RNA degrading agents and uses thereof

Abstract

The present invention includes compounds and compositions, and methods of use thereof, for regulating RNA transcripts, or precursors, isoforms, fragments, or variants thereof, by degradation of the RNA transcript through recruitment or binding of one or more degradation factors (e.g., RNA-binding proteins). The present invention provides a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein the RNA binder is a moiety that binds to a target RNA transcript, the DFL is a degradation factor-recruiting ligand, and L1 is a bivalent linker group that covalently links the RNA binder to the DFL, and the DFL binds to or recruits a degradation factor.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 589,907, filed October 12, 2023, U.S. Provisional Patent Application No. 63 / 499,879, filed May 3, 2023, U.S. Provisional Patent Application No. 63 / 489,644, filed March 10, 2023, and U.S. Provisional Patent Application No. 63 / 384,839, filed November 23, 2022, the entire contents of each of which are incorporated herein by reference.

[0002] The present invention relates to compounds and methods of use for modulating the activity of RNA transcripts, as well as their isoforms, variants, and fragments, through modulating their degradation and / or otherwise modulating their activity. The present invention also provides methods for treating various diseases and conditions mediated by target RNA transcripts, such as those described in this disclosure.

[0003] (Sequence Listing) This application contains a Sequence Listing, which has been submitted via EFS in .xml format and is incorporated herein by reference. The ST.26 copy, created on October 26, 2023, is named 394457-013WO_SL.SIP and is 89,934 bytes in size. [Background technology]

[0004] Both coding and messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs) play numerous important regulatory roles in cells. The sum of all RNAs transcribed from DNA (both coding and noncoding) comprises the transcriptome, and all cell biology originates from the transcriptome. All endogenous mammalian diseases ultimately originate from or are regulated by the transcriptome, either directly by RNA or through expressed proteins. Therefore, there is the potential to intervene in all human diseases, whether protein-mediated or RNA-mediated, by modulating the translation or regulatory function of the corresponding mRNA or ncRNA.

[0005] RNA quality control (QC) mechanisms are diverse and ubiquitous. After transcription, RNA must undergo processing to produce its active form. RNA processing includes various endonucleolytic and exonucleolytic cleavage of sequences at either end of the initial transcript, cleavage of internal sequences (e.g., internal transcribed spacers and introns), nucleotide editing, and various types of functionalization via chemical modification. In particular, most cellular RNAs undergo multiple processing reactions with alternative pathways (e.g., alternative splicing) that result in different products. Multiple RNAs from otherwise similar or identical RNA primary transcripts result in increased functional diversity of RNA and protein species encoded by individual genes.

[0006] mRNA decay is a process that leads to the programmed degradation of mRNA. This process is enabled by the association of mRNA with specific RNA-binding proteins (RBPs). Therefore, mRNA degradation can directly affect the steady-state level of the translatable pool of mRNA in vivo. Eukaryotic mRNA degradation occurs primarily through the enzymatic removal of nucleotides in the 5'-3' direction and is catalyzed by Xrn1. mRNAs are also degraded in the 3'-5' direction by multisubunit protein complexes called exosomes, the catalytic subunit of which is Rrp44. The contribution of 3'-5' degradation to overall mRNA turnover is higher in metazoans compared to low levels in eukaryotes.

[0007] Although RNA QC machinery typically operates to eliminate incorrectly or incompletely processed RNA, harnessing the normal activity of these nucleases and QC pathways to selectively degrade (or not degrade) disease-causing (or disease-treating) RNA targets would lead to novel and novel approaches to treating a variety of diseases.

[0008] Therefore, there is a broad need for agents that selectively inhibit or eliminate target RNA. The present invention achieves this by using bifunctional or chimeric molecules and compositions that (i) bind to target RNA transcripts and (ii) recruit degradation factors, such as RNA-binding proteins (RBPs), that activate the RNA degradation machinery to degrade the target RNA or otherwise interfere with the function of the target RNA (e.g., the availability of RNA for translation into active protein). The compounds of the present invention and their pharmaceutically acceptable compositions meet these requirements and provide other related benefits as described herein. Summary of the Invention [Means for solving the problem]

[0009] In one aspect, the present invention provides a compound of formula B: [ka] or a pharmaceutically acceptable salt thereof, wherein: The RNA binder is a moiety that binds to a target RNA transcript, DFL is a degrader-recruiting ligand; L 1 is a bivalent linker group covalently linking said RNA binder to said DFL; The DFL is provided as a compound or a pharmaceutically acceptable salt thereof that binds to or recruits a degrading factor.

[0010] In some embodiments, the RNA binder is an oligonucleotide, a polypeptide, or an RNA-binding small molecule (rSM). In some embodiments, the RNA binder is an oligonucleotide. In some embodiments, the RNA binder is an rSM.

[0011] More specifically, in one aspect, the present invention provides two compounds of formula A: [ka] or a pharmaceutically acceptable salt thereof, wherein: rSM is an RNA-binding small molecule that binds to a target RNA transcript; DFL is a degrader-recruiting ligand; L 1 is a divalent linker group covalently linking the rSM to the DFL; The DFL is provided as a compound or a pharmaceutically acceptable salt thereof that binds to or recruits a degrading factor.

[0012] In some embodiments, [ka] is a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B [ka] and Y is N or CH; Z 1 is N, C=O or CR 2 and Z 2 is N, C=O, or CR 3 However, Z 1 and Z 2 are not both N or C=O, Each R 1 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - and R 2 and R 3 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - or R 2 and R 3 are m R's along with the carbons to which they are attached. 5and the ring is a 4-8 membered saturated or partially unsaturated monocyclic carbocycle, an 8-10 membered bicyclic aromatic carbocycle having 1-2 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from oxygen, sulfur, or nitrogen, oxygen, and sulfur; Each R 4 are independently -R, halogen, =O, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; Each R 5 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; -L 2 -teeth, [ka] wherein -X- is covalently bonded to ring B and -X- is NR 6 , -O-, -CR 6 R 7 - or -S-, and -C(R 8 )2- or -C(R 10)2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 6 and R 7 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R), or -SR; Each R 8 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R or -L 1 - and R 9 is -R and is halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R)2, or -SR, or R 8 and R 9 together with the atoms to which they are attached, m R 5 and the ring is a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and each R 10 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; or R 8 and R10 or R 9 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 6-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -L 1 - is a covalent bond or C 1-8 a divalent straight or branched hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-; 1 , R 2 , R 3 , or R 8 One and only one of -L 1 - and -L 1 - one end of which is covalently linked to rSM, each -Cy- is an optionally substituted 3- to 8-membered saturated or partially unsaturated divalent monocyclic carbocycle, an optionally substituted phenylene, an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic or bridged bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; q is 0, 1, 2, 3, or 4; and r is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, ring A is [ka] is selected from.

[0014] In some embodiments, ring B is [ka] is.

[0015] In some embodiments, R 1 -L 1 -It is.

[0016] In some embodiments, R 2 -L 1 -It is.

[0017] In some embodiments, R 3 -L1 -It is.

[0018] In some embodiments, R 4 are H, =O, Me, Et, iPr, [ka] is selected from.

[0019] In some embodiments, R 8 -L 1 -It is.

[0020] In some embodiments, -L 2 -teeth, [ka] is selected from.

[0021] In some embodiments, the compound is a compound of formula II-a or II-b: [ka] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound is a compound of formula IIIa: [ka] or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the compound has formula IV-a [ka] or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, [ka] is a compound of formula Ic: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 12-membered bicyclic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered tricyclic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is [ka] and Y is N or CH; Z 1 is N, C=O or CR 2 and Z 2 is N, C=O, or CR 3 However, Z 1 and Z 2 are not both N or C=O, Each R 1 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - and R 2 and R 3are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - or R 2 and R 3 are m R's along with the carbons to which they are attached. 5 and the ring is a 4- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 4 are independently -R, halogen, =O, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R or a divalent straight or branched chain C 1-8 a hydrocarbon chain wherein 1, 2, 3, or 4 methylene units of said chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO2-; Each R 5are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; -L 2 -teeth, [ka] wherein -X- is covalently bonded to ring B and -X- is NR 6 , -O-, -CR 6 R 7 -, -C(O)-, -S- or S(O)2-, and -C(R 8 )2- or -C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 6 and R 7 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R), or -SR; Each R 8 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - or two R's 8form, together with the carbon atoms to which they are attached, a 3- to 6-membered carbocyclic ring, R 9 is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R)2, or -SR, or R 8 and R 9 are m R's along with the atoms to which they are attached. 5 and forming a ring substituted with a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 10 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R, or two R 10 together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic ring, or R 9 and R 10 are m R's along with the atoms to which they are attached. 5 wherein the ring is a 6-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -L 1- is a bivalent linker group that covalently attaches the RNA binder to the DFL, where R 1 , R 2 , R 3 , R 8 , or R 11 One and only one of -L 1 - and -L 1 - one end of which is covalently attached to an RNA binder, each -Cy- is an optionally substituted 3- to 8-membered saturated or partially unsaturated divalent monocyclic carbocycle, an optionally substituted phenylene, an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic or bridged bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 11 is H, C 1-3 Alkyl, or -L 1 - and m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4.

[0025] In some embodiments, ring A is [ka] is selected from.

[0026] In some embodiments, ring B is [ka] is.

[0027] In some embodiments, R 1 -L 1 -It is.

[0028] In some embodiments, R 2 -L 1 -It is.

[0029] In some embodiments, R 3 -L 1 -It is.

[0030] In some embodiments, R 4 are H, =O, Me, Et, iPr, [ka] is selected from.

[0031] In some embodiments, R 8 -L 1 -It is.

[0032] In some embodiments, R 11 is H, C 1-3 Alkyl, or -L 1 -It is.

[0033] In some embodiments, -L 2 -teeth, [ka] [ka] is.

[0034] In some embodiments, the compound is a compound of formula IX-a, IX-b, IX-c, XVI-a, XVI-b, or XVI-c: [ka] or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the compound is a compound of formula Xa, Xb, Xc, XVII-a, XVII-b, or XVII-c: [ka] or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the compound is a compound of formula XI-a, XI-b, XI-c, XVIII-a, XVIII-b, or XVIII-c: [ka] or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the compound is a compound of formula XII-a, XII-b, XII-c, XIX-a, XIX-b, or XIX-c: [ka] or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the compound is a compound of formula XIII-a, XIII-b, XIII-c, XX-a, XX-b, or XX-c: [ka] or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the compound is a compound of formula XIV-a, XIV-b, XIV-c, XXI-a, XXI-b, or XXI-c: [ka] or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the compound is a compound of formula XV-a or XXII-a: [ka] or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the compound is a compound of Formula XXIII-a, Formula XXIII-b, or Formula XXIII-c: [ka] or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the compound is a compound of formula XXIII-d, formula XXIII-e, or formula XXIII-f: [ka] or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the compound is a compound of formula XXIV-a: [ka] or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the compound is a compound of formula XXIV: [ka] or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the compound is a compound of formula XXV-a: [ka] or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the compound is a compound of formula XXV-b: [ka] or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the degradation factor is a protein that binds to or interacts with RNA (RBP), and the interaction of the RBP with the RNA results in the modulation of the target RNA transcript in vivo.

[0048] In some embodiments, the RBP is part of a CCR4-NOT (carbon catabolite repression negative in the absence of TATA) complex.

[0049] In some embodiments, the RBP is CNOT7.

[0050] In some embodiments, the DFL does not bind to the active site of CNOT7.

[0051] In some embodiments, the DFL binds to CNOT7 without inhibiting the enzymatic activity of CNOT7 and / or the CCR4-NOT complex.

[0052] In some embodiments, the target RNA transcript is an mRNA or a precursor, isoform, unspliced ​​isoform, splice intermediate, fragment, or variant thereof.

[0053] In some embodiments, the target RNA transcript is selected from any one of Table C or Table D below, or a precursor, isoform, unspliced ​​isoform, splice intermediate, fragment, or variant thereof.

[0054] In some embodiments, the rSM is selected from any one of those described in the section entitled Exemplary rSMs.

[0055] In some embodiments, the rSM is one listed in Table 2.

[0056] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0057] In another aspect, the present invention provides a method of modifying the amount of a protein in a cell, the method comprising administering a compound or composition as described herein, or a pharmaceutically acceptable salt thereof, that acts on a target RNA transcript or a precursor, isoform, fragment, or variant thereof, in an amount sufficient to modify the amount of the protein in the cell.

[0058] In some embodiments, modifying the amount of a protein in the cell reduces the amount of the protein in the cell.

[0059] In another aspect, the present invention provides a method for modulating the availability of a target RNA transcript or an isoform, fragment, or variant thereof for protein translation, the method comprising contacting said target RNA transcript, or a precursor, isoform, fragment, or variant thereof, with said compound or composition, or a pharmaceutically acceptable salt thereof, that binds to said target RNA transcript, or an isoform, fragment, or variant thereof.

[0060] Another aspect of the present invention provides a method of modulating translation of a target protein or precursor thereof, comprising contacting a target RNA transcript or precursor, isoform, fragment, or variant thereof with said compound, or composition, or a pharmaceutically acceptable salt thereof, as described herein.

[0061] Another aspect of the invention provides a method of decreasing the half-life or increasing the degradation of a target RNA transcript or precursor, isoform, fragment, or variant thereof, the method comprising contacting the target RNA transcript or precursor, isoform, fragment, or variant thereof with a compound or composition described herein, or a pharmaceutically acceptable salt thereof.

[0062] Another aspect of the present invention provides a method of treating a disease, the method comprising administering to a subject in need thereof a compound or composition described herein, or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the disease is characterized by abnormal levels of a protein in cells.

[0064] In some embodiments, the disease is one listed in Table C or D.

[0065] In some embodiments, the disease is cancer.

[0066] In some embodiments, the RBP is CNOT7. [Brief explanation of the drawings]

[0067] [Figure 1] Figure 1 shows a schematic diagram of the CCR4-NOT complex, the primary mediator of death.

[0068] [Figure 2] Figure 2 shows an exemplary compound docked to the CNOT7 protein. An exit vector is shown to allow for the attachment of a linker.

[0069] [Figure 3] FIG. 3 shows the binding of compound I-1 to CNOT7 as determined by SPR.

[0070] [Figure 4] FIG. 4 shows the binding of selected compounds to CNOT7 as determined by SPR.

[0071] [Figure 5] Figure 5 provides a schematic diagram of a surface plasmon resonance (SPR) experiment to examine whether CNOT7-binding compounds bind to the active site of CNOT7.

[0072] [Figure 6] FIG. 6 shows exemplary results of an AMP competition assay by SPR to investigate CNOT7 binding properties.

[0073] [Figure 7] FIG. 7 shows exemplary results of an AMP competition assay by SPR to investigate CNOT7 binding properties.

[0074] [Figure 8] FIG. 8 shows RNA degradation by CNOT7 and CNOT7 mutant proteins.

[0075] [Figure 9] Figure 9 shows a schematic of a biochemical assay for evaluating bifunctional degraders, including SEQ ID NO:40.

[0076] [Figure 10] FIG. 10 shows the increased degradation of RNA by the action of bifunctional degrading agents.

[0077] [Figure 11] FIG. 11 shows that CNOT7 binders do not interfere with CNOT7 function.

[0078] [Figure 12] FIG. 12 shows a schematic diagram of the reporter construct for the cellular bifunctional degradation assay.

[0079] [Figure 13] FIG. 13 shows a schematic of a cellular assay for evaluating bifunctional degraders.

[0080] [Figure 14] FIG. 14 shows intracellular degradation of RNA by the action of CNOT7.

[0081] [Figure 15]FIG. 15 shows a schematic of a cellular assay for evaluating bifunctional degraders for degradation of endogenous proteins.

[0082] [Figure 16] FIG. 16 shows the degradation of endogenous RNA by the action of CNOT7.

[0083] [Figure 17] FIG. 17 shows the structures of I-329 and I-371.

[0084] [Figure 18] FIG. 18 shows heterobifunctional molecules that can promote the degradation of RNA by CNOT7.

[0085] [Figure 19A] Figure 19A shows heterobifunctional molecules that can promote the degradation of RNA by CNOT7. Figure 19B shows heterobifunctional molecules that can promote the degradation of RNA by CNOT7. [Figure 19B] Figure 19A shows heterobifunctional molecules that can promote the degradation of RNA by CNOT7. Figure 19B shows heterobifunctional molecules that can promote the degradation of RNA by CNOT7.

[0086] [Figure 20] FIG. 20 shows additional biochemical degrader data for compounds I-371 and I-397.

[0087] [Figure 21A] Figures 21A and 21B show the results of a CNOT7 inhibition assay. Two of the three CNOT7 binding moieties (i.e., baits) evaluated slightly inhibited CNOT7 activity (I-243 and I-330), while the CNOT7 binding moiety I-198 did not inhibit CNOT7 activity. [Figure 21B]Figures 21A and 21B show the results of a CNOT7 inhibition assay. Two of the three CNOT7 binding moieties (i.e., baits) evaluated slightly inhibited CNOT7 activity (I-243 and I-330), while the CNOT7 binding moiety I-198 did not inhibit CNOT7 activity.

[0088] [Figure 22] Figure 22 shows the results of the CNOT7:CNOT1 recombinant assay. The data indicate that neither the CNOT7 binding moieties (i.e., baits) evaluated nor the three C CNOT7 heterobifunctional CNOT7 binding moieties linked to rSM (I-317, I-496, and ARK I-397) inhibited or enhanced the killing activity of the CNOT7:CNOT1 complex. As expected, the known CNOT7 active site binder Compound A (see Figure 11) was able to inhibit CNOT7 activity. Note that the CCR4NOT complex contains proteins other than CNOT7 that have killing activity, such as CNOT6.

[0089] [Figure 23A] Figures 23A and 23B show the results of a biochemical AMP-Glo ​​assay to measure killing. The data show that, as expected, AMP increased over the time course in all heterobifunctional compound conditions, with more AMP produced in response to the heterobifunctional compound compared to the DMSO background. [Figure 23B] Figures 23A and 23B show the results of a biochemical AMP-Glo ​​assay to measure killing. The data show that, as expected, AMP increased over the time course in all heterobifunctional compound conditions, with more AMP produced in response to the heterobifunctional compound compared to the DMSO background.

[0090] [Figure 24] FIG. 24 shows the results of a stable CNOT7 cell line assay (see Example 23).

[0091] [Figure 25] FIG. 25 shows the results of a PC9 HiBiT cell line assay (see Example 24). DETAILED DESCRIPTION OF THE INVENTION

[0092] 1. General Description, Definitions of Certain Embodiments of the Invention In one aspect, the present invention provides a bifunctional compound of formula B: [ka] or a pharmaceutically acceptable salt thereof, wherein: The RNA binder is a moiety that binds to a target RNA transcript, DFL is a degrader-recruiting ligand; -L 1 - is a bivalent linker group covalently linking said RNA binder to said DFL, the DFL is a compound that binds to or recruits a degradation factor; The DFL binds to or recruits one or more degradation factors that degrade the target RNA transcript.

[0093] In some embodiments, the RNA binder is an oligonucleotide, peptide, oligosaccharide, or RNA-binding small molecule (rSM). In some embodiments, the RNA binder is an oligonucleotide. In some embodiments, the RNA binder is an rSM. In some embodiments, the DFL binds to an RBP. In some embodiments, the present invention provides bifunctional compositions comprising an RNA binder and a DFL useful as a regulator of targeted degradation of various target RNA transcripts, which are then degraded and / or otherwise inhibited by the bifunctional compositions described herein. An advantage of the compositions provided in the present disclosure is that they are capable of a wide range of pharmacological activity consistent with the degradation / inhibition of target RNA transcripts from virtually any RNA class or family.

[0094] In some embodiments, the composition comprises an RNA binder such as an oligonucleotide, and the composition binds to RNA via the oligonucleotide.The oligonucleotide that binds to RNA is well known.Generally, the oligonucleotide that binds to target RNA has a nucleic acid sequence that is complementary to the nucleic acid sequence in target RNA.The binding of the oligonucleotide that has a complementary sequence to the target RNA sequence is stable and highly specific.In some embodiments, the composition that comprises an RNA binder such as an oligonucleotide is optimized for intracellular delivery.The optimization of oligonucleotide and the composition that comprises oligonucleotide for intracellular delivery has been well established.

[0095] In some embodiments, the composition comprises an RNA binder. In some embodiments, the RNA binder is an oligonucleotide. In some embodiments, the oligonucleotide can specifically bind to an RNA target. In some embodiments, the oligonucleotide comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more nucleotides. In some embodiments, the oligonucleotide consists of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more nucleotides. In some embodiments, the oligonucleotide is modified for therapeutic delivery.

[0096] In some embodiments, the oligonucleotide is an antisense oligonucleotide (ASO). In some embodiments, the ASO is a therapeutic ASO. Non-limiting examples of therapeutic ASOs include mipomersen, custilsen, fomivirsen, oblimersen, eteplirsen, nusinersen, inotersen, givosiran, golodirsen, and viltrasen.

[0097] In one aspect, the present invention provides a bifunctional compound of formula A: [ka] or a pharmaceutically acceptable salt thereof, wherein: the rSM is an RNA-binding small molecule that binds to a target RNA transcript; DFL is a degrader-recruiting ligand; -L 1 - is a bivalent linker group covalently linking said rSM to said DFL, The DFL binds to or recruits one or more degradation factors that degrade the target RNA transcript.

[0098] In some embodiments, [ka] is a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B [ka] and Y is N or CH; Z 1 is N, C=O or CR 2 and Z 2 is N, C=O, or CR 3However, Z 1 and Z 2 are not both N or C=O, Each R 1 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - and R 2 and R 3 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - or R 2 and R 3 together with the carbons to which they are attached, m R 5 and the ring is a 4- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 4 are independently -R, halogen, =O, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; Each R5 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; -L 2 -teeth, [ka] wherein -X- is covalently bonded to ring B and -X- is NR 6 , -O-, -CR 6 R 7 - or -S-, and -C(R 8 )2- or -C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 6 and R 7 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R), or -SR; Each R 8 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R or -L 1 - and R 9is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R)2, or -SR, or R 8 and R 9 together with the atoms to which they are attached, m R 5 and the ring is a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and each R 10 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; or R 8 and R 10 or R 9 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 6-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -L 1 - is a covalent bond or C 1-8a divalent straight or branched hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-; 1 , R 2 , R 3 , or R 8 One and only one of the -L 1 - and -L 1 - one end of which is covalently attached to rSM, each -Cy- is an optionally substituted 3- to 8-membered saturated or partially unsaturated divalent monocyclic carbocycle, an optionally substituted phenylene, an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic or bridged bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4.

[0099] As generally defined above, ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, ring A is phenyl. In some embodiments, ring A is an 8- to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, ring A is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0101] In some embodiments, ring A is [ka] is selected from.

[0102] In some embodiments, ring A is [ka] is selected from.

[0103] In some embodiments, ring A is selected from those shown in Table 1 below.

[0104] As generally defined above, ring B is [ka] is.

[0105] In some embodiments, ring B is [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] is.

[0106] In some embodiments, ring B is [ka] is.

[0107] In some embodiments, ring B is [ka] is selected from.

[0108] In some embodiments, ring B is [ka] is.

[0109] In some embodiments, ring B is [ka] is selected from.

[0110] In some embodiments, ring B is [ka] is.

[0111] In some embodiments, ring B is [ka] is selected from.

[0112] In some embodiments, ring B is [ka] is.

[0113] In some embodiments, ring B is [ka] is.

[0114] In some embodiments, ring B is [ka] is selected from.

[0115] In some embodiments, ring B is selected from those shown in Table 1 below.

[0116] As generally defined above, Y is N or CH.

[0117] In some embodiments, Y is N. In some embodiments, Y is CH.

[0118] In some embodiments, Y is CH. In some embodiments, Y is R 4 is replaced by

[0119] In some embodiments, Y is selected from those shown in Table 1 below.

[0120] Generally as defined above, Z 1 is N, C=O, or CR 2 is.

[0121] In some embodiments, Z 1 is N. In some embodiments, Z 1 is C=O. In some embodiments, Z 1 is CR 2 is.

[0122] In some embodiments, Z 1 is selected from those shown in Table 1 below.

[0123] Generally as defined above, Z 2 is N, C=O, or CR 3 is.

[0124] In some embodiments, Z 2 is N. In some embodiments, Z 2 is C=O. In some embodiments, Z 2 is CR 3 is.

