WO2022060951A1 - Compositions for modulating splicing - Google Patents

Compositions for modulating splicing Download PDF

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WO2022060951A1
WO2022060951A1 PCT/US2021/050622 US2021050622W WO2022060951A1 WO 2022060951 A1 WO2022060951 A1 WO 2022060951A1 US 2021050622 W US2021050622 W US 2021050622W WO 2022060951 A1 WO2022060951 A1 WO 2022060951A1
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substituted
unsubstituted
compound
hydrogen
ring
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PCT/US2021/050622
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French (fr)
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Michael Luzzio
Brian Lucas
Daniel Brian HORNE
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Skyhawk Therapeutics, Inc.
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Publication of WO2022060951A1 publication Critical patent/WO2022060951A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • BACKGROUND [0002] The majority of protein-coding genes in the human genome are composed of multiple exons (coding regions) that are separated by introns (non-coding regions). Gene expression results in a single precursor messenger RNA (pre-mRNA). The intron sequences are subsequently removed from the pre-mRNA by a process called splicing, which results in the mature messenger RNA (mRNA). By including different combinations of exons, alternative splicing gives rise to multiple mRNAs encoding distinct protein isoforms. The spliceosome, an intracellular complex of multiple proteins and ribonucleoproteins, catalyzes splicing.
  • oligonucleotides as therapeutics include unfavorable pharmacokinetics, lack of oral bioavailability, and lack of blood-brain-barrier penetration, with the latter precluding delivery to the brain or spinal cord after parenteral drug administration for the treatment of diseases (e.g., neurological diseases, brain cancers).
  • diseases e.g., neurological diseases, brain cancers.
  • oligonucleotides are not taken up effectively into solid tumors without a complex delivery system such as lipid nanoparticles. Further, most of the oligonucleotides taken up into cells and tissues remain in non- functional compartments (e.g., endosomes) and does not gain access to the cytosol and/or nucleus where the target is located.
  • oligonucleotide therapies require access to complementary base pairs of the target.
  • This approach assumes that pre-mRNA sequences exist as a linear strand of RNA in the cell.
  • pre-mRNA is rarely linear; it has complex - 1 - WSGR Docket No.51503-744601 secondary and tertiary structure.
  • cis-acting elements e.g., protein binding elements
  • trans-acting factors e.g., splicing complex components
  • These features can be potency-and efficacy-limiting for oligonucleotide therapies.
  • SMSMs small molecule splicing modulators
  • Small molecules have been essential in uncovering the mechanisms, regulations, and functions of many cellular processes, including DNA replication, transcription, and translation. While several recent reports have described screens for small molecule effectors of splicing, only a small number of constitutive or alternative splicing modulators have been identified and many of the small- molecule inhibitors lack specificity, lack selectivity, lack potency, exhibit toxicity, or are not orally available.
  • RNA transcriptome Targeting the RNA transcriptome with small-molecule modulators represents an untapped therapeutic approach to treat a variety of RNA-mediated diseases. Accordingly, there remains a need to develop small-molecule RNA modulators useful as therapeutic agents. There is need in the art for novel modulators of splicing or splicing-dependent processes. Provided herein are small molecule splicing modulators and uses thereof that fulfill this need.
  • a compound of Formula (I) wherein, A 1 is N or CR A1 ; A 2 is N or CR A2 ; A 3 is N or CR A3 ; provided that when A 2 and A 3 are each N, then A 1 is N; each R A1 , R A2 , and R A3 is independently hydrogen, F, Cl, –OR 1 , substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C 1 –C 4 heteroalkyl, substituted or unsubstituted C 3 –C 4 cycloalkyl, or substituted or unsubstituted C2–C3 heterocycloalkyl; ring B is saturated or unsaturated, substituted or unsubstituted monocyclic heterocyclic ring; ring Q is substituted or unsubstituted - 2
  • a is 0. In some embodiments, a is 1. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, a is 0 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, c is 0 and d is 0. In some embodiments, c is 0 and d is 1.
  • c is 1 and d is 0. In some embodiments, c is 1 and d is 1. [0008] In one aspect, described herein is a compound of Formula (II) Formula (II) wherein, R A is hydrogen, F, Cl, –OR 1 , substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C 1 –C 4 haloalkyl, substituted or unsubstituted C 1 –C 4 heteroalkyl, substituted or unsubstituted C3–C4 cycloalkyl, or substituted or unsubstituted C2–C3 heterocycloalkyl; ring B is saturated or unsaturated, substituted or unsubstituted monocyclic heterocyclic ring; ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Z is CR 2 ; W is substituted or unsubstituted C 1 -
  • a is 0. In some embodiments, a is 1. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, a is 0 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, c is 0 and d is 0. In some embodiments, c is 0 and d is 1. In some embodiments, c is 1 and d is 0.
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier.
  • methods of modulating splicing comprising contacting a compound disclosed herein to cells, wherein the compound modulates splicing at a splice site - 5 - WSGR Docket No.51503-744601 sequence of a pre-mRNA that encodes a mRNA, wherein the mRNA encodes a target protein or a functional RNA.
  • Also provided herein are methods of treating a disease or condition comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, to a subject in need thereof.
  • methods of treating a disease or condition comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, to a subject in need thereof.
  • SMSM small molecule that binds a target RNA
  • a target polynucleotide e.g., a pre- mRNA.
  • an SMSM can bind directly or indirectly to a target polynucleotide, e.g., RNA (e.g., a pre-mRNA) with a mutated, non-mutated, bulged and/or aberrant splice site, resulting in modulation of splicing of the target polynucleotide.
  • a target polynucleotide e.g., RNA (e.g., a pre-mRNA) with a mutated, non-mutated, bulged and/or aberrant splice site
  • an SMSM can bind directly or indirectly to a protein, e.g., a spliceosome protein or a ribonuclear protein, resulting in steric modulation of the protein and modulation of splicing of a target RNA.
  • an SMSM can bind directly or indirectly to a spliceosome component, e.g., a spliceosome protein or snRNA resulting in steric modulation of the spliceosome protein or snRNA and modulation of splicing of target polynucleotide.
  • a spliceosome component e.g., a spliceosome protein or snRNA resulting in steric modulation of the spliceosome protein or snRNA and modulation of splicing of target polynucleotide.
  • a spliceosome component e.g., a spliceosome protein or snRNA resulting in steric modulation of the spliceosome protein or snRNA and modulation of splicing of target polynucleotide.
  • These terms specifically exclude compounds consisting of oligonucleotides.
  • small molecule compounds that may bind to one or
  • RNA ribonucleic acid
  • RNA ribonucleic acid
  • biological context e.g., the RNA may be in the nucleus, circulating in the blood, in vitro, cell lysate, or isolated or pure form
  • physical form e.g., the RNA may be in single-, double-, or triple-stranded form (including RNA-DNA hybrids)
  • the RNA is 20, 22, 50, 75, or 100 or more nucleotides in length. In some embodiments, the RNA is 250 or more nucleotides in length. In some embodiments, the RNA is 350, 450, 500, 600, 750, or 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000, or more nucleotides in length. In some embodiments, the RNA is between 250 and 1,000 nucleotides in length. In some embodiments, the RNA is a pre-RNA, pre-miRNA, or pretranscript.
  • the RNA is a non-coding RNA (ncRNA), messenger RNA (mRNA), micro-RNA (miRNA), a ribozyme, riboswitch, lncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA, ceRNA, pseudo- gene, viral RNA, fungal RNA, parasitic RNA, or bacterial RNA.
  • ncRNA non-coding RNA
  • mRNA messenger RNA
  • miRNA micro-RNA
  • a ribozyme ribozyme
  • riboswitch ribozyme
  • riboswitch ribozyme
  • riboswitch ribozyme
  • riboswitch ribozyme
  • riboswitch ribozyme
  • riboswitch ribozyme
  • riboswitch ribozyme
  • riboswitch ribozyme
  • steric mechanisms include, but are not limited to, steric hindrance, steric shielding, steric attraction, chain crossing, steric repulsions, steric inhibition of resonance, and steric inhibition of protonation.
  • Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of hydrogen, unless indicated otherwise.
  • the definitions described herein apply irrespective of whether the terms in question appear alone or in combination. It is contemplated that the definitions described herein can be appended to form chemically-relevant combinations, such as e.g.
  • heterocycloalkylaryl “haloalkylheteroaryl”, “arylalkylheterocycloalkyl”, or “alkoxyalkyl”.
  • the last member of the combination is the radical which is binding to the rest of the molecule.
  • the other members of the combination are attached to the binding radical in reversed order in respect of the literal sequence, e.g. the combination arylalkylheterocycloalkyl refers to a heterocycloalkyl-radical which is substituted by an alkyl which is substituted by an aryl.
  • the term “one or more” refers to the range from one substituent to the highest possible number of substitution, i.e.
  • 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.
  • optional substituents are independently selected from D, oxo, 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.
  • C 1 -C x includes C 1 -C 2 , C 1 -C 3 ... C 1 -C x .
  • 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.
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • alkyl 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, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl, C 2 -C 8 alkyl, C 3 -C 8 alkyl and C 4 -C 8 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2- methylhexyl, 1-ethyl-propyl, and the like.
  • the alkyl is methyl or ethyl.
  • the alkyl is -CH(CH 3 ) 2 or -C(CH 3 ) 3 . Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted .
  • Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a - 9 - WSGR Docket No.51503-744601 radical group.
  • the alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-.
  • the alkylene is -CH 2 -.
  • the alkylene is -CH 2 CH 2 -.
  • the alkylene is -CH 2 CH 2 CH 2 -.
  • an alkylene group may be optionally substituted.
  • 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. [0031] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R a is H or an alkyl.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkynyl group has the formula -C ⁇ C-R a , wherein R a refers to the remaining portions of the alkynyl group.
  • R a is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Non-limiting examples of an alkynyl group include -C ⁇ CH, -C ⁇ CCH3 -C ⁇ CCH2CH3, -CH 2 C ⁇ CH.
  • aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer. Aromatics can be optionally substituted.
  • aromatic includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
  • aryl refers to a radical comprising at least one aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl.
  • an aryl group can be a monoradical or a diradical (i.e., an arylene group).
  • an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group comprises a fully reduced cycloalkyl group defined herein (e.g., 1,2,3,4- - 10 - WSGR Docket No.51503-744601 tetrahydronaphthalene).
  • aryl comprises a cycloalkyl group
  • the aryl is bonded to the rest of the molecule through an aromatic ring carbon atom.
  • An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems.
  • haloalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms.
  • haloalkyl examples include monofluoro-, difluoro-or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.
  • perhaloalkyl denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms.
  • haloalkoxy denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by same or different halogen atoms, particularly fluoro atoms.
  • haloalkoxyl include monofluoro-, difluoro-or trifluoro-methoxy, - ethoxy or -propoxy, for example 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy.
  • bicyclic ring system denotes two rings which are fused to each other via a common single or double bond (annelated bicyclic ring system), via a sequence of three or more common atoms (bridged bicyclic ring system) or via a common single atom (spiro bicyclic ring system).
  • Bicyclic ring systems can be saturated, partially unsaturated, unsaturated or aromatic.
  • Bicyclic ring systems can comprise heteroatoms selected from N, O and S.
  • Carbocyclic or “carbocycle” refer to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are saturated or partially unsaturated.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom).
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms.
  • Monocyclic cycloalkyl radicals - 11 - WSGR Docket No.51503-744601 include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl.
  • Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.
  • bridged refers to any ring structure with two or more rings that contains a bridge connecting two bridgehead atoms.
  • the bridgehead atoms are defined as atoms that are the part of the skeletal framework of the molecule and which are bonded to three or more other skeletal atoms.
  • the bridgehead atoms are C, N, or P.
  • the bridge is a single atom or a chain of atoms that connects two bridgehead atoms.
  • the bridge is a valence bond that connects two bridgehead atoms.
  • the bridged ring system is cycloalkyl. In some embodiments, the bridged ring system is heterocycloalkyl.
  • fused refers to any ring structure described herein which is fused to an existing ring structure.
  • fused ring is a heterocyclyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with one or more N, S, and O atoms.
  • fused heterocyclyl or heteroaryl ring structures include 6-5 fused heterocycle, 6-6 fused heterocycle, 5-6 fused heterocycle, 5-5 fused heterocycle, 7-5 fused heterocycle, and 5-7 fused heterocycle.
  • haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2- dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a C1-C6 fluoroalkyl.
  • a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2- trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C 1 -C 6 heteroalkyl.
  • heteroalkyl groups include, but are not limited to -OCH2OMe, -OCH2CH2OH, - OCH2CH2OMe, or -OCH2CH2OCH2CH2NH2.
  • heteroalkylene or “heteroalkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group in which one or more skeletal atoms of the hydrocarbon chain are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g.
  • heteroalkylene group may be optionally substituted.
  • Representative heteroalkylene groups include, but are not limited to -OCH 2 CH 2 O-, -OCH 2 CH 2 OCH 2 CH 2 O-, or -OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 O-.
  • heterocycloalkyl refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized.
  • the nitrogen atom may be optionally quaternized.
  • the heterocycloalkyl radical is partially or fully saturated.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, t
  • heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms.
  • heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • heterocycloalkyl when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the - 13 - WSGR Docket No.51503-744601 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.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) that includes at least one heteroatom selected from nitrogen, oxygen and sulfur, wherein each heterocyclic group has from 3 to 12 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds.
  • Non-aromatic heterocyclic groups include rings having 3 to 12 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 12 atoms in its ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • heteroaryl is monocyclic or bicyclic.
  • monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl.
  • a heteroaryl contains 0-6 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0- 1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C 1 -C 9 heteroaryl. In some embodiments, monocyclic heteroaryl is a 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.
  • 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 - 15 - WSGR Docket No.51503-744601 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: .
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes (p.o.), intraduodenal routes (i.d.), parenteral injection (including intravenous (i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), intravascular or infusion (inf.)), topical (top.) and rectal (p.r.) administration.
  • oral routes p.o.
  • intraduodenal routes i.d.
  • parenteral injection including intravenous (i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), intravascular or infusion (inf.)
  • topical top.
  • rectal rectal
  • the compounds and compositions described herein are administered orally.
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • effective amount or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated; for example a reduction and/or alleviation of one or more signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses can be an amount of an agent that provides a clinically significant decrease in one or more disease symptoms.
  • An appropriate “effective” amount may be determined using techniques, such as a dose escalation study, in individual cases.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in amount, potency or duration a desired effect.
  • the term “enhancing” can refer to the ability to increase or prolong splicing, either in amount, potency or duration, of a target.
  • the term “subject” or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • the term “animal” as used herein comprises human beings and non-human animals.
  • a “non-human animal” is a mammal, for example a rodent such as rat or a mouse.
  • a non-human animal is a mouse.
  • composition and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients to be administered to a subject, e.g., a human in need thereof.
  • pharmaceutical combination means a product that results from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g., a compound described herein and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a compound described herein and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g., administration of three or more active ingredients.
  • pharmaceutically acceptable denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.
  • “Pharmaceutically acceptable” can refer to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable excipient can be used interchangeably and denote any - 17 - WSGR Docket No.51503-744601 pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, excipients, preservatives or lubricants used in formulating pharmaceutical products.
  • pharmaceutically acceptable salts denotes salts which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable salts include both acid and base addition salts.
  • a “pharmaceutically acceptable salt” can refer to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and/or does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting an SMSM compound of any one of Formulas (I)-(Ig) with an acid.
  • Pharmaceutically acceptable salts are also obtained by reacting a compound of any one of Formulas (I)-(Ig) or with a base to form a salt.
  • nucleic acid generally refers to one or more nucleobases, nucleosides, or nucleotides, and the term includes polynucleobases, polynucleosides, and polynucleotides.
  • 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.
  • a ribonucleoprotein (RNP) refers to a nucleoprotein that contains RNA.
  • a RNP can be a complex of a ribonucleic acid and an RNA-binding protein. Such a combination can also be referred to as a protein-RNA complex. These complexes can function in a number of biological functions that include, but are not limited to, DNA replication, gene expression, metabolism of RNA, and pre-mRNA splicing. Examples of RNPs include the ribosome, the enzyme telomerase, vault ribonucleoproteins, RNase P, heterogeneous nuclear RNPs (hnRNPs) and small nuclear RNPs (snRNPs).
  • RNA transcripts from protein-coding genes and mRNA processing intermediates are generally bound by proteins in the nuclei of eukaryotic cells. From the time nascent transcripts first emerge from RNA polymerase (e.g., RNA polymerase II) until mature mRNAs are transported into the cytoplasm, the RNA molecules are associated with an abundant set of splicing complex components (e.g., nuclear proteins and snRNAs). These proteins can be components of hnRNPs, which can contain heterogeneous nuclear RNA (hnRNA) (e.g., pre-mRNA and nuclear RNA complexes) of various sizes.
  • hnRNA heterogeneous nuclear RNA
  • Splicing complex components function in splicing and/or splicing regulation.
  • Splicing complex components can include, but are not limited to, ribonuclear proteins (RNPs), splicing - 18 - WSGR Docket No.51503-744601 proteins, small nuclear RNAs (snRNAs), small nuclear ribonucleoproteins (snRNPs), and heterogeneous nuclear ribonucleoproteins (hnRNPs).
  • Splicing complex components include, but are not limited to, those that may be required for splicing, such as constitutive splicing, alternative splicing, regulated splicing and splicing of specific messages or groups of messages.
  • SR proteins serine arginine rich proteins
  • RRMs RNA-recognition motifs
  • RS domain C-terminal rich in arginine and serine residues
  • SR proteins in human include, but are not limited to, SC35, SRp55, SRp40, SRm300, SFRS10, TASR-1, TASR-2, SF2/ASF, 9G8, SRp75, SRp30c, SRp20 and P54/SFRS11.
  • Other splicing complex components in human that can be involved in splice site selection include, but are not limited to, U2 snRNA auxiliary factors (e.g. U2AF65, U2AF35), Urp/U2AF1-RS2, SF1/BBP, CBP80, CBP 20, SF1 and PTB/hnRNP1.
  • hnRNP proteins in humans include, but are not limited to, A1, A2/B1, L, M, K, U, F, H, G, R, I and C1/C2.
  • Human genes encoding hnRNPs include HNRNPA0, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3, HNRNPA2B1, HNRNPAB, HNRNPB1, HNRNPC, HNRNPCL1, HNRNPD, HNRPDL, HNRNPF, HNRNPH1, HNRNPH2, HNRNPH3, HNRNPK, HNRNPL, HNRPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1, HNRNPUL2, HNRNPUL3, and FMR1.
  • Splicing complex components may be stably or transiently associated with a snRNP or with a transcript.
  • the term “intron” refers to both the DNA sequence within a gene and the corresponding sequence in the unprocessed RNA transcript. As part of the RNA processing pathway, introns can be removed by RNA splicing either shortly after or concurrent with transcription. Introns are found in the genes of most organisms and many viruses. They can be located in a wide range of genes, including those that generate proteins, ribosomal RNA (rRNA), and transfer RNA (tRNA).
  • rRNA ribosomal RNA
  • tRNA transfer RNA
  • An “exon” can be any part of a gene that encodes a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing.
  • the term “exon” refers to both the DNA sequence within a gene and to the corresponding sequence in RNA transcripts.
  • a “spliceosome” can be assembled from snRNAs and protein complexes. The spliceosome can remove introns from a transcribed pre-mRNA.
  • SMSMs Small Molecule Splicing Modulators
  • the SMSMs of this disclosure can: 1) interfere with the formation and/or function and/or other properties of splicing complexes, spliceosomes, and/or their components such as hnRNPs, snRNPs, SR-proteins and other splicing factors or elements, resulting in the prevention or induction of a splicing event in a pre-mRNA molecule.
  • splicing post-transcriptional regulation
  • gene products such as hnRNPs, snRNPs, SR-proteins and other splicing factors, which can subsequently be involved in the formation and/or function of a spliceosome or splicing complex component
  • the small molecules of this disclosure are different from and are not related to antisense or antigene oligonucleotides.
  • Described herein are compounds modifying splicing of gene products for use in the treatment, prevention and/or delay of progression of diseases or conditions.
  • a is 0. In some embodiments, a is 1. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, a is 0 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 1. In some embodiments, d is 1.
  • the compound of Formula (I) has the structure of Formula (Ia): [0076] In some embodiments, the compound of Formula (I) has the structure of Formula (Ib): - 22 - WSGR Docket No.51503-744601 [0077] In some embodiments, the compound of Formula (I) has the structure of Formula (Ic): [0078] In some embodiments, the compound of Formula (I) has the structure of Formula (Id): [0079] In some embodiments, the compound of Formula (I) has the structure of Formula (Ie): - 23 - WSGR Docket No.51503-744601 [0080] In some embodiments, the compound of Formula (I) has the structure of Formula (If): [0080]
  • R A2 is hydrogen. In some embodiments, each A 1 and A 2 is independently N, and A 3 is CR A3 . In some embodiments, R A3 is hydrogen. In some embodiments, each A 1 , A 2 , and A 3 is independently N. In some embodiments, A 1 is CR A1 , A 2 is N, and A 3 is CR A3 . [0084] In some embodiments, A 1 is N. In some embodiments, A 1 is CR A1 . In some embodiments, A 2 is N. In some embodiments, A 2 is CR A2 . In some embodiments, A 3 is N. In some embodiments, A 3 is CR A3 .
  • each A 1 , A 2 , and A 3 is N.
  • each R A1 , R A2 , and R A3 is independently hydrogen.
  • each R A1 , R A2 , and R A3 is independently halogen and hydrogen.
  • R A1 is H.
  • R A1 is halogen.
  • R A1 is F or Cl.
  • R A1 is –OR 1 .
  • R A1 is substituted or unsubstituted C 1 –C 4 alkyl.
  • R A1 is substituted or unsubstituted C1–C4 haloalkyl.
  • R A1 is substituted or unsubstituted C1–C4 heteroalkyl. In some embodiments, R A1 is substituted or unsubstituted C3–C4 cycloalkyl. In some embodiments, R A1 is substituted or unsubstituted C 2 –C 3 heterocycloalkyl. [0087] In some embodiments, R A2 is H. In some embodiments, R A2 is halogen. In some embodiments, R A2 is F or Cl. In some embodiments, R A2 is –OR 1 . In some embodiments, R A2 is substituted or unsubstituted C 1 –C 4 alkyl.
  • R A2 is substituted or unsubstituted C 1 –C 4 haloalkyl. In some embodiments, R A2 is substituted or unsubstituted C 1 –C 4 heteroalkyl. In some embodiments, R A2 is substituted or unsubstituted C3–C4 cycloalkyl. In some embodiments, R A2 is substituted or unsubstituted C 2 –C 3 heterocycloalkyl. [0088] In some embodiments, R A3 is H. In some embodiments, R A3 is halogen. In some embodiments, R A3 is F or Cl. In some embodiments, R A3 is –OR 1 .
  • R A3 is substituted or unsubstituted C1–C4 alkyl. In some embodiments, R A3 is substituted or unsubstituted C 1 –C 4 haloalkyl. In some embodiments, R A3 is substituted or unsubstituted C 1 –C 4 heteroalkyl. In some embodiments, R A3 is substituted or unsubstituted C3–C4 cycloalkyl. In some embodiments, R A3 is substituted or unsubstituted C2–C3 heterocycloalkyl. - 25 - WSGR Docket No.51503-744601 [0089] In some embodiments, Z is CR 2 , wherein R 2 is hydrogen.
  • Z is CR 2 , wherein R 2 is C 1 –C 4 alkyl.
  • W is substituted or unsubstituted C 1 -C 3 alkylene. In some embodiments, W is substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is substituted or unsubstituted C3–C8 cycloalkylene. In some embodiments, W is substituted or unsubstituted C 2 –C 7 heterocycloalkylene. In some embodiments, W is unsubstituted C 1 -C 3 alkylene. In some embodiments, W is unsubstituted C2 alkylene.
  • W is C1- C3 alkylene substituted with halogen. In some embodiments, W is substituted with one or more substituents selected from halogen, OH, C 1 –C 4 alkyl, and amino. In some embodiments, W is C 1 - C3 alkylene substituted with F. In some embodiments, W is -CH2CF2-. [0091] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is substituted or unsubstituted C 1 –C 4 alkyl. In some embodiments, R 1 is substituted or unsubstituted C 1 –C 4 haloalkyl.
  • R 1 is substituted or unsubstituted C 1 –C 4 heteroalkyl. In some embodiments, R 1 is substituted or unsubstituted C3–C6 cycloalkyl. In some embodiments, R 1 is substituted or unsubstituted C2–C5 heterocycloalkyl. In some embodiments, R 1 is substituted or unsubstituted aryl. In some embodiments, R 1 is or substituted or unsubstituted heteroaryl.
  • R A is hydrogen, F, Cl, –OR 1 , substituted or unsubstituted C 1 –C 4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C4 cycloalkyl, or substituted or unsubstituted C2–C3 heterocycloalkyl; ring B is saturated or unsaturated, substituted or unsubstituted monocyclic heterocyclic ring; ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Z is CR 2 ; - 26 - WSGR Docket No.51503-744601 W is substituted or unsubstituted C1-C3 alkylene,
  • a is 0. In some embodiments, a is 1. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, a is 0 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, c is 0 and d is 0. In some embodiments, c is 0 and d is 1.
  • c is 1 and d is 0. In some embodiments, c is 1 and d is 1. [0094] In some embodiments, described herein is a compound of Formula (II). In some embodiments, described herein is a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of a compound of Formula (II).
  • the compound of Formula (II) has the structure of Formula (IIa): [0096] In some embodiments, the compound of Formula (II) has the structure of Formula (IIb): - 28 - WSGR Docket No.51503-744601 [0097] In some embodiments, the compound of Formula (II) has the structure of Formula (IIc): [0098] In some embodiments, the compound of Formula (II) has the structure of Formula (IId): - 29 - WSGR Docket No.51503-744601 Formula (IId).
  • the compound of Formula (II) has the structure of Formula (IIe): [0100] In some embodiments, the compound of Formula (II) has the structure of Formula (IIf): [0101] In some embodiments, the compound of Formula (II) has the structure of Formula (IIg): - 30 - WSGR Docket No.51503-744601 Formula (IIg). [0102] In some embodiments, a compound of Formula (II) has a structure of formula (IIh): [0103] In some embodiments, W is substituted or unsubstituted C 1 -C 3 alkylene. In some embodiments, W is unsubstituted C1-C3 alkylene.
  • W is -CH2-. In some embodiments, W is –CH2CH2–. In some embodiments, W is –CH2CH2CH2–. In some embodiments, W is substituted C 1 -C 3 alkylene. In some embodiments, W is C 1 -C 3 alkylene substituted with halogen. In some embodiments, W is C 1 -C 3 alkylene substituted with F. In some embodiments, W is substituted with one or more substituents selected from halogen, OH, C1–C4 alkyl, and amino. In some embodiments, W is -CH 2 CF 2 -.
  • R is hydrogen, substituted or unsubstituted C 1 –C 4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C 3 –C 5 cycloalkyl, or substituted or unsubstituted C 2 –C 4 heterocycloalkyl.
  • R is hydrogen.
  • R is -CH 3 , - CH2CH3, -CH2F, -CHF2, or -CF3.
  • R 16 is hydrogen. In some embodiments, R 16 is halogen.
  • R 16 is F.
  • R 17 is hydrogen.
  • R 17 is halogen.
  • R 17 is F.
  • each R 15 and R 18 is - 31 - WSGR Docket No.51503-744601 independently selected from hydrogen, deuterium, F, -CH3, and -OCH3.
  • R 15 and R 18 are both hydrogen.
  • R 15 and R 18 are both -CH 3 .
  • R 15 is hydrogen and R 18 is -CH 3 .
