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 haloalkyl, or substituted or unsubstituted C 1 -C 4 heteroal
  • a compound of Formula (II), Formula (II’) or 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) or Formula (IF) 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 1, 4 dioxane, tetrahydrofuran or dimethylformamide.
  • a compound of Formula (II), Formula (IF) or 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.
  • the compound of Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’) 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’), Formula (II”), Formula (II*), or Formula (Ila’).
  • the one or more chiral centers is a chiral auxiliary.
  • the compound of Formula (I’ is a compound of Formula (I’a):
  • a compound of Formula (IF) is a compound of Formula (II’ a):
  • a compound of Formula (IV) is a compound of Formula (IVaa):
  • a process of preparing a compound of Formula (II’ a) comprises the step of reacting a compound of Formula (X):
  • Formula (X) with a base such as potassium t-butoxide 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):
  • the process comprises the step of reacting a 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 (/( - ⁇ -J-mandelic acid in the presence of a solvent, such as methyl ethyl ketone.
  • a chiral resolving agent such as (/( - ⁇ -J-mandelic acid in the presence of 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 the compound of Formula (II) with a compound of Formula (III)
  • Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
  • R X1 is 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 alkyl ene-OR 31 ; each R X2 and R X3 is independently hydrogen,
  • a compound of Formula (II) is reacting 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).
  • Formula (IV) wherein each variable within Formula (I), Formula (II), and Formula (IV) is as described above for 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).
  • Formula (IVa) wherein each variable within Formula (I), Formula (II), and Formula (IVa) is as described above for 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).
  • Formula (V) wherein each variable within Formula (I), Formula (II), and Formula (V) is as described above for 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).
  • Formula (VI) wherein each variable within Formula (I), Formula (II), and Formula (VI) is as described above for 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 (VII) has a structure of Formula (Vila):
  • Formula (Vila); and a compound of Formula (VIII) has a structure of Formula (Villa):
  • Yi, Y2, and Y3 are each independently N or CH comprising reacting a compound of Formula (VIII’)
  • a compound of Formula (VII’) has a structure of Formula (Vila’):
  • Formula (Vila’); and a compound of Formula (VIII’) has a structure of Formula (Villa’):
  • a compound of Formula (VII”) has a structure of Formula (Vila”):
  • Formula (Vila”); and a compound of Formula (VIII”) has a structure of Formula (Villa”):
  • a compound of Formula (I) is a compound of Formula (la)
  • 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 (lb)
  • a compound of Formula (I) is a compound of Formula (Ic)
  • a compound of Formula (I) is a compound of Formula (Id)
  • a compound of Formula (I) is a compound of Formula (le)
  • a compound of Formula (I) is a compound of Formula (If)
  • Y 1 is N, Y 2 is N, and Y 3 is CH. In some embodiments, Y 1 is N, Y 2 is CH, and Y 3 is N. In some embodiments, Y 1 is N, Y 2 is N, and Y 3 is N.
  • 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 CH 3 . In some embodiments, 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 .
  • 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. In some embodiments, 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 -.
  • 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.
  • R X1 is -CH 3 . In some embodiments, 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 -OCH 2 CH 3 . 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. 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. In some embodiments, the 6-membered 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-membered heteroaryl is l-methylpyridin-2(lH)-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.
  • 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-l-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.
  • 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.
  • 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 (la)
  • a compound of Formula (II) is a compound of Formula (Ila) or Formula (lib)
  • a compound of Formula (II) is a compound of Formula (lie) or Formula (lid):
  • a compound of Formula (II) is a compound of Formula (lie) or Formula (Ilf):
  • a compound of Formula (II) is a compound of Formula (Ilg) or Formula (Ilh):
  • a compound of Formula (II) is a compound of Formula (IF) or Formula (Ilj):
  • a compound of Formula (II) is a compound of Formula (Ilk) or Formula (III):
  • Y 1 is N, Y 2 is N, and Y 3 is CH. In some embodiments, Y 1 is N, Y 2 is CH, and Y 3 is N. In some embodiments, Y 1 is N, Y 2 is N, and Y 3 is N.
  • 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.
  • 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 Ci- C4heteroalkyl substituted with oxo and -CH 3 . In some embodiments, R is /c/7-buty I oxy carbonyl. In some embodiments, each R 15 and R 18 is independently hydrogen or substituted or unsubstituted Ci- C4 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.
  • 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. In some embodiments, 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 15 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.
  • 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 -. In some embodiments, 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.
  • R X1 is -CH 3 .
  • R X1 is - CH 2 CH 3 .
  • R X1 is -CH 2 CH 2 CH 3 .
  • R X1 is -OCH 3 .
  • R X1 is -OCH 2 CH 3 . 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.
  • a compound of Formula (II) is a compound of Formula (Ilaaa)
  • a compound of Formula (IV) is a compound of Formula (IVaaa)
  • R X1 is hydrogen, -CN, substituted or unsubstituted C 1 -C 8 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 ; each R X2 and R X3 is independently hydrogen, -OR 31 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 haloalkyl, or substituted or un
  • 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.
  • Formula (I), Formula (III), Formula (IV), Formula (IVa) Formula (I), Formula (III), Formula (IVa), Formula (V), or Formula (VI)
  • ring Q is substituted or unsubstituted heteroaryl.
  • a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI) is substituted or unsubstituted heteroaryl.
  • 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 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. [0124] 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.
  • ring Q is
  • 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 , -
  • 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:
  • 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
  • each R Q is independently hydrogen or -F.
  • each R Q is hydrogen
  • ring P is substituted or unsubstituted heteroaryl.
  • 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:
  • 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
  • each R B is independently H, deuterium, -F, -Cl, -CN, -CH 3 , -CF 3 ,- OH, or -OCH 3 . [0146] In some embodiments, 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:
  • ring Q is selected from the group consisting of:
  • ring Q is selected from the group consisting of:
  • 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.
  • ring Q is: , wherein each A 1 , A 2 , A 3 , and A 4 is independently N, -NR Y1 -, -O-, -S-, or
  • each R A1 is H.
  • each R Y1 is H.
  • ring Q is .
  • ring Q is .
  • 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(CH 3 ). 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 ). In some embodiments, A 3 is CH, C(CH 3 ), N, N(CH 3 ), or C(CH 3 ).
  • R is substituted or unsubstituted C 1 -C 4 heteroalkyl.
  • R is C 1 -C 4 heteroalkyl substituted by a t-butyl group.
  • 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. 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. [0161] In some embodiments, ring Q is fully aromatic. In some embodiments, ring Q is partially unsaturated.
  • ring Q is 2-OH phenyl substituted by a halogen, such as Cl.
  • 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.
  • ring Q is . In some embodiments, ring Q is
  • ring Q is: , wherein each A 1 , A 2 , A 3 , and A 4 is independently N, -NR Y1 -, -O-, -S-, -
  • 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 CD2CD 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 CD2CD 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 CD2CD 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.
  • R Y1 one or more hydrogens in R Y1 are replaced by deuterium.
  • R Y1 is H.
  • R Y1 is methyl.
  • R Y1 is methyl, ethyl, CF 3 , CHF 2 , or CH 2 CF 3 .
  • R Y1 is CD 3 or CD2CD 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 CD2CD 3 .
  • 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. In some embodiments, A 3 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.
  • R Y1 one or more hydrogens in R Y1 are replaced by deuterium.
  • R Y1 is H.
  • R Y1 is methyl.
  • R Y1 is methyl, ethyl, CF 3 , CHF 2 , or CH 2 CF 3 .
  • R Y1 is CD 3 or CD2CD 3 .
  • a 3 is N(CH 3 ).
  • a 4 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 CD2CD 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. 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 CDi or CD2CD 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 -.
  • 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 C3-C5 cycloalkyl, or substituted or unsubstituted C 2 - C 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 , -CH 2 OH, -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. In some embodiments, 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.
  • 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.
  • 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 15 , 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. In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are F.
  • R 11 is H, D, or F. In some embodiments, R 11 is D. In some embodiments, R 11 is H. In some embodiments, R 11 is F.
  • R 12 is H, D, or F. In some embodiments, R 12 is D. In some embodiments, R 12 is H. In some embodiments, R 12 is F.
  • 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.
  • R 14 is H, D, or F. In some embodiments, R 14 is D. In some embodiments, R 14 is H. In some embodiments, R 14 is F.
  • 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.
  • 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. In some embodiments, 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.
  • one of R 11 , R 12 , R 13 , R 14 , R 16 , 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 15 , 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.
  • 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 .
  • 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 .
  • 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.
  • 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.
  • 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 .
  • 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 .
  • R 20 is F or -OCH 3 .
  • 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.
  • R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , and R 18 are F.
  • at least one of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 is F.
  • one of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 is F.
  • at least two of R 11 , R 12 , R 13 , R 14 , R 16 , R 19 , R 20 , and R 17 are F.
  • 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 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 , 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 15 , 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 15 , and R 17 comprise a fluorine.
  • At least one of W, R 11 , R 12 , R 13 , R 14 , R 15 , R 15 , R 17 , R 19 , R 20 , 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 , R 19 , R 20 , and R 18 comprises a fluorine.
  • W comprises a fluorine.
  • X is absent.
  • X is -O-.
  • X is -S-.
  • X is -NR X1 -.
  • X is N-C 1 -C 6 alkyl.
  • X is N-methyl.
  • X is N-C 1 -C 6 cycloalkyl.
  • X is N-cyclopropyl.
  • X is -CR X2 R X3 -.
  • Z is C.
  • Z is CR 5 . In some embodiments, 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. In some embodiments, each R 31 is independently hydrogen, deuterium, or C 1 -C 4 alkyl. In some embodiments, each R 31 is independently hydrogen, deuterium, or methyl. In some embodiments, R 31 is H. In some embodiments, 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. In some embodiments, R2 is halogen. In some embodiments, R2 is OH. In some embodiments, R2 is -OR 31 . 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.
  • 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
  • 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. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981.
  • stereoisomers are obtained by stereoselective synthesis.
  • 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.
  • ( ⁇ ) or racemic indicates that the product is a racemic mixture of enantiomers.
  • ( ⁇ ) (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.
  • the product is pure and a single enantiomer, but absolute stereochemistry is not identified, but relative stereochemistry is known and indicated.
  • Example 1 Preparation of tert-butyl (lS,2R,3R,5R)-3-((5-(4-chloro-2- (methoxymethoxy)phenyl)pyrazin-2-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate.
  • Step 1 Preparation of tert-butyl (lS,2R,3R,5R)-2-fluoro-3-((5-(methylthio)pyrazin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • the resulting mixture was placed in a preheated oil bath and was stirred for 24 hours at 120°C then removed from heat, allowed to cool to room temperature and quenched with water/ice.