[0125] In some embodiments, Z 2 is selected from those shown in Table 1 below.

[0126] Generally as defined above, each R 1 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 -It is.

[0127] In some embodiments, R 1 is R. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -NC. In some embodiments, R 1 is —C(O)OR. In some embodiments, R1 is —OC(O)R. In some embodiments, R 1 is —C(O)N(R). In some embodiments, R 1 is —N(R)C(O)R. In some embodiments, R 1 is —N(R)C(O)N(R). In some embodiments, R 1 is -OC(O)N(R) 2である。 In some embodiments, R 1 is -N(R)C(O)OR 。 In some embodiments, R 1 is -OR. In some embodiments, R 1 is -N(R). In some embodiments, R 1 is —NO. In some embodiments, R 1 is -N3. In some embodiments, R 1 is -SR. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is —S(O)N(R). In some embodiments, R 1 is -NRS(O)R. In some embodiments, R 1 -L 1 -It is.

[0128] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is an optionally substituted C 1-6 In some embodiments, R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 1is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0129] In some embodiments, R 1 is C 1-8 In some embodiments, R is a divalent straight or branched hydrocarbon chain. 1 is C 1-8 A divalent straight or branched hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0130] In some embodiments, R 1 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0131] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0132] As generally defined above, R 2 and R 3are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - or R 2 and R 3 together with the carbons to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0133] In some embodiments, R 2 is R. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -NC. In some embodiments, R 2 is —C(O)OR. In some embodiments, R 2 is —OC(O)R. In some embodiments, R 2 is —C(O)N(R). In some embodiments, R 2 is —N(R)C(O)R. In some embodiments, R 2 is —N(R)C(O)N(R). In some embodiments, R 2 is —OC(O)N(R). In some embodiments, R 2 is —N(R)C(O)OR. In some embodiments, R 2 is -OR. In some embodiments, R 2 is -N(R). In some embodiments, R 2is —NO. In some embodiments, R 2 is -N3. In some embodiments, R 2 is -SR. In some embodiments, R 2 is —S(O)R. In some embodiments, R 2 is —S(O)R. In some embodiments, R 2 is —S(O)N(R). In some embodiments, R 2 is -NRS(O)R. In some embodiments, R 2 -L 1 -It is.

[0134] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is an optionally substituted C 1-6 In some embodiments, R 2 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 2 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0135] In some embodiments, R 2 is a divalent straight or branched C 1-8 In some embodiments, R 2is a divalent straight or branched C hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, -Cy-.

[0136] In some embodiments, R 2 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0137] In some embodiments, R 3 is R. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is -NC. In some embodiments, R 3 is —C(O)OR. In some embodiments, R 3 is —OC(O)R. In some embodiments, R 3 is —C(O)N(R). In some embodiments, R 3 is —N(R)C(O)R. In some embodiments, R 3 is —N(R)C(O)N(R). In some embodiments, R 3 is -OC(O)N(R) 2である。 In some embodiments, R 3 is -N(R)C(O)OR 。 In some embodiments, R 3 is -OR. In some embodiments, R 3 is -N(R). In some embodiments, R 3is —NO. In some embodiments, R 3 is -N3. In some embodiments, R 3 is -SR. In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)N(R). In some embodiments, R 3 is -NRS(O)R. In some embodiments, R 3 -L 1 -It is.

[0138] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an optionally substituted C 1-6 In some embodiments, R 3 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 3 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0139] In some embodiments, R 3 is C 1-8 In some embodiments, R is a divalent straight or branched hydrocarbon chain. 3 is C 1-8A divalent straight or branched hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced or with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0140] In some embodiments, R 3 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0141] In some embodiments, R2 and R3, together with the carbons to which they are attached, form a 4-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0142] In some embodiments, R 2 and R 3 together with the carbon to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 and R 3 together with the carbon to which they are attached form a phenyl. In some embodiments, R 2 and R 3together with the carbons to which they are attached form an 8-10 membered bicyclic aromatic carbocyclic ring. 2 and R 3 together with the carbon to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and R 3 together with the carbon to which they are attached form a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and R 3 together with the carbons to which they are attached form an 8-10 membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0143] In some embodiments, R 2 and R 3 together with the carbon to which they are attached form a cyclohexane ring. 2 and R 3 together with the carbon to which they are attached form a cyclopentane ring.

[0144] In some embodiments, R 2 and R 3 is selected from those shown in Table 1 below.

[0145] Generally as defined above, each R 4 are independently -R, halogen, =O, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R.

[0146] In some embodiments, R 4 is R. In some embodiments, R4 is a halogen. In some embodiments, R 4 is ═O. In some embodiments, R 4 is -CN. In some embodiments, R 4 is -NC. In some embodiments, R 4 is —C(O)OR. In some embodiments, R 4 is —OC(O)R. In some embodiments, R 4 is —C(O)N(R). In some embodiments, R 4 is —N(R)C(O)R. In some embodiments, R 4 is —N(R)C(O)N(R). In some embodiments, R 4 is -OC(O)N(R) 2である。 In some embodiments, R 4 is -N(R)C(O)OR 。 In some embodiments, R 4 is -OR. In some embodiments, R 4 is -N(R). In some embodiments, R 4 is —NO. In some embodiments, R 4 is -N3. In some embodiments, R 4 is -SR. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)N(R). In some embodiments, R 4 is -NRS(O)R.

[0147] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted C 1-6 In some embodiments, R 4 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 4 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0148] In some embodiments, R 4 are H, =O, Me, Et, iPr, [ka] is selected from.

[0149] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0150] Generally as defined above, each R 5 is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0151] In some embodiments, R 5 is R. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is -CN. In some embodiments, R 5 is -NC. In some embodiments, R 5 is —C(O)OR. In some embodiments, R5 is —OC(O)R. In some embodiments, R 5 is —C(O)N(R). In some embodiments, R 5 is —N(R)C(O)R. In some embodiments, R 5 is —N(R)C(O)N(R). In some embodiments, R 5 is —OC(O)N(R). In some embodiments, R 5 is -N(R)C(O)OR 。 In some embodiments, R 5 is -OR. In some embodiments, R 5 is -N(R). In some embodiments, R 5 is —NO. In some embodiments, R 5 is -N3. In some embodiments, R 5 is -SR. In some embodiments, R 5 is —S(O)R. In some embodiments, R 5 is —S(O)R. In some embodiments, R 5 is —S(O)N(R). In some embodiments, R 5 is -NRS(O)R.

[0152] In some embodiments, R 5 is selected from those shown in Table 1 below.

[0153] Generally as defined above, -L 2 -teeth, [ka] is.

[0154] In some embodiments, -L 2 -teeth, [ka] In some embodiments, -L 2 -teeth, [ka] is.

[0155] X is NR as generally defined above. 6 , O, C.R. 6 R 7 , or S.

[0156] As generally defined above, R 6 and R 7 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R)2, or -SR.

[0157] In some embodiments, R 6 is R. In some embodiments, R 6 is a halogen. In some embodiments, R 6 is -CN. In some embodiments, R 6 is -NC. In some embodiments, R 6 is —C(O)OR. In some embodiments, R 6 is —OC(O)R. In some embodiments, R 6 is -OR. In some embodiments, R 6 is -N(R). In some embodiments, R 6 is -SR.

[0158] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is an optionally substituted C 1-6 In some embodiments, R 6 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 6is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0159] In some embodiments, R 6 is selected from H, Me, Et, iPr, and OH.

[0160] In some embodiments, R 6 is selected from those shown in Table 1 below.

[0161] In some embodiments, R 7 is R. In some embodiments, R 7 is a halogen. In some embodiments, R 7 is -CN. In some embodiments, R 7 is -NC. In some embodiments, R 7 is —C(O)OR. In some embodiments, R 7 is —OC(O)R. In some embodiments, R 7 is -OR. In some embodiments, R 7 is -N(R). In some embodiments, R 7 is -SR.

[0162] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is an optionally substituted C 1-6 In some embodiments, R 7 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 7is optionally substituted phenyl. In some embodiments, R 7 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 7 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0163] In some embodiments, R 7 is selected from H, Me, Et, iPr, and OH.

[0164] In some embodiments, R 7 is selected from those shown in Table 1 below.

[0165] In some embodiments, X is selected from NH, O, S, NMe, CHMe, CHOH, C(Me)2, and C(Me)OH.

[0166] In some embodiments, X is selected from those shown in Table 1 below.

[0167] Generally as defined above, each R 8 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 -It is.

[0168] In some embodiments, R8 is R. In some embodiments, R 8 is a halogen. In some embodiments, R 8 is -CN. In some embodiments, R 8 is -NC. In some embodiments, R 8 is —C(O)OR. In some embodiments, R 8 is —OC(O)R. In some embodiments, R 8 is —C(O)N(R). In some embodiments, R 8 is —N(R)C(O)R. In some embodiments, R 8 is —N(R)C(O)N(R). In some embodiments, R 8 is —OC(O)N(R). In some embodiments, R 8 is -N(R)C(O)OR 。 In some embodiments, R 8 is -OR. In some embodiments, R 8 is -N(R). In some embodiments, R 8 is —NO. In some embodiments, R 8 is -N3. In some embodiments, R 8 is -SR. In some embodiments, R 8 is —S(O)R. In some embodiments, R 8 is —S(O)R. In some embodiments, R 8 is —S(O)N(R). In some embodiments, R 8 is -NRS(O)R. In some embodiments, R 8 -L 1 -It is.

[0169] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is an optionally substituted C 1-6 In some embodiments, R 8 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 8is optionally substituted phenyl. In some embodiments, R 8 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 8 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0170] In some embodiments, R 8 is C 1-8 In some embodiments, R is a divalent straight or branched hydrocarbon chain. 8 is C 1-8 a divalent straight or branched hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, -Cy-.

[0171] In some embodiments, —C(R 8)2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0172] In some embodiments, —C(R 8 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 8 )2- is optionally replaced by phenyl. In some embodiments, -C(R 8 )2- is optionally replaced by an 8- to 10-membered bicyclic aromatic carbocyclic ring. 8 )2- is optionally replaced by a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R 8 )2- is optionally replaced by a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 )2- is optionally replaced by an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0173] In some embodiments, —C(R 8 )2-An example is [ka] can be optionally replaced with .

[0174] In some embodiments, R 8are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0175] In some embodiments, R 8 is selected from those shown in Table 1 below.

[0176] As generally defined above, R 9 is —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, —OR, —N(R)2, or —SR.

[0177] In some embodiments, R 9 is R. In some embodiments, R 9 is a halogen. In some embodiments, R 9 is -CN. In some embodiments, R 9 is -NC. In some embodiments, R 9 is —C(O)OR. In some embodiments, R 9 is —OC(O)R. In some embodiments, R 9 is -OR. In some embodiments, R 9 is -N(R). In some embodiments, R 9 is -SR.

[0178] In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is an optionally substituted C 1-6 In some embodiments, R 9 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 9 is optionally substituted phenyl. In some embodiments, R 9 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 9is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 9 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 9 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0179] In some embodiments, R 9 is selected from H, Me, Et, iPr, and OH.

[0180] In some embodiments, R 9 is selected from those shown in Table 1 below.

[0181] In some embodiments, R 8 and R 9 are m R's along with the atoms to which they are attached. 5 and the ring is a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0182] As generally defined above, R 10 is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0183] In some embodiments, R 10 is R. In some embodiments, R 10 is a halogen. In some embodiments, R 10 is -CN. In some embodiments, R10 is -NC. In some embodiments, R 10 is —C(O)OR. In some embodiments, R 10 is —OC(O)R. In some embodiments, R 10 is —C(O)N(R). In some embodiments, R 10 is —N(R)C(O)R. In some embodiments, R 10 is —N(R)C(O)N(R). In some embodiments, R 10 is —OC(O)N(R). In some embodiments, R 10 is -N(R)C(O)OR 。 In some embodiments, R 10 is -OR. In some embodiments, R 10 is -N(R). In some embodiments, R 10 is —NO. In some embodiments, R 10 is -N3. In some embodiments, R 10 is -SR. In some embodiments, R 10 is —S(O)R. In some embodiments, R 10 is —S(O)R. In some embodiments, R 10 is —S(O)N(R). In some embodiments, R 10 is -NRS(O)R.

[0184] In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is an optionally substituted C 1-6 In some embodiments, R 10 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 10 is optionally substituted phenyl. In some embodiments, R 10 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 10is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 10 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 10 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0185] In some embodiments, —C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0186] In some embodiments, —C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 10 )2- is optionally replaced by phenyl. In some embodiments, -C(R 10 )2- is optionally replaced by an 8- to 10-membered bicyclic aromatic carbocyclic ring. 10 )2- is optionally replaced by a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R 10 )2- is optionally replaced by a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.10 )2- is optionally replaced by an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0187] In some embodiments, —C(R 10 )2-An example of [ka] is optionally replaced by

[0188] In some embodiments, R 10 is selected from H, Me, Et, iPr, and CH3OH.

[0189] In some embodiments, R 10 is selected from those shown in Table 1 below.

[0190] In some embodiments, R 8 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 6-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0191] In some embodiments, R 9 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0192] In some embodiments, -L 2 -teeth, [ka] is selected from.

[0193] In some embodiments, -L2 is selected from those shown in Table 1 below.

[0194] As generally defined above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3.

[0195] As generally defined above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3.

[0196] As generally defined above, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3.

[0197] As generally defined above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1, 2, or 3.

[0198] As generally defined above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 1, 2, or 3.

[0199] Exemplary embodiments of the present invention [ka] The compounds are listed in Tables 1 and 1A below.

[0200] Exemplary embodiments of the present invention [ka] The compounds are listed below in Tables 1, 1A, and 1B.

[0201] Exemplary embodiments of the present invention [ka] The compounds are listed below in Tables 1, 1A, 1B, and 1C.

[0202] In some embodiments, [ka] is a compound of formula Ic: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 12-membered bicyclic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered tricyclic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is [ka] and Y is N or CH; Z 1 is N, C=O or CR 2 and Z 2 is N, C=O, or CR 3 However, Z 1 and Z 2 are not both N or C=O, Each R 1 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - and R 2 and R 3are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - or R 2 and R 3 are m R's along with the carbons to which they are attached. 5 and the ring is a 4- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 4 are independently -R, halogen, =O, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R or C 1-8 a divalent linear or branched hydrocarbon chain in which one, two, three, or four methylene units of said chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO2-; Each R 5are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; -L 2 -but, [ka] wherein -X- is covalently bonded to ring B and -X- is NR 6 , -O-, -CR 6 R 7 -, -C(O)-, -S- or S(O)2-, and -C(R 8 )2- or -C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 6 and R 7 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R), or -SR; Each R 8 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - or two R's 8form, together with the carbon atoms to which they are attached, a 3- to 6-membered carbocyclic ring, R 9 is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R)2, or -SR, or R 8 and R 9 are m R's along with the atoms to which they are attached. 5 and forming a ring substituted with a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 10 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R, or two R 10 form a 3- to 6-membered carbocyclic ring together with the carbon atom to which they are attached, or R 9 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 6-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -L 1 - is a bivalent linker group that covalently attaches the RNA binder to the DFL, and R1 , R 2 , R 3 , R 8 , or R 11 One and only one of -L 1 - and -L 1 - one end of which is covalently attached to an RNA binder, each -Cy- is an optionally substituted 3- to 8-membered saturated or partially unsaturated divalent monocyclic carbocycle, an optionally substituted phenylene, an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic or bridged bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 11 is H, C 1-3 Alkyl, or -L 1 - and m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4.

[0203] As generally defined above, Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-12 membered bicyclic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered tricyclic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0204] In some embodiments, ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, ring A is phenyl. In some embodiments, ring A is an 8- to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, ring A is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8- to 12-membered bicyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8-12 membered tricyclic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0205] In some embodiments, ring A is [ka] is selected from.

[0206] In some embodiments, ring A is [ka] is selected from.

[0207] In some embodiments, ring A is selected from those shown in Table 1 below.

[0208] In some embodiments, ring A is selected from those shown in Table 1A below.

[0209] In some embodiments, ring A is selected from those shown in Table 1B below.

[0210] In some embodiments, ring A is selected from those shown in Table 1C below.

[0211] Ring B, as generally defined above, is [ka] is.

[0212] In some embodiments, ring B is [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] is.

[0213] In some embodiments, ring B is [ka] is.

[0214] In some embodiments, ring B is [ka] is selected from.

[0215] In some embodiments, ring B is [ka] is.

[0216] In some embodiments, ring B is [ka] is selected from.

[0217] In some embodiments, ring B is [ka] is.

[0218] In some embodiments, ring B is [ka] is selected from.

[0219] In some embodiments, ring B is [ka] is.

[0220] In some embodiments, ring B is [ka] is.

[0221] In some embodiments, ring B is [ka] is selected from.

[0222] In some embodiments, ring B is selected from those shown in Table 1 below.

[0223] In some embodiments, ring B is selected from one of those shown in Table 1A below.

[0224] In some embodiments, ring B is selected from one of those shown in Table 1B below.

[0225] In some embodiments, ring B is selected from one of those shown in Table 1C below.

[0226] As generally defined above, Y is N or CH.

[0227] In some embodiments, Y is N. In some embodiments, Y is CH.

[0228] In some embodiments, Y is CH. In some embodiments, Y is R 4 is replaced by

[0229] In some embodiments, Y is selected from those shown in Table 1 below.

[0230] In some embodiments, Y is selected from those shown in Table 1A below.

[0231] In some embodiments, Y is selected from those shown in Table 1B below.

[0232] In some embodiments, Y is selected from one of those shown in Table 1C below.

[0233] Generally as defined above, Z 1 is N, C=O, or CR 2 is.

[0234] In some embodiments, Z 1 is N. In some embodiments, Z 1 is C=O. In some embodiments, Z 1 is CR 2 is.

[0235] In some embodiments, Z 1 is selected from those shown in Table 1 below.

[0236] In some embodiments, Z 1 is selected from those shown in Table 1A below.

[0237] In some embodiments, Z 1 is selected from those shown in Table 1B below.

[0238] In some embodiments, Z 1 is selected from one of those shown in Table 1C below.

[0239] Generally as defined above, Z 2is N, C=O, or CR 3 is.

[0240] In some embodiments, Z 2 is N. In some embodiments, Z 2 is C=O. In some embodiments, Z 2 is CR 3 is.

[0241] In some embodiments, Z 2 is selected from those shown in Table 1 below.

[0242] In some embodiments, Z 2 is selected from those shown in Table 1A below.

[0243] In some embodiments, Z 2 is selected from those shown in Table 1B below.

[0244] In some embodiments, Z 2 is selected from those shown in Table 1C below.

[0245] Generally as defined above, each R 1 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 -It is.

[0246] In some embodiments, R 1 is R. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -NC. In some embodiments, R 1 is —C(O)OR. In some embodiments, R 1is —OC(O)R. In some embodiments, R 1 is —C(O)N(R). In some embodiments, R 1 is —N(R)C(O)R. In some embodiments, R 1 is —N(R)C(O)N(R). In some embodiments, R 1 is -OC(O)N(R) 2である。 In some embodiments, R 1 is -N(R)C(O)OR 。 In some embodiments, R 1 is -OR. In some embodiments, R 1 is -N(R). In some embodiments, R 1 is —NO. In some embodiments, R 1 is -N3. In some embodiments, R 1 is -SR. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is —S(O)N(R). In some embodiments, R 1 is -NRS(O)R. In some embodiments, R 1 -L 1 -It is.

[0247] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is an optionally substituted C 1-6 In some embodiments, R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 1is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0248] In some embodiments, R 1 is C 1-8 In some embodiments, R is a divalent straight or branched hydrocarbon chain. 1 is C 1-8 a divalent straight or branched hydrocarbon chain in which 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0249] In some embodiments, R 1 is C 1-16 In some embodiments, R is a divalent straight or branched hydrocarbon chain. 1 is C 1-16a divalent straight or branched hydrocarbon chain in which 1, 2, 3, 4, 5, or 6 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0250] In some embodiments, R 1 are H, F, Cl, -CN, OH, OMe, Me, Et, i-Pr, [ka] is selected from.

[0251] In some embodiments, R 1 are H, F, Cl, -CN, OH, OMe, Me, Et, i-Pr, [ka] is selected from.

[0252] In some embodiments, R 1 are H, F, Cl, -CN, OH, OMe, Me, Et, i-Pr, [ka] is selected from.

[0253] In some embodiments, R 1 -L 1 - and [ka] is selected from.

[0254] In some embodiments, R 1-L 1 - and [ka] is selected from.

[0255] In some embodiments, R 1 -L 1 - and [ka] is selected from.

[0256] In some embodiments, R 1 -L 1 - and [ka] [ka] [ka] is selected from.

[0257] In some embodiments, R 1 -L 1 - and [ka] is selected from.

[0258] In some embodiments, R 1 Ha-L 1 and is selected from those shown in Table 3 below.

[0259] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0260] In some embodiments, R 1 is selected from those shown in Table 1A below.

[0261] In some embodiments, R 1 is selected from those shown in Table 1B below.

[0262] In some embodiments, R 1 is selected from those shown in Table 1C below.

[0263] As generally defined above, R 2 and R 3 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or -L 1 - or R 2 and R 3 are m R's along with the carbons to which they are attached. 5 and the ring is a 4-8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0264] In some embodiments, R 2 is R. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -NC. In some embodiments, R 2 is —C(O)OR. In some embodiments, R 2 is —OC(O)R. In some embodiments, R 2 is —C(O)N(R). In some embodiments, R2 is —N(R)C(O)R. In some embodiments, R 2 is —N(R)C(O)N(R). In some embodiments, R 2 is —OC(O)N(R). In some embodiments, R 2 is —N(R)C(O)OR. In some embodiments, R 2 is -OR. In some embodiments, R 2 is -N(R). In some embodiments, R 2 is —NO. In some embodiments, R 2 is -N3. In some embodiments, R 2 is -SR. In some embodiments, R 2 is —S(O)R. In some embodiments, R 2 is —S(O)R. In some embodiments, R 2 is —S(O)N(R). In some embodiments, R 2 is -NRS(O)R. In some embodiments, R 2 -L 1 -It is.

[0265] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is an optionally substituted C 1-6 In some embodiments, R 2 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 2 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0266] In some embodiments, R 2 is a divalent straight or branched C 1-8 In some embodiments, R 2 is a divalent straight or branched chain C 1-8 a hydrocarbon chain in which 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0267] In some embodiments, R 2 is a divalent straight or branched C 1-16 In some embodiments, R 2 is a divalent straight or branched C 1-1 and 6 hydrocarbon chains in which 1, 2, 3, 4, 5, or 6 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, -Cy-.

[0268] In some embodiments, R 2 are H, F, Cl, OH, OMe, Me, Et, i-Pr,, [ka] is selected from.

[0269] In some embodiments, R 2 are H, F, Cl, OH, OMe, Me, Et, i-Pr, [ka] is selected from.

[0270] In some embodiments, R 2 are H, F, Cl, OH, OMe, Me, Et, i-Pr, [ka] is selected from.

[0271] In some embodiments, R 2 -L 1 - and [ka] is selected from.

[0272] In some embodiments, R 2 -L 1 - and [ka] is selected from.

[0273] In some embodiments, R 2 -L 1 - and [ka] is selected from.

[0274] In some embodiments, R2 -L 1 - and [ka] [ka] [ka] is selected from.

[0275] In some embodiments, R 2 Ha-L 1 and is selected from those shown in Table 3 below.

[0276] In some embodiments, R 3 is R. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is -NC. In some embodiments, R 3 is —C(O)OR. In some embodiments, R 3 is —OC(O)R. In some embodiments, R 3 is —C(O)N(R). In some embodiments, R 3 is —N(R)C(O)R. In some embodiments, R 3 is —N(R)C(O)N(R). In some embodiments, R 3 is -OC(O)N(R) 2である。 In some embodiments, R 3 is -N(R)C(O)OR 。 In some embodiments, R 3 is -OR. In some embodiments, R 3 is -N(R). In some embodiments, R 3 is —NO. In some embodiments, R 3 is -N3. In some embodiments, R 3 is -SR. In some embodiments, R 3is —S(O)R. In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)N(R). In some embodiments, R 3 is -NRS(O)R. In some embodiments, R 3 -L 1 -It is.

