Compositions useful for modulating splicing

Abstract

Described herein are compounds that modulate splicing of a pre-mRNA, encoded by genes, and methods of treating diseases and conditions associated with gene expression or activity of proteins encoded by genes.

Description

WSGR Docket No.51503-778.606 COMPOSITIONS USEFUL FOR MODULATING SPLICING CROSS REFERENCE

[0001] This application claims the benefit of priority to U.S. Provisional Application No.63 / 672,397, filed July 17, 2024, which is incorporated herein by reference in its entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronicallyin XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on May 28, 2025, is named 51503-778_606_SL.xml and is 12,514 bytes in size. BACKGROUND

[0003] Spinocerebellar Ataxia 3 (SCA3 or Machado-Joseph Disease) is a rare, inherited,neurodegenerative, autosomal dominant disease. It is characterized by progressive degeneration of the brainstem, cerebellum and spinal cord, however, neurons in other areas of the brain are also affected. Presenting features include gait problems, speech difficulties, clumsiness, and often visual blurring and diplopia; saccadic eye movements become slow and ophthalmoparesis develops, resulting initially in up-gaze restriction. Ambulation becomes increasingly difficult, leading to the need for assistive devices 10 to 15 years following onset. Late in the disease course, individuals are wheelchair bound and have severe dysarthria, dysphagia, facial and temporal atrophy. The disease progresses relentlessly until death occurs at any time from 6 to approximately 30 years after onset through pulmonary complications.

[0004] SCA3 is caused by CAG tri-nucleotide repeats in exon 10 of the Ataxin 3 (ATXN3) gene.ATXN3 encodes for a deubiquitinase with wide-ranging functions, but it does not appear to be an essential gene. Disease causing variants of the ATXN3 gene have approximately 40 to over 200 CAG tri-nucleotide repeats in exon 10. Expanded CAG repeats in the ATXN3 gene are translated 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. There are currently no treatments for SCA3. SUMMARY

[0005] In one aspect, described herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof: - 1 -WSGR Docket No.51503-778.606Formula (I) wherein R21, R22, R23and R24are as defined herein.

[0006] Also provided herein are pharmaceutical compositions comprising a compound disclosedherein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0007] In some aspects, described herein, is a method of modulating splicing of a Ataxin3 (ATXN3)pre-mRNA, comprising contacting a small molecule splicing modulator compound disclosed herein (SMSM) to the ATXN3 pre-mRNA with a splice site sequence or cells comprising the ATXN3 pre- mRNA, wherein the SMSM binds to the ATXN3 pre-mRNA and modulates splicing of the ATXN3 pre-mRNA in a cell of a subject to produce a spliced product of the ATXN3 pre-mRNA.

[0008] In some aspects, described herein, is a method of treating, preventing, delaying of progress,or ameliorating symptoms of a disease or a condition associated with Ataxin 3 (ATXN3) expression level or activity level in a subject in need thereof, comprising administering a therapeutically effective amount of a small molecule splicing modulator compound disclosed herein (SMSM), wherein the SMSM binds to a pre-mRNA encoded by ATXN3 and modulates splicing of the ATXN3 pre-mRNA in a cell of the subject to produce a spliced product of the ATXN3 pre-mRNA, wherein the amount of full length ATXN3 is reduced. INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are hereinincorporated 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

[0010] Unless otherwise defined, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods, and materials are described below. - 2 -WSGR Docket No.51503-778.606 Definitions

[0011] The term “small molecule splicing modulator” or “SMSM” denotes a small moleculecompound that binds to a cell component (e.g., DNA, RNA, pre-mRNA, protein, RNP, snRNA, carbohydrates, lipids, co–factors, nutrients, and / or metabolites) and modulates splicing. For example, a SMSM can bind to a polynucleotide, e.g., an RNA (e.g., a pre-mRNA) with an aberrant splice site, resulting in steric modulation of the polynucleotide. For example, a SMSM can bind to a protein, e.g., a spliceosome protein or a ribonuclear protein, resulting in steric modulation of the protein. For example, a SMSM can bind to a spliceosome component, e.g., a spliceosome protein or snRNA resulting in steric modulation of the spliceosome protein or snRNA. For example, a SMSM is a compound of Formula (I). The term “small molecule splicing modulator” or “SMSM” specifically excludes compounds consisting of oligonucleotides.

[0012] “Steric alteration,” “steric modification,” or “steric modulation” herein refers to changes inthe spatial orientation of chemical moieties with respect to each other. A person of ordinary skill in the art would recognize steric mechanisms include, but are not limited to, steric hindrance, steric shielding, steric attraction, chain crossing, steric repulsions, steric inhibition of resonance, and steric inhibition of protonation.

[0013] Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structuresherein indicates the presence of a hydrogen, unless indicated otherwise.

[0014] The definitions described herein apply irrespective of whether the terms in question appearalone or in combination. It is contemplated that the definitions described herein can be appended to form chemically relevant combinations, such as e.g., “heterocycloalkylaryl,” “haloalkylheteroaryl,” “arylalkylheterocycloalkyl,” or “alkoxyalkyl.” The last member of the combination is the radical which is binding to the rest of the molecule. The other members of the combination are attached to the binding radical in reversed order in respect of the literal sequence, e.g., the combination arylalkylheterocycloalkyl refers to a heterocycloalkyl–radical which is substituted with an alkyl which is substituted with an aryl.

[0015] When indicating the number of substituents, the term “one or more” refers to the range fromone substituent to the highest possible number of substitutions, i.e., replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0016] The term “optional” or “optionally” denotes that a subsequently described event orcircumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

[0017] The term “substituent” denotes an atom or a group of atoms replacing a hydrogen atom onthe parent molecule.

[0018] The term “substituted” denotes that a specified group bears one or more substituents. Whereany group can carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same. The term “unsubstituted” means - 3 -WSGR Docket No.51503-778.606 that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted with one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitutions, i.e., replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0019] The terms “compound(s) of this disclosure,” “compound(s) of the present disclosure,” “smallmolecule steric modulator,” “small molecule splicing modulator,” “steric modulator,” “splicing modulator,” “compounds that modify splicing,” and “compounds modifying splicing” are interchangeably used herein and refer to compounds as disclosed herein and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof.

[0020] The following abbreviations are used throughout the specification: acetic acid (AcOH); ethylacetate (EtOAc); butyl alcohol (n–BuOH); 1,2–dichloroethane (DCE); dichloromethane (CH2Cl2, DCM); diisopropylethylamine (Diipea); dimethylformamide (DMF); hydrogen chloride (HCl); methanol (MeOH); methoxymethyl bromide (MOMBr); N–methyl–2–pyrrolidone (NMP); methyl Iodide (MeI); n–propanol (n–PrOH); p–methoxybenzyl (PMB); triethylamine (Et3N); [1,1’– Bis(diphenylphosphino)ferrocene] dichloropalladium(II); (Pd(dppf)Cl2); sodium ethane thiolate (EtSNa); sodium acetate (NaOAc); sodium hydride (NaH); sodium hydroxide (NaOH); tetrahydropyran (THP); tetrahydrofuran (THF).

[0021] As used herein, C1–Cx includes C1–C2, C1–C3... C1–Cx. By way of example only, a groupdesignated as “C1–C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1–C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso–propyl, n–butyl, iso–butyl, sec– butyl, and t–butyl.

[0022] The term “oxo” refers to the =O substituent.

[0023] “Carboxyl” refers to -COOH.

[0024] “Cyano” refers to -CN.

[0025] The term “thioxo” refers to the =S substituent.

[0026] “Amidinyl” refers to a radical of the formula -C(=NRa)-N(Ra)2 wherein each Ra isindependently a hydrogen, a C1-C6 alkyl, C1-C6 haloalkyl, C3-C6cycloalkyl, or 3-6 membered heterocycloalkyl. In some embodiments, an amidinyl is C(=NH)NH2. In some embodiments, an amidinyl is C(=NH)NH(C1-C6 alkyl).

[0027] The term “halo,” “halogen,” and “halide” are used interchangeably herein and denote fluoro,chloro, bromo, or iodo.

[0028] The term “alkyl” refers to a straight or branched hydrocarbon chain radical, having from oneto twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An alkyl comprising up to 10 carbon atoms is referred to as a C1–C10 alkyl, likewise, for example, an alkyl - 4 -WSGR Docket No.51503-778.606 comprising up to 6 carbon atoms is a C1–C6 alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, C1–C10alkyl, C1–C9alkyl, C1–C8alkyl, C1–C7alkyl, C1–C6alkyl, C1–C5alkyl, C1–C4alkyl, C1–C3alkyl, C1–C2alkyl, C2–C8alkyl, C3–C8alkyl and C4–C8alkyl. Representative alkylgroups include, but are not limited to, methyl, ethyl, n–propyl, 1–methylethyl (i–propyl), n–butyl, i–butyl, s–butyl, n–pentyl, 1,1–dimethylethyl (t–butyl), 3–methylhexyl, 2–methylhexyl, 1–ethyl–propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, the alkyl is – CH(CH3)2or –C(CH3)3. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below. “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group. In some embodiments, the alkylene is –CH2–, –CH2CH2–, or –CH2CH2CH2–. In some embodiments, the alkylene is –CH2–. In some embodiments, the alkylene is –CH2CH2–. In some embodiments, the alkylene is –CH2CH2CH2–.

[0029] The term “alkoxy” refers to a radical of the formula –OR where R is an alkyl radical asdefined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy.

[0030] 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.

[0031] The term “alkenyl” refers to a type of alkyl group in which at least one carbon–carbondouble bond is present. In one embodiment, an alkenyl group has the formula –C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non–limiting examples of an alkenyl group include –CH=CH2, –C(CH3)=CH2, –CH=CHCH3, –C(CH3)=CHCH3, and – CH2CH=CH2.

[0032] The term “alkynyl” refers to a type of alkyl group in which at least one carbon–carbon triplethe remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. 3 2CH3, –CH2

[0033] “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, furanyl, quinolinyl). - 5 -WSGR Docket No.51503-778.606

[0034] The term “aryl” refers to a radical derived from a hydrocarbon ring system comprising atleast one aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar–”(such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group is partially reduced to form a cycloalkyl group defined herein. In some embodiments, an aryl group is fully reduced to form a cycloalkyl group defined herein.

[0035] The term “haloalkyl” denotes an alkyl group wherein at least one of the hydrogen atoms ofthe alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloalkyl include monofluoro–, difluoro–or trifluoro–methyl, –ethyl or –propyl, for example, 3,3,3–trifluoropropyl, 2–fluoroethyl, 2,2,2–trifluoroethyl, fluoromethyl, or trifluoromethyl. The term “perhaloalkyl” denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Exemplary haloalkyl groups further include trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2–trifluoroethyl, 1,2– difluoroethyl, 3–bromo–2–fluoropropyl, 1,2–dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0036] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted with one ormore 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 include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0037] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted with one ormore amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0038] “Cyanoalkyl” refers to an alkyl radical, as defined above, that is substituted with one or morecyano 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 include, for example, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, or cyanopentyl.

[0039] The term “haloalkoxy” denotes an alkoxy group wherein at least one of the hydrogen atomsof the alkoxy group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloalkoxyl include monofluoro–, difluoro–or trifluoro–methoxy, –ethoxy or –propoxy, for example, 3,3,3–trifluoropropoxy, 2–fluoroethoxy, 2,2,2–trifluoroethoxy, fluoromethoxy, or trifluoromethoxy. The term “perhaloalkoxy” denotes an alkoxy group where all hydrogen atoms of - 6 -WSGR Docket No.51503-778.606 the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxyl further include trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2–trifluoroethoxy, 1,2–difluoroethoxy, 3–bromo–2–fluoropropoxy, 1,2–dibromoethoxy, and the like. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.

[0040] The term “bicyclic ring system” denotes two rings which are fused to each other via acommon single or double bond (annelated bicyclic ring system), via a sequence of three or more common atoms (bridged bicyclic ring system) or via a common single atom (spiro bicyclic ring system). Bicyclic ring systems can be saturated, partially unsaturated, unsaturated, or aromatic. Bicyclic ring systems can comprise heteroatoms selected from N, O, and S.

[0041] The terms “carbocyclic” or “carbocycle” refer to a ring or ring system where the atomsforming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.

[0042] The term “cycloalkyl” refers to a monocyclic or polycyclic non–aromatic radical, whereineach of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non–aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2–dihydronaphthalenyl, 1,4–dihydronaphthalenyl, tetrainyl, decalinyl, 3,4– dihydronaphthalenyl–1(2H)–one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.

[0043] The term “bridged” refers to any ring structure with two or more rings that contains a bridgeconnecting two bridgehead atoms. The bridgehead atoms are defined as atoms that are the part of the skeletal framework of the molecule and which are bonded to three or more other skeletal atoms. In some embodiments, the bridgehead atoms are C, N, or P. In some embodiments, the bridge is a single atom or a chain of atoms that connects two bridgehead atoms. In some embodiments, the bridge is a - 7 -WSGR Docket No.51503-778.606 valence bond that connects two bridgehead atoms. In some embodiments, the bridged ring system is cycloalkyl. In some embodiments, the bridged ring system is heterocycloalkyl.

[0044] The term “fused” refers to any ring structure described herein which is fused to an existingring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with one or more N, S, and O atoms. The non–limiting examples of fused heterocyclyl or heteroaryl ring structures include 6–5 fused heterocycle, 6–6 fused heterocycle, 5–6 fused heterocycle, 5–5 fused heterocycle, 7–5 fused heterocycle, and 5–7 fused heterocycle.

[0045] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replacedby a fluorine atom. In one aspect, a fluoroalkyl is a C1–C6fluoroalkyl. In some embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2–trifluoroethyl, 1– fluoromethyl–2–fluoroethyl, and the like.

[0046] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of thealkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., –NH–, –N(alkyl)–, or – N(aryl)–), sulfur (e.g., –S–, –S(=O)–, or –S(=O)2–), or combinations thereof. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C1–C6heteroalkyl. Representative heteroalkyl groups include, but are not limited to –OCH2OMe, –OCH2CH2OH, –OCH2CH2OMe, or – OCH2CH2OCH2CH2NH2. In some embodiments, a heteroalkyl contains one skeletal heteroatom. In some embodiments, a heteroalkyl contains 1-3 skeletal heteroatoms.

[0047] The term “heteroalkylene” refers to an alkyl radical as described above where one or morecarbon atoms of the alkyl is replaced with a O, N or S atom. “Heteroalkylene” or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkylene groups include, but are not limited to –OCH2CH2O–, –OCH2CH2OCH2CH2O–, or – OCH2CH2OCH2CH2OCH2CH2O–.

[0048] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least oneheteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non–aromatic ring atom) or bridged ring systems. 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 atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially or fully - 8 -WSGR Docket No.51503-778.606 saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2–oxopiperazinyl, 2–oxopiperidinyl, 2–oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4–piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1–oxo– thiomorpholinyl, 1,1–dioxo–thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 0–2 N atoms, 0–2 O atoms, 0–2 P atoms, and 0–1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1–3 N atoms, 0–1 O atoms, and 0–1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.

[0049] The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings (also known asheteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) that includes at least one heteroatom selected from nitrogen, oxygen and sulfur, wherein each heterocyclic group has from 3 to 12 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds. Non–aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 12 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 12 atoms in its ring system. The heterocyclic groups include benzo–fused ring systems. Examples of non–aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6– tetrahydropyridinyl, pyrrolin–2–yl, pyrrolin–3–yl, indolinyl, 2H–pyranyl, 4H–pyranyl, dioxanyl, 1,3– dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3–azabicyclo[3.1.0]hexanyl, 3–azabicyclo[4.1.0]heptanyl, 3 h–indolyl, indolin–2–onyl, isoindolin–1–onyl, isoindoline–1,3–dionyl, 3,4–dihydroisoquinolin– 1(2H)–onyl, 3,4–dihydroquinolin–2(1H)–onyl, isoindoline–1,3–dithionyl, benzo[d]oxazol–2(3H)– onyl, 1H–benzo[d]imidazol–2(3H)–onyl, benzo[d]thiazol–2(3H)–onyl, and quinolizinyl. Examples of - 9 -WSGR Docket No.51503-778.606 aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C–attached (or C–linked) or N– attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol–1–yl (N–attached) or pyrrol–3–yl (C–attached). Further, a group derived from imidazole includes imidazol–1–yl or imidazol–3–yl (both N–attached) or imidazol–2–yl, imidazol–4–yl or imidazol–5–yl (all C–attached). The heterocyclic groups include benzo–fused ring systems. Non–aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin–2–one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0050] The term “heteroaryl” refers to an aryl group that includes one or more ring heteroatomsselected from nitrogen, oxygen, and sulfur. The heteroaryl can be monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8–naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8–naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0–6 N atoms in the ring. In some embodiments, a heteroaryl contains 1–4 N atoms in the ring. In some embodiments, a heteroaryl contains 4–6 N atoms in the ring. In some embodiments, a heteroaryl contains 0–4 N atoms, 0–1 O atoms, 0–1 P atoms, and 0–1 S atoms in the ring. In some embodiments, a heteroaryl contains 1–4 N atoms, 0–1 O atoms, and 0–1 S atoms in the ring. In some embodiments, heteroaryl is a C1–C9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C1–C5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5–membered or 6–membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6–C9 heteroaryl. In some embodiments, a heteroaryl group is partially reduced to form a heterocycloalkyl group defined herein. In some embodiments, a heteroaryl group is fully reduced to form a heterocycloalkyl group defined herein. - 10 -WSGR Docket No.51503-778.606

[0051] The term “moiety” refers to a specific segment or functional group of a molecule. Chemicalmoieties are often recognized chemical entities embedded in or appended to a molecule.

[0052] The term “optionally substituted” or “substituted” means that the referenced group isoptionally substituted with one or more additional group(s) individually and independently selected from D, halogen, –CN, –NH2, –NH(alkyl), –N(alkyl)2, –OH, –CO2H, –CO2alkyl, –C(=O)NH2, – C(=O)NH(alkyl), –C(=O)N(alkyl)2, –S(=O)2NH2, –S(=O)2NH(alkyl), –S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, –CN, –NH2, – NH(CH3), –N(CH3)2, –OH, –CO2H, –CO2(C1–C4alkyl), –C(=O)NH2, –C(=O)NH(C1–C4alkyl), – C(=O)N(C1–C4alkyl)2, –S(=O)2NH2, –S(=O)2NH(C1–C4alkyl), –S(=O)2N(C1–C4alkyl)2, C1–C4alkyl, C3–C6cycloalkyl, C1–C4fluoroalkyl, C1–C4heteroalkyl, C1–C4alkoxy, C1–C4fluoroalkoxy, –SC1–C4alkyl, –S(=O)C1–C4alkyl, and –S(=O)2(C1–C4alkyl). In some embodiments, optional substituents are independently selected from D, halogen, –CN, –NH2, –OH, –NH(CH3), –N(CH3)2, – NH(cyclopropyl), –CH3, –CH2CH3, –CF3, –OCH3, and –OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

[0053] The term “tautomer” refers to a proton shift from one atom of a molecule to another atom ofthe same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:.

[0054] The term “subject” or “patient” encompasses mammals. Examples of mammals include, butare not limited to, any member of the mammalian class: humans, non–human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as - 11 -WSGR Docket No.51503-778.606 rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. The term “animal” as used herein comprises human beings and non–human animals. In one embodiment, a “non–human animal” is a mammal, for example a rodent such as rat or a mouse. In one embodiment, a non–human animal is a mouse.

[0055] The term “pharmaceutically acceptable” denotes an attribute of a material which is useful inpreparing a pharmaceutical composition that is generally safe, non toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use. “Pharmaceutically acceptable” can refer a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0056] The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier”and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non– toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, excipients, preservatives or lubricants used in formulating pharmaceutical products.

[0057] The term “pharmaceutically acceptable salts” denotes salts which are not biologically orotherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. A “pharmaceutically acceptable salt” can refer to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and / or does not abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting a SMSM compound of the present disclosure with acids. Pharmaceutically acceptable salts are also obtained by reacting a compound of the present disclosure with a base to form a salt.

[0058] As used herein, a “small molecular weight compound” can be used interchangeably with“small molecule” or “small organic molecule.” Small molecules refer to compounds other than peptides or oligonucleotides; and typically have molecular weights of less than about 2000 Daltons, e.g., less than about 900 Daltons. Small Molecule Splicing Modulators (SMSMs)

[0059] It has now been found that compounds of this disclosure, and pharmaceutically acceptablecompositions thereof, are effective as agents for use in treating, preventing, or ameliorating a disease or a condition associated with a 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 modulators (SMSMs). These SMSMs can modulate - 12 -WSGR Docket No.51503-778.606 specific splicing events in specific pre-mRNA molecules. The small molecules of this disclosure are different from and are not related to antisense or antigene oligonucleotides.