  • R 15 is -CH 3 and R 18 is hydrogen.
  • each R 4 and R 5 is independently hydrogen, and R 6 is substituted or unsubstituted heteroaryl.
  • each R 4 and R 5 is independently hydrogen, and R 6 is unsubstituted heteroaryl.
  • ring B is 5-, 6-, 7-, or 8- membered heterocyclic ring. In some embodiments, ring B is 5-membered heterocyclic ring. In some embodiments, ring B is 5- membered heterocyclic ring having 1, 2, or 3 nitrogen atoms. In some embodiments, ring B is 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. In some embodiments, ring B is 6- membered heterocyclic ring. In some embodiments, ring B is 6- membered heterocyclic ring having 1, 2, or 3 nitrogen atoms.
  • ring B is 6- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. In some embodiments, ring B is 6- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 sulfur atom. In some embodiments, ring B is saturated. In some embodiments, ring B is unsaturated. In some embodiments, ring B contains one carbon-carbon double bond. In some embodiments, ring B contains two carbon-carbon double bonds. In some embodiments, ring B contains three carbon-carbon double bonds. [0108] In some embodiments, ring B is a 5-memjbered heterocyclic ring selected from: - 32 - WSGR Docket No.51503-744601 .
  • ring B is 6- membered heterocyclic ring selected from: - 33 - WSGR Docket No.51503-744601 , - 34 - WSGR Docket No.51503-744601 wherein each R z is independently hydrogen, halogen, -CN, -OR 3 , substituted or unsubstituted C 1 - C4alkyl, or substituted or unsubstituted C1-C4haloalkyl; and R 3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C 1 –C 4 heteroalkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; or two R z taken together form an oxo.
  • ring B is 6- membered heterocyclic ring selected from: - 35 - WSGR Docket No.51503-744601 wherein each R z is independently hydrogen, halogen, -CN, -OR 3 , substituted or unsubstituted C1- C4alkyl, or substituted or unsubstituted C1-C4haloalkyl; and R 3 is hydrogen, substituted or unsubstituted C 1 –C 4 alkyl, substituted or unsubstituted C 1 –C 4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; or two R z taken together form an oxo.
  • R z is hydrogen. In some embodiments, R z is methyl. - 36 - WSGR Docket No.51503-744601 [0113] In some embodiments, ring . some embodiments, ring B is some embodiments, ring . some embodiments, ring B is some embodiments, ring . some embodiments, ring B is . some embodiments, ring - 37 - WSGR Docket No.51503-744601 . [0114] In some embodiments, ring B is 6- membered heterocyclic ring selected from: , .
  • ring B is 7- membered heterocyclic ring. In some embodiments, ring B is 7- membered heterocyclic ring having 1, 2, or 3 nitrogen atoms. In some embodiments, ring B is 7- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. In some embodiments, ring B is 7- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 sulfur atom.
  • ring B is 7- membered heterocyclic ring selected from: - 38 - WSGR Docket No.51503-744601 , - 39 - WSGR Docket No.51503-744601 wherein each R z is independently hydrogen, halogen, -CN, -OR 3 , substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted C1-C4haloalkyl; and R 3 is hydrogen, substituted or unsubstituted C 1 –C 4 alkyl, substituted or unsubstituted C 1 –C 4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; or two R z taken together form an oxo.
  • ring B is 7- membered heterocyclic ring selected from: wherein each R z is independently hydrogen, halogen, -CN, -OR 3 , substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted C1-C4haloalkyl; and R 3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C 1 –C 4 heteroalkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; or two R z taken together form an oxo.
  • ring B is 7- membered heterocyclic ring selected from: - 40 - WSGR Docket No.51503-744601 . [0118] In some embodiments, ring B is . [0119] In some embodiments, ring B is 6- membered heterocyclic ring selected from: - 41 - WSGR Docket No.51503-744601 - 42 - WSGR Docket No.51503-744601 [0120] wherein each R z is independently hydrogen, halogen, -CN, -OR 3 , substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted C 1 -C 4 haloalkyl, or two R z taken together form an oxo; and R 3 is hydrogen, substituted or unsubstituted C 1 –C 4 alkyl, substituted or unsubstituted C1–C4 haloal
  • ring B is 6- membered heterocyclic ring selected from: , [0122] wherein each R z is independently hydrogen, halogen, -CN, -OR 3 , substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted C1-C4haloalkyl, or two R z taken together form an oxo; and R 3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C 1 –C 4 haloalkyl, substituted or unsubstituted C 1 –C 4 heteroalkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, or substituted or unsubstituted C 2 –C 5 heterocycloalkyl.
  • each R z is independently hydrogen. - 43 - WSGR Docket No.51503-744601 .
  • ring B is 6- membered heterocyclic ring selected from: . [0125] In some embodiments ring B is 7- membered heterocyclic ring. In some embodiments ring B is 7- membered heterocyclic ring having 1, 2, or 3 nitrogen atoms. In some embodiments ring B is 7- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. In some embodiments ring B is 7- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 sulfur atom.
  • ring B is 7- membered heterocyclic ring selected from: - 44 - WSGR Docket No.51503-744601 , - 45 - WSGR Docket No.51503-744601 [0126] wherein each R z is independently hydrogen, halogen, -CN, -OR 3 , substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted C 1 -C 4 haloalkyl, or two R z taken together form an oxo; and R 3 is hydrogen, substituted or unsubstituted C 1 –C 4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C 3 –C 6 cycloalkyl, or substituted or unsubstituted C 2 –C 5 heterocycloalky
  • ring B is 7- membered heterocyclic ring selected from: [0128] wherein each R z is independently hydrogen, halogen, -CN, -OR 3 , substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted C 1 -C 4 haloalkyl, or two R z taken together form an oxo; and R 3 is hydrogen, substituted or unsubstituted C 1 –C 4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl.
  • ring B is 7- membered heterocyclic ring selected from: - 46 - WSGR Docket No.51503-744601 .
  • each R z is independently hydrogen, halogen, -CN, -OR 3 , substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted C 1 -C 4 haloalkyl; and R 3 is hydrogen, substituted or unsubstituted C 1 –C 4 alkyl, substituted or unsubstituted C 1 –C 4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl.
  • each R z taken together form an oxo.
  • each R z is independently hydrogen, F, -CN, - OCH3, -OCF3, substituted or unsubstituted C1–C4 alkyl, or substituted or unsubstituted C1–C4 haloalkyl.
  • each R z is independently hydrogen, F, -CN, -OCH3, -OCF3, - CH 3 , or -CF 3 .
  • each R z is hydrogen.
  • ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • each R Q is independently selected from hydrogen, –F, –Cl, -CN, –OH, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, –CF3, –OCH3, -OCH2CH3, -CH2OCH3, -OCH2CH2CH3, and -OCH(CH3)2.
  • ring Q is substituted or unsubstituted heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl.
  • ring Q is substituted or unsubstituted 6-membered monocyclic heteroaryl.
  • , - 49 - WSGR Docket No.51503-744601 each R Q is independently hydrogen, deuterium, –F, –Cl, -CN, – OH, -CH 3 ,–CF 3, or –OCH 3.
  • each R Q is independently hydrogen or –F.
  • each R Q is hydrogen.
  • R 4 is H.
  • R 4 is deuterium.
  • R 4 is halogen.
  • R 4 and R 5 are each independently hydrogen, deuterium, or C 1 - C 4 alkyl. In some embodiments, R 4 and R 5 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , - CH(CH3)2, -CF3, or cyclopropyl. In some embodiments, R 4 and R 5 are each independently hydrogen, -CH3, -CH(CH3)2, -CF3, or cyclopropyl. In some embodiments, R 4 and R 5 are each independently hydrogen, -CH 3 , or -CF 3 .
  • R 4 and R 5 are each hydrogen. - 50 - WSGR Docket No.51503-744601 [0143]
  • R 4 is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or cyclopropyl.
  • R 4 is hydrogen.
  • R 4 is -CH 3 .
  • R 5 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , or cyclopropyl.
  • R 5 is hydrogen.
  • R 5 is -CH3.
  • R 6 is substituted or unsubstituted heterocycloalkyl. In some embodiments, R 6 is substituted or unsubstituted aryl. In some embodiments, R 6 is substituted or unsubstituted heteroaryl. [0146] In some embodiments, R 6 is substituted or unsubstituted 4-membered cycloalkyl. In some embodiments, R 6 is substituted or unsubstituted 5-membered cycloalkyl. In some embodiments, R 6 is substituted or unsubstituted 6-membered cycloalkyl. In some embodiments, R 6 is substituted or unsubstituted 5-membered heterocycloalkyl.
  • R 6 is substituted or unsubstituted 6-membered heterocycloalkyl. In some embodiments, R 6 is substituted or unsubstituted 6-membered heterocycloalkyl containing 1-3 nitrogens, 0-1 oxygen and 0-1 sulfur. In some embodiments, R 6 is substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 6 is substituted or unsubstituted 5-membered heteroaryl containing 1-4 nitrogens, 0-1 oxygen and 0-1 sulfur. In some embodiments, R 6 is substituted or unsubstituted aryl.
  • two R 8 groups on the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted C 2 - C 10 heterocycloalkyl.
  • each R 7 is independently H.
  • each R 7 is independently substituted or unsubstituted C1-C6alkyl. In some embodiments, R 7 is independently substituted or unsubstituted C 1 -C 6 haloalkyl. In some embodiments, R 7 is independently substituted or unsubstituted C 1 -C 6 heteroalkyl. In some embodiments, R 7 is independently substituted or unsubstituted C3-C8cycloalkyl. In some embodiments, R 7 is independently substituted or unsubstituted C 2 -C 7 heterocycloalkyl. In some embodiments, R 7 is independently substituted or unsubstituted aryl. In some embodiments, R 7 is independently substituted or unsubstituted heteroaryl.
  • each R 7 is independently H or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 7 is independently H or substituted or unsubstituted C 1 -C 3 alkyl. In some embodiments, R 7 is H. In some embodiments, R 7 is methyl. [0149] In some embodiments, each R 4 and R 5 is independently H, D, halogen, or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 4 and R 5 is hydrogen. In some embodiments, R 4 is hydrogen and R 5 is CH3. In some embodiments, R 4 is CH3 and R 5 is hydrogen.
  • R 6 is optionally substituted C 1 -C 4 alkyl or C 1 -C 4 heteroalkyl.
  • R 6 is C1-C4alkyl or C1-C4heteroalkyl optionally substituted with cycloalkyl, heterocycloalkyl, heteroaryl, or aryl, each of which is monocyclic or bicyclic and each of which is optionally substituted.
  • q is 0. In some embodiments, q is 1. In some embodiments, q is 2.
  • each R 8 is independently H. In some embodiments, each R 8 is independently substituted or unsubstituted C1-C6alkyl. In some embodiments, each R 8 is independently substituted or unsubstituted C 1 -C 6 haloalkyl. In some embodiments, each R 8 is independently substituted or unsubstituted aryl. In some embodiments, each R 8 is independently substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R 8 is independently -OR 7 . In some embodiments, each R 8 is independently -N(R 7 )2. In some embodiments, each R 8 is independently -CH 2 OR 7 .
  • W is substituted or unsubstituted C1-C3 alkylene. In some embodiments, W is –CH 2 –. In some embodiments, W is –CH 2 CH 2 –. 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 substituted C 2 alkylene.
  • W is C 2 alkylene substituted with halo. In some embodiments, W is C 2 alkylene substituted with F. In some embodiments, W is CH 2 CF 2 .
  • R is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C 3 –C 5 cycloalkyl, or substituted or unsubstituted C 2 –C 4 heterocycloalkyl. In some embodiments, R is hydrogen.
  • R is substituted or unsubstituted C1–C4 alkyl. In some embodiments, R is substituted or unsubstituted C1–C4 fluoroalkyl. In some embodiments, R is substituted or unsubstituted C 1 –C 4 heteroalkyl. In some embodiments, R is substituted or unsubstituted C3–C5 cycloalkyl. In some embodiments, R is substituted or unsubstituted C2–C4 heterocycloalkyl. In some embodiments, R is -CH3, - CH 2 CH 3 , -CH 2 F, -CHF 2 , or -CF 3 . In some embodiments, R is hydrogen.
  • R is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, - CH2CH2OH, -CH2CH2CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, 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, - CHF2, -CF3, cyclopropyl, or oxetanyl.
  • R is hydrogen, -CH3, -CH2CH3, - CH2OH, -CH2CH2OH, -CH2CN, cyclopropyl, or oxetanyl.
  • R is hydrogen, -CH 3 , -CH 2 OH, -CH 2 CN, -CHF 2 , -CF 3 , or cyclopropyl.
  • R is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , cyclopropyl, or oxetanyl.
  • R is -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. - 54 - WSGR Docket No.51503-744601 [0158]
  • one or more of R 11 , R 12 , and R 16 is independently selected from F, –OR 1 , substituted or unsubstituted C 1 –C 4 alkyl, a substituted or unsubstituted C 1 –C 4 fluoroalkyl, and substituted or unsubstituted C 1 –C 4 heteroalkyl.
  • R 11 , R 12 , and R 16 is independently selected from F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, - CHF2, and -CF3.
  • R 11 , R 12 , and R 16 are hydrogen.
  • one or more of R 16 and R 17 is independently selected from F, –OR 1 , substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl.
  • R 11 and R 13 are each hydrogen, and R 12 and R 14 are each C 1 -C 3 alkyl. In some embodiments, R 11 and R 13 are each hydrogen, and R 12 and R 14 are each methyl. [0159] In some embodiments, one or more of R 16 and R 17 is independently selected from F, - OH, -OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 . In some embodiments, R 16 and R 17 are hydrogen. In some embodiments, each R 16 , R 15 , and R 20 is independently hydrogen, and R 19 is halogen.
  • each R 16 , R 15 , and R 20 is independently hydrogen, and R 19 is F.
  • R 2 is hydrogen, -CH 3 , or -OCH 3 .
  • R 2 is hydrogen.
  • R 2 is substituted or unsubstituted C1–C4 alkyl.
  • R 2 is substituted or unsubstituted C1–C4 haloalkyl.
  • each R 15 and R 18 is independently selected from hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1–C3 alkyl, substituted or unsubstituted C1–C3 fluoroalkyl, and substituted or unsubstituted C1–C3 heteroalkyl.
  • each R 15 and R 18 is independently selected from hydrogen, deuterium, F, -CH 3 , and -OCH 3 .
  • R 15 and R 18 are both hydrogen.
  • R 15 and R 18 are both -CH3.
  • R 15 is hydrogen and R 18 is - CH3.
  • R 15 is -CH3 and R 18 is hydrogen.
  • R 15 and R 18 are selected from hydrogen, deuterium, F, –OR 1 , substituted or unsubstituted C1–C3 alkyl, substituted or unsubstituted C1–C3 fluoroalkyl, and substituted or unsubstituted C1–C3 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, - CH2CH2OH, -CH2NHCH3, -CH2N(CH3)2, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -CH2F, -CHF2, and -CF3.
  • 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 .
  • R 15 and R 18 are selected from hydrogen, deuterium, F, -CH 3 , - OCH3, -OCF3, -CH2F, -CHF2, and -CF3.
  • R 15 and R 18 are selected from hydrogen, deuterium, F, -CH3, and -OCH3.
  • R 15 is F and R 18 is hydrogen.
  • 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. [0164] In some embodiments, one or more of R 19 and R 20 is independently selected from F, - OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. In some embodiments, R 19 is F. In some embodiments, R 20 is F. In some embodiments, R 19 is hydrogen.
  • R 20 is hydrogen. In some embodiments, R 19 and R 20 are hydrogen. In some embodiments, R 19 is independently selected from H, F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and - CF 3 . In some embodiments, R 19 is H or F. In some embodiments, R 20 is independently selected from H, F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. In some embodiments, R 20 is H or F.
  • R 11 is -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3, H, D, or F. In some embodiments, 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. [0166] In some embodiments, R 12 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, 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 -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, 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. [0168] In some embodiments, R 14 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, 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 -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, R 15 is H, D, F, CH2F, CHF2, CF3, or CH3. 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 , CHF2, or CH2F. In some embodiments, R 15 is F. [0170] In some embodiments, R 16 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F.
  • R 16 is H, D, or F. In some embodiments, R 16 is D. In In some embodiments, R 16 is H. some embodiments, R 16 is F. [0171] In some embodiments, R 17 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, 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. [0172] In some embodiments, R 18 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F.
  • R 18 is H, D, F, CH2F, CHF2, CF3, or CH3. In some embodiments, R 18 is H or D. In - 56 - WSGR Docket No.51503-744601 some embodiments, R 18 is F, CH2F, CHF2, CF3, or CH3. In some embodiments, R 18 is F, CF3, CHF 2 , or CH 2 F. In some embodiments, R 18 is F. [0173] In some embodiments, R 19 is -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3, H, D, or F. In some embodiments, R 19 is hydrogen.
  • R 19 is H, F, -OH, -OCH3, -OCH2CH3, - OCH2CH2OH, -OCH2CN, -OCF3, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2F, - CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 .
  • R 19 is H, F, -OH, - OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3.
  • R 19 is F or - OCH3.
  • R 20 is hydrogen.
  • R 20 is H, F, -OH, -OCH 3 , -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, - CH2CN, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, and -CH2CF3.
  • R 20 is -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3, H, D, or F.
  • R 20 is H, F, -OH, - OCH 3 , -OCF 3 , -CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , and -CF 3 . In some embodiments, R 20 is F or - OCH3. [0175] In some embodiments, at least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 is F. In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 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 16 , R 17 , R 18 , R 19 and R 20 is F. In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 is F. In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 are F.
  • At least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 comprises a fluorine, e.g., F or C 1 –C 4 fluoroalkyl such as CH 2 F, CF 3 , CHF 2 , and CH 3 CH 2 F.
  • at least one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 is F or C 1 –C 4 fluoroalkyl.
  • one of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 comprises a fluorine. In some embodiments, at least two of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 comprise a fluorine. In some embodiments, at least one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 comprises a fluorine. In some embodiments, one of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 comprises a fluorine.
  • At least two of R 11 , R 12 , R 13 , R 14 , R 16 , and R 17 comprise a fluorine.
  • at least one of W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 comprises a fluorine, e.g., F or C1–C4 fluoroalkyl such as CH2F, CF3, CHF2, and CH3CH2F.
  • one of W, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 comprises a fluorine.
  • W comprises a fluorine.
  • a 1 is N. In some embodiments, A 1 is CR A1 . In some embodiments, R A1 is hydrogen, F, Cl, or -CH3. In some embodiments, R A1 is hydrogen. In some embodiments, R A1 is deuterium. - 57 - WSGR Docket No.51503-744601 [0178] In some embodiments, A 2 is N. In some embodiments, A 2 is CR A2 . In some embodiments, R A2 is hydrogen, F, Cl, or -CH 3 . In some embodiments, R A2 is hydrogen. In some embodiments, R A2 is deuterium. [0179] In some embodiments, A 3 is N.
  • a 3 is CR A3 .
  • R A3 is hydrogen, F, Cl, or -CH3.
  • R A3 is hydrogen.
  • R A3 is deuterium.
  • the abundance of deuterium in each of R A , R A1 , R A2 , R A3 , R Q , R Z , R 1 , R 2 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and/or R 20 is independently at least 1%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium.
  • one or more of R A , R A1 , R A2 , R A3 , R Q , R Z , R 1 , R 2 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and/or R 20 groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • R A1 , R A2 , R A3 , R Q , R Z , R 1 , R 2 , R 4 , R 5 , R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and/or R 20 are substituted with one or more group(s) individually and independently selected from halogen (e.g., F), -CN, -NH2, -OH, -NH(CH 3 ), -N(CH 3 ) 2 , - NH(cyclopropyl), -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
  • halogen e.g., F
  • -CN -NH2, -OH, -NH(CH 3 ), -N(CH 3 ) 2 , - NH(cyclopropyl), -CH 3 , -CH 2 CH
  • substituted groups are substituted with one or two of the preceding groups.
  • a method of modulating splicing comprising contacting a compound of any one of the preceding claims to cells, wherein the compound modulates - 58 - WSGR Docket No.51503-744601 splicing at a splice site sequence of a pre-mRNA that encodes a mRNA, wherein the mRNA encodes a target protein or a functional RNA.
  • disclosed herein is a method of treating a disease or condition comprising administering a compound of the present invention.
  • a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of a compound from Tables 1-4 is disclosed herein.
  • an SMSM 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.
  • stereoisomers are obtained by stereoselective synthesis.
  • compounds described herein are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • the design of a prodrug increases the effective water solubility.
  • An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active - 59 - WSGR Docket No.51503-744601 moiety.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • prodrugs are designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • some of the herein-described compounds may be a prodrug for another derivative or active compound.
  • sites on the aromatic ring portion of compounds described herein are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group.
  • the compounds described herein are labeled isotopically (e.g.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 3 6 cl.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain - 60 - WSGR Docket No.51503-744601 therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • Compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts.
  • the type of pharmaceutical acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesul
  • compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms, particularly solvates.
  • Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • solvates of compounds described herein are conveniently prepared or formed - 61 - WSGR Docket No.51503-744601 during the processes described herein.
  • the compounds provided herein can exist in unsolvated as well as solvated forms.
  • an SMSM has a molecular weight of at most about 2000 Daltons, 1500 Daltons, 1000 Daltons or 900 Daltons. In some embodiments, an SMSM has a molecular weight of at least 100 Daltons, 200 Daltons, 300 Daltons, 400 Daltons or 500 Daltons. In some embodiments, an SMSM does not comprise a phosphodiester linkage.
  • Step 3 Synthesis of (E)-3-(4-bromo-3-(methoxymethoxy)phenyl)acrylic acid.
  • a solution of NaOH (366 mg, 9.16 mmol) in H 2 O (15 mL) was added slowly to a stirred solution of (E)-ethyl 3-(4-bromo-3-(methoxymethoxy)phenyl)acrylate (1.44 g, 4.58 mmol) in MeOH (15 mL) at rt. Then the mixture was stirred at 50 o C for 16 h and cooled to room temperature.
  • a scheme for preparing an SMSM described herein is Scheme 1: each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 2: each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 3: - 64 - WSGR Docket No.51503-744601 each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 4: each A is independently N or CR Q as described above.
  • - 65 - WSGR Docket No.51503-744601 is Scheme 5: each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 6: each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 7: - 66 - WSGR Docket No.51503-744601 each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 8: each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 9: each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 10: - 67 - WSGR Docket No.51503-744601 each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 11: each A is independently N or CR Q as described above.
  • - 68 - WSGR Docket No.51503-744601 is Scheme 12: each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 13: each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 14: - 69 - WSGR Docket No.51503-744601 each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 15: each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 16: each A is independently N or CR Q as described above.
  • a scheme for preparing an SMSM described herein is Scheme 17: P O O O each A is independently N or CR Q as described above. [0220] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 18: each A is independently N or CR Q as described above.
  • each R S1 represents alkyl, such as C1-C3alkyl; each R S2 represents attachment to a cyclic base amine such described above; each R S3 - 71 - WSGR Docket No.51503-744601 represents the variables R 4 , R 5 , or R 6 above; each G1 represents a boronic acid/ester group (e.g., -OH, -OMe, pinacolester); P1 represents a phenol protecting group (e.g., -OMe, -OMOM, - OPMB, -OTBS); and P2 represents a protecting group.
  • a boronic acid/ester group e.g., -OH, -OMe, pinacolester
  • P1 represents a phenol protecting group (e.g., -OMe, -OMOM, - OPMB, -OTBS)
  • P2 represents a protecting group.
  • Table 1 Exemplary Compounds. - 72 - WSGR Docket No.51503-744601 - 73 - WSGR Docket No.51503-744601 Table 2 – Exemplary Compounds. - 74 - WSGR Docket No.51503-744601 - 75 - WSGR Docket No.51503-744601 Table 3 – Exemplary Compounds. - 76 -
  • compositions [0223]
  • the compounds described herein are formulated into pharmaceutical compositions.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a pharmaceutical composition can be a mixture of an SMSM described herein with one or more other chemical components (i.e.
  • compositions described herein can be administered to the subject in a variety of ways, including parenterally, intravenously, intradermally, intramuscularly, colonically, rectally or intraperitoneally.
  • the small molecule splicing modulator or a pharmaceutically acceptable salt thereof is administered by intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection of the subject.
  • the pharmaceutical compositions can be administered parenterally, intravenously, intramuscularly or orally.
  • the oral agents comprising a small molecule splicing modulator can be in any suitable form for oral administration, such as liquid, tablets, capsules, or the like.
  • the oral formulations can be further coated or treated to prevent or reduce dissolution in stomach.
  • the compositions of the present disclosure can be administered to a subject using any suitable methods known in the art. Suitable formulations for use in the present disclosure and methods of delivery are generally well known in the art.
  • the small molecule splicing modulators described herein can be formulated as pharmaceutical compositions with a pharmaceutically acceptable diluent, carrier or excipient.
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions including pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, such as, for - 81 - WSGR Docket No.51503-744601 example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.
  • compositions described herein can be administrable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections
  • intranasal buccal
  • topical or transdermal administration routes e.g., topical or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • the pharmaceutical formulation is in the form of a tablet.
  • pharmaceutical formulations containing an SMSM described herein are in the form of a capsule.
  • liquid formulation dosage forms for oral administration are in the form of aqueous suspensions or solutions selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.
  • an SMSM described herein can be formulated for use as an aerosol, a mist or a powder.
  • the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.
  • an SMSM described herein can be prepared as transdermal dosage forms.
  • an SMSM described herein can be formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection.
  • an SMSM described herein can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
  • an SMSM described herein can be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.
  • Splicing Modulation [0229] The present disclosure contemplates use of small molecules with favorable drug properties that modulate the activity of splicing of a target RNA.
  • SMSMs small molecule splicing modulators
  • the SMSMs bind and modulate target RNA.
  • a library of SMSMs that bind and modulate one or more target RNAs.
  • the target RNA - 82 - WSGR Docket No.51503-744601 is mRNA.
  • the target RNA is mRNA a noncoding RNA.
  • the target RNA is a pre-mRNA.
  • the target RNA is hnRNA.
  • the small molecules modulate splicing of the target RNA. In some embodiments, a small molecule provided herein modulates splicing at a sequence of the target RNA. In some embodiments, a small molecule provided herein modulates splicing at a cryptic splice site sequence of the target RNA. In some embodiments, a small molecule provided herein binds to a target RNA. In some embodiments, a small molecule provided herein binds to a splicing complex component. In some embodiments, a small molecule provided herein binds to a target RNA and a splicing complex component.
  • splicing event in a pre- mRNA molecule
  • methods of preventing or inducing a splicing event in a pre- mRNA molecule comprising contacting the pre-mRNA molecule and/or other elements of the splicing machinery (e.g., within a cell) with a compound provided herein to prevent or induce the splicing event in the pre-mRNA molecule.
  • the splicing event that is prevented or induced can be, e.g., an aberrant splicing event, a constitutive splicing event or an alternate splicing event.
  • a method of identifying a compound capable of preventing or inducing a splicing event in a pre-mRNA molecule comprising contacting the compound with splicing elements and/or factors involved in alternative, aberrant and/or constitutive splicing as described herein (e.g., within cells) under conditions whereby a positive (prevention or induction of splicing) or negative (no prevention or induction of splicing) effect is produced and detected and identifying a compound that produces a positive effect as a compound capable of preventing or inducing a splicing event.
  • a small molecule compound described herein in a pharmaceutically acceptable carrier prevents or induces an alternative or aberrant splicing event in a pre-mRNA molecule.
  • the small molecule compounds provided herein are not antisense or antigene oligonucleotides. Tables 1-4 show the chemical structure of exemplary compounds and is not intended to be all-inclusive.
