Compositions Useful for Modulating Splicing

Abstract

The present application discloses compounds of formula (I) that modulate the splicing of pre-mRNA encoded by a gene, and methods of treating diseases and conditions associated with the gene expression or activity of the protein encoded by the gene, such as spinocerebellar ataxia 3 (SCA3 or Machado-Joseph disease). TIFF2026503578000219.tif7566

Description

Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 480,564, filed January 19, 2023, which is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format, and is incorporated herein by reference in its entirety. The XML copy created on January 16, 2024, is named 51503-770_603_SL.SIP and is 12,471 bytes in size. [Background technology]

[0003] Spinocerebellar ataxia 3 (SCA3, or Machado-Joseph disease) is a rare, inherited, autosomal dominant neurodegenerative disorder. It is characterized by progressive degeneration of the brainstem, cerebellum, and spinal cord, although neurons in other brain regions are also affected. Presenting symptoms include walking problems, difficulty speaking, clumsiness, and often visual blurring and diplopia, accompanied by slowed eye movements and increased intraocular pressure, initially limiting upward gaze. Gait becomes increasingly difficult, leading to the need for assistive devices 10–15 years after onset. Late in the disease course, patients become wheelchair-bound and develop severe dysphagia, dysphagia, and facial and temporal atrophy. The disease progresses relentlessly through pulmonary complications, leading to death anywhere from 6 to approximately 30 years after onset.

[0004] SCA3 is caused by a CAG trinucleotide repeat in exon 10 of the ataxin-3 (ATXN3) gene. ATXN3 encodes a deubiquitin kinase with a wide range of functions but is not believed to be an essential gene. Disease-causing variants of the ATXN3 gene contain approximately 40 to more than 200 CAG trinucleotide repeats in exon 10. The expanded CAG repeat in the ATXN3 gene translates into expanded polyglutamine repeats (polyQ) in the ataxin-3 protein, and this toxic ataxin-3 protein is associated with aggregates. The polyglutamine-expanded ataxin-3 protein in these aggregates is ubiquitinated, and the aggregates contain other proteins, including heat shock proteins and transcription factors. Aggregates are frequently observed in the brain tissue of SCA3 patients. Currently, there is no cure for SCA3. Summary of the Invention

[0005] In one aspect, the disclosure provides a compound of formula (I):

[0006] [ka]

[0007] (In the formula, R 21 , R 23 , and R 24 is as defined in this disclosure), or a pharmaceutically acceptable salt thereof.

[0008] Also provided in this disclosure is a pharmaceutical composition comprising a compound disclosed in this disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0009] In some aspects, the present disclosure describes a method for regulating the splicing of ataxin 3 (ATXN3) pre-mRNA, comprising contacting a splice site sequence or cell containing ataxin 3 (ATXN3) pre-mRNA with a small molecule splicing modulator compound (SMSM) disclosed in the present disclosure, wherein the SMSM binds to the ATXN3 pre-mRNA and regulates the splicing of the ATXN3 pre-mRNA in the subject's cell to produce a spliced ​​product of the ATXN3 pre-mRNA.

[0010] In some aspects, the present disclosure describes a method for treating, preventing, delaying progression of, or ameliorating symptoms of a disease or condition associated with ataxin 3 (ATXN3) expression or activity levels in a subject in need thereof, comprising administering a therapeutically effective amount of a small molecule splicing modulator (SMSM) disclosed in the present disclosure, wherein the SMSM binds to a pre-mRNA encoded by ATXN3 and regulates splicing of the ATXN3 pre-mRNA in the subject's cells to produce a spliced ​​product of the ATXN3 pre-mRNA and reduce the amount of full-length ATXN3.

[0011] Incorporation by Reference 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 OF THE INVENTION

[0012] Unless otherwise defined, all technical and scientific terms used in this disclosure 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 in this disclosure can be used in the practice or testing of this disclosure, suitable methods and materials are described below.

[0013] definition The term "small molecule splicing regulator" or "SMSM" refers to a small molecule compound that binds to cellular components (e.g., DNA, RNA, pre-mRNA, protein, RNP, snRNA, carbohydrate, lipid, cofactor, nutrient, and / or metabolite) and regulates splicing. For example, SMSM can bind to polynucleotides such as RNA (e.g., pre-mRNA) with aberrant splice sites, thereby regulating the conformation of the polynucleotide. For example, SMSM can bind to proteins such as spliceosomal proteins or ribonucleoproteins, thereby regulating the conformation of the protein. For example, SMSM can bind to spliceosomal components, such as spliceosomal proteins or snRNAs, thereby regulating the conformation of the spliceosomal proteins or snRNAs. For example, SMSM is a compound of Formula (I). The term "small molecule splicing regulator" or "SMSM" specifically excludes compounds consisting of oligonucleotides.

[0014] As used herein, "conformational alteration," "conformational modification," or "conformational adjustment" refers to a change in the spatial orientation of chemical moieties relative to one another. Those skilled in the art will recognize steric mechanisms, including, but not limited to, steric hindrance, steric shielding, steric attraction, chain crossing, steric repulsion, steric inhibition of resonance, and steric inhibition of protonation.

[0015] Any open valency appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein indicates the presence of a hydrogen, unless otherwise indicated.

[0016] The definitions set forth in this disclosure apply regardless of whether the terms in question appear alone or in combination. It is anticipated that the definitions set forth in this disclosure can be added to form chemically relevant combinations, such as, for example, "heterocycloalkylaryl," "haloalkylheteroaryl," "arylalkylheterocycloalkyl," or "alkoxyalkyl." The last member of the combination is the radical that is attached to the rest of the molecule. The other members of the combination are attached to the linking radical in reverse order relative to the literal sequence, for example, the combination arylalkylheterocycloalkyl refers to a heterocycloalkyl radical substituted by an alkyl substituted by an aryl.

[0017] When referring to the number of substituents, the term "one or more" refers to a range from one substituent to the maximum number of substituents possible, i.e., from replacement of one hydrogen to replacement of all hydrogens by substituents.

[0018] The term "optional" or "optionally" means that the subsequently described event or circumstance may occur, but need not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0019] The term "substituent" means an atom or group of atoms that replaces a hydrogen atom on a parent molecule.

[0020] The term "substituted" means that the specified group has one or more substituents. Any group may have multiple substituents, and when a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When referring to the number of substituents, the term "one or more" means from one substituent to the maximum number of substituents possible, i.e., from replacement of one hydrogen to replacement of all hydrogens by substituents.

[0021] The terms "compounds of the disclosure," "compounds disclosed herein," "small molecule conformational modulators," "small molecule splicing modulators," "conformational modulators," "splicing modulators," "compounds that modify splicing," and "compounds that modify splicing" are used interchangeably herein and refer to the compounds disclosed herein, as well as stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof.

[0022] The following abbreviations are used throughout this specification: acetic acid (AcOH), ethyl acetate (EtOAc), butyl alcohol (n-BuOH), 1,2-dichloroethane (DCE), dichloromethane (CHCl, DCM), diisopropylethylamine (Diipea), dimethylformamide (DMF), hydrogen chloride (HCl), methanol (MeOH), methoxymethyl bromide (MOMBr), N-methyl-2-pyrrolidone (NMP), methyl iodide (MeI), n-propanol (n-PrOH), p-methoxybenzyl (PMB), triethylamine (EtN), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), (Pd(dppf)Cl). 、Sodium ethanethiolate (EtSNa), sodium acetate (NaOAc), sodium hydride (NaH), sodium hydroxide (NaOH), tetrahydropyran (THP), tetrahydrofuran (THF).

[0023] As used herein, C1-C x is C1-C2, C1-C3... C1-C x By way of example only, a group designated as "C1-C4" indicates that there are from 1 to 4 carbon atoms present in the moiety, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms in the group. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from 1 to 4 carbon atoms present in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0024] The term "oxo" refers to a ═O substituent.

[0025] "Carboxyl" refers to --COOH.

[0026] "Cyano" refers to -CN.

[0027] The term "thioxo" refers to the ═S substituent.

[0028] "Amidinyl" is a compound of the formula -C(=NR a )-N(R a )2, where each R a are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl. In some embodiments, the amidinyl is C(=NH)NH2. In some embodiments, the amidinyl is C(=NH)NH(C1-C6 alkyl).

[0029] The terms "halo," "halogen," and "halide" are used interchangeably in this disclosure and refer to fluoro, chloro, bromo, or iodo.

[0030] The term "alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing up to 10 carbon atoms is C1-C 10 Similarly, when referred to as alkyl, for example, an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl. Alkyl containing other numbers of carbon atoms (and other moieties defined herein) are represented similarly. Alkyl groups include C1-C 10 Examples of alkyl include, but are not limited to, 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, alkyl is methyl or ethyl. In some embodiments, alkyl is —CH(CH3)2 or —C(CH3)3. Unless otherwise expressly stated herein, alkyl groups may be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group. In some embodiments, alkylene is -CH-, -CHCH-, or -CHCHCH-. In some embodiments, alkylene is -CH-. In some embodiments, alkylene is -CHCH-. In some embodiments, alkylene is -CHCHCH-. In some embodiments, alkylene is -CHCHCH-.

[0031] The term "alkoxy" refers to a radical of formula -OR, where R is an alkyl radical as defined herein. Unless otherwise expressly stated herein, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy. In some embodiments, an alkoxy is methoxy. In some embodiments, an alkoxy is ethoxy.

[0032] The term "alkylamino" refers to a radical of the formula -NHR or -NRR, where each R is independently an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0033] 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(R)=CR2, where R refers to the remainder of the alkenyl group, which can be the same or different. In some embodiments, R is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0034] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0035] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. An aromatic may be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, furanyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0036] The term "aryl" refers to a radical derived from a hydrocarbon ring system containing at least one aromatic ring, where each of the atoms forming the ring is a carbon atom. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless otherwise expressly stated herein, the term "aryl" or the prefix "ar-" (e.g., in aralkyl) is intended to include aryl radicals that are optionally substituted. In some embodiments, an aryl group is partially reduced to form a cycloalkyl group, as defined herein. In some embodiments, an aryl group is fully reduced to form a cycloalkyl group, as defined herein.

[0037] The term "haloalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced by the same or different halogen atoms, specifically, a fluoro atom. Examples of haloalkyl include monofluoro-, difluoro-, or trifluoro-methyl, -ethyl, or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl. The term "perhaloalkyl" refers to an alkyl group in which all of the alkyl group's hydrogen atoms have been replaced by the same or different halogen atoms. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless otherwise expressly stated herein, a haloalkyl group may be optionally substituted.

[0038] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0039] Aminoalkyl refers to an alkyl radical substituted with one or more amines, as defined above. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Examples of aminoalkyl include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0040] Cyanoalkyl refers to an alkyl radical, as defined above, substituted with one or more cyano groups. In some embodiments, the alkyl is substituted with one cyano group. In some embodiments, the alkyl is substituted with one, two, or three cyano groups. Aminoalkyl includes, for example, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, or cyanopentyl.

[0041] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced with the same or different halogen atom, specifically a fluoro atom. Examples of haloalkoxyl include monofluoro-, difluoro-, or trifluoro-methoxy, -ethoxy, or -propoxy, such as 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy. The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms of the alkoxy group have been replaced with the same or different halogen atoms. Examples of haloalkoxyl include trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, etc. Unless otherwise expressly stated in this specification, a haloalkoxy group may be optionally substituted.

[0042] The term "bicyclic ring system" refers to two rings fused together through a common single or double bond (annealed bicyclic ring system), through an arrangement of three or more common atoms (bridged bicyclic ring system), or through a single common atom (spiro bicyclic ring system). Bicyclic ring systems can be saturated, partially unsaturated, unsaturated, or aromatic. Bicyclic ring systems can contain heteroatoms selected from N, O, and S.

[0043] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. That is, this term distinguishes carbocyclic rings from "heterocyclic" rings or "heterocycles," which contain at least one atom other than carbon in the ring backbone. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl.

[0044] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case the cycloalkyl is attached through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl groups 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, tetraynyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclic[1.1.1]pentyl. Unless otherwise expressly stated in the specification, cycloalkyl groups may be optionally substituted.

[0045] The term "bridge" refers to any ring structure having two or more rings that includes a bridge connecting two bridgehead atoms. A bridgehead atom is defined as an atom that is part of the skeletal framework of a molecule and is bonded to three or more other skeletal atoms. In some embodiments, the bridgehead atom is C, N, or P. In some embodiments, the bridge is a single atom or a chain of atoms connecting two bridgehead atoms. In some embodiments, the bridge is a valence bond connecting two bridgehead atoms. In some embodiments, the bridged ring system is a cycloalkyl. In some embodiments, the bridged ring system is a heterocycloalkyl.

[0046] The term "fused" refers to any ring structure described herein that 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 that becomes part of the fused heterocyclyl ring or fused heteroaryl ring may be replaced with one or more N, S, and O atoms. Non-limiting examples of fused heterocyclyl or heteroaryl ring structures include 6-5 fused heterocycles, 6-6 fused heterocycles, 5-6 fused heterocycles, 5-5 fused heterocycles, 7-5 fused heterocycles, and 5-7 fused heterocycles.

[0047] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl. In some embodiments, the fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0048] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)-), sulfur (e.g., -S-, -S(=O)-, or -S(=O)-), or combinations thereof. In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C-C heteroalkyl. Representative heteroalkyl groups include, but are not limited to, -OCHOMe, -OCHCHOH, -OCHCHOMe, or -OCHCHOCHCHNH. In some embodiments, a heteroalkyl contains 1 skeletal heteroatom. In some embodiments, a heteroalkyl contains 1 to 3 skeletal heteroatoms.

[0049] The term "heteroalkylene" refers to an alkyl radical as defined above in which one or more carbon atoms of the alkyl have been replaced with an O, N, or S atom. A "heteroalkylene" or "heteroalkylene chain" refers to a straight or branched divalent heteroalkyl chain connecting the remainder of the molecule to the radical group. Unless stated otherwise specifically in the specification, a heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkylene groups include, but are not limited to, -OCH2CHO-, -OCH2CHOCH2CHO-, or -OCH2CHOCH2CHOCH2CHO-.