[0277] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an optionally substituted C 1-6 In some embodiments, R 3 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 3 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0278] In some embodiments, R 3 is C 1-8 In some embodiments, R is a divalent straight or branched hydrocarbon chain. 3 is C 1-8a divalent straight or branched hydrocarbon chain in which 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0279] In some embodiments, R 3 is a divalent straight or branched C 1-16 In some embodiments, R 3 is a divalent straight or branched C hydrocarbon chain wherein 1, 2, 3, 4, 5, or 6 methylene units of the chain are independently and optionally -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-

[0280] In some embodiments, R 3 are H, F, Cl, OH, -OMe, Me, Et, CF3, CN, -C(O)NH2, i-Pr, [ka] is selected from.

[0281] In some embodiments, R 3 teeth, [ka] is selected from.

[0282] In some embodiments, R 3 teeth, [ka] is selected from.

[0283] In some embodiments, R 3 teeth, [ka] is selected from.

[0284] In some embodiments, R 3 -L 1 - and [ka] is selected from.

[0285] In some embodiments, R 3 -L 1 - and [ka] is selected from.

[0286] In some embodiments, R 3 -L 1 - and [ka] is selected from.

[0287] In some embodiments, R 3 -L 1 - and [ka] [ka] [ka] is selected from.

[0288] In some embodiments, R 3 Ha-L 1 and is selected from those shown in Table 3 below.

[0289] In some embodiments, R2 and R3, together with the carbons to which they are attached, form a 4-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0290] In some embodiments, R 2 and R 3 together with the carbon to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 and R 3 together with the carbon to which they are attached form a phenyl. In some embodiments, R 2 and R 3 together with the carbons to which they are attached form an 8-10 membered bicyclic aromatic carbocyclic ring. 2 and R 3 together with the carbon to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and R 3 together with the carbon to which they are attached form a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and R 3together with the carbons to which they are attached form an 8-10 membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0291] In some embodiments, R 2 and R 3 together with the carbons to which they are attached form a cyclohexanylene ring. 2 and R 3 together with the carbons to which they are attached form a cyclopentanylene ring.

[0292] In some embodiments, R 2 and R 3 is selected from those shown in Table 1 below.

[0293] In some embodiments, R 2 and R 3 is selected from those shown in Table 1A below.

[0294] In some embodiments, R 2 and R 3 is selected from those shown in Table 1B below.

[0295] In some embodiments, R 2 and R 3 is selected from one of those shown in Table 1C below.

[0296] Generally as defined above, each R 4 are independently -R, halogen, =O, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R or C 1-8A divalent straight or branched hydrocarbon chain in which 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO2-.

[0297] In some embodiments, R 4 is R. In some embodiments, R 4 is a halogen. In some embodiments, R 4 is ═O. In some embodiments, R 4 is -CN. In some embodiments, R 4 is -NC. In some embodiments, R 4 is —C(O)OR. In some embodiments, R 4 is —OC(O)R. In some embodiments, R 4 is —C(O)N(R). In some embodiments, R 4 is —N(R)C(O)R. In some embodiments, R 4 is —N(R)C(O)N(R). In some embodiments, R 4 is -OC(O)N(R) 2である。 In some embodiments, R 4 is -N(R)C(O)OR 。 In some embodiments, R 4 is -OR. In some embodiments, R 4 is -N(R). In some embodiments, R 4 is —NO. In some embodiments, R 4 is -N3. In some embodiments, R 4 is -SR. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)N(R). In some embodiments, R 4 is -NRS(O)R. In some embodiments, R 4 is C1-8 A divalent straight or branched hydrocarbon chain in which 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO2-.

[0298] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted C 1-6 In some embodiments, R 4 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 4 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0299] In some embodiments, R 4 are H, =O, Me, Et, iPr, [ka] is selected from.

[0300] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0301] In some embodiments, R 4 is selected from those shown in Table 1A below.

[0302] In some embodiments, R 4 is selected from those shown in Table 1B below.

[0303] In some embodiments, R 4 is selected from those shown in Table 1C below.

[0304] Generally as defined above, each R 5 is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0305] In some embodiments, R 5 is R. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is -CN. In some embodiments, R 5 is -NC. In some embodiments, R 5 is —C(O)OR. In some embodiments, R 5 is —OC(O)R. In some embodiments, R 5 is —C(O)N(R). In some embodiments, R 5 is —N(R)C(O)R. In some embodiments, R 5 is —N(R)C(O)N(R). In some embodiments, R 5 is —OC(O)N(R). In some embodiments, R 5 is -N(R)C(O)OR 。 In some embodiments, R 5 is -OR. In some embodiments, R 5 is -N(R). In some embodiments, R5 is —NO. In some embodiments, R 5 is -N3. In some embodiments, R 5 is -SR. In some embodiments, R 5 is —S(O)R. In some embodiments, R 5 is —S(O)R. In some embodiments, R 5 is —S(O)N(R). In some embodiments, R 5 is -NRS(O)R.

[0306] In some embodiments, R 5 is selected from those shown in Table 1 below.

[0307] In some embodiments, R 5 is selected from those shown in Table 1A below.

[0308] In some embodiments, R 5 is selected from those shown in Table 1B below.

[0309] In some embodiments, R5 is selected from those shown in Table 1C below.

[0310] Generally as defined above, -L 2 -teeth, [ka] is.

[0311] In some embodiments, -L 2 -teeth, [ka] In some embodiments, -L 2 -teeth, [ka] In some embodiments, -L 2 -teeth, [ka] In some embodiments, -L 2 -teeth, [ka] In some embodiments, -L 2 -teeth, [ka] is.

[0312] As generally defined above, R 6 and R 7 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R)2, or -SR.

[0313] In some embodiments, R 6 is R. In some embodiments, R 6 is a halogen. In some embodiments, R 6 is -CN. In some embodiments, R 6 is -NC. In some embodiments, R 6 is —C(O)OR. In some embodiments, R 6 is —OC(O)R. In some embodiments, R 6 is -OR. In some embodiments, R 6 is -N(R). In some embodiments, R 6 is -SR.

[0314] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is an optionally substituted C 1-6 In some embodiments, R 6 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R6 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 6 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0315] In some embodiments, R 6 is selected from H, Me, Et, iPr, F, and OH.

[0316] In some embodiments, R 6 is selected from those shown in Table 1 below.

[0317] In some embodiments, R 6 is selected from those shown in Table 1A below.

[0318] In some embodiments, R 6 is selected from those shown in Table 1B below.

[0319] In some embodiments, R 6 is selected from one of those shown in Table 1C below.

[0320] In some embodiments, R 7 is R. In some embodiments, R 7 is a halogen. In some embodiments, R 7 is -CN. In some embodiments, R 7 is -NC. In some embodiments, R 7 is —C(O)OR. In some embodiments, R 7is —OC(O)R. In some embodiments, R 7 is -OR. In some embodiments, R 7 is -N(R). In some embodiments, R 7 is -SR.

[0321] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is an optionally substituted C 1-6 In some embodiments, R 7 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 7 is optionally substituted phenyl. In some embodiments, R 7 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 7 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0322] In some embodiments, R 7 is selected from H, Me, Et, iPr, F, and OH.

[0323] In some embodiments, R 7 is selected from those shown in Table 1 below.

[0324] In some embodiments, R 7 is selected from those shown in Table 1A below.

[0325] In some embodiments, R7 is selected from those shown in Table 1B below.

[0326] In some embodiments, R 7 is selected from one of those shown in Table 1C below.

[0327] X is a bond, NR 6 , O, C.R. 6 R 7 -C(O)-, -S-, or -S(O)2-.

[0328] In some embodiments, X is selected from a bond, NH, O, S, SO, C(O), NMe, CF, CHMe, CHOH, C(Me) and C(Me)OH.

[0329] In some embodiments, X is selected from those shown in Table 1 below.

[0330] In some embodiments, X is selected from those shown in Table 1A below.

[0331] In some embodiments, X is selected from those shown in Table 1B below.

[0332] In some embodiments, X is selected from those shown in Table 1C below.

[0333] Generally as defined above, each R 8 are independently -R, halogen, -CN, -NC, and are C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, -L 1 - or two R's 8 together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic ring.

[0334] In some embodiments, R 8 is R. In some embodiments, R 8 is a halogen. In some embodiments, R 8 is -CN. In some embodiments, R 8 is -NC. In some embodiments, R 8 is —C(O)OR. In some embodiments, R 8 is —OC(O)R. In some embodiments, R 8 is —C(O)N(R). In some embodiments, R 8 is —N(R)C(O)R. In some embodiments, R 8 is —N(R)C(O)N(R). In some embodiments, R 8 is —OC(O)N(R). In some embodiments, R 8 is -N(R)C(O)OR 。 In some embodiments, R 8 is -OR. In some embodiments, R 8 is -N(R). In some embodiments, R 8 is —NO. In some embodiments, R 8 is -N3. In some embodiments, R 8 is -SR. In some embodiments, R 8 is —S(O)R. In some embodiments, R 8 is —S(O)R. In some embodiments, R 8 is —S(O)N(R). In some embodiments, R 8 is -NRS(O)R. In some embodiments, R 8 -L 1 In some embodiments, two R 8 together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic ring.

[0335] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is an optionally substituted C 1-6 In some embodiments, R8 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 8 is optionally substituted phenyl. In some embodiments, R 8 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 8 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0336] In some embodiments, R 8 is C 1-8 In some embodiments, R is a divalent straight or branched hydrocarbon chain. 8 is a divalent straight or branched chain C 1-8 a hydrocarbon chain in which 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0337] In some embodiments, R 8 is a divalent straight or branched C 1-16 In some embodiments, R 8 is a divalent straight or branched chain C 1-16a hydrocarbon chain in which 1, 2, 3, 4, 5, or 6 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, -Cy-.

[0338] In some embodiments, —C(R 8 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0339] In some embodiments, —C(R 8 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 8 )2- is optionally replaced by phenyl. In some embodiments, -C(R 8 )2- is optionally replaced by an 8- to 10-membered bicyclic aromatic carbocyclic ring. 8 )2- is optionally replaced by a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R 8 )2- is optionally replaced by a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R8 )2- is optionally replaced by an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0340] In some embodiments, —C(R 8 )2-An example is [ka] can be optionally replaced with .

[0341] In some embodiments, R 8 are H, F, Cl, OH, -OMe, Me, Et, i-Pr, [ka] is selected from.

[0342] In some embodiments, R 8 are H, F, Cl, OH, -OMe, Me, Et, i-Pr, [ka] is selected from.

[0343] In some embodiments, R 8 -L 1 - and [ka] is selected from.

[0344] In some embodiments, R 8 -L 1 - and [ka] is selected from.

[0345] In some embodiments, R 8 -L 1 - and [ka] is selected from.

[0346] In some embodiments, R 8 -L 1 - and [ka] is selected from.

[0347] In some embodiments, R 8 -L 1 - and [ka] is selected from.

[0348] In some embodiments, R 8 -L 1 - and [ka] [ka] [ka] is selected from.

[0349] In some embodiments, -L 1 -teeth, [ka] is selected from.

[0350] In some embodiments, -L 1 -teeth, [ka] [ka] is selected from.

[0351] In some embodiments, -L 1 - and [ka] is selected from.

[0352] In some embodiments, R 8 Ha-L 1 and is selected from those shown in Table 3 below.

[0353] In some embodiments, two R 8 together with the carbon atoms to which they are attached form a cyclopropane ring.

[0354] In some embodiments, two R 8 together with the carbon atoms to which they are attached form a cyclobutane ring.

[0355] In some embodiments, R 8 is selected from those shown in Table 1 below.

[0356] In some embodiments, R 8 is selected from those shown in Table 1A below.

[0357] In some embodiments, R 8 is selected from those shown in Table 1B below.

[0358] In some embodiments, R 8 is selected from one of those shown in Table 1C below.

[0359] As generally defined above, R 9 is —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, —OR, —N(R)2, or —SR.

[0360] In some embodiments, R 9 is R. In some embodiments, R9 is a halogen. In some embodiments, R 9 is -CN. In some embodiments, R 9 is -NC. In some embodiments, R 9 is —C(O)OR. In some embodiments, R 9 is —OC(O)R. In some embodiments, R 9 is -OR. In some embodiments, R 9 is -N(R). In some embodiments, R 9 is -SR.

[0361] In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is an optionally substituted C 1-6 In some embodiments, R 9 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 9 is optionally substituted phenyl. In some embodiments, R 9 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 9 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 9 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 9 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0362] In some embodiments, R 9 H, Me, Et, iPr, [ka] and OH.

[0363] In some embodiments, R 9 is selected from those shown in Table 1 below.

[0364] In some embodiments, R 9 is selected from those shown in Table 1A below.

[0365] In some embodiments, R 9 is selected from those shown in Table 1B below.

[0366] In some embodiments, R 9 is selected from one of those shown in Table 1C below.

[0367] In some embodiments, R 8 and R 9 are m R's along with the atoms to which they are attached. 5 and the ring is a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0368] As generally defined above, R 10 is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0369] In some embodiments, R 10 is R. In some embodiments, R 10 is a halogen. In some embodiments, R 10 is -CN. In some embodiments, R 10 is -NC. In some embodiments, R 10 is —C(O)OR. In some embodiments, R 10is —OC(O)R. In some embodiments, R 10 is —C(O)N(R). In some embodiments, R 10 is —N(R)C(O)R. In some embodiments, R 10 is —N(R)C(O)N(R). In some embodiments, R 10 is —OC(O)N(R). In some embodiments, R 10 is -N(R)C(O)OR 。 In some embodiments, R 10 is -OR. In some embodiments, R 10 is -N(R). In some embodiments, R 10 is —NO. In some embodiments, R 10 is -N3. In some embodiments, R 10 is -SR. In some embodiments, R 10 is —S(O)R. In some embodiments, R 10 is —S(O)R. In some embodiments, R 10 is —S(O)N(R). In some embodiments, R 10 is -NRS(O)R.

[0370] In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is an optionally substituted C 1-6 In some embodiments, R 10 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 10 is optionally substituted phenyl. In some embodiments, R 10 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 10 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 10is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 10 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0371] In some embodiments, —C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0372] In some embodiments, —C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 10 )2- is optionally replaced by phenyl. In some embodiments, -C(R 10 )2- is optionally replaced by an 8- to 10-membered bicyclic aromatic carbocyclic ring. 10 )2- is optionally replaced by a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R 10 )2- is optionally replaced by a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 10 )2- is optionally replaced by an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0373] In some embodiments, —C(R 10 )2-An example is [ka] is optionally replaced by

[0374] In some embodiments, two R 10 form a cyclopropane ring together with the carbon atoms to which they are attached.

[0375] In some embodiments, R 10 H, Me, Et, iPr, [ka] , CF3, [ka] and CH3OH.

[0376] In some embodiments, R 10 -L 1 - and [ka] is selected from.

[0377] In some embodiments, R 10 -L 1 - and [ka] is selected from.

[0378] In some embodiments, R 10 -L 1 - and [ka] is selected from.

[0379] In some embodiments, R 10 -L 1 - and [ka] is selected from.

[0380] In some embodiments, R 10 -L 1 - and [ka] is selected from.

[0381] In some embodiments, R 10 -L 1 - and [ka] [ka] is selected from.

[0382] In some embodiments, R 10 -L 1 and is selected from those shown in Table 3 below.

[0383] In some embodiments, R 10 is selected from those shown in Table 1 below.

[0384] In some embodiments, R 10 is selected from those shown in Table 1A below.

[0385] In some embodiments, R 10 is selected from those shown in Table 1B below.

[0386] In some embodiments, R10 is selected from those shown in Table 1C below.

[0387] In some embodiments, R8 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 6-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0388] In some embodiments, R 9 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0389] Generally as defined above, -L 1 - is a bivalent linker group that covalently attaches the RNA binder to the DFL, and R 1 , R 2 , R 3 , R 8 , or R 11 One and only one of -L 1 - and -L 1 -One end of which is covalently attached to rSM.

[0390] In some embodiments, -L 1 - is defined in the embodiments described in the section entitled Linker below.

[0391] In some embodiments, -L 1 - is a covalent bond or a divalent straight or branched C 1-8a hydrocarbon chain wherein 1, 2, 3, or 4 methylene units of the chain are independently and optionally -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, - 1, 2, 3, 4, 5, 6, or 7 methylene units are optionally replaced by -OCH2CH2- or -CH2CH2O-; R 1 , R 2 , R 3 , R 8 , or R 11 One and only one of the -L 1 - and -L 1 One end of - is covalently attached to rSM.

[0392] In some embodiments, -L 1 - is a covalent bond or a divalent straight or branched chain C 1-16 a hydrocarbon chain wherein 1, 2, 3, 4, 5, or 6 methylene units of the chain are independently and optionally -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO 2-, -SON(R)-, -(R)NSO-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-, and 1, 2, 3, 4, 5, 6, or 7 methylene units are optionally replaced by -OCHCH- or -CHCHO-, wherein R 1 , R 2 , R 3 , R 8 , or R 11 One and only one of the -L 1- and -L 1 -One end of which is covalently attached to rSM.

[0393] As generally defined above, R 11 is H, C 1-3 Alkyl, or -L 1 -It is.

[0394] In some embodiments, R 11 is H. In some embodiments, R 11 is C 1-3 In some embodiments, R 11 -L 1 -It is.

[0395] In some embodiments, R 11 -L 1 - and [ka] is selected from.

[0396] In some embodiments, R 11 -L 1 - and [ka] is selected from.

[0397] In some embodiments, R 11 -L 1 - and [ka] is selected from.

[0398] In some embodiments, R 11 -L 1 - and [ka] [ka] is selected from.

[0399] In some embodiments, R 11 Ha-L 1 and is selected from those shown in Table 3 below.

[0400] In some embodiments, R 11 is selected from those shown in Table 1A below.

[0401] In some embodiments, R 11 is selected from those shown in Table 1B below.

[0402] In some embodiments, R 11 is selected from those shown in Table 1C below.

[0403] In some embodiments, -L 2 -teeth, [ka] [ka] [ka] is.

[0404] In some embodiments, -L 2 -teeth, [ka] is selected from.

[0405] In some embodiments, -L 2 is selected from those shown in Table 1 below.

[0406] In some embodiments, -L 2 is selected from those shown in Table 1A below.

[0407] In some embodiments, -L2 is selected from those shown in Table 1B below.

[0408] In some embodiments, -L 2 is selected from those shown in Table 1C below.

[0409] As generally defined above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3.

[0410] As generally defined above, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3.

[0411] As generally defined above, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3.

[0412] As generally defined above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1, 2, or 3.

[0413] As generally defined above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 1, 2, or 3.

[0414] Exemplary embodiments of the present invention [ka] The compounds are listed in Table 1 below.

[0415] Exemplary embodiments of the present invention [ka] The compounds are listed in Table 1A below.

[0416] Exemplary embodiments of the present invention [ka] The compounds are listed in Table 1B below.

[0417] Exemplary embodiments of the present invention [ka] The compounds are listed in Table 1C below.

[0418] Further exemplary compounds of the invention are described below, and of formula A or B [ka] The moieties are shown in the formula below:

[0419] In some embodiments, the present invention provides a compound of formula II-a or II-b: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , -L 2 -, -L 1 Each of -, X, -Cy-, n, q, and r is as defined above and as described alone and in combination in the embodiments of the present disclosure to provide a compound or a pharmaceutically acceptable salt thereof.

[0420] In some embodiments, the present invention provides a compound of formula III-a: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , -L 1 Each of -, X, -Cy-, and n is as defined above and as described alone and in combination in the embodiments of the present disclosure to provide a compound or a pharmaceutically acceptable salt thereof.

[0421] In some embodiments, the present invention provides a compound of formula IV-a or IV-b: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 2 , R 3 , R 4 , -L 1 Each of -, -Cy-, and n is as defined above and as described alone and in combination in the embodiments herein to provide a compound or a pharmaceutically acceptable salt thereof.

[0422] In some embodiments, the present invention provides a compound of formula IV-c or IV-d: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , -L 1 Each of -, -Cy-, and n is as defined above and as described alone and in combination in the embodiments herein to provide a compound or a pharmaceutically acceptable salt thereof.

[0423] In some embodiments, the present invention provides a compound of formula Va: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 4 , R 5 , R 6 , R 7 , -L 1 Each of -, X, -Cy-, m, and n is as defined above and as described alone and in combination in the embodiments herein to provide a compound or a pharmaceutically acceptable salt thereof.

[0424] In some embodiments, the present invention provides a compound of formula VI-a or VI-b: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 2 , R 3 , R 4 , R 5 , -L 1 Each of -, -Cy-, m, and n is as defined above and as described alone and in combination in the embodiments herein to provide a compound or a pharmaceutically acceptable salt thereof.

[0425] In some embodiments, the present invention provides a compound of formula VI-c or VI-d: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , -L 1 Each of -, -Cy-, m, and n is as defined above and as described alone and in combination in the embodiments herein to provide a compound or a pharmaceutically acceptable salt thereof.

[0426] In some embodiments, the present invention provides a compound of formula VII-a: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 4 , R 5 , R 6 , R 7 , -L 1Each of -, X, -Cy-, m, and n is as defined above and as described alone and in combination in the embodiments herein to provide a compound or a pharmaceutically acceptable salt thereof.

[0427] In some embodiments, the present invention provides a compound of formula VIII-a or VIII-b: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 2 , R 3 , R 4 , R 5 , -L 1 Each of -, -Cy-, m, and n is as defined above and as described alone and in combination in the embodiments herein to provide a compound or a pharmaceutically acceptable salt thereof.

[0428] In some embodiments, the present invention provides a compound of formula VIII-c or VIII-d: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , -L 1 Each of -, -Cy-, m, and n is as defined above and as described alone and in combination in the embodiments herein to provide a compound or a pharmaceutically acceptable salt thereof.

[0429] Further exemplary compounds of the invention are described below, and of formula A or B [ka] The moieties are shown in the formula below:

[0430] In some embodiments, the present invention provides a compound of formula IX-a, formula IX-b, or formula IX-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 1 , R 3 , R 4 , R 8 , R 9 , R 10 , -L 1 Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0431] In some embodiments, the present invention provides a compound of formula Xa, formula Xb, or formula Xc: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 1 , R 3 , R 8 , R 9 , R 10 , -L 1 Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0432] In some embodiments, the present invention provides a compound of formula XI-a, formula XI-b, or formula XI-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 3 , R 8 , R 9 , R 10 , -L 1Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0433] In some embodiments, the present invention provides a compound of formula XII-a, formula XII-b, or formula XII-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 3 , R 8 , R 10 , -L 1 Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0434] In some embodiments, the present invention provides a compound of formula XIII-a, formula XIII-b, or formula XIII-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 8 , R 10 , -L 1 Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0435] In some embodiments, the present invention provides a compound of formula XIV-a, formula XIV-b, or formula XIV-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 8 , R 10 , -L 1Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0436] In some embodiments, the present invention provides a compound of formula XV-a: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 8 and R 1 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0437] In some embodiments, the present invention provides a compound of formula XVI-a, formula XVI-b, or formula XVI-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 1 , R 3 , R 4 , R 9 , R 10 , -L 1 Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0438] In some embodiments, the present invention provides a compound of formula XVII-a, formula XVII-b, or formula XVII-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 1 , R 3 , R 9 , R 10 , -L 1Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0439] In some embodiments, the present invention provides a compound of formula XVIII-a, formula XVIII-b, or formula XVIII-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 3 , R 9 , R 10 , -L 1 Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0440] In some embodiments, the present invention provides a compound of formula XIX-a, formula XIX-b, or formula XIX-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 3 , R 10 , -L 1 Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0441] In some embodiments, the present invention provides a compound of formula XX-a, formula XX-b, or formula XX-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 10 , -L 1Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0442] In some embodiments, the present invention provides a compound of formula XXI-a, formula XXI-b, or formula XXI-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 10 , -L 1 Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0443] In some embodiments, the present invention provides a compound of formula XXII-a: [ka] or a pharmaceutically acceptable salt thereof, wherein: -L 1 -, -Cy-, and R 1 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0444] In some embodiments, the present invention provides a compound of formula XXIII-a, formula XXIII-b, or formula XXIII-c: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 1 , R 3 , R 10 , -L 1 Each of -, -Cy- provides a compound or a pharmaceutically acceptable salt thereof, as defined above and as described alone and in combination in the embodiments herein.