  • a method of treating a subject with a disease or condition comprises administering a small molecule splicing modulator compound (SMSM) to a subject with a disease or condition, wherein the SMSM is selected from the group consisting of the SMSMs of Tables 1-4.
  • SMSM small molecule splicing modulator compound
  • the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the polynucleotide is a pre-mRNA. In some embodiments, the method further comprises administering an additional therapeutic molecule to the subject.
  • the SMSM is a compound described herein. In some embodiments, the SMSM is selected from the group consisting of SMSMs of Tables 1-4. - 83 - WSGR Docket No.51503-744601 [0234] The compounds and formulations described herein are also useful as therapeutic agents in the treatment of disease involving aberrant and/or alternate splicing.
  • a method of treating a subject having a condition or disorder associated with an alternative or aberrant splicing event in a pre-mRNA molecule comprises administering to the subject a therapeutically effective amount of a compound described herein to modulate an alternative splicing event or prevent an aberrant splicing event, thereby treating the subject.
  • the method can, e.g., restore a correct splicing event in a pre-mRNA molecule.
  • the method can, e.g., utilize a small molecule compound described herein in a pharmaceutically acceptable carrier.
  • Formulations containing the small molecules described herein can comprise a physiologically or pharmaceutically acceptable carrier, such as an aqueous carrier.
  • formulations for use in the methods described herein include, but are not limited to, those suitable for oral administration, parenteral administration, including subcutaneous, intradermal, intramuscular, intravenous and intra-arterial administration, as well as topical administration (e.g., administration of an aerosolized formulation of respirable particles to the lungs of a patient afflicted with cystic fibrosis or lung cancer or a cream or lotion formulation for transdermal administration of patients with psoriasis).
  • topical administration e.g., administration of an aerosolized formulation of respirable particles to the lungs of a patient afflicted with cystic fibrosis or lung cancer or a cream or lotion formulation for transdermal administration of patients with psoriasis.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art.
  • the most suitable route of administration in any given case may depend upon the subject, the nature and severity of the condition being treated, and the particular active compound, which is being used, as would be readily determined by one of skill in the art.
  • Also provided herein are methods for the use of a compound described herein having the characteristics set forth above for the preparation of a medicament for upregulating or downregulating RNA expression in a patient having a disorder associated with aberrant or alternate splicing of a pre-mRNA molecule, as discussed above.
  • the medicament upregulates gene expression.
  • the medicament downregulates gene expression.
  • the compound can be admixed with, inter alia, a pharmaceutically acceptable carrier.
  • the carrier may be a solid or a liquid.
  • One or more compounds may be incorporated in any combination in the formulations described herein, which may be prepared by any of the well-known techniques of pharmacy, such as admixing the components, and/or including one or more accessory therapeutic ingredients.
  • the present disclosure identifies low molecular weight compounds (sometimes referred to herein as small molecules, which block mRNA splicing and/or enhance (facilitate, augment) mRNA splicing.
  • the splicing that can be regulated by the methods described herein include alternative splicing, e.g., exon skipping, intron retention, pseudoexons skipping, exon exclusion, partial intron exclusion and others.
  • modulation of splicing can be accomplished in the presence of, or in the absence of, antisense oligonucleotides (AOs) that are specific for splicing sequences of interest.
  • AOs antisense oligonucleotides
  • a small molecule and an AO act synergistically.
  • the method can comprise administering an SMSM, or a composition comprising an SMSM, to a subject, wherein the SMSM binds to a pre-mRNA or a splicing complex component and modulates splicing of the pre-mRNA to inhibit expression of one or more isoforms of a transcript.
  • the method can comprise administering an SMSM, or a composition comprising an SMSM, to a subject, wherein the SMSM binds to a pre-mRNA or a splicing complex component and modulates the splicing of the pre-mRNA to increase expression of one or more isoforms of a transcript.
  • a number of diseases are associated with expression of an aberrant gene product (e.g., an RNA transcript or protein) of a gene.
  • an aberrant gene product e.g., an RNA transcript or protein
  • aberrant amounts of a RNA transcript may lead to disease due to corresponding changes in protein expression.
  • Changes in the amount of a particular RNA transcript may be the result of several factors.
  • changes in the amount of RNA transcripts may be due to an aberrant level of transcription of a particular gene, such as by the perturbation of a transcription factor or a portion of the transcription process, resulting in a change in the expression level of a particular RNA transcript.
  • changes in the splicing of particular RNA transcripts can change the levels of a particular RNA transcript.
  • Changes to the stability of a particular RNA transcript or to components that maintain RNA transcript stability, such as the process of poly-A tail incorporation or an effect on certain factors or proteins that bind to and stabilize RNA transcripts may lead to changes in the levels of a particular RNA transcript.
  • the level of translation of particular RNA transcripts can also affect the amount of those transcripts, affecting or upregulating RNA transcript decay processes.
  • RNA transport or RNA sequestration may also lead to changes in functional levels of RNA transcripts, and may have an effect on the stability, further processing, or translation of the RNA transcripts.
  • methods for modulating the amount of one, two, three or more RNA transcripts encoded by a pre-mRNA comprising contacting a cell with an SMSM compound or a pharmaceutically acceptable salt thereof.
  • the cell is contacted with an SMSM compound or a pharmaceutically acceptable salt thereof in a cell culture.
  • the cell is contacted with an SMSM compound or a - 85 - WSGR Docket No.51503-744601 pharmaceutically acceptable salt thereof in a subject (e.g., a non-human animal subject or a human subject).
  • a subject e.g., a non-human animal subject or a human subject.
  • binding of an SMSM compound or a pharmaceutically acceptable salt thereof to pre-mRNA prevents splicing out of one or more exons and/or introns and/or proteins thereof, from the population of pre-mRNAs to produce mRNA encoding the target protein or functional RNA.
  • the cell comprises a population of pre-mRNAs transcribed from the gene encoding the target protein or functional RNA, wherein the population of pre-mRNAs comprises a mutation that causes the splicing out of one or more exons, and wherein an SMSM compound or a pharmaceutically acceptable salt thereof binds to the mutation that causes the splicing out of the one or more exons in the population of pre-mRNAs.
  • the binding of an SMSM compound or a pharmaceutically acceptable salt thereof to the mutation that causes the splicing out of the one or more exons prevents splicing out of the one or more exons from the population of pre-mRNAs to produce mRNA encoding the target protein or functional RNA.
  • the condition is a disease or disorder.
  • the method further comprises assessing protein expression.
  • an SMSM compound or a pharmaceutically acceptable salt thereof binds to a targeted portion of a pre-mRNA.
  • the binding of an SMSM compound or a pharmaceutically acceptable salt thereof catalyzes the inclusion of a missing exon or removal of an undesired retained intron or portions thereof, resulting in healthy mRNA and proteins. In some embodiments, the binding of an SMSM compound or a pharmaceutically acceptable salt thereof has minimal to no effect on non-diseased cells. SMSM Targets [0244] Aberrant splicing of mRNA, such as pre-mRNA, can result in a defective protein and can cause a disease or a disorder in a subject. The compositions and methods described herein can reduce this aberrant splicing of mRNA, such as pre-mRNA, and treat a disease or a disorder caused by this aberrant splicing.
  • RNA transcripts Diseases associated with changes to RNA transcript amount are often treated with a focus on the aberrant protein expression.
  • the processes responsible for the aberrant changes in RNA levels such as components of the splicing process or associated transcription factors or associated stability factors, could be targeted by treatment with a small molecule, it would be possible to restore protein expression levels such that the unwanted effects of the expression of - 86 - WSGR Docket No.51503-744601 aberrant levels of RNA transcripts or associated proteins. Therefore, there is a need for methods of modulating the amount of RNA transcripts encoded by certain genes as a way to prevent or treat diseases associated with aberrant expression of the RNA transcripts or associated proteins.
  • compositions and methods described herein can be used for treating a human disease or disorder associated with aberrant splicing, such as aberrant pre-mRNA splicing.
  • the compositions and methods described herein can be used for treating a human disease or disorder by modulating mRNA, such as pre-mRNA.
  • the compositions and methods described herein can be used for treating a human disease or disorder by modulating splicing of a nucleic acid even when that nucleic acid is not aberrantly spliced in the pathogenesis of the disease or disorder being treated.
  • an effective amount in the context of the administration of an SMSM compound or a pharmaceutically acceptable salt thereof, or composition or medicament thereof refers to an amount of an SMSM compound or a pharmaceutically acceptable salt thereof to a patient which has a therapeutic effect and/or beneficial effect.
  • an effective amount in the context of the administration of an SMSM compound or a pharmaceutically acceptable salt thereof, or composition or medicament thereof to a patient results in one, two or more of the following effects: (i) reduces or ameliorates the severity of a disease; (ii) delays onset of a disease; (iii) inhibits the progression of a disease; (iv) reduces hospitalization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the quality of life of a subject; (viii) reduces the number of symptoms associated with a disease; (ix) reduces or ameliorates the severity of a symptom associated with a disease; (x) reduces the duration of a symptom associated with a disease associated; (xi) prevents the recurrence of a symptom associated with a disease; (xii) inhibits the development or onset of a symptom of a disease; and/or (xiii) inhibits of
  • an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to restore the amount of a RNA transcript of a gene to the amount of the RNA transcript detectable in healthy patients or cells from healthy patients.
  • an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to restore the amount an RNA isoform and/or protein isoform of gene to the amount of the RNA isoform and/or protein isoform detectable in healthy patients or cells from healthy patients.
  • an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to decrease the aberrant amount of an RNA transcript of a gene which is associated with a disease. In some embodiments, an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to decrease the amount of the aberrant expression of an isoform of a gene. In some embodiments, an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to result in a substantial change in the amount of an RNA transcript (e.g., mRNA transcript), alternative splice variant or isoform.
  • an RNA transcript e.g., mRNA transcript
  • an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to increase or decrease the amount of an RNA transcript (e.g., an mRNA transcript) of gene which is beneficial for the prevention and/or treatment of a disease.
  • an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to increase or decrease the amount of an alternative splice variant of an RNA transcript of a gene which is beneficial for the prevention and/or treatment of a disease.
  • an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to increase or decrease the amount of an isoform of gene which is beneficial for the prevention and/or treatment of a disease.
  • an SMSM described herein can be used in the preparation of medicaments for the treatment of diseases or conditions described herein.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment can involve administration of pharmaceutical compositions that includes at least one SMSM described herein or a pharmaceutically acceptable salt, thereof, in a therapeutically effective amount to a subject.
  • an SMSM described herein can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition.
  • compositions containing an SMSM described herein can be administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • the dose of drug being administered may be temporarily reduced or temporarily suspended for a - 88 - WSGR Docket No.51503-744601 certain length of time (i.e., a “drug holiday”).
  • Doses employed for adult human treatment typically range of 0.01mg-5000 mg per day or from about 1 mg to about 1000 mg per day. In some embodiments, a desired dose is conveniently presented in a single dose or in divided doses.
  • dosages of the co-administered compounds can vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth.
  • the compound provided herein when co-administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially. If administration is simultaneous, the multiple therapeutic agents can be, by way of example only, provided in a single, unified form, or in multiple forms.
  • compositions described herein can be administered to the subject in a variety of ways, including parenterally, intravenously, intradermally, intramuscularly, colonically, rectally or intraperitoneally.
  • the small molecule splicing modulator or a pharmaceutically acceptable salt thereof is administered by intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection of the subject.
  • the pharmaceutical compositions can be administered parenterally, intravenously, intramuscularly or orally.
  • the oral agents comprising a small molecule splicing modulator can be in any suitable form for oral administration, such as liquid, tablets, capsules, or the like.
  • compositions of the present disclosure can be administered to a subject using any suitable methods known in the art. Suitable formulations for use in the present disclosure and methods of delivery are generally well known in the art.
  • the small molecule splicing modulators described herein can be formulated as pharmaceutical compositions with a pharmaceutically acceptable diluent, carrier or excipient.
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions including pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, such as, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.
  • compositions described herein can be administrable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections
  • intranasal buccal
  • topical or transdermal administration routes e.g., topical or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, - 89 - WSGR Docket No.51503-744601 liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • the pharmaceutical compositions described herein are administered orally. In some embodiments, the pharmaceutical compositions described herein are administered topically.
  • the pharmaceutical compositions described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments.
  • the pharmaceutical compositions described herein are administered topically to the skin.
  • the pharmaceutical compositions described herein are administered by inhalation.
  • the pharmaceutical compositions described herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.
  • the pharmaceutical compositions described herein are formulated as eye drops.
  • the pharmaceutical compositions described herein are: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation to the mammal; and/or (e) administered by nasal administration to the mammal; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.
  • the pharmaceutical compositions described herein are administered orally to the mammal.
  • an SMSM described herein is administered in a local rather than systemic manner. In some embodiments, an SMSM described herein is administered topically. In some embodiments, an SMSM described herein is administered systemically.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium - 90 - WSGR Docket No.51503-744601 stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium - 90 - WSGR Dock
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • SMSMs suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • SMSMs utilized in the methods of the disclosure can be, e.g., administered at dosages that may be varied depending upon the requirements of the subject the severity of the condition being treated and/or imaged, and/or the SMSM being employed.
  • dosages can be empirically determined considering the type and stage of disease diagnosed in a particular subject and/or the type of imaging modality being used in conjunction with the SMSMs.
  • the dose administered to a subject should be sufficient to affect a beneficial diagnostic or therapeutic response in the subject.
  • the size of the dose also can be - 91 - WSGR Docket No.51503-744601 determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a SMSM in a particular subject.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. Toxicity and therapeutic efficacy of such compounds can be determined by procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • Therapeutic index data obtained from cell culture assays and/or animal studies can be used in predicting the therapeutic index in vivo and formulating a range of dosages for use in subjects, such as human subjects. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the concentration of the test compound which achieves a half-maximal inhibition of symptoms as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
  • compositions of the present disclosure can be administered as frequently as necessary, including hourly, daily, weekly or monthly.
  • any of the aforementioned aspects are further embodiments comprising single administrations of an effective amount of an SMSM described herein, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
  • any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of an SMSM described herein, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the method comprises a drug holiday, wherein the administration of an SMSM described herein is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • Combination Therapies it is appropriate to administer at least one SMSM described herein in combination with another therapeutic agent.
  • a compound SMSM described herein can be co-administered with a second therapeutic agent, wherein SMSM and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • an SMSM may be administered in combination with one or more other SMSMs.
  • a SMSM may be administered to a subject in need thereof prior to, concurrent with, or following the administration of other therapeutic agents.
  • SMSMs may be administered to a subject at least 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1.5 hours, 1 hour, or 30 minutes before the starting time of the administration of the other therapeutic agent(s). In certain embodiments, they may be administered concurrent with the administration of the other therapeutic agent(s). In other words, in these embodiments, SMSMs are administrated at the same time when the administration of the other therapeutic agent(s) starts.
  • SMSMs may be administered following the starting time of administration of the - 93 - WSGR Docket No.51503-744601 other therapeutic agent(s) (e.g., at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours after the starting time of administration of the other therapeutic agents).
  • SMSMs may be administered at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours after the completion of administration of the other therapeutic agents.
  • these SMSMs are administered for a sufficient period of time so that the disease or condition is prevented or reduced.
  • Such sufficient period of time may be identical to, or different from, the period during which other therapeutic agent(s) are administered.
  • multiple doses of SMSMs are administered for each administration of another therapeutic agent or a combination of multiple other therapeutic agents.
  • an appropriate dosage of a SMSM is combined with a specific timing and/or a particular route to achieve the optimum effect in preventing or reducing the disease or condition.
  • an SMSM may be administered to a human orally at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours 8 hours, 9 hours, 10 hours, 11 hours or 12 hours; or at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days; or at least 1 week, 2 weeks, 3 weeks or 4 weeks; or at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months; prior to or after the beginning or the completion, of the administration of another therapeutic agent or a combination of other therapeutic agents.
  • the subjects that can be treated with the SMSMs and methods described herein can be any subject that produces mRNA that is subject to alternative splicing, e.g., the subject may be a eukaryotic subject, such as a plant or an animal.
  • the subject is a mammal, e.g., human.
  • the subject is a human.
  • the subject is a non-human animal.
  • the subject is a fetus, an embryo, or a child.
  • the subject is a non-human primate such as chimpanzee, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the subject is prenatal (e.g., a fetus), a child (e.g., a neonate, an infant, a toddler, a preadolescent), an adolescent, a pubescent, or an adult (e.g., an early adult, a middle aged adult, a senior citizen).
  • reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.
  • the starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.
  • the starting materials can be available from commercial sources or can be readily prepared. By way of example only, provided are schemes for preparing the Examples described herein.
  • Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • Examples can be made using known techniques and further chemically modified, in some embodiments, to facilitate intranuclear transfer to, e.g., a splicing complex component, a spliceosome or a pre–mRNA molecule.
  • a splicing complex component e.g., a spliceosome or a pre–mRNA molecule.
  • One of ordinary skill in the art will appreciate the standard medicinal chemistry approaches for chemical modifications for intranuclear transfer (e.g., reducing charge, optimizing size, and/or modifying lipophilicity).
  • Stereochemistry [0276] ( ⁇ ) 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 - 96 - WSGR Docket No.51503-744601 (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.
  • Example 1 Synthesis of SMSM 1-12. - 97 - WSGR Docket No.51503-744601
  • Example 2 Synthesis of SMSM 1-9.
  • Example 3 Synthesis of SMSM 1-11. - 99 - WSGR Docket No.51503-744601 [0281]
  • Example 5 Synthesis of SMSM 1-15. - 100 - WSGR Docket No.51503-744601 [0282]
  • Example 6 Synthesis of SMSM 1-24. - 101 - WSGR Docket No.51503-744601 [0284]
  • Example 8 Synthesis of SMSM 2-12. - 102 - WSGR Docket No.51503-744601 [0286]
  • Example 10 Synthesis of SMSM 2-13.
  • Example 12 Synthesis of SMSM 2-15. - 104 - WSGR Docket No.51503-744601 [0290]
  • Example 14 Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 1).
  • Step 1 Synthesis of 3,6-dichloro-N-methylpyridazine-4-carboxamide.
  • DCM 3,6-dichloropyridazine-4-carboxylic acid
  • oxalyl chloride 1.5 mL, 17.7 mmol
  • Step 2 Synthesis of (1R,3s,5S)-tert-butyl 3-(6-chloro-4- (methylcarbamoyl)pyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (INT-1).
  • Step 3 Synthesis of (1R,3s,5S)-tert-butyl 3-(3-chloro-6-methyl-5,7-dioxo-6,7 - dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 4 Synthesis of tert-butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-6-methyl-5,7-dioxo-6,7-dihydropyrimido[4,5- c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 5 Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6-methyl- 5,7 -dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 1).
  • Example 15 Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-5-oxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 2).
  • Step 1 Synthesis of (1R,3s,5S)-tert-butyl 3-(3-chloro-6-methyl-5-oxo-6,7- dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 2 Synthesis of tert-butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-6-methyl-5-oxo-6,7-dihydropyrimido[4,5- c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 3 Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6-methyl- 5-oxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 2).
  • Example 16 Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7 - oxo-7,8-dihydro-5H-pyridazino[3,4-d][1,3]oxazin-3-yl)-3-(methoxymethoxy)phenyl)-N- methylacrylamide (Compound 3).
  • Step 1 Synthesis of 3-(((1R,3s,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo [3.2.1]octan-3-yl)amino)-6-chloropyridazine-4-carboxylic acid.
  • Step 2 Synthesis of (1R,3s,5S)-tert-butyl 3-(6-chloro-4- (methoxy(methyl)carbamoyl)pyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane-8- carboxylate.
  • Step 3 Synthesis of (1R,3s,5S)-tert-butyl 3-(6-chloro-4-formylpyridazin-3-ylamino)- 8 -azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 4 Synthesis of (1R,3s,5S)-tert-butyl 3-(6-chloro-4-(hydroxymethyl)pyridazin-3- ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 5 Synthesis of (1R,3s,5S)-tert-butyl 3-(6-chloro-2-oxo-2,4-dihydro-1H- pyrido[2,3-d][1,3]oxazin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 6 Synthesis of tert-butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-7-oxo-5H-pyridazino[3,4-d][1,3]oxazin-8(7H)- yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 7 Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-oxo-7,8- dihydro-5H-pyridazino[3,4-d][1,3]oxazin-3-yl)-3-(methoxymethoxy)phenyl)-N- methylacrylamide.
  • Example 17 Synthesis of (E)-3-(4-(8-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7- oxo-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)-3-hydroxyphenyl)-N-methylacrylamide (Compound 4).
  • Step 1 Synthesis of tert-butyl (1R,3s,5S)-3-((6-chloro-4-((Z)-3-methoxy-3-oxoprop- 1-en-1-yl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 2 Synthesis of tert-butyl (1R,3S,5S)-3-((6-chloro-4-(3-methoxy-3- oxopropyl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 3 Synthesis of tert-butyl (1R,3S,5S)-3-(3-chloro-7-oxo-6,7-dihydropyrido[2,3- c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 4 Synthesis of tert-butyl (1R,3S,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-7-oxo-6,7-dihydropyrido[2,3-c]pyridazin- 8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Example 18 Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 5).
  • Step 1 Synthesis of tert-butyl (1R,3S)-3-((6-chloro-4- ((methylamino)methyl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • tert- Butyl (1R,3s,5S)-3-((6-chloro-4-formylpyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (3.2 g, 8.71 mmol) was dissolved in MeNH3/THF (4M, 100 mL), and the resulting mixture was sealed and heated at 50 °C for 2 h.
  • Step 2 Synthesis of tert-butyl (1R,3s,5S)-3-((6-chloro-4-((N-methyl-1H-imidazole-1- carboxamido)methyl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 3 Synthesis of tert-butyl (1R,3s,5S)-3-(3-chloro-6-methyl-7-oxo-6,7- dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 4 Synthesis of tert-butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-6-methyl-7-oxo-6,7-dihydropyrimido[4,5- c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 5 Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6-methyl- 7-oxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 5).
  • Example 19 Synthesis of SMSM 3-12. - 116 - WSGR Docket No.51503-744601 [0321]
  • Example 20 Synthesis of SMSM 3-9. - 117 - WSGR Docket No.51503-744601 [0322]
  • Example 21 Synthesis of SMSM 3-11. - 118 - WSGR Docket No.51503-744601 [0324]
  • Example 23 Synthesis of SMSM 3-10. - 119 - WSGR Docket No.51503-744601 [0325]
  • Example 24 Synthesis of SMSM 3-15.
  • Example 25 Synthesis of SMSM 3-17. - 121 - WSGR Docket No.51503-744601 [0328]
  • Example 27 Synthesis of SMSM 3-24. [0330]
  • Example 29 Synthesis of (E)-3-(4-(8-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7- oxo-7,8-dihydropyrido[2,3-c]pyridazin-3-yl)-3-hydroxyphenyl)-N-methylacrylamide (Compound 6).
  • Step 1 Synthesis of tert-butyl (1R,3s,5S)-3-(3-chloro-7-oxopyrido[2,3-c]pyridazin- 8(7H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 2 Synthesis of tert-butyl (1R,3S,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-7-oxopyrido[2,3-c]pyridazin-8(7H)-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate.
  • Step 3 Synthesis of (E)-3-(4-(8-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-oxo-7,8- dihydropyrido[2,3-c]pyridazin-3-yl)-3-hydroxyphenyl)-N-methylacrylamide.
  • Example 30 Synthesis of SMSM 4-8. - 124 - WSGR Docket No.51503-744601 [0335]
  • Example 31 Synthesis of SMSM 4-7. - 125 - WSGR Docket No.51503-744601 [0337]
  • Example 33 Synthesis of SMSM 4-15. - 126 - WSGR Docket No.51503-744601 [0338]
  • Example 34 Synthesis of SMSM 4-24.
  • Example 35 Biological assay for lowering of Huntingtin Protein
  • Compounds were tested on GM04724 (CAG 70/20) Huntington’s disease patient lymphoblast cells at doses ranging from 10 ⁇ M to 0.6 nM.4,500 cells/well were seeded in 384 well plates. Compounds were incubated for 48 hours. mHTT protein levels were assessed by the 2B7–MW1 assay via Mesoscale Discovery (MSD) as previously reported (Macdonald et al., 2014).
  • MSD Mesoscale Discovery
  • the antibody pair is comprised of previously characterized monoclonals (2B7 and MW1) interrogating two regions for HTT conformation and biological properties: the N17 domain and the polyQ domain (Baldo et al., 2012; Ko et., 2001).2B7–MW1 is dependent on subject/animal specific levels of HTT at the time of treatment.2B7–MW1 is dependent on polyQ expansion (e.g., the higher the expansion the higher the signal) and on mHTT size (e.g., a similar polyQ will give higher signal with smaller HTT size). The results are shown in Table 5 below.

Abstract

Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.