[0060] In one aspect, a SMSM described herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof:Formula (I) wherein, - R21is 5 membered heteroaryl, provided that the 5 membered heteroaryl is not thiophenyl or furanyl, wherein the 5 membered heteroaryl is unsubstituted or substituted with 1, 2, or 3, independently selected R1Agroups; each R1Ais independently selected from halo, CN, NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, -C(=O)OH, -C(=O)C1-6alkyl, - C(=O)C1-6 haloalkyl, and -C(=O)C1-6 alkoxy; or, - R21is phenyl or 6 membered heteroaryl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R1Agroups; each R1Ais independently selected from halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, -C(=O)OH, -C(=O)C1- 6 alkyl, -C(=O)C1-6 haloalkyl, and -C(=O)C1-6 alkoxy; - R22is selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, wherein the C1-6 alkyl and C1-6 alkoxy are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - R23is selected from the group consisting of H, azido, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 heteroalkyl, -(C1-6 alkylene)-C3-10 cycloalkyl, -(C1-6 alkylene)-4-10 membered heterocycloalkyl, -(C1-6 heteroalkylene)-C3-10 cycloalkyl, -(C1-6 heteroalkylene)-4-10 membered heterocycloalkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, ORa3, SRa3, C(=O)Rb3, C(=O)ORb3, NRc3Rd3, C(=O)NRc3Rd3, - OC(=O)NRc3Rd3, NRc3C(=O)Rb3, NRc3C(=O)ORb3, NRc3C(=O)NRc3Rd3, NRc3S(=O)2Rb3, NRc3S(=O)2NRc3Rd3, S(O)NRc3Rd3, and S(O)2NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 heteroalkyl, C1-6 alkylene, C1-6 heteroalkylene, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R20groups; - 13 -WSGR Docket No.51503-778.606 - R24is selected from the group consisting of H, azido, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa4, C(=O)Rb4, C(=O)ORb4, NRc4Rd4, C(=O)NRc4Rd4, - OC(=O)NRc4Rd4, NRc4C(=O)Rb4, NRc4C(=O)ORb4, NRc4C(=O)NRc4Rd4, NRc4S(=O)2Rb4, NRc4S(=O)2NRc4Rd4, S(O)NRc4Rd4, and S(O)2NRc4Rd4, wherein the C1-6alkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - each Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkoxy, - (C1-6alkylene)-C1-6alkoxy, C3-10cycloalkyl, -(C1-6alkylene)-C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -(C1-6alkylene)-C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; or Rc3and Rd3together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; or Rc4and Rd4together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; and - each R20is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1- 4 alkoxy, -(C1-4 alkyl)-(C1-4 alkoxy), -(C1-4 alkoxy)-(C1-4 alkoxy), C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, amino, C1- 4 alkylamino, di(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1- 4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylsulfonylamino, aminosulfonyl, C1- 4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1- 4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1- 4 alkylaminocarbonylamino, di(C1-4 alkyl)aminocarbonylamino, and amidinyl.

[0061] In some embodiments of a compound of Formula (I) or a pharmaceutically acceptable saltthereof, - R21is 5 membered heteroaryl, provided that the 5 membered heteroaryl is not thiophenyl or furanyl, wherein the 5 membered heteroaryl is unsubstituted or substituted with 1, 2, or 3, independently selected R1Agroups; each R1Ais independently selected from halo, CN, NO2, - 14 -WSGR Docket No.51503-778.606 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, -C(=O)OH, -C(=O)C1-6 alkyl, -C(=O)C1-6 haloalkyl, and -C(=O)C1-6 alkoxy; - R22selected from the group consisting of C1-6alkyl and C1-6alkoxy wherein the C1-6alkyl, and C1-6alkoxy are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - R23is selected from the group consisting of H, oxo, azido, halo, CN, NO2, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -(C1-6alkylene)-cycloalkyl, ORa3, SRa3, C(=O)Rb3, C(=O)ORb3, NRc3Rd3, C(=O)NRc3Rd3, -OC(=O)NRc3Rd3, NRc3C(=O)Rb3, NRc3C(=O)ORb3, NRc3C(=O)NRc3Rd3, NRc3S(=O)2Rb3, NRc3S(=O)2NRc3Rd3, S(O)NRc3Rd3, and S(O)2NRc3Rd3, wherein the alkyl, alkylene, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are each unsubstituted or substituted with 1, 2, 3, or 4 independently selected R20groups; - R24is selected from the group consisting of H, azido, halo, CN, NO2, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - each Ra3, Rb3, Rc3, and Rd3is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R20groups; or Rc3and Rd3together with the N atom to which they are connected, come together to form a heteroaryl or heterocycloalkyl ring, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R20groups; and - each R20is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, amino, carbamyl, or carbamoyl.

[0062] In some embodiments of a compound of Formula (I) or a pharmaceutically acceptable saltthereof, - R21is phenyl or 6 membered heteroaryl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R1Agroups; each R1Ais independently selected from halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, -C(=O)OH, - C(=O)C1-6 alkyl, -C(=O)C1-6 haloalkyl, and -C(=O)C1-6 alkoxy; - R22selected from the group consisting of C1-6 alkyl and C1-6 alkoxy wherein the C1-6 alkyl, and C1-6 alkoxy are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - R23is selected from the group consisting of H, oxo, azido, halo, CN, NO2, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -(C1-6 alkylene)-cycloalkyl, - 15 -WSGR Docket No.51503-778.606 ORa3, SRa3, C(=O)Rb3, C(=O)ORb3, NRc3Rd3, C(=O)NRc3Rd3, -OC(=O)NRc3Rd3, NRc3C(=O)Rb3, NRc3C(=O)ORb3, NRc3C(=O)NRc3Rd3, NRc3S(=O)2Rb3, NRc3S(=O)2NRc3Rd3, S(O)NRc3Rd3, and S(O)2NRc3Rd3, wherein the alkyl, alkylene, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are each unsubstituted or substituted with 1, 2, 3, or 4 independently selected R20groups; - R24is selected from the group consisting of H, azido, halo, CN, NO2, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - each Ra3, Rb3, Rc3, and Rd3is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R20groups; or Rc3and Rd3together with the N atom to which they are connected, come together to form a heteroaryl or heterocycloalkyl ring, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R20groups; and - each R20is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, amino, carbamyl, or carbamoyl.

[0063] In some embodiments, R24 is halogen. In some embodiments, R24 is -Br. In someembodiments, R24is -F. In some embodiments, R24is -Cl. In some embodiments, R24is -I.

[0064] In some embodiments, R24 is selected from the group consisting of H, azido, halo, CN, NO2,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, ORa4, C(=O)Rb4, C(=O)ORb4, NRc4Rd4, C(=O)NRc4Rd4, - OC(=O)NRc4Rd4, NRc4C(=O)Rb4, NRc4C(=O)ORb4, NRc4C(=O)NRc4Rd4, NRc4S(=O)2Rb4, NRc4S(=O)2NRc4Rd4, S(O)NRc4Rd4, and S(O)2NRc4Rd4, wherein the C1-6 alkyl, C3-10 cycloalkyl, C6- 10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups. In some embodiments, R24is selected from the group consisting of H, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, OH, C1-6 alkoxyl, and C1-6 haloalkyl. In some embodiments, R24is selected from the group consisting of H, halo, CN, C1-6 alkyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, OH, C1-6 alkoxyl, and C1-6 haloalkyl. In some embodiments, R24is selected from the group consisting of hydrogen, OH, halo, CN, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkoxyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C2-4 alkenyl, and substituted or unsubstituted C2-4 alkynyl. In some embodiments, R24is hydrogen. In some embodiments, R24is halogen. In some embodiments, R24is -Br. In some embodiments, R24is -F. In some embodiments, R24is -Cl. In some embodiments, R24is -CN. In some - 16 -WSGR Docket No.51503-778.606 embodiments, R24is OH. In some embodiments, R24is C1-4 alkyl. In some embodiments, R24is methyl. In some embodiments, R24is C1-4 haloalkyl. In some embodiments, R24is C1-4 alkoxyl. In some embodiments, R24is methyl. In some embodiments, R24is ethyl. In some embodiments, R24is cycloalkyl. In some embodiments, R24is cyclopropyl. In some embodiments, R24is C2-4alkenyl. In some embodiments, R24is C2-4alkynyl. In some embodiments, R24is ethynyl. In some embodiment, R24is propynyl. In some embodiment, R24is. In some embodiments, R24is C3-10cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups. In some embodiments, R24is C6-10aryl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups. In some embodiments, R24is 5-10 membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups. In some embodiments, R24is 5-6 membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups. In some embodiments, R24is. In some embodiments, R24is 4-10 membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups. In some embodiments, R24is 5-6 membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups.selected from the group consisting

[0066] In some embodiments, R21 is thiazolyl, which is substituted or unsubstituted. In someembodiments, R21is unsubstituted thiazolyl. In some embodiments, R21is substituted thiazolyl. In some embodiments, R21is isothiazolyl, which is substituted or unsubstituted. In some embodiments, R21is unsubstituted isothiazolyl. In some embodiments, R21is substituted isothiazolyl. In some embodiments, R21is oxazolyl, which is substituted or unsubstituted. In some embodiments, R21is unsubstituted oxazolyl. In some embodiments, R21is substituted oxazolyl. In some embodiments, R21is thiadiazolyl, which is substituted or unsubstituted. In some embodiments, R21is unsubstituted thiadiazolyl. In some embodiments, R21is substituted thiadiazolyl. - 17 -WSGR Docket No.51503-778.606

[0067] In some embodiments,some embodiments,embodiments,. some embodiments, R21is. In some embodiments, R21is. , . some embodiments,. some embodiments,. some embodiments,. some embodiments, R21is

[0068] In some embodiments, R21 is unsubstituted. In some embodiments, R21 is substituted with 1,2, or 3, independently selected R1Agroups; wherein each R1Ais independently selected from halo, CN, NO2, alkyl, alkenyl, C2-6 alkynyl, alkoxy, -C(=O)OH, an ether group, or an ester group, each of which is unsubstituted or substituted. In some embodiments, R21is substituted with 1, 2, or 3 substituents independently selected R1Agroups; wherein each R1Ais independently selected from halo, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy. In some embodiments, R21is substituted with 1, 2, or 3 substituents independently selected R1Agroups; wherein each R1Ais independently selected from halo, C1-3alkyl, C1-3haloalkyl, and C1-3alkoxy. In some embodiments,, wherein represents asingle or a double bond; each of A1, A2, A3, and A5 is independently selected from the groupconsisting of O, S, N, NH, NR1A, CH, and CR1A; and A4 is N or C, provided that is not thiophenyl or furanyl. In some embodiments, each R1Ais independently selected from halo, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R1Ais halo. In some embodiments, R1Ais fluoro, chloro, bromo, or iodo. In some embodiments, R1Ais fluoro. In some embodiments, R1Ais chloro. In some embodiments, R1Ais bromo. In some embodiments, R1Ais iodo. - 18 -WSGR Docket No.51503-778.606

[0069] In some embodiments, R21 is unsubstituted or substituted 6 membered heteroaryl. In someembodiments, R21is unsubstituted 6 membered heteroaryl. In some embodiments, R21is substituted 6 membered heteroaryl. In some embodiments, R21is 6 membered heteroaryl substituted with 1, 2, 3, or 4 independently selected R1Agroups; wherein each R1Ais independently selected from halo, CN, NO2, alkyl, alkenyl, C2-6alkynyl, alkoxy, -C(=O)OH, an ether group, or an ester group, each of which is unsubstituted or substituted. In some embodiments, R21is 6 membered heteroaryl substituted with 1, 2, 3, or 4 substituents independently selected R1Agroups; wherein each R1Ais independently selected from halo, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy. In some embodiments, R21is 6 membered heteroaryl substituted with 1, 2, 3, or 4 substituents independently selected R1Agroups; wherein each R1Ais independently selected from halo, C1-3alkyl, C1-3haloalkyl, and C1-3alkoxy.

[0070] In some embodiments, R21 is 6 membered heteroaryl represented brepresents a single or a double bond; each of A1, A2, A3, A5 and A6 is independently selectedfrom the group consisting of O, S, N, NH, NR1A, CH, and CR1A; and A4 is selected from the group consisting of N and C.

[0071] In some embodiments, R21 is 6 membered heteroaryl represented brepresents a single or a double bond; each of A1, A2, A3, A5 and A6 is independently selectedfrom the group consisting of O, S, N, NH, NR1A, CH, and CR1A; and A4is selected from the group consisting of N and C. In some embodiments, R21is unsubstituted or substituted 6 membered heteroaryl, wherein the heteroaryl comprises 1, 2 or 3 nitrogen. In some embodiments, R21is unsubstituted or substituted pyridine or pyrimidine. In some embodiments, R21is unsubstituted or substituted pyridine. In some embodiments, R21is unsubstituted or substituted pyrimidine. In some embodiments, each R1Ais independently selected from halo, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R1Ais halo. In some embodiments, R1Ais fluoro, chloro, bromo, or iodo. In some embodiments, R1Ais fluoro. In some embodiments, R1Ais chloro. In some embodiments, R1Ais bromo. In some embodiments, R1Ais iodo.

[0072] In some embodiments, R21 is selected from the group consisting- 19 -WSGR Docket No.51503-778.606

[0073] In some embodiments, R21 is unsubstituted pyridinyl. In some embodiments, R21 issubstituted pyridinyl. In some embodiments, R21is unsubstituted pyrimidinyl. In some embodiments, R21is substituted pyrimidinyl.

[0074] In some embodiments,some embodiments,

[0075] In some embodiments, R21 is substituted phenyl. In some embodiments, R21 is unsubstitutedphenyl. In some embodiments, R21is phenyl substituted with 1, 2, 3, or 4 independently selected R1Agroups; wherein each R1Ais independently selected from halo, CN, NO2, alkyl, alkenyl, C2- 6 alkynyl, alkoxy, -C(=O)OH, an ether group, or an ester group, each of which is unsubstituted or substituted. In some embodiments, R21is phenyl substituted with 1, 2, or 3 substituents independently selected R1Agroups; wherein each R1Ais independently selected from halo, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy. In some embodiments, R21is phenyl substituted with 1, 2, or 3 substituents independently selected R1Agroups; wherein each R1Ais independently selected from halo, C1-3alkyl, C1-3haloalkyl, and C1-3alkoxy. In some embodiments, each R1Ais independently selected from halo, CN, NO2, C1-3alkyl, C1-3haloalkyl, and C1-3alkoxy. In some embodiments, each R1Ais independently selected from halo, C1-3alkyl, C1-3haloalkyl, and C1-3alkoxy. In some embodiments, each R1Ais independently selected from halo, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R1Ais halo. In some embodiments, R1Ais fluoro, chloro, bromo, or iodo. In some embodiments, R1Ais fluoro. In some embodiments, R1Ais chloro. In some embodiments, R1Ais bromo. In some eiodo. In some embodiments, R21 is. In some embodiments, R21- 20 -WSGR Docket No.51503-778.606.

[0076] In some embodiments, R22 is C1-6 alkyl. In some embodiments, R22 is C1-6 alkoxy. In someembodiments, R22is C1-4 alkyl. In some embodiments, R22is C1-4 alkoxy. In some embodiments, R22is C1-2 alkyl. In some embodiments, R22is C1-2 alkoxy. In some embodiments, R22is -CH3. In some embodiments, R22is -CH2CH3. In some embodiments, R22is -OCH3.

[0077] In some embodiments, R23 is H.

[0078] In some embodiments, R23 is substituted with 1, 2, 3, or 4 independently selected R20 groups.In some embodiments, R23is substituted with 1, 2, 3, or 4 independently selected R20groups, wherein each R20group is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, amino, C1-3alkyl, C1-3alkoxy, C1-3haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, carbamyl, and carbamoyl. In some embodiments, R23is substituted with 1, 2, or 3 independently selected R20groups, wherein each R20group is independently selected from the group consisting of OH, halo, C1- 3haloalkoxy, and C1-3alkoxy. In some embodiments, R23is substituted with 1, 2, or 3 independently selected R20groups, wherein each R20group is independently selected from the group consisting of OH, halo, C1-3alkyl, C1-3haloalkyl, amino, C1-3haloalkoxy, and C1-3alkoxy. In some embodiments, R23is substituted with 1, 2, or 3 independently selected R20groups, wherein each R20group is independently selected from the group consisting of OH, halo, amino, C1-3haloalkoxy, and C1-3alkoxy. In some embodiments, R20group is OH. In some embodiments, R20group is halo. In some embodiments, R20group is amino. In some embodiments, R20group is C1-3alkoxy. In some embodiments, R20group is C1-3haloalkoxy (e.g., -OCF3 or -OCHF2).

[0079] In some embodiments, R23 is substituted with 1, 2, 3, or 4 independently selected R20 groups.In some embodiments, R23is substituted with 1 or 2 independently selected R20groups. In some embodiments, each R20is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-4alkyl, C2-4alkenyl,2 C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)-(C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, amino, C1-4alkylamino, and di(C1-4alkyl)aminol. In some embodiments, each R20is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4hydroxyalkyl, C1-4alkoxy, C1-4haloalkoxy, amino, C1-4alkylamino, and di(C1-4alkyl)amino. In some embodiments, each R20is independently selected from the group consisting of OH, halo, oxo, C1-4alkyl, C1-4haloalkyl, C1-4hydroxyalkyl, C1-4alkoxy, C1-4haloalkoxy, amino, C1-4alkylamino, and di(C1-- 21 -WSGR Docket No.51503-778.606 4 alkyl)amino. In some embodiments, each R20is independently selected from the group consisting of halo, amino, C1-4 alkylamino, and di(C1-4 alkyl)amino. In some embodiments, each R20is independently selected from the group consisting of halo and amino. In some embodiments, R23is substituted with an amino group.

[0080] In some embodiments, R23 is substituted or unsubstituted C1-6 alkyl. In some embodiments,R23is C1-6alkyl, wherein C1-6alkyl is substituted with 1, 2, or 3 independently selected R20groups. In some embodiments, R23is C1-6alkyl, wherein C1-6alkyl is substituted with 1, 2, or 3 independently selected R20groups, wherein each R20group is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, amino, C1-3alkyl, C1-3haloalkoxy, C1-3alkoxy, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, carbamyl, and carbamoyl. In some embodiments, R23is C1-6alkyl, wherein C1-6alkyl is substituted with 1, 2, or 3 independently selected R20groups, wherein each R20group is independently selected from the group consisting of OH, halo, amino, C1-3haloalkoxy, and C1-3alkoxy. In some embodiments, R23is C1-6alkyl, wherein C1-6alkyl is substituted with 1, 2, or 3 independently selected R20groups, wherein each R20group is independently selected from the group consisting of OH, halo, amino, and C1-3alkoxy.

[0081] In some embodiments, R23 is substituted or unsubstituted C1-6 alkenyl. In some embodiments,R23is C1-6alkenyl, wherein C1-6alkenyl is substituted with 1, 2, or 3 independently selected R20groups.

[0082] In some embodiments, R23 is substituted or unsubstituted C1-6 alkynyl. In some embodiments,R23is C1-6alkynyl, wherein C1-6alkynyl is substituted with 1, 2, or 3 independently selected R20groups.

[0083] In some embodiments, R23 is substituted or unsubstituted C1-6 alkyl or substituted orunsubstituted C1-6 heteroalkyl. In some embodiments, R23is substituted or unsubstituted C1-6 heteroalkyl. In some embodiments, the C1-6 heteroalkyl is -CH2CH(NH2)CH2-S(=O)2-CH3 or - CH2CH(NH2)CH2-S(=O)-CH3. In some embodiments, R23is -CH2CH(NH2)CH2-S(=O)2-CH3. In some embodiments, R23is -CH2CH(NH2)CH2-S(=O)-CH3. In some embodiments, R23is CH2CHNH2CH3. In some embodiments, R23is CH2CHNH2CH2OH. In some embodiments, R23is CH2CHNH2CH2CH3. In some embodiments, R23is CH2CHNH2CH2CH2OH. In some embodiments, R23is CH2CHNH2CH2CH2F. In some embodiments, R23is CH2CHNH2CH2CHF2. In some embodiments,R23 is CH2CHNH2CH2CH(CH3)2. In some embodiments, R23 is CH2CHNH2CHFCH3. In someembodiments, R23is CH2CHNH2CH2F. In some embodiments, R23is CH2CHNH2CH2OCH3. In some embodiments, R23is CH2CHNH2CH2OCD3.