[0050] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise expressly stated in the specification, a heterocycloalkyl radical may be a monocyclic or bicyclic ring system, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or a bridged ring system. In some embodiments, a heterocycloalkyl is monocyclic. In some embodiments, a heterocycloalkyl is bicyclic. In some embodiments, a heterocycloalkyl is partially saturated. In some embodiments, a heterocycloalkyl is fully saturated. The nitrogen, carbon, or sulfur atom in a heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially saturated 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 specified, heterocycloalkyls have 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have 2 to 10 carbons and 1 or 2 N atoms in the ring.In some embodiments, a heterocycloalkyl has 2 to 10 carbons and 3 or 4 N atoms in the ring. In some embodiments, a heterocycloalkyl has 2 to 12 carbons, 0 to 2 N atoms, 0 to 2 O atoms, 0 to 2 P atoms, and 0 to 1 S atoms in the ring. In some embodiments, a heterocycloalkyl has 2 to 12 carbons, 1 to 3 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless otherwise expressly stated in this specification, a heterocycloalkyl group may be optionally substituted.

[0051] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings (also known as heterocyclic groups) containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, with heterocyclic groups each having 3 to 12 atoms in their ring system, provided that no ring contains 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) contain rings having 3 to 12 atoms in their ring system, and aromatic heterocyclic groups contain rings having 5 to 12 atoms in their ring system. 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, homopiperiperidinyl, 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, dithiazole ... oranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3h-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.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 possible. For example, groups derived from pyrrole include both pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). 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.

[0052] The term "heteroaryl" refers to an aryl group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryls may be monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, 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, heteroaryl has 0 to 6 N atoms in the ring. In some embodiments, the heteroaryl has 1-4 N atoms in the ring. In some embodiments, the heteroaryl has 4-6 N atoms in the ring. In some embodiments, the heteroaryl has 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl has 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl.In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl. In some embodiments, the heteroaryl group is partially reduced to form a heterocycloalkyl group as defined herein. In some embodiments, the heteroaryl group is fully reduced to form a heterocycloalkyl group as defined herein.

[0053] The term "residue" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized as chemical entities that are embedded within or appended to a molecule.

[0054] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from D, halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)(C-C alkyl). In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -NH(cyclopropyl), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituents are substituted with one or two of the preceding groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0055] The term "tautomer" refers to a proton migration 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 the migration of a hydrogen atom, which involves switching a single bond and an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomer interconversions include the following:

[0056] [ka]

[0057] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral (po), intraduodenal (id), parenteral injection (including intravenous (iv), subcutaneous (sc), intraperitoneal (ip), intramuscular (im), intravascular or infusion (inf.)), topical (top.), and rectal (pr.) administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described in the present disclosure. In some embodiments, the compounds and compositions described in the present disclosure are administered orally.

[0058] As used in this disclosure, terms such as "co-administration" are intended to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which the therapeutic agents are administered by the same or different routes of administration, or at the same time or at different times.

[0059] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian class, e.g., humans, non-human primates such as chimpanzees, and other ape and monkey species, livestock such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, laboratory animals such as rodents, e.g., rats, mice, and guinea pigs, etc. In one aspect, a mammal is a human. The term "animal" as used herein includes human and non-human animals. In one embodiment, a "non-human animal" is a mammal, e.g., a rodent such as a rat or a mouse. In one embodiment, the non-human animal is a mouse.

[0060] The term "pharmaceutically acceptable" refers to the attributes of a material that is generally safe, non-toxic, and not biologically or otherwise undesirable, and that is useful in preparing pharmaceutical compositions that are acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable" can refer to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material can 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 included.

[0061] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" may be used interchangeably and can refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, excipient, preservative, or lubricant used in formulating a pharmaceutical product.

[0062] The term "pharmaceutically acceptable salt" refers to a salt that is 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 the organism to which it is administered and / or does not abrogate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting an SMSM compound of the present disclosure with an acid. Pharmaceutically acceptable salts can also be obtained by reacting a compound of the present disclosure with a base to form a salt.

[0063] As used herein, the term "low molecular weight compound" can be used interchangeably with "small molecule" or "small organic molecule." A small molecule refers to a compound other than a peptide or oligonucleotide, and typically has a molecular weight of less than about 2000 daltons, e.g., less than about 900 daltons.

[0064] Small molecule splicing regulators (SMSMs) It has been found that the compounds of the present disclosure and their pharmaceutically acceptable compositions are effective as drugs for treating, preventing, or improving diseases or symptoms related to target RNA.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 regulators (SMSMs).These SMSMs can regulate specific splicing events in specific pre-mRNA molecules.The small molecules of the present disclosure are different from and not related to antisense oligonucleotides or antigene oligonucleotides.

[0065] In one embodiment, the SMSM described in this disclosure is a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof:

[0066] [ka]

[0067] During the ceremony, -R 21 is unsubstituted or contains 1, 2, or 3 independently selected R 1A furanyl substituted with a group, and each R 1A are independently halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C(=O)OH, -C(=O)C 1-6 Alkyl, -C(=O)C 1-6 Haloalkyl, and -C(=O)C 1-6 alkoxy; -R 23 H, azide, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, -(C 1-6 Alkylene)-C 3-10 Cycloalkyl, -(C 1-6 alkylene)-4 to 10-membered heterocycloalkyl, -(C 1-6 Heteroalkylene)-C 3-10 Cycloalkyl, -(C 1-6 Heteroalkylene)-4 to 10-membered heterocycloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, OR a3 , S.R. a3 , C(=O)R b3 , C(=O)OR b3 , N.R. c3 R d3 , C(=O)NR c3 R d3 , -OC(=O)NR c3 R d3 , N.R. c3 C(=O)R b3 , N.R. c3 C(=O)OR b3 , N.R. c3 C(=O)NR c3 Rd3 , N.R. c3 S(=O)2R b3 , N.R. c3 S(=O)NR c3 R d3 , S(O)NR c3 R d3 , and S(O)NR c3 R d3 wherein C is selected from the group consisting of 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 3-10 Cycloalkyl, C 6-10 The aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl each optionally have 1, 2, 3, or 4 independently selected R 20 may be substituted by a group, -R 24 is a halo, -Each R a3 , R b3 , R c3 , and R d3 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -(C 1-6 Alkylene)-C 1-6 Alkoxy, C 3-10 Cycloalkyl, -(C 1-6 Alkylene)-C 3-10 Cycloalkyl, C 6-10 independently selected from the group consisting of aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -(C 1-6 Alkylene)-C 3-10 Cycloalkyl, C 6-10The aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl each optionally have 1, 2, 3, or 4 independently selected R 20 may be substituted by a group, or R c3 and R d3 together with the N atom to which they are attached to form a 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl ring, each of which is selected from 1, 2, 3, or 4 independently selected R 20 optionally substituted by groups, and -Each R 20 are independently OH, SH, CN, NO2, halo, oxo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -(C 1-4 alkyl)-(C 1-4 alkoxy), -(C 1-4 Alkoxy)-(C 1-4 Alkoxy), C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl)carbamyl, carbamoyl, C 1-4 Alkylcarbamoyl, di(C 1-4 alkyl)carbamoyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonylamino, C 1-4 Alkyl sulfonyl amino, amino sulfonyl, C 1-4 Alkylaminosulfonyl, di(C 1-4 Alkyl)aminosulfonyl, aminosulfonylamino, C1-4 Alkylaminosulfonylamino, di(C 1-4 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4 Alkylaminocarbonylamino, di(C 1-4 alkyl)aminocarbonylamino, and amidinyl.

[0068] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, -R 21 is unsubstituted or contains 1, 2, or 3 independently selected R 1A furanyl substituted with a group, wherein each R 1A are independently halo, CN, NO2, alkyl, alkenyl, C 2-6 selected from an alkynyl, an alkoxy, a —C(═O)OH, an ether group, or an ester group, each of which is unsubstituted or substituted; -R 23 is H, oxo, azido, halo, CN, NO2, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, OR a3 , S.R. a3 , C(=O)R b3 , C(=O)OR b3 , N.R. c3 R d3 , C(=O)NR c3 R d3 , -OC(=O)NR c3 R d3 , N.R. c3 C(=O)R b3 , N.R. c3 C(=O)OR b3 , N.R. c3 C(=O)NR c3 R d3 , N.R. c3 S(=O)2R b3 , N.R. c3 S(=O)NR c3 R d3 , S(O)NR c3 R d3 , and S(O)NR c3 Rd3 wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are each unsubstituted or selected from 1, 2, 3, or 4 independently selected R 20 is substituted with a group, -R 24 is a halo, -R a3 , R b3 , R c3 , and R d3 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each of which is unsubstituted or contains 1, 2, 3, or 4 independently selected R 20 is substituted with a group, Each R c3 and R d3 together with the N atom to which they are attached, together form a heteroaryl or heterocycloalkyl ring, each of which is unsubstituted or contains 1, 2, 3, or 4 independently selected R 20 is substituted with a group, and -Each R 20 is independently selected from the group consisting of OH, SH, CN, NO, halo, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, amino, carbamyl, or carbamoyl.

[0069] In some embodiments, R 24 is a halogen. In some embodiments, R 24 is -Br. In some embodiments, R 24 is -F. In some embodiments, R 24 is -Cl. In some embodiments, R 24 is -I.

[0070] In some embodiments, R 21is unsubstituted or substituted furanyl. In some embodiments, R 21 is unsubstituted furanyl. In some embodiments, R 21 is substituted furanyl. In some embodiments, R 21 is one, two, or three independently selected R 1A furanyl substituted with a group, and each R 1A are independently halo, CN, NO2, alkyl, alkenyl, C 2-6 In some embodiments, R is selected from an alkynyl, an alkoxy, a —C(═O)OH, an ether group, or an ester group, each of which is unsubstituted or substituted. 21 are independently selected R 1A and furanyl substituted with 1, 2, or 3 substituents of the group R 1A independently, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 In some embodiments, R 21 are independently selected R 1A and furanyl substituted with 1, 2, or 3 substituents of the group R 1A independently, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 In some embodiments, each R 1A are independently halo, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 In some embodiments, R 1A are each independently a halo, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 In some embodiments, each R 1A independently, halo, C 1-3 Alkyl, and C 1-3 In some embodiments, R is selected from haloalkyl. 1A is halo. In some embodiments, R 1Ais fluoro, chloro, bromo, or iodo. In some embodiments, R 1A is fluoro. In some embodiments, R 1A is chloro. In some other embodiments, R 1A is bromo. In some embodiments, R 1A is iodine.

[0071] In some embodiments, R 21 teeth, [ka] is.

[0072] In some embodiments, R 21 teeth,

[0073] [ka] In some embodiments, R 21 teeth,

[0074] [ka] is.

[0075] In some embodiments, R 23 is H.

[0076] In some embodiments, R 23 is one, two, or three independently selected R 20 groups, and each R 20 The groups are independently OH, SH, CN, NO2, halo, oxo, amino, C 1-3 Alkyl, C 1-3 In some embodiments, R is selected from the group consisting of alkoxy, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, carbamyl, and carbamoyl. 23 is one, two, or three independently selected R 20 groups, and each R 20The groups are independently OH, halo, and C 1-3 In some embodiments, R is selected from the group consisting of alkoxy. 23 is one, two, or three independently selected R 20 groups, and each R 20 The groups are independently OH, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, amino, and C 1-3 In some embodiments, R is selected from the group consisting of alkoxy. 23 is one, two, or three independently selected R 20 groups, and each R 20 The groups are independently OH, halo, amino, and C 1-3 In some embodiments, R is selected from the group consisting of alkoxy. 20 is —OH. In some embodiments, R 20 In some embodiments, R 20 The group is amino. In some embodiments, R 20 The group is C 1-3 It is an alkoxy.

[0077] In some embodiments, R 23 is a substituted or unsubstituted C 1-6 In some embodiments, R 23 is C 1-6 alkyl, C 1-6 Alkyl is one, two, or three independently selected R 20 In some embodiments, R 23 is C 1-6 alkyl, C 1-6 Alkyl is one, two, or three independently selected R 20 groups, and each R 20 The groups are independently OH, SH, CN, NO2, halo, oxo, amino, C 1-3 Alkyl, C 1-3 In some embodiments, R is selected from the group consisting of alkoxy, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, carbamyl, and carbamoyl. 23 is C1-6 alkyl, C 1-6 Alkyl is one, two, or three independently selected R 20 groups, and each R 20 The groups are independently OH, halo, and C 1~3 In some embodiments, R is selected from the group consisting of alkoxy. 23 is C 1-6 alkyl, C 1-6 Alkyl is one, two, or three independently selected R 20 groups, and each R 20 The groups are independently OH, halo, amino, and C 1-3 alkoxy is selected from the group consisting of:

[0078] In some embodiments, R 23 is a substituted or unsubstituted C 1-6 In some embodiments, R is alkenyl. 23 is C 1-6 alkenyl, wherein C 1-6 Alkenyl is one, two, or three independently selected R 20 is substituted with a group.

[0079] In some embodiments, R 23 is a substituted or unsubstituted C 1-6 In some embodiments, R is alkynyl. 23 is C 1-6 Alkynyl, C 1-6 Alkynyl is one, two, or three independently selected R 20 The group is substituted.

[0080] R 23 is hydrogen, deuterium, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 1-6 haloalkyl, and in some embodiments, R 23 is a substituted or unsubstituted C 1-6 In some embodiments, C is heteroalkyl. 1-6Heteroalkyl is —CHCH(NH)CH—S(═O)—CH or —CHCH(NH)CH—S(═O)—CH. In some embodiments, R 23 is —CHCH(NH)CH—S(═O)—CH. In some embodiments, R 23 is —CHCH(NH)CH—S(═O)—CH. In some embodiments, R 23 is —CHCHNHCH. In some embodiments, R 23 is CH2CHNH2CH2OH. In some embodiments, R 23 is CH2CHNH2CH2CH3. In some embodiments, R 23 is CH2CHNH2CH2CH2OH. In some embodiments, R 23 is CH2CHNH2CH2CH2F. In some embodiments, R 23 is CH2CHNH2CH2CHF2. In some embodiments, R 23 is CH2CHNH2CH2CH(CH3)2. In some embodiments, R 23 is CH2CHNH2CHFCH3. In some embodiments, R 23 is CH2CHNH2CH2F. In some embodiments, R 23 is CH2CHNH2CH2OCH3. In some embodiments, R 23 is CH2CHNH2CH2OCD3.