Description

WSGR Docket No.51503-744601 COMPOSITIONS FOR MODULATING SPLICING CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No.63/079,365 filed on September 16, 2020; U.S. Provisional Application No.63/079,469 filed on September 16, 2020; U.S. Provisional Application No.63/079,470 filed on September 16, 2020; and U.S. Provisional Application No.63/079,435 filed on September 16, 2020, the disclosures of which are hereby incorporated by reference in their entirety. BACKGROUND [0002] The majority of protein-coding genes in the human genome are composed of multiple exons (coding regions) that are separated by introns (non-coding regions). Gene expression results in a single precursor messenger RNA (pre-mRNA). The intron sequences are subsequently removed from the pre-mRNA by a process called splicing, which results in the mature messenger RNA (mRNA). By including different combinations of exons, alternative splicing gives rise to multiple mRNAs encoding distinct protein isoforms. The spliceosome, an intracellular complex of multiple proteins and ribonucleoproteins, catalyzes splicing. [0003] Current therapeutic approaches to direct and control mRNA expression require methods such as gene therapy, genome editing, or a wide range of oligonucleotide technologies (antisense, RNAi, etc.). Gene therapy and genome editing act upstream of transcription of mRNA by influencing the DNA code and thereby changing mRNA expression. Oligonucleotides modulate the action of RNA via canonical base/base hybridization. The appeal of this approach is in the design of the basic pharmacophore of an oligonucleotide, which can be defined in a straightforward fashion by known base pairing to the target sequence subject. Each of these therapeutic modalities suffers from substantial technical, clinical, and regulatory challenges. Some limitations of oligonucleotides as therapeutics (e.g., antisense, RNAi) include unfavorable pharmacokinetics, lack of oral bioavailability, and lack of blood-brain-barrier penetration, with the latter precluding delivery to the brain or spinal cord after parenteral drug administration for the treatment of diseases (e.g., neurological diseases, brain cancers). In addition, oligonucleotides are not taken up effectively into solid tumors without a complex delivery system such as lipid nanoparticles. Further, most of the oligonucleotides taken up into cells and tissues remain in non- functional compartments (e.g., endosomes) and does not gain access to the cytosol and/or nucleus where the target is located. [0004] Additionally, to anneal to a target, oligonucleotide therapies require access to complementary base pairs of the target. This approach assumes that pre-mRNA sequences exist as a linear strand of RNA in the cell. However, pre-mRNA is rarely linear; it has complex - 1 - WSGR Docket No.51503-744601 secondary and tertiary structure. Further, cis-acting elements (e.g., protein binding elements) and trans-acting factors (e.g., splicing complex components) can create additional two-dimensional and three-dimensional complexity (e.g., by binding to the pre-mRNA). These features can be potency-and efficacy-limiting for oligonucleotide therapies. SUMMARY [0005] The novel small molecule splicing modulators (SMSMs) described herein do not suffer from the limitations above, nor the structural and steric hindrances that greatly limit oligonucleotide therapies (e.g., by blocking hybridization to pre-mRNA targets). Small molecules have been essential in uncovering the mechanisms, regulations, and functions of many cellular processes, including DNA replication, transcription, and translation. While several recent reports have described screens for small molecule effectors of splicing, only a small number of constitutive or alternative splicing modulators have been identified and many of the small- molecule inhibitors lack specificity, lack selectivity, lack potency, exhibit toxicity, or are not orally available. Targeting the RNA transcriptome with small-molecule modulators represents an untapped therapeutic approach to treat a variety of RNA-mediated diseases. Accordingly, there remains a need to develop small-molecule RNA modulators useful as therapeutic agents. There is need in the art for novel modulators of splicing or splicing-dependent processes. Provided herein are small molecule splicing modulators and uses thereof that fulfill this need. [0006] In one aspect, described herein is a compound of Formula (I):
Figure imgf000003_0001
Formula (I) wherein, A1 is N or CRA1; A2 is N or CRA2; A3 is N or CRA3; provided that when A2 and A3 are each N, then A1 is N; each RA1, RA2, and RA3 is independently hydrogen, F, Cl, –OR1, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C4 cycloalkyl, or substituted or unsubstituted C2–C3 heterocycloalkyl; ring B is saturated or unsaturated, substituted or unsubstituted monocyclic heterocyclic ring; ring Q is substituted or unsubstituted - 2 - WSGR Docket No.51503-744601 aryl or substituted or unsubstituted heteroaryl; Z is CR2; 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; 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; each R1 is independently hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is hydrogen, substituted or unsubstituted C1–C4 alkyl, or substituted or unsubstituted C1–C4 haloalkyl; each R4 and R5 is independently H, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, - N(R7)2, -CH2OR7, -C(=O)R7, -C(=O)OR7, -C(=O)N(R7)2, -S(=O)R7, -S(=O)2R7, or - NR7C(=O)R7; R6 is -C(=O)R7, -C(=O)OR7, -C(=O)N(R8)2, -C=(O)N(OR7)(R7), -P(=O)(R8)2, - P(=O)(R8)N(R8)2, -S(=O)R8, -S(=O)2R8, -S(=O)(=NR7)R7, -N(R8)C(=O)R8, N(R8)S(=O)R8, N(R8)S(=O)2R8, -C(=O)N(R8)S(=O)2R8, -N(R8)C(=O)N(R8)2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R7 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2- C7heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R8 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, -N(R7)2, -CH2OR7, -C(=O)R7, -C(=O)OR7, -C(=O)N(R7)2, -S(=O)R7, - S(=O)2R7, or -NR7C(=O)R7; or two R8 groups on the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted C2- C10heterocycloalkyl; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; a is 0 or 1; b is 0; c is 0, 1, or 2; and d is 0, 1, or 2, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof. - 3 - WSGR Docket No.51503-744601 [0007] In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, a is 0 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, c is 0 and d is 0. In some embodiments, c is 0 and d is 1. In some embodiments, c is 1 and d is 0. In some embodiments, c is 1 and d is 1. [0008] In one aspect, described herein is a compound of Formula (II)
Figure imgf000005_0001
Formula (II) wherein, RA is hydrogen, F, Cl, –OR1, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C4 cycloalkyl, or substituted or unsubstituted C2–C3 heterocycloalkyl; ring B is saturated or unsaturated, substituted or unsubstituted monocyclic heterocyclic ring; ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Z is CR2; 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; 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; each R1 is independently hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3– C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is hydrogen, substituted or unsubstituted C1– C4 alkyl, or substituted or unsubstituted C1–C4 haloalkyl; each R4 and R5 is independently H, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, - 4 - WSGR Docket No.51503-744601 substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, - N(R7)2, -CH2OR7, -C(=O)R7, -C(=O)OR7, -C(=O)N(R7)2, -S(=O)R7, -S(=O)2R7, or - NR7C(=O)R7; R6 is -C(=O)R7, -C(=O)OR7, -C(=O)N(R8)2, -C=(O)N(OR7)(R7), -P(=O)(R8)2, - P(=O)(R8)N(R8)2, -S(=O)R8, -S(=O)2R8, -S(=O)(=NR7)R7, -N(R8)C(=O)R8, N(R8)S(=O)R8, N(R8)S(=O)2R8, -C(=O)N(R8)S(=O)2R8, -N(R8)C(=O)N(R8)2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R7 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2- C7heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R8 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, -N(R7)2, -CH2OR7, -C(=O)R7, -C(=O)OR7, -C(=O)N(R7)2, -S(=O)R7, - S(=O)2R7, or -NR7C(=O)R7; or two R8 groups on the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted C2- C10heterocycloalkyl; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; a is 0 or 1; b is 0; c is 0, 1, or 2; and d is 0, 1, or 2, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof. In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, a is 0 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, c is 0 and d is 0. In some embodiments, c is 0 and d is 1. In some embodiments, c is 1 and d is 0. In some embodiments, c is 1 and d is 1. [0009] Also provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient or carrier. [0010] Also provided herein are methods of modulating splicing comprising contacting a compound disclosed herein to cells, wherein the compound modulates splicing at a splice site - 5 - WSGR Docket No.51503-744601 sequence of a pre-mRNA that encodes a mRNA, wherein the mRNA encodes a target protein or a functional RNA. [0011] Also provided herein are methods of treating a disease or condition comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, to a subject in need thereof. [0012] Also provided herein are uses of a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for the treatment of a condition or disease. INCORPORATION BY REFERENCE [0013] 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 [0014] 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. [0015] 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 [0016] The terms “compound(s) of this disclosure”, “compound(s) of the present disclosure”, “small molecule steric modulator(s)”, “small molecule splicing modulator(s)” “steric modulator(s)”, “splicing modulator(s)”, “compound(s) that modify splicing” and “compound(s) modifying splicing”, “SMSM” or “small molecule that binds a target RNA,” are interchangeably used herein and refer to compounds as disclosed herein and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof. The terms “compound(s) of this disclosure”, “compound(s) of the present disclosure”, “small molecule steric modulator(s)”, “small molecule splicing modulator(s)” “steric modulator(s)”, “splicing modulator(s)”, “compound(s) that modify splicing” and “compound(s) modifying splicing”, “SMSM” or “small molecule that binds a target RNA,” denote a small molecule compound that binds to a cell - 6 - WSGR Docket No.51503-744601 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. [0017] The term “RNA” (ribonucleic acid) as used herein, means naturally-occurring or synthetic oligoribonucleotides independent of source (e.g., the RNA may be produced by a human, animal, plant, virus, or bacterium, or may be synthetic in origin), biological context (e.g., the RNA may be in the nucleus, circulating in the blood, in vitro, cell lysate, or isolated or pure form), or physical form (e.g., the RNA may be in single-, double-, or triple-stranded form (including RNA-DNA hybrids), may include epigenetic modifications, native post-transcriptional modifications, artificial modifications (e.g., obtained by chemical or in vitro modification), or other modifications, may be bound to, e.g., metal ions, small molecules, proteins such as chaperones, or co-factors, or may be in a denatured, partially denatured, or folded state including any native or unnatural secondary or tertiary structure such as quadruplexes, hairpins, triplexes, three way junctions (3WJs), four way junctions (4WJs), parallel-Y junctions, hairpins, bulge loops, pseudoknots, and internal loops, etc., and any transient forms or structures adopted by the RNA). In some embodiments, the RNA is 20, 22, 50, 75, or 100 or more nucleotides in length. In some embodiments, the RNA is 250 or more nucleotides in length. In some embodiments, the RNA is 350, 450, 500, 600, 750, or 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000, or more nucleotides in length. In some embodiments, the RNA is between 250 and 1,000 nucleotides in length. In some embodiments, the RNA is a pre-RNA, pre-miRNA, or pretranscript. In some embodiments, the RNA is a non-coding RNA (ncRNA), messenger RNA (mRNA), micro-RNA (miRNA), a ribozyme, riboswitch, lncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA, ceRNA, pseudo- gene, viral RNA, fungal RNA, parasitic RNA, or bacterial RNA. - 7 - WSGR Docket No.51503-744601 [0018] “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. [0019] Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of hydrogen, unless indicated otherwise. [0020] The definitions described herein apply irrespective of whether the terms in question appear alone or in combination. It is contemplated that the definitions described herein can be appended to form chemically-relevant combinations, such as e.g. “heterocycloalkylaryl”, “haloalkylheteroaryl”, “arylalkylheterocycloalkyl”, or “alkoxyalkyl”. The last member of the combination is the radical which is binding to the rest of the molecule. The other members of the combination are attached to the binding radical in reversed order in respect of the literal sequence, e.g. the combination arylalkylheterocycloalkyl refers to a heterocycloalkyl-radical which is substituted by an alkyl which is substituted by an aryl. [0021] 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. [0022] The term “substituent” denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. [0023] 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. In some embodiments, an optionally substituted or substituted group is substituted with one or more substituents selected from D, oxo, 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 embodiments, optional substituents are independently selected from D, oxo, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), - C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, - - 8 - WSGR Docket No.51503-744601 SC1-C4 alkyl, -S(=O)C1-C4 alkyl, and -S(=O)2(C1-C4 alkyl). In some embodiments, optional substituents are independently selected from D, oxo, 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. [0024] The following abbreviations are used throughout the specification: acetic acid (AcOH); ethyl acetate (EtOAc); n-butyl alcohol (n-BuOH); 1,2-dichloroethane (DCE); dichloromethane (CH2Cl2, DCM); diisopropylethylamine (DIPEA); dimethylformamide (DMF); hydrogen chloride (HCl); methanol (MeOH); methoxymethyl bromide (MOMBr); N-methyl-2-pyrrolidone (NMP); methyl iodide (MeI); n-propanol (n-PrOH); p-methoxybenzyl (PMB); triethylamine (NEt3); [1,1’- Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (Pd(dppf)Cl2); sodium ethane thiolate (EtSNa); sodium acetate (NaOAc); sodium hydride (NaH); sodium hydroxide (NaOH); tetrahydropyran (THP); tetrahydrofuran (THF). [0025] As used herein, C1-Cx includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. [0026] The term “oxo” refers to the =O substituent. [0027] The term “thioxo” refers to the =S substituent. [0028] The term “halo”, “halogen”, and “halide” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. [0029] The term “alkyl” refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An alkyl comprising up to 10 carbon atoms is referred to as a C1-C10 alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, C1-C10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2- methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, the alkyl is -CH(CH3)2 or -C(CH3)3. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted . “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a - 9 - WSGR Docket No.51503-744601 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-. Unless otherwise specifically stated in the specification, an alkylene group may be optionally substituted. [0030] 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. [0031] 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 (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non- limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, - C(CH3)=CHCH3, and -CH2CH=CH2. [0032] 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 alkynyl group has the formula -C≡C-Ra, wherein Ra refers to the remaining portions of the alkynyl group. In some embodiments, Ra is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH3 -C≡CCH2CH3, -CH2C≡CH. [0033] The term “aromatic” refers to a planar ring having a delocalized ^-electron system containing 4n+2 ^ electrons, where n is an integer. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl). [0034] 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- - 10 - WSGR Docket No.51503-744601 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. [0035] 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. [0036] 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. [0037] 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. [0038] 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. [0039] 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 - 11 - WSGR Docket No.51503-744601 include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. [0040] 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. [0041] 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. [0042] 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. [0043] 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. [0044] 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 - 12 - WSGR Docket No.51503-744601 embodiments, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C1-C6 heteroalkyl. Representative heteroalkyl groups include, but are not limited to -OCH2OMe, -OCH2CH2OH, - OCH2CH2OMe, or -OCH2CH2OCH2CH2NH2. [0045] The term “heteroalkylene” or “heteroalkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group in which one or more skeletal atoms of the hydrocarbon chain 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. Unless stated otherwise specifically in the specification, the heteroalkylene group may be optionally substituted. Representative heteroalkylene groups include, but are not limited to -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-. [0046] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the - 13 - WSGR Docket No.51503-744601 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. [0047] The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) that includes at least one heteroatom selected from nitrogen, oxygen and sulfur, wherein each heterocyclic group has from 3 to 12 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 12 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 12 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3 h-indolyl, indolin-2-onyl, isoindolin-1- onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)- onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic. - 14 - WSGR Docket No.51503-744601 [0048] The term “heteroaryl” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl is monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0- 1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl. In some embodiments, a heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, a heteroaryl group comprises a fully reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl comprises a cycloalkyl or heterocycloalkyl group, the heteroaryl is bonded to the rest of the molecule through a heteroaromatic ring carbon or hetero atom. A heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. [0049] 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. [0050] 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 - 15 - WSGR Docket No.51503-744601 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 imgf000017_0001
. [0051] The terms “administer,” “administering”, “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes (p.o.), intraduodenal routes (i.d.), parenteral injection (including intravenous (i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), intravascular or infusion (inf.)), topical (top.) and rectal (p.r.) administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. [0052] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. [0053] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated; for example a reduction and/or alleviation of one or more signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses can be an amount of an agent that provides a clinically significant decrease in one or more disease symptoms. An appropriate “effective” amount may be determined using techniques, such as a dose escalation study, in individual cases. [0054] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in amount, potency or duration a desired effect. For example, in regard to enhancing splicing of a - 16 - WSGR Docket No.51503-744601 target, the term “enhancing” can refer to the ability to increase or prolong splicing, either in amount, potency or duration, of a target. [0055] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. The term “animal” as used herein comprises human beings and non-human animals. In one embodiment, a “non-human animal” is a mammal, for example a rodent such as rat or a mouse. In one embodiment, a non-human animal is a mouse. [0056] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients to be administered to a subject, e.g., a human in need thereof. [0057] The term “pharmaceutical combination” as used herein, means a product that results from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound described herein and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound described herein and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients. [0058] The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use. “Pharmaceutically acceptable” can refer to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. [0059] The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any - 17 - WSGR Docket No.51503-744601 pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, excipients, preservatives or lubricants used in formulating pharmaceutical products. [0060] The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. A “pharmaceutically acceptable salt” can refer to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and/or does not abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting an SMSM compound of any one of Formulas (I)-(Ig) with an acid. Pharmaceutically acceptable salts are also obtained by reacting a compound of any one of Formulas (I)-(Ig) or with a base to form a salt. [0061] The term “nucleic acid” as used herein generally refers to one or more nucleobases, nucleosides, or nucleotides, and the term includes polynucleobases, polynucleosides, and polynucleotides. [0062] 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. [0063] A ribonucleoprotein (RNP) refers to a nucleoprotein that contains RNA. A RNP can be a complex of a ribonucleic acid and an RNA-binding protein. Such a combination can also be referred to as a protein-RNA complex. These complexes can function in a number of biological functions that include, but are not limited to, DNA replication, gene expression, metabolism of RNA, and pre-mRNA splicing. Examples of RNPs include the ribosome, the enzyme telomerase, vault ribonucleoproteins, RNase P, heterogeneous nuclear RNPs (hnRNPs) and small nuclear RNPs (snRNPs). [0064] Nascent RNA transcripts from protein-coding genes and mRNA processing intermediates, collectively referred to as pre-mRNA, are generally bound by proteins in the nuclei of eukaryotic cells. From the time nascent transcripts first emerge from RNA polymerase (e.g., RNA polymerase II) until mature mRNAs are transported into the cytoplasm, the RNA molecules are associated with an abundant set of splicing complex components (e.g., nuclear proteins and snRNAs). These proteins can be components of hnRNPs, which can contain heterogeneous nuclear RNA (hnRNA) (e.g., pre-mRNA and nuclear RNA complexes) of various sizes. [0065] Splicing complex components function in splicing and/or splicing regulation. Splicing complex components can include, but are not limited to, ribonuclear proteins (RNPs), splicing - 18 - WSGR Docket No.51503-744601 proteins, small nuclear RNAs (snRNAs), small nuclear ribonucleoproteins (snRNPs), and heterogeneous nuclear ribonucleoproteins (hnRNPs). Splicing complex components include, but are not limited to, those that may be required for splicing, such as constitutive splicing, alternative splicing, regulated splicing and splicing of specific messages or groups of messages. A group of related proteins, the serine arginine rich proteins (SR proteins), can function in constitutive pre- mRNA splicing and may also regulate alternative splice-site selection in a concentration- dependent manner. SR proteins typically have a modular structure that consists of one or two RNA-recognition motifs (RRMs) and a C-terminal rich in arginine and serine residues (RS domain). Their activity in alternative splicing may be antagonized by members of the hnRNP A/B family of proteins. Splicing complex components can also include proteins that are associated with one or more snRNAs. SR proteins in human include, but are not limited to, SC35, SRp55, SRp40, SRm300, SFRS10, TASR-1, TASR-2, SF2/ASF, 9G8, SRp75, SRp30c, SRp20 and P54/SFRS11. Other splicing complex components in human that can be involved in splice site selection include, but are not limited to, U2 snRNA auxiliary factors (e.g. U2AF65, U2AF35), Urp/U2AF1-RS2, SF1/BBP, CBP80, CBP 20, SF1 and PTB/hnRNP1. hnRNP proteins in humans include, but are not limited to, A1, A2/B1, L, M, K, U, F, H, G, R, I and C1/C2. Human genes encoding hnRNPs include HNRNPA0, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3, HNRNPA2B1, HNRNPAB, HNRNPB1, HNRNPC, HNRNPCL1, HNRNPD, HNRPDL, HNRNPF, HNRNPH1, HNRNPH2, HNRNPH3, HNRNPK, HNRNPL, HNRPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1, HNRNPUL2, HNRNPUL3, and FMR1. Splicing complex components may be stably or transiently associated with a snRNP or with a transcript. [0066] The term “intron” refers to both the DNA sequence within a gene and the corresponding sequence in the unprocessed RNA transcript. As part of the RNA processing pathway, introns can be removed by RNA splicing either shortly after or concurrent with transcription. Introns are found in the genes of most organisms and many viruses. They can be located in a wide range of genes, including those that generate proteins, ribosomal RNA (rRNA), and transfer RNA (tRNA). [0067] An “exon” can be any part of a gene that encodes a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term “exon” refers to both the DNA sequence within a gene and to the corresponding sequence in RNA transcripts. [0068] A “spliceosome” can be assembled from snRNAs and protein complexes. The spliceosome can remove introns from a transcribed pre-mRNA. [0069] Small Molecule Splicing Modulators (SMSMs) [0070] The present disclosure provides the unexpected discovery that certain small chemical molecules can modify splicing events in pre-mRNA molecules, herein referred to as small molecule splicing modulators (SMSMs). These SMSMs can modulate specific splicing events in - 19 - WSGR Docket No.51503-744601 specific pre-mRNA molecules and are useful, therefore, in treating, preventing, or ameliorating a disease or condition associated with a specific RNA. These SMSMs can operate by a variety of mechanisms to modify splicing events. For example, the SMSMs of this disclosure can: 1) interfere with the formation and/or function and/or other properties of splicing complexes, spliceosomes, and/or their components such as hnRNPs, snRNPs, SR-proteins and other splicing factors or elements, resulting in the prevention or induction of a splicing event in a pre-mRNA molecule. As another example; 2) prevent and/or modify post-transcriptional regulation (e.g., splicing) of gene products, such as hnRNPs, snRNPs, SR-proteins and other splicing factors, which can subsequently be involved in the formation and/or function of a spliceosome or splicing complex component; 3) prevent and/or modify phosphorylation, glycosylation and/or other modifications of gene products including, but not limited to, hnRNPs, snRNPs, SR-proteins and other splicing factors, which can subsequently be involved in the formation and/or function of a spliceosome or splicing complex component; 4) bind to and/or otherwise affect specific pre- mRNA so that a specific splicing event is prevented or induced, e.g., via a mechanism that does not involve base pairing with RNA in a sequence-specific manner. The small molecules of this disclosure are different from and are not related to antisense or antigene oligonucleotides. [0071] Described herein are compounds modifying splicing of gene products for use in the treatment, prevention and/or delay of progression of diseases or conditions. [0072] In one aspect, described herein is a compound that has the structure of Formula (I):
Figure imgf000021_0001
wherein, A1 is N or CRA1, A2 is N or CRA2, A3 is N or CRA3; provided that when A2 and A3 are each N, then A1 is N; each RA1, RA2, and RA3 is independently hydrogen, F, Cl, –OR1, substituted or unsubstituted C1– C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C4 cycloalkyl, or substituted or unsubstituted C2–C3 heterocycloalkyl; - 20 - WSGR Docket No.51503-744601 ring B is saturated or unsaturated, substituted or unsubstituted monocyclic heterocyclic ring; ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Z is CR2; 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; 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; each R1 is independently hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is hydrogen, substituted or unsubstituted C1–C4 alkyl, or substituted or unsubstituted C1–C4 haloalkyl; each R4 and R5 is independently H, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, -N(R7)2, -CH2OR7, -C(=O)R7, -C(=O)OR7, - C(=O)N(R7)2, -S(=O)R7, -S(=O)2R7, or -NR7C(=O)R7; R6 is -C(=O)R7, -C(=O)OR7, -C(=O)N(R8)2, -C=(O)N(OR7)(R7), -P(=O)(R8)2, - P(=O)(R8)N(R8)2, -S(=O)R8, -S(=O)2R8, -S(=O)(=NR7)R7, -N(R8)C(=O)R8, N(R8)S(=O)R8, N(R8)S(=O)2R8, -C(=O)N(R8)S(=O)2R8, -N(R8)C(=O)N(R8)2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R7 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R8 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, -N(R7)2, -CH2OR7, -C(=O)R7, -C(=O)OR7, -C(=O)N(R7)2, -S(=O)R7, - S(=O)2R7, or -NR7C(=O)R7; or two R8 groups on the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted C2- C10heterocycloalkyl; - 21 - WSGR Docket No.51503-744601 each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; a is 0 or 1; b is 0; c is 0, 1, or 2; and d is 0, 1, or 2, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof. [0073] In some embodiments, described herein is a compound of Formula (I). In some embodiments, described herein is a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of a compound of Formula (I). [0074] In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, a is 0 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, c is 0 and d is 0. In some embodiments, c is 0 and d is 1. In some embodiments, c is 1 and d is 0. In some embodiments, c is 1 and d is 1. [0075] In some embodiments, the compound of Formula (I) has the structure of Formula (Ia):
Figure imgf000023_0001
[0076] In some embodiments, the compound of Formula (I) has the structure of Formula (Ib): - 22 - WSGR Docket No.51503-744601
Figure imgf000024_0001
[0077] In some embodiments, the compound of Formula (I) has the structure of Formula (Ic):
Figure imgf000024_0002
[0078] In some embodiments, the compound of Formula (I) has the structure of Formula (Id):
Figure imgf000024_0003
[0079] In some embodiments, the compound of Formula (I) has the structure of Formula (Ie): - 23 - WSGR Docket No.51503-744601
Figure imgf000025_0001
[0080] In some embodiments, the compound of Formula (I) has the structure of Formula (If):
Figure imgf000025_0002
[0081] In some embodiments, the compound of Formula (I) has the structure of Formula (Ig):
Figure imgf000025_0003
[0082] In some embodiments, a compound of Formula (I) has a structure of formula (Ih): - 24 - WSGR Docket No.51503-744601
Figure imgf000026_0001
[0083] In some embodiments, A1 and A3 are each independently N, and A2 is CRA2. In some embodiments, RA2 is hydrogen. In some embodiments, each A1 and A2 is independently N, and A3 is CRA3. In some embodiments, RA3 is hydrogen. In some embodiments, each A1, A2, and A3 is independently N. In some embodiments, A1 is CRA1, A2 is N, and A3 is CRA3. [0084] In some embodiments, A1 is N. In some embodiments, A1 is CRA1. In some embodiments, A2 is N. In some embodiments, A2 is CRA2. In some embodiments, A3 is N. In some embodiments, A3 is CRA3. In some embodiments, each A1, A2, and A3 is N. [0085] In some embodiments, each RA1, RA2, and RA3 is independently hydrogen. In some embodiments, each RA1, RA2, and RA3 is independently halogen and hydrogen. [0086] In some embodiments, RA1 is H. In some embodiments, RA1 is halogen. In some embodiments, RA1 is F or Cl. In some embodiments, RA1 is –OR1. In some embodiments, RA1 is substituted or unsubstituted C1–C4 alkyl. In some embodiments, RA1 is substituted or unsubstituted C1–C4 haloalkyl. In some embodiments, RA1 is substituted or unsubstituted C1–C4 heteroalkyl. In some embodiments, RA1 is substituted or unsubstituted C3–C4 cycloalkyl. In some embodiments, RA1 is substituted or unsubstituted C2–C3 heterocycloalkyl. [0087] In some embodiments, RA2 is H. In some embodiments, RA2 is halogen. In some embodiments, RA2 is F or Cl. In some embodiments, RA2 is –OR1. In some embodiments, RA2 is substituted or unsubstituted C1–C4 alkyl. In some embodiments, RA2 is substituted or unsubstituted C1–C4 haloalkyl. In some embodiments, RA2 is substituted or unsubstituted C1–C4 heteroalkyl. In some embodiments, RA2 is substituted or unsubstituted C3–C4 cycloalkyl. In some embodiments, RA2 is substituted or unsubstituted C2–C3 heterocycloalkyl. [0088] In some embodiments, RA3 is H. In some embodiments, RA3 is halogen. In some embodiments, RA3 is F or Cl. In some embodiments, RA3 is –OR1. In some embodiments, RA3 is substituted or unsubstituted C1–C4 alkyl. In some embodiments, RA3 is substituted or unsubstituted C1–C4 haloalkyl. In some embodiments, RA3 is substituted or unsubstituted C1–C4 heteroalkyl. In some embodiments, RA3 is substituted or unsubstituted C3–C4 cycloalkyl. In some embodiments, RA3 is substituted or unsubstituted C2–C3 heterocycloalkyl. - 25 - WSGR Docket No.51503-744601 [0089] In some embodiments, Z is CR2, wherein R2 is hydrogen. In some embodiments, Z is CR2, wherein R2 is C1–C4 alkyl. [0090] In some embodiments, W is substituted or unsubstituted C1-C3 alkylene. In some embodiments, W is substituted or unsubstituted C2-C3 alkenylene. In some embodiments, W is substituted or unsubstituted C3–C8 cycloalkylene. In some embodiments, W is substituted or unsubstituted C2–C7 heterocycloalkylene. In some embodiments, W is unsubstituted C1-C3 alkylene. In some embodiments, W is unsubstituted C2 alkylene. In some embodiments, W is C1- C3 alkylene substituted with halogen. In some embodiments, W is substituted with one or more substituents selected from halogen, OH, C1–C4 alkyl, and amino. In some embodiments, W is C1- C3 alkylene substituted with F. In some embodiments, W is -CH2CF2-. [0091] In some embodiments, R1 is hydrogen. In some embodiments, R1 is substituted or unsubstituted C1–C4 alkyl. In some embodiments, R1 is substituted or unsubstituted C1–C4 haloalkyl. In some embodiments, R1 is substituted or unsubstituted C1–C4 heteroalkyl. In some embodiments, R1 is substituted or unsubstituted C3–C6 cycloalkyl. In some embodiments, R1 is substituted or unsubstituted C2–C5 heterocycloalkyl. In some embodiments, R1 is substituted or unsubstituted aryl. In some embodiments, R1 is or substituted or unsubstituted heteroaryl. [0092] In one aspect, described herein is a compound that has the structure of Formula (II)
Figure imgf000027_0001
Formula (II) wherein, RA is hydrogen, F, Cl, –OR1, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C4 cycloalkyl, or substituted or unsubstituted C2–C3 heterocycloalkyl; ring B is saturated or unsaturated, substituted or unsubstituted monocyclic heterocyclic ring; ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Z is CR2; - 26 - WSGR Docket No.51503-744601 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; 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; each R1 is independently hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is hydrogen, substituted or unsubstituted C1–C4 alkyl, or substituted or unsubstituted C1–C4 haloalkyl; each R4 and R5 is independently H, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, -N(R7)2, -CH2OR7, -C(=O)R7, -C(=O)OR7, - C(=O)N(R7)2, -S(=O)R7, -S(=O)2R7, or -NR7C(=O)R7; R6 is -C(=O)R7, -C(=O)OR7, -C(=O)N(R8)2, -C=(O)N(OR7)(R7), -P(=O)(R8)2, - P(=O)(R8)N(R8)2, -S(=O)R8, -S(=O)2R8, -S(=O)(=NR7)R7, -N(R8)C(=O)R8, N(R8)S(=O)R8, N(R8)S(=O)2R8, -C(=O)N(R8)S(=O)2R8, -N(R8)C(=O)N(R8)2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R7 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R8 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, -N(R7)2, -CH2OR7, -C(=O)R7, -C(=O)OR7, -C(=O)N(R7)2, -S(=O)R7, - S(=O)2R7, or -NR7C(=O)R7; or two R8 groups on the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted C2- C10heterocycloalkyl; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; - 27 - WSGR Docket No.51503-744601 each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; a is 0 or 1; b is 0; c is 0, 1, or 2; and d is 0, 1, or 2, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof. [0093] In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, a is 0 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, c is 0 and d is 0. In some embodiments, c is 0 and d is 1. In some embodiments, c is 1 and d is 0. In some embodiments, c is 1 and d is 1. [0094] In some embodiments, described herein is a compound of Formula (II). In some embodiments, described herein is a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of a compound of Formula (II). [0095] In some embodiments, the compound of Formula (II) has the structure of Formula (IIa):
Figure imgf000029_0001
[0096] In some embodiments, the compound of Formula (II) has the structure of Formula (IIb): - 28 - WSGR Docket No.51503-744601
Figure imgf000030_0001
[0097] In some embodiments, the compound of Formula (II) has the structure of Formula (IIc):
Figure imgf000030_0002
[0098] In some embodiments, the compound of Formula (II) has the structure of Formula (IId):
Figure imgf000030_0003
- 29 - WSGR Docket No.51503-744601 Formula (IId). [0099] In some embodiments, the compound of Formula (II) has the structure of Formula (IIe):
Figure imgf000031_0001
[0100] In some embodiments, the compound of Formula (II) has the structure of Formula (IIf):
Figure imgf000031_0002
[0101] In some embodiments, the compound of Formula (II) has the structure of Formula (IIg): - 30 - WSGR Docket No.51503-744601
Figure imgf000032_0001
Formula (IIg). [0102] In some embodiments, a compound of Formula (II) has a structure of formula (IIh):
Figure imgf000032_0002
[0103] In some embodiments, W is substituted or unsubstituted C1-C3 alkylene. In some embodiments, W is 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 C1-C3 alkylene. In some embodiments, W is C1-C3 alkylene substituted with halogen. In some embodiments, W is C1-C3 alkylene substituted with F. In some embodiments, W is substituted with one or more substituents selected from halogen, OH, C1–C4 alkyl, and amino. In some embodiments, W is -CH2CF2-. [0104] In some embodiments, R is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C5 cycloalkyl, or substituted or unsubstituted C2–C4 heterocycloalkyl. In some embodiments, R is hydrogen. In some embodiments, R is -CH3, - CH2CH3, -CH2F, -CHF2, or -CF3. [0105] In some embodiments, R16 is hydrogen. In some embodiments, R16 is halogen. In some embodiments, R16 is F. In some embodiments, R17 is hydrogen. In some embodiments, R17 is halogen. In some embodiments, R17 is F. In some embodiments, each R15 and R18 is - 31 - WSGR Docket No.51503-744601 independently selected from hydrogen, deuterium, F, -CH3, and -OCH3. In some embodiments, R15 and R18 are both hydrogen. In some embodiments, R15 and R18 are both -CH3. In some embodiments, R15 is hydrogen and R18 is -CH3. In some embodiments, R15 is -CH3 and R18 is hydrogen. [0106] In some embodiments, each R4 and R5 is independently hydrogen, and R6 is -C(=O)R7, - C(=O)OR7, -C(=O)N(R8)2. In some embodiments, each R4 and R5 is independently hydrogen, and R6 is -C(=O)NHCH3 or -C(=O)N(CH3)2. In some embodiments, each R4 and R5 is independently hydrogen, and R6 is -C(=O)NHCH3. In some embodiments, each R4 and R5 is independently hydrogen, and R6 is substituted or unsubstituted heteroaryl. In some embodiments, each R4 and R5 is independently hydrogen, and R6 is unsubstituted heteroaryl. [0107] In some embodiments, ring B is 5-, 6-, 7-, or 8- membered heterocyclic ring. In some embodiments, ring B is 5-membered heterocyclic ring. In some embodiments, ring B is 5- membered heterocyclic ring having 1, 2, or 3 nitrogen atoms. In some embodiments, ring B is 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. In some embodiments, ring B is 6- membered heterocyclic ring. In some embodiments, ring B is 6- membered heterocyclic ring having 1, 2, or 3 nitrogen atoms. In some embodiments, ring B is 6- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. In some embodiments, ring B is 6- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 sulfur atom. In some embodiments, ring B is saturated. In some embodiments, ring B is unsaturated. In some embodiments, ring B contains one carbon-carbon double bond. In some embodiments, ring B contains two carbon-carbon double bonds. In some embodiments, ring B contains three carbon-carbon double bonds. [0108] In some embodiments, ring B is a 5-memjbered heterocyclic ring selected from:
Figure imgf000033_0001
- 32 - WSGR Docket No.51503-744601
Figure imgf000034_0002
. [0110] In some embodiments, ring B is 6- membered heterocyclic ring selected from:
Figure imgf000034_0001
- 33 - WSGR Docket No.51503-744601
Figure imgf000035_0001
, - 34 - WSGR Docket No.51503-744601
Figure imgf000036_0001
wherein each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1- C4alkyl, or substituted or unsubstituted C1-C4haloalkyl; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; or two Rz taken together form an oxo.