[0084] In some embodiments, R23 is substituted or unsubstituted C1-6 heteroalkyl. In someembodiments, R23is C1-6 heteroalkyl, wherein the C1-6 heteroalkyl is substituted with 1, 2, or 3 independently selected R20groups. In some embodiments, R23is C1-6 heteroalkyl, wherein the C1-6 heteroalkyl is substituted with 1, 2, or 3 independently selected R20groups, wherein each R20group is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, amino, C1-3alkyl, - 22 -WSGR Docket No.51503-778.606 C1-3alkoxy, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, carbamyl, and carbamoyl. In some embodiments, R23is C1-6 heteroalkyl, wherein the C1-6 heteroalkyl is substituted with 1, 2, or 3 independently selected R20groups, wherein each R20group is independently selected from the group consisting of OH, halo, and C1-3alkoxy. In some embodiments, R23is C1-6heteroalkyl, wherein the C1-6heteroalkyl is substituted with 1, 2, or 3 independently selected R20groups, wherein each R20group is independently selected from the group consisting of OH, halo, amino, and C1-3alkoxy.

[0085] In some embodiments, R23 is substituted or unsubstituted -(C1-6 alkylene)-C3-10 cycloalkyl. Insome embodiments, R23is -(C1-6alkylene)-C3-10cycloalkyl, wherein -(C1-6alkylene)-C3-10cycloalkyl is substituted with 1, 2, or 3 independently selected R20groups. In some embodiments, the C1-6alkylene is C1-3alkylene. In some embodiments, the C1-6alkylene is CH2. In some embodiments, the C3-10cycloalkyl is an optionally substituted 3-6 membered ring. In some embodiments, the C3-10cycloalkyl is an optionally substituted 3 membered ring. In some embodiments, the C3-10cycloalkyl is an optionally substituted 4 membered ring. In some embodiments, the C3-10cycloalkyl is an optionally substituted 5 membered ring. In some embodiments, the C3-10cycloalkyl is an optionallysubstituted 6 membered ring. In some embodiments, the C3-10 cycloalkyl is, ,.

[0086] In some embodiments, R23 is substituted or unsubstituted -(C1-6 alkylene)-4-10 memberedheterocycloalkyl. In some embodiments, R23is -(C1-6alkylene)-4-10 membered heterocycloalkyl, wherein -(C1-6alkylene)-4-10 membered heterocycloalkyl is substituted with 1, 2, or 3 independently selected R20groups. In some embodiments, the C1-6alkylene is C1-3alkylene. In some embodiments, the C1-6alkylene is CH2. In some embodiments, the 4-10 membered heterocycloalkyl is an optionally substituted 4-6 membered ring. In some embodiments, the 4-10 membered heterocycloalkyl is an optionally substituted 4 membered ring. In some embodiments, the 4-10 membered heterocycloalkyl is an optionally substituted 5 membered ring. In some embodiments, the 4-10 membered heterocycloalkyl is an optionally substituted 6 membered ring. In some embodiments, the 4-10 membered heterocycloalkyl contains 0-1 oxygen and 0-2 nitrogen atoms. In some embodiments, the- 23 -WSGR Docket No.51503-778.606.

[0087] In some embodiments, R23 is substituted or unsubstituted -(C1-6 heteroalkylene)-C3-10cycloalkyl. In some embodiments, R23is -(C1-6heteroalkylene)-C3-10cycloalkyl, wherein -(C1-6heteroalkylene)-C3-10cycloalkyl is substituted with 1, 2, or 3 independently selected R20groups. In some embodiments, the heteroalkylene is C1-3heteroalkylene. In some embodiments, the C3-10cycloalkyl is an optionally substituted 3-6 membered ring. In some embodiments, the C3-10cycloalkyl is an optionally substituted 3 membered ring. In some embodiments, the C3-10cycloalkyl is an optionally substituted 4 membered ring. In some embodiments, the C3-10cycloalkyl is an optionally substituted 5 membered ring. In some embodiments, the C3-10cycloalkyl is an optionally substituted 6 membered ring. In some embodiments, the heteroalkylene is C1-3heteroalkylene. In someembodiments, the C3-10 cycloalkyl

[0088] In some embodiments, R23 is substituted or unsubstituted -(C1-6 heteroalkylene)-4-10membered heterocycloalkyl. In some embodiments, R23is -(C1-6heteroalkylene)-4-10 membered heterocycloalkyl, wherein -(C1-6heteroalkylene)-4-10 membered heterocycloalkyl is substituted with 1, 2, or 3 independently selected R20groups. In some embodiments, the heteroalkylene is C1-3heteroalkylene. In some embodiments, the 4-10 membered heterocycloalkyl is an optionally substituted 4-6 membered ring. In some embodiments, the 4-10 membered heterocycloalkyl is an optionally substituted 4 membered ring. In some embodiments, the 4-10 membered heterocycloalkyl is an optionally substituted 5 membered ring. In some embodiments, the 4-10 membered heterocycloalkyl is an optionally substituted 6 membered ring. In some embodiments, the 4-10 membered heterocycloalkyl contains 0-1 oxygen and 0-2 nitrogen atoms. In some embodiments, the- 24 -WSGR Docket No.51503-778.606.

[0089] In some embodiments, R23 is any one selected from the group consisting of:,- 25 -WSGR Docket No.51503-778.606- 26 -WSGR Docket No.51503-778.606embodiments, R23 is any one selected from the group consisting of:some embodiments,some embodiments,some

[0090] In some embodiments, R23 is selected from the group consisting of cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups. In some embodiments, R23is C3-10cycloalkyl, which is unsubstituted or substituted. In some embodiments, R23is C4-6cycloalkyl, which is unsubstituted or substituted. In some embodiments, R23is C4-6cycloalkyl, which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R20groups. In some embodiments, R23is C4-6cycloalkyl, which is unsubstituted or substituted with 1 to 4 substituents selected from halo and amino. In some embodiments, R23is C4-6cycloalkyl, which is unsubstituted or substituted with 1 to 4 substituents selected from C1-4haloalkyl, halo and amino. In some embodiments, R23is C6cycloalkyl, which is unsubstituted or substituted with 1 to 4 substituents selected from halo and amino. In some embodiments, R23is C4cycloalkyl, which is unsubstituted or substituted. In some embodiments, R23is C5cycloalkyl, which is unsubstituted or substituted. In some embodiments, R23is C6cycloalkyl, which is unsubstituted or substituted. In some embodiments, R23is a saturated ring. In some embodiments, R23is a partially saturated ring. In some embodiments, R23is a saturated cycloalkyl. In some embodiments, R23is a partially saturated cycloalkyl. In some - 27 -WSGR Docket No.51503-778.606 embodiments, R23is a partially saturated cycloalkyl such as cyclohexenyl. In some embodiments, R23comprises one double bond in the ring. In some embodiments, R23is . In some embodiments,, .

[0091] In some embodiments, R23 is 4-10 membered heterocycloalkyl, which is unsubstituted orsubstituted. In some embodiments, R23is 5-6 membered heterocycloalkyl, which is unsubstituted or substituted. In some embodiments, R23is 6 membered heterocycloalkyl, which is unsubstituted or substituted. In some embodiments, the heterocycloalkyl comprises 1-2 ring nitrogen. In some embodiments, the heterocycloalkyl comprises 1 ring oxygen. In some embodiments, theheterocycloalkyl is a cyclic ether. In some embodiments, R23is . In some embodiments,R23is . In some embodiments, R23is . In some embodiments, R23is .

[0092] In some embodiments, R23 is C6-10 aryl, which is unsubstituted or substituted. In someembodiments, R23is 5-10 membered heteroaryl, which is unsubstituted or substituted.

[0093] In some embodiments, R23 is an unsubstituted ring.

[0094] In some embodiments, each R20 is independently selected from the group consisting of OH,SH, CN, NO2, halo, oxo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)-(C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, amino, C1-- 28 -WSGR Docket No.51503-778.606 4 alkylamino, di(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4alkylsulfonylamino, aminosulfonyl, C1-4alkylaminosulfonyl, di(C1-4alkyl)aminosulfonyl, aminosulfonylamino, C1-4alkylaminosulfonylamino, di(C1-4alkyl)aminosulfonylamino, aminocarbonylamino, C1-4alkylaminocarbonylamino, di(C1-4alkyl)aminocarbonylamino, and amidinyl. In some embodiments, each R20is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -C1-4haloalkoxy, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, carbamyl, and amidinyl. In some embodiments, each R20is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-4alkyl, C1-4haloalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -C1-4haloalkoxy, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, amino, carbamyl C1-4alkylamino, di(C1-4alkyl)amino, and amidinyl. In some embodiments, R20is OH. In some embodiments, R20is NH2. In some embodiments, R20is SH. In some embodiments, R20is CN. In some embodiments, R20is F. In some embodiments, R20is carbamyl.

[0095] In some embodiments, each Ra4, Rb4, Rc4, Rd4, Ra3, Rb3, Rc3, and Rd3 is independently selectedfrom the group consisting of H, C1-6alkyl, C1-6hydroxyalkyl, and C1-6haloalkyl. In some embodiments, each Ra4, Rb4, Rc4, Rd4,Ra3, Rb3, Rc3, and Rd3is independently selected from the group consisting of H and C1-6alkyl. In some embodiments, each Ra4, Rb4, Rc4, Rd4,Ra3, Rb3, Rc3, and Rd3is independently selected from the group consisting of H and C1-3alkyl. In some embodiments, each Ra4, Rb4, Rc4, Rd4, Ra3, Rb3, Rc3, and Rd3is hydrogen.

[0096] In some embodiments, the compound is of the Formula (IIa):wherein R21and R22each has the meaning defined in Formula (I); each R20a, R20b, and R20cis independently selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)-(C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, C1-4heteroalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, - (C1-3alkylene)-C3-10cycloalkyl, -(C1-3alkylene)-4-10 membered heterocycloalkyl, -(C1-3heteroalkylene)-C3-10cycloalkyl, -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl, amidinyl, - 29 -WSGR Docket No.51503-778.606 amino, C1-4 alkylamino, di(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4alkylsulfonylamino, aminosulfonyl, C1-4alkylaminosulfonyl, di(C1-4alkyl)aminosulfonyl, aminosulfonylamino, C1-4alkylaminosulfonylamino, di(C1-4alkyl)aminosulfonylamino, aminocarbonylamino, C1-4alkylaminocarbonylamino, and di(C1-4alkyl)aminocarbonylamino, wherein: each of the cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, SH, -CN, oxo, NO2, OH, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4aminoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, and amino, or R20aand R20bare taken together to form a =NH or =N(C1-4alkyl), or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments of the compound of the Formula (IIa) or a pharmaceutically acceptablesalt thereof, each R20a, R20b, and R20cis independently selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)-(C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, carbamyl, C1-4alkylcarbamyl, di(C1-4alkyl)carbamyl, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C1-4alkylcarbonyl, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4alkylsulfonylamino, aminosulfonyl, C1-4alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1- 4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino.

[0098] In some embodiments, R20a is methyl. In some embodiments, R20a is ethyl. In someembodiments, R20ais CH2OH. In some embodiments, R20ais CH2CH2OH. In some embodiments, R20ais CH2CH2F. In some embodiments, R20ais CH2CHF2. In some embodiments, R20ais CH2CH(CH3)2. In some embodiments, R20cis NH2. In some embodiments, R20bis hydrogen. In some embodiments, R20ais 4-6 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3 alkylene)-C3- 10 cycloalkyl. In some embodiments, R20ais -(C1-3 alkylene)-4-10 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3 heteroalkylene)-C3-10 cycloalkyl. In some embodiments, R20ais -(C1-3 heteroalkylene)-4-10 membered heterocycloalkyl. In some embodiments, the C3-10 cycloalkyl is- 30 -WSGR Docket No.51503-778.606embodiments, the C3-10 cycloalkyl is a 3-5 membered ring, which isheterocycloalkyl is a 4-5 membered ring, which is optionally substituted. In some embodiments, R20ais C1-4 heteroalkyl. In some embodiments, R20ais C1-4 alkyl. In some embodiments, R20ais optionally substituted C1-4 heteroalkyl. In some embodiments, R20ais optionally substituted C1-4 alkyl.

[0099] In some embodiments, the compound is of the Formula (IIb):Formula (IIb), wherein R21and R22each has the meaning defined in Formula (I); R20ais selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)- (C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, C1-4heteroalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, -(C1-3alkylene)-C3-10cycloalkyl, -(C1-3alkylene)-4-10 membered heterocycloalkyl, -(C1-3heteroalkylene)-C3-10cycloalkyl, -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl, amidinyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, carbamyl, C1-4alkylcarbamyl, di(C1-4alkyl)carbamyl, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C1-4alkylcarbonyl, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino, wherein - 31 -WSGR Docket No.51503-778.606 each of the cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, SH, -CN, oxo, NO2, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4aminoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, and amino, or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments of the compound of the Formula (IIb) or a pharmaceutically acceptablesalt thereof, R20ais selected from the group consisting of OH, SH, CN, NO2, halo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)- (C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, carbamyl, C1-4alkylcarbamyl, di(C1-4alkyl)carbamyl, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C1-4alkylcarbonyl, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4alkylsulfonylamino, aminosulfonyl, C1-4alkylaminosulfonyl, di(C1-4alkyl)aminosulfonyl, aminosulfonylamino, C1-4alkylaminosulfonylamino, di(C1-4alkyl)aminosulfonylamino, aminocarbonylamino, C1-4alkylaminocarbonylamino, and di(C1-4alkyl)aminocarbonylamino.

[0101] In some embodiments, R20a is methyl. In some embodiments, R20a is ethyl. In someembodiments, R20ais CH2OH. In some embodiments, R20ais CH2CH2OH. In some embodiments, R20ais CH2CH2F. In some embodiments, R20ais CH2CHF2. In some embodiments, R20ais CH2CH(CH3)2. In some embodiments, R20ais 4-6 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-4-10 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3heteroalkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3 heteroalkylene)-4-10 membered heterocycloalkyl. In some embodiments,membered ring, which is optionally substituted. In some embodiments, the 4-10 memberedembodiments, the 4-10 membered heterocycloalkyl is a 4-5 membered ring, which is optionally - 32 -WSGR Docket No.51503-778.606 substituted. In some embodiments, R20ais C1-4 heteroalkyl. In some embodiments, R20ais C1-4 alkyl. In some embodiments, R20ais optionally substituted C1-4 heteroalkyl. In some embodiments, R20ais optionally substituted C1-4alkyl.

[0102] In some embodiments, the compound is of the Formula (IIIa):Formula (IIIa), wherein R21, R22and R24each has the meaning defined in Formula (I); each R20a, R20b, and R20cis independently selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)-(C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, C1-4heteroalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, - (C1-3alkylene)-C3-10cycloalkyl, -(C1-3alkylene)-4-10 membered heterocycloalkyl, -(C1-3heteroalkylene)-C3-10cycloalkyl, -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl, amidinyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, carbamyl, C1-4alkylcarbamyl, di(C1-4alkyl)carbamyl, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C1-4alkylcarbonyl, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4alkylsulfonylamino, aminosulfonyl, C1-4alkylaminosulfonyl, di(C1-4alkyl)aminosulfonyl, aminosulfonylamino, C1-4alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino, wherein: each of the cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, SH, -CN, oxo, NO2, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 aminoalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and amino, or R20aand R20bare taken together to form a =NH or =N(C1-4 alkyl), or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments of the compound of the Formula (IIIa) or a pharmaceuticallyacceptable salt thereof, each R20a, R20b, and R20cis independently selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1- 4 hydroxyalkyl, C1-4 alkoxy, -(C1-4 alkyl)-(C1-4 alkoxy), -(C1-4 alkoxy)-(C1-4 alkoxy), C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C1- 4 alkylamino, di(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, - 33 -WSGR Docket No.51503-778.606 C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1- 4 alkylcarbonylamino, C1-4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4alkyl)aminosulfonyl, aminosulfonylamino, C1-4alkylaminosulfonylamino, di(C1-4alkyl)aminosulfonylamino, aminocarbonylamino, C1-4alkylaminocarbonylamino, and di(C1-4alkyl)aminocarbonylamino.

[0104] In some embodiments, R20a is methyl. In some embodiments, R20a is ethyl. In someembodiments, R20ais CH2OH. In some embodiments, R20ais CH2CH2OH. In some embodiments, R20ais CH2CH2F. In some embodiments, R20ais CH2CHF2. In some embodiments, R20ais CH2CH(CH3)2. In some embodiments, R20cis NH2. In some embodiments, R20bis hydrogen. In some embodiments, R20ais 4-6 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-4-10 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3heteroalkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl. In some embodiments, the C3-10cycloalkyl isoptionally substituted. In some embodiments, the 4-10 membered heterocycloalkyl is,some embodiments, the 4-10 memberedheterocycloalkyl is a 4-5 membered ring, which is optionally substituted. In some embodiments, R20ais C1-4 heteroalkyl. In some embodiments, R20ais C1-4 alkyl. In some embodiments, R20ais optionally substituted C1-4 heteroalkyl. In some embodiments, R20ais optionally substituted C1-4 alkyl. - 34 -WSGR Docket No.51503-778.606

[0105] In some embodiments, the compound is of the Formula (IIIb):wherein R21, R22and R24each has the meaning defined in Formula (I); R20ais selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)- (C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, C1-4heteroalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, -(C1-3alkylene)-C3-10cycloalkyl, -(C1-3alkylene)-4-10 membered heterocycloalkyl, -(C1-3heteroalkylene)-C3-10cycloalkyl, -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl, amidinyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, carbamyl, C1-4alkylcarbamyl, di(C1-4alkyl)carbamyl, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C1-4alkylcarbonyl, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4alkylsulfonylamino, aminosulfonyl, C1-4alkylaminosulfonyl, di(C1-4alkyl)aminosulfonyl, aminosulfonylamino, C1-4alkylaminosulfonylamino, di(C1-4alkyl)aminosulfonylamino, aminocarbonylamino, C1-4alkylaminocarbonylamino, and di(C1-4alkyl)aminocarbonylamino, wherein each of the cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, SH, -CN, oxo, NO2, OH, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 aminoalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and amino, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments of the compound of the Formula (IIIb) or a pharmaceuticallyacceptable salt thereof, R20ais selected from the group consisting of OH, SH, CN, NO2, halo, C1- 4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, -(C1- 4 alkyl)-(C1-4 alkoxy), -(C1-4 alkoxy)-(C1-4 alkoxy), C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1- 4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1- 4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino.

[0107] In some embodiments, R20a is methyl. In some embodiments, R20a is ethyl. In someembodiments, R20ais CH2OH. In some embodiments, R20ais CH2CH2OH. In some embodiments, R20a- 35 -WSGR Docket No.51503-778.606 is CH2CH2F. In some embodiments, R20ais CH2CHF2. In some embodiments, R20ais CH2CH(CH3)2. In some embodiments, R20ais 4-6 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-4-10 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3heteroalkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl. In some embodiments,membered ring, which is optionally substituted. In some embodiments, the 4-10 memberedembodiments, the 4-10 membered heterocycloalkyl is a 4-5 membered ring, which is optionally substituted. In some embodiments, R20ais C1-4heteroalkyl. In some embodiments, R20ais C1-4alkyl. In some embodiments, R20ais optionally substituted C1-4 heteroalkyl. In some embodiments, R20ais optionally substituted C1-4 alkyl.

[0108] In some embodiments, R24 is C1-6 alkyl. In some embodiments, R24 is methyl. In someembodiments, R24is halo. In some embodiments, R24is fluoro, bromo, or chloro. In some embodiments, R24is hydrogen. In some embodiments, R24is CN. In some embodiments, R24is C3-10 cycloalkyl. In some embodiments, R24is C1-4 alkyl. In some embodiments, R24is C2-4 alkenyl. In some embodiments, R24is C2-4 alkynyl.

[0109] In some embodiments, the compound is of the Formula (IIIc):Formula (IIIc), wherein - 36 -WSGR Docket No.51503-778.606 R21and R22each has the meaning defined in Formula (I); R20ais selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4 alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)- (C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, C1-4heteroalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, -(C1-3alkylene)-C3-10cycloalkyl, -(C1-3alkylene)-4-10 membered heterocycloalkyl, -(C1-3heteroalkylene)-C3-10cycloalkyl, -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl, amidinyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, carbamyl, C1-4alkylcarbamyl, di(C1-4alkyl)carbamyl, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C1-4alkylcarbonyl, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4alkylsulfonylamino, aminosulfonyl, C1-4alkylaminosulfonyl, di(C1-4alkyl)aminosulfonyl, aminosulfonylamino, C1-4alkylaminosulfonylamino, di(C1-4alkyl)aminosulfonylamino, aminocarbonylamino, C1-4alkylaminocarbonylamino, and di(C1-4alkyl)aminocarbonylamino, wherein each of the cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, SH, -CN, oxo, NO2, OH, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4aminoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, and amino, or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments of the compound of the Formula (IIIc) or a pharmaceuticallyacceptable salt thereof, R20ais selected from the group consisting of OH, SH, CN, NO2, halo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)-(C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1- 4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1- 4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino.