[0445] In some embodiments, the present invention provides a compound of formula XXIV-a: [ka] or a pharmaceutically acceptable salt thereof, wherein: -L 1 -, -Cy-, R 3 , and R 8 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0446] In some embodiments, the present invention provides a compound of formula XXV-a: [ka] or a pharmaceutically acceptable salt thereof, wherein: -L 1 -, -Cy-, R 3 , and R 8 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0447] In another aspect, the present invention provides a compound of formula Ib: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is [ka] and Y is N or CH; Z 1 is N, C=O or CR 2 and Z 2 is N, C=O, or CR 3 However, Z 1 and Z 2 are not both N or C=O, Each R 1 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; R 2 and R 3 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; or R 2 and R 3 together with the carbons to which they are attached, m R 5 and the ring is a 4- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 4are independently -R, halogen, =O, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; Each R 5 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; -L 2 -teeth, [ka] wherein -X- is covalently bonded to ring B and -X- is NR 6 , -O-, -CR 6 R 7 - or -S-, and -C(R 8 )2- or -C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 6 and R 7 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R), or -SR; Each R 8are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; R 9 is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R)2, or -SR, or R 8 and R 9 together with the atoms to which they are attached, m R 5 and the ring is a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and each R 10 are independently -R, halogen, CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; or R 8 and R 10 or R 9 and R 10 together with the atoms to which they are attached, form a ring substituted with m R5, said ring being a 6-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4.

[0448] As generally defined above, ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0449] In some embodiments, ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, ring A is phenyl. In some embodiments, ring A is an 8- to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, ring A is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0450] In some embodiments, ring A is [ka] is selected from.

[0451] In some embodiments, ring A is [ka] is selected from.

[0452] In some embodiments, ring A is selected from those shown in Table 1 below.

[0453] Ring B, as generally defined above, is [ka] is.

[0454] In some embodiments, ring B is [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] is.

[0455] In some embodiments, ring B is [ka] is.

[0456] In some embodiments, ring B is [ka] is selected from.

[0457] In some embodiments, ring B is [ka] is.

[0458] In some embodiments, ring B is [ka] is selected from.

[0459] In some embodiments, ring B is [ka] is.

[0460] In some embodiments, ring B is [ka] is selected from.

[0461] In some embodiments, ring B is [ka] is.

[0462] In some embodiments, ring B is [ka] is.

[0463] In some embodiments, ring B is [ka] is selected from.

[0464] In some embodiments, ring B is selected from those shown in Table 1 below.

[0465] As generally defined above, Y is N or CH.

[0466] In some embodiments, Y is N. In some embodiments, Y is CH.

[0467] In some embodiments, Y is CH. In some embodiments, Y is R 4 is replaced by

[0468] In some embodiments, Y is selected from those shown in Table 1 below.

[0469] Generally as defined above, Z 1 is N, C=O, or CR 2 is.

[0470] In some embodiments, Z 1 is N. In some embodiments, Z 1 is C=O. In some embodiments, Z 1 is CR 2 is.

[0471] In some embodiments, Z 1 is selected from those shown in Table 1 below.

[0472] Generally as defined above, Z 2is N, C=O, or CR 3 is.

[0473] In some embodiments, Z 2 is N. In some embodiments, Z 2 is C=O. In some embodiments, Z 2 is CR 3 is.

[0474] In some embodiments, Z 2 is selected from those shown in Table 1 below.

[0475] Generally as defined above, each R 1 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0476] In some embodiments, R 1 is R. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -NC. In some embodiments, R 1 is —C(O)OR. In some embodiments, R 1 is —OC(O)R. In some embodiments, R 1 is —C(O)N(R). In some embodiments, R 1 is —N(R)C(O)R. In some embodiments, R 1 is —N(R)C(O)N(R). In some embodiments, R 1 is -OC(O)N(R) 2である。 In some embodiments, R 1 is -N(R)C(O)OR 。 In some embodiments, R 1is -OR. In some embodiments, R 1 is -N(R). In some embodiments, R 1 is —NO. In some embodiments, R 1 is -N3. In some embodiments, R 1 is -SR. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is —S(O)N(R). In some embodiments, R 1 is -NRS(O)R.

[0477] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is an optionally substituted C 1-6 In some embodiments, R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 1 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0478] In some embodiments, R 1 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0479] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0480] As generally defined above, R 2 and R 3 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R; or R 2 and R 3 together with the carbons to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0481] In some embodiments, R 2 is R. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -NC. In some embodiments, R 2 is —C(O)OR. In some embodiments, R 2 is —OC(O)R. In some embodiments, R 2 is —C(O)N(R). In some embodiments, R 2 is —N(R)C(O)R. In some embodiments, R 2is —N(R)C(O)N(R). In some embodiments, R 2 is —OC(O)N(R). In some embodiments, R 2 is —N(R)C(O)OR. In some embodiments, R 2 is -OR. In some embodiments, R 2 is -N(R). In some embodiments, R 2 is —NO. In some embodiments, R 2 is -N3. In some embodiments, R 2 is -SR. In some embodiments, R 2 is —S(O)R. In some embodiments, R 2 is —S(O)R. In some embodiments, R 2 is —S(O)N(R). In some embodiments, R 2 is -NRS(O)R.

[0482] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is an optionally substituted C 1-6 In some embodiments, R 2 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 2 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0483] In some embodiments, R 2 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0484] In some embodiments, R 3 is R. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is -NC. In some embodiments, R 3 is —C(O)OR. In some embodiments, R 3 is —OC(O)R. In some embodiments, R 3 is —C(O)N(R). In some embodiments, R 3 is —N(R)C(O)R. In some embodiments, R 3 is —N(R)C(O)N(R). In some embodiments, R 3 is -OC(O)N(R) 2である。 In some embodiments, R 3 is -N(R)C(O)OR 。 In some embodiments, R 3 is -OR. In some embodiments, R 3 is -N(R). In some embodiments, R 3 is —NO. In some embodiments, R 3 is -N3. In some embodiments, R 3 is -SR. In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)N(R). In some embodiments, R 3 is -NRS(O)R.

[0485] In some embodiments, R 3is hydrogen. In some embodiments, R 3 is an optionally substituted C 1-6 In some embodiments, R 3 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 3 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0486] In some embodiments, R 3 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0487] In some embodiments, R2 and R3, together with the carbons to which they are attached, form a 4-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0488] In some embodiments, R2 and R 3 together with the carbon to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 and R 3 together with the carbon to which they are attached form a phenyl. In some embodiments, R 2 and R 3 together with the carbons to which they are attached form an 8-10 membered bicyclic aromatic carbocyclic ring. 2 and R 3 together with the carbon to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and R 3 together with the carbon to which they are attached form a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and R 3 together with the carbons to which they are attached form an 8-10 membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0489] In some embodiments, R 2 and R 3 together with the carbon to which they are attached form a cyclohexane ring. 2 and R 3 together with the carbon to which they are attached form a cyclopentane ring.

[0490] In some embodiments, R 2 and R 3 is selected from those shown in Table 1 below.

[0491] Generally as defined above, each R 4are independently -R, halogen, =O, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R.

[0492] In some embodiments, R 4 is R. In some embodiments, R 4 is a halogen. In some embodiments, R 4 is ═O. In some embodiments, R 4 is -CN. In some embodiments, R 4 is -NC. In some embodiments, R 4 is —C(O)OR. In some embodiments, R 4 is —OC(O)R. In some embodiments, R 4 is —C(O)N(R). In some embodiments, R 4 is —N(R)C(O)R. In some embodiments, R 4 is —N(R)C(O)N(R). In some embodiments, R 4 is -OC(O)N(R) 2である。 In some embodiments, R 4 is -N(R)C(O)OR 。 In some embodiments, R 4 is -OR. In some embodiments, R 4 is -N(R). In some embodiments, R 4 is —NO. In some embodiments, R 4 is -N3. In some embodiments, R 4 is -SR. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)N(R). In some embodiments, R 4 is -NRS(O)R.

[0493] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted C 1-6 In some embodiments, R 4 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 4 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0494] In some embodiments, R 4 are H, =O, Me, Et, iPr, [ka] is selected from.

[0495] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0496] Generally as defined above, each R 5is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0497] In some embodiments, R 5 is R. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is -CN. In some embodiments, R 5 is -NC. In some embodiments, R 5 is —C(O)OR. In some embodiments, R 5 is —OC(O)R. In some embodiments, R 5 is —C(O)N(R). In some embodiments, R 5 is —N(R)C(O)R. In some embodiments, R 5 is —N(R)C(O)N(R). In some embodiments, R 5 is —OC(O)N(R). In some embodiments, R 5 is -N(R)C(O)OR 。 In some embodiments, R 5 is -OR. In some embodiments, R 5 is -N(R). In some embodiments, R 5 is —NO. In some embodiments, R 5 is -N3. In some embodiments, R 5 is -SR. In some embodiments, R 5 is —S(O)R. In some embodiments, R 5 is —S(O)R. In some embodiments, R 5 is —S(O)N(R). In some embodiments, R 5 is -NRS(O)R.

[0498] In some embodiments, R5 is selected from those shown in Table 1 below.

[0499] Generally as defined above, -L 2 -teeth, [ka] is.

[0500] In some embodiments, -L 2 -teeth, [ka] In some embodiments, -L 2 -teeth, [ka] is.

[0501] X is NR as generally defined above. 6 , O, C.R. 6 R 7 , or S.

[0502] As generally defined above, R 6 and R 7 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R)2, or -SR.

[0503] In some embodiments, R 6 is R. In some embodiments, R 6 is a halogen. In some embodiments, R 6 is -CN. In some embodiments, R 6 is -NC. In some embodiments, R 6 is —C(O)OR. In some embodiments, R 6 is —OC(O)R. In some embodiments, R 6 is -OR. In some embodiments, R 6 is -N(R). In some embodiments, R6 is -SR.

[0504] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is an optionally substituted C 1-6 In some embodiments, R 6 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 6 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0505] In some embodiments, R 6 is selected from H, Me, Et, iPr, and OH.

[0506] In some embodiments, R 6 is selected from those shown in Table 1 below.

[0507] In some embodiments, R 7 is R. In some embodiments, R 7 is a halogen. In some embodiments, R 7 is -CN. In some embodiments, R 7 is -NC. In some embodiments, R 7 is —C(O)OR. In some embodiments, R 7is —OC(O)R. In some embodiments, R 7 is -OR. In some embodiments, R 7 is -N(R). In some embodiments, R 7 is -SR.

[0508] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is an optionally substituted C 1-6 In some embodiments, R 7 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 7 is optionally substituted phenyl. In some embodiments, R 7 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 7 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0509] In some embodiments, R 7 is selected from H, Me, Et, iPr, and OH.

[0510] In some embodiments, R 7 is selected from those shown in Table 1 below.

[0511] In some embodiments, X is selected from NH, O, S, NMe, CHMe, CHOH, C(Me)2, and C(Me)OH.

[0512] In some embodiments, X is selected from those shown in Table 1 below.

[0513] Generally as defined above, each R 8 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0514] In some embodiments, R 8 is R. In some embodiments, R 8 is a halogen. In some embodiments, R 8 is -CN. In some embodiments, R 8 is -NC. In some embodiments, R 8 is —C(O)OR. In some embodiments, R 8 is —OC(O)R. In some embodiments, R 8 is —C(O)N(R). In some embodiments, R 8 is —N(R)C(O)R. In some embodiments, R 8 is —N(R)C(O)N(R). In some embodiments, R 8 is —OC(O)N(R). In some embodiments, R 8 is -N(R)C(O)OR 。 In some embodiments, R 8 is -OR. In some embodiments, R 8 is -N(R). In some embodiments, R 8 is —NO. In some embodiments, R 8 is -N3. In some embodiments, R 8 is -SR. In some embodiments, R 8 is —S(O)R. In some embodiments, R 8 is —S(O)R. In some embodiments, R 8is —S(O)N(R). In some embodiments, R 8 is -NRS(O)R.

[0515] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is an optionally substituted C 1-6 In some embodiments, R 8 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 8 is optionally substituted phenyl. In some embodiments, R 8 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 8 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0516] In some embodiments, —C(R 8 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0517] In some embodiments, —C(R 8)2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 8 )2- is optionally replaced by phenyl. In some embodiments, -C(R 8 )2- is optionally replaced by an 8- to 10-membered bicyclic aromatic carbocyclic ring. 8 )2- is optionally replaced by a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R 8 )2- is optionally replaced by a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 )2- is optionally replaced by an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0518] In some embodiments, —C(R 8 )2-An example is [ka] can be optionally replaced with .

[0519] In some embodiments, R 8 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0520] In some embodiments, R 8 is selected from those shown in Table 1 below.

[0521] As generally defined above, R 9 is —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, —OR, —N(R)2, or —SR.

[0522] In some embodiments, R 9 is R. In some embodiments, R 9 is a halogen. In some embodiments, R 9 is -CN. In some embodiments, R 9 is -NC. In some embodiments, R 9 is —C(O)OR. In some embodiments, R 9 is —OC(O)R. In some embodiments, R 9 is -OR. In some embodiments, R 9 is -N(R). In some embodiments, R 9 is -SR.

[0523] In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is an optionally substituted C 1-6 In some embodiments, R 9 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 9 is optionally substituted phenyl. In some embodiments, R 9 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 9 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 9 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 9 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0524] In some embodiments, R 9 is selected from H, Me, Et, iPr, and OH.

[0525] In some embodiments, R 9 is selected from those shown in Table 1 below.

[0526] In some embodiments, R 8 and R 9 are m R's along with the atoms to which they are attached. 5 and the ring is a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0527] As generally defined above, R 10 is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0528] In some embodiments, R 10 is R. In some embodiments, R 10 is a halogen. In some embodiments, R 10 is -CN. In some embodiments, R 10 is -NC. In some embodiments, R 10 is —C(O)OR. In some embodiments, R 10 is —OC(O)R. In some embodiments, R 10 is —C(O)N(R). In some embodiments, R 10 is —N(R)C(O)R. In some embodiments, R 10 is —N(R)C(O)N(R). In some embodiments, R 10 is —OC(O)N(R). In some embodiments, R 10 is -N(R)C(O)OR 。 In some embodiments, R 10is -OR. In some embodiments, R 10 is -N(R). In some embodiments, R 10 is —NO. In some embodiments, R 10 is -N3. In some embodiments, R 10 is -SR. In some embodiments, R 10 is —S(O)R. In some embodiments, R 10 is —S(O)R. In some embodiments, R 10 is —S(O)N(R). In some embodiments, R 10 is -NRS(O)R.

[0529] In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is an optionally substituted C 1-6 In some embodiments, R 10 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 10 is optionally substituted phenyl. In some embodiments, R 10 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 10 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 10 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 10 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0530] In some embodiments, —C(R 10)2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0531] In some embodiments, —C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 10 )2- is optionally replaced by phenyl. In some embodiments, -C(R 10 )2- is optionally replaced by an 8- to 10-membered bicyclic aromatic carbocyclic ring. 10 )2- is optionally replaced by a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R 10 )2- is optionally replaced by a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R 10 )2- is optionally replaced by an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0532] In some embodiments, —C(R 10 )2-An example is [ka] is optionally replaced by

[0533] In some embodiments, R 10is selected from H, Me, Et, iPr, and CH3OH.

[0534] In some embodiments, R 10 is selected from those shown in Table 1 below.

[0535] In some embodiments, R 8 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 6-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0536] In some embodiments, R 9 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0537] In some embodiments, -L 2 -teeth, [ka] is selected from.

[0538] In some embodiments, -L 2 is selected from those shown in Table 1 below.

[0539] As generally defined above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3.

[0540] As generally defined above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3.

[0541] As generally defined above, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3.

[0542] As generally defined above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1, 2, or 3.

[0543] As generally defined above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 1, 2, or 3.

[0544] Exemplary DFL compounds of the present invention are listed below in Tables 1 and 1A.

[0545] Exemplary DFL compounds of the present invention are listed below in Tables 1, 1A, and 1B.

[0546] Exemplary DFL compounds of the present invention are listed below in Tables 1, 1A, 1B, and 1C.

[0547] In some embodiments, the present invention provides a compound of formula Id: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 12-membered bicyclic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered tricyclic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is [ka] and Y is N or CH; Z 1 is N, C=O or CR 2 and Z 2 is N, C=O, or CR 3 However, Z 1 and Z 2 are not both N or C=O, Each R 1are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; R 2 and R 3 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; or R 2 and R 3 together with the carbons to which they are attached, m R 5 and the ring is a 4- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 4 are independently -R, halogen, =O, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R or divalent straight or branched chain C 1-8a hydrocarbon chain wherein 1, 2, 3, or 4 methylene units of said chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO2-; Each R 5 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R; -L 2 -but, [ka] wherein -X- is covalently bonded to ring B and -X- is NR 6 , -O-, -CR 6 R 7 -, -C(O)-, -S- or S(O)2-, and -C(R 8 )2- or -C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 6 and R 7 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R), or -SR; Each R 8are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R, or two R 8 form, together with the carbon atoms to which they are attached, a 3- to 6-membered carbocyclic ring, R 9 is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R)2, or -SR, or R 8 and R 9 are m R's along with the atoms to which they are attached. 5 and forming a ring substituted with a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 10 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or two R 10 together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic ring, or R 9 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 6- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6an optionally substituted group selected from an aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 11 is H or a divalent straight or branched chain C 1-8 a hydrocarbon chain in which 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO2-; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; q is 0, 1, 2, 3, or 4; and r is 0, 1, 2, 3, or 4.

[0548] As generally defined above, Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-12 membered bicyclic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered tricyclic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0549] In some embodiments, ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, ring A is phenyl. In some embodiments, ring A is an 8- to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, ring A is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8- to 12-membered bicyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8-12 membered tricyclic heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0550] In some embodiments, ring A is [ka] is selected from.

[0551] In some embodiments, ring A is [ka] is selected from.

[0552] In some embodiments, ring A is selected from those shown in Table 1 below.

[0553] In some embodiments, ring A is selected from those shown in Table 1A below.

[0554] In some embodiments, ring A is selected from those shown in Table 1B below.

[0555] In some embodiments, ring A is selected from those shown in Table 1C below.

[0556] Ring B, as generally defined above, is [ka] is.

[0557] In some embodiments, ring B is [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] In some embodiments, ring B is: [ka] is.

[0558] In some embodiments, ring B is [ka] is.

[0559] In some embodiments, ring B is [ka] is selected from.

[0560] In some embodiments, ring B is [ka] is.

[0561] In some embodiments, ring B is [ka] is selected from.

[0562] In some embodiments, ring B is [ka] is.

[0563] In some embodiments, ring B is [ka] is selected from.

[0564] In some embodiments, ring B is [ka] is.

[0565] In some embodiments, ring B is [ka] is.

[0566] In some embodiments, ring B is [ka] is selected from.

[0567] In some embodiments, ring B is selected from those shown in Table 1 below.

[0568] In some embodiments, ring B is selected from one of those shown in Table 1A below.

[0569] In some embodiments, ring B is selected from one of those shown in Table 1B below.

[0570] In some embodiments, ring B is selected from one of those shown in Table 1C below.

[0571] As generally defined above, Y is N or CH.

[0572] In some embodiments, Y is N. In some embodiments, Y is CH.

[0573] In some embodiments, Y is CH. In some embodiments, Y is R 4 is replaced by

[0574] In some embodiments, Y is selected from those shown in Table 1 below.

[0575] In some embodiments, Y is selected from those shown in Table 1A below.

[0576] In some embodiments, Y is selected from those shown in Table 1B below.

[0577] In some embodiments, Y is selected from one of those shown in Table 1C below.

[0578] Generally as defined above, Z 1 is N, C=O, or CR 2 is.

[0579] In some embodiments, Z 1 is N. In some embodiments, Z 1 is C=O. In some embodiments, Z 1 is CR 2 is.

[0580] In some embodiments, Z 1 is selected from those shown in Table 1 below.

[0581] In some embodiments, Z 1 is selected from those shown in Table 1A below.

[0582] In some embodiments, Z 1 is selected from those shown in Table 1B below.

[0583] In some embodiments, Z 1 is selected from one of those shown in Table 1C below.

[0584] Generally as defined above, Z 2 is N, C=O, or CR 3 is.

[0585] In some embodiments, Z 2 is N. In some embodiments, Z 2 is C=O. In some embodiments, Z 2 is CR 3 is.

[0586] In some embodiments, Z 2 is selected from those shown in Table 1 below.

[0587] In some embodiments, Z 2 is selected from those shown in Table 1A below.

[0588] In some embodiments, Z 2 is selected from those shown in Table 1B below.

[0589] In some embodiments, Z 2 is selected from those shown in Table 1C below.

[0590] Generally as defined above, each R 1 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0591] In some embodiments, R 1 is R. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -NC. In some embodiments, R 1 is —C(O)OR. In some embodiments, R 1 is —OC(O)R. In some embodiments, R 1 is —C(O)N(R). In some embodiments, R 1 is —N(R)C(O)R. In some embodiments, R 1 is —N(R)C(O)N(R). In some embodiments, R 1 is -OC(O)N(R) 2である。 In some embodiments, R 1 is -N(R)C(O)OR 。 In some embodiments, R 1 is -OR. In some embodiments, R 1is -N(R). In some embodiments, R 1 is —NO. In some embodiments, R 1 is -N3. In some embodiments, R 1 is -SR. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1 is —S(O)N(R). In some embodiments, R 1 is -NRS(O)R.

[0592] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is an optionally substituted C 1-6 In some embodiments, R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 1 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0593] In some embodiments, R 1 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0594] In some embodiments, R 1 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0595] In some embodiments, R 1 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0596] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0597] In some embodiments, R 1 is selected from those shown in Table 1A below.

[0598] In some embodiments, R 1 is selected from those shown in Table 1B below.

[0599] In some embodiments, R 1 is selected from those shown in Table 1C below.

[0600] R2 and R3 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, or -NRS(O)2R, as generally defined above, or R 2 and R 3 together with the carbons to which they are attached, m R 5and the ring forms a substituted ring comprising a 4-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0601] In some embodiments, R 2 is R. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -NC. In some embodiments, R 2 is —C(O)OR. In some embodiments, R 2 is —OC(O)R. In some embodiments, R 2 is —C(O)N(R). In some embodiments, R 2 is —N(R)C(O)R. In some embodiments, R 2 is —N(R)C(O)N(R). In some embodiments, R 2 is —OC(O)N(R). In some embodiments, R 2 is —N(R)C(O)OR. In some embodiments, R 2 is -OR. In some embodiments, R 2 is -N(R). In some embodiments, R 2 is —NO. In some embodiments, R 2 is -N3. In some embodiments, R 2 is -SR. In some embodiments, R 2 is —S(O)R. In some embodiments, R 2 is —S(O)R. In some embodiments, R 2 is —S(O)N(R). In some embodiments, R 2 is -NRS(O)R.

[0602] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is an optionally substituted C 1-6 In some embodiments, R 2 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 2 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0603] In some embodiments, R 2 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0604] In some embodiments, R 2 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0605] In some embodiments, R 3 is R. In some embodiments, R 3 is a halogen. In some embodiments, R3 is -CN. In some embodiments, R 3 is -NC. In some embodiments, R 3 is —C(O)OR. In some embodiments, R 3 is —OC(O)R. In some embodiments, R 3 is —C(O)N(R). In some embodiments, R 3 is —N(R)C(O)R. In some embodiments, R 3 is —N(R)C(O)N(R). In some embodiments, R 3 is -OC(O)N(R) 2である。 In some embodiments, R 3 is -N(R)C(O)OR 。 In some embodiments, R 3 is -OR. In some embodiments, R 3 is -N(R). In some embodiments, R 3 is —NO. In some embodiments, R 3 is -N3. In some embodiments, R 3 is -SR. In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)R. In some embodiments, R 3 is —S(O)N(R). In some embodiments, R 3 is -NRS(O)R.

[0606] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an optionally substituted C 1-6 In some embodiments, R 3 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 3is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0607] In some embodiments, R 3 are H, F, Cl, OH, Me, Et, CF3, CN, -C(O)NH2, i-Pr, [ka] is selected from.

[0608] In some embodiments, R 3 are H, F, Cl, OH, Me, Et, CF3, CN, -C(O)NH2, i-Pr, [ka] is selected from.

[0609] In some embodiments, R 3 is selected from H, F, Cl, Me, and Et.