Figure imgf000036_0002
[0112] In some embodiments, ring B is 6- membered heterocyclic ring selected from: - 35 - WSGR Docket No.51503-744601
Figure imgf000037_0001
wherein each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1- C4alkyl, or substituted or unsubstituted C1-C4haloalkyl; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; or two Rz taken together form an oxo. In some embodiments, Rz is hydrogen. In some embodiments, Rz is methyl. - 36 - WSGR Docket No.51503-744601 [0113] In some embodiments, ring
Figure imgf000038_0001
. some embodiments, ring B is
Figure imgf000038_0002
some embodiments, ring
Figure imgf000038_0003
. some embodiments, ring B is some embodiments, ring
Figure imgf000038_0004
. some embodiments, ring B is some embodiments, ring
Figure imgf000038_0006
. some embodiments, ring B is
Figure imgf000038_0005
. some embodiments, ring
Figure imgf000038_0007
Figure imgf000038_0008
- 37 - WSGR Docket No.51503-744601
Figure imgf000039_0002
. [0114] In some embodiments, ring B is 6- membered heterocyclic ring selected from: ,
Figure imgf000039_0001
. [0115] In some embodiments, ring B is 7- membered heterocyclic ring. In some embodiments, ring B is 7- membered heterocyclic ring having 1, 2, or 3 nitrogen atoms. In some embodiments, ring B is 7- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. In some embodiments, ring B is 7- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 sulfur atom. In some embodiments, ring B is 7- membered heterocyclic ring selected from: - 38 - WSGR Docket No.51503-744601
Figure imgf000040_0001
, - 39 - WSGR Docket No.51503-744601
Figure imgf000041_0001
wherein each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted C1-C4haloalkyl; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; or two Rz taken together form an oxo. [0116] In some embodiments, ring B is 7- membered heterocyclic ring selected from:
Figure imgf000041_0002
wherein each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted C1-C4haloalkyl; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; or two Rz taken together form an oxo. [0117] In some embodiments, ring B is 7- membered heterocyclic ring selected from: - 40 - WSGR Docket No.51503-744601
Figure imgf000042_0001
. [0118] In some embodiments, ring B is
Figure imgf000042_0002
Figure imgf000042_0003
. [0119] In some embodiments, ring B is 6- membered heterocyclic ring selected from: - 41 - WSGR Docket No.51503-744601
Figure imgf000043_0001
- 42 - WSGR Docket No.51503-744601 [0120] wherein each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted C1-C4haloalkyl, or two Rz taken together form an oxo; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl. [0121] In some embodiments ring B is 6- membered heterocyclic ring selected from: ,
Figure imgf000044_0001
[0122] wherein each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted C1-C4haloalkyl, or two Rz taken together form an oxo; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl. In some embodiments, each Rz is independently hydrogen.
Figure imgf000044_0002
- 43 - WSGR Docket No.51503-744601
Figure imgf000045_0001
. [0124] In some embodiments ring B is 6- membered heterocyclic ring selected from:
Figure imgf000045_0002
. [0125] In some embodiments ring B is 7- membered heterocyclic ring. In some embodiments ring B is 7- membered heterocyclic ring having 1, 2, or 3 nitrogen atoms. In some embodiments ring B is 7- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. In some embodiments ring B is 7- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 sulfur atom. In some embodiments ring B is 7- membered heterocyclic ring selected from: - 44 - WSGR Docket No.51503-744601
Figure imgf000046_0001
, - 45 - WSGR Docket No.51503-744601
Figure imgf000047_0001
[0126] wherein each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted C1-C4haloalkyl, or two Rz taken together form an oxo; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl. [0127] In some embodiments ring B is 7- membered heterocyclic ring selected from:
Figure imgf000047_0002
[0128] wherein each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted C1-C4haloalkyl, or two Rz taken together form an oxo; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl. [0129] In some embodiments ring B is 7- membered heterocyclic ring selected from: - 46 - WSGR Docket No.51503-744601
Figure imgf000048_0001
. [0131] In some embodiments, each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1-C4alkyl, or substituted or unsubstituted C1-C4haloalkyl; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl. In some embodiments, two Rz taken together form an oxo. In some embodiments, each Rz is independently hydrogen, F, -CN, - OCH3, -OCF3, substituted or unsubstituted C1–C4 alkyl, or substituted or unsubstituted C1–C4 haloalkyl. In some embodiments, each Rz is independently hydrogen, F, -CN, -OCH3, -OCF3, - CH3, or -CF3. In some embodiments, each Rz is hydrogen. [0132] It is understood that throughout the disclosure for the compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig) and Formula (Ih), a carbon-carbon bond at ring B that is shared with the aromatic ring bearing A1, A2, and A3 variables, is a part of the aromatic ring bearing A1, A2, and A3 variables, and is not taken into account for the degree of saturation of ring B. It is understood that throughout the disclosure for the compounds of Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), - 47 - WSGR Docket No.51503-744601 Formula (IId), Formula (IIe), Formula (IIf), Formula (IIg) and Formula (IIh), a carbon-carbon bond at ring B that is shared with pyridazine, is a part of the aromatic pyridazine ring, and is not taken into account for the degree of saturation of ring B. [0133] In some embodiments, ring Q is unsubstituted 2-hydroxy-phenyl. In some embodiments, ring Q is 2–hydroxy–phenyl substituted with 1, 2, or 3 substituents independently selected from: deuterium, halogen, oxo, -OH, -NO2, -CN, -SR1, -S(=O)R1, -S(=O)2R1, -N(R1)2, -C(=O)R1, - OC(=O)R1, -C(=O)OR1, -C(=O)N(R1)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; and each R1 is independently deuterium, hydrogen, substituted or unsubstituted C1–C4 alkyl, -CD3, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0134] In some embodiments, ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [0135] In some embodiments, ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted heteroaryl, wherein if heteroaryl is substituted then it is substituted with 1 or 2 substituents independently selected from: deuterium, halogen, oxo, -OH, -NO2, -CN, –SR1, – S(=O)R1, –S(=O)2R1, –N(R1)2, –C(=O)R1, –OC(=O)R1, –C(=O)OR1, –C(=O)N(R1)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; and each R1 is independently hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, -CD3, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0136] In some embodiments,
Figure imgf000049_0001
, wherein each RQ is independently selected from hydrogen, –F, –Cl, -CN, –OH, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, –CF3, –OCH3, -OCH2CH3, -CH2OCH3, -OCH2CH2CH3, and -OCH(CH3)2. - 48 - WSGR Docket No.51503-744601 [0137] In some embodiments, ring Q is substituted or unsubstituted heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl. In some embodiments, ring Q is substituted or unsubstituted 6-membered monocyclic heteroaryl.
Figure imgf000050_0002
some embodiments,
Figure imgf000050_0001
, - 49 - WSGR Docket No.51503-744601
Figure imgf000051_0001
[0139] In some embodiments, each RQ is independently hydrogen, deuterium, –F, –Cl, -CN, – OH, -CH3,–CF3, or –OCH3. In some embodiments, each RQ is independently hydrogen or –F. In some embodiments, each RQ is hydrogen. [0140] In some embodiments, R4 is H. In some embodiments, R4 is deuterium. In some embodiments, R4 is halogen. In some embodiments, R4 is substituted or unsubstituted C1- C6alkyl. In some embodiments, R4 is substituted or unsubstituted C1-C6haloalkyl. In some embodiments, R4 is substituted or unsubstituted aryl. In some embodiments, R4 is substituted or unsubstituted monocyclic heteroaryl. In some embodiments, R4 is -OR7. In some embodiments, R4 is -N(R7)2. In some embodiments, R4 is -CH2OR7. In some embodiments, R4 is -C(=O)R7. In some embodiments, R4 is - C(=O)OR7. In some embodiments, R4 is -C(=O)N(R7)2. In some embodiments, R4 is -S(=O)R7. In some embodiments, R4 is -S(=O)2R7. In some embodiments, R4 is -NR7C(=O)R7. [0141] In some embodiments, R5 is H. In some embodiments, R5 is deuterium. In some embodiments, R5 is halogen. In some embodiments, R5 is substituted or unsubstituted C1- C6alkyl. In some embodiments, R5 is substituted or unsubstituted C1-C6haloalkyl. In some embodiments, R5 is substituted or unsubstituted aryl. In some embodiments, R5 is substituted or unsubstituted monocyclic heteroaryl. In some embodiments, R5 is -OR7. In some embodiments, R5 is -N(R7)2. In some embodiments, R5 is -CH2OR7. In some embodiments, R5 is -C(=O)R7. In some embodiments, R5 is - C(=O)OR7. In some embodiments, R5 is -C(=O)N(R7)2. In some embodiments, R5 is -S(=O)R7. In some embodiments, R5 is -S(=O)2R7. In some embodiments, R5 is -NR7C(=O)R7. [0142] In some embodiments, R4 and R5 are each independently hydrogen, deuterium, or C1- C4alkyl. In some embodiments, R4 and R5 are each independently hydrogen, -CH3, -CH2CH3, - CH(CH3)2, -CF3, or cyclopropyl. In some embodiments, R4 and R5 are each independently hydrogen, -CH3, -CH(CH3)2, -CF3, or cyclopropyl. In some embodiments, R4 and R5 are each independently hydrogen, -CH3, or -CF3. In some embodiments, R4 and R5 are each hydrogen. - 50 - WSGR Docket No.51503-744601 [0143] In some embodiments, R4 is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or cyclopropyl. In some embodiments, R4 is hydrogen. In some embodiments, R4 is -CH3. In some embodiments, R5 is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or cyclopropyl. In some embodiments, R5 is hydrogen. In some embodiments, R5 is -CH3. [0144] In some embodiments, R6 is -C(=O)R7, -C(=O)OR7, -C(=O)N(R8)2. In some embodiments, R6 is -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, or -C(=O)N(CH3)2. In some embodiments, R6 is -C(=O)NHCH3 or - C(=O)N(CH3)2. In some embodiments, R6 is -C(=O)NHCH3. [0145] In some embodiments, R6 is -C(=O)R7, -C(=O)OR7, -C(=O)N(R8)2, -C=(O)N(OR7)(R7), -P(=O)(R8)2, -P(=O)(R8)N(R8)2, -S(=O)R8, -S(=O)2R8, -S(=O)(=NR7)R7, -N(R8)C(=O)R8, N(R8)S(=O)R8, N(R8)S(=O)2R8, -C(=O)N(R8)S(=O)2R8, -N(R8)C(=O)N(R8)2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R6 is - C(=O)R7. In some embodiments, R6 is -C(=O)OR7. In some embodiments, R6 is -C(=O)N(R8)2. In some embodiments, R6 is -C=(O)N(OR7)(R7). In some embodiments, R6 is -P(=O)(R8)2. In some embodiments, R6 is -P(=O)(R8)N(R8)2. In some embodiments, R6 is -S(=O)R8. In some embodiments, R6 is -S(=O)2R8. In some embodiments, R6 is -S(=O)(=NR7)R7. In some embodiments, R6 is -N(R8)C(=O)R8. In some embodiments, R6 is N(R8)S(=O)R8. In some embodiments, R6 is N(R8)S(=O)2R8. In some embodiments, R6 is -C(=O)N(R8)S(=O)2R8. In some embodiments, R6 is -N(R8)C(=O)N(R8)2. In some embodiments, R6 is substituted or unsubstituted cycloalkyl. In some embodiments, R6 is substituted or unsubstituted heterocycloalkyl. In some embodiments, R6 is substituted or unsubstituted aryl. In some embodiments, R6 is substituted or unsubstituted heteroaryl. [0146] In some embodiments, R6 is substituted or unsubstituted 4-membered cycloalkyl. In some embodiments, R6 is substituted or unsubstituted 5-membered cycloalkyl. In some embodiments, R6 is substituted or unsubstituted 6-membered cycloalkyl. In some embodiments, R6 is substituted or unsubstituted 5-membered heterocycloalkyl. In some embodiments, R6 is substituted or unsubstituted 6-membered heterocycloalkyl. In some embodiments, R6 is substituted or unsubstituted 6-membered heterocycloalkyl containing 1-3 nitrogens, 0-1 oxygen and 0-1 sulfur. In some embodiments, R6 is substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R6 is substituted or unsubstituted 5-membered heteroaryl containing 1-4 nitrogens, 0-1 oxygen and 0-1 sulfur. In some embodiments, R6 is substituted or unsubstituted aryl. In some embodiments, R6 is cycloalkyl, heterocycloalkyl, heteroaryl, or aryl, each optionally substituted with one or more substituents selected from D, oxo, =S, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, - - 51 - WSGR Docket No.51503-744601 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 embodiments, R6 is cycloalkyl, heterocycloalkyl, heteroaryl, or aryl, each optionally substituted with one or more substituents selected from halogen, oxo, =S, C1-C4 alkyl, C1-C4 haloalkyl, OH, CN, and C1-C4 alkoxy. [0147] In some embodiments, two R8 groups on the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted C2- C10heterocycloalkyl. [0148] In some embodiments, each R7 is independently H. In some embodiments, each R7 is independently substituted or unsubstituted C1-C6alkyl. In some embodiments, R7 is independently substituted or unsubstituted C1-C6haloalkyl. In some embodiments, R7 is independently substituted or unsubstituted C1-C6heteroalkyl. In some embodiments, R7 is independently substituted or unsubstituted C3-C8cycloalkyl. In some embodiments, R7 is independently substituted or unsubstituted C2-C7heterocycloalkyl. In some embodiments, R7 is independently substituted or unsubstituted aryl. In some embodiments, R7 is independently substituted or unsubstituted heteroaryl. In some embodiments, each R7 is independently H or substituted or unsubstituted C1-C6alkyl. In some embodiments, each R7 is independently H or substituted or unsubstituted C1-C3alkyl. In some embodiments, R7 is H. In some embodiments, R7 is methyl. [0149] In some embodiments, each R4 and R5 is independently H, D, halogen, or substituted or unsubstituted C1-C6alkyl. In some embodiments, each R4 and R5 is hydrogen. In some embodiments, R4 is hydrogen and R5 is CH3. In some embodiments, R4 is CH3 and R5 is hydrogen. [0150] In some embodiments, R6 is -C(=O)OH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, - C(=O)NH(OH), -C(=O)NH(OCH3), -C(=O)N(CH3)OH, C(=O)N(CH3)OCH3, - N(C(=O)CH3)OH, -O-NH(C(=O)CH3), -P(=O)(OH)2, -PH(=O)(OH), -S(=O)2OH, -S(=O)OH, - S(=O)2CH3, -S(=O)CH3, -S(=O)2NH2, -S(=O)NH2, -S(=O)2NH(CH3), -S(=O)NH(CH3), - S(=O)2N(CH3)2, -S(=O)N(CH3)2, -S(=O)(=NH)CH3, -S(=O)(=NCH3)CH3, -NH(S(=O)2CH3), - C(=O)NH(S(=O)2CH3), -C(=O)NH(S(=O)2N(CH3)2), -NHC(=O)NH(S(=O)2CH3), or - NHC(=O)NH(C(=O)CH3). [0151] In some embodiments, R6 is optionally substituted C1-C4alkyl or C1-C4heteroalkyl. In some embodiments, R6 is C1-C4alkyl or C1-C4heteroalkyl optionally substituted with cycloalkyl, heterocycloalkyl, heteroaryl, or aryl, each of which is monocyclic or bicyclic and each of which is optionally substituted. In some embodiments, R6 is C1-C4alkyl or C1-C4heteroalkyl optionally substituted with 3-6 membered cycloalkyl, heterocycloalkyl, heteroaryl, or aryl, each of which is - 52 - WSGR Docket No.51503-744601 optionally substituted with one or more substituents selected from D, oxo, 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 embodiments, the cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is each optionally substituted with one or more substituents selected from halogen, oxo, =S, C1-C4 alkyl, C1-C4 haloalkyl, OH, CN, and C1-C4 alkoxy.
Figure imgf000054_0001
embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. [0153] In some embodiments, each R8 is independently H, substituted or unsubstituted C1- C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, -N(R7)2, -CH2OR7, -C(=O)R7, - C(=O)OR7, - C(=O)N(R7)2, -S(=O)R7, -S(=O)2R7, or -NR7C(=O)R7. In some embodiments, each R8 is independently H. In some embodiments, each R8 is independently substituted or unsubstituted C1-C6alkyl. In some embodiments, each R8 is independently substituted or unsubstituted C1-C6haloalkyl. In some embodiments, each R8 is independently substituted or unsubstituted aryl. In some embodiments, each R8 is independently substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R8 is independently -OR7. In some embodiments, each R8 is independently -N(R7)2. In some embodiments, each R8 is independently -CH2OR7. In some embodiments, each R8 is independently -C(=O)R7. In some - 53 - WSGR Docket No.51503-744601 embodiments, each R8 is independently -C(=O)OR7. In some embodiments, each R8 is independently - C(=O)N(R7)2. In some embodiments, each R8 is independently -S(=O)R7. In some embodiments, each R8 is independently -S(=O)2R7. In some embodiments, each R8 is independently -NR7C(=O)R7. [0154] In some embodiments, two R8 groups on the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted C2- C10heterocycloalkyl. [0155] In some embodiments, 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 substituted C2 alkylene. In some embodiments, W is C2 alkylene substituted with halo. In some embodiments, W is C2 alkylene substituted with F. In some embodiments, W is CH2CF2. [0156] In some embodiments, R is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C5 cycloalkyl, or substituted or unsubstituted C2–C4 heterocycloalkyl. In some embodiments, R is hydrogen. In some embodiments, R is substituted or unsubstituted C1–C4 alkyl. In some embodiments, R is substituted or unsubstituted C1–C4 fluoroalkyl. In some embodiments, R is substituted or unsubstituted C1–C4 heteroalkyl. In some embodiments, R is substituted or unsubstituted C3–C5 cycloalkyl. In some embodiments, R is substituted or unsubstituted C2–C4 heterocycloalkyl. In some embodiments, R is -CH3, - CH2CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R is hydrogen. [0157] 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. - 54 - WSGR Docket No.51503-744601 [0158] In some embodiments, one or more of R11, R12, and R16 is independently selected from F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl. In some embodiments, one or more of R11, R12, and R16 is independently selected from F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, - CHF2, and -CF3. In some embodiments, R11, R12, and R16 are hydrogen. In some embodiments, one or more of R16 and R17 is independently selected from F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl. In some embodiments, R11 and R13 are each hydrogen, and R12 and R14 are each C1-C3alkyl. In some embodiments, R11 and R13 are each hydrogen, and R12 and R14 are each methyl. [0159] In some embodiments, one or more of R16 and R17 is independently selected from F, - OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. In some embodiments, R16 and R17 are hydrogen. In some embodiments, each R16, R15, and R20 is independently hydrogen, and R19 is halogen. In some embodiments, each R16, R15, and R20 is independently hydrogen, and R19 is F. [0160] In some embodiments, R2 is hydrogen, -CH3, or -OCH3. In some embodiments, R2 is hydrogen. In some embodiments, R2 is substituted or unsubstituted C1–C4 alkyl. In some embodiments, R2 is substituted or unsubstituted C1–C4 haloalkyl. [0161] In some embodiments, each R15 and R18 is independently selected from hydrogen, deuterium, F, –OR1, substituted or unsubstituted C1–C3 alkyl, substituted or unsubstituted C1–C3 fluoroalkyl, and substituted or unsubstituted C1–C3 heteroalkyl. [0162] In some embodiments, each R15 and R18 is independently selected from hydrogen, deuterium, F, -CH3, and -OCH3. In some embodiments, R15 and R18 are both hydrogen. In some embodiments, R15 and R18 are both -CH3. In some embodiments, R15 is hydrogen and R18 is - CH3. In some embodiments, R15 is -CH3 and R18 is hydrogen. [0163] In some embodiments, R15 and R18 are selected from hydrogen, deuterium, F, –OR1, 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. - 55 - WSGR Docket No.51503-744601 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. [0164] In some embodiments, one or more of R19 and R20 is independently selected from F, - OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. In some embodiments, R19 is F. In some embodiments, R20 is F. In some embodiments, R19 is hydrogen. In some embodiments, R20 is hydrogen. In some embodiments, R19 and R20 are hydrogen. In some embodiments, R19 is independently selected from H, F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and - CF3. In some embodiments, R19 is H or F. In some embodiments, R20 is independently selected from H, F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. In some embodiments, R20 is H or F. [0165] In some embodiments, R11 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, R11 is H, D, or F. In some embodiments, R11 is D. In some embodiments, R11 is H. In some embodiments, R11 is F. [0166] In some embodiments, R12 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, R12 is H, D, or F. In some embodiments, R12 is D. In some embodiments, R12 is H. In some embodiments, R12 is F. [0167] In some embodiments, R13 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, R13 is H, D, or F. In some embodiments, R13 is D. In some embodiments, R13 is H. In some embodiments, R13 is F. [0168] In some embodiments, R14 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, R14 is H, D, or F. In some embodiments, R14 is D. In some embodiments, R14 is H. In some embodiments, R14 is F. [0169] In some embodiments, R15 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, 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. [0170] In some embodiments, R16 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, R16 is H, D, or F. In some embodiments, R16 is D. In In some embodiments, R16 is H. some embodiments, R16 is F. [0171] In some embodiments, R17 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, R17 is H, D, or F. In some embodiments, R17 is D. In some embodiments, R17 is H. In some embodiments, R17 is F. [0172] In some embodiments, R18 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, R18 is H, D, F, CH2F, CHF2, CF3, or CH3. In some embodiments, R18 is H or D. In - 56 - WSGR Docket No.51503-744601 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. [0173] In some embodiments, R19 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, 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. [0174] In some embodiments, 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 -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, H, D, or F. In some embodiments, R20 is H, F, -OH, - OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. In some embodiments, R20 is F or - OCH3. [0175] In some embodiments, at least one of R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 is F. In some embodiments, one of R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 is F. In some embodiments, at least two of R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 are F. In some embodiments, at least one of R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 is F. In some embodiments, one of R11, R12, R13, R14, R16, and R17 is F. In some embodiments, at least two of R11, R12, R13, R14, R16, and R17 are F. [0176] In some embodiments, 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. In some embodiments, at least one of W, R11, R12, R13, R14, R15, R16, R17, and R18 comprises a fluorine, e.g., F or C1–C4 fluoroalkyl such as CH2F, CF3, CHF2, and CH3CH2F. In some embodiments, one of W, R11, R12, R13, R14, R15, R16, R17, and R18 comprises a fluorine. In some embodiments, W comprises a fluorine. [0177] In some embodiments, A1 is N. In some embodiments, A1 is CRA1. In some embodiments, RA1 is hydrogen, F, Cl, or -CH3. In some embodiments, RA1 is hydrogen. In some embodiments, RA1 is deuterium. - 57 - WSGR Docket No.51503-744601 [0178] In some embodiments, A2 is N. In some embodiments, A2 is CRA2. In some embodiments, RA2 is hydrogen, F, Cl, or -CH3. In some embodiments, RA2 is hydrogen. In some embodiments, RA2 is deuterium. [0179] In some embodiments, A3 is N. In some embodiments, A3 is CRA3. In some embodiments, RA3 is hydrogen, F, Cl, or -CH3. In some embodiments, RA3 is hydrogen. In some embodiments, RA3 is deuterium. [0180] In some embodiments, the abundance of deuterium in each of RA, RA1, RA2, RA3, RQ, RZ, R1, R2, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17, R18, R19, and/or R20 is independently at least 1%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium. In some embodiments, one or more of RA, RA1, RA2, RA3, RQ, RZ, R1, R2, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17, R18, R19, and/or R20 groups comprise deuterium at a percentage higher than the natural abundance of deuterium. [0181] In some embodiments, RA, RA1, RA2, RA3, RQ, RZ, R1, R2, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17, R18, R19, and/or R20 are substituted with one or more group(s) individually and independently selected from 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 embodiments, RA, RA1, RA2, RA3, RQ, RZ, R1, R2, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17, R18, R19, and/or R20 are substituted with one or more group(s) individually and independently selected from halogen (e.g., F), -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1- C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl, and -S(=O)2(C1-C4 alkyl). In some embodiments, RA1, RA2, RA3, RQ, RZ, R1, R2, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17, R18, R19, and/or R20 are substituted with one or more group(s) individually and independently selected from halogen (e.g., F), -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 on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O). [0182] In one aspect, disclosed herein is a method of modulating splicing comprising contacting a compound of any one of the preceding claims to cells, wherein the compound modulates - 58 - WSGR Docket No.51503-744601 splicing at a splice site sequence of a pre-mRNA that encodes a mRNA, wherein the mRNA encodes a target protein or a functional RNA. [0183] In one aspect, disclosed herein is a method of treating a disease or condition comprising administering a compound of the present invention. [0184] In some embodiments, disclosed herein is a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of a compound from Tables 1-4. In some embodiments, disclosed herein is a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6. [0185] In some embodiments, an SMSM 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. [0186] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active - 59 - WSGR Docket No.51503-744601 moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. [0187] In one aspect, prodrugs are designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacokinetic, pharmacodynamic processes and drug metabolism in vivo, once a pharmaceutically active compound is known, the design of prodrugs of the compound is possible. (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series). [0188] In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound. [0189] In some embodiments, sites on the aromatic ring portion of compounds described herein are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group. [0190] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. [0191] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36 cl. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain - 60 - WSGR Docket No.51503-744601 therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. [0192] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect. [0193] Compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. [0194] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms, particularly solvates. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of compounds described herein are conveniently prepared or formed - 61 - WSGR Docket No.51503-744601 during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. [0195] In some embodiments, an SMSM has a molecular weight of at most about 2000 Daltons, 1500 Daltons, 1000 Daltons or 900 Daltons. In some embodiments, an SMSM has a molecular weight of at least 100 Daltons, 200 Daltons, 300 Daltons, 400 Daltons or 500 Daltons. In some embodiments, an SMSM does not comprise a phosphodiester linkage. Methods of Making Compounds [0196] 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 can be available from commercial sources or can be readily prepared. By way of example only, provided are schemes for preparing the exemplary SMSMs. Boronic Acid Intermediate Synthesis [0197] Synthesis of (E)-3-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan- 2-yl)phenyl)-N-methylacrylamide (B1).