[0111] In some embodiments, R20a is methyl. In some embodiments, R20a is ethyl. In someembodiments, R20ais CH2OH. In some embodiments, R20ais CH2CH2OH. In some embodiments, R20ais CH2CH2F. In some embodiments, R20ais CH2CHF2. In some embodiments, R20ais CH2CH(CH3)2. In some embodiments, R20ais 4-6 membered heterocycloalkyl. In some embodiments, R20ais -(C1- 3 alkylene)-C3-10 cycloalkyl. In some embodiments, R20ais -(C1-3 alkylene)-4-10 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3 heteroalkylene)-C3-10 cycloalkyl. In some embodiments, R20ais -(C1-3 heteroalkylene)-4-10 membered heterocycloalkyl. In some embodiments,the C3-10 cycloalkyl- 37 -WSGR Docket No.51503-778.606membered ring, which is optionally substituted. In some embodiments, the 4-10 memberedembodiments, the 4-10 membered heterocycloalkyl is a 4-5 membered ring, which is optionally substituted. In some embodiments, R20ais C1-4 heteroalkyl. In some embodiments, R20ais C1-4 alkyl. In some embodiments, R20ais optionally substituted C1-4 heteroalkyl. In some embodiments, R20ais optionally substituted C1-4 alkyl.

[0112] In some embodiments, the compound is of the Formula (IIId):wherein R21and R22each has the meaning defined in Formula (I); R20ais selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)- (C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, C1-4heteroalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, -(C1-3alkylene)-C3-10cycloalkyl, -(C1-3alkylene)-4-10 membered heterocycloalkyl, -(C1-3heteroalkylene)-C3-10cycloalkyl, -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl, amidinyl, amino, C1-4 alkylamino, di(C1- 4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1- 4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino, wherein - 38 -WSGR Docket No.51503-778.606 each of the cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, SH, -CN, oxo, NO2, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4aminoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, and amino, wherein each of R20’is independently H or R20as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, R20a is methyl. In some embodiments, R20a is ethyl. In someembodiments, R20ais CH2OH. In some embodiments, R20ais CH2CH2OH. In some embodiments, R20ais CH2CH2F. In some embodiments, R20ais CH2CHF2. In some embodiments, R20ais CH2CH(CH3)2. In some embodiments, R20ais 4-6 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-4-10 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3heteroalkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl. In some embodiments,membered ring, which is optionally substituted. In some embodiments, the 4-10 memberedembodiments, the 4-10 membered heterocycloalkyl is a 4-5 membered ring, which is optionally substituted. In some embodiments, R20ais C1-4 heteroalkyl. In some embodiments, R20ais C1-4 alkyl. In some embodiments, R20ais optionally substituted C1-4 heteroalkyl. In some embodiments, R20ais optionally substituted C1-4 alkyl. - 39 -WSGR Docket No.51503-778.606

[0114] In some embodiments, the compound is of the Formula (IIIe):Formula (IIIe), wherein R21and R22each has the meaning defined in Formula (I); R20ais selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)- (C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, C1-4heteroalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, -(C1-3 alkylene)-C3-10 cycloalkyl, -(C1- 3 alkylene)-4-10 membered heterocycloalkyl, -(C1-3 heteroalkylene)-C3-10 cycloalkyl, -(C1-3 heteroalkylene)-4-10 membered heterocycloalkyl, amidinyl, amino, C1-4alkylamino, di(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1- 4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino, wherein each of the cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, SH, -CN, oxo, NO2, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 aminoalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and amino, wherein R20’is H or R20as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, R20a is methyl. In some embodiments, R20a is ethyl. In someembodiments, R20ais CH2OH. In some embodiments, R20ais CH2CH2OH. In some embodiments, R20ais CH2CH2F. In some embodiments, R20ais CH2CHF2. In some embodiments, R20ais CH2CH(CH3)2. In some embodiments, R20ais 4-6 membered heterocycloalkyl. In some embodiments, R20ais -(C1- 3 alkylene)-C3-10 cycloalkyl. In some embodiments, R20ais -(C1-3 alkylene)-4-10 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3 heteroalkylene)-C3-10 cycloalkyl. In some embodiments, R20ais -(C1-3 heteroalkylene)-4-10 membered heterocycloalkyl. In some embodiments,the C3-10 cycloalkyl- 40 -WSGR Docket No.51503-778.606membered ring, which is optionally substituted. In some embodiments, the 4-10 memberedembodiments, the 4-10 membered heterocycloalkyl is a 4-5 membered ring, which is optionally substituted. In some embodiments, R20ais C1-4 heteroalkyl. In some embodiments, R20ais C1-4 alkyl. In some embodiments, R20ais optionally substituted C1-4 heteroalkyl. In some embodiments, R20ais optionally substituted C1-4 alkyl.

[0116] In some embodiments, the compound is of the Formula (IIIf):wherein R21and R22each has the meaning defined in Formula (I); R20ais selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, -(C1-4alkyl)- (C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, C1-4heteroalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, -(C1-3alkylene)-C3-10cycloalkyl, -(C1-3alkylene)-4-10 membered heterocycloalkyl, -(C1-3heteroalkylene)-C3-10cycloalkyl, -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl, amidinyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, carbamyl, C1-4alkylcarbamyl, di(C1-4alkyl)carbamyl, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C1-4alkylcarbonyl, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4alkylsulfonylamino, aminosulfonyl, C1-4alkylaminosulfonyl, di(C1-4alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, - 41 -WSGR Docket No.51503-778.606 aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino, wherein each of the cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, SH, -CN, oxo, NO2, OH, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4aminoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, and amino, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, R20a is methyl. In some embodiments, R20a is ethyl. In someembodiments, R20ais CH2OH. In some embodiments, R20ais CH2CH2OH. In some embodiments, R20ais CH2CH2F. In some embodiments, R20ais CH2CHF2. In some embodiments, R20ais CH2CH(CH3)2. In some embodiments, R20ais 4-6 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-4-10 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3heteroalkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl. In some embodiments,membered ring, which is optionally substituted. In some embodiments, the 4-10 memberedembodiments, the 4-10 membered heterocycloalkyl is a 4-5 membered ring, which is optionally substituted. In some embodiments, R20ais C1-4 heteroalkyl. In some embodiments, R20ais C1-4 alkyl. In some embodiments, R20ais optionally substituted C1-4 heteroalkyl. In some embodiments, R20ais optionally substituted C1-4 alkyl. - 42 -WSGR Docket No.51503-778.606

[0118] In some embodiments, the compound is of the Formula (IIIg):Formula (IIIg), wherein R21and R22each has the meaning defined in Formula (I); R20ais selected from the group consisting of H, OH, SH, CN, NO2, halo, C1-4 alkyl, C2- 4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, -(C1-4 alkyl)- (C1-4alkoxy), -(C1-4alkoxy)-(C1-4alkoxy), C1-4haloalkoxy, C3-6cycloalkyl, C1-4heteroalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, -(C1-3alkylene)-C3-10cycloalkyl, -(C1-3alkylene)-4-10 membered heterocycloalkyl, -(C1-3heteroalkylene)-C3-10cycloalkyl, -(C1-3heteroalkylene)-4-10 membered heterocycloalkyl, amidinyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, carbamyl, C1-4alkylcarbamyl, di(C1-4alkyl)carbamyl, carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C1-4alkylcarbonyl, C1-4alkoxycarbonyl, C1-4alkylcarbonylamino, C1-4alkylsulfonylamino, aminosulfonyl, C1-4alkylaminosulfonyl, di(C1-4alkyl)aminosulfonyl, aminosulfonylamino, C1-4alkylaminosulfonylamino, di(C1-4alkyl)aminosulfonylamino, aminocarbonylamino, C1-4alkylaminocarbonylamino, and di(C1-4alkyl)aminocarbonylamino, wherein each of the cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, CN, SH, -CN, oxo, NO2, OH, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4haloalkyl, C1-4cyanoalkyl, C1-4aminoalkyl, C1-4hydroxyalkyl, C1-4alkoxy, and amino, or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, R20a is methyl. In some embodiments, R20a is ethyl. In someembodiments, R20ais CH2OH. In some embodiments, R20ais CH2CH2OH. In some embodiments, R20ais CH2CH2F. In some embodiments, R20ais CH2CHF2. In some embodiments, R20ais CH2CH(CH3)2. In some embodiments, R20ais 4-6 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-C3-10cycloalkyl. In some embodiments, R20ais -(C1-3alkylene)-4-10 membered heterocycloalkyl. In some embodiments, R20ais -(C1-3 heteroalkylene)-C3-10 cycloalkyl. In some embodiments, R20ais -(C1-3 heteroalkylene)-4-10 membered heterocycloalkyl. In some embodiments,the C3-10 cycloalkyl- 43 -WSGR Docket No.51503-778.606membered ring, which is optionally substituted. In some embodiments, the 4-10 memberedembodiments, the 4-10 membered heterocycloalkyl is a 4-5 membered ring, which is optionally substituted. In some embodiments, R20ais C1-4 heteroalkyl. In some embodiments, R20ais C1-4 alkyl. In some embodiments, R20ais optionally substituted C1-4 heteroalkyl. In some embodiments, R20ais optionally substituted C1-4 alkyl.

[0120] In some embodiments, the compound is of the Formula (IVa):Formula (IVa) wherein, R21is 5 membered heteroaryl, provided that the 5 membered heteroaryl is not thiophenyl or furanyl, wherein the 5 membered heteroaryl is unsubstituted or substituted with 1, 2, or 3, independently selected R1Agroups; each R1Ais independently selected from halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, -C(=O)OH, -C(=O)C1-6 alkyl, - C(=O)C1-6haloalkyl, and -C(=O)C1-6alkoxy; or, - R21is phenyl or 6 membered heteroaryl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R1Agroups; each R1Ais independently selected from halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, -C(=O)OH, -C(=O)C1- 6 alkyl, -C(=O)C1-6 haloalkyl, and -C(=O)C1-6 alkoxy; - 44 -WSGR Docket No.51503-778.606 - R23is selected from the group consisting of H, azido, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 heteroalkyl, -(C1-6 alkylene)-C3-10 cycloalkyl, -(C1-6 alkylene)-4-10 membered heterocycloalkyl, -(C1-6heteroalkylene)-C3-10cycloalkyl, -(C1-6heteroalkylene)-4-10 membered heterocycloalkyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, ORa3, SRa3, C(=O)Rb3, C(=O)ORb3, NRc3Rd3, C(=O)NRc3Rd3, - OC(=O)NRc3Rd3, NRc3C(=O)Rb3, NRc3C(=O)ORb3, NRc3C(=O)NRc3Rd3, NRc3S(=O)2Rb3, NRc3S(=O)2NRc3Rd3, S(O)NRc3Rd3, and S(O)2NRc3Rd3, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6alkylene, C1-6heteroalkylene, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - R24is selected from the group consisting of H, azido, halo, CN, NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, ORa4, C(=O)Rb4, C(=O)ORb4, NRc4Rd4, C(=O)NRc4Rd4, - OC(=O)NRc4Rd4, NRc4C(=O)Rb4, NRc4C(=O)ORb4, NRc4C(=O)NRc4Rd4, NRc4S(=O)2Rb4, NRc4S(=O)2NRc4Rd4, S(O)NRc4Rd4, and S(O)2NRc4Rd4, wherein the C1-6alkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - each Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4, is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkoxy, - (C1-6alkylene)-C1-6alkoxy, C3-10cycloalkyl, -(C1-6alkylene)-C3-10cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, -(C1-6 alkylene)-C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; or Rc3and Rd3together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; or Rc4and Rd4together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; and - each R20is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1- 4 alkoxy, -(C1-4 alkyl)-(C1-4 alkoxy), -(C1-4 alkoxy)-(C1-4 alkoxy), C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, amino, C1-4 alkylamino, di(C1- 4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1- - 45 -WSGR Docket No.51503-778.606 4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4alkylaminocarbonylamino, di(C1-4alkyl)aminocarbonylamino, and amidinyl.

[0121] In some embodiments, the compound is of the Formula (IVb):Formula (IVb) wherein, R21is 5 membered heteroaryl, provided that the 5 membered heteroaryl is not thiophenyl or furanyl, wherein the 5 membered heteroaryl is unsubstituted or substituted with 1, 2, or 3, independently selected R1Agroups; each R1Ais independently selected from halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, -C(=O)OH, -C(=O)C1-6 alkyl, - C(=O)C1-6 haloalkyl, and -C(=O)C1-6 alkoxy; or, - R21is phenyl or 6 membered heteroaryl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R1Agroups; each R1Ais independently selected from halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, -C(=O)OH, -C(=O)C1- 6 alkyl, -C(=O)C1-6 haloalkyl, and -C(=O)C1-6 alkoxy; - R23is selected from the group consisting of H, azido, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 heteroalkyl, -(C1-6 alkylene)-C3-10 cycloalkyl, -(C1-6 alkylene)-4-10 membered heterocycloalkyl, -(C1-6 heteroalkylene)-C3-10 cycloalkyl, -(C1-6 heteroalkylene)-4-10 membered heterocycloalkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, ORa3, SRa3, C(=O)Rb3, C(=O)ORb3, NRc3Rd3, C(=O)NRc3Rd3, - OC(=O)NRc3Rd3, NRc3C(=O)Rb3, NRc3C(=O)ORb3, NRc3C(=O)NRc3Rd3, NRc3S(=O)2Rb3, NRc3S(=O)2NRc3Rd3, S(O)NRc3Rd3, and S(O)2NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 heteroalkyl, C1-6 alkylene, C1-6 heteroalkylene, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - 46 -WSGR Docket No.51503-778.606 - R24is selected from the group consisting of H, azido, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, ORa4, C(=O)Rb4, C(=O)ORb4, NRc4Rd4, C(=O)NRc4Rd4, - OC(=O)NRc4Rd4, NRc4C(=O)Rb4, NRc4C(=O)ORb4, NRc4C(=O)NRc4Rd4, NRc4S(=O)2Rb4, NRc4S(=O)2NRc4Rd4, S(O)NRc4Rd4, and S(O)2NRc4Rd4, wherein the C1-6alkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - each Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4, is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkoxy, - (C1-6alkylene)-C1-6alkoxy, C3-10cycloalkyl, -(C1-6alkylene)-C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -(C1-6alkylene)-C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; or Rc3and Rd3together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; or Rc4and Rd4together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; and - each R20is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1- 4 alkoxy, -(C1-4 alkyl)-(C1-4 alkoxy), -(C1-4 alkoxy)-(C1-4 alkoxy), C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, amino, C1-4 alkylamino, di(C1- 4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1- 4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, di(C1-4 alkyl)aminocarbonylamino, and amidinyl.

[0122] In some embodiments, a compound of Formula (I) has a structure of Formula (V),- 47 -WSGR Docket No.51503-778.606Formula (V).

[0123] In some embodiments, the compound is selected from Table 1.

[0124] In some embodiments, a SMSM described herein, possesses one or more stereocenters andeach stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof (See, for example, 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.

[0125] In some embodiments, sites on the aromatic ring portion of compounds described herein aresusceptible to various metabolic reactions Therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group.

[0126] In another embodiment, the compounds described herein are labeled isotopically (e.g. with aradioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0127] Compounds described herein include isotopically labeled compounds, which are identical tothose recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such - 48 -WSGR Docket No.51503-778.606 as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F, and36Cl. In one aspect, isotopically labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. As described herein, a variable group as defined in the present disclosure encompasses isotopical isomer of such variable group. For example, a variable group comprising a C-H moiety as described herein encompasses isotopical isomer of such C-H moiety (e.g., C-D, C-T, etc.). Thus, those skilled in the art reading the present disclosure should readily appreciate that a -CH2- moiety as described herein encompasses, e.g., -CD2-.

[0128] In some embodiments, one or more of the substituents disclosed herein comprise deuterium ata percentage higher than the natural abundance of deuterium. In some embodiments, compounds of the instant disclose comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

[0129] In additional or further embodiments, the compounds described herein are metabolized uponadministration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0130] Compounds described herein may be formed as, and / or used as, pharmaceutically acceptablesalts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, - 49 -WSGR Docket No.51503-778.606 tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0131] In some embodiments, the compounds provided herein can exist in unsolvated as well assolvated forms.

[0132] In some embodiments, a SMSM has a molecular weight of at most about 2000 Daltons, 1500Daltons, 1000 Daltons or 900 Daltons. In some embodiments, a SMSM has a molecular weight of at least 100 Daltons, 200 Daltons, 300 Daltons, 400 Daltons or 500 Daltons. In some embodiments, a SMSM does not comprise a phosphodiester linkage. In some embodiments, a SMSM is a compound with a structure set forth in Table 1 below. In some embodiments, a SMSM is a compound with a structure set forth in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, a SMSM is a stereoisomer of a structure set forth in Table 1, or a pharmaceutically acceptable salt thereof. Table 1: Exemplary SMSM compounds- 50 -WSGR Docket No.51503-778.606- 51 -WSGR Docket No.51503-778.606- 52 -WSGR Docket No.51503-778.606- 53 -WSGR Docket No.51503-778.606- 54 -WSGR Docket No.51503-778.606- 55 -WSGR Docket No.51503-778.606- 56 -WSGR Docket No.51503-778.606- 57 -WSGR Docket No.51503-778.606- 58 -WSGR Docket No.51503-778.606- 59 -WSGR Docket No.51503-778.606- 60 -WSGR Docket No.51503-778.606- 61 -WSGR Docket No.51503-778.606Pharmaceutical Compositions

[0133] In some embodiments, the compounds described herein are formulated into pharmaceuticalcompositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical - 62 -WSGR Docket No.51503-778.606 Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999), herein incorporated by reference for such disclosure.

[0134] In some embodiments, disclosed herein is a pharmaceutical composition comprising acompound of the disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the compounds described herein are pharmaceutical compositions comprising a compound of the present disclosure, and a pharmaceutically acceptable excipient or carrier. Splicing Modulation of Target Gene Products

[0135] The present disclosure contemplates use of small molecules with favorable drug propertiesthat modulate the activity of splicing of a target RNA. Provided herein are small molecule splicing modulators (SMSMs) that modulate splicing of a polynucleotide. In some embodiments, the SMSMs bind and modulate target RNA. In some embodiments, provided herein is a library of SMSMs that bind and modulate one or more target RNAs. In some embodiments, the target RNA is mRNA. In some embodiments, the target RNA is a noncoding RNA. In some embodiments, the target RNA is a pre-mRNA. In some embodiments, the target RNA is hnRNA. In some embodiments, the small molecules modulate splicing of the target RNA. In some embodiments, a small molecule provided herein modulates splicing at a sequence of the target RNA. In some embodiments, a small molecule provided herein modulates splicing at a cryptic splice site sequence of the target RNA. In some embodiments, a small molecule provided herein modulates splicing at an alternative splice site sequence of the target RNA. In some embodiments, a small molecule provided herein modulates splicing at a native splice site sequence of the target RNA. In some embodiments, a small molecule provided herein binds to a target RNA. In some embodiments, a small molecule provided herein binds to a splicing complex or a component thereof. In some embodiments, a small molecule provided herein binds to a target RNA and a splicing complex or a component thereof. In some embodiments, a small molecule provided herein modulates binding affinity of a splicing complex component to a target RNA such as a pre-mRNA. In some embodiments, a small molecule provided herein modulates binding affinity of a splicing complex component to a target RNA such as a pre-mRNA at a splice site sequence. In some embodiments, a small molecule provided herein modulates 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.

[0136] Described herein are compounds modifying splicing of gene products, such as Ataxin 3 pre-mRNA for use in the treatment, prevention, and / or delay of progression of diseases or conditions.

[0137] In some embodiments, described herein, is a method of treating, preventing, delaying ofprogress, or ameliorating symptoms of a disease or a condition associated with Ataxin 3 (ATXN3) - 63 -WSGR Docket No.51503-778.606 expression level or activity level 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 modulates splicing of the ATXN3 pre-mRNA in a cell of the subject to produce a spliced product of the ATXN3 pre-mRNA.

[0138] In some embodiments, described herein is a method of treating, preventing, delaying ofprogress, or ameliorating symptoms of a disease or a condition associated with Ataxin 3 (ATXN3) expression level or activity level in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or salt of Formula (I). In some embodiments, described herein is a method of modulating splicing of a Ataxin3 (ATXN3) pre-mRNA, comprising contacting a compound or salt of Formula (I) to the ATXN3 pre-mRNA with a splice site sequence or cells comprising the ATXN3 pre-mRNA, wherein the compound binds to the ATXN3 pre-mRNA and modulates splicing of the ATXN3 pre-mRNA in a cell of a subject to produce a spliced product of the ATXN3 pre-mRNA. In some embodiments, described herein is use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition or disease associated with Ataxin 3 (ATXN3) expression level or activity level.