  • the resulting mixture was extracted with ethyl acetate (3x60 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 2 Preparation of tert-butyl (lS,2R,3R,5R)-2-fluoro-3-(methyl(5- (methylthio)pyrazin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 3A Preparation of tert-butyl (lS,2R,3R,5R)-3-((5-(4-chloro-2- (methoxymethoxy)phenyl) pyrazin-2-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate.
  • Step 3B Preparation of tert-butyl (lS,2R,3R,5R)-3-((5-(4-chloro-2- (methoxymethoxy)phenyl)pyrazin-2-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate.
  • Example 2 Synthesis of (1R,2S,3S)-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).
  • 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.
  • MTBE 3 x 19.2 L
  • 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.
  • Step 2 tert-Butyl 2-fluoro-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (Rac-2-3).
  • Step 3 tert-Butyl 3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate (Rac-2-4).
  • reaction mixture was quenched by adding of IN 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.
  • Step 4 (1R,2S,3S)-tert-Butyl-3-(benzylamino )-2-flu oro-8-azabicyclo
  • Example 3 Synthesis of 6-(6-(((1R ,2R ,3S,5S )-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Formula (I’ a)).
  • Step 1 Synthesis of tert- Butyl 3-((6-chloropyridazin-3-yl)amino)-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate (3-3).
  • DIPEA (26.46 g, 2.5 eq) was added to a solution of 3,6-dichloropyridazine (14.6 g, 1.2 eq) and racemic-3-1 (20.0 g, 81.9 mmol) in DMSO (200 mL) at RT The mixture was stirred at 120 °C for about 24 h. After completion of the reaction (by TLC), the mixture was cooled to room temperature and quenched with H2O (500 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic extracts were concentrated to obtain a solid, which was triturated with EtOAc to yield 3-3 (15 g, 51 % yield) as a pale yellow solid.
  • Step 2 Synthesis of tert-butyl 3-((6-chloropyridazin-3-yl)(methyl)amino)-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate (3-4).
  • Step 3 Synthesis of 1R,2S,3S,5S )-tert-butyl 2-fluoro-3-((6-(5-(methoxymethoxy)-2- methylbenzo[d
  • Step 4 Synthesis 6-(6-(((1R,2S,3S,5S )-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Formula (I’ a)).
  • Example 4 Synthesis of 4-(4-(5-(((1R,3s,5S )-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)-l,3,4-thiadiazol-2-yl)-3-hydroxyphenyl)-l-methylpyridin-2(1H )-one.
  • Step 1 Synthesis of l-bromo-4-chloro-2-(methoxymethoxy)benzene.
  • Step 2 Synthesis of 4-chloro-2-(methoxymethoxy)phenylboronic acid.
  • n-BuLi (5.76 mL, 14.4 mmol) was added to a stirred solution of l-bromo-4-chloro-2- (methoxymethoxy)benzene (3 g, 12 mmol) in 40 mL of THF under nitrogen at -78 °C. After stirring at -78 °C for 40 min, B(OMe)3 (2 g, 19.2 mmol) was added. The mixture was allowed to warm up to room temperarture and stirred for 16 h. NH4CI aqueous solution (10 mL) was added to the mixture. The mxiture was extracted with EtOAc (20 mL X 3).
  • Step 3 Synthesis of tert-butyl (1R,3s,5S )-3-((5-bromo-l,3,4-thiadiazol-2- yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate.
  • Step 4 Synthesis of tert-butyl (1R,3s,5S )-3-((5-(4-chloro-2-(niethoxyniethoxy)phenyl)- l,3,4-thiadiazol-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate.
  • Step 5 Synthesis of tert-butyl (1R,3s,5S )-3-((5-(2-(nieth()xyinetlioxy)-4-(l-methyl-2-oxo- l,2-dihydropyridin-4-yl)phenyl)-l,3,4-thiadiazol-2-yl)(methyl)amino)-9- azabicyclo[3.3.1]nonane-9-carboxylate.
  • Step 6 Synthesis of 4-(4-(5-((( 1R,3s,5S )-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-
  • Example 5 Synthesis of 6-(5-(((1R,3s,5S )-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-
  • Step 1 Synthesis of l-bromo-4-chloro-2-(methoxymethoxy)benzene.
  • Step 2 Synthesis of 4-chloro-2-(methoxymethoxy)phenylboronic acid.
  • n-BuLi (5.76 mL, 14.4 mmol) was added to a stirred solution of l-bromo-4-chloro-2- (methoxymethoxy)benzene (3 g, 12 mmol) in 40 mL of THF under nitrogen at -78 °C. After stirring at -78 °C for 40 min, B(OMe)3 (2 g, 19.2 mmol) was added. The mixture was allowed to warm up to room temperarture and stirred for 16 h. NH4CI aqueous solution (10 mL) was added to the mixture. The mxiture was extracted with EtOAc (20 mL X 3).
  • Step 3 Synthesis of tert-butyl (1R,3s,5S )-3-((5-bromo-1,3,4-thiadiazol-2- yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate.
  • Step 4 Synthesis of tert-butyl (1R,3s,5S )-3-((5-(7-methoxy-2-
  • Step 5 Synthesis of 6-(5-(((1R,3s,5S )-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)- 1,3,4-thiadiazol-2-yl)-7-hydroxy-N -methylquinoline-2-carboxamide.
  • Example 6 Synthesis of 6-(3-(((1R,3s,5S )-8-azabicyclo[3.2.1]octan-3-yI)(methyI)amino)- l,2,4-triazin-6-yl)-5-hydroxy-3-methylbenzo[d] oxazol-2(3H )-one.
  • Step 1 Synthesis of 2-amino-4-methoxyphenol.
  • Step 2 Synthesis of 5-methoxybenzo[d]oxazol-2(3H)-one.
  • Step 3 Synthesis of 6-bromo-5-methoxybenzo[d]oxazol-2(3H)-one.
  • NBS (20.0 g, 112.1 mmol) was added to a mixture of 5-methoxybenzo[d]oxazol-2(3H )-one (18.5 g, 112.1 mmol) and in DMF (50 ml). The mixture was stirred at room temperature for 1 hour, quenched with water (200 mL) and extracted with EtOAc (250 mL X 3).
  • Step 4 Synthesis of 6-bromo-5-methoxy-3-methylbenzo[d] oxazol-2(3H )-one.
  • Step 5 Synthesis of 6-bromo-5-hydroxy-3-methylbenzo[d]o H xazol-2(3H )-one.
  • Step 6 Synthesis of 6-bromo-5-(methoxymethoxy)-3-methylbenzo[d]oxazol-2(3H )-one.
  • Step 7 Synthesis of 5-(methoxymethoxy)-3-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzo [d] oxazol-2(3H )-one.
  • Step 8 Synthesis of 3-(methylsulfinyl)-l,2,4-triazine.
  • Step 9 Synthesis of tert-butyl (1R,3s,5S )-3-((l,2,4-triazin-3-yl)amino)-8- azabicyclo [3.2.1] octane-8-carboxylate.
  • Step 10 Synthesis of tert-butyl (1R,3s,5S )-3-(methyl(l,2,4-triazin-3-yl)amino)-8- azabicyclo [3.2.1] octane-8-carboxylate.
  • Step 11 Synthesis of tert-butyl (1R,3s,5S )-3-((6-bromo-l,2,4-triazin-3- yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 12 Synthesis of tert-butyl (1R,3s,5S )-3-((6-(5-(methoxyniethoxy)-3-niethyl-2-oxo- 2,3-dihydrobenzo[d
  • Step 13 Synthesis of 6-(3-(((1R,3s,5S )-8-azabicyclo[3.2.1]octan-3-yl)(niethyl)aniino)- l,2,4-triazin-6-yl)-5-hydroxy-3-methylbenzo[d

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. 63/061,760 filed on August 5, 2020, and U.S. Provisional Application No. 63/161,231 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 2020/163541.
[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-, -
C(=O)-, -NRX1-, -CRX2RX3-,
Figure imgf000002_0002
, or =CRX1-; RX1 is 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 Ci-C6 heteroalkyl, or -C1-C4 alkyl ene-OR31; each RX2 and RX3 is independently hydrogen, -OR31, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4haloalkyl, 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 Ci- 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) Formula (IV) 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-, -
C(=O)-, -NRX1-, -CRX2RX3-,
Figure imgf000004_0002
, or =CRX1-; RX1 is 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 alkyl ene-OR31; each RX2 and RX3 is independently hydrogen, -OR31, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4haloalkyl, 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 Ci- 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 Ci-Cg 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) wherein each variable within Formula (III) 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 (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).
[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) wherein each variable within Formula (I) 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) wherein each variable within Formula (I) 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) wherein each variable within Formula (I), 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) 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 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; 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 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 monocyclic aryl, or substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic alkyl, substituted or unsubstituted polycyclic heteroalkyl; 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. [0011] In some embodiments, a compound of Formula (II) has a structure of Formula (Ila) or Formula (lib):
Figure imgf000010_0001
Formula (Ila) Formula (lib).
[0012] In some embodiments, a compound of Formula (II) has a structure of Formula (Ila):
Figure imgf000010_0002
Formula (Ila).
[0013] In some embodiments, a compound of Formula (II) has a structure of Formula (lib):
Figure imgf000010_0003
Formula (lib).
[0014] In some embodiments, a compound of Formula (VII) has a structure of Formula (Vila):
Figure imgf000010_0005
Formula (Vila); and a compound of Formula (VIII) has a structure of Formula (Villa):
Figure imgf000010_0004
Formula (Villa).
[0015] 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
[0016] 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
[0017] 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.
[0018] 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
[0019] 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.
[0020] “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.
[0021] Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of hydrogen, unless indicated otherwise.
[0022] 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 chemi cally-relevant combinations, such as e.g. “heterocycloalkylaryl”, “haloalkylheteroaryl”, “arylalkylheterocycloalkyl”, or “alkoxy alkyl”. 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.
[0023] When indicating the number of substituents, the term “one or more” refers to the range from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents.
[0024] The term “substituent” denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule.
[0025] 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.
[0026] The following abbreviations are used throughout the specification: acetic acid (AcOH); ethyl acetate (EtOAc); butyl alcohol (n-BuOH); 1,2-di chloroethane (DCE); di chloromethane (CH2CI2, DCM); diisopropylethylamine (Diipea); dimethylformamide (DMF); hydrogen chloride (HC1); methanol (MeOH); methoxymethyl bromide (MOMBr); N-methyl-2-pyrrolidone (NMP); methyl Iodide (Mel); n-propanol (n-PrOH); p-methoxybenzyl (PMB); triethylamine (Et3N); [1,1’- Bis(diphenylphosphino)ferrocene] dichloropalladium(II); (Pd(dppf)Ch); sodium ethane thiolate (EtSNa); sodium acetate (NaOAc); sodium hydride (NaH); sodium hydroxide (NaOH); tetrahydropyran (THP); tetrahydrofuran (THF).