[0081] In some embodiments, R 23 is a substituted or unsubstituted C 1-6 In some embodiments, R 23 is C 1-6 Heteroalkyl, C 1-6 Heteroalkyl is one, two, or three independently selected R 20 In some embodiments, R 23 is C 1-6 Heteroalkyl, C 1-6 Heteroalkyl is one, two, or three independently selected R 20groups, and each R 20 The groups are independently OH, SH, CN, NO2, halo, oxo, amino, C 1-3 Alkyl, C 1-3 In some embodiments, R is selected from the group consisting of alkoxy, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, carbamyl, and carbamoyl. 23 is C 1-6 Heteroalkyl, C 1-6 Heteroalkyl is one, two, or three independently selected R 20 groups, and each R 20 The groups are independently OH, halo, and C 1-3 In some embodiments, R is selected from the group consisting of alkoxy. 23 is C 1-6 Heteroalkyl, C 1-6 Heteroalkyl is one, two, or three independently selected R 20 groups, and each R 20 The groups are independently OH, halo, amino, and C 1-3 alkoxy is selected from the group consisting of:

[0082] In some embodiments, R 23 is a substituted or unsubstituted (C 1-6 Alkylene)-C 3-10 In some embodiments, R 23 is -(C 1-6 Alkylene)-C 3-10 cycloalkyl, -(C 1-6 Alkylene)-C 3-10 Cycloalkyl is one, two, or three independently selected R 20 In some embodiments, the C 1-6 Alkylene is C 1-3 In some embodiments, C is alkylene. 1-6 Alkylene is CH. In some embodiments, C 3-10 Cycloalkyl is an optionally substituted 3-6 membered ring. In some embodiments, C 3-10The cycloalkyl is an optionally substituted 3-membered ring. 3-10 The cycloalkyl is an optionally substituted 4-membered ring. 3-10 The cycloalkyl is an optionally substituted 5-membered ring. 3-10 The cycloalkyl is an optionally substituted 6-membered ring. In some embodiments, C 3-10 Cycloalkyl is

[0083] [ka]

[0084] [ka]

[0085] [ka]

[0086] [ka]

[0087] [ka]

[0088] [ka]

[0089] [ka]

[0090] [ka]

[0091] [ka]

[0092] [ka]

[0093] In some embodiments, R 23 is a substituted or unsubstituted -(C 1-6 alkylene)-4 to 10-membered heterocycloalkyl. In some embodiments, R 23 is -(C 1-6 alkylene)-4 to 10-membered heterocycloalkyl, 1-6 alkylene)-4 to 10-membered heterocycloalkyl is selected from 1, 2, or 3 independently selected R 20 In some embodiments, the C 1-6 Alkylene is C 1-3 In some embodiments, C is alkylene. 1-6 Alkylene is CH2. In some embodiments, the 4- to 10-membered heterocycloalkyl is an optionally substituted 4- to 6-membered ring. In some embodiments, the 4- to 10-membered heterocycloalkyl is an optionally substituted 4-membered ring. In some embodiments, the 4- to 10-membered heterocycloalkyl is an optionally substituted 5-membered ring. In some embodiments, the 4- to 10-membered heterocycloalkyl is an optionally substituted 6-membered ring. In some embodiments, the 4- to 10-membered heterocycloalkyl contains 0-1 oxygen and 0-2 nitrogen atoms. In some embodiments, the 4- to 10-membered heterocycloalkyl is

[0094] [ka]

[0095] [ka]

[0096]

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[0101]

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[0107] In some embodiments, R 23 is a substituted or unsubstituted -(C 1-6 Heteroalkylene)-C 3-10 In some embodiments, R 23 is -(C 1-6 Heteroalkylene)-C 3-10 cycloalkyl, -(C 1-6 Heteroalkylene)-C 3-10 Cycloalkyl is one, two, or three independently selected R 20 In some embodiments, the heteroalkylene is substituted with a C 1-3 In some embodiments, C is heteroalkylene. 3-10 Cycloalkyl is an optionally substituted 3-6 membered ring. In some embodiments, C 3-10 The cycloalkyl is an optionally substituted three-membered ring. 3-10 A cycloalkyl is an optionally substituted 4-membered ring. In some embodiments, C 3-10 The cycloalkyl is an optionally substituted 5-membered ring. 3-10 The cycloalkyl is an optionally substituted 6-membered ring. In some embodiments, the heteroalkylene is C 1-3 In some embodiments, C is heteroalkylene. 3-10 Cycloalkyl is

[0108] [ka]

[0109] [ka]

[0110] [ka]

[0111] [ka]

[0112] [ka]

[0113] [ka]

[0114] [ka]

[0115] [ka]

[0116] [ka]

[0117] [ka]

[0118] In some embodiments, R 23 is a substituted or unsubstituted -(C 1-6 heteroalkylene)-4 to 10-membered heterocycloalkyl. In some embodiments, R 23 is -(C 1-6 heteroalkylene)-4 to 10-membered heterocycloalkyl, -(C 1-6 heteroalkylene)-4 to 10-membered heterocycloalkyl is selected from 1, 2, or 3 independently selected R 20 In some embodiments, the heteroalkylene is substituted with a C 1-3In some embodiments, the 4- to 10-membered heterocycloalkyl is an optionally substituted 4- to 6-membered ring. In some embodiments, the 4- to 10-membered heterocycloalkyl is an optionally substituted 4-membered ring. In some embodiments, the 4- to 10-membered heterocycloalkyl is an optionally substituted 5-membered ring. In some embodiments, the 4- to 10-membered heterocycloalkyl is an optionally substituted 6-membered ring. In some embodiments, the 4- to 10-membered heterocycloalkyl contains 0 to 1 oxygen and 0 to 2 nitrogen atoms. In some embodiments, the 4- to 10-membered heterocycloalkyl is

[0119] [ka]

[0120] [ka]

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] [ka]

[0131] [ka] is.

[0132] In some embodiments, R 23 teeth,

[0133] [ka]

[0134] [ka]

[0135] [ka]

[0136] [ka]

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[0201] [ka]

[0202] [ka]

[0203] [ka]

[0204] [ka]

[0205] [ka]

[0206] [ka]

[0207] [ka]

[0208] [ka] In some embodiments, R 23 teeth,

[0209] [ka]

[0210] [ka]

[0211] [ka]

[0212] [ka]

[0213] [ka] In some embodiments, R 23 teeth,

[0214] [ka] In some embodiments, R 23 teeth,

[0215] [ka] is.

[0216] In some embodiments, R 23 teeth,

[0217] [ka] In some embodiments, R 23 teeth,

[0218] [ka] In some embodiments, R 23 teeth,

[0219] [ka] is.

[0220] In some embodiments, each R20 are independently OH, SH, CN, NO2, halo, oxo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -(C 1-4 alkyl)-(C 1-4 alkoxy), -(C 1-4 Alkoxy)-(C 1-4 Alkoxy), C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl)carbamyl, carbamoyl, C 1-4 Alkylcarbamoyl, di(C 1-4 alkyl)carbamoyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonylamino, C 1-4 Alkyl sulfonyl amino, amino sulfonyl, C 1-4 Alkylaminosulfonyl, di(C 1-4 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-4 Alkylaminosulfonylamino, di(C 1-4 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4 Alkylaminocarbonylamino, di(C 1-4アルキル ) aminocarbonylamino, and amidinyl. In some embodiments, each R 20 are independently OH, SH, CN, NO2, halo, oxo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, amino, C 1-4 Alkylamino, di(C 1-4 In some embodiments, each R is selected from the group consisting of (alkyl)amino, carbamyl, and amidinyl. 20 are independently OH, SH, CN, NO2, halo, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, amino, carbamyl C 1-4 Alkylamino, di(C 1-4 In some embodiments, R is selected from the group consisting of: 20 is OH. In some embodiments, R 20 is NH. In some embodiments, R 20 is SH. In some embodiments, R 20 is CN. In some embodiments, R 20 is F. In some embodiments, R 20 is carbamyl.

[0221] In some embodiments, R a3 , R b3 , R c3 , and R d3 are each independently H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, and C 1-6 In some embodiments, R is selected from the group consisting of haloalkyl. a3 , R b3 , R c3 , and R d3 are each independently H and C 1-6 In some embodiments, Ra3 , R b3 , R c3 , and R d3 are each independently H and C 1-3 In some embodiments, R a3 , R b3 , R c3 , and R d3 are each hydrogen.

[0222] In some embodiments, the compound is a compound of Formula (IIIa) or a pharmaceutically acceptable salt thereof:

[0223] [ka]

[0224] During the ceremony, R 21 and R 24 each has the meaning defined in formula (I), Each R 20a , R 20b , and R 20c are independently H, OH, SH, CN, NO2, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -(C 1-4 alkyl)-(C 1-4 alkoxy), -(C 1-4 Alkoxy)-(C 1-4 Alkoxy), C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, C 1-4 Heteroalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, -(C 1-3 Alkylene)-C 3-10 Cycloalkyl, -(C 1-3 alkylene)-4 to 10-membered heterocycloalkyl, -(C 1-3 Heteroalkylene)-C3-10 Cycloalkyl, -(C 1-3 Heteroalkylene)-4 to 10-membered heterocycloalkyl, amidinyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl)carbamyl, carbamoyl, C 1-4 Alkylcarbamoyl, di(C 1-4 alkyl)carbamoyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonylamino, C 1-4 Alkyl sulfonyl amino, amino sulfonyl, C 1-4 Alkylaminosulfonyl, di(C 1-4 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-4 Alkylaminosulfonylamino, di(C 1-4 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4 Alkylaminocarbonylamino, and di(C 1-4アルキル ) aminocarbonylamino; Each of the cycloalkyl and heterocycloalkyl is selected from halo, CN, SH, —CN, oxo, NO, OH, C alkyl, C alkenyl, C alkynyl, C haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Aminoalkyl, C1-4 hydroxyalkyl, C 1-4 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkoxy, and amino; or R 20a and R 20b together, =NH or =N(C 1-4 alkyl).

[0225] In some embodiments of the compound of Formula (IIIa) or a pharmaceutically acceptable salt thereof, each R 20a , R 20b , and R20c are independently H, OH, SH, CN, NO2, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -(C 1-4 alkyl)-(C 1-4 alkoxy), -(C 1-4 Alkoxy)-(C 1-4 Alkoxy), C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl)carbamyl, carbamoyl, C 1-4 Alkylcarbamoyl, di(C 1-4 alkyl)carbamoyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonylamino, C 1-4 Alkyl sulfonyl amino, amino sulfonyl, C 1-4 Alkylaminosulfonyl, di(C 1-4 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-4 Alkylaminosulfonylamino, di(C 1-4 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4 Alkylaminocarbonylamino, and di(C 1-4アルキル ) aminocarbonylamino.

[0226] In some embodiments, R 20a is methyl. In some embodiments, R 20 a is ethyl. In some embodiments, R 20a is CH 2OH. In some embodiments, R 20a is CH 2 CH 2 OH. In some embodiments, R 20a is CH2CH2F. In some embodiments, R 20a In some embodiments, R is CHCHF. In some embodiments, R is CHCH(CH). 20c is NH. In some embodiments, R 20b is hydrogen. In some embodiments, R 20a is a 4-6 membered heterocyclic ring. In some embodiments, R 20a is -(C 1-3 Alkylene)-C 3-10 In some embodiments, R 20a is -(C 1-3 alkylene)-4 to 10-membered heterocycloalkyl. In some embodiments, R 20a is -(C 1-3 Heteroalkylene)-C 3-10 In some embodiments, R 20a is -(C 1-3 heteroalkylene)-4 to 10-membered heterocycloalkyl. In some embodiments, C 3-10 Cycloalkyl is

[0227] [ka]

[0228] [ka]

[0229] [ka]

[0230] [ka]

[0231] [ka]

[0232] [ka]

[0233] [ka]

[0234] [ka]

[0235] [ka]

[0236] [ka] In some embodiments, C 3-10 The cycloalkyl is an optionally substituted 3-5 membered ring. In some embodiments, the 4-10 membered heterocycloalkyl is

[0237] [ka]

[0238] [ka]

[0239] [ka]

[0240] [ka]

[0241] [ka]

[0242] [ka]

[0243] [ka]

[0244] [ka]

[0245] [ka]

[0246] [ka]

[0247] [ka]

[0248] [ka]

[0249] [ka] In some embodiments, the 4- to 10-membered heterocycloalkyl is an optionally substituted 4- to 5-membered ring. In some embodiments, R 20 a is C 1-4 In some embodiments, R 20a is C1-4 In some embodiments, R 20a is an optionally substituted C 1-4 In some embodiments, R20a is an optionally substituted C alkyl. 1-4 It is alkyl.

[0250] In some embodiments, the compound is a compound of formula (IIIb) or a pharmaceutically acceptable salt thereof:

[0251] [ka]

[0252] During the ceremony, R 21 and R 24 each has the meaning defined in formula (I), R 20a H, OH, SH, CN, NO2, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -(C 1-4 alkyl)-(C 1-4 alkoxy), -(C 1-4 Alkoxy)-(C 1-4 Alkoxy), C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, C 1-4 Heteroalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, -(C 1-3 Alkylene)-C 3-10 Cycloalkyl, -(C 1-3 alkylene)-4 to 10-membered heterocycloalkyl, -(C 1-3 Heteroalkylene)-C 3-10 Cycloalkyl, -(C 1-3 Heteroalkylene)-4 to 10-membered heterocycloalkyl, amidinyl, amino, C 1-4Alkylamino, di(C 1-4 Alkyl)amino, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl)carbamyl, carbamoyl, C 1-4 Alkylcarbamoyl, di(C 1-4 alkyl)carbamoyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonylamino, C 1-4 Alkyl sulfonyl amino, amino sulfonyl, C 1-4 Alkylaminosulfonyl, di(C 1-4 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-4 Alkylaminosulfonylamino, di(C 1-4 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4 Alkylaminocarbonylamino, and di(C 1-4 cycloalkyl)aminocarbonylamino, wherein each of cycloalkyl and heterocycloalkyl is selected from the group consisting of halo, CN, SH, —CN, oxo, NO, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Aminoalkyl, C 1-4 Hydroxyalkyl, C 1-4 It may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkoxy and amino.

[0253] In some embodiments of the compound of Formula (IIIb) or a pharmaceutically acceptable salt thereof, R 20a OH, SH, CN, NO2, Halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4Alkoxy, -(C 1-4 alkyl)-(C 1-4 alkoxy), -(C 1-4 Alkoxy)-(C 1-4 Alkoxy), C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl)carbamyl, carbamoyl, C 1-4 Alkylcarbamoyl, di(C 1-4 alkyl)carbamoyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonylamino, C 1-4 Alkyl sulfonyl amino, amino sulfonyl, C 1-4 Alkylaminosulfonyl, di(C 1-4 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-4 Alkylaminosulfonylamino, di(C 1-4 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4 Alkylaminocarbonylamino, and di(C 1-4 alkyl)aminocarbonylamino.