[0610] In some embodiments, R2 and R3, together with the carbons to which they are attached, form a 4-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0611] In some embodiments, R 2 and R 3 together with the carbon to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 and R 3 together with the carbon to which they are attached form a phenyl. In some embodiments, R 2 and R 3 together with the carbons to which they are attached form an 8-10 membered bicyclic aromatic carbocyclic ring. 2 and R 3 together with the carbon to which they are attached form a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and R 3 together with the carbon to which they are attached form a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and R 3 together with the carbons to which they are attached form an 8-10 membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0612] In some embodiments, R 2 and R 3 together with the carbon to which they are attached form a cyclohexane ring. 2 and R 3 together with the carbon to which they are attached form a cyclopentane ring.

[0613] In some embodiments, R 2 and R 3 is selected from those shown in Table 1 below.

[0614] In some embodiments, R 2 and R 3is selected from those shown in Table 1A below.

[0615] In some embodiments, R 2 and R 3 is selected from those shown in Table 1B below.

[0616] In some embodiments, R2 and R3 are selected from those shown in Table 1C below.

[0617] Generally as defined above, each R 4 are independently -R, halogen, =O, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or a divalent straight or branched chain C 1-8 A hydrocarbon chain wherein 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO2-.

[0618] In some embodiments, R 4 is R. In some embodiments, R 4 is a halogen. In some embodiments, R 4 is ═O. In some embodiments, R 4 is -CN. In some embodiments, R 4 is -NC. In some embodiments, R 4 is —C(O)OR. In some embodiments, R 4 is —OC(O)R. In some embodiments, R 4 is —C(O)N(R). In some embodiments, R 4 is —N(R)C(O)R. In some embodiments, R 4is —N(R)C(O)N(R). In some embodiments, R 4 is -OC(O)N(R) 2である。 In some embodiments, R 4 is -N(R)C(O)OR 。 In some embodiments, R 4 is -OR. In some embodiments, R 4 is -N(R). In some embodiments, R 4 is —NO. In some embodiments, R 4 is -N3. In some embodiments, R 4 is -SR. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)R. In some embodiments, R 4 is —S(O)N(R). In some embodiments, R 4 is -NRS(O)R. In some embodiments, R 4 is C 1-8 A divalent straight or branched hydrocarbon chain in which 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO2-.

[0619] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted C 1-6 In some embodiments, R 4 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 4is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0620] In some embodiments, R 4 are H, =O, Me, Et, iPr, [ka] is selected from.

[0621] In some embodiments, R 4 are H, =O, Me, Et, iPr, [ka] is selected from.

[0622] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0623] In some embodiments, R 4 is selected from those shown in Table 1A below.

[0624] In some embodiments, R 4 is selected from those shown in Table 1B below.

[0625] In some embodiments, R 4 is selected from those shown in Table 1C below.

[0626] Generally as defined above, each R 5is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0627] In some embodiments, R 5 is R. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is -CN. In some embodiments, R 5 is -NC. In some embodiments, R 5 is —C(O)OR. In some embodiments, R 5 is —OC(O)R. In some embodiments, R 5 is —C(O)N(R). In some embodiments, R 5 is —N(R)C(O)R. In some embodiments, R 5 is —N(R)C(O)N(R). In some embodiments, R 5 is —OC(O)N(R). In some embodiments, R 5 is -N(R)C(O)OR 。 In some embodiments, R 5 is -OR. In some embodiments, R 5 is -N(R). In some embodiments, R 5 is —NO. In some embodiments, R 5 is -N3. In some embodiments, R 5 is -SR. In some embodiments, R 5 is —S(O)R. In some embodiments, R 5 is —S(O)R. In some embodiments, R 5 is —S(O)N(R). In some embodiments, R 5 is -NRS(O)R.

[0628] In some embodiments, R5 is selected from those shown in Table 1 below.

[0629] In some embodiments, R 5 is selected from those shown in Table 1A below.

[0630] In some embodiments, R 5 is selected from those shown in Table 1B below.

[0631] In some embodiments, R5 is selected from those shown in Table 1C below.

[0632] Generally as defined above, -L 2 -teeth, [ka] is.

[0633] In some embodiments, -L 2 -teeth, [ka] In some embodiments, -L 2 -teeth, [ka] is.

[0634] As generally defined above, R 6 and R 7 are each independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R)2, or -SR.

[0635] In some embodiments, R 6 is R. In some embodiments, R 6 is a halogen. In some embodiments, R 6 is -CN. In some embodiments, R 6 is -NC. In some embodiments, R 6is —C(O)OR. In some embodiments, R 6 is —OC(O)R. In some embodiments, R 6 is -OR. In some embodiments, R 6 is -N(R). In some embodiments, R 6 is -SR.

[0636] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is an optionally substituted C 1-6 In some embodiments, R 6 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 6 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0637] In some embodiments, R 6 is selected from H, Me, Et, iPr, F, and OH.

[0638] In some embodiments, R 6 is selected from those shown in Table 1 below.

[0639] In some embodiments, R 6 is selected from those shown in Table 1A below.

[0640] In some embodiments, R 6 is selected from those shown in Table 1B below.

[0641] In some embodiments, R 6 is selected from one of those shown in Table 1C below.

[0642] In some embodiments, R 7 is R. In some embodiments, R 7 is a halogen. In some embodiments, R 7 is -CN. In some embodiments, R 7 is -NC. In some embodiments, R 7 is —C(O)OR. In some embodiments, R 7 is —OC(O)R. In some embodiments, R 7 is -OR. In some embodiments, R 7 is -N(R). In some embodiments, R 7 is -SR.

[0643] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is an optionally substituted C 1-6 In some embodiments, R 7 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 7 is optionally substituted phenyl. In some embodiments, R 7 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 7 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0644] In some embodiments, R 7 is selected from H, Me, Et, iPr, F, and OH.

[0645] In some embodiments, R 7 is selected from those shown in Table 1 below.

[0646] In some embodiments, R 7 is selected from those shown in Table 1A below.

[0647] In some embodiments, R 7 is selected from those shown in Table 1B below.

[0648] In some embodiments, R 7 is selected from one of those shown in Table 1C below.

[0649] X is a bond, NR 6 , O, C.R. 6 R 7 -C(O)-, -S-, or -S(O)2-.

[0650] In some embodiments, X is selected from a bond, NH, O, S, SO, C(O), NMe, CF, CHMe, CHOH, C(Me) and C(Me)OH.

[0651] In some embodiments, X is selected from those shown in Table 1 below.

[0652] In some embodiments, X is selected from those shown in Table 1A below.

[0653] In some embodiments, X is selected from those shown in Table 1B below.

[0654] In some embodiments, X is selected from those shown in Table 1C below.

[0655] Generally as defined above, each R 8 are independently -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -OR, -N(R)2, -NO2, -N3, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or two R 8 However, together with the carbon atoms to which they are attached, they form a 3- to 6-membered carbocyclic ring.

[0656] In some embodiments, R 8 is R. In some embodiments, R 8 is a halogen. In some embodiments, R 8 is -CN. In some embodiments, R 8 is -NC. In some embodiments, R 8 is —C(O)OR. In some embodiments, R 8 is —OC(O)R. In some embodiments, R 8 is —C(O)N(R). In some embodiments, R 8 is —N(R)C(O)R. In some embodiments, R 8 is —N(R)C(O)N(R). In some embodiments, R 8 is —OC(O)N(R). In some embodiments, R 8 is -N(R)C(O)OR 。 In some embodiments, R 8 is -OR. In some embodiments, R 8 is -N(R). In some embodiments, R 8 is —NO. In some embodiments, R 8 is -N3. In some embodiments, R 8 is -SR. In some embodiments, R 8is —S(O)R. In some embodiments, R 8 is —S(O)R. In some embodiments, R 8 is —S(O)N(R). In some embodiments, R 8 is -NRS(O)R. In some embodiments, two R 8 together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic ring.

[0657] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is an optionally substituted C 1-6 In some embodiments, R 8 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 8 is optionally substituted phenyl. In some embodiments, R 8 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 8 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0658] In some embodiments, —C(R 8)2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0659] In some embodiments, —C(R 8 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 8 )2- is optionally replaced by phenyl. In some embodiments, -C(R 8 )2- is optionally replaced by an 8- to 10-membered bicyclic aromatic carbocyclic ring. 8 )2- is optionally replaced by a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R 8 )2- is optionally replaced by a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R 8 )2- is optionally replaced by an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0660] In some embodiments, —C(R 8 )2-An example is [ka] can be optionally replaced with .

[0661] In some embodiments, R 8are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0662] In some embodiments, R 8 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0663] In some embodiments, R 8 are H, F, Cl, OH, Me, Et, i-Pr, [ka] [ka] is selected from.

[0664] In some embodiments, two R 8 together with the carbon atoms to which they are attached form a cyclopropane ring.

[0665] In some embodiments, two R 8 together with the carbon atoms to which they are attached form a cyclobutane ring.

[0666] In some embodiments, R 8 is selected from those shown in Table 1 below.

[0667] In some embodiments, R 8 is selected from those shown in Table 1A below.

[0668] In some embodiments, R 8 is selected from those shown in Table 1B below.

[0669] In some embodiments, R 8is selected from one of those shown in Table 1C below.

[0670] As generally defined above, R 9 is —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, —OR, —N(R)2, or —SR.

[0671] In some embodiments, R 9 is R. In some embodiments, R 9 is a halogen. In some embodiments, R 9 is -CN. In some embodiments, R 9 is -NC. In some embodiments, R 9 is —C(O)OR. In some embodiments, R 9 is —OC(O)R. In some embodiments, R 9 is -OR. In some embodiments, R 9 is -N(R). In some embodiments, R 9 is -SR.

[0672] In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is an optionally substituted C 1-6 In some embodiments, R 9 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 9 is optionally substituted phenyl. In some embodiments, R 9 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 9 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 9 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 9is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0673] In some embodiments, R 9 H, Me, Et, iPr, [ka] and OH.

[0674] In some embodiments, R 9 is selected from those shown in Table 1 below.

[0675] In some embodiments, R 9 is selected from those shown in Table 1A below.

[0676] In some embodiments, R 9 is selected from those shown in Table 1B below.

[0677] In some embodiments, R 9 is selected from one of those shown in Table 1C below.

[0678] In some embodiments, R 8 and R 9 are m R's along with the atoms to which they are attached. 5 and the ring is a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0679] As generally defined above, R 10 is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)N(R), -OC(O)N(R), -N(R)C(O)OR, -OR, -N(R), -NO, -N, -SR, -S(O)R, -S(O)R, -S(O)N(R), or -NRS(O)R.

[0680] In some embodiments, R 10 is R. In some embodiments, R 10 is a halogen. In some embodiments, R 10 is -CN. In some embodiments, R 10 is -NC. In some embodiments, R 10 is —C(O)OR. In some embodiments, R 10 is —OC(O)R. In some embodiments, R 10 is —C(O)N(R). In some embodiments, R 10 is —N(R)C(O)R. In some embodiments, R 10 is —N(R)C(O)N(R). In some embodiments, R 10 is —OC(O)N(R). In some embodiments, R 10 is -N(R)C(O)OR 。 In some embodiments, R 10 is -OR. In some embodiments, R 10 is -N(R). In some embodiments, R 10 is —NO. In some embodiments, R 10 is -N3. In some embodiments, R 10 is -SR. In some embodiments, R 10 is —S(O)R. In some embodiments, R 10 is —S(O)R. In some embodiments, R 10 is —S(O)N(R). In some embodiments, R 10 is -NRS(O)R.

[0681] In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is an optionally substituted C 1-6 In some embodiments, R 10 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 10is optionally substituted phenyl. In some embodiments, R 10 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 10 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 10 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 10 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0682] In some embodiments, —C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0683] In some embodiments, —C(R 10 )2- is optionally replaced by a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 10 )2- is optionally replaced by phenyl. In some embodiments, -C(R 10 )2- is optionally replaced by an 8- to 10-membered bicyclic aromatic carbocyclic ring. 10 )2- is optionally replaced by a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R10 )2- is optionally replaced by a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -C(R 10 )2- is optionally replaced by an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0684] In some embodiments, —C(R 10 )2-An example is [ka] is optionally replaced by

[0685] In some embodiments, two R 10 form a cyclopropane ring together with the carbon atoms to which they are attached.

[0686] In some embodiments, R 10 H, Me, Et, iPr, [ka] and CH3OH.

[0687] In some embodiments, R 10 H, Me, Et, iPr, [ka] is selected from.

[0688] In some embodiments, R 10 is selected from those shown in Table 1 below.

[0689] In some embodiments, R 10 is selected from those shown in Table 1A below.

[0690] In some embodiments, R 10is selected from those shown in Table 1B below.

[0691] In some embodiments, R 10 is selected from those shown in Table 1C below.

[0692] In some embodiments, R 8 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 6-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0693] In some embodiments, R 9 and R 10 are m R's along with the atoms to which they are attached. 5 and the ring is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0694] As generally defined above, R 11 is H or a divalent straight or branched chain C 1-8 A hydrocarbon chain in which 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO2-.

[0695] In some embodiments, R 11 is H. In some embodiments, R 11 is a divalent straight or branched chain C 1-8 A hydrocarbon chain in which 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO2-.

[0696] In some embodiments, R 11 H, Me, Et, iPr, [ka] is selected from.

[0697] In some embodiments, R 11 H, Me, Et, iPr, [ka] is selected from.

[0698] In some embodiments, R 11 is selected from those shown in Table 1A below.

[0699] In some embodiments, R 11 is selected from those shown in Table 1B below.

[0700] In some embodiments, R 11 is selected from those shown in Table 1C below.

[0701] In some embodiments, -L 2 -teeth, [ka] is selected from.

[0702] In some embodiments, -L 2 is selected from those shown in Table 1 below.

[0703] In some embodiments, -L 2 is selected from those shown in Table 1A below.

[0704] In some embodiments, -L 2 is selected from those shown in Table 1B below.

[0705] In some embodiments, -L 2 is selected from those shown in Table 1C below.

[0706] As generally defined above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3.

[0707] As generally defined above, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3.

[0708] As generally defined above, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3.

[0709] As generally defined above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1, 2, or 3.

[0710] As generally defined above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 1, 2, or 3.

[0711] Exemplary DFL compounds of the present invention are listed in Table 1 below.

[0712] Exemplary DFL compounds of the present invention are listed below in Table 1A.

[0713] Exemplary DFL compounds of the present invention are listed below in Table 1B.

[0714] Exemplary DFL compounds of the present invention are listed below in Table 1C.

[0715] In some embodiments, the present invention provides a compound of formula II-c or II-d: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R10 , -L 2 Each of -, X, n, q, and r is as defined above and as described in the embodiments herein, both alone and in combination, to provide a compound or a pharmaceutically acceptable salt thereof.

[0716] In some embodiments, the present invention provides a compound of formula III-b: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , X, and n are each as defined above and as described in the embodiments herein, both alone and in combination, to provide a compound or a pharmaceutically acceptable salt thereof.

[0717] In some embodiments, the present invention provides a compound of formula IV-e or IV-f: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R 3 , R 4 , R 8 , and n are each as defined above and as described alone and in combination in the embodiments herein.

[0718] In some embodiments, the present invention provides a compound of formula IV-g or IV-h: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8and n are each as defined above and as described in the embodiments herein, both alone and in combination, to provide a compound or a pharmaceutically acceptable salt thereof.

[0719] In some embodiments, the present invention provides a compound of formula Vb: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 4 , R 5 , R 6 , R 7 Each of X, m, and n is as defined above and as described in the embodiments herein, both alone and in combination, to provide a compound or a pharmaceutically acceptable salt thereof.

[0720] In some embodiments, the present invention provides a compound of formula VI-e or VI-f: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 Each of m, m, and n is as defined above and as described in the embodiments herein, both alone and in combination, to provide a compound or a pharmaceutically acceptable salt thereof.

[0721] In some embodiments, the present invention provides a compound of formula VI-g or VI-h: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , m, and n are each as defined above and as described in the embodiments herein, both alone and in combination, to provide a compound or a pharmaceutically acceptable salt thereof.

[0722] In some embodiments, the present invention provides a compound of formula VII-b: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 4 , R 5 , R 6 , R 7 Each of X, m, and n is as defined above and as described in the embodiments herein, both alone and in combination, to provide a compound or a pharmaceutically acceptable salt thereof.

[0723] In some embodiments, the present invention provides a compound of formula VIII-e or VIII-f: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , m, and n are each as defined above and as described in the embodiments herein, both alone and in combination, to provide a compound or a pharmaceutically acceptable salt thereof.

[0724] In some embodiments, the present invention provides a compound of formula VIII-g or VIII-h: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, R, R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 , R 8 , m and n are each as defined above and as described in the embodiments herein, both alone and in combination, to provide a compound or a pharmaceutically acceptable salt thereof.

[0725] In some embodiments, the present invention provides a compound of formula IX-d, formula IX-e, or formula IX-f: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 1 , R 3 , R 4 , R 8 , R 9 , and R 10 Each of the following is defined above and is as described alone and in combination in the embodiments herein, providing a compound or a pharmaceutically acceptable salt thereof.

[0726] In some embodiments, R 1 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0727] In some embodiments, R 3 are H, F, Cl, OH, Me, Et, CF3, CN, -C(O)NH2, i-Pr, [ka] is selected from.

[0728] In some embodiments, R 4 are H, =O, Me, Et, iPr, [ka] is selected from.

[0729] In some embodiments, R 8 are H, F, Cl, OH, Me, Et, i-Pr, [ka] is selected from.

[0730] In some embodiments, R 9 H, Me, Et, iPr, [ka] and OH.

[0731] In some embodiments, R 10 H, Me, Et, iPr, [ka] and CH3OH.

[0732] In some embodiments, the present invention provides a compound of formula Xd, formula Xe, or formula Xf: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 1 , R 3 , R 8 , R 9 , R 10 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0733] In some embodiments, the present invention provides a compound of formula XI-d, formula XI-e, or formula XI-f: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 3 , R 8 , R 9 , R 10 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0734] In some embodiments, the present invention provides a compound of formula XII-d, formula XII-e, or formula XII-f: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 3 , R 8 , R 10 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0735] In some embodiments, the present invention provides a compound of formula XIII-d, formula XIII-e, or formula XIII-f: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 8 , R 10 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0736] In some embodiments, the present invention provides a compound of formula XIV-d, formula XIV-e, or formula XIV-f: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 8 , R 10provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0737] In some embodiments, the present invention provides a compound of formula XV-b: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 8 and R 1 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0738] In some embodiments, the present invention provides a compound of formula XXIII-d, formula XXIII-e, or formula XXIII-f: [ka] or a pharmaceutically acceptable salt thereof, wherein: R, R 1 , R 3 , R 10 , R 8 , -Cy-, each of which is as defined above and as described alone and in combination in the embodiments herein, to provide a compound or a pharmaceutically acceptable salt thereof.

[0739] In some embodiments, the present invention provides a compound of formula XXIV-b: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 3 , and R 8 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein.

[0740] In some embodiments, the present invention provides a compound of formula XXV-b: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 3 , and R 8 provides a compound or a pharmaceutically acceptable salt thereof, each of which is as defined above and as described alone and in combination in the embodiments herein. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] Table 1A-1 Table 1A-2 Table 1A-3 Table 1A-4 Table 1A-5 Table 1A-6 Table 1A-7

Table 1A-8

Table 1A-9

Table 1A-10

Table 1A-11

Table 1A-12

Table 1A-13

Table 1A-14

Table 1C-1

Table 1C-2

Table 1C-3

Table 1C-4

Table 1C-5

Table 1C-6

Table 1C-7

Table 1C-8

Table 1C-9

Table 1C-10

Table 1C-11

Table 1C-12

Table 1C-13

Table 1C-14

Table 1C-15

Table 1C-16

Table 1C-17

Table 1C-18

Table 1C-19

Table 1C-20

Table 1C-21

Table 1C-22

[0741] In some embodiments, compoundsは、I-1、I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-11、I-12、I-13、I-14、I-15、I-16、I-17、I-18、I-19、I-20、I-21、 I-22、I-23、I-24、I-25、I-26、I-27、I-28、I-29、I-30、I-31、I-32、I-33、I-34、I-35、I-36、I-37、I-38、I-39、I-40、I-41、I-42、I-43、I- 44、I-45、I-46、I-47、I-48、I-49、I-50、I-51、I-52、I-53、I-54、I-55、I-56、I-57、I-58、I-59、I-60、I-61、I-62、I-63、I-64、I-65、I-66 、I-67、I-68、I-69、I-70、I-71、I-72、I-73、I-74、I-75、I-76、I-77、I-78、I-79、I-80、I-81、I-82、I-83、I-84、I-85、I-86、I-87、I-88、I -89、I-90、I-91、I-92、I-93、I-94、I-95、I-96、I-97、I-98、I-99、I-100、I-101、I-102、I-103、I-104、I-105、I-106、I-107、I-108、I-1 09、I-110、I-111、I-112、I-113、I-114、I-115、I-116、I-117、I-118、I-119、I-120、I-121、I-122、I-123、I-124、I-125、I-126、I-127、I -128、I-129、I-130、I-131、I-132、I-133、I-134、I-135、I-136、I-137、I-138、I-139、I-140、I-141、I-142、I-143、I-144、I-145、I-146 、I-147、I-148、I-149、I-150、I-151、I-152、I-153、I-154、I-155、I-156、I-157、I-158、I-159、I-160、I-161、I-162、I-163 からしまするるまするるます

[0742] In some embodiments, compoundsは、I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-11、I-12、I-13、I-14、I- 15、I-16、I-17、I-18、I-19、I-20、I-21、I-22、I-23、I-24、I-25、I-26、I-27、I-28、I-29、I -30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59 and I-60 are selected.

[0743] In some embodiments, compoundsは、I-1、I-61、I-62、I-63、I-64、I-65、I-66、I-67、I-68、I-69、I-70、I-71 、I-72、I-73、I-74、I-75、I-76、I-77、I-78、I-79、I-80、I-81、I-82、I-83、I-84、I-85、I-8 6、I-87、I-88、I-89、I-90、I-91、I-92、I-93、I-94、I-95、I-96、I-97、I-98、I-99、I-100、I -101、I-102、I-103、I-104、I-105、I-106、I-107、I-108、I-109、I-110、I-111、I-112、I-1 13、I-114、I-115、I-116、I-117、I-118、I-119、I-120、I-121、I-122、I-123、I-124、I-125 、I-126、I-127、I-128、I-129、I-130、I-131、I-132、I-133、I-134、I-135、I-136、I-137、I -138、I-139、I-140、I-141、I-142、I-143、I-144、I-145、I-146、I-147、I-148、I-149、I-1 50、I-151、I-152、I-153、I-154、I-155、I-156、I-157、I-158、I-159、I-160、I-161、I-162 And I-163 is not.

[0744] In some embodiments, the compounds are I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49 、I-50、I-51、I-52、I-53、I-54、I-55、I-56、I-57、I-58、I-59、I-60、I-61、I -62、I-63、I-64、I-65、I-66、I-67、I-68、I-69、I-70、I-71、I-72、I-73、I-74 、I-75、I-76、I-77、I-78、I-79、I-80、I-81、I-82、I-83、I-84、I-85、I-86、I -87、I-88、I-89、I-90、I-91、I-92、I-93、I-94、I-95、I-96、I-97、I-98、I-99 、I-100、I-101、I-102、I-103、I-104、I-105、I-106、I-107、I-108、I-109、I -110、I-111、I-112、I-113、I-114、I-115、I-116、I-117、I-118、I-119、I-1 20、I-121、I-122、I-123、I-124、I-125、I-126、I-127、I-128、I-129、I-130 、I-131、I-132、I-133、I-134、I-135、I-136、I-137、I-138、I-139、I-140、I- 141、I-142、I-143、I-144、I-145、I-146、I-147、I-148、I-149、I-150、I-15 1、I-152、I-153、I-154、I-155、I-156、I-157、I-158、I-159、I-160、I-161、I -162、I-163、I-164、I-165、I-166、I-167、I-168、I-169、I-170、I-171、I-1 72、I-173、I-174、I-175、I-176、I-177、I-178、I-179、I-180、I-181、I-182、Selected from I-183, I-184, I-185, I-186, I-187, I-188, I-189, I-190, I-191, I-192, I-193, I-194, I-195, I-196, I-197, I-198, I-199, I-200, I-201, I-202, I-203, I-204, I-205, I-206, I-207, I-208, I-209, I-210, I-211, I-212, I-213, I-214, I-215, I-216, I-217, I-218, I-219, I-220, I-221, I-222, I-223, I-224, I-225, I-226, I-227, I-228, I-229, I-230, I-231, I-232, I-233, I-234, I-235, I-236, I-237, I-238, I-239, I-240, I-241, I-242, I-243, I-244, I-245, I-246, I-247, I-248, I-249, I-250, I-251, I-252, I-253, I-254, I-255, I-256, I-257, I-258, I-259, I-260, I-261, I-262, I-263, I-264, I-265, I-266, I-267, I-268, I-269, I-270, I-271, I-272, I-273, I-274, I-275, I-276, I-277, I-278, I-279, I-280, I-281, I-282, I-283, I-284, I-285, I-286, I-287, I-288, I-289, I-290, I-291, I-292, I-293, I-294, I-295, I-296, I-297, I-298, I-299, I-300, I-301, I-302, I-303, I-304, I-305, I-306, I-307, I-308, I-309, I-310, I-311, I-312, I-313, I-314, I-315, I-316, I-317, I-318, I-319, I-320, and I-321.