[0139] In some embodiments, the spliced product of the ATXN3 pre-mRNA undergoes non-sensemediated decay (NMD) and / or nuclear retention. In some embodiments, the nonsense-mediated decay (NMD) and / or nuclear retention of the spliced product of the ATXN3 pre-mRNA is promoted. In some embodiments, the nonsense-mediated decay (NMD) and / or nuclear retention of the spliced product of the ATXN3 pre-mRNA is increased compared to a spliced product of the ATXN3 pre- mRNA produced in the absence of the SMSM.

[0140] In some embodiments, described herein is a method of modulating splicing of a Ataxin3(ATXN3) pre-mRNA, comprising contacting a small molecule splicing modulator (SMSM) to the ATXN3 pre-mRNA with a splice site sequence or cells comprising the ATXN3 pre-mRNA, wherein the SMSM binds to the ATXN3 pre-mRNA and modulates splicing of the ATXN3 pre-mRNA in a cell of a subject to produce a spliced product of the ATXN3 pre-mRNA.

[0141] In some embodiments, described herein, is a method of modulating splicing of Ataxin 3(ATXN3) pre-mRNA, comprising contacting a small molecule splicing modulator (SMSM) to the ATXN3 pre-mRNA with a splice site sequence or cells comprising the ATXN3 pre-mRNA, wherein the SMSM binds to the ATXN3 pre-mRNA and modulates splicing of the ATXN3 pre-mRNA in a cell of a subject to produce a spliced product of the ATXN3 pre-mRNA, wherein the splice site sequence comprises UCCUAU / guaagauucugu.

[0142] In some embodiments, described herein, is a method of treating, preventing, delaying ofprogress, or ameliorating symptoms of a disease or condition associated with Ataxin 3 (ATXN3) expression level or activity level in a subject in need thereof, comprising administering a therapeutically effective amount of a small molecule splicing modulator (SMSM) to the subject, wherein the SMSM binds to a ATXN3 pre-mRNA with a splice site sequence and modulates splicing - 64 -WSGR Docket No.51503-778.606 of the ATXN3 pre-mRNA in a cell of the subject, wherein a spliced product of the ATXN3 pre- mRNA undergoes nonsense-mediated decay (NMD), and wherein the splice site sequence comprises UCCUAU / guaagauucugu.

[0143] In some embodiments, the modulating splicing comprises modulating alternative splicing. Insome embodiments, the modulating splicing comprises promoting exon skipping. In some embodiments, the modulating splicing comprises promoting exon inclusion. In some embodiments, the modulating splicing comprises modulating nonsense-mediated mRNA decay (NMD). In some embodiments, the modulating NMD comprises promoting NMD. In some embodiments, the modulating splicing comprises modulating nuclear retention of the spliced product of the pre-mRNA. In some embodiments, the modulating intron retention comprises promoting nuclear retention of the spliced product of the pre-mRNA.

[0144] In some embodiments, the splice site sequence is a native splice site sequence. In someembodiments, the native splice site is a canonical splice site. In some embodiments, the native 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, the SMSM induces splicing at the alternative splice site. In some embodiments, the splicing at the alternative splice site results in a frameshift in a downstream exon in the spliced product. In some embodiments, the downstream exon comprises an in-frame stop codon that is not in frame in the absence of splicing at the alternative splice site. In some embodiments, the in-frame stop codon in the downstream exon is at least 50 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 or at least 60 base pairs upstream of a final exon-exon junction.

[0145] In some embodiments, the splicing of the pre-mRNA at the alternative splice site promotesNMD of the spliced product of the ATXN3 pre-mRNA. In some embodiments, the spliced product comprises an alternative exon. In some embodiments, the SMSM promotes inclusion of the alternative exon in the spliced product. In some embodiments, the alternative exon comprises a poison exon. In some embodiments, the SMSM promotes inclusion of the poison exon in the 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 and wherein 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 termination codon in the poison exon and the 3’ end of the poison exon is at least 50 or at least 60.

[0146] In some embodiments, the cells comprise primary cells. In some embodiments, the cellscomprise disease cells. In some embodiments, the SMSM modulates proliferation or survival of the - 65 -WSGR Docket No.51503-778.606 cells. In some embodiments, the SMSM modulates the expression level of a protein encoded by the spliced product of the pre-mRNA in the cells. Table 2. Exemplary targets for exon inclusionMethods of Treatment

[0147] The compositions and methods described herein can be used for treating a human disease ordisorder associated with aberrant splicing, such as aberrant pre-mRNA splicing. The compositions and methods described herein can be used for treating a human disease or disorder by modulating mRNA, such as pre-mRNA. In some embodiments, the compositions and methods described herein can be used for treating a human disease or disorder by modulating splicing of a nucleic acid even when that nucleic acid is not aberrantly spliced in the pathogenesis of the disease or disorder being treated.

[0148] In some embodiments, an effective amount in the context of the administration of a SMSMor a pharmaceutically acceptable salt thereof, or composition or medicament thereof refers to an amount of a SMSM or a pharmaceutically acceptable salt thereof to a patient which has a therapeutic effect and / or beneficial effect. In certain specific embodiments, an effective amount in the context of the administration of a SMSM or a pharmaceutically acceptable salt thereof, or composition or medicament thereof to a patient results in one, two or more of the following effects: (i) reduces or ameliorates the severity of a disease; (ii) delays onset of a disease; (iii) inhibits the progression of a disease; (iv) reduces hospitalization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the quality of life of a subject; (viii) reduces the number of symptoms associated with a disease; (ix) reduces or ameliorates the severity of a symptom associated with a disease; (x) reduces the duration of a symptom associated with a disease associated; (xi) prevents the recurrence of a symptom associated with a disease; (xii) inhibits the development or onset of a symptom of a disease; and / or (xiii) inhibits of the progression of a symptom associated with a disease. In some embodiments, an effective amount of a 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 the RNA transcript detectable in healthy patients or cells from healthy patients. In other embodiments, an effective amount of a SMSM or a pharmaceutically acceptable salt thereof is an amount effective to restore the amount an RNA isoform and / or protein isoform of a gene to the - 66 -WSGR Docket No.51503-778.606 amount of the RNA isoform and / or protein isoform detectable in healthy patients or cells from healthy patients.

[0149] In some embodiments, an effective amount of a SMSM or a pharmaceutically acceptable saltthereof is an amount effective to decrease the aberrant amount of an RNA transcript of a gene which associated with a disease. In some embodiments, an effective amount of a SMSM or a pharmaceutically acceptable salt thereof is an amount effective to decrease the amount of the aberrant expression of an isoform of a gene. In some embodiments, an effective amount of a SMSM or a pharmaceutically acceptable salt thereof is an amount effective to result in a substantial change in the amount of an RNA transcript (e.g., an mRNA transcript), alternative splice variant, or isoform.

[0150] In some embodiments, an effective amount of a SMSM or a pharmaceutically acceptable saltthereof is an amount effective to increase the amount of an RNA transcript (e.g., an mRNA transcript) of a gene that is beneficial for the prevention and / or treatment of a disease. In some embodiments, an effective amount of a 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 that is beneficial for the prevention and / or treatment of a disease. In some embodiments, an effective amount of a SMSM or a pharmaceutically acceptable salt thereof is an amount effective to increase the amount of an isoform of a gene that is beneficial for the prevention and / or treatment of a disease.

[0151] In some embodiments, an effective amount of a SMSM or a pharmaceutically acceptable saltthereof is an amount effective to decrease the amount of an RNA transcript (e.g., an mRNA transcript) which causes or is related to the symptoms of the condition or disease. In particular embodiments, the SMSM decreases the amount of an RNA transcript that causes or relates to the symptoms of the condition or disease by modulating one or more splicing elements of the RNA transcript. In some embodiments, the SMSM promotes skipping of one or more exons. In some embodiments, the SMSM promotes inclusion of one or more exons. In some embodiments, the SMSM promotes inclusion of one or more exons and / or introns that relate to nonsense-mediated mRNA decay (NMD). In some embodiments, the one or more exons harbor a premature termination codon. In particular embodiments, the premature stop codon is an in-frame codon that does not cause frameshift of the downstream exon(s). In some embodiments, inclusion of the one or more exons causes a reading frameshift in a downstream exon, for example, in the immediately downstream exon, introducing a premature termination codon.

[0152] A method of treating a disease or a condition in a subject in need thereof can compriseadministering 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 a method for the treatment, prevention and / or delay of progression of a disease or a condition associated with a gene listed in Table 2.

[0153] Non-limiting examples of effective amounts of a SMSM or a pharmaceutically acceptablesalt thereof are described herein. For example, the effective amount may be the amount required to - 67 -WSGR Docket No.51503-778.606 prevent and / or treat a disease associated with the aberrant amount of an mRNA transcript of gene in a human subject. In general, the effective amount will be in a range of from about 0.001 mg / kg / day to about 500 mg / kg / day for a patient having a weight in a range of between about 1 kg to about 200 kg. The typical adult subject is expected to have a median weight in a range of between about 70 and about 100 kg.

[0154] In one embodiment, a SMSM described herein can be used in the preparation ofmedicaments for the treatment of diseases or conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, can involve administration of pharmaceutical compositions that include at least one SMSM described herein or a pharmaceutically acceptable salt, thereof, in a therapeutically effective amount to a subject.

[0155] In certain embodiments, a SMSM described herein can be administered for prophylacticand / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or a condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or the condition. Amounts effective for this use depend on the severity and course of the disease or the condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial. In prophylactic applications, compositions containing a SMSM described herein can be administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Methods of Administering

[0156] The compositions described herein can be administered to the subject in a variety of ways, including parenterally, intravenously, intradermally, intramuscularly, colonically, rectally or intraperitoneally. Dosing and Schedules

[0157] The SMSMs utilized in the methods of the disclosure can be, e.g., administered at dosagesthat may be varied depending upon the requirements of the subject, the severity of the condition being treated and / or imaged, and / or the SMSM being employed. For example, dosages can be empirically determined considering the type and stage of disease diagnosed in a particular subject and / or the type of imaging modality being used in conjunction with the SMSMs. The dose administered to a subject, in the context of the present disclosure should be sufficient to affect a beneficial diagnostic or therapeutic response in the subject. The size of the dose also can be determined by the existence, nature, and extent of any adverse side–effects that accompany the administration of a SMSM in a particular subject.

[0158] Within the scope of the present description, the effective amount of a SMSM or apharmaceutically acceptable salt thereof for use in the manufacture of a medicament, the preparation - 68 -WSGR Docket No.51503-778.606 of a pharmaceutical kit or in a method for preventing and / or treating a disease in a human subject in need thereof, is intended to include an amount in a range of from about 1 µg to about 50 grams.

[0159] The compositions of the present disclosure can be administered as frequently as necessary.Subjects

[0160] The subjects that can be treated with the SMSMs and methods described herein can be anysubject that produces mRNA that is subject to alternative splicing, e.g., the subject may be a eukaryotic subject, such as a plant or an animal. In some embodiments, the subject is a mammal, e.g., human. In some embodiments, the subject is a human. In some embodiments, the subject is a non– human animal. In some embodiments, the subject is a fetus, an embryo, or a child. In some embodiments, the subject is a non–human primate such as chimpanzee, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In some embodiments, the subject is prenatal (e.g., a fetus), a child (e.g., a neonate, an infant, a toddler, a preadolescent), an adolescent, a pubescent, or an adult (e.g., an early adult, a middle-aged adult, a senior citizen). Methods of Making Compounds

[0161] Compounds described herein can be synthesized using standard synthetic techniques orusing methods known in the art in combination with methods described herein. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology can be employed. Compounds can be prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials can be available from commercial sources or can be readily prepared. By way of example only, provided are schemes for preparing the SMSMs described herein.

[0162] Suitable reference books and treatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic - 69 -WSGR Docket No.51503-778.606 Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527–29074–5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0–19–509618–5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley– VCH, ISBN: 0–471–19031–4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0–471–60180–2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley–VCH, ISBN: 3–527–29871–1; Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0–471–93022–9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0–471–19095–0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley–Interscience, ISBN: 0–471–57456–2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3–527–29645–X, in 8 volumes; “Organic Reactions” (1942–2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0163] In the reactions described, it may be necessary to protect reactive functional groups, forexample hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. A detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure).

[0164] SMSMs can be made using known techniques and further chemically modified, in someembodiments, to facilitate intranuclear transfer to, e.g., a splicing complex component, a spliceosome or a pre-mRNA molecule. One of ordinary skill in the art will appreciate the standard medicinal chemistry approaches for chemical modifications for intranuclear transfer (e.g., reducing charge, optimizing size, and / or modifying lipophilicity). EXAMPLES

[0165] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma–Aldrich, Acros Organics, Fluka, and Fisher Scientific.

[0166] Example A1. General Synthesis Scheme 1- 70 -WSGR Docket No.51503-778.606Scheme 2

[0167] Alternatively, the intermediates 5 or 5b from scheme 1 (5b being the non-Bocprotected NH analog of 5) can be prepared from the intermediate 4 or 3 through the sequence below, and then converted into final products I as in scheme 1.- 71 -WSGR Docket No.51503-778.606Scheme 3

[0168] General preparation of the intermediates 2 from scheme 1.

[0169] Example A2. Synthesis of Intermediates

[0170] Synthesis of Intermediates of types 3 and 4

[0171] Intermediates 3-1 and 4-1: 6-bromo-2-chloro-5-methyl-N-(pyridin-4- ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (3-1) and tert-butyl (6-bromo-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(pyridin-4-ylmethyl)carbamate (4-1).

[0172] Step 1: 4 The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected - 72 -WSGR Docket No.51503-778.606 without further purification.

[0173] Step 2: 4

[0174] Step 3 3 (36.04 g, 428.99 mmol, 2 equiv) 2 under reduced pressure. The residue was purified by silica gel column chromatography, eluted with

[0175] Step 4 4OH (825 mL)at RT. The resulting mixture was stirred overnight at 120°C. The resulting mixture was concentrated under reduced

[0176] Step 5 3 mixture was concentrated under reduced pressure. The residue was purified by silica gel column

[0177] Step 6 reversed-phase flash chromatography with the following conditions: column, C18; mobile - 73 -WSGR Docket No.51503-778.606 4HCO3), 50% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in 6-bromo-2-chloro-5-methyl-N-(pyridin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4- amine (intermediate 3-1

[0178] Step 7: A solution 6-bromo-2-chloro-5-methyl-N-(pyridin-4-ylmethyl)pyrrolo[2,1- 2 tert-butyl (6-bromo- 2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(pyridin-4-ylmethyl)carbamate (intermediate 4-1,

[0179] Intermediates 3-2 and 4-2: 6-bromo-2-chloro-5-methyl-N-(thiazol-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-2) and tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-yl)(thiazol-2-ylmethyl)carbamate (intermediate 4-2)

[0180] These intermediates were prepared in analogy to the intermediates 3-1 and 4-1, but using step 6, thiazol-2-ylmethanamine.

[0181] Intermediates 3-3 and 4-3: 6-bromo-2-chloro-N-((3-fluoropyridin-4-yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-3) and tert-butyl (6-bromo-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)((3-fluoropyridin-4-yl)methyl)carbamate (intermediate 4-3)

[0182] These intermediates were prepared in analogy to the intermediates 3-1 and 4-1, but using step 6, (3-fluoropyridin-4-yl)methanamine.

[0183] Intermediates 3-4 and 4-4: 6-bromo-2-chloro-5-methyl-N-(pyrimidin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-4) and tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-yl)(pyrimidin-4-ylmethyl)carbamate (intermediate 4-4) - 74 -WSGR Docket No.51503-778.606

[0184] These intermediates were prepared in analogy to the intermediates 3-1 and 4-1, but using step 6, pyrimidin-4-ylmethanamine.

[0185] Intermediates 3-5 and 4-5: 6-bromo-2-chloro-N-(2-fluorobenzyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-5) and tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-yl)(2-fluorobenzyl)carbamate (intermediate 4-5)

[0186] These intermediates were prepared in analogy to the intermediates 3-1 and 4-1, but using step 6, (2-fluorophenyl)methanamine.

[0187] Intermediates 3-6 and 4-6: 6-bromo-2-chloro-N-((3,5-difluoropyridin-4-yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-6) and tert-butyl (6-bromo-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)((3,5-difluoropyridin-4-yl)methyl)carbamate (intermediate 4- 6)

[0188] These intermediates were prepared in analogy to the intermediates 3-1 and 4-1, but using step 6, (3,5-difluoropyridin-4-yl)methanamine.

[0189] Intermediates 3-7 and 4-7: N-benzyl-6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-7) and tert-butyl benzyl(6-bromo-2-chloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-yl)carbamate (intermediate 4-7) - 75 -WSGR Docket No.51503-778.606

[0190] These intermediates were prepared in analogy to the intermediates 3-1 and 4-1, but using step 6, phenylmethanamine.

[0191] Intermediates 3-8 and 4-8: 6-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-8) and tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8)

[0192] These intermediates were prepared in analogy to the intermediates 3-1 and 4-1, but using step 6, isothiazol-3-ylmethanamine.

[0193] Example A3. Synthesis of potassium trifluoroborate salts

[0194] Borate salt 1: Potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)trifluoroborate

[0195] Step 1 2

[0196] Step 2 2 4 filtrate was concentrated under reduced pressure. The residue was purified by silica gel column - 76 -WSGR Docket No.51503-778.606

[0197] Step 3 (340.72 mL, 340.720 mmol, 1 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was layers were concentrated under reduced pressure. The residue was purified by silica gel column

[0198] Step 4 268.226 mmol, 1 equiv) in EtOAc (760 mL) was treated with Pd / C (15.2 g, 20%) at room concentrated under reduced pressure. The residue was purified by silica gel column chromatography,

[0199] 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 eq.) and triphenylphosphine (17.15 g, 65.21 mmol, 1.2 eq.) in DCM (100 mL) and THF (100 mL) was added NBS (11.62 g, 65.28 mmol, 1.2 eq.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The residue was washed with water (2x50 mL) and brine (50 mL). The organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford tert-butyl N-[(2S)-1-bromo-3-fluoropropan-2- yl]carbamate (3.5 g, 25%) as a yellow solid.

[0200] Step 6: A mixture of tert-butyl N-[(2S)-1-bromo-3-fluoropropan-2-yl]carbamate (3.5 g, 13.66 mmol, 1 eq.), copper(I) iodide (0.26 g, 1.37 mmol, 0.1 eq.), triphenylphosphine (0.36 g, 1.37 mmol, 0.1 eq.), Bis(pinacolato) diboron (6.94 g, 27.33 mmol, 2 eq.) and methoxylithium (1.04 g, 27.33 mmol, 2 eq.) in DMF (60 mL) was stirred for 16 h at RT under air atmosphere. The resulting mixture was diluted with water (60 mL) and extracted with MTBE (3 x 100 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0201] 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 eq.) and fluorine potassium hydride (2.57 g, 32.98 mmol, 2 eq.) in MTBE (200 mL) and H2O (2 mL) was stirred for 16 h at room temperature under air atmosphere. The resulting mixture was concentrated under vacuum. The residue was diluted with - 77 -WSGR Docket No.51503-778.606 MTBE (200 mL). The mixture was stirred for 30 min and filtered. The filter cake was diluted with acetone (300 mL) and stirred for another 30 min. The resulting mixture was filtered, and the filter cake was washed with acetone (1x50 mL). The filtrate was concentrated under reduced pressure to afford potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)trifluoroborate (3 g, 64%) as an off-white solid. The crude product was used in the next step directly without further purification.

[0202] Borate salt 2: Potassium ((2R,3S)-2-((tert-butoxycarbonyl)amino)-3- fluorobutyl)trifluoroborate

[0203] Step 1 mL) were added SOCl2 (57.84 mL, 797.38 mmol, 1.5 equiv) and DIEA (185.19 mL, 1063.17 mmol, 2 eq.) in DCM (620ml) dropwise at 0oC. The resulting mixture was stirred for resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0204] Step 2: A solution of 3-(tert-butyl) 4-methyl (4S,5R)-5-methyl-1,2,3-oxathiazolidine-3,4- 2 4 oC under nitrogen atmosphere. The resulting mixture was stirred for 1h at 0oC under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed

[0205] Step 3: A solution of 3-(tert-butyl) 4-methyl (4S,5R)-5-methyl-1,2,3-oxathiazolidine-3,4- 3N.3HF concentrated under reduced pressure. The residue was purified by silica gel column chromatography, (55 g, 48%) as a light yellow oil.

[0206] Step 4: A solution of methyl (2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutanoate (55 4 - 78 -WSGR Docket No.51503-778.606 0o0o0oC. The aqueous layer was extracted with EtOAc (3x400mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography,

[0207] 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 eq.) and triphenylphosphine (103.02 g, 392.77 mmol, 1.85 eq.) in THF (170 mL) and DCM (880 mL) was added NBS (69.91 g, 392.77 mmol, 1.85 eq.) in portions at -20°C under air atmosphere. The resulting mixture was stirred overnight at RT under air atmosphere. The resulting mixture was washed with 1x500 mL of water, washed with brine (1x200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl N- [(2S,3S)-1-bromo-3-fluorobutan-2-yl]carbamate (30 g, 52%) as a light yellow solid.