[0254] In some embodiments, R 20a is methyl. In some embodiments, R 20a is ethyl. In some embodiments, R 20a is CHOH. In some embodiments, R 20a is CH2CH2OH. In some embodiments, R 20a is CH2CH2F. In some embodiments, R 20a is CH2CHF2. In some embodiments, R 20a is CHCH(CH). In some embodiments, R 20ais a 4-6 membered heterocyclic ring. In some embodiments, R 20a is -(C 1-3 Alkylene)-C 3-10 In some embodiments, R 20a is -(C 1-3 alkylene)-4 to 10-membered heterocycloalkyl. In some embodiments, R 20a is -(C 1-3 Heteroalkylene)-C 3-10 In some embodiments, R 20a is -(C 1-3 heteroalkylene)-4 to 10-membered heterocycloalkyl. In some embodiments, C 3-10 Cycloalkyl is

[0255] [ka]

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] [ka]

[0260] [ka]

[0261] [ka]

[0262] [ka]

[0263] [ka] ,or

[0264] [ka] In some embodiments, C 3-10 The cycloalkyl is an optionally substituted 3-5 membered ring. In some embodiments, the 4-10 membered heterocycloalkyl is

[0265] [ka]

[0266] [ka]

[0267] [ka]

[0268] [ka]

[0269] [ka]

[0270] [ka]

[0271] [ka]

[0272] [ka]

[0273] [ka]

[0274] [ka]

[0275] [ka]

[0276] [ka]

[0277] [ka] In some embodiments, the 4- to 10-membered heterocycloalkyl is an optionally substituted 4- to 5-membered ring. In some embodiments, R 20a is C 1-4 In some embodiments, R 20a is C 1-4 In some embodiments, R 20a is an optionally substituted C 1-4 In some embodiments, R 20a is an optionally substituted C 1-4 It is alkyl.

[0278] In some embodiments, R 24 is fluoro, bromo, or chloro. 24is fluoro. In some embodiments, R 24 is promo. In some embodiments, R 24 is chloro.

[0279] In some embodiments, the compound is selected from the compounds in Table 1.

[0280] In some embodiments, the SMSMs described herein possess one or more stereocenters, with each stereocenter independently existing in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as appropriate mixtures thereof. In certain embodiments, the 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 diastereomeric compound / salt pairs, 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 other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof (see, e.g., 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.

[0281] In some embodiments, the 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. A prodrug may be, for example, bioavailable by oral administration, whereas its parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the prodrug is designed to increase its effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the active carboxylic acid once inside cells, where water solubility is beneficial. A further example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to expose the active moiety. In certain embodiments, upon in vivo administration, the 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.

[0282] In one aspect, prodrugs are designed to alter the metabolic stability or transport properties of a drug, to mask side effects or toxicity, to improve the taste of a drug, or to alter other characteristics or properties of a drug. Knowledge of in vivo pharmacokinetics, pharmacodynamic processes, and drug metabolism allows for the design of prodrugs of a pharmaceutically active compound. (See, e.g., 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, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series).

[0283] In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0284] In some embodiments, sites on the aromatic ring moieties of the compounds described herein are susceptible to various metabolic reactions, and incorporation of appropriate substituents on the aromatic ring structure will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogens or alkyl groups.

[0285] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0286] The compounds described herein include isotopically labeled compounds identical to those listed in the various formulas and structures presented herein, but owing to 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 normally found in nature. Examples of isotopes that may be incorporated into the present compounds include, for example: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, and 36 In one embodiment, isotopes of the isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine described herein, e.g., Cl, are used. 3 H and 14 Incorporation of radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium offers certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0287] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite, which is then used to bring about a desired effect, including a desired therapeutic effect.

[0288] The compounds described herein may be formed as and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include: (1) salts of the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or a pharmaceutically acceptable organic acid, such as 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]octa-2 (1) Acid addition salts formed by reacting the parent compound with 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-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, etc.; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as 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, the compounds described herein may coordinate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, etc. In other cases, the 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 containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0289] In some embodiments, the compounds provided in this disclosure can exist in unsolvated and solvated forms.

[0290] In some embodiments, SMSM has a molecular weight of up to about 2000 daltons, 1500 daltons, 1000 daltons, or 900 daltons. In some embodiments, SMSM has a molecular weight of at least 100 daltons, 200 daltons, 300 daltons, 400 daltons, or 500 daltons. In some embodiments, SMSM does not contain phosphodiester bonds. In some embodiments, SMSM is a compound having a structure set forth in Table 1 below.

[0291] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0292] Pharmaceutical Composition 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 the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Overviews of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0293] A pharmaceutical composition can be a mixture of the SMSM described herein with one or more other chemical components (i.e., pharmaceutically acceptable components), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates administration of the compound to an organism.

[0294] The compositions described herein can be administered to a subject in a variety of ways, including parenterally, intravenously, intradermally, intramuscularly, intracolonically, intrarectally, or intraperitoneally. In some embodiments, the small molecule splicing regulator or a pharmaceutically acceptable salt thereof is administered to the subject by intraperitoneal, intramuscular, subcutaneous, or intravenous injection. In some embodiments, the pharmaceutical composition can be administered parenterally, intravenously, intramuscularly, or orally. Oral formulations containing small molecule splicing regulators can be in any form suitable for oral administration, such as liquids, tablets, or capsules. Oral formulations can be further coated or treated to prevent or reduce dissolution in the stomach. The compositions of the present disclosure can be administered to a subject using any suitable method known in the art. Formulations and delivery methods suitable for use in the present disclosure are generally well known in the art. For example, the small molecule splicing regulators described herein can be formulated into pharmaceutical compositions together with pharmaceutically acceptable diluents, carriers, or excipients. The compositions may also contain pharmaceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, etc., for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.

[0295] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulations comprising SMSM described herein are in the form of a capsule. In one aspect, the liquid pharmaceutical dosage form for oral administration is in the form of an aqueous suspension or solution selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0296] For administration by inhalation, the SMSM described herein can be formulated for use as an aerosol, mist, or powder. For buccal or sublingual administration, the compositions can take the form of tablets, lozenges, or gels formulated in conventional manner. In some embodiments, the SMSM described herein can be prepared as a transdermal dosage form. In some embodiments, the SMSM described herein can be formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection. In some embodiments, the 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, the SMSM described herein can be formulated into rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.

[0297] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0298] Splicing regulation of target gene products The present disclosure contemplates the use of small molecules with favorable drug properties that modulate the splicing activity of a target RNA. Provided herein are small molecule splicing modulators (SMSMs) that modulate the splicing of polynucleotides. In some embodiments, the SMSMs bind to and modulate a target RNA. In some embodiments, provided herein are libraries of SMSMs that bind to and modulate one or more target RNAs. In some embodiments, the target RNA is an mRNA. In some embodiments, the target RNA is a non-coding RNA. In some embodiments, the target RNA is a pre-mRNA. In some embodiments, the target RNA is an hnRNA. In some embodiments, the small molecules modulate the splicing of a target RNA. In some embodiments, the small molecules provided herein modulate splicing at a sequence of the target RNA. In some embodiments, the small molecules provided herein modulate splicing at a cryptic splice site sequence of the target RNA. In some embodiments, the small molecules provided herein modulate the splicing of an alternative splice site sequence of the target RNA. In some embodiments, the small molecules provided herein modulate the splicing of a natural splice site sequence of the target RNA. In some embodiments, small molecules provided herein bind to a target RNA. In some embodiments, small molecules provided herein bind to a splicing complex or a component thereof. In some embodiments, small molecules provided herein bind to a target RNA and a splicing complex or a component thereof. In some embodiments, small molecules provided herein modulate the binding affinity of a splicing complex component to a target RNA, such as a pre-mRNA. In some embodiments, small molecules provided herein modulate the binding affinity of a splicing complex component at a natural splice site sequence of a target RNA, such as a pre-mRNA. In some embodiments, small molecules provided herein modulate the binding affinity of a splicing complex component to a target RNA, such as a pre-mRNA, upstream of a splice site sequence or downstream of a splice site sequence.

[0299] Described herein are compounds that modify the splicing of a gene product, such as ataxin 3 pre-mRNA, for use in treating, preventing, and / or delaying the progression of a disease or condition.

[0300] In some embodiments, the present disclosure describes a method for treating, preventing, delaying the progression of, or ameliorating symptoms of a disease or condition associated with ataxin 3 (ATXN3) expression or activity levels in a subject in need thereof, comprising administering a therapeutically effective amount of a small molecule splicing modulator (SMSM), wherein the SMSM binds to a pre-mRNA encoded by ATXN3 and regulates splicing of the ATXN3 pre-mRNA in the subject's cells to produce a spliced ​​product of the ATXN3 pre-mRNA.

[0301] In some embodiments, this disclosure describes a method for treating, preventing, delaying progression of, or ameliorating symptoms of a disease or condition associated with ataxin 3 (ATXN3) expression or activity levels in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (I) or a salt. In some embodiments, this disclosure describes a method for modulating splicing of ataxin 3 (ATXN3) pre-mRNA, the method comprising contacting a compound of Formula (I) or a salt with a splice site sequence comprising ATXN3 pre-mRNA or cellular ATXN3, wherein the compound binds to the ATXN3 pre-mRNA and modulates splicing of the ATXN3 pre-mRNA in the subject's cells to produce a spliced ​​product of the ATXN3 pre-mRNA. In some embodiments, this disclosure describes the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition or disease associated with ataxin 3 (ATXN3) expression or activity levels.

[0302] In some embodiments, the spliced ​​product of ATXN3 pre-mRNA undergoes nonsense-mediated decay (NMD) and / or nuclear retention. In some embodiments, the nonsense-mediated decay (NMD) and / or nuclear retention of the spliced ​​product of ATXN3 pre-mRNA is promoted. In some embodiments, the nonsense-mediated decay (NMD) and / or nuclear retention of the spliced ​​product of ATXN3 pre-mRNA is increased compared to the spliced ​​product of ATXN3 pre-mRNA produced in the absence of SMSM.

[0303] In some embodiments, the present disclosure describes a method for regulating splicing of ataxin 3 (ATXN3) pre-mRNA, wherein SMSM binds to ATXN3 pre-mRNA and regulates splicing of ATXN3 pre-mRNA in a subject's cell to produce a spliced ​​product of ATXN3 pre-mRNA.

[0304] In some embodiments, the present disclosure describes a method for regulating splicing of ATXN3 pre-mRNA, the method comprising contacting a small molecule splicing modulator (SMSM) with ATXN3 pre-mRNA and a splice site sequence or cell comprising ATXN3 pre-mRNA, wherein the SMSM binds to the ATXN3 pre-mRNA and regulates splicing of the ATXN3 pre-mRNA in the subject's cell to produce a spliced ​​product of the ATXN3 pre-mRNA, wherein the splice site sequence comprises UCCUAU / guaagauucugu.

[0305] In some embodiments, the present disclosure describes a method for treating, preventing, delaying the progression of, or ameliorating a disease or symptom associated with ataxin 3 (ATXN3) expression or activity levels in a subject in need thereof, comprising administering a therapeutically effective amount of a small molecule splicing modulator (SMSM), wherein the SMSM binds to ATXN3 pre-mRNA at a splice site sequence and regulates splicing of the ATXN3 pre-mRNA in cells of the subject, wherein the spliced ​​product of the ATXN3 pre-mRNA undergoes nonsense-mediated decay (NMD), and the splice site sequence comprises UCCUAU / guaagauucugu.

[0306] In some embodiments, modulating splicing comprises modulating alternative splicing. In some embodiments, modulating splicing comprises promoting exon skipping. In some embodiments, modulating splicing comprises promoting exon inclusion. In some embodiments, modulating splicing comprises modulating nonsense-mediated mRNA decay (NMD). In some embodiments, modulating NMD comprises promoting NMD. In some embodiments, modulating splicing comprises modulating nuclear retention of spliced ​​products of pre-mRNA. In some embodiments, modulating intron retention comprises promoting nuclear retention of spliced ​​products of pre-mRNA.

[0307] In some embodiments, the splice site sequence is a naturally occurring splice site sequence. In some embodiments, the naturally occurring splice site is a standard splice site. In some embodiments, the naturally occurring splice site is an alternative splice site. In some embodiments, the alternative splice site comprises a 5' splice site sequence. In some embodiments, the alternative splice site sequence comprises UCCUAU / guaagauucugu. In some embodiments, SMSM increases splicing at the alternative splice site. In some embodiments, splicing at the alternative splice site results in a frameshift in the downstream exon of the spliced ​​product. In some embodiments, the downstream exon comprises an in-frame stop codon that would not be in frame without splicing at the alternative splice site. In some embodiments, the in-frame stop codon in the downstream exon is at least 50 base pairs or at least 60 base pairs upstream of the 3' end of the downstream exon. In some embodiments, the in-frame stop codon in the downstream exon is at least 50 base pairs or at least 60 base pairs upstream of the final exon-exon junction.

[0308] In some embodiments, splicing of the pre-mRNA at the alternative splice site promotes NMD of the spliced ​​product of the ATXN3 pre-mRNA. In some embodiments, the spliced ​​product comprises an alternative exon. In some embodiments, SMSM promotes inclusion of the alternative exon in the spliced ​​product. In some embodiments, the alternative exon comprises a poison exon. In some embodiments, SMSM promotes inclusion of the poison exon in the first spliced ​​product. In some embodiments, the poison exon comprises an in-frame stop codon. In some embodiments, the in-frame stop codon is a premature termination codon. In some embodiments, the in-frame stop codon is at least 50 or 60 base pairs upstream of the 3' end of the poison exon. In some embodiments, the in-frame stop codon is less than 60 base pairs upstream of the 3' end of the poison exon, where the exon immediately downstream of the poison exon is not the last exon in the pre-mRNA. In some embodiments, the sum of (a) the number of base pairs in the exon immediately downstream of the poison exon and (b) the number of base pairs between the premature stop codon in the poison exon and the 3' end of the poison exon is at least 50 or at least 60.

[0309] In some embodiments, the cells comprise primary cells. In some embodiments, the cells comprise diseased cells. In some embodiments, SMSM regulates cell proliferation or survival. In some embodiments, SMSM regulates the expression level of a protein encoded by a spliced ​​product of a pre-mRNA in a cell.

[0310] [Table 2]

[0311] Treatment method The compositions and methods described herein can be used to treat human diseases or disorders associated with aberrant splicing, such as aberrant pre-mRNA splicing. The compositions and methods described herein can be used to treat human diseases or disorders by modulating mRNA, such as pre-mRNA. In some embodiments, the compositions and methods described herein can be used to treat human diseases or disorders by modulating the splicing of nucleic acids, even if the nucleic acid is not aberrantly spliced ​​in the etiology of the disease or disorder being treated.