Figure imgf000063_0001
- 62 - WSGR Docket No.51503-744601 [0198] Step 1: Synthesis of 1-bromo-4-iodo-2-(methoxymethoxy)benzene. NaH (2.76 g, 68.8 mmol, 60% in mineral oil) was added to a solution of 2-bromo-5-iodophenol (10.3 g, 34.4 mmol) in DMF (50 mL) at 0 oC. The mixture was stirred at 0 ºC for 30 min before adding bromomethyl methyl ether (4 mL, 32 mmol). The resulting mixture was stirred for additional 30 min before being quenched with water (200 mL). The mixture was extracted EtOAc (200 mL x 2). The combined extracts were washed with water (100 mL x 3), brine (100 mL x 2), dried over Na2SO4, and concentrated to give the title compound (10.9 g, 92% yield) as a brown oil which was used without further purification in the next step.1HNMR (400 MHz, CDCl3): 7.45 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.21 (dd, J = 8.4 Hz, 1.6 Hz, 1H) 5.22 (s, 2H), 3.51 (s, 3H). [0199] Step 2: Synthesis of (E)-ethyl 3-(4-bromo-3-(methoxymethoxy)phenyl)acrylate. A mixture of 1-bromo-4-iodo-2-(methoxymethoxy)benzene (2.0 g, 5.8 mmol), ethyl acrylate (580 mg, 5.8 mmol), Pd(OAc)2 (130 mg, 0.58 mmol), P(o-tol)3 (530 mg, 1.74 mmol) and TEA (1.17 g, 11.6 mmol) in 10 mL of CH3CN was purged with nitrogen and sealed. The mixture was stirred at 80 oC for 3 h, concentrated and purified by silica gel chromatography (0-18% EtOAc/petroleum ether) to give the title compound (1.6 g, 80% yield) as a colorless oil. LCMS: m/z 314.8 [M+H]+; tR = 1.70 min. [0200] Step 3: Synthesis of (E)-3-(4-bromo-3-(methoxymethoxy)phenyl)acrylic acid. A solution of NaOH (366 mg, 9.16 mmol) in H2O (15 mL) was added slowly to a stirred solution of (E)-ethyl 3-(4-bromo-3-(methoxymethoxy)phenyl)acrylate (1.44 g, 4.58 mmol) in MeOH (15 mL) at rt. Then the mixture was stirred at 50 oC for 16 h and cooled to room temperature. HCl (2N aqueous solution) was added to adjust pH = 3. The mixture was then extracted with EtOAc (50 mL x 3), dried over anhydrous Na2SO4, and concentrated to give the title compound (1.17 g, 89% yield) as a white solid, which was used directly in the next step. LCMS: m/z 286.9 [M+H]+; tR = 1.39 min. [0201] Step 4: Synthesis of (E)-3-(4-bromo-3-(methoxymethoxy)phenyl)-N- methylacrylamide. A mixture of (E)-3-(4-bromo-3-(methoxymethoxy)phenyl)acrylic acid (883 mg, 3.08 mmol), methylamine hydrochloride (419 mg, 6.16 mmol), HATU (1.4 g, 3.70 mmol) and DIPEA (1.99 g, 15.4 mmol) in 5 mL of DMF was stirred at room temperature for 2 h. The mixture was quenched with water (60 mL), extracted with EtOAc (60 mL x 3), and concentrated to give the title compound (1.08 g, 89% yield) as a yellow solid, which was used directly to next step without further purification. LCMS: m/z 301.9 [M+H]+; tR = 1.31 min. [0202] Step 5: Synthesis of (E)-3-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-N-methylacrylamide (B1). A mixture of (E)-3-(4-bromo-3- (methoxymethoxy)phenyl)-N-methylacrylamide (300 mg, 1.0 mmol.), 4,4,4',4',5,5,5',5'- - 63 - WSGR Docket No.51503-744601 octamethyl-2,2'-bi(1,3,2-dioxaborolane) (507 mg 2.0 mmol), Pd(dppf)Cl2 (111 mg, 0.15 mmol), and KOAc (198 mg, 2.0 mmol) in 3 mL of 1,4-dioxane was degassed with nitrogen and stirred at 100 oC for 3 h. The mixture was cooled to room temerature, concentrated, and purified by silica gel chromatography (0-50% EtOAc/petroleum ether) to give the title compound (502 mg, 100% yield) as a brown oil LCMS: m/z 348.1 [M+H]+; tR = 1.48 min. [0203] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 1:
Figure imgf000065_0001
each A is independently N or CRQ as described above. [0204] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 2:
Figure imgf000065_0002
each A is independently N or CRQ as described above. [0205] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 3: - 64 - WSGR Docket No.51503-744601
Figure imgf000066_0001
each A is independently N or CRQ as described above. [0206] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 4:
Figure imgf000066_0002
each A is independently N or CRQ as described above. - 65 - WSGR Docket No.51503-744601 [0207] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 5:
Figure imgf000067_0001
each A is independently N or CRQ as described above. [0208] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 6:
Figure imgf000067_0002
each A is independently N or CRQ as described above. [0209] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 7: - 66 - WSGR Docket No.51503-744601
Figure imgf000068_0001
each A is independently N or CRQ as described above. [0210] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 8:
Figure imgf000068_0002
each A is independently N or CRQ as described above. [0211] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 9:
Figure imgf000068_0003
each A is independently N or CRQ as described above. [0212] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 10: - 67 - WSGR Docket No.51503-744601
Figure imgf000069_0001
each A is independently N or CRQ as described above. [0213] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 11:
Figure imgf000069_0002
each A is independently N or CRQ as described above. - 68 - WSGR Docket No.51503-744601 [0214] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 12:
Figure imgf000070_0001
each A is independently N or CRQ as described above. [0215] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 13:
Figure imgf000070_0002
each A is independently N or CRQ as described above. [0216] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 14: - 69 - WSGR Docket No.51503-744601
Figure imgf000071_0001
each A is independently N or CRQ as described above. [0217] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 15:
Figure imgf000071_0002
each A is independently N or CRQ as described above. [0218] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 16:
Figure imgf000071_0003
each A is independently N or CRQ as described above. - 70 - WSGR Docket No.51503-744601 [0219] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 17: P O O O
Figure imgf000072_0001
each A is independently N or CRQ as described above. [0220] In some embodiments, a scheme for preparing an SMSM described herein is Scheme 18:
Figure imgf000072_0002
each A is independently N or CRQ as described above. [0221] Within schemes 1-18, each RS1 represents alkyl, such as C1-C3alkyl; each RS2 represents attachment to a cyclic base amine such
Figure imgf000072_0003
described above; each RS3 - 71 - WSGR Docket No.51503-744601 represents the variables R4, R5, or R6 above; each G1 represents a boronic acid/ester group (e.g., -OH, -OMe, pinacolester); P1 represents a phenol protecting group (e.g., -OMe, -OMOM, - OPMB, -OTBS); and P2 represents a protecting group. [0222] Additional Compounds in Tables 1-4 can be made using the procedures outlined in General Schemes 1-18 above and the examples below. Table 1 – Exemplary Compounds.
Figure imgf000073_0001
- 72 - WSGR Docket No.51503-744601
Figure imgf000074_0001
- 73 - WSGR Docket No.51503-744601
Figure imgf000075_0002
Table 2 – Exemplary Compounds.
Figure imgf000075_0001
- 74 - WSGR Docket No.51503-744601
Figure imgf000076_0001
- 75 - WSGR Docket No.51503-744601
Figure imgf000077_0001
Table 3 – Exemplary Compounds.
Figure imgf000077_0002
- 76 -
Figure imgf000078_0001
- 77 - WSGR Docket No.51503-744601
Figure imgf000079_0001
- 78 - WSGR Docket No.51503-744601 Table 4 – Exemplary Compounds.
Figure imgf000080_0001
- 79 - WSGR Docket No.51503-744601
Figure imgf000081_0001
- 80 - WSGR Docket No.51503-744601 Pharmaceutical Compositions [0223] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. [0224] A pharmaceutical composition can be a mixture of an SMSM described herein with one or more other chemical components (i.e. pharmaceutically acceptable ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism. [0225] The compositions described herein can be administered to the subject in a variety of ways, including parenterally, intravenously, intradermally, intramuscularly, colonically, rectally or intraperitoneally. In some embodiments, the small molecule splicing modulator or a pharmaceutically acceptable salt thereof is administered by intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection of the subject. In some embodiments, the pharmaceutical compositions can be administered parenterally, intravenously, intramuscularly or orally. The oral agents comprising a small molecule splicing modulator can be in any suitable form for oral administration, such as liquid, tablets, capsules, or the like. The oral formulations can be further coated or treated to prevent or reduce dissolution in stomach. The compositions of the present disclosure can be administered to a subject using any suitable methods known in the art. Suitable formulations for use in the present disclosure and methods of delivery are generally well known in the art. For example, the small molecule splicing modulators described herein can be formulated as pharmaceutical compositions with a pharmaceutically acceptable diluent, carrier or excipient. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions including pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, such as, for - 81 - WSGR Docket No.51503-744601 example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc. [0226] Pharmaceutical formulations described herein can be administrable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. [0227] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, pharmaceutical formulations containing an SMSM described herein are in the form of a capsule. In one aspect, liquid formulation dosage forms for oral administration are in the form of aqueous suspensions or solutions selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. [0228] For administration by inhalation, an SMSM described herein can be formulated for use as an aerosol, a mist or a powder. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner. In some embodiments, an SMSM described herein can be prepared as transdermal dosage forms. In some embodiments, an SMSM described herein can be formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection. In some embodiments, an SMSM described herein can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. In some embodiments, an SMSM described herein can be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas. Splicing Modulation [0229] The present disclosure contemplates use of small molecules with favorable drug properties that modulate the activity of splicing of a target RNA. Provided herein are small molecule splicing modulators (SMSMs) that modulate splicing of a target polynucleotide. In some embodiments, the SMSMs bind and modulate target RNA. In some embodiments, provided herein is a library of SMSMs that bind and modulate one or more target RNAs. In some embodiments, the target RNA - 82 - WSGR Docket No.51503-744601 is mRNA. In some embodiments, the target RNA is mRNA a noncoding RNA. In some embodiments, the target RNA is a pre-mRNA. In some embodiments, the target RNA is hnRNA. In some embodiments, the small molecules modulate splicing of the target RNA. In some embodiments, a small molecule provided herein modulates splicing at a sequence of the target RNA. In some embodiments, a small molecule provided herein modulates splicing at a cryptic splice site sequence of the target RNA. In some embodiments, a small molecule provided herein binds to a target RNA. In some embodiments, a small molecule provided herein binds to a splicing complex component. In some embodiments, a small molecule provided herein binds to a target RNA and a splicing complex component. [0230] Thus, provided herein are methods of preventing or inducing a splicing event in a pre- mRNA molecule, comprising contacting the pre-mRNA molecule and/or other elements of the splicing machinery (e.g., within a cell) with a compound provided herein to prevent or induce the splicing event in the pre-mRNA molecule. The splicing event that is prevented or induced can be, e.g., an aberrant splicing event, a constitutive splicing event or an alternate splicing event. [0231] Further provided herein is a method of identifying a compound capable of preventing or inducing a splicing event in a pre-mRNA molecule, comprising contacting the compound with splicing elements and/or factors involved in alternative, aberrant and/or constitutive splicing as described herein (e.g., within cells) under conditions whereby a positive (prevention or induction of splicing) or negative (no prevention or induction of splicing) effect is produced and detected and identifying a compound that produces a positive effect as a compound capable of preventing or inducing a splicing event. [0232] In some embodiments, a small molecule compound described herein in a pharmaceutically acceptable carrier prevents or induces an alternative or aberrant splicing event in a pre-mRNA molecule. As noted above, the small molecule compounds provided herein are not antisense or antigene oligonucleotides. Tables 1-4 show the chemical structure of exemplary compounds and is not intended to be all-inclusive. [0233] In some embodiments, a method of treating a subject with a disease or condition comprises administering a small molecule splicing modulator compound (SMSM) to a subject with a disease or condition, wherein the SMSM is selected from the group consisting of the SMSMs of Tables 1-4. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the polynucleotide is a pre-mRNA. In some embodiments, the method further comprises administering an additional therapeutic molecule to the subject. In some embodiments, the SMSM is a compound described herein. In some embodiments, the SMSM is selected from the group consisting of SMSMs of Tables 1-4. - 83 - WSGR Docket No.51503-744601 [0234] The compounds and formulations described herein are also useful as therapeutic agents in the treatment of disease involving aberrant and/or alternate splicing. Thus, in some embodiments, a method of treating a subject having a condition or disorder associated with an alternative or aberrant splicing event in a pre-mRNA molecule, comprises administering to the subject a therapeutically effective amount of a compound described herein to modulate an alternative splicing event or prevent an aberrant splicing event, thereby treating the subject. The method can, e.g., restore a correct splicing event in a pre-mRNA molecule. The method can, e.g., utilize a small molecule compound described herein in a pharmaceutically acceptable carrier. [0235] Formulations containing the small molecules described herein can comprise a physiologically or pharmaceutically acceptable carrier, such as an aqueous carrier. Thus, formulations for use in the methods described herein include, but are not limited to, those suitable for oral administration, parenteral administration, including subcutaneous, intradermal, intramuscular, intravenous and intra-arterial administration, as well as topical administration (e.g., administration of an aerosolized formulation of respirable particles to the lungs of a patient afflicted with cystic fibrosis or lung cancer or a cream or lotion formulation for transdermal administration of patients with psoriasis). The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. The most suitable route of administration in any given case may depend upon the subject, the nature and severity of the condition being treated, and the particular active compound, which is being used, as would be readily determined by one of skill in the art. [0236] Also provided herein are methods for the use of a compound described herein having the characteristics set forth above for the preparation of a medicament for upregulating or downregulating RNA expression in a patient having a disorder associated with aberrant or alternate splicing of a pre-mRNA molecule, as discussed above. In some embodiments, the medicament upregulates gene expression. In other embodiments, the medicament downregulates gene expression. In the manufacture of at medicament according to the disclosure, the compound can be admixed with, inter alia, a pharmaceutically acceptable carrier. The carrier may be a solid or a liquid. One or more compounds may be incorporated in any combination in the formulations described herein, which may be prepared by any of the well-known techniques of pharmacy, such as admixing the components, and/or including one or more accessory therapeutic ingredients. [0237] The present disclosure identifies low molecular weight compounds (sometimes referred to herein as small molecules, which block mRNA splicing and/or enhance (facilitate, augment) mRNA splicing. The splicing that can be regulated by the methods described herein include alternative splicing, e.g., exon skipping, intron retention, pseudoexons skipping, exon exclusion, partial intron exclusion and others. Depending on factors such as the splicing sequence and the - 84 - WSGR Docket No.51503-744601 RNA (or gene encoding the RNA) or exon involved, modulation of splicing can be accomplished in the presence of, or in the absence of, antisense oligonucleotides (AOs) that are specific for splicing sequences of interest. In some embodiments, a small molecule and an AO act synergistically. [0238] In some embodiments, the present disclosure provides a method of treating a subject afflicted with a disease or condition associated with aberrant splicing of a pre-mRNA. The method can comprise administering an SMSM, or a composition comprising an SMSM, to a subject, wherein the SMSM binds to a pre-mRNA or a splicing complex component and modulates splicing of the pre-mRNA to inhibit expression of one or more isoforms of a transcript. The method can comprise administering an SMSM, or a composition comprising an SMSM, to a subject, wherein the SMSM binds to a pre-mRNA or a splicing complex component and modulates the splicing of the pre-mRNA to increase expression of one or more isoforms of a transcript. [0239] A number of diseases are associated with expression of an aberrant gene product (e.g., an RNA transcript or protein) of a gene. For example, aberrant amounts of a RNA transcript may lead to disease due to corresponding changes in protein expression. Changes in the amount of a particular RNA transcript may be the result of several factors. First, changes in the amount of RNA transcripts may be due to an aberrant level of transcription of a particular gene, such as by the perturbation of a transcription factor or a portion of the transcription process, resulting in a change in the expression level of a particular RNA transcript. Second, changes in the splicing of particular RNA transcripts, such as by perturbation of a particular splicing process or mutations in the gene that lead to modified splicing can change the levels of a particular RNA transcript. Changes to the stability of a particular RNA transcript or to components that maintain RNA transcript stability, such as the process of poly-A tail incorporation or an effect on certain factors or proteins that bind to and stabilize RNA transcripts, may lead to changes in the levels of a particular RNA transcript. The level of translation of particular RNA transcripts can also affect the amount of those transcripts, affecting or upregulating RNA transcript decay processes. Finally, aberrant RNA transport or RNA sequestration may also lead to changes in functional levels of RNA transcripts, and may have an effect on the stability, further processing, or translation of the RNA transcripts. [0240] In some embodiments, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts encoded by a pre-mRNA, comprising contacting a cell with an SMSM compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is contacted with an SMSM compound or a pharmaceutically acceptable salt thereof in a cell culture. In other embodiments, the cell is contacted with an SMSM compound or a - 85 - WSGR Docket No.51503-744601 pharmaceutically acceptable salt thereof in a subject (e.g., a non-human animal subject or a human subject). [0241] In some embodiments, provided herein are methods for treatment, prevention and/or delay of progression of a disease or condition comprising administering an effective amount of a small molecule splicing modulator as described herein to a subject, in particular to a mammal. [0242] In some embodiments, binding of an SMSM compound or a pharmaceutically acceptable salt thereof to pre-mRNA prevents splicing out of one or more exons and/or introns and/or proteins thereof, from the population of pre-mRNAs to produce mRNA encoding the target protein or functional RNA. In some embodiments, the cell comprises a population of pre-mRNAs transcribed from the gene encoding the target protein or functional RNA, wherein the population of pre-mRNAs comprises a mutation that causes the splicing out of one or more exons, and wherein an SMSM compound or a pharmaceutically acceptable salt thereof binds to the mutation that causes the splicing out of the one or more exons in the population of pre-mRNAs. In some embodiments, the binding of an SMSM compound or a pharmaceutically acceptable salt thereof to the mutation that causes the splicing out of the one or more exons prevents splicing out of the one or more exons from the population of pre-mRNAs to produce mRNA encoding the target protein or functional RNA. In some embodiments, the condition is a disease or disorder. In some embodiments, the method further comprises assessing protein expression. In some embodiments, an SMSM compound or a pharmaceutically acceptable salt thereof binds to a targeted portion of a pre-mRNA. [0243] In some embodiments, the binding of an SMSM compound or a pharmaceutically acceptable salt thereof catalyzes the inclusion of a missing exon or removal of an undesired retained intron or portions thereof, resulting in healthy mRNA and proteins. In some embodiments, the binding of an SMSM compound or a pharmaceutically acceptable salt thereof has minimal to no effect on non-diseased cells. SMSM Targets [0244] Aberrant splicing of mRNA, such as pre-mRNA, can result in a defective protein and can cause a disease or a disorder in a subject. The compositions and methods described herein can reduce this aberrant splicing of mRNA, such as pre-mRNA, and treat a disease or a disorder caused by this aberrant splicing. [0245] Diseases associated with changes to RNA transcript amount are often treated with a focus on the aberrant protein expression. However, if the processes responsible for the aberrant changes in RNA levels, such as components of the splicing process or associated transcription factors or associated stability factors, could be targeted by treatment with a small molecule, it would be possible to restore protein expression levels such that the unwanted effects of the expression of - 86 - WSGR Docket No.51503-744601 aberrant levels of RNA transcripts or associated proteins. Therefore, there is a need for methods of modulating the amount of RNA transcripts encoded by certain genes as a way to prevent or treat diseases associated with aberrant expression of the RNA transcripts or associated proteins. Methods of Treatment [0246] The compositions and methods described herein can be used for treating a human disease or disorder associated with aberrant splicing, such as aberrant pre-mRNA splicing. The compositions and methods described herein can be used for treating a human disease or disorder by modulating mRNA, such as pre-mRNA. In some embodiments, the compositions and methods described herein can be used for treating a human disease or disorder by modulating splicing of a nucleic acid even when that nucleic acid is not aberrantly spliced in the pathogenesis of the disease or disorder being treated. [0247] In some embodiments, an effective amount in the context of the administration of an SMSM compound or a pharmaceutically acceptable salt thereof, or composition or medicament thereof refers to an amount of an SMSM compound or a pharmaceutically acceptable salt thereof to a patient which has a therapeutic effect and/or beneficial effect. In certain specific embodiments, an effective amount in the context of the administration of an SMSM compound or a pharmaceutically acceptable salt thereof, or composition or medicament thereof to a patient results in one, two or more of the following effects: (i) reduces or ameliorates the severity of a disease; (ii) delays onset of a disease; (iii) inhibits the progression of a disease; (iv) reduces hospitalization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the quality of life of a subject; (viii) reduces the number of symptoms associated with a disease; (ix) reduces or ameliorates the severity of a symptom associated with a disease; (x) reduces the duration of a symptom associated with a disease associated; (xi) prevents the recurrence of a symptom associated with a disease; (xii) inhibits the development or onset of a symptom of a disease; and/or (xiii) inhibits of the progression of a symptom associated with a disease. In some embodiments, an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to restore the amount of a RNA transcript of a gene to the amount of the RNA transcript detectable in healthy patients or cells from healthy patients. In other embodiments, an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to restore the amount an RNA isoform and/or protein isoform of gene to the amount of the RNA isoform and/or protein isoform detectable in healthy patients or cells from healthy patients. - 87 - WSGR Docket No.51503-744601 [0248] In some embodiments, an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to decrease the aberrant amount of an RNA transcript of a gene which is associated with a disease. In some embodiments, an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to decrease the amount of the aberrant expression of an isoform of a gene. In some embodiments, an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to result in a substantial change in the amount of an RNA transcript (e.g., mRNA transcript), alternative splice variant or isoform. [0249] In some embodiments, an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to increase or decrease the amount of an RNA transcript (e.g., an mRNA transcript) of gene which is beneficial for the prevention and/or treatment of a disease. In some embodiments, an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to increase or decrease the amount of an alternative splice variant of an RNA transcript of a gene which is beneficial for the prevention and/or treatment of a disease. In some embodiments, an effective amount of an SMSM compound or a pharmaceutically acceptable salt thereof is an amount effective to increase or decrease the amount of an isoform of gene which is beneficial for the prevention and/or treatment of a disease. [0250] In one embodiment, an SMSM described herein can be used in the preparation of medicaments for the treatment of diseases or conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, can involve administration of pharmaceutical compositions that includes at least one SMSM described herein or a pharmaceutically acceptable salt, thereof, in a therapeutically effective amount to a subject. [0251] In certain embodiments, an SMSM described herein can be administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial. In prophylactic applications, compositions containing an SMSM described herein can be administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. In certain embodiments, the dose of drug being administered may be temporarily reduced or temporarily suspended for a - 88 - WSGR Docket No.51503-744601 certain length of time (i.e., a “drug holiday”). Doses employed for adult human treatment typically range of 0.01mg-5000 mg per day or from about 1 mg to about 1000 mg per day. In some embodiments, a desired dose is conveniently presented in a single dose or in divided doses. [0252] For combination therapies described herein, dosages of the co-administered compounds can vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially. If administration is simultaneous, the multiple therapeutic agents can be, by way of example only, provided in a single, unified form, or in multiple forms. Methods of Administering [0253] The compositions described herein can be administered to the subject in a variety of ways, including parenterally, intravenously, intradermally, intramuscularly, colonically, rectally or intraperitoneally. In some embodiments, the small molecule splicing modulator or a pharmaceutically acceptable salt thereof is administered by intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection of the subject. In some embodiments, the pharmaceutical compositions can be administered parenterally, intravenously, intramuscularly or orally. The oral agents comprising a small molecule splicing modulator can be in any suitable form for oral administration, such as liquid, tablets, capsules, or the like. The oral formulations can be further coated or treated to prevent or reduce dissolution in stomach. The compositions of the present disclosure can be administered to a subject using any suitable methods known in the art. Suitable formulations for use in the present disclosure and methods of delivery are generally well known in the art. For example, the small molecule splicing modulators described herein can be formulated as pharmaceutical compositions with a pharmaceutically acceptable diluent, carrier or excipient. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions including pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, such as, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc. [0254] Pharmaceutical formulations described herein can be administrable to a subject in a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injections), intranasal, buccal, topical or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, - 89 - WSGR Docket No.51503-744601 liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. [0255] In some embodiments, the pharmaceutical compositions described herein are administered orally. In some embodiments, the pharmaceutical compositions described herein are administered topically. In such embodiments, the pharmaceutical compositions described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments. In some embodiments, the pharmaceutical compositions described herein are administered topically to the skin. In some embodiments, the pharmaceutical compositions described herein are administered by inhalation. In some embodiments, the pharmaceutical compositions described herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like. In some embodiments, the pharmaceutical compositions described herein are formulated as eye drops. In some embodiments, the pharmaceutical compositions described herein are: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation to the mammal; and/or (e) administered by nasal administration to the mammal; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal. In some embodiments, the pharmaceutical compositions described herein are administered orally to the mammal. In certain embodiments, an SMSM described herein is administered in a local rather than systemic manner. In some embodiments, an SMSM described herein is administered topically. In some embodiments, an SMSM described herein is administered systemically. [0256] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium - 90 - WSGR Docket No.51503-744601 stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. [0257] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. [0258] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. [0259] SMSMs suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against contamination from microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Dosing and Schedules [0260] The SMSMs utilized in the methods of the disclosure can be, e.g., administered at dosages that may be varied depending upon the requirements of the subject the severity of the condition being treated and/or imaged, and/or the SMSM being employed. For example, dosages can be empirically determined considering the type and stage of disease diagnosed in a particular subject and/or the type of imaging modality being used in conjunction with the SMSMs. The dose administered to a subject, in the context of the present disclosure should be sufficient to affect a beneficial diagnostic or therapeutic response in the subject. The size of the dose also can be - 91 - WSGR Docket No.51503-744601 determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a SMSM in a particular subject. [0261] It is advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. Toxicity and therapeutic efficacy of such compounds can be determined by procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue to minimize potential damage to uninfected cells and, thereby, reduce side effects. [0262] Therapeutic index data obtained from cell culture assays and/or animal studies can be used in predicting the therapeutic index in vivo and formulating a range of dosages for use in subjects, such as human subjects. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the disclosure, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the concentration of the test compound which achieves a half-maximal inhibition of symptoms as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography. Various animal models and clinical assays for evaluating effectiveness of a particular SMSM in preventing or reducing a disease or condition are known in the art may be used in the present disclosure. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of - 92 - WSGR Docket No.51503-744601 administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g. Fingl et al, 1975, In: The Pharmacological Basis of Therapeutics. Ch.1 pi). [0263] The compositions of the present disclosure can be administered as frequently as necessary, including hourly, daily, weekly or monthly. [0264] In any of the aforementioned aspects are further embodiments comprising single administrations of an effective amount of an SMSM described herein, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously. [0265] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of an SMSM described herein, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of an SMSM described herein is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. Combination Therapies [0266] In certain instances, it is appropriate to administer at least one SMSM described herein in combination with another therapeutic agent. For example, a compound SMSM described herein can be co-administered with a second therapeutic agent, wherein SMSM and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. [0267] In some embodiments, an SMSM may be administered in combination with one or more other SMSMs. [0268] A SMSM may be administered to a subject in need thereof prior to, concurrent with, or following the administration of other therapeutic agents. For instance, SMSMs may be administered to a subject at least 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1.5 hours, 1 hour, or 30 minutes before the starting time of the administration of the other therapeutic agent(s). In certain embodiments, they may be administered concurrent with the administration of the other therapeutic agent(s). In other words, in these embodiments, SMSMs are administrated at the same time when the administration of the other therapeutic agent(s) starts. In other embodiments, SMSMs may be administered following the starting time of administration of the - 93 - WSGR Docket No.51503-744601 other therapeutic agent(s) (e.g., at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours after the starting time of administration of the other therapeutic agents). Alternatively, SMSMs may be administered at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours after the completion of administration of the other therapeutic agents. Generally, these SMSMs are administered for a sufficient period of time so that the disease or condition is prevented or reduced. Such sufficient period of time may be identical to, or different from, the period during which other therapeutic agent(s) are administered. In certain embodiments, multiple doses of SMSMs are administered for each administration of another therapeutic agent or a combination of multiple other therapeutic agents. [0269] In certain embodiments, an appropriate dosage of a SMSM is combined with a specific timing and/or a particular route to achieve the optimum effect in preventing or reducing the disease or condition. For instance, an SMSM may be administered to a human orally at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours 8 hours, 9 hours, 10 hours, 11 hours or 12 hours; or at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days; or at least 1 week, 2 weeks, 3 weeks or 4 weeks; or at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months; prior to or after the beginning or the completion, of the administration of another therapeutic agent or a combination of other therapeutic agents. Subjects [0270] The subjects that can be treated with the SMSMs and methods described herein can be any subject that produces mRNA that is subject to alternative splicing, e.g., the subject may be a eukaryotic subject, such as a plant or an animal. In some embodiments, the subject is a mammal, e.g., human. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a fetus, an embryo, or a child. In some embodiments, the subject is a non-human primate such as chimpanzee, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In some embodiments, the subject is prenatal (e.g., a fetus), a child (e.g., a neonate, an infant, a toddler, a preadolescent), an adolescent, a pubescent, or an adult (e.g., an early adult, a middle aged adult, a senior citizen). EXAMPLES [0271] 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 - 94 - WSGR Docket No.51503-744601 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. [0272] The following abbreviations are used: BrettPhos Pd G3 - [(2-Di-cyclohexylphosphino- 3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′ -biphenyl)]palladium(II) methanesulfonate methanesulfonate; CDI – 1,1’-carbonyldiimidazole; DCM – dichloromethane; DIPEA – N,N-diisopropylethylamine; DDQ - 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DMSO - dimethyl sulfoxide; DMF - N,N-dimethylformamide; EtOAc - ethyl acetate; EtOH - ethyl alcohol; Grubbs II Catalyst - dichloro[1,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II); HATU - 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;HPLC – high pressure liquid chromatography; LCMS – liquid chromatography mass spectrometer; LDA – lithium diisopropylamide; MeCN – acetonitrile; MeOH - methyl alcohol; MOM – methoxymethyl acetal; MOMBr – bromomethyl methyl ether; PE - petroleum ether; SFC - supercritical fluid chromatography; TBAF - tetrabutylammonium fluoride; TEA – triethylamine; TFA – trifluoroacetic acid; THF- tetrahydrofuran; X-Phos - 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; h – hour; min – minute; rt – room temperature (22-25 °C); g – grams; mL - milliliters; mg – milligrams; mmol – millimoles. [0273] 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 - 95 - WSGR Docket No.51503-744601 Structure”, 4th Ed., Wiley Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527– 29074–5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0–19–509618–5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley–VCH, ISBN: 0–471– 19031–4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0–471–60180–2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley–VCH, ISBN: 3–527–29871–1; Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0–471–93022–9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0–471–19095–0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley–Interscience, ISBN: 0–471–57456–2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3–527–29645–X, in 8 volumes; “Organic Reactions” (1942–2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. [0274] 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). [0275] Examples can be made using known techniques and further chemically modified, in some embodiments, to facilitate intranuclear transfer to, e.g., a splicing complex component, a spliceosome or a pre–mRNA molecule. One of ordinary skill in the art will appreciate the standard medicinal chemistry approaches for chemical modifications for intranuclear transfer (e.g., reducing charge, optimizing size, and/or modifying lipophilicity). Stereochemistry: [0276] (±) 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 - 96 - WSGR Docket No.51503-744601 (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. [0277] Example 1: Synthesis of SMSM 1-12.