[0208] 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 for 16h at RT under air atmosphere. The resulting mixture was diluted with water (500mL). The resulting mixture was filtered, the filter cake was washed with MTBE (1x100 mL). The resulting mixture was extracted with MTBE (3 x300 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification.

[0209] 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 eq.) and KHF2 (8.8 g, 112.67 mmol, 2.35 eq.) in MTBE (600 mL) and H2O (4 mL) was stirred for 16h at RT under air atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with MTBE. The mixture was stirred for 30 min and filtered. The filter cake was diluted with acetone (800 mL) and stirred for another 30 min. The resulting mixture was filtered, and the filter cake was washed with acetone (1x50 mL). The filtrate was concentrated under reduced pressure. This resulted in potassium ((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)trifluoroborate (8 g, 56%) as a white solid.

[0210] Borate salt 3: Potassium (2-((tert-butoxycarbonyl)amino)-3-(1- fluorocyclopropyl)propyl)trifluoroborate - 79 -WSGR Docket No.51503-778.606

[0211] Step 1: To a stirred solution 1-fluorocyclopropane-1-carboxylic acid (15g, 144.12 mmol, 1 eq.) in THF (150 mL) was added 2M LiAlH4-THF (78 mL, 158.53 mmol) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 3h at RT under nitrogen atmosphere. The reaction was quenched by the addition of water (2 mL) and 1N NaOH (2 mL) at 0oC. The resulting mixture was filtered, the filter cake was washed with THF (3x100 mL) and the filtrate dried over anhydrous Na2SO4 and then concentrated under reduced pressure (at 20oC) to get (1- fluorocyclopropyl)methanol (13 g, 96%) as a light yellow oil.

[0212] Step 2 o ooC. The reaction was 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel

[0213] Step 3 o o 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by

[0214] Step 4 2 0o2 - 80 -WSGR Docket No.51503-778.606 K2CO3 2SO4. After filtration, the filtrate was

[0215] Step 5: The amino moiety was protected with a Boc group using (Boc)2O to form tert-butyl 2- [(tert-butoxycarbonyl)amino]-3-(1-fluorocyclopropyl)propanoate.

[0216] Step 6 LiAlH4o

[0217] Step 7: To a stirred mixture of tert-butyl N-[1-(1-fluorocyclopropyl)-3-hydroxypropan-2- yl]carbamate (7.5 g, 32.15 mmol, 1 eq.) and triphenylphosphine (15.60 g, 59.48 mmol, 1.85 eq.) in DCM (150 mL) and THF (30 mL) was added NBS (10.59 g, 59.48 mmol, 1.85 eq.) in portions at - 20°C under nitrogen atmosphere. The resulting mixture was stirred for 16h at RT under nitrogen atmosphere. The residue was diluted with DCM (150 mL) and washed with water (2x50 mL) and brine (50 mL). The organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl N-[1- bromo-3-(1-fluorocyclopropyl)propan-2-yl]carbamate (4.2 g, 44%) as a white solid.

[0218] Step 8: To a mixture of tert-butyl N-[1-bromo-3-(1-fluorocyclopropyl)propan-2-yl]carbamate (4.2 g, 14.18 mmol, 1 eq.), copper(I) iodide (0.27 g, 1.42 mmol, 0.1 eq.), triphenylphosphine (0.48 g, atmosphere. The resulting mixture was diluted with water (60 mL) and extracted with MTBE (3 x 100 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0219] Step 9: A mixture of tert-butyl N-[1-(1-fluorocyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)propan-2-yl]carbamate (4.5 g, 13.110 mmol, 1 equiv) and fluorine potassium hydride (2.05 g, 26.220 mmol, 2 equiv) in MTBE (300 mL) and H2O (3 mL) was stirred for 16 h at room temperature under air atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with MTBE (300 mL). The mixture was stirred for 30min and - 81 -WSGR Docket No.51503-778.606 filtered. The filter cake was diluted with acetone (400 mL) and stirred for another 30 min. The resulting mixture was filtered, and the filter cake was washed with acetone (1x50 mL). The filtrate was concentrated under reduced pressure to afford potassium (2-((tert-butoxycarbonyl)amino)-3-(1- fluorocyclopropyl)propyl)trifluoroborate (2.5 g, 59%) as a white solid. The crude product was used in the next step directly without further purification.

[0220] Borate salt 4: potassium (R)-(2-((tert-butoxycarbonyl)amino)-4,4,4- trifluorobutyl)trifluoroborate

[0221] Step 1: To an ice -cooled solution of (2S)-2-[(tert-butoxycarbonyl)amino]-4,4,4- trifluorobutanoic acid (4 g, 15.55 mmol, 1 eq.) and DIEA (2.41 g, 18.66 mmol, 1.2 eq.) in THF (40 mL) was added dropwise isopropyl chloroformate (2.10 g, 17.11 mmol, 1.1 eq.). The cooling bath was removed, and the mixture was stirred at 23 °C for 2h. The mixture was filtered to remove the white precipitate, and the filtrate was treated with LiBH4 (0.68 g, 31.10 mmol, 2 eq.) 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 x 25 mL). The combined organic extracts were dried (MgS04), filtered, then concentrated under vacuum. 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.

[0222] 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 eq.),triphenylphosphine (4.39 g, 16.73 mmol, 1.85 eq.) in THF (8 mL) and DCM (40 mL) were added NBS (2.98 g, 16.73 mmol, 1.85 eq.) in portions at -20°C under air atmosphere. The resulting mixture was stirred for additional overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl N-[(2S)-1-bromo-4,4,4- trifluorobutan-2-yl]carbamate (1.1 g, 40%) as a white oil.

[0223] 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 eq.) copper(I) iodide (0.07 g, 0.36 mmol, 0.1 eq.) methoxylithium (0.27 g, 7.18 mmol, 2 eq.) triphenylphosphine (0.12 g, 0.47 mmol, 0.13 eq.) 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 eq.) in DMF (11 mL) was stirred for overnight at RT under air atmosphere. The resulting mixture was filtered, the filter cake was washed with water and tert-Butyl methyl ether (3x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification.

[0224] 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 eq.) and KHF2(0.49 g, 6.23 mmol, 2 eq.) in 2-methoxy-2-methylpropane (100 mL) was stirred for overnight at RT under air atmosphere. - 82 -WSGR Docket No.51503-778.606 The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with MTBE (300 mL). The mixture was stirred for 30 min and filtered. The filter cake was diluted with acetone (400 mL) and stirred for another 30 min. The resulting mixture was filtered, and the filter cake was washed with acetone (1 x 50 mL). The filtrate was concentrated under reduced pressure to afford potassium (R)-(2-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutyl)trifluoroborate (500 mg, 55%) as a white solid.

[0225] Borate salt 5: Potassium (R)-(2-((tert-butoxycarbonyl)amino)-4- (trifluoromethoxy)butyl)trifluoroborate

[0226] 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 eq.), triphenylphosphine (23.09 g, 88.01 mmol, 1.85 eq.) in DCM (200 mL) and THF (50 mL) was added NBS (15.67 g, 88.01 mmol, 1.85 eq.) in portions at -20°C under air atmosphere. The resulting mixture was stirred overnight at RT under air atmosphere. The resulting mixture was washed with 3 x 200 mL of water. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl N-[(2S)-1-bromo-4-(trifluoromethoxy)butan-2-yl]carbamate (8 g, 50%) as a colorless oil.

[0227] Step 2: A mixture of tert-butyl N-[(2S)-1-bromo-4-(trifluoromethoxy)butan-2-yl]carbamate (5.5 g, 16.36 mmol, 1 eq.), methoxylithium (1.24 g, 32.72 mmol, 2 eq.), copper(I) iodide (0.31 g, 1.63 mmol, 0.1 eq.), triphenylphosphine (0.56 g, 2.13 mmol, 0.13 eq.) 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 eq.) in DMF (60 mL) was stirred for overnight at RT under air atmosphere. The residue was diluted with water (200 mL) and filtered; the filter cake was washed with MTBE (3x30 mL). The filtrate was extracted with MTBE (3x80 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. 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 in the next step directly without further purification.

[0228] Step 3: To a stirred mixture of 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 fluorine potassium hydride (2.24 g, 28.704 mmol, 2 equiv) in MTBE (200 mL) and H2O (5 mL) at room temperature under air atmosphere. The resulting mixture was stirred for overnight at room temperature under air atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with MTBE (200mL). The precipitated solids were collected by filtration and washed with - 83 -WSGR Docket No.51503-778.606 MTBE (3x20 mL). The residue was purified by trituration with acetone (200mL). The resulting mixture was filtered, the filter cake was washed with acetone (3x20 mL). The filtrate was concentrated under reduced pressure. This resulted in potassium (R)-(2-((tert-butoxycarbonyl)amino)- 4-(trifluoromethoxy)butyl)trifluoroborate (3 g, 57%) as a white solid.

[0229] Borate salt 6: Potassium (R)-(2-((tert-butoxycarbonyl)amino)-4- (difluoromethoxy)butyl)trifluoroborate

[0230] Step 1: To a mixture of benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate (10 2O (10 mL) was added The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel

[0231] Step 2: To a stirred solution of benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4- 4

[0232] Step 3: To a stirred solution of tert-butyl N-[(2S)-4-(difluoromethoxy)-1-hydroxybutan-2-

[0233] 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 eq.), methoxylithium (0.37 g, 9.74 mmol, 2 eq.), copper(I) iodide tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.61 g, 6.330 mmol, - 84 -WSGR Docket No.51503-778.606 (difluoromethoxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)carbamate (1.77g, purification.

[0234] Step 5: A mixture of tert-butyl (R)-(4-(difluoromethoxy)-1-(4,4,5,5-tetramethyl-1,3,2- 2 min and filtered. The filter cake was diluted with acetone (100 mL) and stirred for another 30 min. The resulting mixture was filtered, and the filter cake was washed with acetone (1x50 mL). The R)-(2-((tert-

[0235] Preparation of the (N-acyloxy)phtalimide esters

[0236] (N-acyloxy)phtalimide ester 1: 1,3-dioxoisoindolin-2-yl (2R,3S)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate

[0237] To a stirred solution of (2R,3S)-3-[(tert-butoxycarbonyl)amino]oxane-2-carboxylic acid (1 g, 4.07 mmol, 1 equiv), NHPI (0.60 g, 3.67 mmol, 0.9 equiv.) and DMAP (0.05 g, 0.41 mmol, 0.1 equiv) in DCM (15 mL) was added DIC (0.46 g, 3.67 mmol, 0.9 equiv.) dropwise at RT under nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 30 min. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% TFA), 10% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in 1,3-dioxoisoindol-2-yl (2R,3S)-3-[(tert-butoxycarbonyl)amino]oxane-2- carboxylate (1.3 g, 82%) as an off-white solid.

[0238] (N-acyloxy)phtalimide ester 2: 1,3-dioxoisoindolin-2-yl (2S,3S)-3-((tert-butoxycarbonyl)amino)tetrahydrofuran-2-carboxylate

[0239] This derivative was prepared in analogy to the preparation of the (N-acyloxy)phtalimide ester compound 1, but using (2S,3S)-3-((tert-butoxycarbonyl)amino)tetrahydrofuran-2-carboxylic acid. - 85 -WSGR Docket No.51503-778.606

[0240] (N-acyloxy)phtalimide ester 3: 1,3-dioxoisoindolin-2-yl (1SR,2SR)-2-((tert-butoxycarbonyl)amino)-4,4-difluorocyclohexane-1-carboxylate

[0241] This derivative was prepared in analogy to the preparation of the (N-acyloxy)phtalimide ester compound 1, but using (1SR,2SR)-2-((tert-butoxycarbonyl)amino)-4,4-difluorocyclohexane-1- carboxylic acid.

[0242] (N-acyloxy)phtalimide ester 4: 1,3-dioxoisoindolin-2-yl (1RS,6SR)-6-((tert-butoxycarbonyl)amino)-4-fluorocyclohex-3-ene-1-carboxylate

[0243] This derivative was prepared in analogy to the preparation of the (N-acyloxy)phtalimide ester compound 1, but using (1RS,6SR)-6-((tert-butoxycarbonyl)amino)-4-fluorocyclohex-3-ene-1- carboxylic acid.

[0244] Preparation of (1SR,6SR)-6-((tert-butoxycarbonyl)amino)-4-fluorocyclohex-3-ene-1- carboxylic acid:

[0245] To a stirred solution of Et3N.3HF (2.38 g, 14.76 mmol, 2.00 equiv.) and TEA (0.75 g, 7.37 mmol, 1 equiv.) in N,N-Dimethylacetamide (22 mL) was added N,N-Diethyl-S,S-difluoro- sulfiliminium tetrafluoroborate (5.06 g, 22.12 mmol, 3 equiv.) and methyl (1RS,2SR)-2-((tert- butoxycarbonyl)amino)-4-oxocyclohexane-1-carboxylate (2 g, 7.37 mmol, 1 equiv.) at RT under air atmosphere. The resulting mixture was stirred at room temperature for 24 h under air atmosphere. The desired regioisomeric F-alkene (0.60g) was isolated by prep-HPLC. Hydrolysis of the ester provided the title compound ready to use in the next step.

[0246] (N-acyloxy)phtalimide ester 5: 1,3-dioxoisoindolin-2-yl (3R,4S)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylate

[0247] This derivative was prepared in analogy to the preparation of the (N-acyloxy)phtalimide ester compound 1, but using (3R,4S)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid. - 86 -WSGR Docket No.51503-778.606

[0248] (N-acyloxy)phtalimide ester 6: 1,3-dioxoisoindolin-2-yl (3R,4S)-4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-3-carboxylate

[0249] This derivative was prepared in analogy to the preparation of the (N-acyloxy)phtalimide ester compound 1, but using (3R,4S)-4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-3-carboxylic acid.

[0250] Synthesis of compounds of Table 1

[0251] General procedures

[0252] General procedure 1. Cross coupling reaction between an intermediate of type 3 or 4 with a trifluoroborate salt:

[0253] A mixture of an intermediate 3 or 4 (1 eq.), with a potassium trifluoroborate salt (1.5 eq.),Pd2(dba)3 or Pd(Amphos)2Cl2 2CO3 2 concentrated under reduced pressure. The residue was purified by silica gel column chromatography or preparative HPLC, to afford the desired compound of type 5b or 5.

[0254] General procedure 2. Decarboxylative cross coupling between an intermediate of type 8 with a (N-acyloxy)phtalimide ester:

[0255] To a stirred solution of (N-acyloxy)phtalimide ester (1.3 equiv.), Zn (1.34 g, 20.44 mmol, 8 equiv.) and an iodo intermediate 8, (1.00 equiv.) in DMAC (10 mL) was added (A solution of NiCl2.glyme (0.5equiv) and 5-methoxypyridine-2-carboximidamide hydrochloride (0.19 g, 1.022 mmol, 0.4 equiv) in DMAc (2ml) was stirred at room temperature for 15 min under nitrogen atmosphere.) dropwise at RT under nitrogen atmosphere. The resulting mixture was stirred at RT for an additional 1h. The residue was purified by reversed-phase flash chromatography resulting in the corresponding intermediate 5.

[0256] General procedure 3: Conversion of a Bromo derivatives 3 into a iodo derivatives 8.

[0257] A solution of a bromo intermediate 3 (1.0 equiv.), CuI (0.4 equiv.), NaI (1.5 equiv.) and(1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.4 equiv.) in dioxane (6 mL / mmol) was stirred at 80°C for 2days under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water - 87 -WSGR Docket No.51503-778.606 (0.1% TFA), 30% to 100% gradient in 10 min; detector, UV 254 nm to provide the corresponding iodo derivatives 8.

[0258] Example 1. Synthesis of specific compounds

[0259] Compound 1.

[0260] 6-((2R,3S)-2-amino-3-fluorobutyl)-7-bromo-2-chloro-5-methyl-N-(pyridin-4- ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0261] Step 1: Using the general cross coupling reaction procedure 1, between 6-bromo-2-chloro-5-methyl-N-(pyridin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-1) and potassium((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)trifluoroborate (borate salt 2) was obtainedtert-butyl ((2R,3S)-1-(2-chloro-5-methyl-4-((pyridin-4-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6- yl)-3-fluorobutan-2-yl)carbamate (500 mg, 38%) as a colorless oil.

[0262] Step 2: To a stirred solution of tert-butyl ((2R,3S)-1-(2-chloro-5-methyl-4-((pyridin-4- ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluorobutan-2-yl)carbamate (200 mg, 0.43 mmol, 1 equiv.) in THF (4 mL) were added NBS (84.5 mg, 0.475 mmol, 1.1 equiv.) in portions at -40°C under air atmosphere. The resulting mixture was stirred for an additional 2h at RT and concentrated under vacuo. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl ((2R,3S)-1-(7-bromo-2-chloro-5- methyl-4-((pyridin-4-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluorobutan-2-yl)carbamate (100 mg, 43%) as a yellow solid.

[0263] Step 3: To a stirred solution of tert-butyl ((2R,3S)-1-(7-bromo-2-chloro-5-methyl-4-((pyridin- 4-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluorobutan-2-yl)carbamate (100 mg, 0.185 mmol, 1 equiv.) in DCM (2 mL) was added HCl(gas) in 1,4-dioxane (1 mL, 4 M) dropwise at 0°C under air atmosphere. The resulting mixture was stirred for an additional 2h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 50 mL / min mL / min; Gradient: 20% B to 50% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.93) to afford 6-((2R,3S)-2-amino-3-fluorobutyl)-7-bromo-2-chloro-5-methyl-N-(pyridin-4- ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (20 mg, 23%). LC-MS-(ES, m / z): [M+H]+= 440.85.

[0264] Compound 2. - 88 -WSGR Docket No.51503-778.606

[0265] 6-((2R,3S)-2-amino-3-fluorobutyl)-2-chloro-5-methyl-7-(prop-1-yn-1-yl)-N-(pyridin-4- ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0266] Step 1: A mixture of tert-butyl ((2R,3S)-1-(7-bromo-2-chloro-5-methyl-4-((pyridin-4- ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluorobutan-2-yl)carbamate (intermediate obtained in the example of Compound 1, step 2; 175 mg, 0.323 mmol, 1 equiv.), tributyl(prop-1-yn-1- yl)stannane (127.55 mg, 0.388 mmol, 1.2 equiv), Pd2(dba)3(29.5 mg, 0.032 mmol, 0.1 equiv.) and APAC 116629 (23.1 mg, 0.065 mmol, 0.2 equiv.) in 1,4-dioxane (2 mL) was stirred for overnight at 80°C under nitrogen atmosphere. The residue was concentrated under vacuo and the residue purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 50% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl ((2R,3S)-1-(2-chloro-5-methyl-7-(prop-1-yn-1-yl)-4-((pyridin-4- ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluorobutan-2-yl)carbamate (100 mg, 62%) as a yellow solid.

[0267] Step 2: To a stirred solution of tert-butyl ((2R,3S)-1-(2-chloro-5-methyl-7-(prop-1-yn-1-yl)-4- ((pyridin-4-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluorobutan-2-yl)carbamate (100 mg, 0.200 mmol, 1 equiv) in DCM (2 mL) was added TFA (0.5 mL) dropwise at 0°C under air atmosphere. The resulting mixture was stirred for an additional 1h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following (10 mmol / L NH4HCO3+ 0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 50% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.80 / 11.98) to afford 6-((2R,3S)-2-amino-3-fluorobutyl)-2-chloro-5-methyl-7-(prop-1-yn-1-yl)-N-(pyridin-4- ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (4 mg, 4%). LC-MS-(ES, m / z): [M+H]+= 401.05.

[0268] Compound 3.

[0269] (R)-6-(2-amino-3-fluoropropyl)-7-bromo-2-chloro-5-methyl-N-(pyridin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine - 89 -WSGR Docket No.51503-778.606

[0270] In analogy to the example of Compound 1, but using in step 1, potassium (R)-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)trifluoroborate (Borate salt 1), 30 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 429.00.

[0271] Compound 4.

[0272] (R)-6-(2-amino-3-fluoropropyl)-2-chloro-5-methyl-7-(prop-1-yn-1-yl)-N-(pyridin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0273] Step 1: A mixture of tert-butyl (R)-(1-(7-bromo-2-chloro-5-methyl-4-((pyridin-4- ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluoropropan-2-yl)carbamate (intermediate obtained in the example of Compound 3, 200 mg, 0.379 mmol, 1 equiv), tributyl(prop-1-yn-1- yl)stannane (149.6 mg, 0.455 mmol, 1.2 equiv.), Pd2(dba)3(34.7 mg, 0.038 mmol, 0.1 equiv.) and bis(adamantan-1-yl)(butyl)phosphane (27.2 mg, 0.076 mmol, 0.2 equiv.) in 1,4-dioxane (4 mL) was stirred for overnight at 80°C under nitrogen atmosphere. After concentration under vacuo, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (10mmol / L NH4HCO3), 50% to 90% gradient in 10 min; detector, UV 254 nm. This provided 100 mg (54%) of tert-butyl (R)-(1-(2-chloro-5-methyl-7-(prop-1-yn-1-yl)-4- ((pyridin-4-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluoropropan-2-yl)carbamate as a brown solid.