[0312] In some embodiments, an effective amount in the context of administration of SMSM or a pharmaceutically acceptable salt thereof, or a composition or medicament thereof, refers to the amount of SMSM or a pharmaceutically acceptable salt thereof to a patient that has a therapeutic and / or beneficial effect. In certain specific embodiments, an effective amount in the context of administration of SMSM or a pharmaceutically acceptable salt thereof, or a composition or medicament thereof to a patient, results in one, two, or more of the following effects: (i) reducing or ameliorating the severity of the disease, (ii) delaying the onset of the disease, (iii) preventing the progression of the disease, (iv) reducing the subject's hospitalization, (v) reducing the subject's length of hospitalization, (vi) increasing the subject's survival rate, (vii) improving the subject's quality of life, (viii) reducing the number of symptoms associated with the disease, (ix) reducing or ameliorating the severity of symptoms associated with the disease, (x) reducing the duration of relevant symptoms associated with the disease, (xi) preventing the recurrence of symptoms associated with the disease, (xii) preventing the appearance or development of symptoms of the disease, and / or (xiii) preventing the progression of symptoms associated with the disease. In some embodiments, an effective amount of SMSM or a pharmaceutically acceptable salt thereof is an amount effective to restore the amount of an RNA transcript of a gene to the amount of detectable RNA transcript in a healthy patient or cells derived from a healthy patient. In other embodiments, an effective amount of SMSM or a pharmaceutically acceptable salt thereof is an amount effective to restore the amount of an RNA isoform and / or protein isoform of a gene to the amount of detectable RNA isoform and / or protein isoform in a healthy patient or cells derived from a healthy patient.

[0313] In some embodiments, an effective amount of SMSM or a pharmaceutically acceptable salt thereof is an amount effective to reduce the abnormal amount of RNA transcripts of a gene associated with a disease. In some embodiments, an effective amount of SMSM or a pharmaceutically acceptable salt thereof is an amount effective to reduce the abnormal expression amount of an isoform of a gene. In some embodiments, an effective amount of SMSM or a pharmaceutically acceptable salt thereof is an amount effective to substantially alter the amount of an RNA transcript (e.g., an mRNA transcript), alternative splice variant, or isoform.

[0314] In some embodiments, an effective amount of SMSM or a pharmaceutically acceptable salt thereof is an amount effective to increase the amount of an RNA transcript (e.g., an mRNA transcript) of a gene beneficial to the prevention and / or treatment of a disease. In some embodiments, an effective amount of SMSM or a pharmaceutically acceptable salt thereof is an amount effective to increase the amount of an alternative splice variant of an RNA transcript of a gene beneficial to the prevention and / or treatment of a disease. In some embodiments, an effective amount of SMSM or a pharmaceutically acceptable salt thereof is an amount effective to increase the amount of an isoform of a gene beneficial to the prevention and / or treatment of a disease.

[0315] In some embodiments, an effective amount of SMSM or a pharmaceutically acceptable salt thereof is an amount effective to reduce the amount of an RNA transcript (e.g., an mRNA transcript) causing or associated with symptoms of a condition or disease. In certain embodiments, SMSM reduces the amount of an RNA transcript causing or associated with symptoms of a condition or disease by modulating one or more splicing elements of the RNA transcript. In some embodiments, SMSM promotes skipping of one or more exons. In some embodiments, SMSM promotes inclusion of one or more exons. In some embodiments, SMSM promotes inclusion of one or more exons and / or introns associated with nonsense-mediated mRNA decay (NMD). In some embodiments, the one or more exons carry a premature stop codon. In certain embodiments, the premature stop codon is an in-frame codon that does not cause a frameshift of a downstream exon. In some embodiments, the inclusion of one or more exons causes a reading frame shift in a downstream exon, such as the immediately downstream exon, resulting in the introduction of a premature stop codon.

[0316] A method of treating a disease or condition in a subject in need thereof can include administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to methods for treating, preventing, and / or delaying progression of a disease or condition associated with a gene listed in Table 2.

[0317] Non-limiting examples of effective amounts of SMSM or a pharmaceutically acceptable salt thereof are described herein. For example, an effective amount can be the amount necessary to prevent and / or treat a disease associated with abnormal amounts of mRNA transcripts of a gene in a human subject. Generally, an effective amount is in the range of about 0.001 mg / kg / day to about 500 mg / kg / day for a patient having a body weight in the range of about 1 kg to about 200 kg. A typical adult subject is expected to have a median body weight in the range of about 70 to about 100 kg.

[0318] In one embodiment, the SMSM described herein can be used in the preparation of a medicament for treating a disease or condition described herein. Additionally, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment can comprise administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one SMSM described herein, or a pharmaceutically acceptable salt thereof.

[0319] In certain embodiments, the 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 symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials. In prophylactic applications, compositions containing SMSM described herein can be administered to patients susceptible to or otherwise at risk of a particular disease, disorder, or condition.

[0320] Administration method The compositions described herein can be administered to a subject in a variety of ways, including parenterally, intravenously, intradermally, intramuscularly, colonically, rectally, or intraperitoneally. In some embodiments, the small molecule splicing regulator (SMSM) or a pharmaceutically acceptable salt thereof is administered to the subject by intraperitoneal, intramuscular, subcutaneous, or intravenous injection. In some embodiments, the pharmaceutical composition can be administered parenterally, intravenously, intramuscularly, or orally. Oral formulations containing small molecule splicing regulators can be in any form suitable for oral administration, such as liquids, tablets, or capsules. The compositions of the present disclosure can be administered to a subject using any suitable method known in the art. Formulations and delivery methods suitable for use in the present disclosure are generally well known in the art. For example, the small molecule splicing regulators described herein can be formulated into pharmaceutical compositions together with pharmaceutically acceptable diluents, carriers, or excipients.

[0321] Dosage and Schedule The SMSM utilized in the methods of the present disclosure can be administered in dosages that can vary depending, for example, on the subject's requirements, the severity of the condition being treated and / or imaged, and / or the SMSM used. For example, dosages can be empirically determined taking into account the type and stage of disease diagnosed in a particular subject and / or the type of imaging method used in conjunction with the SMSM. In the context of the present disclosure, 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 can also be determined by the existence, nature, and extent of any adverse side effects associated with the administration of SMSM in a particular subject.

[0322] Within the scope of this description, an effective amount of SMSM or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament, preparation of a pharmaceutical kit, or method for preventing and / or treating a disease in a human subject in need thereof is intended to include an amount in the range of about 1 μg to about 50 grams.

[0323] The compositions of the present disclosure can be administered as frequently as needed.

[0324] subject A subject that can be treated with the SMSM and methods described herein can be any subject that produces mRNA that undergoes alternative splicing; for example, the subject can be a eukaryotic subject, such as a plant or an animal. In some embodiments, the subject is a mammal, e.g., a 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, embryo, or child. In some embodiments, the subject is a non-human primate, such as a chimpanzee, as well as other ape and monkey species, livestock, e.g., cows, horses, sheep, goats, pigs, domestic animals, e.g., rabbits, dogs, and cats, or laboratory animals, e.g., rodents, such as rats, mice, and guinea pigs.

[0325] In some embodiments, the subject is a prenatal (e.g., fetus), child (e.g., newborn, infant, toddler, pre-adolescent child), adolescent, adolescent, or adult (e.g., early adult, middle-aged adult, elderly).

[0326] Manufacturing method for making compounds The compounds described herein can be synthesized using standard synthetic techniques or methods known in the art in combination with the manufacturing methods described herein. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology can be used. The compounds can be prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, such as variations in solvents, reaction temperatures, reaction times, and various chemical reagents and other reaction conditions. Starting materials may be available from commercial sources or can be readily prepared. By way of example only, a scheme for preparing the SMSM described herein is provided.

[0327] Suitable references and papers detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing the preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley Interscience, New York, 1992. Further suitable references and papers detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC“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, TWG “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0, Stowell, JC, "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, 8 volumes, "Organic Reactions" (1942-2000) John Wiley & Sons, over 55 volumes, and "Chemistry of Functional Groups" John Wiley & Sons, 73 volumes.

[0328] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, if necessary in the final product to avoid undesired participation in the reaction. Detailed descriptions of techniques applicable to the creation of protecting groups and their removal are found 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 disclosures.

[0329] SMSMs can be made using known techniques and, in some embodiments, can be further chemically modified to facilitate nuclear import, for example, into splicing complex components, spliceosomes, or pre-mRNA molecules. Those skilled in the art will understand standard medicinal chemistry approaches for chemical modification (e.g., charge reduction, size optimization, and / or lipophilicity modification) for nuclear import.

[0330] Example These examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein. The starting materials and reagents used in the synthesis of the compounds described herein may be synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fisher Scientific.

[0331] Example A1: General synthetic scheme 1

[0332] [ka]

[0333] Example A2: Synthesis of intermediates. Synthesis of type 4 intermediate Intermediate 4-1: tert-butyl (6-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate

[0334] [ka] Step 1: A mixture of 6-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (15 g, 56.20 mmol, 1 equiv.), furan-2-ylmethanamine (6.55 g, 67.44 mmol, 1.2 equiv.), and DIEA (14.53 g, 112.40 mmol, 2 equiv.) in DMSO (150 mL) was stirred at 100 °C for 2 h under atmospheric pressure. The mixture was allowed to cool to room temperature. Water (2 mL) was then added to quench the reaction. The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give 6-bromo-2-chloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (16 g, 87%) as a pale yellow solid. LC-MS (ES, m / z): [M+H] + = 328.90.

[0335] Step 2: A mixture of 6-bromo-2-chloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4 g, 12.211 mmol, 1 equiv.), (Boc)2O (5.33 g, 24.42 mmol, 2 equiv.), TEA (2.47 g, 24.42 mmol, 2 equiv.), and DMAP (0.15 g, 1.22 mmol, 0.1 equiv.) in DCM (40 mL) was stirred at room temperature under atmospheric pressure for 4 hours. The resulting mixture was washed with water (1 × 50 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give tert-butyl N-{6-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl}-N-(furan-2-ylmethyl)carbamate (5 g, 96%) as a pale yellow solid. LC-MS (ES, m / z): [M+H] + = 429.00.

[0336] Example A3: Synthesis of potassium trifluoroborate Borate 1: Potassium ((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)trifluoroborate

[0337] [ka] Step 1: To a stirred solution of imidazole (144.76 g, 2126.3 mmol, 4 equiv.) in DCM (3720 mL), SOCl (57.84 mL, 797.38 mmol, 1.5 equiv.) and DIEA (185.19 mL, 1063.17 mmol, 2 equiv.) were added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. To the above mixture, a solution of methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate (124 g, 531.587 mmol, 1 equiv.) in DCM (620 mL) was added at 0 °C. ℃The resulting mixture was further stirred at room temperature overnight. The resulting mixture was washed with 3×800 mL of HCl (0.5 M). The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0338] Step 2: A solution of 3-(tert-butyl) 4-methyl(4S,5R)-5-methyl-1,2,3-oxathiazolidine-3,4-dicarboxylate 2-oxide (144 g, 515.55 mmol, 1 equiv.) in HO (1008 mL) and acetonitrile (1872 mL) was heated with NaIO (132.33 g, 618.66 mmol, 1.2 equiv.) and ruthenium(iv) oxide hydrate (1.56 g, 10.31 mmol, 0.02 equiv.) under a nitrogen atmosphere for 0.5 min. ℃ The resulting mixture was stirred at 0° C. for 1 hour under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (5×1000 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 3-(tert-butyl) 4-methyl(4S,5R)-5-methyl-1,2,3-oxathiazolidine-3,4-dicarboxylate 2,2-dioxide (145 g, 95%) as a pale yellow oil.

[0339] Step 3: A solution of 3-(tert-butyl) 4-methyl(4S,5R)-5-methyl-1,2,3-oxathiazolidine-3,4-dicarboxylate 2,2-dioxide (144 g, 487.62 mmol, 1 equiv.) in THF (975 mL) was treated with EtN.3HF (430.11 mL, 3169.55 mmol, 6.5 equiv.) at 60° C. under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 3 days. The mixture was neutralized to pH 7 with NaOH (20%). The aqueous layer was extracted with ethyl acetate (3×800 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give methyl (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutanoate (55 g, 48%) as a pale yellow oil.

[0340] Step 4: A solution of methyl (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutanoate (55 g, 233.79 mmol, 1 equiv.) in EtOH (500 mL) was heated under nitrogen atmosphere for 0.5 min at 47°C. ℃ The resulting mixture was stirred overnight at 0 °C under a nitrogen atmosphere. ℃ The reaction mixture was quenched by adding water / ice (500 mL) at rt. The aqueous layer was extracted with EtOAc (3 × 400 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl N-[(2R,3S)-3-fluoro-1-hydroxybutan-2-yl]carbamate (46 g, 95%) as a yellow solid.

[0341] Step 5: To a stirred mixture of tert-butyl N-[(2R,3S)-3-fluoro-1-hydroxybutan-2-yl]carbamate (44 g, 212.31 mmol, 1 equiv.) and triphenylphosphine (103.02 g, 392.77 mmol, 1.85 equiv.) in THF (170 mL) and DCM (880 mL), NBS (69.91 g, 392.77 mmol, 1.85 equiv.) was added in several portions under air at −20° C. The resulting mixture was stirred overnight at room temperature under air. The resulting mixture was washed with 1×500 mL of water, washed with brine (1×200 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give tert-butyl N-[(2S,3S)-1-bromo-3-fluorobutan-2-yl]carbamate (30 g, 52%) as a pale yellow solid.

[0342] Step 6: A mixture of tert-butyl N-[(2S,3S)-1-bromo-3-fluorobutan-2-yl]carbamate (15.2 g, 56.27 mmol, 1 eq.), copper(I) iodide (1.07 g, 5.63 mmol, 0.1 eq.), triphenylphosphine (1.92 g, 7.31 mmol, 0.13 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (18.57 g, 73.15 mmol, 1.3 eq.), and methoxylithium (4.27 g, 112.53 mmol, 2 eq.) in DMF (150 mL) was stirred at room temperature under atmospheric pressure for 16 hours. The resulting mixture was diluted with water (500 mL). The resulting mixture was filtered, and the filter cake was washed with MTBE (1×100 mL). The resulting mixture was extracted with MTBE (3×300 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification.