Figure imgf000098_0001
- 97 - WSGR Docket No.51503-744601 [0278] Example 2: Synthesis of SMSM 1-9.
Figure imgf000099_0001
- 98 - WSGR Docket No.51503-744601 [0279] Example 3: Synthesis of SMSM 1-11.
Figure imgf000100_0001
- 99 - WSGR Docket No.51503-744601 [0281] Example 5: Synthesis of SMSM 1-15.
Figure imgf000101_0001
- 100 - WSGR Docket No.51503-744601 [0282] Example 6: Synthesis of SMSM 1-24.
Figure imgf000102_0001
- 101 - WSGR Docket No.51503-744601 [0284] Example 8: Synthesis of SMSM 2-12.
Figure imgf000103_0001
- 102 - WSGR Docket No.51503-744601 [0286] Example 10: Synthesis of SMSM 2-13.
Figure imgf000104_0001
- 103 - WSGR Docket No.51503-744601 [0288] Example 12: Synthesis of SMSM 2-15.
Figure imgf000105_0001
- 104 - WSGR Docket No.51503-744601 [0290] Example 14: Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 1).
Figure imgf000106_0001
[0291] Step 1: Synthesis of 3,6-dichloro-N-methylpyridazine-4-carboxamide. To a solution of 3,6-dichloropyridazine-4-carboxylic acid (3.0 g, 15.5 mmol) in DCM (40 mL) were added oxalyl chloride (1.5 mL, 17.7 mmol) and two drops of DMF. The mixture was stirred at room temperature for 1 h. After concentration, the residue was dissolved in DCM (40 mL). To the above solution were added MeNH2•HCl (2.4 g, 37.3 mmol) and TEA (4 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by silica flash chromatography (0-3% MeOH/DCM) to give the title compound (1.87 g, 59% yield) as a brown solid. LCMS: m/z 206.1[M+1]+; tR=1.20 min. [0292] Step 2: Synthesis of (1R,3s,5S)-tert-butyl 3-(6-chloro-4- (methylcarbamoyl)pyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (INT-1). A solution of 3,6-dichloro-N-methylpyridazine-4-carboxamide (1.8 g, 8.8 mmol), (1R,3s,5S)- tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (2.2 g, 9.7 mmol) and DIPEA (2 mL) in DMSO (10 mL) was heated to 130 ºC for 4 h. The mixture was quenched with water and extracted with EtOAc (40 mL x 3). The extracts were washed with water (20 mL x 2), brine (20 mL x 2), dried over Na2SO4, and concentrated. The residue was purified by silica flash - 105 - WSGR Docket No.51503-744601 chromatography (0-30% EtOAc/DCM) to the title compound (2.02 g, 58% yield) as a yellow solid. LCMS: m/z 396.2 [M+H]+; tR = 1.77 min. [0293] Step 3: Synthesis of (1R,3s,5S)-tert-butyl 3-(3-chloro-6-methyl-5,7-dioxo-6,7 - dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a solution of (1R,3s,5S)-tert-butyl 3-(6-chloro-4-(methylcarbamoyl)pyridazin-3- ylamino)-8- azabicyclo[3.2.1]octane-8-carboxylate (850 mg.2.15 mmol) in THF (30 mL) were added NaH (258 mg, 6.45 mmol, 60% in mineral oil) and CDI (1.04 g, 6.45 mmol). The mixture was stirred at room temperature for 1 h, quenched with water and extracted with EtOAc (30 mL x 2). The extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified on silica flash column (0-30% EtOAc/DCM) to give the title compound (550 mg, 61% yield) as a white solid. LCMS: m/z 444.1 [M+Na]+; tR = 1.94 min. [0294] Step 4: Synthesis of tert-butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-6-methyl-5,7-dioxo-6,7-dihydropyrimido[4,5- c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a solution of (1R,3s,5S)- tert-butyl 3-(3-chloro-6-methyl-5,7-dioxo-6,7-dihydropyrimido[4,5-c] pyridazin-8(5H)-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.25 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added (E)-3-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)-N-methylacrylamide (B1, 105 mg, 0.30 mmol) and K2CO3 (70 mg, 0.50 mmol) and Pd(dppf)Cl2 (20 mg, 0.03 mmol). Then the mixture was stirred at 100 oC for 3 h under nitrogen atmosphere. After cooling to room temperature, water (30 mL) was added. The mixture was extracted with EtOAc (20 mL x 3), the organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography (0- 10% MeOH/DCM) to give the title compound (120 mg, 79% yield) as a yellow oil. LCMS: m/z 607.2 [M+Na]+; tR = 1.87 min. [0295] Step 5: Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6-methyl- 5,7 -dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 1). To a solution of tert-butyl (1R,3s,5S)-3-(3-(2- (methoxymethoxy)-4-((E)-3-(methylamino)-3-oxoprop-1-en-1-yl)phenyl)-6-methyl-5,7-dioxo- 6,7-dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.20 mmol) in DCM (5 mL) was added TFA (1 mL). Then the mixture was stirred at room temperature for 4 h. The mixture was neutralized with 7 M NH3/MeOH to a pH of 8. After concentration, the residue was purified by Prep-HPLC (ACN and H2O with 0.05% NH4HCO3 as mobile phase, Column: XtimateTM 10 ^m, 150Å, 21.2 × 250mm) to give the title compound (48.6 mg, 53% yield) as a white solid. LCMS: m/z 463.0 [M+1]+; tR = 1.39 min.1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.19-8.07 (m, 2H), 7.40 (d, J = 15.6 Hz, 1H), 7.23-7.16 (m, - 106 - WSGR Docket No.51503-744601 2H), 6.65 (m, J = 15.6 Hz ,1H), 5.98-5.83 (m, 1H), 3.62-3.60 (m, 2H), 3.30 (s, 3H), 2.78-2.68 (m, 5H), 1.85 – 1.68 (m, 4H), 1.66-1.55 (m, 2H). [0296] Example 15: Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-5-oxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 2).
Figure imgf000108_0002
Figure imgf000108_0001
[0297] Step 1: Synthesis of (1R,3s,5S)-tert-butyl 3-(3-chloro-6-methyl-5-oxo-6,7- dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. A solution of (1R,3s,5S)-tert-butyl 3-(6-chloro-4-(methylcarbamoyl)pyridazin-3-ylamino)-8- azabicyclo[3.2.1]octane-8-carboxylate (INT-1, 1.5 g, 3.8 mmol), paraformaldehyde (2.28 g, 76.0 mmol), and p-toluenesulfonic acid monohydrate (98 mg, 0.52 mmol) in toluene (30 mL) was heated at 110 ºC for 16 h. The mixture was concentrated, and the residue was purified by silica flash chromatography (0-20% EtOAc/DCM) to give the title compound (0.7 g, 45% yield) as a yellow solid. LCMS: m/z 430.2 [M+Na]+; tR = 1.81 min. [0298] Step 2: Synthesis of tert-butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-6-methyl-5-oxo-6,7-dihydropyrimido[4,5- c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a solution of tert-butyl (1R,3s,5S)-3-(3-chloro-6-methyl-5-oxo-6,7-dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.25 mmol) in 1,4-dioxane (10 mL) and water (1 mL) were added (E)-3-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2- yl)phenyl)-N-methylacrylamide (B1, 105 mg, 0.30 mmol), K2CO3 (70 mg, 0.50 mmol), and Pd(dppf)Cl2 (20 mg, 0.03 mmol). Then the mixture was stirred at 100 oC for 3 h under nitrogen atmosphere. After cooling to room temperature, water (30 mL) was added. The mixture was - 107 - WSGR Docket No.51503-744601 extracted with EtOAc (20 mL x 3). the organic layers were combined, washed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography (0-10% MeOH/DCM) to give the title compound (110 mg, 74% yield) as a yellow solid. LCMS: m/z 593.3 [M+1]+; tR = 1.76 min. [0299] Step 3: Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6-methyl- 5-oxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 2). To a solution of tert-butyl (1R,3s,5S)-3-(3-(2- (methoxymethoxy)-4-((E)-3-(methylamino)-3-oxoprop-1-en-1-yl)phenyl)-6-methyl-5-oxo-6,7- dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.19 mmol) in DCM (5 mL) was added TFA (1 mL). Then the mixture was stirred at room temperature for 4 h. The mixture was neutralized with 7 M NH3/MeOH to a pH of 8. After concentration, the residue was purified by Prep-HPLC (ACN and H2O with 0.05% NH4HCO3 as mobile phase, Column: XtimateTM , 10 ^m, 150 Å, 21.2 × 250mm) to give the title compound (22.1 mg, X% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.12-8.08 (m, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 15.7 Hz, 1H), 7.15-7.13 (m, 2H), 6.63 (d, J = 15.8 Hz, 1H), 5.21-5.18 (m, 1H), 4.82 (s, 2H), 3.55-3.54 (m, 2H), 3.03 (s, 3H), 2.72-2.67 (m, 3H), 1.91 – 1.61 (m, 8H). LCMS: m/z 449.0 [M+1]+; tR = 1.37 min. [0300] Example 16: Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7 - oxo-7,8-dihydro-5H-pyridazino[3,4-d][1,3]oxazin-3-yl)-3-(methoxymethoxy)phenyl)-N- methylacrylamide (Compound 3). - 108 - WSGR Docket No.51503-744601
Figure imgf000110_0001
[0301] Step 1: Synthesis of 3-(((1R,3s,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo [3.2.1]octan-3-yl)amino)-6-chloropyridazine-4-carboxylic acid. To a solution of 3,6- dichloropyridazine-4-carboxylic acid (1.9 g, 10.0 mmol) in 1,4-dioxane (30 mL) was added tert- butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (4.5 g, 20.0 mmol) and DIPEA (3.9 g, 30.0 mmol). Then the mixture was stirred at 100 oC for 3 h. The organic layers were concentrated and the residue was purified by silica gel column chromatography (6% MeOH/DCM) to give 3-(((1R,3s,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3- yl)amino)-6-chloropyridazine-4-carboxylic acid (1.2 g, 32% yield) as a yellow oil. LCMS: m/z 327.1 [M-55]+; tR = 1.80 min. [0302] Step 2: Synthesis of (1R,3s,5S)-tert-butyl 3-(6-chloro-4- (methoxy(methyl)carbamoyl)pyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane-8- carboxylate. A mixture of 3-((1R,3s,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan- 3- ylamino)-6-chloropyridazine-4-carboxylic acid (3.82 g, 10.0 mmol), N,O- dimethylhydroxylamine hydrochloride (1.45 g, 15.0 mmol), HATU (4.56 g, 12.0 mmol) and DIPEA (3 mL) in DMF (15 mL) was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with EtOAc (50 mL x 3). The extracts were washed with water (30 mL x 3), brine (20 mL x 3), dried over Na2SO4 and concentrated. The residue was - 109 - WSGR Docket No.51503-744601 purified by silica flash chromatography (0-30% EtOAc/DCM) to give (1R,3s,5S)-tert-butyl 3-(6- chloro-4-(methoxy(methyl)carbamoyl)pyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane-8- carboxylate (4.0 g, 94% yield) as an off-white solid. LCMS: m/z 426.2 [M+H]+; tR = 1.80 min. [0303] Step 3: Synthesis of (1R,3s,5S)-tert-butyl 3-(6-chloro-4-formylpyridazin-3-ylamino)- 8 -azabicyclo[3.2.1]octane-8-carboxylate. To a cold (-78 ºC) solution of (1R,3s,5S)-tert-butyl 3-(6-chloro-4-(methoxy(methyl)carbamoyl)pyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane-8- carboxylate (3.0 g, 7.0 mmol) in THF (40 mL) was added LiAlH4 (0.6 g, 15.7 mmol) in portions. The mixture was stirred at -40 ºC for 2 h, quenched with 1 N HCl at -40 ºC, and extracted with EtOAc (40 mL x 3). The extracts were dried over Na2SO4 and concentrated to give (1R,3s,5S)-tert-butyl 3-(6-chloro-4-formylpyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane- 8-carboxylate (2.5 g, 97% yield) as a red solid. LCMS: m/z 389.1 [M+Na]+; tR = 1.91 min. [0304] Step 4: Synthesis of (1R,3s,5S)-tert-butyl 3-(6-chloro-4-(hydroxymethyl)pyridazin-3- ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a solution of (1R,3s,5S)-tert-butyl 3-(6- chloro-4-formylpyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.5 g, 6.8 mmol) in THF (30 mL) was added NaBH4 (0.52 g, 13.6 mmol). The mixture was stirred at room temperature for 1 h, quenched with water and extracted with EtOAc (40 mL x 3). The extracts were dried over Na2SO4, concentrated to give (1R,3s,5S)-tert-butyl 3-(6-chloro-4- (hydroxymethyl)pyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.2 g, 88% yield) as a yellow solid. LCMS: m/z 369.1 [M+H]+; tR = 1.71 min. [0305] Step 5: Synthesis of (1R,3s,5S)-tert-butyl 3-(6-chloro-2-oxo-2,4-dihydro-1H- pyrido[2,3-d][1,3]oxazin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. DIPEA (1 mL) and triphosgene (0.6, 2.03 mmol) were added to a solution of (1R,3s,5S)-tert-butyl 3-(6-chloro-4- (hydroxymethyl)pyridazin-3-ylamino)- 8-azabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 4.07 mmol) in THF (20 mL). The mixture was stirred at room temperature for 40 min. The reaction was quenched with water and extracted with EtOAc (50 mL x 3). The extracts were dried over Na2SO4, filtered, and the residue was purified by silica gel flash chromatography (0-70% EtOAc/petroleum ether) to give (1R,3s,5S)-tert-butyl 3-(6-chloro-2-oxo-2,4-dihydro-1H- pyrido[2,3-d][1,3]oxazin-1-yl) -8-azabicyclo[3.2.1]octane-8-carboxylate (0.62 g, 39% yield) as a yellow solid. LCMS: m/z 417.2 [M+Na]+; tR = 1.79 min. [0306] Step 6: Synthesis of tert-butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-7-oxo-5H-pyridazino[3,4-d][1,3]oxazin-8(7H)- yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a solution of (1R,3s,5S)-tert-butyl 3-(6- chloro-2-oxo-2,4-dihydro-1H-pyrido[2,3-d][1,3]oxazin-1-yl) -8-azabicyclo[3.2.1]octane-8- carboxylate (100 mg, 0.25 mmol) in 1,4-dioxane (5 mL) and water (1 mL) were added (E)-3-(3- (methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methylacrylamide - 110 - WSGR Docket No.51503-744601 (104 mg, 0.30 mmol), K3PO4 (106 mg, 0.50 mmol), and Pd(dppf)Cl2 (18 mg, 0.03 mmol). The mixture was stirred at 100 oC for 2 h under nitrogen atmosphere. Water (30 mL) was added, the mixture extracted with EtOAc (20 mL x 3), the organic layers washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (0-10% MeOH/DCM) to give tert-butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)- 4-((E)-3-(methylamino)-3-oxoprop-1-en-1-yl)phenyl)-7-oxo-5H-pyridazino[3,4-d][1,3]oxazin- 8(7H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (98 mg, 67% yield) as a yellow oil. LCMS: m/z 580.3 [M+1]+; tR = 1.78 min. [0307] Step 7: Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-oxo-7,8- dihydro-5H-pyridazino[3,4-d][1,3]oxazin-3-yl)-3-(methoxymethoxy)phenyl)-N- methylacrylamide. To a solution of tert-butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-7-oxo-5H-pyridazino[3,4-d][1,3]oxazin-8(7H)-yl)- 8-azabicyclo[3.2.1]octane-8-carboxylate (98 mg, 0.17 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 4 h, then the mixture was neutralized with 7 M NH3 in methanol to pH of 8, and the solution concentrated. The residue was purified by Prep-HPLC (ACN and H2O with 0.05% NH4HCO3 as mobile phase) to give (E)-3-(4-(8- ((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-oxo- 7,8-dihydro-5H-pyridazino[3,4- d][1,3]oxazin-3-yl)-3-(methoxymethoxy)phenyl)-N-methylacrylamide (12.3 mg, 17% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.13-8.09 (m, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 15.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 15.8 Hz, 1H), 5.39 (s, 2H), 5.10-5.11(m, 1H), 3.66-3.60 (m, 2H), 2.73-2.67 (m, 3H), 2.62-2.56 (m, 2H), 1.83-1.65 (m, 6H).LCMS: m/z 436.0 [M+H]+; tR = 1.35 min. [0308] Example 17: Synthesis of (E)-3-(4-(8-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7- oxo-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)-3-hydroxyphenyl)-N-methylacrylamide (Compound 4). - 111 - WSGR Docket No.51503-744601
Figure imgf000113_0001
[0309] Step 1: Synthesis of tert-butyl (1R,3s,5S)-3-((6-chloro-4-((Z)-3-methoxy-3-oxoprop- 1-en-1-yl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (4.56 g, 14.34 mmol) in THF (50 mL) was added LDA (7.2 mL, 14.34 mmol, 2M in THF) at -40 °C. After stirring at -40 °C for 30 min, tert-butyl (1R,3s,5S)-3-((6-chloro-4-formylpyridazin-3-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (3.5 g, 9.56 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred at -40 °C for further 30 min, quenched with saturated aqueous NH4Cl (10 mL), and the solution extracted with EtOAc (100 mL x 2). The combined organic solvents were washed with brine (100 mL), dried over anhydrous MgSO4, concentrated in vacuo, and purified by silica gel flash chromatography (5-30% EtOAc/petroleum ether) to give tert-butyl (1R,3s,5S)-3-((6-chloro-4-((Z)-3-methoxy-3-oxoprop-1-en-1-yl)pyridazin-3- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (4.0 g, 99% yield) as a yellow solid. LCMS: m/z = 423.2 [M+18]+ , tR = 1.83 min. [0310] Step 2: Synthesis of tert-butyl (1R,3S,5S)-3-((6-chloro-4-(3-methoxy-3- oxopropyl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. A mixture of tert-butyl (1R,3S,5S)-3-((6-chloro-4-((Z)-3-methoxy-3-oxoprop-1-en-1-yl)pyridazin-3- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.36 mmol) and PtO2 (161.1 mg, 0.71 mmol) in EtOAc (12 mL) was stirred under H2 at room temperature for 2.5 h. The mixture was filtered and the filtrate concentrated. The residue was purified by silica gel column chromatography (0-60% EtOAc/petroleum ether) to give tert-butyl (1R,3S,5S)-3-((6-chloro-4- (3-methoxy-3-oxopropyl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (750 mg, 75% yield) as a white solid. LCMS: m/z = 425.2 [M+H]+ , tR = 1.82 min. - 112 - WSGR Docket No.51503-744601 [0311] Step 3: Synthesis of tert-butyl (1R,3S,5S)-3-(3-chloro-7-oxo-6,7-dihydropyrido[2,3- c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. A mixture of tert-butyl (1R,3S,5S)-3-((6-chloro-4-(3-methoxy-3-oxopropyl)pyridazin-3-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 2.35 mmol) and K2CO3 (2.6 g, 18.8 mmol) in CH3CN (15 mL) was refluxed for 48 h. The mixture was filtered and the filtrate concentrated. The residue was purified by silica gel column chromatography (0-66% EtOAc/petroleum ether) to give tert-butyl (1R,3S,5S)-3-(3-chloro-7-oxo-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (450 mg, 48% yield) as a white solid. LCMS: m/z = 415.1 [M+23]+ , tR = 1.82 min. [0312] Step 4: Synthesis of tert-butyl (1R,3S,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-7-oxo-6,7-dihydropyrido[2,3-c]pyridazin- 8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. A mixture of tert-butyl (1R,3S,5S)-3-(3- chloro-7-oxo-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8- carboxylate (90 mg, 0.23 mmol), (E)-3-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-N-methylacrylamide (159.1 mg, 0.46 mmol), Pd(dppf)Cl2 (16.8 mg, 0.02 mmol), and K2CO3 (95 mg, 0.69 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was degassed with N2 and stirred at 100 °C for 1.5 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (gradient elution 0-100% EtOAc/petroleum ether to 4% MeOH/CH2Cl2) to give tert-butyl (1R,3S,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-7-oxo-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)- yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (110 mg, 83% yield) as a light yellow solid. LCMS: m/z = 578.3 [M+1]+ , tR = 1.76 min. [0313] Step 5: Synthesis of (E)-3-(4-(8-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-oxo- 5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)-3-hydroxyphenyl)-N-methylacrylamide. To a solution of tert-butyl (1R,3S,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3-(methylamino)-3- oxoprop-1-en-1-yl)phenyl)-7-oxo-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.19 mmol) in DCM (2 mL) was added TFA (4 mL). The solution was stirred at room temperature for 3 h, then concentrated and purified by prep-TLC (dichloromethane/0.2% NH3 in methanol = 25/1) to give (E)-3-(4-(8-((1R,3S,5S)-8- azabicyclo[3.2.1]octan-3-yl)-7-oxo-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)-3- hydroxyphenyl)-N-methylacrylamide (68 mg, 70% yield) as a light yellow solid.1H NMR (400 MHz, MeOD-d4) δ 8.28 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 16.0 Hz, 1H), 7.24-7.14 (m, 2H), 6.65 (d, J = 16.0 Hz, 1H), 5.68-5.52 (m, 1H), 4.22-4.16 (m, 2H), 3.15-3.04 (m, 4H), 2.86 (s, 3H), 2.82-2.73 (m, 2H), 2.26-2.16 (m, 4H), 1.99-1.88 (m, 2H). LCMS: m/z = 434.2 [M+1]+ , tR = 1.35 min. - 113 - WSGR Docket No.51503-744601 [0314] Example 18: Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 5).