[0027] 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, zso-propyl, //-butyl, iso-butyl, secbutyl, and /-butyl.
[0028] The term “oxo” refers to the =0 substituent.
[0029] The term “thioxo” refers to the =S substituent.
[0030] The term “halo”, “halogen”, and “halide” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo.
[0031] 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, Ci-C8 alkyl, C1-C7 alkyl, Ci-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, //-propyl, 1 -methylethyl (z-propyl), zz-butyl, z-butyl, .s- butyl, //-pentyl, 1,1 -dimethyl ethyl (/-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-.
[0032] 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.
[0033] 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.
[0034] 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)=CRa2, 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 (/'.c., 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.
[0035] 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, -OCCH3 -C=CCH2CH3, - CH2C=CH.
[0036] The term “aromatic” refers to a planar ring having a delocalized n-electron system containing 4n+2 n electrons, where n is an integer. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups e.g., phenyl, naphthal enyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
[0037] 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.
[0038] 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. [0039] 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.
[0040] 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.
[0041] 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.
[0042] 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-l(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[l.l.l]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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, tri chloromethoxy, 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.
[0047] 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.
[0048] 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, -OCIUClUOMe, or - OCH2CH2OCH2CH2NH2. [0049] 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-.
[0050] 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[l,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 0 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. [0051] 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-l-onyl, isoindoline- 1,3 -di onyl, 3,4- dihydroisoquinolin-l(2H)-onyl, 3,4-dihydroquinolin-2(lH)-onyl, isoindoline- 1, 3 -dithi onyl, benzo[d]oxazol-2(3H)-onyl, lH-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-l-yl ( N -attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-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 (=0) 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.
[0052] 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 0 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.
[0053] 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(CI-C4 alkyl), - C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(CI-C4 alkyl), -S(=O)2N(CI-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)Ci-C4 alkyl, and -S(=O)2(Ci-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 (=0). In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, =0, -NH(CH3), -N(CH3)2, - NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and - OCF3.
[0054] 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
[0055] 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.
[0056] 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 imgf000021_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-, - xi X2n X3
Figure imgf000021_0002
, or =CRX1-; RX1 is 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 alkyl ene-OR31; each RX2 and RX3 is independently hydrogen, -OR31, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; each
Figure imgf000021_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 Ci- 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 imgf000022_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 imgf000022_0002
Formula (III) Formula (IV) 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).
[0057] In some embodiments, a compound of Formula (II) has a structure of Formula (Ila) or Formula (lib):
Figure imgf000022_0003
Formula (Ila) Formula (lib).
[0058] 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.
[0059] 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_0001
Formula (I’) wherein,
Yi, Y2, and Y3 are each independently N or CH; 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-, -C(=O)-, -NRX1-, -CR^R®-,
Figure imgf000023_0002
, or
=CRX1-; RX1 is 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 imgf000023_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 imgf000024_0001
Formula (IF) 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 (IF) is as described above for Formula (F); with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI)
Figure imgf000024_0002
Formula (III) Formula (IV) 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’).
[0060] In some embodiments of a compound of Formula (I’), two or more of Yi, Y2, and Y3 are N. [0061] In one aspect, described herein is a process for preparing a compound of Formula (F), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
Figure imgf000024_0003
Formula (I’) wherein,
Yi, Y2, and Y3 are each independently N or CH; 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-, -C(=O)-, -NRX1-, -CRX2RX3-,
Figure imgf000025_0001
, or
=CRX1-; RX1 is 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 imgf000025_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 imgf000025_0002
Formula (II*) wherein HAL represents a halogen; with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI)
Figure imgf000026_0002
Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I’).
[0062] In some embodimetns, HAL is Cl. In some embodimetns, HAL is F. In some embodimetns, HAL is Br. In some embodimetns, HAL is I.
[0063] In one aspect, described herein is a process for preparing a compound of Formula (F), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
Figure imgf000026_0003
Formula (I’) wherein,
Yi, Y2, and Y3 are each independently N or CH; 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-, -C(=O)-, -NRX1-, -CR^R13-,
Figure imgf000026_0001
, or
=CRX1-; RX1 is 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 imgf000026_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, 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 (Ila’)
Figure imgf000027_0001
Formula (Ila’) with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI)
Figure imgf000027_0002
Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I’).
[0064] 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 imgf000027_0003
Formula (F) wherein,
Yi, Y2, and Y3 are each independently N or CH; 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-, -C(=O)-, -NRX1-, -CR^R®-,
Figure imgf000027_0004
, or =CRX1-; RX1 is 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 imgf000028_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, 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 (I )
Figure imgf000028_0002
Formula (IP) wherein HAL represents a halogen; with a compound of Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI)
Figure imgf000028_0001
Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I’). [0065] In some embodiments, R is a protecting group, e.g. /c/7-butyloxycarbonyl (Boc).
[0066] 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_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-, -
C(=O)-, -NRX I-, -CRX2RX3-,
Figure imgf000029_0002
, or =CRX1-; RX1 is 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 alkyl ene-OR31; each RX2 and RX3 is independently hydrogen, -OR31, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; each is independently a single or a double bond; Z is N, C
Figure imgf000029_0003
or CR5; R5 is hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted Ci- 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 imgf000030_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 imgf000030_0002
Formula (III) Formula (IV) Formula (IVa) Formula (V) Formula (VI) to produce a compound of Formula (I);
[0067] wherein each variable within Formula (III), Formula (IV), Formula (IVa), Formula (V), and Formula (VI) is as described above for Formula (I”).
[0068] In some embodiments, a compound of Formula (II), Formula (II’) or 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) or Formula (IF) 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 1, 4 dioxane, tetrahydrofuran or dimethylformamide. In some embodiments, a compound of Formula (II), Formula (IF) or 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.
[0069] In some embodiments, the compound of Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’) 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’), Formula (II”), Formula (II*), or Formula (Ila’). In some embodiments, the one or more chiral centers is a chiral auxiliary. In some embodiments, the chiral auxiliary is -S(=O)(=NRL1)RL1.
[0070] In some embodiments the compound of Formula (I’), is a compound of Formula (I’a):
Figure imgf000031_0001
Formula (I’ a).
[0071] In some embodiments, a compound of Formula (IF) is a compound of Formula (II’ a):
Figure imgf000031_0002
Formula (II’ a).
[0072] In some embodiments, a compound of Formula (IV) is a compound of Formula (IVaa):
Figure imgf000031_0003
Formula (IVaa).
[0073] In some embodiments, a process of preparing a compound of Formula (II’ a) comprises the step of reacting a compound of Formula (X):
Figure imgf000031_0004
Formula (X) with a base, such as potassium t-butoxide in a solvent, such as dimethylformamide and a methylation agent, such as methyl iodide.
[0074] 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 imgf000031_0005
Formula (XI) with a compound of Formula (XII):
Figure imgf000032_0001
Formula (XII) in the presence of a base such as V,V-Diisopropylethylamine and a solvent such as dimethyl sulfoxide.
[0075] 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 imgf000032_0002
Formula (XIII) in a solvent, such as ethanol in the presence of a palladium catalyst under a hydrogen atmosphere. [0076] 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 (/( -<-J-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%.
[0077] In some embodiments of a process for preparing a compound of Formula (I), the process comprises the step of reacting the compound of Formula (II) with a compound of Formula (III)
Figure imgf000032_0003
Formula (III) to produce a compound of Formula (I).
[0078] 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 imgf000033_0001
to produce a compound of Formula (I).
[0079] 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 imgf000033_0002
Formula (IVa) to produce a compound of Formula (I).
[0080] 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 (V)
Figure imgf000033_0003
Formula (V) to produce a compound of Formula (I).
[0081] 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 a compound of Formula (VI)
Figure imgf000033_0004
Formula (VI) to produce a compound of Formula (I).
[0082] 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 imgf000034_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-, - xi X2n X3
Figure imgf000034_0003
, or =CRX1-; RX1 is 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 alkyl ene-OR31; each RX2 and RX3 is independently hydrogen, -OR31, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4haloalkyl, or substituted or unsubstituted C1-C4 heteroalkyl; each
Figure imgf000034_0002
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 Ci- 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 imgf000035_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 imgf000035_0002
Formula (III) wherein each variable within Formula (III) 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 (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).
[0083] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000035_0003
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000035_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 (IV)
Figure imgf000036_0001
Formula (IV) 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).
[0084] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000036_0002
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000036_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 (IV)
Figure imgf000037_0001
Formula (IVa) 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).
[0085] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000037_0002
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000037_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 imgf000037_0004
Formula (V) 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).
[0086] In another aspect described herein, is a process for preparing a compound of Formula (I)
Figure imgf000038_0001
Formula (I) comprising reacting a compound of Formula (II)
Figure imgf000038_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 (VI)
Figure imgf000038_0003
Formula (VI) wherein each variable within Formula (I), Formula (II), 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).
[0087] 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.
[0088] In another aspect described herein, is a process for preparing a compound of Formula (VII)
Figure imgf000039_0003
Formula (VII) comprising reacting a compound of Formula (VIII)
Figure imgf000039_0001
Formula (VIII) wherein R3 is a halogen, such as Cl, Br, or I; or O-CH2CF3 with a compound of Formula (IX)
Figure imgf000039_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 monocyclic aryl, or substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic alkyl, substituted or unsubstituted polycyclic heteroalkyl; 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.
[0089] In some embodiments, a compound of Formula (VII) has a structure of Formula (Vila):
Figure imgf000040_0001
Formula (Vila); and a compound of Formula (VIII) has a structure of Formula (Villa):
Figure imgf000040_0002
Formula (Villa).
[0090] In another aspect described herein, is a process for preparing a compound of Formula (VII’)
Figure imgf000040_0003
Formula (VII’) wherein,
Yi, Y2, and Y3 are each independently N or CH comprising reacting a compound of Formula (VIII’)
Figure imgf000040_0004
Formula (VIII’) wherein R3 is a halogen, such as Cl, Br, or I; or O-CH2CF3 with a compound of Formula (IX)
Figure imgf000040_0005
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 monocyclic aryl, or substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic alkyl, substituted or unsubstituted polycyclic heteroalkyl; 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.
[0091] In some embodiments, a compound of Formula (VII’) has a structure of Formula (Vila’):
Figure imgf000041_0001
Formula (Vila’); and a compound of Formula (VIII’) has a structure of Formula (Villa’):
Figure imgf000041_0002
Formula (Villa’).