[0745] In some embodiments, compounds are from I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-11、I-12、I-13、I-14、I-15 、I-16、I-17、I-18、I-19、I-20、I-21、I-22、I-23、I-24、I-25、I-26、I-27、 I-28、I-29、I-30、I-31、I-32、I-33、I-34、I-35、I-36、I-37、I-38、I-39、I -40、I-41、I-42、I-43、I-44、I-45、I-46、I-47、I-48、I-49、I-50、I-51、I- 52、I-53、I-54、I-55、I-56、I-57、I-58、I-59、I-60、I-164、I-165、I-166、 I-167、I-168、I-169、I-170、I-171、I-172、I-173、I-174、I-175、I-176、I -177、I-178、I-179、I-180、I-181、I-182、I-183、I-184、I-185、I-186、I- 187、I-188、I-189、I-190、I-191、I-192、I-193、I-194、I-195、I-196、I-1 97、I-198、I-199、I-200、I-201、I-202、I-203、I-204、I-205、I-206、I-20 7、I-208、I-209、I-210、I-211、I-212、I-213、I-214、I-215、I-216、I-217 、I-218、I-219、I-220、I-221、I-222、I-223、I-224、I-225、I-226、I-227、 I-228、I-229、I-230、I-231、I-232、I-233、I-234、I-235、I-236、I-237、I -238、I-239、I-240、I-241、I-242、I-243、I-244、I-245、I-246、I-247、I- 248、I-249、I-250、I-251、I-252、I-253、I-254、I-255、I-256、I-257、I-2 58、I-259、I-260、I-261、I-262、I-263、I-264、I-265、I-266、I-267、I-26 8、I-269、I-270、I-271、I-272、I-273、I-274、I-275、I-276、I-277、I-278、I-279、I-280、I-281、I-282、I-283、I-284、I-285、I-286、I-287、I-288、I-289、I -290、I-291、I-292、I-293、I-294、I-295、I-296、I-297、I-298、I-299、I-300、I- 301、I-302、I-303、I-304、I-305、I-306、I-307、I-308、I-309、I-310、I-311、I-3 12、I-313、I-314、I-315、I-316、I-317、I-318、I-319、I-320、and I-321 are selected from.、

[0746] In some embodiments, compoundsは、I-164、I-165、I-166、I-167、I-168、I-169、I-170、I-171、I-172、I-173、I-174、I-175、I-176、I-177、I-178、I-179、I-180、I-18 1、I-182、I-183、I-184、I-185、I-186、I-187、I-188、I-189、I-190、I-191 、I-192、I-193、I-194、I-195、I-196、I-197、I-198、I-199、I-200、I-201、 I-202、I-203、I-204、I-205、I-206、I-207、I-208、I-209、I-210、I-211、 I-212、I-213、I-214、I-215、I-216、I-217、I-218、I-219、I-220、I-221、I -222、I-223、I-224、I-225、I-226、I-227、I-228、I-229、I-230、I-231、I- 232、I-233、I-234、I-235、I-236、I-237、I-238、I-239、I-240、I-241、I-2 42、I-243、I-244、I-245、I-246、I-247、I-248、I-249、I-250、I-251、I-2 52、I-253、I-254、I-255、I-256、I-257、I-258、I-259、I-260、I-261、I-26 2、I-263、I-264、I-265、I-266、I-267、I-268、I-269、I-270、I-271、I-272 、I-273、I-274、I-275、I-276、I-277、I-278、I-279、I-280、I-281、I-282、 I-283、I-284、I-285、I-286、I-287、I-288、I-289、I-290、I-291、I-292、I -293、I-294、I-295、I-296、I-297、I-298、I-299、I-300、I-301、I-302、I- 303、I-304、I-305、I-306、I-307、I-308、I-309、I-310、I-311、I-312、I-3 13、I-314、I-315、I-316、I-317、I-318、I-319、I-320, and I-321 are selected.

[0747] In some embodiments, the compound is: I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-69, I-60, I-61, I-62, I-68, I-69 9、I-50、I-51、I-52、I-53、I-54、I-55、I-56、I-57、I-58、I-59、I-60、I-61、 I-62、I-63、I-64、I-65、I-66、I-67、I-68、I-69、I-70、I-71、I-72、I-73、I-7 4、I-75、I-76、I-77、I-78、I-79、I-80、I-81、I-82、I-83、I-84、I-85、I-86、 I-87、I-88、I-89、I-90、I-91、I-92、I-93、I-94、I-95、I-96、I-97、I-98、I-9 9、I-100、I-101、I-102、I-103、I-104、I-105、I-106、I-107、I-108、I-109、 I-110、I-111、I-112、I-113、I-114、I-115、I-116、I-117、I-118、I-119、I-1 20、I-121、I-122、I-123、I-124、I-125、I-126、I-127、I-128、I-129、I-130 、I-131、I-132、I-133、I-134、I-135、I-136、I-137、I-138、I-139、I-140、I- 141、I-142、I-143、I-144、I-145、I-146、I-147、I-148、I-149、I-150、I-15 1、I-152、I-153、I-154、I-155、I-156、I-157、I-158、I-159、I-160、I-161、I -162、I-163、I-164、I-165、I-166、I-167、I-168、I-169、I-170、I-171、I-1 72、I-173、I-174、I-175、I-176、I-177、I-178、I-179、I-180、I-181、I-182、I-183、I-184、I-185、I-186、I-187、I-188、I-189、I-190、I-191、I-192、I-193、I-194、I-195、I-196、I-197、I-198、I-199、I-200、I-201、I-202、I-203、I-204、I-205、I-206、I-207、I-208、I-209、I-210、I-211、I-212、I-213、I-214、I-215、I-216、I-217、I-218、I-219、I-220、I-221、I-222、I-223、I-224、I-225、I-226、I-227、I-228、I-229、I-230、I-231、I-232、I-233、I-234、I-235、I-236、I-237、I-238、I-239、I-240、I-241、I-242、I-243、I-244、I-245、I-246、I-247、I-248、I-249、I-250、I-251、I-252、I-253、I-254、I-255、I-256、I-257、I-258、I-259、I-260、I-261、I-262、I-263、I-264、I-265、I-266、I-267、I-268、I-269、I-270、I-271、I-272、I-273、I-274、I-275、I-276、I-277、I-278、I-279、I-280、I-281、I-282、I-283、I-284、I-285、I-286、I-287、I-288、I-289、I-290、I-291、I-292、I-293、I-294、I-295、I-296、I-297、I-298、I-299、I-300、I-301、I-302、I-303、I-304、I-305、I-306、I-307、I-308、I-309、I-310、I-311、I-312、I-313、I-314、I-315、I-316、I-317、I-318、I-319、I-320、I-321、I-322、I-323、I-324、I-325、I-326、I-327、I-328、I-329、I-330、I-331、I-332、I-333、I-334、I-335、I-336、I-337、I-338、I-339、I-340、I-341、I-342、I-343、I-344、I-345、I-346、I-347、I-348、I-349、I-350、I-351、I-352、I-353、I-354、I-355、I-356、I-357、I-358、I-359、I-360 、I-361、I-362、I-363、I-364、I-365、I-366、I-367、I-368、I-369、I-370、I-371、I-372 、I-373、I-374、I-375、I-376、I-377、I-378、I-379、I-380、I-381、I-382、I-383、I-384 、I-385、I-386、I-387、I-388、I-389、I-390、I-391、I-392、I-393、I-394、I-395、I-396 、I-397、I-398、I-399、I-400、I-401、I-402、I-403、I-404、I-405、I-406、I-407、I-408 、I-409、I-410、I-411、I-412、I-413、I-414、I-415、I-416、I-417、I-418、I-419、I-420 、I-421、I-422、I-423、I-424、I-425、I-426、I-427、I-428、I-429、I-430、I-431、I-432 、I-433、I-434、I-435、I-436、I-437、I-438、I-439、I-440、I-441, and I-442 will be selected。、

[0748] In some embodiments, the compound is I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-5 0、I-51、I-52、I-53、I-54、I-55、I-56、I-57、I-58、I-59、I-60、I-164、I-16 5、I-166、I-167、I-168、I-169、I-170、I-171、I-172、I-173、I-174、I-175、 I-176、I-177、I-178、I-179、I-180、I-181、I-182、I-183、I-184、I-185、I- 186、I-187、I-188、I-189、I-190、I-191、I-192、I-193、I-194、I-195、I-196 、I-197、I-198、I-199、I-200、I-201、I-202、I-203、I-204、I-205、I-206、I -207、I-208、I-209、I-210、I-211、I-212、I-213、I-214、I-215、I-216、I-2 17、I-218、I-219、I-220、I-221、I-222、I-223、I-224、I-225、I-226、I-227 、I-228、I-229、I-230、I-231、I-232、I-233、I-234、I-235、I-236、I-237、I- 238、I-239、I-240、I-241、I-242、I-243、I-244、I-245、I-246、I-247、I-24 8、I-249、I-250、I-251、I-252、I-253、I-254、I-255、I-256、I-257、I-258、I -259、I-260、I-261、I-262、I-263、I-264、I-265、I-266、I-267、I-268、I-2 69、I-270、I-271、I-272、I-273、I-274、I-275、I-276、I-277、I-278、I-279、Selected from I-280, I-281, I-282, I-283, I-284, I-285, I-286, I-287, I-288, I-289, I-290, I-291, I-292, I-293, I-294, I-295, I-296, I-297, I-298, I-299, I-300, I-301, I-302, I-303, I-304, I-305, I-306, I-307, I-308, I-309, I-310, I-311, I-312, I-313, I-314, I-315, I-316, I-317, I-318, I-319, I-320, I-321, I-322, I-323, I-324, I-325, I-326, I-327, I-328, I-329, I-330, I-331, I-332, I-333, I-334, I-335, I-336, I-337, I-338, I-339, I-340, I-341, I-342, I-343, I-344, I-345, I-346, I-347, I-348, I-349, I-350, I-351, I-352, I-353, I-354, I-355, I-356, I-357, I-358, I-359, I-360, I-361, I-362, I-363, I-364, I-365, I-366, I-367, I-368, I-369, I-370, I-371, I-372, I-373, I-374, I-375, I-376, I-377, I-378, I-379, I-380, I-381, I-382, I-383, I-384, I-385, I-386, I-387, I-388, I-389, I-390, I-391, I-392, I-393, I-394, I-395, I-396, I-397, I-398, I-399, I-400, I-401, I-402, I-403, I-404, I-405, I-406, I-407, I-408, I-409, I-410, I-411, I-412, I-413, I-414, I-415, I-416, I-417, I-418, I-419, I-420, I-421, I-422, I-423, I-424, I-425, I-426, I-427, I-428, I-429, I-430, I-431, I-432, I-433, I-434, I-435, I-436, I-437, I-438, I-439, I-440, I-441, and I-442.

[0749] In some embodiments, compounds are I-322、I-323、I-324、I-325、I-326、I-327、I-328、I-329、I-330、I-331、I-332、I-333、I-334、I -335、I-336、I-337、I-338、I-339、I-340、I-341、I-342、I-343、I-344、I-345、I-346、I-347、I-348、I-349、I-350 、I-351、I-352、I-353、I-354、I-355、I-356、I-357、I-358、I-359、I-360、I-361、I-362、I-363、I-364、I-365、I-3 66、I-367、I-368、I-369、I-370、I-371、I-372、I-373、I-374、I-375、I-376、I-377、I-378、I-379、I-380、I-381、I -382、I-383、I-384、I-385、I-386、I-387、I-388、I-389、I-390、I-391、I-392、I-393、I-394、I-395、I-396、I-39 7、I-398、I-399、I-400、I-401、I-402、I-403、I-404、I-405、I-406、I-407、I-408、I-409、I-410、I-411、I-412、I- 413、I-414、I-415、I-416、I-417、I-418、I-419、I-420、I-421、I-422、I-423、I-424、I-425、I-426、I-427、I-428、 I-429、I-430、I-431、I-432、I-433、I-434、I-435、I-436、I-437、I-438、I-439、I-440、I-441、and I-442 are selected.

[0750] In some embodiments, the compound is: I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-69, I-60, I-61, I-62, I-68, I-69 9、I-50、I-51、I-52、I-53、I-54、I-55、I-56、I-57、I-58、I-59、I-60、I-61、 I-62、I-63、I-64、I-65、I-66、I-67、I-68、I-69、I-70、I-71、I-72、I-73、I-7 4、I-75、I-76、I-77、I-78、I-79、I-80、I-81、I-82、I-83、I-84、I-85、I-86、 I-87、I-88、I-89、I-90、I-91、I-92、I-93、I-94、I-95、I-96、I-97、I-98、I-9 9、I-100、I-101、I-102、I-103、I-104、I-105、I-106、I-107、I-108、I-109、 I-110、I-111、I-112、I-113、I-114、I-115、I-116、I-117、I-118、I-119、I-1 20、I-121、I-122、I-123、I-124、I-125、I-126、I-127、I-128、I-129、I-130 、I-131、I-132、I-133、I-134、I-135、I-136、I-137、I-138、I-139、I-140、I- 141、I-142、I-143、I-144、I-145、I-146、I-147、I-148、I-149、I-150、I-15 1、I-152、I-153、I-154、I-155、I-156、I-157、I-158、I-159、I-160、I-161、I -162、I-163、I-164、I-165、I-166、I-167、I-168、I-169、I-170、I-171、I-1 72、I-173、I-174、I-175、I-176、I-177、I-178、I-179、I-180、I-181、I-182、I-183、I-184、I-185、I-186、I-187、I-188、I-189、I-190、I-191、I-192、I-193、I-194、I-195、I-196、I-197、I-198、I-199、I-200、I-201、I-202、I-203、I-204、I-205、I-206、I-207、I-208、I-209、I-210、I-211、I-212、I-213、I-214、I-215、I-216、I-217、I-218、I-219、I-220、I-221、I-222、I-223、I-224、I-225、I-226、I-227、I-228、I-229、I-230、I-231、I-232、I-233、I-234、I-235、I-236、I-237、I-238、I-239、I-240、I-241、I-242、I-243、I-244、I-245、I-246、I-247、I-248、I-249、I-250、I-251、I-252、I-253、I-254、I-255、I-256、I-257、I-258、I-259、I-260、I-261、I-262、I-263、I-264、I-265、I-266、I-267、I-268、I-269、I-270、I-271、I-272、I-273、I-274、I-275、I-276、I-277、I-278、I-279、I-280、I-281、I-282、I-283、I-284、I-285、I-286、I-287、I-288、I-289、I-290、I-291、I-292、I-293、I-294、I-295、I-296、I-297、I-298、I-299、I-300、I-301、I-302、I-303、I-304、I-305、I-306、I-307、I-308、I-309、I-310、I-311、I-312、I-313、I-314、I-315、I-316、I-317、I-318、I-319、I-320、I-321、I-322、I-323、I-324、I-325、I-326、I-327、I-328、I-329、I-330、I-331、I-332、I-333、I-334、I-335、I-336、I-337、I-338、I-339、I-340、I-341、I-342、I-343、I-344、I-345、I-346、I-347、I-348、I-349、I-350、I-351、I-352、I-353、I-354、I-355、I-356、I-357、I-358、I-359、I-360、I-361、I-362、I-363、I-364、I-365、I-366、I-367、I-368、I-369、I-370、I-371、I-372、I-373、I-374、I-375、I-376、I-377、I-378、I-379、I-380、I-381、I-382、I-383、I-384、I-385、I-386、I-387、I-388、I-389、I-390、I-391、I-392、I-393、I-394、I-395、I-396、I-397、I-398、I-399、I-400、I-401、I-402、I-403、I-404、I-405、I-406、I-407、I-408、I-409、I-410、I-411、I-412、I-413、I-414、I-415、I-416、I-417、I-418、I-419、I-420、I-421、I-422、I-423、I-424、I-425、I-426、I-427、I-428、I-429、I-430、I-431、I-432、I-433、I-434、I-435、I-436、I-437、I-438、I-439、I-440、I-441、I-442、I-443、I-444、I-445、I-446、I-447、I-448、I-449、I-450、I-451、I-452、I-453、I-454、I-455、I-456、I-457、I-458、I-459、I-460、I-461、I-462、I-463、I-464、I-465、I-466、I-467、I-468、I-469、I-470、I-471、I-472、I-473、I-474、I-475、I-476、I-477、I-478、I-479、I-480、I-481、I-482、I-483、I-484、I-485、I-486、I-487、I-488、I-489、I-490、I-491、I-492、I-493、I-494、I-495、I-496、I-497、I-498、I-499、I-500、I-501、I-502、I-503、I-504、I-505、I-506、I-507、I-508、I-509、I-510、I-511、I-512、I-513、I-514、Selected from I-515, I-516, I-517, I-518, I-519, I-520, I-521, I-522, I-523, I-524, I-525, I-526, I-527, I-528, I-529, I-530, I-531, I-532, and I-533.

[0751] In some embodiments, the compound is I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-5 0、I-51、I-52、I-53、I-54、I-55、I-56、I-57、I-58、I-59、I-60、I-164、I-16 5、I-166、I-167、I-168、I-169、I-170、I-171、I-172、I-173、I-174、I-175、 I-176、I-177、I-178、I-179、I-180、I-181、I-182、I-183、I-184、I-185、I- 186、I-187、I-188、I-189、I-190、I-191、I-192、I-193、I-194、I-195、I-196 、I-197、I-198、I-199、I-200、I-201、I-202、I-203、I-204、I-205、I-206、I -207、I-208、I-209、I-210、I-211、I-212、I-213、I-214、I-215、I-216、I-2 17、I-218、I-219、I-220、I-221、I-222、I-223、I-224、I-225、I-226、I-227 、I-228、I-229、I-230、I-231、I-232、I-233、I-234、I-235、I-236、I-237、I- 238、I-239、I-240、I-241、I-242、I-243、I-244、I-245、I-246、I-247、I-24 8、I-249、I-250、I-251、I-252、I-253、I-254、I-255、I-256、I-257、I-258、I -259、I-260、I-261、I-262、I-263、I-264、I-265、I-266、I-267、I-268、I-2 69、I-270、I-271、I-272、I-273、I-274、I-275、I-276、I-277、I-278、I-279、I-280、I-281、I-282、I-283、I-284、I-285、I-286、I-287、I-288、I-289、I-290、I-291、I-292、I-293、I-294、I-295、I-296、I-297、I-298、I-299、I-300、I-301、I-302、I-303、I-304、I-305、I-306、I-307、I-308、I-309、I-310、I-311、I-312、I-313、I-314、I-315、I-316、I-317、I-318、I-319、I-320、I-321、I-322、I-323、I-324、I-325、I-326、I-327、I-328、I-329、I-330、I-331、I-332、I-333、I-334、I-335、I-336、I-337、I-338、I-339、I-340、I-341、I-342、I-343、I-344、I-345、I-346、I-347、I-348、I-349、I-350、I-351、I-352、I-353、I-354、I-355、I-356、I-357、I-358、I-359、I-360、I-361、I-362、I-363、I-364、I-365、I-366、I-367、I-368、I-369、I-370、I-371、I-372、I-373、I-374、I-375、I-376、I-377、I-378、I-379、I-380、I-381、I-382、I-383、I-384、I-385、I-386、I-387、I-388、I-389、I-390、I-391、I-392、I-393、I-394、I-395、I-396、I-397、I-398、I-399、I-400、I-401、I-402、I-403、I-404、I-405、I-406、I-407、I-408、I-409、I-410、I-411、I-412、I-413、I-414、I-415、I-416、I-417、I-418、I-419、I-420、I-421、I-422、I-423、I-424、I-425、I-426、I-427、I-428、I-429、I-430、I-431、I-432、I-433、I-434、I-435、I-436、I-437、I-438、I-439、I-440、I-441、I-442、I-443、I-444、I-445、I-446、I-447、I-448、I-449、I-450、I-451、I-452、I-453、I-454、I-455、I-456、I -457、I-458、I-459、I-460、I-461、I-462、I-463、I-464、I-465、I-466、I-467、I- 468、I-469、I-470、I-471、I-472、I-473、I-474、I-475、I-476、I-477、I-478、I-4 79、I-480、I-481、I-482、I-483、I-484、I-485、I-486、I-487、I-488、I-489、I-490 、I-491、I-492、I-493、I-494、I-495、I-496、I-497、I-498、I-499、I-500、I-501、 I-502、I-503、I-504、I-505、I-506、I-507、I-508、I-509、I-510、I-511、I-512、I- 513、I-514、I-515、I-516、I-517、I-518、I-519、I-520、I-521、I-522、I-523、I-5 24、I-525、I-526、I-527、I-528、I-529、I-530、I-531、I-532、and I-533 からしまするるします。、

[0752] In some embodiments, the compound is I-443, I-444, I-445, I-446, I-447, I-448, I-449, I-450, I-451, I-452, I-453, I-454, I-455, I-456, I-457, I-458, I-459, I-460, I-461, I-462, I-463, I-464, I-465, I-466, I-467, I-468, I-469, I-470, I-471, I-472, I-473, I-474, I-475, I-476, I-477, I-478, I-479, I-480, I-481, I-482, I-483, I-484, I-485, I-486, I-487, I-488, I-489, I-490, I-501, I-502, I-503, I-504, I-505, I-506, I-507, I-508, I-509, I-601, I-602, I-603, I-604, I-605, I-606, I-607, I-608, I-609, I-610, I-611, I-612, I-613, I-614, I-615, I-616, I-617, I-618, I-619, I-620, I-621, I-622, I-623, I-624, I-625, I-626, I-627, 464, I-465, I-466, I-467, I-468, I-469, I-470, I-471, I-472, I-473, I-474, I-475, I -476, I-477, I-478, I-479, I-480, I-481, I-482, I-483, I-484, I-485, I-486, I-487, I -488, I-489, I-490, I-491, I-492, I-493, I-494, I-495, I-496, I-497, I-498, I-499, I-500, I-501, I-502, I-503, I-504, I-505, I-506, I-507, I-508, I-509, I-510, I-511 , I-512, I-513, I-514, I-515, I-516, I-517, I-518, I-519, I-520, I-521, I-522, I-523, I-524, I-525, I-526, I-527, I-528, I-529, I-530, I-531, I-532, and I-533.

[0753] In some embodiments, the compound is selected from I-534, I-535, I-536, and I-537.

[0754] In some embodiments, the compound is selected from those shown in Table 1 below. In some embodiments, the compound is selected from one of those shown in Table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from those shown in Table 1A below. In some embodiments, the compound is selected from one of those shown in Table 1A above, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from those shown in Table 1B below. In some embodiments, the compound is selected from one of those shown in Table 1B above, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from one of those shown in Table 1C below. In some embodiments, the compound is selected from one of those shown in Table 1C above, or a pharmaceutically acceptable salt thereof.

[0755] In some embodiments, the compounds of the present invention can be used as CNOT7 binders. In some embodiments, the compounds of the present invention can be used to regulate the activity of CNOT7. In some embodiments, the compounds of the present invention can be used to inhibit the activity of CNOT7. The inhibition and / or degradation of CNOT7 has been shown to suppress metastasis and cell proliferation, which is beneficial, for example, in the treatment of cancer. See, for example, Ren et al. FEBS Open Bio 10, 2020, 847-860, or Faraji et al. PLOS Genetics 12(1)e1005820, 2016.