[0274] Step 2: To a stirred solution of tert-butyl (R)-(1-(2-chloro-5-methyl-7-(prop-1-yn-1-yl)-4- ((pyridin-4-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluoropropan-2-yl)carbamate (100 mg, 0.205 mmol, 1 equiv) in DCM (2 mL) was added TFA (0.5 mL) dropwise at 0°C under air atmosphere. The resulting mixture was stirred for an additional 1h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following FA), Mobile Phase B: ACN; Flow rate: 50mL / min; Gradient: 7% B to 28% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 6.25) to afford (R)-6-(2-amino-3-fluoropropyl)-2-chloro-5- - 90 -WSGR Docket No.51503-778.606 methyl-7-(prop-1-yn-1-yl)-N-(pyridin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (20 mg, 23%). LC-MS-(ES, m / z): [M+H]+= 387.15.

[0275] Compound 5.

[0276] 6-((2R,3S)-2-amino-3-fluorobutyl)-7-bromo-2-chloro-5-methyl-N-(thiazol-2- ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0277] In analogy to the example of Compound 1, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(thiazol-2-ylmethyl)carbamate (Intermediate 4-2), 55 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 449.05.

[0278] Compound 6.

[0279] 6-((2R,3S)-2-amino-3-fluorobutyl)-2,7-dichloro-5-methyl-N-(thiazol-2-ylmethyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine

[0280] Step 1: Using the general cross coupling reaction procedure 1, between tert-butyl (6-bromo- 2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(thiazol-2-ylmethyl)carbamate (Intermediate 4-2) and potassium ((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)trifluoroborate (borate salt 2)was obtained tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(thiazol-2-ylmethyl)carbamate (450 mg, 43%) as a white solid.

[0281] Step 2: To a stirred of tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)- 2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(thiazol-2-ylmethyl)carbamate (200 mg, 0.351 under reduced pressure. The residue was purified by reversed-phase flash chromatography with the in 30 min; detector, UV 254 nm. This provided tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)- 3-fluorobutyl)-2,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(thiazol-2-ylmethyl)carbamate - 91 -WSGR Docket No.51503-778.606

[0282] Step 3: A solution of tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)- 2,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(thiazol-2-ylmethyl)carbamate (150 mg, 0.231 mmol, 1 equiv.) in DCM (3 mL) was treated with TFA (1 ml) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at RT under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture / residue was basified to pH 8 with DIEA. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 6-((2R,3S)-2-amino-3-fluorobutyl)-2,7-dichloro-5-methyl-N- (thiazol-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (55 mg, 53%). LC-MS-(ES, m / z): [M+H]+= 403.05.

[0283] Compound 7.

[0284] 6-((2R,3S)-2-amino-3-fluorobutyl)-7-bromo-2-chloro-N-((3-fluoropyridin-4-yl)methyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0285] In analogy to the example of Compound 1, but using in step 1, 6-bromo-2-chloro-N-((3-fluoropyridin-4-yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-3), 106 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 461.10.

[0286] Compound 8.

[0287] 6-((2R,3S)-2-amino-3-fluorobutyl)-7-bromo-2-chloro-5-methyl-N-(pyrimidin-4- ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0288] In analogy to the example of Compound 1, but using in step 1, 6-bromo-2-chloro-5-methyl-N-(pyrimidin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-4), 15 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 441.05.

[0289] Compound 9.

[0290] 6-((2R,3S)-2-amino-3-fluorobutyl)-2,7-dichloro-N-((3-fluoropyridin-4-yl)methyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine - 92 -WSGR Docket No.51503-778.606

[0291] In analogy to the example of Compound 6, but using in step 1, 6-bromo-2-chloro-N-((3-fluoropyridin-4-yl)methyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-3), 86 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 415.15.

[0292] Compound 10.

[0293] 6-((2R,3S)-2-amino-3-fluorobutyl)-2,7-dichloro-5-methyl-N-(pyrimidin-4- ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0294] In analogy to the example of Compound 6, but using in step 1, 6-bromo-2-chloro-5-methyl-N-(pyrimidin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-4), 5 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 397.10.

[0295] Compound 11.

[0296] 6-((2R,3S)-2-amino-3-fluorobutyl)-7-bromo-2-chloro-N-(2-fluorobenzyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0297] In analogy to the example of Compound 1, but using in step 1, 6-bromo-2-chloro-N-(2-fluorobenzyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-5), 78 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 458.20.

[0298] Compound 12.

[0299] 6-((2R,3S)-2-amino-3-fluorobutyl)-7-bromo-2-chloro-N-((3,5-difluoropyridin-4-yl)methyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine - 93 -WSGR Docket No.51503-778.606

[0300] In analogy to the example of Compound 1, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)((3,5-difluoropyridin-4-yl)methyl)carbamate (intermediate 4-6), 35 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 477.10.

[0301] Compound 13.

[0302] 6-((2R,3S)-2-amino-3-fluorobutyl)-2,7-dichloro-N-((3,5-difluoropyridin-4-yl)methyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0303] In analogy to the example of Compound 6, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)((3,5-difluoropyridin-4-yl)methyl)carbamate (intermediate 4-6), 25 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 433.10.

[0304] Compound 14.

[0305] 6-((2R,3S)-2-amino-3-fluorobutyl)-2,7-dichloro-N-(2-fluorobenzyl)-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine

[0306] In analogy to the example of Compound 6, but using in step 1, 6-bromo-2-chloro-N-(2-fluorobenzyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-5), 32 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 414.15.

[0307] Compound 15.

[0308] 6-((2R,3S)-2-amino-3-fluorobutyl)-N-benzyl-2,7-dichloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine - 94 -WSGR Docket No.51503-778.606

[0309] In analogy to the example of Compound 6, but using in step 1, N-benzyl-6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-7), 66 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 396.10.

[0310] Compound 16.

[0311] 6-((2R,3S)-2-amino-3-fluorobutyl)-2-chloro-5,7-dimethyl-N-(thiazol-2-ylmethyl)pyrrolo[2,1- f][1,2,4]triazin-4-amine

[0312] Step 1: Into a 40mL vial were added tert-butyl (7-bromo-6-((2R,3S)-2-((tert- butoxycarbonyl)amino)-3-fluorobutyl)-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(thiazol-2- ylmethyl)carbamate (intermediate in the example of Compound 5, 210 mg, 0.324 mmol, 1.00 equiv), water (1.75 mL), trimethyl-1,3,5,2,4,6-trioxatriborinane (60.9 mg, 0.486 mmol, 1.5 equiv), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23.7 mg, 0.032 mmol, 0.1 equiv) and K2CO3(89.4 mg, 0.648 mmol, 2 equiv.) at RT. The resulting mixture was stirred overnight at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to RT and concentrated under vacuo. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 100% gradient in 18 min; detector, UV 254 nm. This resulted in tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3- fluorobutyl)-2-chloro-5,7-dimethylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(thiazol-2-ylmethyl)carbamate (110 mg, 58% yield) as a yellow solid.

[0313] Step 2: Into a 8mL vial were added tert-butyl (6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3- fluorobutyl)-2-chloro-5,7-dimethylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(thiazol-2-ylmethyl)carbamate (134 mg, 0.231 mmol, 1 equiv), DCM (1 mL) and TFA (0.5 mL) at RT. The resulting mixture was stirred for 1h at RT. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1mL) and purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in 6-((2R,3S)-2-amino-3-fluorobutyl)-2- chloro-5,7-dimethyl-N-(thiazol-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (30 mg). LC-MS-(ES, m / z): [M+H]+= 383.10. - 95 -WSGR Docket No.51503-778.606

[0314] Compound 17.

[0315] 6-((2R,3S)-2-amino-3-fluorobutyl)-N-benzyl-2-chloro-5,7-dimethylpyrrolo[2,1- f][1,2,4]triazin-4-amine

[0316] In analogy to the example of Compound 16, using tert-butyl ((2R,3S)-1-(4-(benzylamino)-7-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluorobutan-2-yl)carbamate (intermediate in the example of Compound 21), 23 mg of the title compound was obtained. LC-MS- (ES, m / z): [M+H]+= 375.15.

[0317] Compound 18.

[0318] 6-((2R,3S)-2-amino-3-fluorobutyl)-2-chloro-N-(2-fluorobenzyl)-5,7-dimethylpyrrolo[2,1- f][1,2,4]triazin-4-amine

[0319] In analogy to the example of Compound 16, using tert-butyl ((2R,3S)-1-(7-bromo-2-chloro-4-((2-fluorobenzyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluorobutan-2-yl)carbamate (intermediate in the example of Compound 11), 74 mg of the title compound was obtained. LC-MS- (ES, m / z): [M+H]+= 394.15.

[0320] Compound 19.

[0321] 6-((2R,3S)-2-amino-3-fluorobutyl)-2-chloro-5,7-dimethyl-N-(pyrimidin-4- ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0322] In analogy to the example of Compound 16, using tert-butyl ((2R,3S)-1-(7-bromo-2-chloro-5-methyl-4-((pyrimidin-4-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluorobutan-2- yl)carbamate (intermediate in the example of Compound 8), 4 mg of the title compound was obtained. LC-MS-(ES, m / z): [M+H]+= 377.95.

[0323] Compound 20. - 96 -WSGR Docket No.51503-778.606

[0324] 6-((2R,3S)-2-amino-3-fluorobutyl)-2-chloro-N-((3-fluoropyridin-4-yl)methyl)-5,7- dimethylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0325] In analogy to the example of Compound 16, using tert-butyl ((2R,3S)-1-(7-bromo-2-chloro-4-(((3-fluoropyridin-4-yl)methyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)-3-fluorobutan-2- yl)carbamate (intermediate in the example of Compound 7), 53 mg of the title compound was obtained. LC-MS-(ES, m / z): [M+H]+= 395.15.

[0326] Compound 21.

[0327] 6-((2R,3S)-2-amino-3-fluorobutyl)-N-benzyl-7-bromo-2-chloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine

[0328] In analogy to the example of Compound 1, but using in step 1, N-benzyl-6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-7), 32 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 439.05.

[0329] Compound 22.

[0330] 6-((2R,3S)-2-amino-3-fluorobutyl)-2,7-dichloro-N-(isothiazol-3-ylmethyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0331] In analogy to the example of Compound 6, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8), 20 mg of the title compound was made. LC-MS-(ES, m / z): [M+H]+= 403.05.

[0332] Compound 23.

[0333] 6-((2R,3S)-2-amino-3-fluorobutyl)-2-chloro-N-(isothiazol-3-ylmethyl)-5,7- dimethylpyrrolo[2,1-f][1,2,4]triazin-4-amine - 97 -WSGR Docket No.51503-778.606

[0334] In analogy to the example of Compound 16, using tert-butyl (7-bromo-6-((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-fluorobutyl)-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol- 3-ylmethyl)carbamate (intermediate in the example of Compound 24), 32 mg of the title compound was made. LC-MS-(ES, m / z): [M+H]+= 383.10.

[0335] Compound 24.

[0336] 6-((2R,3S)-2-amino-3-fluorobutyl)-2,7-dichloro-N-(isothiazol-3-ylmethyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0337] In analogy to the example of Compound 6, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8), 25 mg of the title compound was made. LC-MS-(ES, m / z): [M+H]+= 449.05.

[0338] Compound 25.

[0339] 6-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-N-benzyl-7-bromo-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0340] Step 1: To a stirred solution of N-benzyl-6-bromo-2-chloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine (intermediate 3-7, 5.5 g, 15.64 mmol, 1.00 equiv) and (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine (1.11 g, 7.82 mmol, 0.5 equiv) in dioxane (55 mL) were added CuI (1.49 g, 7.82 mmol, 0.5 equiv) and NaI (3.05 g, 20.33 mmol, 1.3 equiv) at RT. The resulting mixture was stirred at 100°C for 2 days under nitrogen atmosphere. The mixture was neutralized to pH 7 with NH3·H2O. The aqueous layer was extracted with EtOAc (3x100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford N-benzyl-2-chloro-6-iodo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (4.5 g, 72%) as a yellow solid. - 98 -WSGR Docket No.51503-778.606

[0341] Step 2: Into a 20 mL vial were added 5-methoxypyridine-2-carboximidamide hydrochloride (588 mg, 3.13 mmol, 0.5 equiv), dichloronickel;1,2-dimethoxyethane (689 mg, 3.13 mmol, 0.5 equiv) and DMAc (20 mL) at RT. After stirred for 15 min, the mixture was added to a stirred solution of 1,3- dioxoisoindolin-2-yl (3R,4S)-4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-3-carboxylate (intermediate (N-acyloxy)phatalimide ester 6, 3.67 g, 9.406 mmol, 1.5 equiv), Zn (3.28 g, 50.17 mmol, 8 equiv) and N-benzyl-2-chloro-6-iodo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (2.5 g, 6.27 mmol, 1 equiv) in DMAc (20 mL) and stirred at RT for 1h under nitrogen atmosphere. The reaction was quenched with Water / Ice (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 100% gradient in20 min; detector, UV 254 nm and purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl ((3R,4S)-3-(4-(benzylamino)-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)tetrahydro-2H-pyran-4-yl)carbamate (100 mg, 3%) as a yellow solid.

[0342] Step 3: To a solution of tert-butyl ((3R,4S)-3-(4-(benzylamino)-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)tetrahydro-2H-pyran-4-yl)carbamate (50 mg, 0.106 mmol, 1 equiv) in THF (2 mL) were added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (19.7 mg, 0.069 mmol, 0.65 equiv) at -68°C. After stirring for 1h at RT under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with PE / EA (5:1) to afford tert-butyl ((3R,4S)-3-(4-(benzylamino)-7-bromo-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)tetrahydro-2H-pyran-4-yl)carbamate (40 mg, 68%) as a yellow solid.

[0343] Step 4: To a stirred solution of tert-butyl ((3R,4S)-3-(4-(benzylamino)-7-bromo-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)tetrahydro-2H-pyran-4-yl)carbamate (50 mg, 0.090 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) at 0°C and stirred for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the A: Water (10mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 50 mL / min mL / min; Gradient: 30% B to 60% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 10.32) to afford 6-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-N-benzyl-7-bromo-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (25 mg, 61%). LC-MS-(ES, m / z): [M+H]+= 452.00.

[0344] Compound 26.

[0345] 6-((2R,3S)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-7-bromo-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine - 99 -WSGR Docket No.51503-778.606

[0346] In analogy to the example of Compound 25, but using in step 2 the 1,3-dioxoisoindolin-2-yl(2R,3S)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate ((N-acyloxy)phtalimide ester 1), 5 mg of the title compound was obtained. LC-MS-(ES, m / z): [M+H]+= 449.95.

[0347] Compound 27.

[0348] 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)-N-benzyl-7-bromo-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0349] In analogy to the example of Compound 25, but using in step 2 the 1,3-dioxoisoindolin-2-yl(3R,4S)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylate ((N-acyloxy)phtalimide ester 5), 23 mg of the title compound was made. LC-MS-(ES, m / z): [M+H]+= 450.06.

[0350] Compound 28.

[0351] 6-((2R,3S)-3-aminotetrahydrofuran-2-yl)-N-benzyl-7-bromo-2-chloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine

[0352] In analogy to the example of Compound 25, but using in step 2 the 1,3-dioxoisoindolin-2-yl(2S,3S)-3-((tert-butoxycarbonyl)amino)tetrahydrofuran-2-carboxylate ((N-acyloxy)phtalimide ester 2), 21 mg of the title compound was made. LC-MS-(ES, m / z): [M+H]+= 436.05.

[0353] Compound 29.

[0354] 6-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-N-benzyl-2,7-dichloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine - 100 -WSGR Docket No.51503-778.606

[0355] Step 1: To a stirred solution of N-benzyl-6-bromo-2-chloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine (intermediate 3-7, 5.5 g, 15.64 mmol, 1.00 equiv) and (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine (1.11 g, 7.82 mmol, 0.5 equiv) in dioxane (55 mL) were added CuI (1.49 g, 7.82 mmol, 0.5 equiv) and NaI (3.05 g, 20.33 mmol, 1.3 equiv) at RT. The resulting mixture was stirred at 100°C for 2 days under nitrogen atmosphere. The mixture was neutralized to pH 7 with NH3·H2O. The aqueous layer was extracted with EtOAc (3x100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford N-benzyl-2-chloro-6-iodo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (4.5 g, 72%) as a yellow solid.

[0356] Step 2: Into a 20 mL vial were added 5-methoxypyridine-2-carboximidamide hydrochloride (588 mg, 3.13 mmol, 0.5 equiv), dichloronickel;1,2-dimethoxyethane (689 mg, 3.13 mmol, 0.5 equiv) and DMAc (20 mL) at RT. After stirred for 15 min, the mixture was added to a stirred solution of 1,3- dioxoisoindolin-2-yl (3R,4S)-4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-3-carboxylate (intermediate (N-acyloxy)phatalimide ester 6, 3.67 g, 9.406 mmol, 1.5 equiv), Zn (3.28 g, 50.17 mmol, 8 equiv) and N-benzyl-2-chloro-6-iodo-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (2.5 g, 6.27 mmol, 1 equiv) in DMAc (20 mL) and stirred at RT for 1h under nitrogen atmosphere. The reaction was quenched with Water / Ice (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 100% gradient in20 min; detector, UV 254 nm and purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl ((3R,4S)-3-(4-(benzylamino)-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)tetrahydro-2H-pyran-4-yl)carbamate (100 mg, 3%) as a yellow solid.

[0357] Step 3: To a solution of tert-butyl ((3R,4S)-3-(4-(benzylamino)-2-chloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)tetrahydro-2H-pyran-4-yl)carbamate (50 mg, 0.106 mmol, 1 equiv) in THF (2 mL) were added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (14.6 mg, 0.074 mmol, 0.7 equiv) at -68°C. After stirring for 1h at RT under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with PE / EA (5:1) to afford tert-butyl ((3R,4S)-3-(4-(benzylamino)-2,7-dichloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-6-yl)tetrahydro-2H-pyran-4-yl)carbamate (20 mg, 37%) as a yellow solid. - 101 -WSGR Docket No.51503-778.606

[0358] Step 4: To a stirred solution of tert-butyl ((3R,4S)-3-(4-(benzylamino)-2,7-dichloro-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)tetrahydro-2H-pyran-4-yl)carbamate (50 mg, 0.099 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) at 0°C and stirred for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the A: Water (10mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 50 mL / min mL / min; Gradient: 30% B to 60% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 10.32) to afford 6-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-N-benzyl-2,7-dichloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine (6 mg, 14%). LC-MS-(ES, m / z): [M+H]+= 406.05.

[0359] Compound 30.

[0360] 6-((2R,3S)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-2,7-dichloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine

[0361] In analogy to the example of Compound 29, but using in step 2 the 1,3-dioxoisoindolin-2-yl(2R,3S)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate ((N-acyloxy)phtalimide ester 1), 5 mg of the title compound was obtained. LC-MS-(ES, m / z): [M+H]+= 406.05.

[0362] Compound 31.

[0363] 6-((2R,3S)-3-aminotetrahydrofuran-2-yl)-N-benzyl-2,7-dichloro-5-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine

[0364] In analogy to the example of Compound 29, but using in step 2 the 1,3-dioxoisoindolin-2-yl(2S,3S)-3-((tert-butoxycarbonyl)amino)tetrahydrofuran-2-carboxylate ((N-acyloxy)phtalimide ester 2), 18 mg of the title compound was obtained. LC-MS-(ES, m / z): [M+H]+= 392.00.

[0365] Compound 32.

[0366] (R)-6-(2-amino-4-(trifluoromethoxy)butyl)-N-benzyl-7-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine - 102 -WSGR Docket No.51503-778.606

[0367] In analogy to the example of Compound 1, but using in step 1, N-benzyl-6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-7) and potassium (R)-(2-((tert- butoxycarbonyl)amino)-4-(trifluoromethoxy)butyl)trifluoroborate (Borate salt 5), 10 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 506.05.

[0368] Compound 33.

[0369] (R)-6-(2-amino-4-(trifluoromethoxy)butyl)-N-benzyl-2,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0370] In analogy to the example of Compound 6, but using in step 1, N-benzyl-6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-7) and potassium (R)-(2-((tert- butoxycarbonyl)amino)-4-(trifluoromethoxy)butyl)trifluoroborate (Borate salt 5), 26 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 462.10.