[0092] In another aspect described herein, is a process for preparing a compound of Formula (VII”)
Figure imgf000041_0003
Formula (VII”) comprising reacting a compound of Formula (VIII”)
Figure imgf000041_0004
Formula (VIII”) wherein R3 is a halogen, such as Cl, Br, or I; or O-CH2CF3 with a compound of Formula (IX)
Figure imgf000041_0005
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 monocyclic aryl, or substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic alkyl, substituted or unsubstituted polycyclic heteroalkyl; 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.
[0093] In some embodiments, a compound of Formula (VII”) has a structure of Formula (Vila”):
Figure imgf000042_0003
Formula (Vila”); and a compound of Formula (VIII”) has a structure of Formula (Villa”):
Figure imgf000042_0001
Formula (Villa”).
[0094] In some embodiments, a compound of Formula (I) is a compound of Formula (la)
Figure imgf000042_0002
Formula (la).
[0095] 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.
[0096] In some embodiments, a compound of Formula (I) is a compound of Formula (lb)
Figure imgf000043_0001
Formula (lb).
[0097] In some embodiments, a compound of Formula (I) is a compound of Formula (Ic)
Figure imgf000043_0002
Formula (Ic).
[0098] In some embodiments, a compound of Formula (I) is a compound of Formula (Id)
Figure imgf000043_0003
Formula (Id).
[0099] In some embodiments, a compound of Formula (I) is a compound of Formula (le)
Figure imgf000043_0004
Formula (le).
[0100] In some embodiments, a compound of Formula (I) is a compound of Formula (If)
Figure imgf000043_0005
Formula (If).
[0101] In some embodiments, Y1 is N, Y2 is N, and Y3 is CH. In some embodiments, Y1 is N, Y2 is CH, and Y3 is N. In some embodiments, Y1 is N, Y2 is N, and Y3 is N. 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 l-methylpyridin-2(lH)-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-l-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.
[0102] In some embodiments, a compound of Formula (I) is a compound of Formula (la)
Figure imgf000045_0001
Formula (la).
[0103] In some embodiments, a compound of Formula (II) is a compound of Formula (Ila) or Formula (lib)
Figure imgf000045_0002
Formula (Ila) Formula (lib). [0104] In some embodiments, a compound of Formula (II) is a compound of Formula (lie) or Formula (lid):
Figure imgf000046_0001
Formula (lie) Formula (lid).
[0105] In some embodiments, a compound of Formula (II) is a compound of Formula (lie) or Formula (Ilf):
Figure imgf000046_0002
Formula (lie) Formula (Ilf).
[0106] In some embodiments, a compound of Formula (II) is a compound of Formula (Ilg) or Formula (Ilh):
Figure imgf000046_0003
Formula (IIg) Formula (IIh).
[0107] In some embodiments, a compound of Formula (II) is a compound of Formula (IF) or Formula (Ilj):
Figure imgf000046_0004
Formula (Hi) Formula (Ilj).
[0108] In some embodiments, a compound of Formula (II) is a compound of Formula (Ilk) or Formula (III):
Figure imgf000047_0001
Formula (Ilk) Formula (III).
[0109] In some embodiments, Y1 is N, Y2 is N, and Y3 is CH. In some embodiments, Y1 is N, Y2 is CH, and Y3 is N. In some embodiments, Y1 is N, Y2 is N, and Y3 is N. 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 Ci- C4heteroalkyl substituted with oxo and -CH3. In some embodiments, R is /c/7-buty I oxy carbonyl. In some embodiments, each R15 and R18 is independently hydrogen or substituted or unsubstituted Ci- 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 R15 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.
[0110] In some embodiments, a compound of Formula (II) is a compound of Formula (Ilaaa)
Figure imgf000048_0001
Formula (Ilaaa).
[0111] In some embodiments, a compound of Formula (IV) is a compound of Formula (IVaaa)
Figure imgf000048_0002
Formula (IVaaa).
[0112] In one aspect, described herein is a compound of Formula (II),
Figure imgf000048_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, -O-, -S-, -C(=O)-, -NRX1-, -CRX2RX3 or =CRX1-; RX1 is hydrogen, -CN,
Figure imgf000048_0004
substituted or unsubstituted C1-C8 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 imgf000048_0005
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 Cs 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-C6haloalkyl, substituted or unsubstituted C 1 -C , heteroalkyl, substituted or unsubstituted Cs-Cs 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.
[0113] In one aspect, described herein is a compound of Formula (III),
Figure imgf000049_0001
Formul (III) 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 (IV),
Figure imgf000049_0002
Formula (IV) 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 (IVa),
Figure imgf000050_0001
Formula (IVa) 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 (V),
Figure imgf000050_0002
Formula (V) 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 (VI)
Figure imgf000050_0003
Formula (VI) wherein ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
[0118] In one aspect, described herein is a compound of Formula (VII),
Figure imgf000050_0004
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 monocyclic aryl, or substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic alkyl, substituted or unsubstituted polycyclic heteroalkyl; and each R31 and R32 is independently hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Ci-Cr, 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.
[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 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.
[0120] In some embodiments of a compound of Formula (I), Formula (III), Formula (TV), Formula (IVa), Formula (V), or Formula (VI), ring Q is substituted or unsubstituted phenyl.
[0121] In some embodiments of a compound of Formula (I), Formula (III), Formula (TV), 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)OR 1, -C( O)N(R | )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2- Cr, 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.
[0122] In some embodiments, each R31 is independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4haloalkyl, 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.
[0123] In some embodiments, ring Q is 2-hydroxy-phenyl substituted with 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. 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- Cr, alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, and substituted or unsubstituted C2-C7 heterocycloalkyl.
[0125] In some embodiments, each R31 is independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4haloalkyl, 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.
[0126] 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.
[0127] In some embodiments, each R31 is independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4haloalkyl, 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.
[0128] In some embodiments, ring Q is
Figure imgf000052_0001
[0129] 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. [0130] 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.
[0131] In some embodiments, ring Q is substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl.
[0132] In some embodiments, ring Q is substituted or unsubstituted 6-membered monocyclic heteroaryl.
[0133] In some embodiments, ring Q is 6-membered monocyclic heteroaryl selected from:
Figure imgf000053_0001
[0134] 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.
[0135] In some embodiments, each RQ is independently hydrogen, -F, -Cl, -CN, -OH, -CH3,-CF3, or -OCH3
[0136] In some embodiments, each RQ is independently hydrogen or -F.
[0137] In some embodiments, each RQ is hydrogen.
[0138] In some embodiments, ring P is substituted or unsubstituted heteroaryl.
[0139] In some embodiments, ring P is heteroaryl selected from the group consisting of:
Figure imgf000053_0002
Figure imgf000054_0001
[0140] 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.
[0141] 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.
[0142] In some embodiments, ring P is heteroaryl selected from the group consisting of:
Figure imgf000054_0002
[0143] 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.
[0144] 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
[0145] In some embodiments, each RB is independently H, deuterium, -F, -Cl, -CN, -CH3, -CF3,- OH, or -OCH3. [0146] In some embodiments, each RB is independently -F or -OCH3.
[0147] In some embodiments, RB1 is hydrogen, deuterium, -CH3, -CF3, or -CD3.
[0148] In some embodiments, m is 0 or 1.
[0149] 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.
[0150] In some embodiments, each R31 is independently hydrogen, deuterium, substituted or unsubstituted C1-C4 alkyl, -CD3, substituted or unsubstituted C1-C4haloalkyl, 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.
[0151] In some embodiments, ring Q is selected from the group consisting of:
Figure imgf000055_0001
[0153] In some embodiments, ring Q is selected from the group consisting of:
Figure imgf000056_0001
, and
[0154] In some embodiments, ring Q is selected from the group consisting of:
Figure imgf000056_0002
Figure imgf000057_0001
[0155] 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.
[0156] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula
(IVa), Formula (V), or Formula (VI), ring Q is:
Figure imgf000057_0002
, wherein each A1, A2, A3, and A4 is independently N, -NRY1-, -O-, -S-, or
CRA1; each RA1 is independently hydrogen, halogen =0, 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 imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0004
Figure imgf000058_0003
Figure imgf000058_0005
Figure imgf000058_0006
Figure imgf000058_0007
Figure imgf000058_0009
Figure imgf000058_0008
Figure imgf000058_0010
Figure imgf000058_0016
Figure imgf000058_0011
Figure imgf000058_0012
Figure imgf000058_0013
Figure imgf000058_0014
Figure imgf000058_0015
. In some embodiments, ring
Figure imgf000059_0001
some embodiments, ring Q is
Figure imgf000059_0014
Figure imgf000059_0015
Figure imgf000059_0013
Figure imgf000059_0008
Figure imgf000059_0009
Figure imgf000059_0006
Figure imgf000059_0007
Figure imgf000059_0012
Figure imgf000059_0005
Figure imgf000059_0010
Figure imgf000059_0003
Figure imgf000059_0004
Figure imgf000059_0011
. In some embodiments, ring Q is
Figure imgf000059_0002
[0157] In some embodiments, A1 is CH, CH2, CF, CF2, C(CH3), N, N(CHs), 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, CHs), 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).
[0158] 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).
[0159] In some embodiments, ring Q is optionally substituted phenyl. In some embodiments, ring Q is optionally substituted naphthyl.
[0160] 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. [0161] In some embodiments, ring Q is fully aromatic. In some embodiments, ring Q is partially unsaturated.
[0162] In some embodiments, ring Q is 2-OH phenyl substituted by a halogen, such as Cl.
[0163] 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.
[0164] In some embodiments, ring Q is
Figure imgf000061_0001
. In some embodiments, ring Q is
Figure imgf000061_0002
[0165] In some embodiments of a compound of Formula (I), Formula (III), Formula (IV), Formula (IVa), Formula (V), or Formula (VI), ring Q is:
Figure imgf000061_0003
, 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 =0, or substituted or unsubstituted C1-C6 alkyl; and each RY1 is independently hydrogen or substituted or unsubstituted Ci-C6 alkyl.
[0166] In some embodiments, A1 is CH, CH2, CF, C(CHs), 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(CHs). 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
[0167] 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
[0168] 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).
[0169] 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 CDi or CD2CD3.
[0170] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’)In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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 Cs-Cs 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-.
[0171] In some embodiments of a compound of Formula (I), Formula (F), Formula (I”), Formula (II), Formula (II’), Formula (II' '), Formula (II*), or Formula (Ila’), 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- C 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.
[0172] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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. [0173] In some embodiments of a compound of Formula (I), Formula (F), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), 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, R15, 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.