[0343] Step 7: A mixture of tert-butyl N-[(2R,3S)-3-fluoro-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl]carbamate (15.2 g, 47.92 mmol, 1 equiv.) and KHF (8.8 g, 112.67 mmol, 2.35 equiv.) in MTBE (600 mL) and HO (4 mL) was stirred at room temperature under air for 16 hours. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with MTBE. The mixture was stirred for 30 minutes and filtered. The filter cake was diluted with acetone (800 mL) and stirred for an additional 30 minutes. The resulting mixture was filtered, and the filter cake was washed with acetone (1 × 50 mL). The filtrate was concentrated under reduced pressure. This gave potassium ((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)trifluoroborate (8 g, 56%) as a white solid.

[0344] Borate 2: Potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)trifluoroborate

[0345] [ka] Step 1: To a stirred solution of imidazole (96.79 g, 1421.71 mmol, 4 equiv) in DCM (3000 mL) was added SOCl (38.67 mL, 533.14 mmol, 1.5 equiv) and DIEA (123.82 mL, 710.85 mmol, 2 equiv) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. To the mixture was added dropwise a solution of tert-butyl N-[(2S)-1-(benzyloxy)-3-hydroxypropan-2-yl]carbamate (100 g, 355.43 mmol, 1 equiv) in DCM (500 mL) at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was washed with 3 × 1000 mL of HCl (0.5 mol / L) and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0346] Step 2: A solution of tert-butyl (4R)-4-[(benzyloxy)methyl]-2-oxo-1,2 lambda 4,3-oxathiazolidine-3-carboxylate (122 g, 372.63 mmol, 1 equiv.) in HO (854 mL) and acetonitrile (1586 mL) was treated with NaIO (95.64 g, 447.16 mmol, 1.2 equiv.) and ruthenium(iv) oxide hydrate (1.13 g, 7.45 mmol, 0.02 equiv.) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (4×1000 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give tert-butyl (4R)-4-[(benzyloxy)methyl]-2,2-dioxo-1,2 lambda 6,3-oxathiazolidine-3-carboxylate (117 g, 91%) as a pale yellow solid.

[0347] Step 3: A solution of tert-butyl (4R)-4-[(benzyloxy)methyl]-2,2-dioxo-1,2 lambda 6,3-oxathiazolidine-3-carboxylate (117 g, 340.72 mmol, 1 equiv.) in THF (1725 mL) was treated with TBAF (340.72 mL, 340.720 mmol, 1 equiv.) under a nitrogen atmosphere at 0° C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by adding citric acid (10%) (1500 mL) at room temperature. The aqueous layer was extracted with EtOAc (3×1000 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give tert-butyl N-[(2R)-1-(benzyloxy)-3-fluoropropan-2-yl]carbamate (76 g, 79%) as a colorless oil.

[0348] Step 4: A solution of tert-butyl N-[(2R)-1-(benzyloxy)-3-fluoropropan-2-yl]carbamate (76 g, 268.226 mmol, 1 equiv.) in EtOAc (760 mL) was treated with Pd / C (15.2 g, 20%) at room temperature. The resulting mixture was stirred overnight at 50° C. under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give tert-butyl N-[(2R)-1-fluoro-3-hydroxypropan-2-yl]carbamate (49.8 g, 96%) as a colorless oil.

[0349] Step 5: To a stirred mixture of tert-butyl N-[(2R)-1-fluoro-3-hydroxypropan-2-yl]carbamate (10.5 g, 54.34 mmol, 1 equiv.) and triphenylphosphine (17.15 g, 65.21 mmol, 1.2 equiv.) in DCM (100 mL) and THF (100 mL), NBS (11.62 g, 65.28 mmol, 1.2 equiv.) was added portionwise under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The residue was washed with water (2×50 mL) and brine (50 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give tert-butyl N-[(2S)-1-bromo-3-fluoropropan-2-yl]carbamate (3.5 g, 25%) as a yellow solid.

[0350] Step 6: A mixture of tert-butyl N-[(2S)-1-bromo-3-fluoropropan-2-yl]carbamate (3.5 g, 13.66 mmol, 1 equiv.), copper(I) iodide (0.26 g, 1.37 mmol, 0.1 equiv.), triphenylphosphine (0.36 g, 1.37 mmol, 0.1 equiv.), bis(pinacolato)diboron (6.94 g, 27.33 mmol, 2 equiv.), and methoxylithium (1.04 g, 27.33 mmol, 2 equiv.) in DMF (60 mL) was stirred at room temperature under atmospheric pressure for 16 hours. The resulting mixture was diluted with water (60 mL) and extracted with MTBE (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0351] Step 7: A mixture of tert-butyl N-[(2R)-1-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl]carbamate (5 g, 16.49 mmol, 1 equiv.) and potassium fluoride (2.57 g, 32.98 mmol, 2 equiv.) in MTBE (200 mL) and HO (2 mL) was stirred at room temperature under an air atmosphere for 16 hours. The resulting mixture was concentrated in vacuo. The residue was diluted with MTBE (200 mL). The mixture was stirred for 30 minutes and filtered. The filter cake was diluted with acetone (300 mL) and stirred for an additional 30 minutes. The resulting mixture was filtered, and the filter cake was washed with acetone (1 × 50 mL). The filtrate was concentrated under reduced pressure to give potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)trifluoroborate (3 g, 64%) as an off-white solid. The crude product was used directly in the next step without further purification.

[0352] Borate 3: Potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-(difluoromethoxy)propyl)trifluoroborate

[0353] [ka] Step 1: To a stirred solution of tert-butyl (4S)-4-(hydroxymethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (20 g, 86.471 mmol, 1 equiv.) in DCM (800 mL) and HO (800 mL), (bromodifluoromethyl)trimethylsilane (52.69 g, 259.41 mmol, 3 equiv.) and potassium acetate (50.92 g, 518.83 mmol, 6 equiv.) were added portionwise under a nitrogen atmosphere at 10 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 24 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with CHCl (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give tert-butyl (4R)-4-[(difluoromethoxy)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (21 g, 86.33%) as a yellow oil.

[0354] Step 2: To a stirred solution of tert-butyl (4R)-4-[(difluoromethoxy)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1 g, 3.55 mmol, 1 equiv.) in MeCN (20 mL) was added bismuth tribromide (1.28 g, 2.84 mmol, 0.2 equiv.) in several portions at 0 °C under atmospheric pressure. The resulting mixture was stirred at room temperature under atmospheric pressure for 2 hours. The resulting mixture was diluted with HO (5 mL). The resulting mixture was filtered, and the filter cake was washed with MeCN (20 mL) (2 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give tert-butyl N-[(2R)-1-(difluoromethoxy)-3-hydroxypropan-2-yl]carbamate (2.4 g, 70%) as a yellow oil.

[0355] Step 3: To a stirred mixture of tert-butyl N-[(2R)-1-(difluoromethoxy)-3-hydroxypropan-2-yl]carbamate (1 g, 4.14 mmol, 1 equiv.) and triphenylphosphine (2.01 g, 7.67 mmol, 1.85 equiv.) in THF (4 mL) and DCM (20 mL), NBS (1.36 g, 7.67 mmol, 1.85 equiv.) was added portionwise under air at −20° C. The resulting mixture was stirred overnight at room temperature under air. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give tert-butyl N-[(2S)-1-bromo-3-(difluoromethoxy)propan-2-yl]carbamate (380 mg, 30.14%) as a yellow oil.

[0356] Step 4: A stirred mixture of tert-butyl N-[(2S)-1-bromo-3-(difluoromethoxy)propan-2-yl]carbamate (380 mg, 1.25 mmol, 1 equiv.), methoxylithium (95 mg, 2.50 mmol, 2 equiv.), copper(I) iodide (23.8 mg, 0.125 mmol, 0.1 equiv.), triphenylphosphine (43 mg, 0.16 mmol, 0.13 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (412 mg, 1.62 mmol, 1.3 equiv.) in DMF (4 mL) was stirred at room temperature under atmospheric pressure. The resulting mixture was stirred overnight at room temperature under atmospheric pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was filtered, and the filter cake was washed with MTBE (3 × 10 mL). The resulting mixture was extracted with MTBE (3 × 20 mL). The combined organic layers were washed with saturated brine (1 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0357] Step 5: tert-Butyl N-[(2R)-1-(difluoromethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl]carbamate (2 g, 5.69 mmol, 1 equiv.) and KHF (0.89 g, 11.39 mmol, 2 equiv.) were added to a stirred mixture of HO (2 mL) and MTBE (200 mL) at room temperature under air. The resulting mixture was stirred overnight at 25 °C under air. The resulting mixture was concentrated under vacuum. The residue was dissolved in MTBE (200 mL). The precipitated solid was collected by filtration and washed with MTBE (3 × 10 mL). The residue was dissolved in acetone (200 mL). The resulting mixture was filtered, and the filter cake was washed with acetone (3 × 10 mL). The filtrate was concentrated under reduced pressure. This gave potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-(difluoromethoxy)propyl)trifluoroborate (1.1 g, 58%) as a white solid.

[0358] Borate 4: Potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)trifluoroborate

[0359] [ka] Step 1: To an ice-cold solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxypropanoic acid (5 g, 22.81 mmol, 1 equiv.) and DIEA (3.54 g, 27.37 mmol, 1.2 equiv.) in THF (40 mL) was added isopropyl chloroformate (3.07 g, 25.09 mmol, 1.1 equiv.) dropwise. The cold bath was removed, and the mixture was stirred at 23 °C for 2 h. The mixture was filtered to remove a white precipitate, and the filtrate was treated with NaBH (1.73 g, 45.61 mmol, 2 equiv.), resulting in vigorous gas evolution. The mixture was stirred at room temperature for 2 h, and brine (25 mL) was added. The mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were dried (MgSO), filtered, and then concentrated in vacuo. The residue was purified by silica gel flash chromatography to give tert-butyl N-[(2R)-1-hydroxy-3-methoxypropan-2-yl]carbamate (2.5 g, 53%) as a white solid.

[0360] Step 2: To a stirred solution of tert-butyl N-[(2R)-1-hydroxy-3-methoxypropan-2-yl]carbamate (2.5 g, 12.180 mmol, 1 equiv.), triphenylphosphine (5.91 g, 22.53 mmol, 1.85 equiv.) in THF (8 mL) and DCM (40 mL), NBS (4.01 g, 22.53 mmol, 1.85 equiv.) was added portionwise under atmospheric pressure at −20° C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to afford tert-butyl N-[(2S)-1-bromo-3-methoxypropan-2-yl]carbamate (1.2 g, 37%) as a white oil.

[0361] Step 3: A mixture of tert-butyl N-[(2S)-1-bromo-3-methoxypropan-2-yl]carbamate (1.2 g, 4.47 mmol, 1 equiv.), copper(I) iodide (0.09 g, 0.448 mmol, 0.1 equiv.), methoxylithium (0.34 g, 8.950 mmol, 2 equiv.), triphenylphosphine (0.15 g, 0.582 mmol, 0.13 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.71 mL, 5.817 mmol, 1.3 equiv.) in DMF (11 mL) was stirred overnight at room temperature under atmospheric pressure. The resulting mixture was filtered, and the filter cake was washed with water and tert-butyl methyl ether (3 × 20 mL). The resulting mixture was extracted with MTBE (3 x 100 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0362] Step 4: A mixture of tert-butyl N-[(2R)-1-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl]carbamate (1.2 g, 3.807 mmol, 1 equiv.) and KHF2 (0.59 g, 7.614 mmol, 2 equiv.) in 2-methoxy-2-methylpropane (100 mL) was stirred overnight at room temperature under atmospheric pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with MTBE (300 mL). The mixture was stirred for 30 minutes and filtered. The filter cake was suspended in acetone (400 mL) and stirred for an additional 30 minutes. The resulting mixture was filtered, and the filter cake was washed with acetone (1 × 50 mL). The filtrate was concentrated under reduced pressure. This gave potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)trifluoroborate (500 mg, 51%) as a white solid.

[0363] Borate 5: Potassium (S)-(2-((tert-butoxycarbonyl)amino)propyl)trifluoroborate

[0364] [ka] Step 1: To a stirred mixture of tert-butyl N-[(2S)-1-hydroxypropan-2-yl]carbamate (10 g, 57.07 mmol, 1 equiv.) and triphenylphosphine (18.01 g, 64.48 mmol, 1.2 equiv.) in THF (100 mL) and DCM (100 mL), NBS (12.19 g, 68.48 mmol, 1.2 equiv.) was added portionwise under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The residue was diluted with DCM (200 mL) and washed with water (2 × 100 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give tert-butyl N-[(2S)-1-bromopropan-2-yl]carbamate (6 g, 44%) as a yellow solid.

[0365] Step 2: A mixture of tert-butyl N-(1-bromopropan-2-yl)carbamate (4 g, 16.80 mmol, 1 equiv.), copper(I) iodide (0.32 g, 1.68 mmol, 0.1 equiv.), triphenylphosphine (0.44 g, 1.68 mmol, 0.13 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.55 g, 21.84 mmol, 1.3 equiv.), and methoxylithium (0.83 g, 21.84 mmol, 1.3 equiv.) in dimethylformamide (80 mL) was stirred at room temperature under atmospheric pressure for 16 h. The resulting mixture was diluted with water (200 mL) and extracted with tert-butyl methyl ether (3 × 100 mL). The organic phase was concentrated in vacuo and the crude product was used directly in the next step without further purification.

[0366] Step 3: To a stirred mixture of tert-butyl N-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl]carbamate (4 g, 14.03 mmol, 1 equiv.) in tert-butyl methyl ether (40 mL) was added KHF (2.19 g, 28.05 mmol, 2 equiv.) and water (1 mL) at room temperature under atmospheric pressure. The resulting mixture was stirred overnight. The resulting mixture was concentrated in vacuo to leave a residue. The residue was diluted with tert-butyl methyl ether (100 mL). The mixture was stirred for 30 minutes and filtered. The filter cake was diluted with acetone (300 mL) and stirred for an additional 30 minutes. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give potassium (S)-(2-((tert-butoxycarbonyl)amino)propyl)trifluoroborate (2 g, 54%) as a pale yellow solid. The crude product was used directly in the next step without further purification.

[0367] Borate 6: Potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-(methoxy-d3)propyl)trifluoroborate

[0368] [ka] Step 1: A mixture of (2S)-methyl 2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate (5 g, 22.806 mmol, 1 equiv.), CD3I (33.72 g, 232.62 mmol, 10.2 equiv.), and Ag2O (26.95 g, 116.31 mmol, 5.1 equiv.) in ACN (100 mL) was stirred at room temperature in the dark under a nitrogen atmosphere for 3 days. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl (S)-(1-methoxy-3-(methoxy-d3)-1-oxopropan-2-yl)-l2-azanecarboxylate (5 g, 93%) as a colorless oil.