[0756] In one aspect, the present invention provides bifunctional compounds comprising one of the CNOT7 binders described herein conjugated to a ubiquitin-binding moiety capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase. An example of an E3 ubiquitin ligase is cereblon. In some embodiments, the bifunctional compound has the formula C: [ka] or a pharmaceutically acceptable salt thereof, wherein: UBM is a ubiquitin-binding moiety that can bind to ubiquitin ligase, DFL is a degrader-recruiting ligand; -L 1 - is a divalent linker group covalently linking a UBM to said DFL; DFL binds to CNOT7. 1 - groups include those described above in the context of Formula A or shown in Table 3. Exemplary UBM moieties include those described in WO2019 / 060742, which is incorporated herein by reference in its entirety.

[0757] 2. Compounds and Related Definitions As generally described above, the present invention provides a bifunctional compound of formula A [ka] or a pharmaceutically acceptable salt thereof, wherein: rSM is an RNA-binding small molecule that binds to a target RNA transcript; DFL is a degrader-recruiting ligand; -L 1 - is a bivalent linker group covalently linking said rSM to said DFL, DFLs provide compounds, or pharmaceutically acceptable salts thereof, that bind to or recruit one or more degradation factors that degrade target RNA transcripts.

[0758] RNA-binding small molecules (rSM) In one aspect, the present disclosure provides a bifunctional compound of formula A, wherein the compound comprises an rSM. Various rSMs known in the art can be used in accordance with the present invention. In some embodiments, the rSM can be linked to a linker L at any available modifiable C atom or heteroatom, such as an N, O, S, or P atom, of the rSM. 1 In the context of a C atom, "modifiable" means 1) the ability to be modified from its known structure to covalently bond to L via a chemical reaction such as oxidation, reduction, nucleophilic substitution, or crosslinking reaction; 1or 1) a C atom that can participate in a chemical reaction such as oxidation, reduction, nucleophilic substitution, or crosslinking reaction due to unsaturation or the presence of a leaving group attached to the C atom. For example, a C=O group, a C=N group, or a C-Br group are "modifiable." Similarly, a modifiable heteroatom is a heteroatom that can be modified by bonding with L. 1 It may be attached to an H atom that can be displaced by a bond with or may be modified by the presence of a leaving group attached to an unsaturated or heteroatom.

[0759] In some embodiments, the rSM is a small molecule or a pharmaceutically acceptable salt thereof. In some embodiments, the rSM has a molecular weight (MW) of 1000 or less. In some embodiments, the rSM has a MW of about 750 or less. In some embodiments, the rSM has a MW of about 600 or less. In some embodiments, the rSM has a MW of about 500 or less. In some embodiments, the rSM has a MW of about 100 to about 1000. In some embodiments, the rSM has a MW of about 150 to about 800, about 150 to about 600, about 150 to about 400, about 150 to about 350, about 200 to about 350, or about 200 to about 450.

[0760] In some embodiments, the rSM or compound of Formula A has a K of 1 μM, 500 nM, 100 nM, 50 nM, 10 nM, 1 nM, 500 pM, 10 pM, or 1 pM under biological conditions. d In some embodiments, the rSM or compound binds to the target RNA transcript, or its isoform, fragment, or variant, with a K of 0.1 nM to 500 nM, 10 nM to 250 nM, 0.001 to 25 μM, 0.01 to 25 μM, 0.1 to 25 μM, 0.1 to 15 μM, 0.01 to 10 μM, 0.001 to 1 μM, 0.001 to 0.1 μM, or 0.001 to 0.01 μM. d and binds to the target RNA transcript or its isoform, fragment, or variant.

[0761] Exemplary rSM In some embodiments, the rSM is [ka] and rSM is L 1 In some embodiments, the rSM is covalently linked to [ka] and rSM is [ka] In some embodiments, the rSM is covalently linked to [ka] and rSM is L 1 In some embodiments, the rSM is covalently linked to [ka] and the rSM is covalently attached to any of the compounds in Table 1. In some embodiments, the rSM is [ka] and rSM is covalently attached to any of the compounds in Table 1A.

[0762] In some embodiments, the rSM is [ka] and rSM is covalently attached to any of the compounds in Table 1B.

[0763] In some embodiments, the rSM is [ka] and rSM is covalently attached to any of the compounds in Table 1C.

[0764] In some embodiments, the rSM is one of the following: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is selected from L at any available modifiable C, N, or O atom. 1 is covalently bonded to

[0765] In some embodiments, the rSM is a G-quadruplex binder, such as one of those described in Peng, W. et al., J. Med. Chem. 2018, 61, 6629-6646, which is incorporated herein by reference.

[0766] In some embodiments, the rSM is a compound described in Shi, Y. et al., Cell Chem. Biol. 2019, 26, 319-330. [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 and the document is incorporated herein by reference.

[0767] In some embodiments, the rSM is a compound disclosed in Velagapudi, SP et al. (2014), “Sequence-based design of bioactive small molecules that target precursor microRNAs,” Nat. Chem. Biol. 10, 291, which is incorporated herein by reference, for example, the following: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, or O atom. 1 is covalently bonded to

[0768] In some embodiments, the rSM comprises a MALAT-1 binder, such as: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, or O atom. 1 is covalently bonded to

[0769] In some embodiments, the rSM is a G-quadruplex binder, such as: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C or N atom. 1 is covalently bonded to

[0770] In some embodiments, the rSM is one of the following compounds: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, S or O atom. 1 is covalently bonded to

[0771] In some embodiments, the rSM is one of those described in J. Med. Chem. 2018, 61(15), 6501-6517, or U.S. Pat. No. 8,729,263, each of which is incorporated herein by reference. For example, the rSM may be a compound according to Formula I from U.S. Pat. No. 8,729,263: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is defined therein, and rSM is selected from L at any available modifiable C, N, O, S, or P atom. 1 is covalently bonded to

[0772] In some embodiments, the rSM is described in U.S. Patent No. 9,040,712, which is incorporated herein by reference. For example, in some embodiments, the rSM is a compound according to formula X from U.S. Patent No. 9,040,712: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is defined therein, and rSM is selected from L at any available modifiable C, N, O, S, or P atom. 1 is covalently bonded to

[0773] In some embodiments, the rSM is selected from one of those described in Angelbello, AJ, et al., "Small molecule targeting of RNA structures in neurological disorders," Annals of the New York Academy of Sciences, 2020 Jul;1471(1):57-71, which is incorporated herein by reference, or a pharmaceutically acceptable salt thereof, and the rSM is L at any available modifiable C, N, O, S, or P atom. 1 In some embodiments, the rSM is one of the following: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 is covalently bonded to

[0774] In some embodiments, the rSM is selected from one of those shown in Table 2A below, or a pharmaceutically acceptable salt thereof, and the rSM is L at any available modifiable C, N, O, S, or P atom. 1 is covalently bonded to

[0775] In some embodiments, the rSM is a compound of formula IX: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Pat. No. 9,150,612, which is incorporated herein by reference in its entirety.

[0776] In some embodiments, the rSM is a compound of formula X [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is covalently bonded to L at any available modifiable C, N, O, S, or P atom; wherein each variable is as defined in U.S. Patent No. 9,550,769, which is incorporated herein by reference in its entirety. In some embodiments, the above variable L 1 teeth, [ka] where each variable is as defined in U.S. Pat. No. 9,550,769.

[0777] In some embodiments, the rSM is selected from one of those disclosed in U.S. Pat. No. 10,157,261, the entirety of which is incorporated herein by reference, and the rSM is L at any available modifiable C, N, O, S, or P atom. 1 is covalently bonded to

[0778] In some embodiments, the rSM is a compound of formula XI: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Pat. No. 9,586,944, which is incorporated herein by reference in its entirety.

[0779] In some embodiments, the rSM is a compound of formula XII: [ka] where H is a group of the structure [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Pat. No. 9,795,687, which is incorporated herein by reference in its entirety.

[0780] In some embodiments, the rSM is a compound selected from one of the following: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 is covalently bound to, or Another compound disclosed in WO2018 / 151810, the entire contents of which are incorporated herein by reference.

[0781] In some embodiments, the rSM is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 is covalently bonded to or another compound disclosed in WO2018 / 152414, the entirety of which is incorporated herein by reference.

[0782] In some embodiments, the rSM is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 is covalently bound to, or Another compound disclosed in U.S. Patent No. 2018 / 0334678, the entire contents of which are incorporated herein by reference.

[0783] In some embodiments, the rSM is a compound of formula XIII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Patent Application Publication No. 2018 / 0296532, which is incorporated herein by reference in its entirety.

[0784] In some embodiments, the rSM is a compound of formula XIV: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in WO 2018 / 098297, which is incorporated herein by reference in its entirety.

[0785] In some embodiments, the rSM is a compound of formula XV, XVI, or XVII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Patent Application Publication No. 2019 / 0152924, which is incorporated herein by reference in its entirety.

[0786] In some embodiments, the rSM is a compound of formula XVIII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in WO 2019 / 005993, the entire contents of which are incorporated herein by reference.

[0787] In some embodiments, the rSM is a compound of formula XIX: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in WO 2018 / 232039, which is incorporated herein by reference in its entirety.

[0788] In some embodiments, the rSM is a compound of formula XX: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in WO 2019 / 005980, the entire contents of which are incorporated herein by reference.

[0789] In some embodiments, the rSM is a compound of formula XXI: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in WO 2018 / 226622, which is incorporated herein by reference in its entirety.

[0790] In some embodiments, the rSM is a compound of formula XXII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to

[0791] wherein each variable is as defined in WO 2018 / 098446, which is incorporated herein by reference in its entirety.

[0792] In some embodiments, the rSM is a compound of formula XXIII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is covalently bonded to L1 at any available modifiable C, N, O, S, or P atom; wherein each variable is as defined in WO 2017 / 087364, which is incorporated herein by reference in its entirety.

[0793] In some embodiments, the rSM is ataluren. [ka] or a deuterated analog thereof or a pharmaceutically acceptable salt thereof as disclosed in U.S. Patent No. 2018 / 0333397 or WO2017 / 087364, each of which is incorporated herein by reference.

[0794] In some embodiments, the rSM is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S, or P atom as described in U.S. Patent Application Publication No. 2018 / 147228. 1 and is incorporated herein by reference in its entirety.

[0795] In some embodiments, the rSM is a compound of formula XXIV: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Pat. No. 9,969,754, which is incorporated herein by reference in its entirety.

[0796] In some embodiments, the rSM is a compound of formula XXV-i: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Patent No. 9,371,336, which is incorporated herein by reference in its entirety. In some embodiments, the rSM is a compound disclosed in U.S. Patent No. 9,371,336, or a pharmaceutically acceptable salt thereof.

[0797] In some embodiments, the rSM is a compound of formula XXV-ii: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Patent No. 9,617,268, which is incorporated herein by reference in its entirety. In some embodiments, the rSM is a compound disclosed in U.S. Patent No. 9,617,268, or a pharmaceutically acceptable salt thereof.

[0798] In some embodiments, the rSM is a compound of formula XXVI: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Patent No. 2019 / 0000844, which is incorporated herein by reference in its entirety. In some embodiments, the rSM is a compound disclosed in U.S. Patent No. 2019 / 0000844, or a pharmaceutically acceptable salt thereof.

[0799] In some embodiments, the rSM is a compound of formula XXVII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Patent No. 2018 / 0161456, which is incorporated herein by reference in its entirety. In some embodiments, the rSM is a compound disclosed in U.S. Patent No. 2018 / 0161456, or a pharmaceutically acceptable salt thereof.

[0800] In some embodiments, the rSM is a compound of formula XXVIII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Patent No. 10,195,202, which is incorporated herein by reference in its entirety. In some embodiments, the rSM is a compound disclosed in U.S. Patent No. 10,195,202, or a pharmaceutically acceptable salt thereof.

[0801] In some embodiments, the rSM is a compound of formula XXIX-XXXIII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in WO 2019 / 028440, which is incorporated herein by reference in its entirety. In some embodiments, the rSM is a compound disclosed in WO 2019 / 028440, or a pharmaceutically acceptable salt thereof.

[0802] In some embodiments, rSM is a compound of formula XXXIV-XLXI: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is covalently bonded to L1 at any available modifiable C, N, O, S, or P atom; wherein each variable is as defined in WO 2019 / 060917, which is incorporated herein by reference in its entirety. In some embodiments, the rSM is a compound disclosed in WO 2019 / 060917, or a pharmaceutically acceptable salt thereof.

[0803] In some embodiments, the rSM is a compound of formula XLXII or XLXIII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Pat. No. 9,879,007, which is incorporated herein by reference in its entirety.

[0804] In some embodiments, the rSM is a compound of formula XLXIV or XLXV: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in WO 2019 / 191229, the entire contents of which are incorporated herein by reference.

[0805] In some embodiments, the rSM is a compound of formula XLXVI: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in WO 2019 / 191092, the entire contents of which are incorporated herein by reference.

[0806] In some embodiments, rSM is a compound of formula XLXVII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in U.S. Patent Application Publication No. 2019 / 315773, which is incorporated herein by reference in its entirety.

[0807] In some embodiments, the rSM is a compound of formula LVIII, LIX, or LX: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in WO 2019 / 199972, the entire contents of which are incorporated herein by reference. Such compounds are useful, for example, for modulating splicing of the FOXM1 gene for use in treating cancer.

[0808] In some embodiments, the rSM is a compound of formula LXI: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1covalently bonded to wherein each variable is as defined in Formula (I) of WO 2020 / 005873, the entire contents of which are incorporated herein by reference. Such compounds are useful, for example, for regulating RNA targets that mediate Huntington's disease. In some embodiments, the compound is a compound of Formula (Ibb1) as described herein. [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 wherein each variable is as defined therein.

[0809] In some embodiments, the rSM is a compound of formula LXII or LXIII [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1 covalently bonded to wherein each variable is as defined in WO 2020 / 005877, the entire contents of which are incorporated herein by reference. Such compounds are useful, for example, for binding to HTT RNA transcripts for use in treating diseases such as Huntington's disease.

[0810] In some embodiments, the rSM is a compound of formula LXIV, LXV, LXVI, or LXVII: [ka] or a pharmaceutically acceptable salt thereof, wherein rSM is L at any available modifiable C, N, O, S or P atom. 1wherein each variable is as defined in WO 2020 / 005882, the entire contents of which are incorporated herein by reference. Such compounds are useful, for example, for binding to HTT RNA transcripts for use in treating diseases such as Huntington's disease.

[0811] In some embodiments, the rSM is selected from one of those set forth in U.S. Patent Nos. 8,729,263, 9,545,404, 9,856,474, or 7,838,657, each of which is incorporated herein by reference.

[0812] In some embodiments, the rSM is selected from one of those shown in Table 2 below, or a pharmaceutically acceptable salt thereof, and the rSM is L at any available modifiable C, N, O, S, or P atom. 1 is covalently bonded to [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18] [Table 2-19] [Table 2-20] [Table 2-21] [Table 2-22]

[0813] Degradation factors and RNA-binding proteins (RBPs) In one aspect, the present disclosure provides a composition comprising an RNA binder that binds to a target RNA transcript and a degrader recruiting ligand (DFL), wherein the DFL binds to or recruits a degrader.

[0814] In one aspect, the present disclosure provides a composition comprising an attenuator ligand that binds to a degradation factor, wherein the degradation factor is a protein that binds to or interacts with an RNA (RBP), and wherein the interaction of the RBP with the RNA results in modulation of a target RNA transcript in vivo.

[0815] The degradation factors provided herein are any proteins, polypeptides, or biological molecules present in cells that regulate target RNA when brought into proximity with the target RNA. Regulating RNA as provided herein includes destabilizing RNA, stabilizing RNA, degrading RNA, or acting on RNA in any other capacity. Degradation factors include any proteins that interfere with the stability and / or activity of RNA. In some embodiments, the degradation factor is an RNA destabilizing protein, a nuclease, or an RNA-binding protein. It should be understood that nucleases and RNA-binding proteins are not mutually exclusive; for example, some RNA-binding proteins also have nuclease activity. In some embodiments, the present disclosure provides bifunctional compounds or compositions that affect the recruitment of target RNA to nucleases that can degrade the target RNA, or that affect the recruitment of target RNA to RNA-binding proteins (RBPs) that destabilize the target RNA toward degradation by either the RNA degradation machinery of a cell or tissue.

[0816] In some embodiments, the DFL binds to or attracts a protein complex that can degrade or otherwise regulate RNA function (e.g., availability of protein translation). In some embodiments, the protein complex is the CCR4-NOT (carbon catabolite repression negative in the absence of TATA) complex.

[0817] CCR4-NOT complex In some embodiments, DFLs bind to or attract protein complexes that can degrade or otherwise regulate RNA function. In some embodiments, DFLs bind to protein complexes. In some embodiments, DFLs bind to one or more RBPs that are part of a protein complex. Binding of one or more RBPs is expected to bring the complete protein complex into proximity with the target RNA. In some embodiments, DFLs bind to the CCR4-NOT (carbon catabolite repression negative in the absence of TATA) complex or an RBP that is a member of the CCR4-NOT complex. The CCR4-NOT complex is a large, highly conserved, multifunctional assembly of proteins involved in different aspects of mRNA metabolism. Without wishing to be bound by theory, the CCR4-NOT complex is thought to play a role in deadenylation-dependent mRNA turnover. RBPs that are part of the CCR4-NOT complex include CNOT1, CNOT2, CNOT3, CNOT6, CNOT6L, CNOT7, CNOT8, CNOT9, CNOT10, and CNOT11. The functions of the CCR4-NOT complex and each RBP that constitutes the complex are discussed, for example, in Shirai et al. Multifunctional roles of the mammalian CCR4-NOT complex in physiological phenomena, Frontiers in Genetics, 2014, 5, Article 286, which is incorporated by reference.

[0818] In some embodiments, the RBP is CNOT7.

[0819] CNOT7 In some embodiments, the RBP is CNOT7. In some embodiments, the disclosed compound or composition comprises a small molecule CNOT7 ligand as a DFL. CNOT7 is a member of the CCR4-NOT complex. Without wishing to be bound by theory, CNOT7 is thought to act as an exonuclease. It is thought to induce target RNA degradation (e.g., via deadenylation) directly or in conjunction with other members of the CCR4-NOT complex. CNOT7 is widely expressed in the human body.

[0820] In some embodiments, the present disclosure provides compounds that bind to CNOT7 but do not bind to the active site of CNOT7. In some embodiments, the present disclosure provides compounds and compositions thereof, wherein DFL binds to CNOT7 without inhibiting the enzymatic activity of CNOT7 and / or the CCR4-NOT complex. By binding to CNOT7 at a site other than the active site, CNOT7 maintains its ability to act on and / or degrade RNA. Thus, in one embodiment, the compositions provided herein can bind both the target RNA and CNOT7, bringing CNOT7 into the vicinity of the target RNA and allowing CNOT7 to act on (e.g., degrade) the target RNA because CNOT7 is still functional.

[0821] In some embodiments, the compositions provided herein bind to CNOT7, thereby bringing another component of the CCR4-NOT complex into proximity with the target RNA. By binding to both the target RNA and CNOT7, the compounds provided herein enable the CCR4-NOT complex to act on the target RNA. The CCR4-NOT complex can act on the target RNA through any of its enzymatic capabilities. In some embodiments, the CCR4-NOT complex acts on the target RNA through the action of CNOT7, which can act on and / or degrade RNA. In some embodiments, the CCR4-NOT complex acts on the target RNA through the action of an enzymatic component other than CNOT7. In some embodiments, the CCR4-NOT complex acts on the target RNA through the action of CNOT6, which has exonuclease activity and can act on and / or degrade RNA.

[0822] In some embodiments, the present disclosure provides compounds that bind to the active site of CNOT7. By binding to both the target RNA and the active site of CNOT7, the compounds provided herein enable the CCR4-NOT complex to act on the target RNA by bringing one or more components of the complex into proximity with CNOT7. For compounds that bind to the active site of CNOT7, the CCR4-NOT complex can act on the target RNA through any of its enzymatic capabilities. In some embodiments, the CCR4-NOT complex acts on the target RNA through the action of CNOT7, whether bound to the active site or not, and can act on and / or degrade RNA even if its activity is suppressed compared to CNOT7 not bound to the active site. In some embodiments, the CCR4-NOT complex acts on the target RNA through the action of an enzymatic component other than CNOT7. In some embodiments, the CCR4-NOT complex acts on the target RNA through the action of CNOT6, which has exonuclease activity and can act on and / or degrade RNA.

[0823] In some embodiments of any of the compositions, compounds, and methods provided herein, the composition or compound binds to or interacts with a target RNA, and the target RNA transcript is mRNA or a precursor, isoform, unspliced ​​isoform, splice intermediate, fragment, or variant thereof. In some embodiments of any of the compositions, compounds, and methods provided herein, the composition or compound binds to or interacts with a target RNA, and the target RNA transcript is selected from one of those listed in Table C or Table D, or a precursor, isoform, unspliced ​​isoform, splice intermediate, fragment, or variant thereof. In some embodiments of any of the compositions, compounds, and methods provided herein, the composition and compound comprises an rSM that binds to the target RNA. In some embodiments of any of the compositions, compounds, and methods provided herein, the rSM is selected from any one of those listed in the section entitled Exemplary rSMs. In some embodiments of any of the compositions, compounds, and methods provided herein, the rSM is one of those listed in Table 2.

[0824] In some embodiments of any of the compositions, compounds, and methods provided herein, the composition is a pharmaceutical composition. In some embodiments of any of the compositions, compounds, and methods provided herein, the pharmaceutical composition comprises any of the compounds or compositions provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0825] In one aspect, the present invention provides methods and compositions for the diagnosis and prognosis of cell proliferation disorders (e.g., cancer) and the treatment of these disorders by regulating (e.g., degrading) target RNA transcripts.Cell proliferation disorders described herein include, for example, cancer, obesity, and proliferation-dependent diseases.Such disorders can be diagnosed using methods known in the art.

[0826] In one aspect, the present invention provides methods and compositions for treating cancer by modulating (e.g., degrading) target RNA transcripts. In some embodiments, cancer is driven or characterized by the overexpression of a protein (e.g., an oncogenic protein), and the cancer is treated by modulating (e.g., degrading) the target RNA transcript corresponding to the overexpressed protein. In one aspect, the present invention provides methods and compositions for treating cancer.

[0827] It should be understood that the compositions, compounds, and methods provided in the present disclosure allow for the regulation of the amount of target RNA, and thereby the regulation of the amount or protein level of the protein expressed from the target RNA.Thus, in some embodiments, the present disclosure provides compositions and compounds for a method for modifying the amount of protein in a cell.In some embodiments, these methods include administering any of the compositions or compounds provided in the present disclosure, or a pharmaceutically acceptable salt thereof, that act on target RNA transcripts or their precursors, isoforms, fragments, or variants, in an amount sufficient to modify the amount of protein in a cell.In some embodiments, modifying the amount of protein in a cell includes reducing the amount of protein in a cell, or is the same as reducing the amount of protein in a cell.

[0828] It will be understood that the compositions, compounds, and methods provided herein allow for regulating the availability of a target RNA transcript, or its precursor, isoform, fragment, or variant, for protein translation. Thus, in some embodiments, the present disclosure provides compositions and compounds for methods of regulating the availability of a target RNA transcript, or its precursor, isoform, fragment, or variant, for protein translation. In some embodiments, these methods include contacting a target RNA transcript, or its precursor, isoform, fragment, or variant, with any of the compounds or compositions provided herein, or a pharmaceutically acceptable salt thereof, that bind to the target RNA transcript, or its isoform, fragment, or variant.

[0829] The compositions, compounds and methods provided in the present disclosure can regulate the translation of target protein or its variants.Thus, in some embodiments, the present disclosure provides compositions and compounds for methods, comprising contacting a target RNA transcript or its precursor, isoform, fragment or variant with any of the compounds or compositions provided in the present disclosure or its pharmaceutically acceptable salt.

[0830] It will be understood that the compositions, compounds, and methods provided herein can reduce the half-life or increase the degradation of a target RNA transcript or its precursor, isoform, fragment, or variant. Thus, in some embodiments, the present disclosure provides compositions and compounds for a method, comprising contacting a target RNA transcript or its precursor, isoform, fragment, or variant with any of the compounds or compositions provided herein, or a pharmaceutically acceptable salt thereof.