[0174] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0175] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0176] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0177] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0178] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0179] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), 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. [0180] In some embodiments of a compound of Formula (I), Formula (F), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0181] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0182] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0183] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, at least one of W, R11, R12, R13, R14, R15, R15, 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.
[0184] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R11, R12, R19, R20 and R16 are hydrogen.
[0185] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0186] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0187] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0188] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0189] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0190] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0191] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, R11, R12, R19, R20 and R16 are hydrogen.
[0192] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0193] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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.
[0194] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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
[0195] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), 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, R15, R19, R20, and R17 comprises a fluorine. In some embodiments, at least two of R11, R12, R13, R14, R15, and R17 comprise a fluorine.
[0196] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (IF), Formula (II”), Formula (II*), or Formula (Ila’), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, at least one of W, R11, R12, R13, R14, R15, R15, 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 imgf000069_0001
Figure imgf000069_0002
[0198] In some embodiments,
Figure imgf000070_0001
is selected from the group consisting of
Figure imgf000070_0011
Figure imgf000070_0008
Figure imgf000070_0007
Figure imgf000070_0003
Figure imgf000070_0009
Figure imgf000070_0010
Figure imgf000070_0002
Figure imgf000070_0006
Figure imgf000070_0005
Figure imgf000070_0004
the group consisting of
Figure imgf000070_0013
Figure imgf000070_0012
[0199] In some embodiments,
Figure imgf000071_0001
is selected from the group consisting of
Figure imgf000071_0002
Figure imgf000071_0003
Figure imgf000071_0004
Figure imgf000071_0005
Figure imgf000071_0006
Figure imgf000071_0011
Figure imgf000071_0007
Figure imgf000071_0009
In some embodiments,
Figure imgf000071_0010
Figure imgf000071_0008
selected from the group consisting
Figure imgf000072_0001
Figure imgf000072_0002
[0200] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II’ ’), Formula (II*), or Formula (Ila’), X is absent.
[0201] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (IF ’), Formula (II*), or Formula (Ila’), X is -O-.
[0202] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II’ ’), Formula (II*), or Formula (Ila’), X is -S-.
[0203] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II’ ’), Formula (II*), or Formula (Ila’), X is -C(=O)-.
[0204] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (IF ’), Formula (II*), or Formula (Ila’), 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.
[0205] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II’ ’), Formula (II*), or Formula (Ila’), X is -CRX2RX3-.
[0206] In some embodiments of a compound of Formula (I), Formula (F), Formula (I”), Formula
(II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), X is
Figure imgf000072_0003
[0207] In some embodiments of a compound of Formula (I), Formula (F), Formula (I”), Formula (II), Formula (II’), Formula (IF ’), Formula (II*), or Formula (Ila’), X is or =CRX1-.
[0208] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II’ ’), Formula (II*), or Formula (Ila’), Z is N.
[0209] In some embodiments of a compound of Formula (I), Formula (I’), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), Z is C. [0210] In some embodiments of a compound of Formula (I), Formula (F), Formula (I”), Formula (II), Formula (II’), Formula (II”), Formula (II*), or Formula (Ila’), Z is CR5. In some embodiments, Z is CH
[0211] 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.
[0212] 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, - NR3 IS( O)2R3 IR32, -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.
[0213] 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. 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.
[0214] 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.
[0215] 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. 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.
[0216] 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
[0217] 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. [0218] The following abbreviations are used: DCM - dichloromethane; DIPEA - N,N- diisopropylethylamine; DMSO - dimethyl sulfoxide; DMF - N,N-dimethylformamide; EDCI - N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide; Et20 - 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 - l-Chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); SFC - supercritical fluid chromatography; THFtetrahydrofuran; TMSC1 - trimethylsilyl chloride; h - hour; min - minute; rt - room temperature (22-25 °C); g - grams; mL - milliliters; mg - milligrams; mmol - millimoles.
[0219] 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: 3 527-29074-5; 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) “Modem 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. [0220] 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:
[0221] (±) 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.
[0222] Example 1: Preparation of tert-butyl (lS,2R,3R,5R)-3-((5-(4-chloro-2- (methoxymethoxy)phenyl)pyrazin-2-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate.
[0223] Step 1: Preparation of tert-butyl (lS,2R,3R,5R)-2-fluoro-3-((5-(methylthio)pyrazin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
[0224] To a stirred mixture of 2-bromo-5-(methylthio)pyrazine (1 g, 4.876 mmol) and tert-butyl (l S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate (1.31 g, 5.364 mmol) in dimethyl sulfoxide (10 mL) was added N,N-diisopropylethylamine (2.52 g, 19.504 mmol) dropwise at room temperature under nitrogen. The resulting mixture was placed in a preheated oil bath and was stirred for 24 hours at 120°C then removed from heat, allowed to cool to room temperature and quenched with water/ice. The resulting mixture was extracted with ethyl acetate (3x60 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, (ethyl acetate/petr oleum ether: 1 :3) which gave after isolation tert-butyl (1 S,2R,3R,5R)-2-fluoro-3-((5-(methylthio)pyrazin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (340 mg, 18.92%) as a yellow solid, [M-tBu+H]+= 313.1. [0225] Step 2: Preparation of tert-butyl (lS,2R,3R,5R)-2-fluoro-3-(methyl(5- (methylthio)pyrazin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
[0226] To a stirred mixture of tert-butyl (lS,2R,3R,5R)-2-fluoro-3-((5-(methylthio)pyrazin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (340 mg, 0.923 mmol) in dimethylformamide (4 mL) at 0°C under dry nitrogen was added portion-wise sodium hydride (44.28 mg, 1.108 mmol). The resulting mixture was stirred for 20 min at 0°C followed by the addition of methyl iodide (157.17 mg, 1.108 mmol) dropwise at 0°C. The cooling bath was removed, and the mixture was stirred for additional 1 hour at room temperature. The reaction was then cooled to 0°C and carefully quenched with water/ice. The resulting mixture was extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (2x40 mL), dried over anhydrous Na2SO4, fdtered, and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether: 1 :4) which gave after isolation tert-butyl (lS,2R,3R,5R)-2-fluoro-3-(methyl(5-(methylthio)pyrazin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (240 mg) as a yellow solid.
[0227] Step 3A: Preparation of tert-butyl (lS,2R,3R,5R)-3-((5-(4-chloro-2- (methoxymethoxy)phenyl) pyrazin-2-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate.
[0228] To a solution of tert-butyl (lS,2R,3R,5R)-2-fluoro-3-(methyl(5-(methylthio)pyrazin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.261 mmol) and 4-chloro-2- (methoxymethoxy)phenylboronic acid (169.74 mg, 0.783 mmol) in tetrahydrofuran (2.5 mL) under dry nitrogen was added copper(I)-3-methylsalicylate (168.39 mg, 0.783 mmol) and tetrakis(triphenylphosphine)palladium(0) (45.32 mg, 0.039 mmol). The resulting mixture was placed in a preheated oil bath and was stirred for 2 hours at 70°C then removed from heat, allowed to cool to room temperature under nitrogen. The desired product, tert-butyl (lS,2R,3R,5R)-3-((5-(4-chloro- 2-(methoxymethoxy) phenyl)pyrazin-2-yl)(methyl)amino)-2-fluoro-8-azabicyclo[3.2.1] octane-8- carboxylate was observed by LCMS, [M +H]+= 506.9.
[0229] Step 3B: Preparation of tert-butyl (lS,2R,3R,5R)-3-((5-(4-chloro-2- (methoxymethoxy)phenyl)pyrazin-2-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate.
[0230] To a solution of tert-butyl (lS,2R,3R,5R)-2-fluoro-3-(methyl(5-(methylthio)pyrazin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.136 mmol) and 4-chloro-2- (methoxymethoxy)phenylboronic acid (88.10 mg, 0.408 mmol, 3.00) in tetrahydrofuran (1.5 mL) under dry nitrogen was added copper(I)-3-methylsalicylate (87.40 mg, 0.408 mmol, 3) and tetrakis(triphenylphosphine)palladium(0) (23.52 mg, 0.020 mmol, 0.15). The resulting mixture was placed in a preheated oil bath and was stirred for 2 hours at 70°C then removed from heat, allowed to cool to room temperature under nitrogen. The desired product, tert-butyl (lS,2R,3R,5R)-3-((5-(4- chloro-2-(methoxymethoxy)phenyl)pyrazin-2-yl)amino)-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate was observed by LCMS, [M +H]+ = 492.9.
[0231] Example 2: Synthesis of (1R,2S,3S)-tert-Butyl 3-amino-2-fluoro-8- azabicyclo [3.2.1] octane-8-carboxylate.
Figure imgf000078_0001
[0232] Step 1: tert-Butyl 3-((triethylsilyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2-2).
[0233] 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), tri ethylchlorosilane (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.
[0234] Step 2: tert-Butyl 2-fluoro-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (Rac-2-3).
[0235] 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 and the precipitated solid was stirred for 2 h. This solid was filltered and dried to obtain Rac-2-3 (3.2 Kg, 62%) as an off white solid. JH NMR (400 MHz, CDCU): 8 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).
[0236] Step 3: tert-Butyl 3-(benzylamino)-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylate (Rac-2-4).
[0237] 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 IN 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. 'H 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 ( /z): 335 (M+H).
[0238] Step 4: (1R,2S,3S)-tert-Butyl-3-(benzylamino )-2-flu oro-8-azabicyclo|3.2.1 |octane-8- carboxylate (2-4).
[0239] 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 4 as an off-white solid (0.225 kg, 98% chiral purity, 22.5%). [0240] Step 5: (lR,2S,3S,5S)-tert-Butyl 3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8- carboxylate (2-5).
[0241] 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- 6): 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%.
[0242] Example 3: Synthesis of 6-(6-(((1R ,2R ,3S,5S )-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Formula (I’ a)).
Figure imgf000080_0001
Formula (I’ a)
[0243] Step 1: Synthesis of tert- Butyl 3-((6-chloropyridazin-3-yl)amino)-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate (3-3).
[0244] DIPEA (26.46 g, 2.5 eq) was added to a solution of 3,6-dichloropyridazine (14.6 g, 1.2 eq) and racemic-3-1 (20.0 g, 81.9 mmol) in DMSO (200 mL) at RT The mixture was stirred at 120 °C for about 24 h. After completion of the reaction (by TLC), the mixture was cooled to room temperature and quenched with H2O (500 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic extracts were concentrated to obtain a solid, which was triturated with EtOAc to yield 3-3 (15 g, 51 % yield) as a pale yellow solid.
[0245] Step 2: Synthesis of tert-butyl 3-((6-chloropyridazin-3-yl)(methyl)amino)-2-fluoro-8- azabicyclo[3.2.1]octane-8-carboxylate (3-4).