[0369] Step 2: To a stirred solution of (S)-(1-methoxy-3-(methoxy-d3)-1-oxopropan-2-yl)-l2-azanecarboxylate (5.4 g, 22.854 mmol, 1 equiv.) in MeOH (30 mL) and THF (30 mL) was added 2 M LiBH4 (1.00 g, 45.708 mmol, 2 equiv.) under a nitrogen atmosphere. ℃ The resulting mixture was added dropwise at rt over 5 min. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered, and the filter cake was washed with EtOAc (2 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl (R)-(1-hydroxy-3-(methoxy-d3)propan-2-yl)-I2-azanecarboxylate (4.3 g, 90.34%) as a pale yellow oil.

[0370] Step 3: To a 1000 mL three-necked round-bottom flask, tert-butyl (R)-(1-hydroxy-3-(methoxy-d3)propan-2-yl)-l2-azanecarboxylate (10 g, 48.01 mmol, 1 equiv.), THF (40 mL), and triphenylphosphine (22.67 g, 86.42 mmol, 1.8 equiv.) were added in one portion at room temperature. Subsequently, NBS (15.38 g, 86.425 mmol, 1.8 equiv.) was added in portions at −20° C. The resulting mixture was stirred under a nitrogen atmosphere at −20° C. for 16 hours. The resulting mixture was washed with 2×200 mL of water. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give tert-butyl (S)-(1-bromo-3-(methoxy-d3)propan-2-yl)-l2-azanecarboxylate (4 g, 30.72%) as a yellow oil.

[0371] Step 4: To a 250 mL three-necked round-bottom flask was added tert-butyl (S)-(1-bromo-3-(methoxy-d3)propan-2-yl)-l2-azanecarboxylate (4 g, 14.75 mmol, 1 equiv.), copper(I) iodide (0.28 g, 1.47 mmol, 0.1 equiv.), methoxylithium (1.12 g, 29.50 mmol, 2 equiv.), triphenylphosphine (0.50 g, 1.92 mmol, 0.13 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.87 g, 19.17 mmol, 1.3 equiv.) in DMF (40 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was washed with water (2 × 200 mL). The resulting mixture was extracted with MTBE (3 × 200 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (R)-(1-(methoxy-d)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-l2-azanecarboxylate (3 g, 64%) as a yellow oil.

[0372] Step 5: In a 1000 mL round-bottom flask, a solution of tert-butyl (R)-(1-(methoxy-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)-l2-azanecarboxylate (3 g, 10.52 mmol, 1 equiv.) and KHF2 (1.64 g, 21.04 mmol, 2 equiv.) in HO (5 mL) and MTBE (100 mL) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with MTBE (100 mL). The resulting mixture was filtered, and the filter cake was washed with acetone (300 mL). The filtrate was concentrated under reduced pressure to give potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-(methoxy-d3)propyl)trifluoroborate (2.4 g, 86%) as a white solid.

[0373] Borate 7: Potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-cyclopropyl)trifluoroborate

[0374] [ka] Step 1: To a 1000 mL three-necked round-bottom flask, methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclopropylpropanoate (13 g, 53.43 mmol, 1 equiv.) in MeOH (260 mL) and LiBH4 (3.49 g, 160.29 mmol, 3 equiv.) was added dropwise at room temperature. The resulting mixture was stirred at room temperature under air for 8 hours. The resulting mixture was diluted with water (300 mL). The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (3 × 300 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give tert-butyl N-[(2S)-1-cyclopropyl-3-hydroxypropan-2-yl]carbamate (13 g, 96%) as a white solid.

[0375] Step 2: To a 1000 mL three-necked round-bottom flask, tert-butyl N-[(2S)-1-cyclopropyl-3-hydroxypropan-2-yl]carbamate (13.4 g, 62.24 mmol, 1 equiv.) and triphenylphosphine (29.39 g, 112.03 mmol, 1.8 equiv.) in THF (260 mL) and DCM (50 mL) were added portionwise at room temperature, followed by the addition of NBS (19.94 g, 112.03 mmol, 1.8 equiv.) to the above mixture portionwise at −20° C. The resulting mixture was stirred at −20° C. for 16 hours under a nitrogen atmosphere. The resulting mixture was washed with water (2×200 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give tert-butyl N-[(2S)-1-bromo-3-cyclopropylpropan-2-yl]carbamate (10.6 g, 61%) as a yellow oil.

[0376] Step 3: In a bottom flask, a mixture of tert-butyl N-[(2S)-1-bromo-3-cyclopropylpropan-2-yl]carbamate (10.6 g, 38.10 mmol, 1 equiv.), methoxylithium (2.89 g, 76.21 mmol, 2 equiv.), copper(I) iodide (0.73 g, 3.81 mmol, 0.1 equiv.), triphenylphosphine (1.30 g, 4.95 mmol, 0.13 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (12.58 g, 49.53 mmol, 1.3 equiv.) in DMF (100 mL) was stirred at room temperature for 16 hours. The resulting mixture was washed with water (2 × 200 mL). The resulting mixture was extracted with MTBE (3 × 300 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl N-[(2R)-1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl]carbamate (5 g, 40%) as a colorless oil.

[0377] Step 4: To a 1000 mL round-bottom flask, tert-butyl N-[(2R)-1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-yl]carbamate (5.2 g, 15.99 mmol, 1 equiv.) and potassium fluoride (2.50 g, 31.97 mmol, 2 equiv.) in MTBE (300 mL) and HO (10 mL) were added at room temperature. The resulting mixture was stirred at room temperature under atmospheric pressure for 16 hours. The resulting mixture was filtered, and the filter cake was washed with MTBE (1000 mL). The filtrate was concentrated under reduced pressure to give potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-cyclopropyl)trifluoroborate (2.8 g, 65%) as a white solid.

[0378] Borate 8: Potassium (R)-(2-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutyl)trifluoroborate

[0379] [ka] Step 1: To an ice-cold solution of (2S)-2-[(tert-butoxycarbonyl)amino]-4,4,4-trifluorobutanoic acid (4 g, 15.55 mmol, 1 equiv.) and DIEA (2.41 g, 18.66 mmol, 1.2 equiv.) in THF (40 mL) was added isopropyl chloroformate (2.10 g, 17.11 mmol, 1.1 equiv.) dropwise. The cooling bath was removed, and the mixture was stirred at 23 °C for 2 h. The mixture was filtered to remove a white precipitate, and the filtrate was treated with LiBH (0.68 g, 31.10 mmol, 2 equiv.), resulting in vigorous gas evolution. The mixture was stirred at room temperature for 2 h. Brine (25 mL) was added. The mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were dried (MgSO), filtered, and then concentrated in vacuo. The residue was purified by silica gel flash chromatography to give tert-butyl N-[(2S)-4,4,4-trifluoro-1-hydroxybutan-2-yl]carbamate (2.2 g, 58%) as a white solid.

[0380] Step 2: To a stirred solution of tert-butyl N-[(2S)-4,4,4-trifluoro-1-hydroxybutan-2-yl]carbamate (2.2 g, 9.04 mmol, 1 equiv.), triphenylphosphine (4.39 g, 16.73 mmol, 1.85 equiv.) in THF (8 mL) and DCM (40 mL) was added NBS (2.98 g, 16.73 mmol, 1.85 equiv.) in several portions at −20° C. under atmospheric pressure. The resulting mixture was further stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give tert-butyl N-[(2S)-1-bromo-4,4,4-trifluorobutan-2-yl]carbamate (1.1 g, 40%) as a white oil.

[0381] Step 3: A mixture of tert-butyl N-[(2S)-1-bromo-4,4,4-trifluorobutan-2-yl]carbamate (1.1 g, 3.59 mmol, 1 equiv.), copper(I) iodide (0.07 g, 0.36 mmol, 0.1 equiv.), methoxylithium (0.27 g, 7.18 mmol, 2 equiv.), triphenylphosphine (0.12 g, 0.47 mmol, 0.13 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.37 mL, 4.67 mmol, 1.3 equiv.) in DMF (11 mL) was stirred overnight at room temperature under air. The resulting mixture was filtered, and the filter cake was washed with water and tert-butyl methyl ether (3×10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification.

[0382] Step 4: A mixture of tert-butyl N-[(2R)-4,4,4-trifluoro-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl]carbamate (1.1 g, 3.11 mmol, 1 equiv.) and KHF2 (0.49 g, 6.23 mmol, 2 equiv.) in 2-methoxy-2-methylpropane (100 mL) was stirred overnight at room temperature under atmospheric pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with MTBE (300 mL). The mixture was stirred for 30 minutes and filtered. The filter cake was diluted with acetone (400 mL) and stirred for an additional 30 minutes. The resulting mixture was filtered, and the filter cake was washed with acetone (1 × 50 mL). The filtrate was concentrated under reduced pressure to give potassium (R)-(2-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutyl)trifluoroborate (500 mg, 55%) as a white solid.

[0383] Borate 9: (R)-(2-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)butyl) potassium trifluoroborate

[0384] [ka] Step 1: To a stirred mixture of tert-butyl N-[(2S)-1-hydroxy-4-(trifluoromethoxy)butan-2-yl]carbamate (13 g, 47.57 mmol, 1 equiv.), triphenylphosphine (23.09 g, 88.01 mmol, 1.85 equiv.) in DCM (200 mL) and THF (50 mL), NBS (15.67 g, 88.01 mmol, 1.85 equiv.) was added portionwise under air at −20° C. The resulting mixture was stirred at room temperature under air overnight. The resulting mixture was washed with water (3×200 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give tert-butyl N-[(2S)-1-bromo-4-(trifluoromethoxy)butan-2-yl]carbamate (8 g, 50%) as a colorless oil.

[0385] Step 2: A mixture of tert-butyl N-[(2S)-1-bromo-4-(trifluoromethoxy)butan-2-yl]carbamate (5.5 g, 16.36 mmol, 1 equiv.), methoxylithium (1.24 g, 32.72 mmol, 2 equiv.), copper(I) iodide (0.31 g, 1.63 mmol, 0.1 equiv.), triphenylphosphine (0.56 g, 2.13 mmol, 0.13 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.40 g, 21.27 mmol, 1.3 equiv.) in DMF (60 mL) was stirred overnight at room temperature under air. The residue was diluted with water (200 mL), filtered, and the filter cake was washed with MTBE (3 × 30 mL). The filtrate was extracted with MTBE (3 × 80 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product, tert-butyl N-[(2R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)butan-2-yl]carbamate, was used directly in the next step without further purification.

[0386] Step 3: tert-Butyl N-[(2R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)butan-2-yl]carbamate (5.5 g, 14.352 mmol, 1 equiv.) and potassium fluoride (2.24 g, 28.704 mmol, 2 equiv.) were added to a stirred mixture of MTBE (200 mL) and HO (5 mL) at room temperature under air. The resulting mixture was stirred overnight at room temperature under air. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with MTBE (200 mL). The precipitated solid was collected by filtration and washed with MTBE (3 × 20 mL). The residue was purified by trituration with acetone (200 mL). The resulting mixture was filtered, and the filter cake was washed with acetone (3 × 20 mL). The filtrate was concentrated under reduced pressure. This gave potassium (R)-(2-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)butyl)trifluoroborate (3 g, 57%) as a white solid.

[0387] Borate 10: (R)-(2-((tert-butoxycarbonyl)amino)-4-(difluoromethoxy)butyl)trifluoroborate potassium

[0388] [ka] Step 1: To a mixture of benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate (10 g, 32.32 mmol, 1 equiv.) in DCM (100 mL) and HO (10 mL), (bromodifluoromethyl)trimethylsilane (6.57 g, 32.32 mmol, 1 equiv.) and KOAc (12.69 g, 129.30 mmol, 4 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. The resulting mixture was washed with water (1 × 50 mL). The aqueous layer was extracted with DCM (2 × 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-(difluoromethoxy)butanoate (8.5 g, 73%) as a colorless oil.

[0389] Step 2: To a stirred solution of benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-(difluoromethoxy)butanoate (8.5 g, 23.65 mmol, 1 equiv.) in THF (160 mL) was added a THF solution of LiAlH (1.80 g, 47.31 mmol, 2 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was then quenched by the addition of water and 10% aqueous NaOH (2 mL) at 0 °C. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl N-[(2S)-4-(difluoromethoxy)-1-hydroxybutan-2-yl]carbamate (3.1 g, 51%) as a yellow oil.

[0390] Step 3: To a stirred solution of tert-butyl N-[(2S)-4-(difluoromethoxy)-1-hydroxybutan-2-yl]carbamate (3.1 g, 12.144 mmol, 1 equiv.) and triphenylphosphine (5.89 g, 22.47 mmol, 1.85 equiv.) in THF (12 mL) and DCM (62 mL) was added NBS (4.00 g, 22.47 mmol, 1.85 equiv.) in several portions at −20° C. The resulting mixture was stirred at room temperature under air for 16 hours. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give tert-butyl N-[(2S)-1-bromo-4-(difluoromethoxy)butan-2-yl]carbamate (1.55 g, 40%) as a colorless oil.

[0391] Step 4: A stirred mixture of tert-butyl N-[(2S)-1-bromo-4-(difluoromethoxy)butan-2-yl]carbamate (1.55 g, 4.87 mmol, 1 equiv.), methoxylithium (0.37 g, 9.74 mmol, 2 equiv.), copper(I) iodide (0.09 g, 0.49 mmol, 0.1 equiv.), triphenylphosphine (0.17 g, 0.633 mmol, 0.13 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.61 g, 6.330 mmol, 1.3 equiv.) in DMF (150 mL) was stirred at room temperature under air for 16 hours. The residue was diluted with water (2 mL) and MTBE (200 mL). The resulting mixture was filtered, and the filter cake was washed with MTBE (2 × 50 mL). The aqueous layer was extracted with MTBE (2 × 100 mL). The resulting mixture was concentrated under reduced pressure to give tert-butyl (R)-(4-(difluoromethoxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)carbamate (1.77 g, 99%) as a yellow semi-solid. The crude product was used directly in the next step without further purification.