[0831] Linker The linker, -L, in the formulae described herein is generally as defined above. 1 - is a divalent group connecting the rSM, RNA binder, or UBM to the ligand of the decomposer ligand (DFL). In some embodiments, for example, for compounds of Formula Ia and embodiments thereof, -L 1 - is a covalent bond or a divalent straight or branched chain C 1-8 a hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SON(R)-, -(R)NS02-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-;1 , R 2 , R 3 , or R 8 One and only one of the -L 1 - and -L 1 One end of -L is covalently attached to rSM. In some embodiments, for example, for compounds of formula Id and embodiments thereof, -L 1 - is a covalent bond or C 1-8 A divalent straight or branched hydrocarbon chain wherein one, two, three, or four methylene units of the chain are independently and optionally -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO- , -SO2-, -SON(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, -Cy-, and 1, 2, 3, 4, 5, 6, or 7 methylene units are optionally replaced by -OCH2CH2- or -CH2CH2O-, and R 1 , R 2 , R 3 , R 8 , or R 11 One and only one of the -L 1 - and -L 1 One end of -L is covalently attached to rSM. 1 - is a covalent bond or a divalent saturated or unsaturated, straight or branched chain, optionally substituted C 1-50 is a hydrocarbon chain, wherein -L 1 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 methylene units in - are independently replaced by: -Cy 2-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N( R)-, -N(R)C(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(N(R)2)-, amino acids, [ka] is selected from: Each-Cy 2 - is an independently optionally substituted bivalent ring selected from phenylenyl, 8-12-membered bicyclic arylenyl, 3-8-membered saturated carbocyclylene or partially unsaturated carbocyclylenyl, 8-12-membered bicyclic saturated carbocyclylenyl or partially unsaturated carbocyclylenyl, 3-8-membered saturated heterocyclylenyl or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-12-membered bicyclic saturated heterocyclylenyl or partially unsaturated heterocyclylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6-membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10-membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each q is independently 1, 2, or 3.

[0832] In some embodiments, -L 1 - is a covalent bond. In some embodiments, -L 1 - is optionally replaced by a bivalent saturated or unsaturated, linear or branched C 1-50 is a hydrocarbon chain, wherein -L 1 -0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 methylene units of -Cy 2-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N( R)-, -N(R)C(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(N(R)2)-, amino acids, [ka] is replaced by

[0833] In some embodiments, -L 1 - is a divalent, saturated or unsaturated, straight or branched chain, optionally substituted C 1-50 , C 1-40 , C 1-30 , C 1-20 , C 1-15 , C 1-10 , C 1-5 , C 2-50 , C 2-40 , C 2-30 , C 2-20 , C 2-15 , C 2-10 , C 3-50 , C 3-40 , C 3-30 , C 3-20 , C 3-15 , C 3-10 , C 4-50 , C 4-40 , C 4-30 , C 4-20 , C 4-15 , C 4-10 , C 5-50 , C 5-40 , C 5-30 , C 5-20 , C 5-15 , C 5-10 , C 6-50 , C 6-40 , C 6-30 , C 6-20 , C 6-15 , C 7-50 , C 7-40 , C 7-30 , C7-20 , C 7-15 , C 8-50 , C 8-40 , C 8-30 , C 8-20 , C 8-15 , C 10-50 , C 10-40 , C 10-30 , C 10-20 , C 10-15 , C 12-50 , C 12-40 , C 12-30 , C 12-20 , C 15-50 , C 15-40 , C 15-30 , C 15-20 , C 20-50 , C 20-40 , or C 20-30 is a hydrocarbon chain, wherein L 1 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 methylene units of -Cy 2 -, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N( R)-, -N(R)C(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(N(R)2)-, amino acids, [ka] is replaced by

[0834] In some embodiments, -L 1 - is a divalent saturated or unsaturated, straight or branched chain, optionally substituted C 1-50 , C 1-40 , C 1-30 , C 1-20 , C 1-15 , C 1-10 , C 1-5 , C 2-50 , C 2-40 , C 2-30 , C2-20 , C 2-15 , C 2-10 , C 3-50 , C 3-40 , C 3-30 , C 3-20 , C 3-15 , C 3-10 , C 4-50 , C 4-40 , C 4-30 , C 4-20 , C 4-15 , C 4-10 , C 5-50 , C 5-40 , C 5-30 , C 5-20 , C 5-15 , C 5-10 , C 6-50 , C 6-40 , C 6-30 , C 6-20 , C 6-15 , C 7-50 , C 7-40 , C 7-30 , C 7-20 , C 7-15 , C 8-50 , C 8-40 , C 8-30 , C 8-20 , C 8-15 , C 10-50 , C 10-40 , C 10-30 , C 10-20 , C 10-15 , C 12-50 , C 12-40 , C 12-30 , C 12-20 , C 15-50 , C 15-40 , C 15-30 , C 15-20 , C 20-50 , C 20-40 , or C 20-30 is a hydrocarbon chain, wherein -L 1 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 methylene units in -Cy are independently replaced by: 2-, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -N(R)S(O)2-, -S(O)2N(R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N (R)-, -N(R)C(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -Si(R)2-, -Si(OH)(R)-, -Si(OH)2-, -P(O)(OR)-, -P(O)(R)-, -P(O)(NR2)-, amino acids, [ka] is selected from.

[0835] In some embodiments, -L 1 - is a divalent, saturated or unsaturated, linear or branched, optionally substituted C1-50, C1-40, C1-30, C1-20, C1-15, C1-10, C1-5, C2-50, C2-40, C2-30, C2-20, C2-15, C2-10, C3-50, C3-40, C3-30, C3-20, C3-15, C3-10, C4-50, C4-40, C4-30, C4-20, C4-15, C4-10, C5-50, C5-40, C5-30, C5-20 , C5-15, C5-10, C6-50, C6-40, C6-30, C6-20, C6-15, C7-50, C7-40, C7-30, C7-20, C7-15, C8-50, C8-40, C8-30, C8-20, C8-15, C10 -50, C10-40, C10-30, C10-20, C10-15, C12-50, C12-40, C12-30, C12-20, C15-50, C15-40, C15-30, C15-20, C20-50, C20-40, or C 20-30 is a hydrocarbon chain, wherein -L 1 -0, 1, 2, 3, 4, 5, 6, 7, or 8 methylene units in --Cy 2 -, -O-, -N(R)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-, amino acids, [ka] is.

[0836] In some embodiments, -L 1 - has 1, 2, 3, 4, 5, or 6 PEG units, [ka] In some embodiments, -L 1 - comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 PEG units. 1 - means 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 units, or 1, 2, 3, 4, 5, or [ka] It contains six units.

[0837] In some embodiments, -L 1 - is a saturated chain. In some embodiments, -L 1 - contains at least one unsaturated pair of carbon atoms, i.e., at least one double or triple carbon-carbon bond. 1 - contains 1, 2, 3, 4, or 5 double or triple carbon-carbon bonds. 1 - is a linear hydrocarbon chain, where -L 1 The methylene units of - are optionally replaced or replaced as described above. 1 - is a saturated and linear hydrocarbon chain, where -L 1 The methylene unit of - is optionally replaced or replaced as described above.

[0838] In some embodiments, -L 1- is substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 "optional substituents" as defined herein. In some embodiments, each substituent is selected from the group consisting of deuterium, halogen, -CN, -OR, -NR, -SR, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, one or more C 1-4 Phenyl optionally substituted with alkyl, -CO2R, -OR, -CONR2, -NR2 or halogen; an 8- to 10-membered bicyclic aromatic carbocycle; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; nitrogen, oxygen, or sulfur; or C optionally substituted with -CN, -OR, -N(R)2, -SR. 1-6 Aliphatic groups, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic rings, one or more C 1-4 phenyl optionally substituted with alkyl, -CO2R, -OR, -CON(R)2, -N(R)2 or halogen; an 8-10 membered bicyclic aromatic carbocycle; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or C 1-6 An aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms, or two substituents attached to the same carbon atom, which together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic carbocycle or a 3- to 6-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0839] As noted above, in some embodiments, L 1wherein the methylene units are replaced with amino acids. The amino acids may be naturally occurring or non-naturally occurring. In some embodiments, the amino acids are selected from non-polar or branched-chain amino acids (BCAAs). In some embodiments, the amino acids are selected from valine, isoleucine, leucine, methionine, alanine, proline, glycine, phenylalanine, tyrosine, tryptophan, histidine, asparagine, glutamine, serine threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, cysteine, selenocysteine, or tyrosine. In some embodiments, the amino acids are L-amino acids. In some embodiments, the amino acids are D-amino acids.

[0840] In some embodiments, -L 1 is selected from those shown in Table 3 below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 3-25 Table 3-26 Table 3-27 [Table 3-28]

[0841] In some embodiments, L 1 is selected from those shown in Table 1 above.

[0842] In some embodiments, L 1 is selected from those shown in Table 1A above. In some embodiments, L 1 is selected from those shown in Table 1B above. 1 is selected from those shown in Table 1C above.

[0843] In some embodiments, the compound of formula A is [ka] These include, but are not limited to: definition

[0844] As used in this disclosure, "nucleoside" refers to a molecule consisting of a guanine (G), adenine (A), thymine (T), uridine (U), or cytidine (C) base covalently linked to a pentose sugar, while "nucleotide" or "mononucleotide" refers to a nucleoside phosphorylated at one of the hydroxyl groups of the pentose sugar. "Nucleoside" also encompasses analogs of G, A, T, C, or U, as well as natural or unnatural nucleic acid building blocks in which the base, sugar, and / or phosphate backbone have been modified or replaced. Nucleoside analogs are known in the art and include those described herein. Also included are endogenously post-transcriptionally modified nucleosides, such as methylated nucleosides.

[0845] Linear nucleic acid molecules are said to have a "5' end" (5' terminus) and a "3' end" (3' terminus) because, except with respect to adenylation (described elsewhere herein), mononucleotides are joined unidirectionally via phosphodiester bonds (or analogs) to form oligonucleotides, such that the phosphate (or analog) on ​​the 5' carbon of one mononucleotide sugar is linked to the oxygen on the 3' carbon of the adjacent mononucleotide sugar. Thus, an end of an oligonucleotide is referred to as the "5' end" if its 5' phosphate (or analog) is not linked to the oxygen on the 3' carbon of the mononucleotide sugar, and as the "3' end" if its 3' oxygen is not linked to the 5' phosphate (or analog) of the subsequent mononucleotide sugar. As used herein, a "terminal nucleotide" is the nucleotide at the end of the 3' or 5' terminus. The 3' or 5' end may alternatively terminate at a 3'-OH or 5'-OH if the terminal nucleotide is not phosphorylated.

[0846] As used herein, the term "nucleic acid" refers to a covalently linked sequence of nucleotides in which the 3' position of the sugar of one nucleotide is linked to the 5' position of the sugar of the next nucleotide by a phosphodiester bond (i.e., a 3' to 5' phosphodiester bond), and the nucleotides are linked in a specific sequence, i.e., the linear order of the nucleotides. "Nucleic acid" also includes analogs of the foregoing, in which one or more nucleotides are modified at the base, sugar, or phosphodiester. Such analogs are known in the art and include those described elsewhere herein. As used herein, "polynucleotide" or "polynucleic acid" refers to a long nucleic acid sequence of many nucleotides (or analogs thereof). For example, a polynucleotide (or polynucleic acid) can be, but is not limited to, 60, 61-1,000, or more than 201-1,000, or more than 1,000 nucleotides in length. As used herein, an "oligonucleotide" or "oligonucleic acid" refers to a short polynucleotide or portion of a polynucleotide. For example, but not limited to, oligonucleotides may be 5-10, 10-60, or 10-200 nucleotides i...

Claims

1. Compound of Formula B: 【Chemistry 439】 or a pharmaceutically acceptable salt thereof, wherein: an RNA binder is a moiety that binds to a target RNA transcript; DFL is a degrader-recruiting ligand; -L １ - is a bivalent linker group covalently linking said RNA binder to said DFL, A compound or a pharmaceutically acceptable salt thereof, wherein the DFL binds to or recruits a degrading factor.

2. The compound of claim 1 , wherein the RNA binder is an oligonucleotide, a polypeptide, or an RNA-binding small molecule (rSM).

3. The compound of claim 1 , wherein the RNA binder is an oligonucleotide.

4. The compound of claim 1 , wherein the RNA binder is an rSM.

5. Compound of Formula A: 【Chemical 440】 or a pharmaceutically acceptable salt thereof, wherein: the rSM is an RNA-binding small molecule that binds to a target RNA transcript; DFL is a degrader-recruiting ligand; -L １ - is a bivalent linker group covalently linking the rSM to the DFL; A compound or a pharmaceutically acceptable salt thereof, wherein the DFL binds to or recruits a degrading factor.

6. 6. The compound of claim 5, 【Chemistry 441】 is a compound of formula Ia: 【Chemistry 442】 or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is 【Chemistry 443】 and Y is N or CH; Z １ is N, C=O or CR ２ and Z ２ is N, C=O, or CR ３ However, Z １ and Z ２ are not both N or C=O, Each R １ are independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , -NRS(O) ２ R or -L １ - and R ２ and R ３ are each independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , -NRS(O) ２ R or -L １ - or R ２ and R ３ together with the carbons to which they are attached, m R ５ and the ring is a 4-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R ４ are independently —R, halogen, ═O, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , or -NRS(O) ２ R, Each R ５ are independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , or -NRS(O) ２ R, -L ２ -but, 【Chemistry 444】 wherein —X— is covalently bonded to ring B and —X— is NR ６ , -O-, -CR ６ R ７ - or -S-, and -C(R ８ ) ２ - or -C(R １０ ) ２ - is optionally replaced by a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ６ and R ７ are each independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, —OR, or —N(R) ２ or -SR, Each R ８ are independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , -NRS(O) ２ R or -L １ - and R ９ is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R) ２ or -SR, or R ８ and R ９ together with the atoms to which they are attached, m R ５ and the ring is a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and each R １０ are independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O)2R, -S(O) ２ N (R) ２ , or -NRS(O) ２ R or R ８ and R １０ or R ９ and R １０ together with the atoms to which they are attached, m R ５ and forming a ring substituted with a 6-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C １－６ an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -L １ - is a covalent bond or C １－８ a divalent straight or branched hydrocarbon chain in which one, two, or three methylene units of the chain are independently and optionally replaced by —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)—, —C(O)N(R)—, —(R)NC(O)—, —OC(O)N(R)—, —(R)NC(O)O—, —N(R)C(O)N(R)—, —S—, —SO—, —SO2—, —SON(R)—, —(R)NSO2—, —C(S)—, —C(S)O—, —OC(S)—, —C(S)N(R)—, —(R)NC(S)—, —(R)NC(S)N(R)—, or —Cy-; １ , R ２ , R ３ , or R ８ But, -L １ -, and only one end of -L1- is covalently bound to rSM, each -Cy- is an optionally substituted 3- to 8-membered saturated or partially unsaturated divalent monocyclic carbocycle, optionally substituted phenylene, an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic or bridged bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; q is 0, 1, 2, 3, or 4; A compound wherein r is 0, 1, 2, 3, or 4.

7. Ring A is 【Chemistry 445】 7. The compound according to claim 5 or 6, selected from:

8. Ring B is 【Chemistry 446】 The compound according to any one of claims 5 to 7, wherein

9. R １ But, -L １ The compound according to any one of claims 5 to 8, wherein

10. R ２ But, -L １ The compound according to any one of claims 5 to 8, wherein

11. R ３ Ha-L １ The compound according to any one of claims 5 to 8, wherein

12. R ４ が、H、=O、Me、Et、irr、 【Chemistry 447】 The compound according to any one of claims 5 to 11, selected from:

13. R ８ Ha-L １ The compound according to any one of claims 5 to 8, wherein

14. -L ２ -but, 【Chemistry 448】 The compound according to any one of claims 5 to 13, selected from:

15. The compound is a compound of formula II-a or II-b: 【Chemistry 449】 or a pharmaceutically acceptable salt thereof.

16. The compound has the formula III-a: [Chemical 450] or a pharmaceutically acceptable salt thereof.

17. The compound is a compound of formula IV-a: 【Chemistry 451】 or a pharmaceutically acceptable salt thereof. 【Request Item 18】 【Chemistry 452】 is a compound of formula Ic: 【Chemistry 453】 or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 12-membered bicyclic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered tricyclic heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is 【Chemical 454】 and Y is N or CH; Z １ is N, C=O or CR ２ and Z ２ is N, C=O, or CR ３ However, Z １ and Z ２ are not both N or C=O, Each R １ are independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , -NRS(O) ２ R or -L １ - and R ２ and R ３ are each independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , -NRS(O) ２ R or -L １ - or R ２ and R ３ together with the carbons to which they are attached, m R ５ and the ring is a 4-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R ４ are independently —R, halogen, ═O, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , -NRS(O) ２ R, or a divalent straight or branched chain C １－８ a hydrocarbon chain wherein one, two, three, or four methylene units of the chain are selected from the group consisting of -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -S-, -SO-, or -SO ２ independently and optionally replaced by -, Each R ５ are independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , or -NRS(O) ２ R, -L ２ -but, 【Chemistry 455】 wherein —X— is covalently bonded to ring B and —X— is NR ６ , -O-, -CR ６ R ７ -, -C(O)-, -S- or S(O) ２ - and -C(R ８ ) ２ - or -C(R １０ ) ２ - is optionally replaced by a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ６ and R ７ are each independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, —OR, or —N(R) ２ or -SR, Each R ８ are independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , -NRS(O) ２ R or -L １ - or two R ８ together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic ring, R ９ is -R, halogen, -CN, -NC, -C(O)OR, -OC(O)R, -OR, -N(R) ２ , or -SR, or R ８ and R ９ together with the atoms to which they are attached, m R ５ and forming a ring substituted with a 5-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R １０ are independently —R, halogen, —CN, —NC, —C(O)OR, —OC(O)R, or —C(O)N(R) ２ , -N(R)C(O)R, -N(R)C(O)N(R) ２ , -OC(O)N(R) ２ , -N(R)C(O)OR, -OR, -N(R) ２ , -NO ２ , -N ３ , -SR, -S(O)R, -S(O) ２ R, -S(O) ２ N (R) ２ , or -NRS(O) ２ R, or two R １０ together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic ring, or R ９ and R １０ together with the atoms to which they are attached, m R ５ forming a ring substituted with instances of Each R is independently hydrogen or C １－６ an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; -L １ - is a bivalent linker group covalently linking the rSM to the DFL, and R １ , R ２ , R ３ , R ８ , or R １１ One and only one of -L １ - and -L １ - one end of which is covalently linked to the rSM, each -Cy- is an optionally substituted 3- to 8-membered saturated or partially unsaturated divalent monocyclic carbocycle, optionally substituted phenylene, an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocycle having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic or bridged bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R １１ But H, C １－３ alkyl, or -L １ - and m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; q is 0, 1, 2, 3, or 4; 6. The compound of claim 5, wherein r is 0, 1, 2, 3, or 4.

19. Ring A is 【Chemistry 456】 19. The compound of claim 18, selected from:

20. Ring B is 【Chemistry 457】 20. The compound of claim 18 or claim 19, wherein:

21. R １ But, -L １ The compound according to any one of claims 18 to 20, wherein

22. R ２ But, -L １ The compound according to any one of claims 18 to 20, wherein

23. R ３ But, -L １ The compound according to any one of claims 18 to 20, wherein

24. R ４ が、H、=O、Me、Et、irr、 【Chemistry 458】 The compound according to any one of claims 18 to 23, selected from:

25. R ８ But, -L １ The compound according to any one of claims 18 to 20, wherein

26. R １１ But H, C1- ３ alkyl, or -L １ The compound according to any one of claims 18 to 20, wherein

27. -L ２ -but, 【Chemistry 459】 【Chemical 460】 The compound according to any one of claims 18 to 20, selected from:

28. The compound is a compound of formula IX-a, IX-b, IX-c, XVI-a, XVI-b, or XVI-c: 【Chemistry 461】 or a pharmaceutically acceptable salt thereof.

29. The compound is a compound of formula X-a, X-b, X-c, XVII-a, XVII-b, or XVII-c: 【Chemistry 462】 or a pharmaceutically acceptable salt thereof.

30. The compound is a compound of formula XI-a, XI-b, XI-c, XVIII-a, XVIII-b, or XVIII-c: 【Chemical 463】 or a pharmaceutically acceptable salt thereof.

31. The compound is a compound of formula XII-a, XII-b, XII-c, XIX-a, XIX-b, or XIX-c: 【Chemical 464】 or a pharmaceutically acceptable salt thereof.

32. The compound is a compound of formula XIII-a, XIII-b, XIII-c, XX-a, XX-b, or XX-c: 【Chemical 465】 or a pharmaceutically acceptable salt thereof.

33. The compound is a compound of formula XIV-a, XIV-b, XIV-c, XXI-a, XXI-b, or XXI-c: 【Chemical 466】 or a pharmaceutically acceptable salt thereof.

34. The compound is a compound of formula XV-a or XXII-a: 【Chemistry 467】 or a pharmaceutically acceptable salt thereof.

35. The compound is a compound of formula XXIII-a, formula XXIII-b, or formula XXIII-c: 【Chemical 468】 or a pharmaceutically acceptable salt thereof.

36. The compound is a compound of formula XXIII-d, formula XXIII-e, or formula XXIII-f: 【Chemistry 469】 or a pharmaceutically acceptable salt thereof.

37. The compound is a compound of formula XXIV-a: 【Chemistry 470】 or a pharmaceutically acceptable salt thereof.

38. The compound is a compound of formula XXIV-b: 【Chemistry 471】 or a pharmaceutically acceptable salt thereof.

39. The compound is a compound of formula XXV-a: 【Chemistry 472】 or a pharmaceutically acceptable salt thereof.

40. The compound is a compound of formula XXV-b: 【Chemistry 473】 or a pharmaceutically acceptable salt thereof.

41. 41. The compound of any one of claims 1 to 40, wherein the degradation factor is a protein that binds to or interacts with RNA (RBP), and the interaction of RBP with RNA results in modulation of target RNA transcripts in vivo.

42. 40. The compound of claim 39, wherein the RBP is part of the CCR4-NOT (carbon catabolite repression negative in the absence of TATA) complex.

43. 43. The compound of claim 41 or claim 42, wherein the RBP is CNOT7.

44. 44. The compound of claim 43, wherein the DFL does not bind to the active site of CNOT7.

45. 45. The compound of claim 44, wherein the DFL binds to CNOT7 without interfering with the enzymatic activity of the CNOT7 and / or the CCR4-NOT complex.

46. 46. ​​The compound of any one of claims 1 to 45, wherein the target RNA transcript is mRNA, or a precursor, isoform, unspliced ​​isoform, splice intermediate, fragment, or variant thereof.

47. 47. The compound of any one of claims 1 to 46, wherein the target RNA transcript is selected from one of those listed in Table C or Table D, or a precursor, isoform, unspliced ​​isoform, splice intermediate, fragment, or variant thereof.

48. 48. The compound of any one of claims 1 to 47, wherein the rSM is selected from any one of those described in the paragraph under the heading RNA-binding small molecules (rSM).

49. 49. The compound of any one of claims 1 to 48, wherein the rSM is one of those shown in Table 2.

50. 50. A pharmaceutical composition comprising a compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

51. 51. A method of modulating the amount of a protein in a cell, comprising administering a compound or composition according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, that acts on a target RNA transcript or a precursor, isoform, fragment, or variant thereof, in an amount sufficient to modulate the amount of said protein in said cell.

52. 48. The method of claim 47, wherein modulating the amount of a protein in a cell comprises reducing the amount of a protein in the cell.

53. 53. A method of modulating the availability for protein translation of a target RNA transcript or a precursor, isoform, fragment, or variant thereof, comprising contacting the target RNA transcript or a precursor, isoform, fragment, or variant thereof with a compound or composition according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, that binds to the target RNA transcript or an isoform, fragment, or variant thereof.

54. 54. A method of modulating translation of a target protein or precursor thereof, comprising contacting a target RNA transcript or precursor, isoform, fragment, or variant thereof with a compound or composition of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

55. 55. A method of decreasing the half-life or increasing the degradation of a target RNA transcript or precursor, isoform, fragment, or variant thereof, comprising contacting the target RNA transcript or said precursor, isoform, fragment, or variant thereof with the compound or composition of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof.

56. 56. A method of treating a disease, comprising administering to a subject in need thereof a compound or composition according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof.

57. 57. The method of claim 56, wherein the disease is characterized by abnormal levels of a protein in a cell.

58. 58. The method of claim 57, wherein the disease is one of those listed in Table C or Table D.

59. 59. The method of claim 58, wherein the disease is cancer.

60. 60. The method of any one of claims 51 to 59, wherein the RBP is CNOT7.

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