[0246] Potassium t-butoxide (4.74 g, 3.0 eq) was added to a stirred solution of 3-3 (5.0 g, 14.06 mmol) in 75 mL of DMF at 10 °C. After stirring for 1 h at 25 °C, methyl iodide (4.5 mL, 5.0 eq) was added to the mixture at 10 °C. The reaction was stirred at room temperature for 5 h, quenched with 75 mL of water to provide a solid. The solid was collected by filtration and dried in vacuo to provide 3-4 (4.2 g, 80% yield) as an off-white solid.
[0247] Step 3: Synthesis of 1R,2S,3S,5S )-tert-butyl 2-fluoro-3-((6-(5-(methoxymethoxy)-2- methylbenzo[d|oxazol-6-yl)pyridazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (3-6).
[0248] A mixture of 3-4 (13.0 g, 35.12 mmol), 3-5 (22.4 g, 2.0 eq) and K3PO4 (59.88 g, 8 eq) in 1,4- dioxane (292.0 mL) and water (98.0 mL) was degassed with nitrogen and Pd-X-Phos-Gz (2.62 g, 0.1 eq) was added to reaction mixture. The resulting mixture was heated to 100 °C and stirred for 3 h at the same temperature. The mixture was cooled to RT, quenched with ice water and extracted with EtOAc (3 x 250 mL). The organic extracts were dried over sodium sulphate and concentrated to give a solid. The solid was crystalized from EtOAc/hexane to give 3-6 (17.0 g, 91% yield) as an off-white solid.
[0249] Step 4: Synthesis 6-(6-(((1R,2S,3S,5S )-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Formula (I’ a)).
[0250] TFA (136.0 mL) was slowly added to a stirred solution of 3-6 (17.0 g, 32.2 mmol) in DCM (170.0 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The volatiles were distilled under vacuum and the residue was treated with cold saturated aqueous NaHCO3 solution to a pH of 9 and extracted with ethyl acetate (3 x 500 mL). The combined organic extracts were washed with brine (500 mL), dried over sodium sulphate and concentrated to give a solid which was triturated with chilled n -hexane and the resulting solids were collected by fdtration. This solid was slurried in IPA (4 vol) and heated to 40 °C, this temperature was maintained for 1 h. The suspension was cooled to 25 °C, stirred for 2 h, the solids were collected by filtration and dried to afford Formula (I’a) (8.6 g, 70% yield) as an off-white solid.
[0251] Example 4: Synthesis of 4-(4-(5-(((1R,3s,5S )-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)-l,3,4-thiadiazol-2-yl)-3-hydroxyphenyl)-l-methylpyridin-2(1H )-one.
Figure imgf000081_0001
[0252] Step 1: Synthesis of l-bromo-4-chloro-2-(methoxymethoxy)benzene.
[0253] NaH (185 g, 46.3 mmol, 60% in mineral oil) was added to a stirred solution of 2-bromo-5- chlorophenol (8 g, 38.6 mmol) in 150 mL of DMF at 0 °C. After stirring at 0 °C for 30 min, MOMBr (7.25 g, 58 mmol) was added. The mixture was then stirred at room temperature for 2 h, quenched with NH4CI aqueous solution (15 mL), extracted with EtOAc (30 mL X 3). The combined organic solvents were dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (0-10% EtOAc/petroleum ether) to give 8.1 g of l-bromo-4-chloro-2-(methoxymethoxy)benzene as colorless oil (84% yield). 'HNMR (500 MHz, Chloroform-d ) δ 7.45 (d, J= 8.5 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.89 (dd, J= 8.4, 2.3 Hz, 1H), 5.24 (s, 2H), 3.51 (s, 3H). LCMS: fa = 1.51 min.
[0254] Step 2: Synthesis of 4-chloro-2-(methoxymethoxy)phenylboronic acid.
[0255] n-BuLi (5.76 mL, 14.4 mmol) was added to a stirred solution of l-bromo-4-chloro-2- (methoxymethoxy)benzene (3 g, 12 mmol) in 40 mL of THF under nitrogen at -78 °C. After stirring at -78 °C for 40 min, B(OMe)3 (2 g, 19.2 mmol) was added. The mixture was allowed to warm up to room temperarture and stirred for 16 h. NH4CI aqueous solution (10 mL) was added to the mixture. The mxiture was extracted with EtOAc (20 mL X 3). The commbined orgainc solvents were washed with brine (10 mL), dried over NazSO4, concentrated and recrystalized from 3% EtOAc/petroleum ether to give 1.6 g of 4-chloro-2-(methoxymethoxy)phenylboronic acid as off white solid (62% yield). LCMS: m/z 199.1 [M-0H]+; fa = 1.65 min.
[0256] Step 3: Synthesis of tert-butyl (1R,3s,5S )-3-((5-bromo-l,3,4-thiadiazol-2- yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate.
[0257] A mixture of tert-butyl (17?,3s,5S)-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (2.2 g, 8.66 mmol), 2,5-dibromo-l,3,4-thiadiazole (2.54 g, 10.39 mmol) and DIPEA (3.35 g, 25.98 mmol) in 24 mL of DMSO was stirred at 130 °C for 4 h. After cooling to room temperature, the mixture was cooled to room temperature, diluted with H2O (100 mL), extracted by EtOAc (100 mL x 3). After removal of solvent, the crude product was purified by silica gel column (30% EtOAc/petroleum ether) to give 3.2 g of tert-butyl ( 1R,3s,5S )-3-((5-bromo- l ,3,4-thiadiazol-2- yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate as brown oil (89% yield). LCMS: m/z 363.0 [M-55]+; fa = 1.99 min.
[0258] Step 4: Synthesis of tert-butyl (1R,3s,5S )-3-((5-(4-chloro-2-(niethoxyniethoxy)phenyl)- l,3,4-thiadiazol-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate.
[0259] A mixture of tert-butyl (1R,3s,5S )-3-((5-bromo-l,3,4-thiadiazol-2-yl)(methyl)amino)-9- azabicyclo[3.3.1]nonane-9-carboxylate (300 mg, 1.87 mmol), 4-chloro-2- (methoxymethoxy)phenylboronic acid (444 mg, 2.06 mmol), Pd(dppf)C12 (274 mg, 0.37 mmol), K2CO3 (516 mg, 3.74 mmol) in 6 mL of dioxane and 2 mL of H2O. The mixture was degassed and stirred at 100 °C for 1 h, concentrated and purified by silica gel column (20-30% EtOAc/petr oleum ether) to give 250 mg of tert-butyl (1R,3s,5S )-3-((5-(4-chloro-2-(methoxymethoxy)phenyl)-l,3,4- thiadiazol-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate as yellow solid (68% yield). LCMS: m/z 509.3 [M+H]+; fa = 2.12 min.
[0260] Step 5: Synthesis of tert-butyl (1R,3s,5S )-3-((5-(2-(nieth()xyinetlioxy)-4-(l-methyl-2-oxo- l,2-dihydropyridin-4-yl)phenyl)-l,3,4-thiadiazol-2-yl)(methyl)amino)-9- azabicyclo[3.3.1]nonane-9-carboxylate.
[0261] A mixture of tert-butyl (1R,3s,5S )-3-((5-(4-chloro-2-(methoxymethoxy)phenyl)-l,3,4- thiadiazol-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.20 mmol), (1- methyl-2-oxo-l,2-dihydropyridin-4-yl)boronic acid (36 mg 0.24 mmol), Xphos-Pd-G2 (31 mg, 0.04 mmol) and K3PO4 (83 mg, 0.39 mmol) in 3 mL of dioxane and 1 mL of H2O was added. The mixture was degassed and stirred at 100 °C for 1 h, concentrated and purified by silica gel column (75-85% EtOAc/petroleum ether) to give 100 mg of tert-butyl (1R,3s,5S )-3-((5-(2-(methoxymethoxy)-4-(l- methyl-2-oxo-l,2-dihydropyridin-4-yl)phenyl)-l,3,4-thiadiazol-2-yl)(methyl)amino)-9- azabicyclo[3.3.1]nonane-9-carboxylate as yellow oil (87% yield). LCMS: m/z 582.3 [M+H]+; fa = 1.85 min.
[0262] Step 6: Synthesis of 4-(4-(5-((( 1R,3s,5S )-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-
1.3.4-thiadiazol-2-yl)-3-hydroxyphenyl)-l-methylpyridin-2(1H )-one.
[0263] 4 mL of HC1 in dioxane (4 N) was added to a stirred solution of tert-butyl (1R,3s,5S )-3-((5- (2-(methoxymethoxy)-4-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)phenyl)-l,3,4-thiadiazol-2- yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.17 mmol) in 5 mL of CH2Q2. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated, NH3MeOH (7 N) was added to make pH = 9, concentrated and purified by silica gel column (10- 20% MeOH/CH2Cl2) to give 55 mg of 4-(4-(5-(((1R,3s,5S )-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)-l,3,4-thiadiazol-2-yl)-3-hydroxyphenyl)-l-methylpyridin-2(1H )-one as yellow solid (73% yield). 1H NMR (400 MHz, DMSO-d6 ) 5 8.07 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.39 - 7.23 (m, 2H), 6.69 (d, J = 1.9 Hz, 1H), 6.59 (dd, J = 7.1, 2.0 Hz, 1H), 5.24 - 5.08 (m, 1H), 3.77 (s, 2H), 3.48 (s, 3H), 3.00 (s, 3H), 2.38 - 2.24 (m, 2H), 2.09 - 1.70 (m, 8H). LCMS: m/z 438.3 [M+H]+; fa=1.25 min.
[0264] Example 5: Synthesis of 6-(5-(((1R,3s,5S )-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-
1.3.4-thiadiazol-2-yl)-7-hydroxy-N-methyIquinoline-2-carboxamide.
Figure imgf000084_0001
Figure imgf000084_0003
,
Figure imgf000084_0002
[0265] Step 1: Synthesis of l-bromo-4-chloro-2-(methoxymethoxy)benzene.
[0266] NaH (185 g, 46.3 mmol, 60% in mineral oil) was added to a stirred solution of 2-bromo-5- chlorophenol (8 g, 38.6 mmol) in 150 mL of DMF at 0 °C. After stirring at 0 °C for 30 min, MOMBr (7.25 g, 58 mmol) was added. The mixture was then stirred at room temperature for 2 h, quenched with NH4CI aqueous solution (15 mL), extracted with EtOAc (30 mL X 3). The combined organic solvents were dried over anhydrous NazSOr, concentrated and purified by silica gel chromatography (0-10% EtOAc/petroleum ether) to give 8.1 g of l-bromo-4-chloro-2-(methoxymethoxy)benzene as colorless oil (84% yield). *HNMR (500 MHz, Chloroform-rZ) 5 7.45 (d, J= 8.5 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.89 (dd, J= 8.4, 2.3 Hz, 1H), 5.24 (s, 2H), 3.51 (s, 3H). LCMS: ZR = 1.51 min.