[0371] Compound 34.

[0372] (R)-6-(2-amino-4-(difluoromethoxy)butyl)-N-benzyl-7-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0373] In analogy to the example of Compound 1, but using in step 1, N-benzyl-6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-7) and potassium (R)-(2-((tert- butoxycarbonyl)amino)-4-(difluoromethoxy)butyl)trifluoroborate (Borate salt 6), 41 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 488.06.

[0374] Compound 35.

[0375] (R)-6-(2-amino-4-(difluoromethoxy)butyl)-N-benzyl-2,7-dichloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine - 103 -WSGR Docket No.51503-778.606

[0376] In analogy to the example of Compound 6, but using in step 1, N-benzyl-6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-7) and potassium (R)-(2-((tert- butoxycarbonyl)amino)-4-(difluoromethoxy)butyl)trifluoroborate (Borate salt 6), 43 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 444.11.

[0377] Compound 36.

[0378] 6-((2R,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2,7-dichloro-N-(isothiazol-3-ylmethyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0379] In analogy to the example of Compound 29, but using in step 1, 6-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-8) and in step 2, 1,3-dioxoisoindolin-2-yl (2R,3S)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate ((N-acyloxy)phtalimide ester 1), 7 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 412.95.

[0380] Compound 37.

[0381] 6-((2R,3S)-3-aminotetrahydro-2H-pyran-2-yl)-7-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0382] In analogy to the example of Compound 25, but using in step 1, 6-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-8) and in step 2, 1,3-dioxoisoindolin-2-yl (2R,3S)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate ((N-acyloxy)phtalimide ester 1), 12 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 458.90.

[0383] Compound 38. - 104 -WSGR Docket No.51503-778.606

[0384] (R)-6-(2-amino-4,4,4-trifluorobutyl)-2,7-dichloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0385] In analogy to the example of Compound 6, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8) and potassium (R)-(2-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutyl)trifluoroborate (Borate salt 4), 4 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 439.04.

[0386] Compound 39.

[0387] (R)-6-(2-amino-4,4,4-trifluorobutyl)-7-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0388] In analogy to the example of Compound 1, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8) and potassium (R)-(2-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutyl)trifluoroborate (Borate salt 4), 30 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 482.99.

[0389] Compound 40.

[0390] (R)-6-(2-amino-4-(trifluoromethoxy)butyl)-2,7-dichloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0391] In analogy to the example of Compound 6, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8) and potassium (R)-(2-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)butyl)trifluoroborate (Borate salt 5), 29 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 469.05. - 105 -WSGR Docket No.51503-778.606

[0392] Compound 41.

[0393] (R)-6-(2-amino-4-(trifluoromethoxy)butyl)-7-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0394] In analogy to the example of Compound 1, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8) and potassium (R)-(2-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)butyl)trifluoroborate (Borate salt 5), 25 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 513.00.

[0395] Compound 42.

[0396] (R)-6-(2-amino-3-(1-fluorocyclopropyl)propyl)-2,7-dichloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0397] In analogy to the example of Compound 6, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8) and potassium (2-((tert-butoxycarbonyl)amino)-3-(1-fluorocyclopropyl)propyl)trifluoroborate (Borate salt 3), the racemic title compound was obtained.

[0398] The enantiomers were separated by chiral prep HPLC using the following conditions: 3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 30; Wave Length: 254 / 220 nm; RT1(min): 8.93; RT2(min): 10.84; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 0.5 mL; Number of runs: 8, to afford 8 mg of the title compound. LC-MS-(ES, m / z): [M+H]+= 429.08.

[0399] Compound 43.

[0400] (R)-6-(2-amino-4-(difluoromethoxy)butyl)-7-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine - 106 -WSGR Docket No.51503-778.606

[0401] In analogy to the example of Compound 1, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8) and potassium (R)-(2-((tert-butoxycarbonyl)amino)-4-(difluoromethoxy)butyl)trifluoroborate (Borate salt 6), 36 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 495.05.

[0402] Compound 44.

[0403] (R)-6-(2-amino-4-(difluoromethoxy)butyl)-2,7-dichloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0404] In analogy to the example of Compound 6, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8) and potassium (R)-(2-((tert-butoxycarbonyl)amino)-4-(difluoromethoxy)butyl)trifluoroborate (Borate salt 6), 19 mg of the title compound was prepared. LC-MS-(ES, m / z): [M+H]+= 451.10.

[0405] Compound 45.

[0406] 6-((1R,2S)-2-amino-4,4-difluorocyclohexyl)-7-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0407] In analogy to the example of Compound 25, but using in step 1, 6-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-8) and in step 2, 1,3-dioxoisoindolin-2-yl (1SR,2SR)-2-((tert-butoxycarbonyl)amino)-4,4-difluorocyclohexane-1- carboxylate ((N-acyloxy)phtalimide ester 3), the racemic title compound was obtained.

[0408] The enantiomers were separated by chiral prep HPLC using the following conditions: 3-MeOH), Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 30; Wave Length: 255 / 285 nm; RT1(min): - 107 -WSGR Docket No.51503-778.606 9.93; RT2(min): 15.82; Sample Solvent: ETOH; Injection Volume: 1 mL; Number of runs: 2), to afford 20 mg of the title compound. LC-MS-(ES, m / z): [M+H]+= 492.90.

[0409] Compound 46.

[0410] 6-((1R,2S)-2-amino-4,4-difluorocyclohexyl)-2,7-dichloro-N-(isothiazol-3-ylmethyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0411] In analogy to the example of Compound 29, but using in step 1, 6-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-8) and in step 2, 1,3-dioxoisoindolin-2-yl (1SR,2SR)-2-((tert-butoxycarbonyl)amino)-4,4-difluorocyclohexane-1- carboxylate ((N-acyloxy)phtalimide ester 3), the racemic title compound was obtained.

[0412] The enantiomers were separated by chiral prep HPLC using the following conditions: 3-MeOH), Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 30; Wave Length: 255 / 285 nm; RT1(min): 9.85; RT2(min): 15.96; Sample Solvent: ETOH; Injection Volume: 1 mL; Number of runs: 2), to afford 15 mg of the title compound. LC-MS-(ES, m / z): [M+H]+= 446.95.

[0413] Compound 47.

[0414] 6-((1R,6S)-6-amino-4-fluorocyclohex-3-en-1-yl)-7-bromo-2-chloro-N-(isothiazol-3- ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0415] In analogy to the example of Compound 25, but using in step 1, 6-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-8) and in step 2, 1,3-dioxoisoindolin-2-yl (1RS,6SR)-6-((tert-butoxycarbonyl)amino)-4-fluorocyclohex-3-ene-1- carboxylate ((N-acyloxy)phtalimide ester 4), the racemic title compound was obtained.

[0416] The enantiomers were separated by chiral prep HPLC using the following conditions: 3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 30; Wave Length: 258 / 284 nm; RT1(min): 10.037; RT2(min): 13.542; Sample Solvent: MEOH: DCM=1: 1; Injection Volume: 0.8 mL; Number of runs: 8), to afford 10 mg of the title compound. LC-MS-(ES, m / z): [M+H]+= 473.00. - 108 -WSGR Docket No.51503-778.606

[0417] Compound 48.

[0418] 6-((1R,6S)-6-amino-4-fluorocyclohex-3-en-1-yl)-2,7-dichloro-N-(isothiazol-3-ylmethyl)-5- methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0419] In analogy to the example of Compound 29, but using in step 1, 6-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate 3-8) and in step 2, 1,3-dioxoisoindolin-2-yl (1RS,6SR)-6-((tert-butoxycarbonyl)amino)-4-fluorocyclohex-3-ene-1- carboxylate ((N-acyloxy)phtalimide ester 4), the racemic title compound was obtained.

[0420] The enantiomers were separated by chiral prep HPLC using the following conditions: 3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 20; Wave Length: 254 / 220 nm; RT1(min): 13.981; RT2(min): 17.968; Sample Solvent: MEOH: DCM=1: 1; Injection Volume: 1.2 mL; Number of runs: 5), to afford 11 mg of the title compound. LC-MS-(ES, m / z): [M+H]+= 427.10.

[0421] Compound 49.

[0422] (R)-6-(2-amino-3-(1-fluorocyclopropyl)propyl)-7-bromo-2-chloro-N-(isothiazol-3-ylmethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

[0423] In analogy to the example of Compound 1, but using in step 1, tert-butyl (6-bromo-2-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)(isothiazol-3-ylmethyl)carbamate (intermediate 4-8) and potassium (2-((tert-butoxycarbonyl)amino)-3-(1-fluorocyclopropyl)propyl)trifluoroborate (Borate salt 3), the racemic title compound was obtained.

[0424] The enantiomers were separated by chiral prep HPLC using the following conditions: 3-MeOH), Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 30; Wave Length: 256 / 205 nm; RT1(min): 14.819; RT2(min): 26.305; Sample Solvent: ETOH: DCM=1: 1; Injection Volume: 1 mL; Number of runs: 2., to afford 9 mg of the title compound. LC-MS-(ES, m / z): [M+H]+= 473.02.

[0425] Example B: ATXN3 Quantitative Splicing Assay.- 109 -WSGR Docket No.51503-778.606

[0426] Human neuroblastoma SK-N-MC cells were plated in 384-well plates at 20,000 cells / well. Twenty-four hours after plating, cells were treated with compounds for 24 h at appropriate concentrations ranging from 30 µM to 0.6 nM (0.3% DMSO). Treated cells were lysed in 15 µL of lysis buffer, and cDNA was synthesized using the Fast Advanced Cells-to-Ct kit. Two µL of each cDNA was used in qPCR reactions to confirm the exon 4 skipped transcripts of ATXN3. A second set of primers / probe E4E5 was used to detect the transcripts containing exon 4. The third set of primers / probe E8E9 was used to detect total gene level of ATXN3. The qPCR reactions wereprepared in 384-well plates in 10 µL volume, using TaqMan Fast Advanced Master Mix withprimers and probes shown in the table below. Reactions were run in a Quant Studio 6 qPCR instrument with default settings.

[0427] The primers and probes are listed below in Table 3.Table 3.

[0428] Results are shown below in Table 4.Table 4 * IC50 / EC50- 110 -WSGR Docket No.51503-778.606

[0429] Example C. Efflux ratio determination in MDCK-MDR1 cells (P-gp efflux ratio)

[0430] L of cell culture medium were added to each well of a 96-well HTS Transwellplate insert and reservoir, respectively. Subsequently the transwell plates were incubated at 37°C, 5% CO25cells / mL (NIH) with Transwell plate. Cells were cultivated for 4-8 days in a cell culture incubator at 37°C, 5% CO2, 95% - 111 -WSGR Docket No.51503-778.606 relative humidity. Cell culture medium was replaced every other day, beginning no later than 24 hours after initial plating.

[0431] 10 mM stock solutions of test compounds were prepared in DMSO. The stock solutions of positive controls were prepared in DMSO at the concentration of 10 mM. Propranolol and digoxin were used as control compounds in this assay.

[0432] Medium was removed from the reservoir and each Transwell insert and replaced with prewarmed fresh culture medium. Transepithelial electrical resistance (TEER) across the monolayer was measured using Millicell Epithelial Volt-Ohm measuring system (Millipore, USA). The Plate was returned to the incubator once the measurement was done. The TEER value was calculated according to the following equation: TEER measurement (ohms) x Area of membrane (cm2) = TEER value (ohm•cm2) TEER value should be greater than 42 ohm•cm2, which indicates the well-qualified MDCK-MDR1 monolayer.

[0433] The MDCK-MDR1 plate was removed from the incubator and washed twice with pre- warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37°C for 30 minutes. The stock solution of the control compounds were diluted in DMSO to get 1 mM solutions and then diluted with the incubation system was 0.5%.

[0434] alprazolam, 200 nM caffeine, 200 nM labetalol and 100 nM tolbutamide) in a new 96-well plate as the in the same plate for matrix equivalent and vortexed at 1000 rpm for 10 minutes. Wells in the receiver serum albumin.

[0435] (100 nM alprazolam, 200 nM caffeine, 200 nM labetalol and 100 nM tolbutamide) in a new 96-well albumin was added in the same plate for matrix equivalent and vortexed at 1000 rpm for 10 minutes.

[0436] containing 1% bovine serum albumin. The apical to basolateral direction and the basolateral to apical direction need to be assayed at the same time. The plates were incubated at 37 °C for 2 hours. At the - 112 -WSGR Docket No.51503-778.606 nM alprazolam, 200 nM caffeine, 200 nM labetalol and 100 nM tolbutamide) in a new 96-well plate containing IS (100 nM alprazolam, 200 nM caffeine, 200 nM labetalol and 100 nM tolbutamide) in a for matrix equivilant. Samples were vortexed for 10 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 µL of the supernatant was mixed with an appropriate volume of ultra-pure water before LC-MS / MS analysis.

[0437] To determine the lucifer yellow leakage after 2-hour transport period, stock solution of Lucifer yellow was prepared in DMSO and diluted with HBSS (10 mM HEPES, 15 mM glucose, pH each Transwell insert (apical compartment), followed by filling the wells in the receiver plate basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates. The lucifer yellow fluorescence (to monitor monolayer integrity) signal was measured in a fluorescence plate reader at 480 nM excitation and 530 nM emission.

[0438] Apparent permeability (Papp) can be calculated for drug transport assays using the following equation:Where: Papp is apparent permeability (cm / s x 10-6) VA is the volume (in mL) in the acceptor well Area is the surface area of the membrane (0.143 cm2for Transwell-96 Well Permeable Supports) time is the total transport time in seconds. Efflux ratio can be determined using the following equation:- 113 -WSGR Docket No.51503-778.606

[0439] Where Papp (B-A) indicates the apparent permeability coefficient in basolateral to apical direction, and Papp (A-B) indicates the apparent permeability coefficient in apical to basolateral direction.

[0440] Mass balance (% recovery) can be determined using the following equation:

[0441]

[0442] Lucifer yellow leakage of monolayer can be calculated using the following equation:

[0443] Where Iacceptor is the fluorescence intensity in the acceptor well (0.3 mL), and Idonor is the fluorescence intensity in the donor well (0.1 mL) and expressed as % leakage. Lucifer yellow percentage amount transported values should be less than 1.5 %. However, if the Papp determined in that transwell is qualitatively similar to that determined in the replicate transwells, based upon the scientific judgement of the responsible scientist, then the monolayer is considered acceptable.

[0444] Results are shown below in Table 5.Table 5- 114 -WSGR Docket No.51503-778.606- 115 -WSGR Docket No.51503-778.606- 116 -WSGR Docket No.51503-778.606- 117 -WSGR Docket No.51503-778.606- 118 -WSGR Docket No.51503-778.606- 119 -WSGR Docket No.51503-778.606- 120 -

Claims

WSGR Docket No.51503-778.606 CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I) wherein, - R21is 5 membered heteroaryl, provided that the 5 membered heteroaryl is not thiophenyl or furanyl, wherein the 5 membered heteroaryl is unsubstituted or substituted with 1, 2, or 3, independently selected R1Agroups; each R1Ais independently selected from halo, CN, NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, -C(=O)OH, -C(=O)C1-6alkyl, - C(=O)C1-6haloalkyl, and -C(=O)C1-6alkoxy; or, - R21is phenyl or 6 membered heteroaryl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R1Agroups; each R1Ais independently selected from halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, -C(=O)OH, -C(=O)C1- 6 alkyl, -C(=O)C1-6 haloalkyl, and -C(=O)C1-6 alkoxy; - R22is selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, wherein the C1-6 alkyl and C1-6 alkoxy are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - R23is selected from the group consisting of H, azido, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 heteroalkyl, -(C1-6 alkylene)-C3-10 cycloalkyl, -(C1-6 alkylene)-4-10 membered heterocycloalkyl, -(C1-6 heteroalkylene)-C3-10 cycloalkyl, -(C1-6 heteroalkylene)-4-10 membered heterocycloalkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, ORa3, SRa3, C(=O)Rb3, C(=O)ORb3, NRc3Rd3, C(=O)NRc3Rd3, - OC(=O)NRc3Rd3, NRc3C(=O)Rb3, NRc3C(=O)ORb3, NRc3C(=O)NRc3Rd3, NRc3S(=O)2Rb3, NRc3S(=O)2NRc3Rd3, S(O)NRc3Rd3, and S(O)2NRc3Rd3, wherein the C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 heteroalkyl, C1-6 alkylene, C1-6 heteroalkylene, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R20groups; - 121 -WSGR Docket No.51503-778.606 - R24is selected from the group consisting of H, azido, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa4, C(=O)Rb4, C(=O)ORb4, NRc4Rd4, C(=O)NRc4Rd4, - OC(=O)NRc4Rd4, NRc4C(=O)Rb4, NRc4C(=O)ORb4, NRc4C(=O)NRc4Rd4, NRc4S(=O)2Rb4, NRc4S(=O)2NRc4Rd4, S(O)NRc4Rd4, and S(O)2NRc4Rd4, wherein the C1-6alkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; - each Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4is independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkoxy, - (C1-6alkylene)-C1-6alkoxy, C3-10cycloalkyl, -(C1-6alkylene)-C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -(C1-6alkylene)-C3-10cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; or Rc3and Rd3together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; or Rc4and Rd4together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, or 4 independently selected R20groups; and - each R20is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1- 4 alkoxy, -(C1-4 alkyl)-(C1-4 alkoxy), -(C1-4 alkoxy)-(C1-4 alkoxy), C1-4 haloalkoxy, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, amino, C1- 4 alkylamino, di(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carbamoyl, C1-4 alkylcarbamoyl, di(C1-4 alkyl)carbamoyl, C1-4 alkylcarbonyl, C1- 4 alkoxycarbonyl, C1-4 alkylcarbonylamino, C1-4 alkylsulfonylamino, aminosulfonyl, C1- 4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1- 4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1- 4 alkylaminocarbonylamino, di(C1-4 alkyl)aminocarbonylamino, and amidinyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, whereinwherein represents a single or a double bond; each of A1, A2, A3, and A5 is independentlyselected from the group consisting of O, S, N, NH, NR1A, CH, and CR1A; and A4 is N or C; - 122 -WSGR Docket No.51503-778.606 provided that R21is not thiophenyl or furanyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R21 is4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R1A isindependently selected from C1-6 alkyl, C1-6 haloalkyl, and halo.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1A isfluoro.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R21unsubstituted or substituted pyridine, or unsubstituted or substituted pyrimidine.

7. The compound of claim 1 or 6, or a pharmaceutically acceptable salt thereof, wherein R21 isselected from the group consisting<img src='' class="img-anchor img-center" img-id="IMGF000124_0002" / >8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, whereinR23is substituted or unsubstituted C1-6alkyl or substituted or unsubstituted C1-6heteroalkyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R23 is C1-6 alkyl,which is substituted with 1, 2, 3, or 4 independently selected R20groups.

10. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, whereinR23is -(C1-6alkylene)-C3-10cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups.

11. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, whereinR23is -(C1-6alkylene)-C3-6cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups.

12. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, whereinR23is C3-10cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R23 is C5-6cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups. - 123 -WSGR Docket No.51503-778.60614. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, whereinR23is 4-10 membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R23 is 5-6membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R20groups.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, whereinR24is selected from the group consisting of fluoro, chloro, and bromo.

17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, whereinR24is selected from the group consisting of H, halo, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R20groups.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, whereinR22is selected from the group consisting of C1-6alkyl and C1-6alkoxy.

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, whereinR22is selected from the group consisting of C1-4alkyl and C1-4alkoxy.

20. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, whereinR22is selected from the group consisting of C1-2alkyl and C1-2alkoxy.

21. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, whereinR22is selected from the group consisting of -CH3and -OCH3.

22. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, whereinR22is -CH3.

23. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, whereinR22is -OCH3.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, whereineach R20is independently selected from the group consisting of OH, halo, C1-4 alkyl, C1- 4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and amino.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, whereineach R20is independently selected from the group consisting of halo, C1-4 haloalkoxy, and amino.

26. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound isselected from Table 1.

27. A pharmaceutical composition comprising a compound of any one of the preceding claims, or apharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. - 124 -WSGR Docket No.51503-778.60628. A method of treating, preventing, delaying of progress, or ameliorating symptoms of a disease ora condition associated with ATXN3 expression level or activity level in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or salt of any one of claims 1-26.

29. A method of modulating splicing of a ATXN3 pre-mRNA, comprising contacting a compound orsalt of any one of claims 1-26 to the ATXN3 pre-mRNA with a splice site sequence or cells comprising the ATXN3 pre-mRNA, wherein the compound binds to the ATXN3 pre-mRNA and modulates splicing of the ATXN3 pre-mRNA in a cell of a subject to produce a spliced product of the ATXN3 pre-mRNA.

30. Use of a compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for the treatment of a condition or disease associated with ATXN3 expression level or activity level. - 125 -

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