Figure imgf000115_0001
[0315] Step 1: Synthesis of tert-butyl (1R,3S)-3-((6-chloro-4- ((methylamino)methyl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. tert- Butyl (1R,3s,5S)-3-((6-chloro-4-formylpyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (3.2 g, 8.71 mmol) was dissolved in MeNH3/THF (4M, 100 mL), and the resulting mixture was sealed and heated at 50 °C for 2 h. The solvent and excess methylamine were removed in vacuo to give the crude as a yellow oil, which was dissolved in methanol (50 mL) and cooled to 0 °C. Sodium borohydride (661 mg, 17.5 mmol) was added in portions and the resulting mixture was stirred for 1 h at 25 °C. The mixture was concentrated and the residue dissolved in dichloromethane (100 mL). This solution was washed with 2% aqueous NaOH, saturated aqueous NaHCO3, and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (0-2% MeOH/DCM) to afford tert-butyl (1R,3S)-3-((6-chloro-4-((methylamino)methyl)pyridazin-3-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (3.4 g, 72% yield) as a yellow solid. LCMS: m/z 382.2 [M+H]+; tR = 1.85 min. [0316] Step 2: Synthesis of tert-butyl (1R,3s,5S)-3-((6-chloro-4-((N-methyl-1H-imidazole-1- carboxamido)methyl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. Pyridine (1.52 mL, 18.9 mmol) and 1,1'-carbonylbis-1H-imidazole (2.04 g, 12.6 mmol) were added to a solution of tert-butyl (1R,3S)-3-((6-chloro-4-((methylamino)methyl)pyridazin-3- - 114 - WSGR Docket No.51503-744601 yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 6.29 mmol ) in dichloromethane (80 mL). The reaction was stirred at room temperature 2 h, then concentrated. The residue was purified by silica gel column chromatography (2-5% MeOH/DCM) to afford tert-butyl (1R,3s,5S)-3-((6-chloro-4-((N-methyl-1H-imidazole-1-carboxamido)methyl)pyridazin-3- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 80% yield) as a white solid. LCMS: m/z 576.3 [M+H]+; tR = 1.54 min. [0317] Step 3: Synthesis of tert-butyl (1R,3s,5S)-3-(3-chloro-6-methyl-7-oxo-6,7- dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. DIPEA (2.52 mL, 14.49 mmol) was added to a solution of tert-butyl (1R,3s,5S)-3-((6-chloro-4- ((N-methyl-1H-imidazole-1-carboxamido)methyl)pyridazin-3-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (2.3 g, 4.83 mmol ) in DMF (10 mL). The reaction solution was stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2% MeOH/DCM) to give tert-butyl (1R,3s,5S)-3-(3-chloro-6-methyl-7-oxo-6,7- dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.1 g, 90% yield) as a beige solid. LCMS: m/z 308.1 [M-Boc]+; tR = 1.89 min. [0318] Step 4: Synthesis of tert-butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-6-methyl-7-oxo-6,7-dihydropyrimido[4,5- c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. A mixture of tert-butyl (1R,3s,5S)-3-(3-chloro-6-methyl-7-oxo-6,7-dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.61mmol), (E)-3-(3-(methoxymethoxy)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methylacrylamide (252 mg, 0.73 mmol), XPhos Pd G2 (73 mg, 0.091 mmol) and K3PO4 (259 mg, 1.22 mmol) in 1,4-dioxane (3 mL) and H2O (0.3 mL) was degassed with nitrogen and then stirred at 100 °C for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (0-2% MeOH in DCM) to afford tert-butyl (1R,3s,5S)-3-(3-(2- (methoxymethoxy)-4-((E)-3-(methylamino)-3-oxoprop-1-en-1-yl)phenyl)-6-methyl-7-oxo-6,7- dihydropyrimido[4,5-c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (260 mg, 71% yield) as a beige solid. LCMS: m/z 593.1 [M+H]+; tR = 1.72 min. [0319] Step 5: Synthesis of (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-6-methyl- 7-oxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (Compound 5). tert-Butyl (1R,3s,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-6-methyl-7-oxo-6,7-dihydropyrimido[4,5- - 115 - WSGR Docket No.51503-744601 c]pyridazin-8(5H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (260 mg, 0.42 mmol) was added to a solution of HCl/dioxane (20 mL, 4N). The resulting suspension was stirred at 25 °C for 1.5 h and concentrated. The residue was basified to pH=9 by using NH3/MeOH and purified by prep-TLC (DCM:MeOH = 20:1) to provide (E)-3-(4-(8-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3- yl)-6-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl)-3-hydroxyphenyl)-N- methylacrylamide (65.6 mg, 33% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.09 (d, J = 4.8 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 15.7 Hz, 1H), 7.18 (d, J = 7.8 Hz, 2H), 6.66 (d, J = 15.8 Hz, 1H), 5.20 (s, 1H), 4.50 (s, 2H), 3.53 (s, 3H), 2.92 (s, 3H), 2.69 (m, 5H), 1.81 – 1.63 (m, 4H), 1.54 (s, 2H). LCMS: m/z 449.0 [M+H]+; tR = 1.41min [0320] Example 19: Synthesis of SMSM 3-12.
Figure imgf000117_0001
- 116 - WSGR Docket No.51503-744601 [0321] Example 20: Synthesis of SMSM 3-9.
Figure imgf000118_0001
- 117 - WSGR Docket No.51503-744601 [0322] Example 21: Synthesis of SMSM 3-11.
Figure imgf000119_0001
- 118 - WSGR Docket No.51503-744601 [0324] Example 23: Synthesis of SMSM 3-10.
Figure imgf000120_0001
- 119 - WSGR Docket No.51503-744601 [0325] Example 24: Synthesis of SMSM 3-15.
Figure imgf000121_0001
- 120 - WSGR Docket No.51503-744601 [0326] Example 25: Synthesis of SMSM 3-17.
Figure imgf000122_0001
- 121 - WSGR Docket No.51503-744601 [0328] Example 27: Synthesis of SMSM 3-24.
Figure imgf000123_0001
[0330] Example 29: Synthesis of (E)-3-(4-(8-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7- oxo-7,8-dihydropyrido[2,3-c]pyridazin-3-yl)-3-hydroxyphenyl)-N-methylacrylamide (Compound 6). - 122 - WSGR Docket No.51503-744601
Figure imgf000124_0001
[0331] Step 1: Synthesis of tert-butyl (1R,3s,5S)-3-(3-chloro-7-oxopyrido[2,3-c]pyridazin- 8(7H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. K2CO3 (818 mg, 5.9 mmol) was added to a solution of tert-butyl (1R,3s,5S)-3-((6-chloro-4-((Z)-3-methoxy-3-oxoprop-1-en-1- yl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.18 mmol) in MeOH (20 mL). The reaction mixture was stirred at 20 °C for 7 h. The reaction was quenched with water (40 mL), extracted with EtOAc (3x100 mL), the organic layers combined, dried over anhydrous MgSO4, and concentrated in vacuo to give tert-butyl (1R,3s,5S)-3-(3-chloro-7- oxopyrido[2,3-c]pyridazin-8(7H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (380 mg, 82% yield) as a white foam. LCMS: m/z 291.1 [M –99 ]+ , tR = 1.87 min. [0332] Step 2: Synthesis of tert-butyl (1R,3S,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3- (methylamino)-3-oxoprop-1-en-1-yl)phenyl)-7-oxopyrido[2,3-c]pyridazin-8(7H)-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate. A mixture of tert-butyl (1R,3S,5S)-3-(3-chloro-7- oxopyrido[2,3-c]pyridazin-8(7H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.2 mmol), (E)-3-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N- methylacrylamide (71.1 mg, 0.2 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), and K2CO3 (84.9 mg, 0.61 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was degassed with N2 and stirred at 100 °C for 1.5 h. The mixture was concentrated and purified by silica gel column chromatography (gradient elution 0-100% EtOAc/petroleum ether to 4% MeOH/CH2Cl2) to give tert-butyl (1R,3S,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3-(methylamino)-3-oxoprop-1-en-1-yl)phenyl)-7- oxopyrido[2,3-c]pyridazin-8(7H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (95 mg, 81% yield) as a light yellow solid. LCMS: m/z = 576.3 [M+H]+ , tR = 1.79 min. [0333] Step 3: Synthesis of (E)-3-(4-(8-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-oxo-7,8- dihydropyrido[2,3-c]pyridazin-3-yl)-3-hydroxyphenyl)-N-methylacrylamide. To a solution of tert-butyl (1R,3S,5S)-3-(3-(2-(methoxymethoxy)-4-((E)-3-(methylamino)-3-oxoprop-1-en-1- yl)phenyl)-7-oxopyrido[2,3-c]pyridazin-8(7H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (95 - 123 - WSGR Docket No.51503-744601 mg, 0.17 mmol) in DCM (2 mL) was added TFA (4 mL). The solution was stirred at room temperature for 3 h, then concentrated and purified by prep-TLC (dichloromethane/0.2% NH3 in methanol = 25/1) to give (E)-3-(4-(8-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-oxo-7,8- dihydropyrido[2,3-c]pyridazin-3-yl)-3-hydroxyphenyl)-N-methylacrylamide (49 mg, 69 % yield) as light yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.15-8.08 (m, 1H), 8.04-7.97 (m, 2H), 7.40 (d, J = 15.6 Hz, 1H), 7.24-7.19 (m, 2H), 6.94 (d, J = 9.6 Hz, 1H), 6.66 (d, J = 15.6 Hz, 1H), 6.15-5.94 (m, 1H), 3.61 (s, 2H), 2.92-2.78 (m, 2H), 2.73 (d, J = 4.8 Hz, 3H), 1.88-1.70 (m, 4H), 1.60-1.50 (m, 2H). LCMS: m/z = 432.2 [M+H]+ , tR = 1.38 min [0334] Example 30: Synthesis of SMSM 4-8.
Figure imgf000125_0001
- 124 - WSGR Docket No.51503-744601 [0335] Example 31: Synthesis of SMSM 4-7.
Figure imgf000126_0001
- 125 - WSGR Docket No.51503-744601 [0337] Example 33: Synthesis of SMSM 4-15.
Figure imgf000127_0001
- 126 - WSGR Docket No.51503-744601 [0338] Example 34: Synthesis of SMSM 4-24.
Figure imgf000128_0001
[0339] Example 35: Biological assay for lowering of Huntingtin Protein [0340] Compounds were tested on GM04724 (CAG 70/20) Huntington’s disease patient lymphoblast cells at doses ranging from 10 µM to 0.6 nM.4,500 cells/well were seeded in 384 well plates. Compounds were incubated for 48 hours. mHTT protein levels were assessed by the 2B7–MW1 assay via Mesoscale Discovery (MSD) as previously reported (Macdonald et al., 2014). The antibody pair is comprised of previously characterized monoclonals (2B7 and MW1) interrogating two regions for HTT conformation and biological properties: the N17 domain and the polyQ domain (Baldo et al., 2012; Ko et., 2001).2B7–MW1 is dependent on subject/animal specific levels of HTT at the time of treatment.2B7–MW1 is dependent on polyQ expansion (e.g., the higher the expansion the higher the signal) and on mHTT size (e.g., a similar polyQ will give higher signal with smaller HTT size). The results are shown in Table 5 below. [0341] Table 5 - * EC50 range (nM): 0.01 ≤ A ≤ 15; 16 ≤ B ≤ 50; 51 ≤ C ≤ 100; 101 ≤ D ≤ 500; 501 ≤ E ≤ 10,000.
Figure imgf000128_0002
- 127 -

Claims

WSGR Docket No.51503-744601 CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I):
Figure imgf000129_0001
Formula (I) wherein, A1 is N or CRA1, A2 is N or CRA2, A3 is N or CRA3; provided that when A2 and A3 are each N, then A1 is N; each RA1, RA2, and RA3 is independently hydrogen, F, Cl, –OR1, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C4 cycloalkyl, or substituted or unsubstituted C2–C3 heterocycloalkyl; ring B is saturated or unsaturated, substituted or unsubstituted monocyclic heterocyclic ring; ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Z is CR2; 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; 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; each R1 is independently hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; - 128 - WSGR Docket No.51503-744601 R2 is hydrogen, substituted or unsubstituted C1–C4 alkyl, or substituted or unsubstituted C1– C4 haloalkyl; each R4 and R5 is independently H, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, -N(R7)2, -CH2OR7, - C(=O)R7, - C(=O)OR7, -C(=O)N(R7)2, -S(=O)R7, -S(=O)2R7, or -NR7C(=O)R7; R6 is -C(=O)R7, -C(=O)OR7, -C(=O)N(R8)2, -C=(O)N(OR7)(R7), -P(=O)(R8)2, - P(=O)(R8)N(R8)2, -S(=O)R8, -S(=O)2R8, -S(=O)(=NR7)R7, -N(R8)C(=O)R8, N(R8)S(=O)R8, N(R8)S(=O)2R8, -C(=O)N(R8)S(=O)2R8, -N(R8)C(=O)N(R8)2, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R7 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R8 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, -OR7, -N(R7)2, -CH2OR7, -C(=O)R7, - C(=O)OR7, - C(=O)N(R7)2, -S(=O)R7, -S(=O)2R7, or -NR7C(=O)R7; or two R8 groups on the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form substituted or unsubstituted C2-C10heterocycloalkyl; each R11, R12, R13, R14, R16, R17, R19, and R20 is independently selected from the group consisting of hydrogen, F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; each R15 and R18 is independently selected from the group consisting of hydrogen, F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; a is 0 or 1; b is 0; c is 0, 1, or 2; and d is 0, 1, or 2, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof. 2. The compound of claim 1, wherein the compound of Formula (I) has the structure of Formula (Ia): - 129 - WSGR Docket No.51503-744601
Figure imgf000131_0001
3. The compound of claim 1 or 2, wherein the compound of Formula (I) has the structure of Formula (Ib):
Figure imgf000131_0002
4. The compound of claim 1 or 2, wherein the compound of Formula (I) has the structure of Formula (Ic): - 130 - WSGR Docket No.51503-744601
Figure imgf000132_0001
5. The compound of claim 1, wherein the compound of Formula (I) has the structure of Formula (Id):
Figure imgf000132_0002
6. The compound of claim 1 or 5, wherein the compound of Formula (I) has the structure of Formula (Ie): - 131 - WSGR Docket No.51503-744601
Figure imgf000133_0001
7. The compound of claim 1 or 5, wherein the compound of Formula (I) has the structure of Formula (If):
Figure imgf000133_0002
8. The compound of any one of claims 1-7, wherein ring B is 5-, 6-, 7-, or 8- membered heterocyclic ring. 9. The compound of claim 8, wherein ring B is 6- membered heterocyclic ring. 10. The compound of claim 9, wherein ring B is 6- membered heterocyclic ring having 1, 2, or 3 nitrogen atoms. 11. The compound of claim 8 or 9, wherein ring B is 6- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. 12. The compound of claim 8 or 9, wherein ring B is 6- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 sulfur atom. - 132 - WSGR Docket No.51503-744601 13. The compound of claim 8 or 9, wherein ring B is 6- membered heterocyclic ring selected from:
Figure imgf000134_0001
- 133 - WSGR Docket No.51503-744601
Figure imgf000135_0001
, - 134 - WSGR Docket No.51503-744601
Figure imgf000136_0001
each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1- C4alkyl, or substituted or unsubstituted C1-C4haloalkyl, or two Rz taken together form an oxo; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl. 14. The compound of claim 8 or 9, wherein ring B is 6- membered heterocyclic ring selected from: - 135 - WSGR Docket No.51503-744601
Figure imgf000137_0001
each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1- C4alkyl, or substituted or unsubstituted C1-C4haloalkyl, or two Rz taken together form an oxo; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl. 15. The compound of claim 8 or 9, wherein ring B is 6- membered heterocyclic ring selected from: - 136 - WSGR Docket No.51503-744601
Figure imgf000138_0001
. 16. The compound of claim 8, wherein ring B is 7- membered heterocyclic ring. 17. The compound of claim 16, wherein ring B is 7- membered heterocyclic ring having 1, 2, or 3 nitrogen atoms. 18. The compound of claim 16 or 17, wherein ring B is 7- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. 19. The compound of claim 16 or 17, wherein ring B is 7- membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 sulfur atom. 20. The compound of claim 16 or 17, wherein ring B is 7- membered heterocyclic ring selected from: - 137 - WSGR Docket No.51503-744601
Figure imgf000139_0001
, - 138 - WSGR Docket No.51503-744601
Figure imgf000140_0001
each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1- C4alkyl, or substituted or unsubstituted C1-C4haloalkyl, or two Rz taken together form an oxo; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl. 21. The compound of claim 16 or 17, wherein ring B is 7- membered heterocyclic ring selected from:
Figure imgf000140_0002
, wherein each Rz is independently hydrogen, halogen, -CN, -OR3, substituted or unsubstituted C1- C4alkyl, or substituted or unsubstituted C1-C4haloalkyl, or two Rz taken together form an oxo; and R3 is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl. - 139 - WSGR Docket No.51503-744601 22. The compound of claim 16 or 17, wherein ring B is 7- membered heterocyclic ring selected from:
Figure imgf000141_0001
23. The compound of claim 8, wherein ring B is a 5-membered heterocyclic ring. 24. The compound of claim 23, wherein ring B is a 5-membered heterocyclic ring having 1 or 2 nitrogen atoms. 25. The compound of claim 23, wherein ring B is a 5-membered heterocyclic ring having 1 or 2 nitrogen atoms and 1 oxygen atom. 26. The compound of claim 23, wherein ring B is a 5-membered heterocyclic ring selected from:
Figure imgf000141_0002
27. The compound of claim 26, wherein ring B is selected from:
Figure imgf000141_0003
28. The compound of any one of claims 13, 14, 20, 21, or 26, wherein each Rz is independently hydrogen, F, -CN, -OCH3, -OCF3, -CH3, or -CF3. 29. The compound of any one of claims 13, 14, 20, 21, or 26, wherein each Rz is hydrogen. - 140 - WSGR Docket No.51503-744601 30. The compound of any one of claims 1-29, wherein ring Q is 2–hydroxy–phenyl substituted with 1, 2, or 3 substituents independently selected from: deuterium, halogen, -OH, -NO2, -CN, -SR1, -S(=O)R1, -S(=O)2R1, -N(R1)2, -C(=O)R1, - OC(=O)R1, -C(=O)OR1, -C(=O)N(R1)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; and each R1 is independently hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, - CD3, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 31. The compound of claim 30, wherein ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. 32. The compound of claim 31, wherein ring Q is 2–hydroxy–phenyl substituted with substituted or unsubstituted heteroaryl, wherein if heteroaryl is substituted then it is substituted with 1 or 2 substituents independently selected from: deuterium, halogen, -OH, -NO2, -CN, –SR1, –S(=O)R1, –S(=O)2R1, –N(R1)2, –C(=O)R1, – OC(=O)R1, –C(=O)OR1, –C(=O)N(R1)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; and each R1 is independently hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, - CD3, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 33. The compound of any one of claims 1–32, wherein:
Figure imgf000142_0001
, wherein - 141 - WSGR Docket No.51503-744601 each RQ is independently selected from hydrogen,–F, –Cl, -CN, –OH, -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, –CF3, –OCH3, -OCH2CH3, -CH2OCH3, -OCH2CH2CH3, and - OCH(CH3)2. 34. The compound of any one of claims 1-32, wherein ring Q is substituted or unsubstituted heteroaryl. 35. The compound of claim 34, wherein ring Q is substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl. 36. The compound of claim 34, wherein ring Q is substituted or unsubstituted 6-membered monocyclic heteroaryl. 37.
Figure imgf000143_0001
each RQ is independently selected from hydrogen, –F, –Cl, -CN, –OH, -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, –CF3, –OCH3, -OCH2CH3, -CH2OCH3, -OCH2CH2CH3, and - OCH(CH3)2. 38. The compound of claim 33 or 37, wherein each RQ is independently hydrogen, deuterium, – F, –Cl, -CN, –OH, -CH3,–CF3, or –OCH3. 39. The compound of claim 33 or 37, wherein each RQ is independently hydrogen or –F. 40. The compound of claim 33 or 37, wherein each RQ is hydrogen. 41. The compound of any one of claims 1–40, wherein R4 and R5 are each independently hydrogen, deuterium, or C1-C4alkyl. 42. The compound of any one of claims 1–40, wherein R4 and R5 are each independently hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or cyclopropyl. 43. The compound of any one of claims 1–40, wherein R4 and R5 are each independently hydrogen, -CH3, -CH(CH3)2, -CF3, or cyclopropyl. - 142 - WSGR Docket No.51503-744601 44. The compound of any one of claims 1–40, wherein R4 and R5 are each independently hydrogen, -CH3, or -CF3. 45. The compound of any one of claims 1–40, wherein R4 and R5 are each hydrogen. 46. The compound of any one of claims 1–45, wherein R6 is -C(=O)CH3, -C(=O)CH2CH3, - C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, or -C(=O)N(CH3)2, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. 47. The compound of any one of claims 1–45, wherein R6 is -C(=O)R7, -C(=O)OR7, - C(=O)N(R8)2. 48. The compound of any one of claims 1–45, wherein R6 is -C(=O)NHCH3 or -C(=O)N(CH3)2. 49. The compound of any one of claims 1–45, wherein R6 is -C(=O)NHCH3. 50. The compound of any one of claims 1–49, wherein W is substituted or unsubstituted C1-C3 alkylene. 51. The compound of claim 50, wherein W is –CH2–. 52. The compound of claim 50, wherein W is –CH2CH2–. 53. The compound of claim 50, wherein W is –CH2CH2CH2–. 54. The compound of any one of claims 1–49, wherein W is substituted or unsubstituted C1-C2 heteroalkylene. 55. The compound of claim 54, wherein W is –CH2OCH2–. 56. The compound of any one of claims 1–55, wherein R is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C5 cycloalkyl, or substituted or unsubstituted C2–C4 heterocycloalkyl. 57. The compound of any one of claims 1–55, wherein R is -CH3, -CH2CH3, -CH2F, -CHF2, or -CF3. 58. The compound of any one of claims 1–55, wherein R is hydrogen. 59. The compound of any one of claims 1-4 or 8–58, wherein one or more of R11, R12, and R16 is independently selected from F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl. 60. The compound of any one of claims 1-4 or 8–58, wherein one or more of R11, R12, and R16 is independently selected from F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. 61. The compound of any one of claims 1-4 or 8–58, wherein R11, R12, and R16 are hydrogen. - 143 - WSGR Docket No.51503-744601 62. The compound of any one of claims 1 or 5–58, wherein one or more of R16 and R17 is independently selected from F, –OR1, substituted or unsubstituted C1–C4 alkyl, a substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl. 63. The compound of any one of claims 1 or 5–58, wherein one or more of R16 and R17 is independently selected from F, -OH, -OCH3, -OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and - CF3. 64. The compound of any one of claims 1 or 5–63, wherein R16 and R17 are hydrogen. 65. The compound of claim 1, wherein R19 is independently selected from H, F, -OH, -OCH3, - OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. 66. The compound of claim 1, wherein R19 is H or F. 67. The compound of claim 1, wherein R20 is independently selected from H, F, -OH, -OCH3, - OCF3, -CH3, -CH2OH, -CH2F, -CHF2, and -CF3. 68. The compound of claim 1, wherein R20 is H or F. 69. The compound of any one of claims 1–68, wherein R2 is hydrogen, -CH3, or -OCH3. 70. The compound of claim 64, wherein R2 is hydrogen. 71. The compound of any one of claims 1–70, wherein each R15 and R18 is independently selected from hydrogen, deuterium, F, –OR1, substituted or unsubstituted C1–C3 alkyl, substituted or unsubstituted C1–C3 fluoroalkyl, and substituted or unsubstituted C1–C3 heteroalkyl. 72. The compound of any one of claims 1–70, wherein each R15 and R18 is independently selected from hydrogen, deuterium, F, -CH3, and -OCH3. 73. The compound of any one of claims 1–70, wherein R15 and R18 are both hydrogen. 74. The compound of any one of claims 1–70, wherein R15 and R18 are both -CH3. 75. The compound of any one of claims 1–70, wherein R15 is hydrogen and R18 is -CH3. 76. The compound of any one of claims 1–70, wherein R15 is -CH3 and R18 is hydrogen. 77. The compound of any one of claims 1-76, wherein each RA, RA1, RA2, and RA3 is independently hydrogen, F, Cl, or -CH3. 78. The compound of any one of claims 1-76, wherein each RA, RA1, RA2, and RA3 is hydrogen. 79. The compound of claim 73, wherein each RA, RA1, RA2, and RA3 is deuterium. 80. The compound of any one of claims 1-79, wherein the abundance of deuterium in each of RA, RA1, RA2, RA3, RQ, RZ, R1, R2, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17, R18, R19, and/or R20 is independently at least 1%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium. - 144 - WSGR Docket No.51503-744601 81. The compound of any one of claims 1-79, wherein one or more of RA, RA1, RA2, RA3, RQ, RZ, R1, R2, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17, R18, R19, and/or R20 groups comprise deuterium at a percentage higher than the natural abundance of deuterium. 82. A pharmaceutical composition comprising a compound of any one of claims 1-81, and a pharmaceutically acceptable excipient or carrier. 83. A method of treating a condition or disease comprising administering a compound of any one of claims 1-81, to a subject in need thereof. 84. A method of modulating splicing, comprising administering a compound of any one of claims 1-81 to cells, wherein the compound modulates splicing at a splice site sequence of a pre-mRNA that encodes a mRNA, wherein the mRNA encodes a target protein or a functional RNA. 85. Use of a compound of any one of claims 1-81, in the manufacture of a medicament for the treatment of a condition or disease. - 145 -
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