[0267] Step 2: Synthesis of 4-chloro-2-(methoxymethoxy)phenylboronic acid.
[0268] n-BuLi (5.76 mL, 14.4 mmol) was added to a stirred solution of l-bromo-4-chloro-2- (methoxymethoxy)benzene (3 g, 12 mmol) in 40 mL of THF under nitrogen at -78 °C. After stirring at -78 °C for 40 min, B(OMe)3 (2 g, 19.2 mmol) was added. The mixture was allowed to warm up to room temperarture and stirred for 16 h. NH4CI aqueous solution (10 mL) was added to the mixture. The mxiture was extracted with EtOAc (20 mL X 3). The commbined orgainc solvents were washed with brine (10 mL), dried over Na2SO4, concentrated and recrystalized from 3% EtOAc/petroleum ether to give 1.6 g of 4-chloro-2-(methoxymethoxy)phenylboronic acid as off white solid (62% yield). LCMS: m/z 199.1 [M-0H]+; tR = 1.65 min.
[0269] Step 3: Synthesis of tert-butyl (1R,3s,5S )-3-((5-bromo-1,3,4-thiadiazol-2- yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate.
[0270] The mixture of tert-butyl (1R,3s,5S )-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9- carboxylate (2.2 g, 8.66 mmol) in 24 mL of DMSO, 2,5-dibromo-l,3,4-thiadiazole (2.54 g, 10.39 mmol), DIPEA (3.35 g, 25.98 mmol) was added at room temperature, the mixture was stirred at 130 °C for 4 h, cooled to room temperature, diluted with H2O (100 mL) and extracted by EtOAc (100 mLx3). After removal of solvent, the crude product was purified by silica gel column (30% EtOAc/petroleum ether) to give 3.2 g of tert-butyl ( l/?,3.s,5,S')-3-((5-bromo- l ,3,4-thiadiazol-2- yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate as brown oil (89% yield). LCMS: m/z 363.0 [M-55]+; tR = 1.99 min.
[0271] Step 4: Synthesis of tert-butyl (1R,3s,5S )-3-((5-(7-methoxy-2-
(methylcarbamoyl)quinolin-6-yl)-1,3,4-thiadiazol-2-yl)(methyl)amino)-9- azabicyclo[3.3.1]nonane-9-carboxylate.
[0272] A mixture of 6-bromo-7-methoxy-A-methylquinoline-2-carboxamide (200 mg, 0.68 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (259 mg, 1.02 mmol), Pd2(dba)s (125 mg, 0.14 mmol), x-Phos (130 mg, 0.27 mmol) and KO Ac (133 mg, 1.36 mmol) in 6 mL of dioxane was degassed and stirred at 100 °C for 3 h. The mixture was cooled to room temerature, tert-butyl (1R,3s,5S )-3-((5-bromo-l,3,4-thiadiazol-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9- carboxylate (227 mg, 0.54 mmol), Pd(dppf)C12 (100 mg, 0.14 mmol), K2CO3 (188 mg, 1.36 mmol) in 9 mL of dioxane and 3 mL of H2O was added. The mixture was degassed and stirred at 100 °C for 2 h, concentrated and purified by silica gel column (70-90% EtOAc/petroleum ether) to give 150 mg of tert-butyl (1R,3s,5S )-3-((5-(7-methoxy-2-(methylcarbamoyl)quinolin-6-yl)-l,3,4-thiadiazol-2- yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate as yellow solid (40% yield). LCMS: m/z 553.3 [M+H]+; tR = 1.97 min.
[0273] Step 5: Synthesis of 6-(5-(((1R,3s,5S )-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)- 1,3,4-thiadiazol-2-yl)-7-hydroxy-N -methylquinoline-2-carboxamide.
[0274] 10 mL of BBr3 (17%) was added to a stirred solution of tert-butyl (1R,3s,5S )-3-((5-(7- methoxy-2-(methylcarbamoyl)quinolin-6-yl)-l,3,4-thiadiazol-2-yl)(methyl)amino)-9- azabicyclo[3.3.1]nonane-9-carboxylate (150 mg, 0.27 mmol) in 3 mL of CH2CI2. The mixture was stirred at room temperature for 16 h, quenched with water (50 mL), added saturated aqueous sodium bicarbonate to adjust pH to 8~9 extracted with CH2CI2 (50 mL X 3). The combined organic solvents were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated and purified by silica gel column (0-20% MeOH/CH2Cl2 to give 20 mg of 6-(5-(((1R,3s,5S )-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)-l,3,4-thiadiazol-2-yl)-7-hydroxy-N-methylquinoline-2-carboxamide as yellow solid (21% yield). LCMS: m/z 439.1 [M+H]+; ZR = 1.36 min. 'H NMR (400 MHz, MeOD-d4) δ 8.50 (s, 1H), 8.38 (d, J= 8.2 Hz, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.53 (s, 1H), 5.38 - 5.25 (m, 1H), 3.80 (s, 2H), 3.12 (s, 3H), 3.02 (s, 3H), 2.44 - 2.31 (m, 2H), 2.24 - 1.95 (m, 8H).
[0275] Example 6: Synthesis of 6-(3-(((1R,3s,5S )-8-azabicyclo[3.2.1]octan-3-yI)(methyI)amino)- l,2,4-triazin-6-yl)-5-hydroxy-3-methylbenzo[d] oxazol-2(3H )-one.
Figure imgf000086_0001
[0276] Step 1: Synthesis of 2-amino-4-methoxyphenol.
[0277] A mixture of 4-methoxy-2-nitrophenol (10 g, 59.17 mmol) and Pd/C (3 g, 10% on activated carbon) in MeOH (25 mb) was stirred at room temperature for 5 h under H2 atmosphere. Then the mixture was filtered and concentrated to give 8.5 g of 2-amino-4-methoxyphenol as yellow oil (97% yield), which was used directly to next step. LCMS: m/z 140.1 [M+H]+; tR = 0.35 min.
[0278] Step 2: Synthesis of 5-methoxybenzo[d]oxazol-2(3H)-one.
[0279] A mixture of 2-amino-4-methoxyphenol (18.5 g, 133 mmol) and CDI (28.05 g, 172.9 mmol) in THF (50 ml) was stirred at 70 °C for 2 hours. After cooling to room temperature, the mixture was quenched with water (400 mb), extracted with EtOAc (500 mb X 3). The combined organic solvents were washed with brine (400 ml X 3), dried over anhydrous Na2SO4 and concentrated to give 31.5 g of 5-methoxybenzo[d]oxazol-2(3H)-one as colorless oil (98% yield), which was used directly to next step. LCMS: m/z 166.2 [M+H]+; tR = 1.61 min.
[0280] Step 3: Synthesis of 6-bromo-5-methoxybenzo[d]oxazol-2(3H)-one. [0281] NBS (20.0 g, 112.1 mmol) was added to a mixture of 5-methoxybenzo[d]oxazol-2(3H )-one (18.5 g, 112.1 mmol) and in DMF (50 ml). The mixture was stirred at room temperature for 1 hour, quenched with water (200 mL) and extracted with EtOAc (250 mL X 3). The combined organic solvents were washed with LiCl aqueous solution (200 mL X 3), dried over anhydrous Na2SC>4, concentrated and purified by silica gel chromatography (0-10% EtOAc/petroleum ether) to give 22.8 g of 6-bromo-5-methoxybenzo[d ]oxazol-2(3H )-one as brown solid (91% yield). LCMS: m/z 245.9 [M+H]+; tR = 1.76 min.
[0282] Step 4: Synthesis of 6-bromo-5-methoxy-3-methylbenzo[d] oxazol-2(3H )-one.
[0283] Mel (26.5 g, 0.18 mol) was added to a mixture of 6-bromo-5-methoxybenzo[d]oxazol-2(3H )- one (22.8 g, 0.09 mol) and K2CO3 (25.8 g, 0.18 mol) in DMF (100 mL). The mixture was stirred at room temperature overnight, quenched with water (200 mL) and extracted with EtOAc (80 mL X 3). The combined organic solvents were washed with LiCl aqueous solution (200 ml X 3), dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to give 23.2 g of 6-bromo-5-methoxy-3-methylbenzo[d]oxazol-2(377)-one as brown solid (96% yield). LCMS: m/z 259.0 [M+H]+; fe = 1.72 min.
[0284] Step 5: Synthesis of 6-bromo-5-hydroxy-3-methylbenzo[d]o H xazol-2(3H )-one.
[0285] To a solution of 6-bromo-5-methoxy-3-methylbenzo[d]oxazol-2(3H)-one (2.3 g, 8.91 mmol) in CH2Q2 (20 mL) was added BBr3 (20 mL, IN in CH2CI2). The mixure was stirred at room temperature for 1 hour, quenched with water (100 mL) and pH value was adjusted to 9~10 with K2CO3. The mixture was extracted with CH2Cl2/MeOH (10: 1, v/v, 120 mL X 3). The combined organic layers were wash with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2 g of 6-bromo-5-hydroxy-3-methylbenzo[d]oxazol-2(3H )-one as yellow oil (71% yield), which was used directly to next step. LCMS: m/z 245.9 [M+H]+; tR = 1.51 min.
[0286] Step 6: Synthesis of 6-bromo-5-(methoxymethoxy)-3-methylbenzo[d]oxazol-2(3H )-one.
[0287] NaH (656 g, 16.4 mmol, 60% in mineral oil) was added to a stirred solution of 6-bromo-5- hydroxy-3-methylbenzo[d]oxazol-2(3H)-one (2.0 g, 8.2 mmol) in 20 mL of DMF at 0 °C. After stirring at 0 °C for 30 min, MOMBr (2.0g, 16.4 mmol) was added. The mixture was then stirred at room temperature for 2 h, quenched with NH4CI aqueous solution (50 mL), extracted with EtOAc (80 mL X 3). The combined organic solvents were with LiCl aqueous solution (50 mL X 3), dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (0-10% EtOAc/petroleum ether) to give 2.0 g of 6-bromo-5-(methoxymethoxy)-3-methylbenzo[d]oxazol- 2(3H )-one as yellow oil (72% yield). LCMS: 289.0 [M+H]+; fa = 1.72 min.