[0392] Step 5: A mixture of tert-butyl (R)-(4-(difluoromethoxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)carbamate (1.77 g, 4.85 mmol, 1 equiv.) and potassium fluorohydride (0.76 g, 9.69 mmol, 2 equiv.) in MTBE (200 mL) and HO (20 mL) was stirred at room temperature under air for 24 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 1 × 150 mL of MTBE (200 mL). The mixture was stirred for 30 minutes and filtered. The filter cake was diluted with acetone (100 mL) and stirred for an additional 30 minutes. The resulting mixture was filtered, and the filter cake was washed with acetone (1 × 50 mL). The filtrate was concentrated under reduced pressure to give potassium (R)-(2-((tert-butoxycarbonyl)amino)-4-(difluoromethoxy)butyl)trifluoroborate (750 mg, 45%) as a white solid.

[0393] Synthesis of compounds in Table 1 Common steps: Cross-coupling reaction between intermediates of type 4 and trifluoroborate A mixture of intermediate 4 (1 equivalent), potassium trifluoroborate (1.5 equivalents), Pd(dba) or Pd(Amphos)Cl (0.1 equivalents), and CsCO (2 equivalents) in toluene / HO (25 / 1) was stirred at 100 °C under a nitrogen atmosphere until the reaction was complete. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound of type 5.

[0394] Example 1: Synthesis of 6-((2R,3S)-2-amino-3-fluorobutyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (Compound 1)

[0395] [ka] Step 1: Using the general cross-linking reaction between tert-butyl (6-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate (Intermediate 4-1) and potassium ((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)trifluoroborate (borate 1), tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate was obtained as a yellow solid. LC-MS-(ES, m / z): [M+H] + = 538.25.

[0396] Step 2: To a stirred solution of tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate (10 g, 3.717 mmol, 1 equiv.) in THF (40 mL) was added NBS (3.97 g, 4.460 mmol, 1.2 equiv.) in several portions at −40° C. under air. The resulting mixture was stirred at room temperature for an additional 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel, mobile phase, MeCN / water (0.1% FA), 50% to 90% gradient in 30 min, detector, UV 254 nm) to give tert-butyl (7-bromo-6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate (4.6 g, 29%) as a yellow solid. LC-MS-(ES, m / z): [M+H] + = 617.75.

[0397] Step 3: To a 40 mL vial was added tert-butyl (7-bromo-6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate (3.4 g, 5.51 mmol, 1 equiv.) in THF (10 mL) and a solution of HCl in dioxane (4 M) at room temperature. The resulting mixture was stirred at room temperature under air for 5 hours. The mixture / residue was neutralized to pH 8 with Et3N. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 30% to 70% gradient in 20 min; detector, UV 254 nm) to give 6-((2R,3S)-2-amino-3-fluorobutyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.2 g, 51%). LC-MS-(ES, m / z): [M+H] + = 416.05.

[0398] Example 2: Synthesis of 6-((2R,3S)-2-amino-3-fluorobutyl)-2,7-dichloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (Compound 2)

[0399] [ka]

[0400] Step 1: Using the general cross-linking reaction between tert-butyl (6-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate (Intermediate 4-1) and potassium ((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)trifluoroborate (borate 1), tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate was obtained as a yellow solid. LC-MS-(ES, m / z): [M+H] + = 538.25.

[0401] Step 2: To a stirred mixture of tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate (100 mg, 0.186 mmol, 1 equiv) in THF (1 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (18 mg, 0.093 mmol, 0.5 equiv) in THF (0.2 ml) dropwise at −40° C. under air. The residue was purified by reversed-phase flash chromatography (conditions: column, C18 silica gel, mobile phase, MeCN / water (0.1% FA), 10%-50% gradient over 10 min, detector, UV 254 nm) to give tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)-2,7-dichloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate (23 mg, 22%) as a yellow solid. LC-MS-(ES, m / z): [M+H] + = 571.80.

[0402] Step 3: To a stirred mixture of tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)-2,7-dichloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(furan-2-ylmethyl)carbamate (23 mg, 0.040 mmol, 1 equiv) in DCM (1 mL) was added dropwise a solution of HCl in 1,4-dioxane (1.00 mL, 4 M) under air at 0° C. The resulting mixture was concentrated in vacuo. The crude product (20 mg) was purified by preparative HPLC (conditions: column: XBridge Shield RP18 OBD column 30*150 mm, 5 m; mobile phase A: water 10 mmol / L NH4HCO3 + 0.05% NH3.H2O), mobile phase B: ACN, flow rate: 50 mL / min, gradient: 20% B to 60% B in 10 min, wavelength: 254 nm / 220 nm, RT1 (min): 11.27) to give 6-((2R,3S)-2-amino-3-fluorobutyl)-2,7-dichloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4 mg, 24%). LC-MS-(ES, m / z): [M+H] + = 372.05.

[0403] Example 3: Synthesis of (R)-6-(2-amino-3-fluoropropyl)-2,7-dichloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (Compound 3)

[0404] [ka]

[0405] The procedure was the same as in Example 2, except that potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)trifluoroborate (borate 2) was used as the trifluoroborate salt in Step 1, to give 1.03 g of the title compound (R)-6-(2-amino-3-fluoropropyl)-2,7-dichloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine. LC-MS-(ES, m / z): [M+H] + = 358.10.

[0406] Example 4: Synthesis of (R)-6-(2-amino-3-fluoropropyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (Compound 4)

[0407] [ka]

[0408] Similar to the preparation of Example 1, but using as trifluoroborate in step 1 potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)trifluoroborate (borate 2), 12 mg of the title compound (R)-6-(2-amino-3-fluoropropyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine was obtained. LC-MS-(ES, m / z): [M+H] + = 401.95.

[0409] Example 5: Synthesis of (R)-6-(2-amino-3-(difluoromethoxy)propyl)-2,7-dichloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (Compound 5)

[0410] [ka]

[0411] Similar to the preparation of Example 2, but using as trifluoroborate in step 1, potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-(difluoromethoxy)propyl)trifluoroborate (borate 3), 21 mg of the title compound (R)-6-(2-amino-3-(difluoromethoxy)propyl)-2,7-dichloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine was obtained. LC-MS-(ES, m / z): [M+H] + = 406.00.

[0412] Example 6: Synthesis of (R)-6-(2-amino-3-(difluoromethoxy)propyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (Compound 6)

[0413] [ka]

[0414] Similar to the preparation of Example 1, but using as trifluoroborate in step 1 potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-(difluoromethoxy)propyl)trifluoroborate (borate 3), 12 mg of the title compound (R)-6-(2-amino-3-(difluoromethoxy)propyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine was obtained. LC-MS-(ES, m / z): [M+H] + = 451.95.

[0415] Example 7. Synthesis of (R)-6-(2-amino-3-methoxypropyl)-2,7-dichloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (Compound 7)

[0416] [ka]

[0417] Used as trifluoroborate salt in step 1, analogously to the preparation of Example 2, was potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)trifluoroborate (borate salt 4), to give 18 mg of the title compound (R)-6-(2-amino-3-methoxypropyl)-2,7-dichloro-N-(furan-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine. LC-MS-(ES, m / z): [M+H] + = 371.85.

[0418] Example B: ATXN3 quantitative splicing assay Human neuroblastoma SK-N-MC cells were seeded at 20,000 cells / well in 384-well plates. 24 hours after plating, cells were treated with compounds at appropriate concentrations ranging from 30 μM to 0.6 nM (0.3% DMSO) for 24 hours. Treated cells were lysed in 15 μL of lysis buffer, and cDNA was synthesized using the Fast Advanced Cells-to-Ct Kit. 2 μL of each cDNA was used in qPCR reactions to confirm exon 4-skipped transcripts of ATXN3. A second set of primers / probes, E4E5, was used to detect exon 4-containing transcripts. A third set of primers / probes, E8E9, was used to detect total ATXN3 gene levels. qPCR reactions were prepared in 384-well plates in 10 μL volumes using TaqMan™ Fast Advanced Master Mix with the primers and probes shown in the table below. Reactions were scanned in a Quant Studio 6 qPCR instrument set to default settings.

[0419] The primers and probes are listed in Table 3 below.

[0420] [Table 3]

[0421] Example C: ATXN3 total protein assay. Human neuroblastoma SK-N-MC cells were seeded at 10,000 cells / well in 384-well plates one day before compound treatment. Compound concentrations were tested at appropriate doses ranging from 30 μM to 0.6 nM. After 48 h of incubation, cells were lysed with 25 μL of lysis buffer containing protease inhibitors, and total ATXN3 protein levels were assessed using a Mesoscale Discovery (MSD) assay developed with a pair of anti-ATXN3 antibodies. The capture and detection antibodies were generated in mouse and rabbit, respectively. An anti-rabbit MSD-ST antibody was used as the secondary antibody.

[0422] ATXN3 recombinant protein was used as a standard. Readouts were captured with 35 μL of MSD read buffer and a multiarray 384-well high-binding plate.

[0423] For parallel viability testing by CellTiter Glo® 2.0, one plate replicate was performed with a seeding density of 4,000 cells / well. Compounds were incubated for 48 hours. Viability measurements were performed by Envision according to the manufacturer's instructions.

[0424] The compounds were tested as outlined in Examples B and C above and the results are shown in Table 4 below.

[0425] [Table 4]

Claims

1. Compounds of formula (I): 【Chemistry 1】 (In the formula, -R ２１ is unsubstituted or is substituted with 1, 2, or 3 independently selected R １Ａ furanyl substituted with a group, and each R １Ａ are independently halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C １－６ Alkoxy, —C(═O)OH, —C(═O)C １－６ Alkyl, —C(═O)C １－６ Haloalkyl, and —C(═O)C １－６ alkoxy; -R ２３ H, azide, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Heteroalkyl, -(C １－６ alkylene)-C ３－１０ cycloalkyl, -(C １－６ alkylene)-4 to 10-membered heterocycloalkyl, -(C １－６ Heteroalkylene)-C ３－１０ cycloalkyl, -(C １－６ heteroalkylene)-4 to 10-membered heterocycloalkyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, OR ａ３ , S.R. ａ３ , C(=O)R ｂ３ , C(=O)OR ｂ３ , N.R. ｃ３ R ｄ３ , C(═O)NR ｃ３ R ｄ３ , -OC(=O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(=O)R ｂ３ , N.R. ｃ３ C(=O)OR ｂ３ , N.R. ｃ３ C(=O)NR ｃ３ R ｄ３ , N.R. ｃ３ S (= O) ２ R ｂ３ , N.R. ｃ３ S (= O) ２ NR ｃ３ R ｄ３ , S(O)NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ wherein the C is selected from the group consisting of １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Heteroalkyl, C １－６ Alkylene, C １－６ Heteroalkylene, C ３－１０ Cycloalkyl, C ６－１０ Aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl each have 1, 2, 3, or 4 independently selected R ２０ optionally substituted by groups, -R ２４ is a halo, -Each R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ are independently H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C １－６ Alkoxy, -(C １－６ alkylene)-C １－６ Alkoxy, C ３－１０ cycloalkyl, -(C １－６ alkylene)-C ３－１０ Cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, -(C １－６ alkylene)-C ３－１０ Cycloalkyl, C ６－１０ Aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl each have 1, 2, 3, or 4 independently selected R ２０ optionally substituted by groups, or R ｃ３ and R ｄ３ together with the N atom to which they are attached to form a 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl ring, each of which is selected from 1, 2, 3, or 4 independently selected R ２０ optionally substituted by groups, and -Each R ２０ are independently OH, SH, CN, NO ２ , Halo, Oxo, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－４ Haloalkyl, C １－４ Cyanoalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, -(C １－４ alkyl)-(C １－４ alkoxy), -(C １－４ alkoxy)-(C １－４ Alkoxy), C １－４ Haloalkoxy, C ３－６ cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, amino, C １－４ Alkylamino, di(C １－４ alkyl)amino, carbamyl, C １－４ Alkylcarbamyl, di(C １－４ alkyl) carbamyl, carbamoyl, C １－４ Alkylcarbamoyl, di(C １－４ alkyl)carbamoyl, C １－４ Alkylcarbonyl, C １－４ Alkoxycarbonyl, C １－４ Alkylcarbonylamino, C １－４ Alkyl sulfonyl amino, amino sulfonyl, C １－４ Alkylaminosulfonyl, di(C １－４ alkyl)aminosulfonyl, aminosulfonylamino, C １－４ Alkylaminosulfonylamino, di(C １－４ alkyl)aminosulfonylamino, aminocarbonylamino, C １－４ Alkylaminocarbonylamino, di(C １－４ alkyl)aminocarbonylamino, and amidinyl), or a pharmaceutically acceptable salt thereof.

2. Each R １Ａ became independent and C １－６ Archi ル、 C １－６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from haloalkyl and halo.

3. R １Ａ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

4. R ２１ but, 【Chemistry 2】 and 【Transformation 3】 4. The compound of claim 1, wherein the compound is selected from the group consisting of:

5. R ２１ but 【Chemistry 4】 5. The compound of claim 1 or 4, wherein:

6. R ２３ is a substituted or unsubstituted C １－６ Alkyl, or substituted or unsubstituted C １－６ The compound of any one of claims 1 to 5, which is heteroalkyl.

7. R ２３ is CH ２ CHNH ２ CH ３ 7. The compound of claim 6, wherein:

8. R ２３ is CH ２ CHNH ２ CH ２ 7. The compound of claim 6, wherein R is OH, or a pharmaceutically acceptable salt thereof.

9. R ２３ is CH ２ CHNH ２ CHFCH ３ 7. The compound of claim 6, wherein:

10. R ２３ is CH ２ CHNH ２ CH ２ CH ２ 7. The compound of claim 6, wherein R is OH, or a pharmaceutically acceptable salt thereof.

11. R ２３ is CH ２ CHNH ２ CH ２ 7. The compound of claim 6, wherein R is H, or a pharmaceutically acceptable salt thereof.

12. R ２３ is CH ２ CHNH ２ CH ２ OCH ３ 7. The compound of claim 6, wherein:

13. R ２３ is CH ２ CHNH ２ CH ２ OCD ３ 13. The compound of claim 12, wherein:

14. R ２４ The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of fluoro, chloro, and bromo.

15. R ２４ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein is -Cl or -Br.

16. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

18. 17. A method for treating, preventing, delaying progression of, or ameliorating symptoms of a disease or condition associated with ATXN3 expression or activity levels in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or salt of any one of claims 1 to 16.

19. A method for modulating splicing of ATXN3 pre-mRNA, comprising contacting a compound or salt of any one of claims 1 to 16 with a splice site sequence or a cell containing the ATXN3 pre-mRNA, wherein the compound binds to the ATXN3 pre-mRNA and modulates splicing of the ATXN3 pre-mRNA in the subject's cell to produce a spliced ​​product of the ATXN3 pre-mRNA.

20. 20. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition or disease associated with the expression or activity level of ATXN3.

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