[0288] Step 7: Synthesis of 5-(methoxymethoxy)-3-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzo [d] oxazol-2(3H )-one. [0289] A mixture of 6-bromo-5-(methoxymethoxy)-3-methylbenzo[d]oxazol-2(3H)-one (2 g, 6.94 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.65 g, 10.41 mmol), Pd(dppf)Ch (51 mg, 0.694 mmol) and KOAc (2.04 g, 20.82 mmol) in 30 mL of dioxane was degassed and stirred at 100 °C for 2 h. After cooling to room temperature, the mixture was concentrated and purified by silica gel column (0-50% EtOAc/petroleum ether) to give 2.0 g of 5-(methoxymethoxy)-3-methyl-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H )-one as yellow oil (87% yield). LCMS: m/z 336.2 [M+H]+; tR = 1.81.
[0290] Step 8: Synthesis of 3-(methylsulfinyl)-l,2,4-triazine.
[0291] /n-CPBA (24 g, 137.79 mmol) was added to a solution of 3-(methylthio)-l,2,4-triazine (5 g, 39.37 mmol) in DCM (500 mL) at 0 °C and the mixture was stirred at 0 °C for 1 h. The mixture was quenched with H2O (200 ml), filtered, extracted with DCM (500ml X 3). The combined organic solvents were washed with saturated NaHCO3 aqueous solution (200 ml), dried over anhydrous Na2SO4 and concentrated to give 5 g of 3-(methylsulfinyl)-l,2,4-triazine as yellow solid (89% yield), which was used directly to next step. LCMS: m/z 144.2[M+H]+; tR = 0.48 min.
[0292] Step 9: Synthesis of tert-butyl (1R,3s,5S )-3-((l,2,4-triazin-3-yl)amino)-8- azabicyclo [3.2.1] octane-8-carboxylate.
[0293] A mixture of tert-butyl (1R,3s,5S )-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 8.85 mmol), 3-(methylsulfinyl)-l,2,4-triazine (4.7 g, 31.57 mmol) and KF (1.5 g, 26.55 mmol) in DMSO (30 ml) was stirred at 100 °C for 2 h. After cooling to room temperature, the mixture was quenched with H2O (40 ml), extracted with EtOAc ( 30 ml X 3). The organic phases washed with brine (100 ml), dried over anhydrous Na2SO4 , concentrated and purified by silica gel column (0-25% EtOAc / petroleum ether) to give 600 mg of tert-butyl (1R,3s,5S )-3-((l,2,4-triazin-3-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (22% yield). LCMS: m/z 250.2 [M-55]+; tR = 1.69 min.
[0294] Step 10: Synthesis of tert-butyl (1R,3s,5S )-3-(methyl(l,2,4-triazin-3-yl)amino)-8- azabicyclo [3.2.1] octane-8-carboxylate.
[0295] NaH (216 mg, 5.41 mmol, 60% in mineral oil) was added to a solution of tert-butyl (1R,3s,5S )-3-((l,2,4-triazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (550 mg, 1.80 mmol) in DMF (6 ml) and stirred at room temperature for 30 min. Then CH3I (512 mg, 3.61 mmol) was added and the reaction was stirred for another 1 h. The mixture was quenched with H2O (30 ml), extracted with EtOAc ( 20 ml X 3). The organic phases washed with saturated LiCl aqueous solution (50 ml), dried over anhydrous Na2SO4, concentrated and purified by silica gel column (0-20% EtOAc/petroleum ether) to give 600 mg of tert-butyl (1R,3s,5S )- 3-(,methyl (1,2,4-triazin-3-yl)amino)- 8-azabicyclo[3.2.1]octane-8-carboxylate (96% yield). LCMS: m/z 264.1 [M-55]+; tR = 1.81 min. [0296] Step 11: Synthesis of tert-butyl (1R,3s,5S )-3-((6-bromo-l,2,4-triazin-3- yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
[0297] A mixture of tert-butyl (1R,3s,5S )-3-(methyl(l,2,4-triazin-3-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (580 mg, 1.82 mmol) and NBS (356 mg, 2.00 mmol) in acetonitrile (6 ml) was stirred at 60 °C for 4 h. The mixture was quenched with H2O (30 ml), extracted with EtOAc ( 20 ml X 3). The organic phases washed with saturated LiCl aqueous solution (50 ml), dried over anhydrous Na2SO4, concentrated and purified by silica gel column (0-25% MeOH/EtOAc) to give 500 mg of tert-butyl (1R, 3s,5S)-3-((6-bromo-l,2,4-triazin-3- yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (75% yield). LCMS: m/z 342.0 [M-55]+; fe = 2.00 min.
[0298] Step 12: Synthesis of tert-butyl (1R,3s,5S )-3-((6-(5-(methoxyniethoxy)-3-niethyl-2-oxo- 2,3-dihydrobenzo[d|oxazol-6-yl)-l,2,4-triazin-3-yl)(methyl)aniino)-8-azabicyclo[3.2.1]octane-8- carboxylate.
[0299] A mixture of (1R,3s,5S )-tert-butyl 3-((6-bromo-l,2,4-triazin-3-yl)(methyl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (178 mg, 0.45 mmol), 5-(methoxymethoxy)-3-methyl-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[ ]oxazol-2(3H )-one (150 mg, 0.45 mmol), Pd(dppf)C12 (33 mg, 0.04 mmol) and K2CO3 (124 mg, 0.90 mmol) in 6 mL of 1,4-dioxane and 2 mL of H2O. The resulting mixture was stirred at 100 °C for 3 hours under nitrogen atmosphere and concentrated. The resiude was purified by silica gel column (20-40% EtOAc/petroleum ether) to give 100 mg of tert-butyl (1R,3s,5S )-3-((6-(5-(methoxymethoxy)-3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)-l,2,4-triazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (42% yield) as a yellow solid. LCMS: m/z 527.2 [M+H]+; fe = 1.96 min.
[0300] Step 13: Synthesis of 6-(3-(((1R,3s,5S )-8-azabicyclo[3.2.1]octan-3-yl)(niethyl)aniino)- l,2,4-triazin-6-yl)-5-hydroxy-3-methylbenzo[d|oxazol-2(3//)-one.
[0301] To a solution of tert-butyl (1R,3s,5S )-3-((6-(5-(methoxymethoxy)-3-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)-l,2,4-triazin-3-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (100 mg, 0.19 mmol) in di chloromethane (3 mL) was added HC1 (4M in dioxane, 1 mL) and the mixture was stirred at room temperature for 2 hours and concentrated. The residues was purified by Prep-HPLC (ACN and H O with 0.05% NH4HCO3 as mobile phase, Column: Xtimate lOum 150A 21.2 × 250mm) to give 20 mg of 6-(3-(((17?,3 ,55)-8-azabicyclo[3.2.1]octan-3- yl)(methyl)amino)-l,2,4-triazin-6-yl)-5-hydroxy-3-methylbenzo[ ]oxazol-2(3/7)-one as yellow solid (yield 28%). LCMS: m/z 383.3 [M+H]+; tR = 1.31 min. 1H NMR (400 MHz, DMSO-d6 ) 5 9.04 (s, 1H), 7.80 (s, 1H), 6.83 (s, 1H), 5.12 - 5.06 (m, 1H), 3.56 - 3.52 (m, 2H), 3.32 (s, 3H), 3.04 (s, 3H), 1.87 - 1.67 (m, 6H), 1.57 - 1.53 (m, 2H).

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 imgf000090_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-, -
C(=O)-, -NRX1-, -CRX2RX3-,
Figure imgf000090_0002
, or =CRX1-; RX1 is 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 haloalky 1, 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 imgf000091_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 imgf000091_0002
Formula (III) Formula (IV) 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).
2. The process of claim 1, wherein a compound of Formula (II) has a structure of Formula (Ila) or Formula (lib):
Figure imgf000091_0003
Formula (Ila) Formula (lib).
3. The process of claim 1 or claim 2, comprising the step of reacting the compound of Formula (II) with a compound of Formula (III)
- 90 -
Figure imgf000092_0001
Formula (III) to produce a compound of Formula (I). 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 imgf000092_0002
Formula (IV) to produce a compound of Formula (I). 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 imgf000092_0003
Formula (V) to produce a compound of Formula (I). The process of claim 1 or claim 2, comprising the step of reacting a compound of Formula (II) with a compound of Formula (VI)
Figure imgf000092_0004
Formula (VI) to produce a compound of Formula (I). A process for preparing a compound of Formula (VII)
Figure imgf000092_0005
Formula (VII) comprising reacting a compound of Formula (VIII)
Figure imgf000093_0001
Formula (VIII) wherein R3 is a halogen, such as Cl, Br, or I; or O-CH2CFs;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 imgf000093_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 monocyclic aryl, or substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic alkyl, substituted or unsubstituted polycyclic heteroalkyl; 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. The process of claim 7, wherein a compound of Formula (VII) has a structure of Formula (Vila):
Figure imgf000093_0004
Formula (Vila); and wherein a compound of Formula (VIII) has a structure of Formula (Villa):
Figure imgf000093_0003
Formula (Villa). The process of any one of claims 1-6, wherein a compound of Formula (I) is a compound of Formula (la)
Figure imgf000094_0001
Formula (la). The process of any one of claims 1-6, wherein a compound of Formula (II) is a compound of Formula (Ilaaa)
Figure imgf000094_0002
Formula (Ilaaa). The process of claim 4, wherein a compound of Formula (IV) is a compound of Formula (IVaaa)
Figure imgf000094_0003
Formula (IVaaa). The process of any one of claims 1-6 further comprising the steps of reacting a compound of Formula (II) with a 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 (III)
Figure imgf000094_0004
Formula (III) wherein Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. A compound of Formula (IV)
Figure imgf000095_0001
Formula (IV) wherein Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. A compound of Formula (IVa)
Figure imgf000095_0002
Formula (IVa) wherein Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. A compound of Formula (V)
Figure imgf000095_0003
Formula (V) wherein Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. A compound of Formula (VI)
Figure imgf000095_0004
Formula (VI) wherein Ring Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. A compound of Formula (VII)
Figure imgf000095_0005
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 monocyclic aryl, or substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted polycyclic aryl, or substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic alkyl, substituted or unsubstituted polycyclic heteroalkyl; 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. The compound of claim 18, wherein R1 is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic cycloalkyl, or substituted or unsubstituted monocyclic heteroaryl. The compound of claim 18, wherein R1 is substituted or unsubstituted polycyclic aryl, substituted or unsubstituted polycyclic heteroaryl, substituted or unsubstituted polycyclic cycloalkyl, or substituted or unsubstituted polycyclic heteroaryl. The compound of claim 18, wherein R2 is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic cycloalkyl, or substituted or unsubstituted monocyclic heteroaryl. The compound of claim 18, 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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