Methods for modulating rna splicing

Abstract

In one aspect, described herein is an intronic recognition element for splicing modifier (iREMS) that can be recognized by a compound provided herein. In another aspect, described herein are methods for modulating the amount of a product of a gene, wherein a precursor RNA transcript transcribed from the gene contains an intronic REMS, and the methods utilizing a compound described herein. More particularly, described herein are methods for modulating the amount of an RNA transcript or protein product encoded by a gene, wherein a precursor RNA transcript transcribed from the gene comprises an intronic REMS, and the methods utilizing a compound described herein. In another aspect, provided herein are artificial gene constructs comprising an intronic REMS, and uses of those artificial gene constructs to modulate protein production. In another aspect, provided herein are methods for altering endogenous genes to comprise an intronic REMS, and the use of a compound described herein to modulate protein produced from such altered endogenous genes.

What is claimed is: 
     
         1 . A method for producing a mature mRNA transcript comprising an iExon, the method comprising contacting a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein one exon is upstream of the intron and the other exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from ABCB8, ABCC3, ADAM17, ADCY3, AGPAT4, ANKRA2, ANXA11, APIP, APPL2, ARHGAP1, ARL15, ASAP1, ASPH, ATAD2B, ATXN1, BECN1, BHMT2, BICD1, BTN3A1, C11orf30, C11orf73, C12orf4, C14orf132, C8orf44, C8orf44-SGK3, C8orf88, CASC3, CASP7, CCDC122, CDH13, CECR7, CENPI, CEP112, CEP192, CHEK1, CMAHP, CNRIP1, COPS7B, CPSF4, CRISPLD2, CRYBG3, CSNK1E, CSNK1G1, DCAF17, DCUN1D4, DDX42, DENND1A, DENND5A, DGKA, DHFR, DIAPH3, DNAJC13, DNMBP, DOCK1, DYRK1A, EIF2B3, ENAH, ENOX1, EP300, ERC1, ERLIN2, ERRFI1, EVC, FAF1, FAIM, FAM126A, FAM13A, FAM162A, FAM174A, FBN2, FER, FHOD3, FOCAD, GALC, GCFC2, GGACT, GLCE, GOLGA4, GOLGB1, GPSM2, GULP1, GXYLT1, HDX, HLTF, HMGA2, HNMT, HSD17B12, HSD17B4, HTT, IFT57, IVD, KDM6A, KIAA1524, KIAA1715, LETM2, LOC400927, LRRC42, LUC7L3, LYRM1, MB21D2, MCM10, MED13L, MEDAG, MEMO1, MFN2, MMS19, MRPL45, MRPS28, MTERF3, MYCBP2, MYLK, MYOF, NGF, NREP, NSUN4, NT5C2, OSMR, OXCT1, PAPD4, PCM1, PDE7A, PDS5B, PDXDC1, PIGN, PIK3CD, PIK3R1, PIKFYVE, PITPNB, PLEKHA1, PLSCR1, PMS1, POMT2, PPARG, PPIP5K2, PPP1R26, PRPF31, PRSS23, PSMA4, PXK, RAF1, RAPGEF1, RARS2, RBKS, RERE, RFWD2, RPA1, RPS10, SAMD4A, SAR1A, SCO1, SEC24A, SENP6, SERGEF, SGK3, SLC12A2, SLC25A17, SLC44A2, SMYD3, SNAP23, SNHG16, SNX7, SOS2, SPATA5, SPIDR, SPRYD7, SRGAP1, SRRM1, STAT1, STXBP6, SUPT20H, TAF2, TASP1, TBC1D15, TCF12, TCF4, TIAM1, TJP2, TMC3, TMEM214, TNRC6A, TNS3, TOE1, TRAF3, TSPAN2, TTC7B, TYW5, UBAP2L, URGCP, VAV2, WDR27, WDR37, WDR91, WNK1, XRN2, ZCCHC8, ZFP82, ZNF138, ZNF232 or ZNF37BP, and wherein Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein: 
         w 1  and w 5  are independently C—R a  or N; 
         w 2  is C—R b  or N; 
         w 3 , w 4  and w 7  are independently C—R 1 , C—R 2 , C—R a  or N; 
         w 6  is C—R 1 , C—R 2 , C—R c  or N; 
         wherein one of w 3 , w 4 , w 6  and w 7  is C—R 1  and one other of w 3 , w 4 , w 6  and w 7  is C—R 2 , provided that, 
         when w 3  is C—R 1 , then w 6  is C—R 2  and w 4  and w 7  are independently C—R a  or N; or, 
         when w 3  is C—R 2 , then w 6  is C—R 1  and w 4  and w 7  are independently C—R a  or N; or, 
         when w 4  is C—R 1 , then w 7  is C—R 2  and w 3  is C—R a  or N and w 6  is C—R c  or N; or, 
         when w 4  is C—R 2 , then w 7  is C—R 1  and w 3  is C—R a  or N and w 6  is C—R c  or N; and, 
         wherein any one, two or three of w 1 , w 2 , w 3 , w 4 , w 5 , w 6  and w 7  may optionally be N; 
         R 1  is C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, C 1-8 -alkoxy-C 1-8 alkyl-amino, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, (amino-C 1-8 alkyl) 2 -amino, (amino-C 1-8 alkyl)(C 1-8 alkyl)amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, amino-C 1-8 alkoxy, C 1-8 alkyl-amino-C 1-8 alkoxy, (C 1-8 alkyl) 2 -amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkoxy, amino-C 2-8 alkenyl, C 1-8 alkyl-amino-C 2-8 alkenyl, (C 1-8 alkyl) 2 -amino-C 2-8 alkenyl, amino-C 2-8 alkynyl, C 1-8 alkyl-amino-C 2-8 alkynyl, (C 1-8 alkyl) 2 -amino-C 2-8 alkynyl, halo-C 1-8 alkyl-amino, (halo-C 1-8 alkyl) 2 -amino, (halo-C 1-8 alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 alkyl, hydroxy-C 1-8 alkoxy-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl) 2 -amino, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino-C 1-8 alkoxy, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkoxy, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkoxy, hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl-amino, [(hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, [(hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl](C 1-8 alkyl)amino, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-C 1-8 alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 alkyl, heterocyclyl-C 1-8 alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2 -amino, (heterocyclyl-C 1-8 alkyl)(C 1-8 alkyl)amino, heterocyclyl-C 1-8 alkyl-amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 cycloalkyl, aryl-C 1-8 alkyl-amino, (aryl-C 1-8 alkyl) 2 -amino, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl, (aryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-C 1-8 alkoxy, heteroaryl-amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl) 2 -amino, (heteroaryl-C 1-8 alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl, (heteroaryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl or (heteroaryl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; 
         wherein, each instance of heterocyclyl, C 3-14 cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R 3  substituents and optionally, with one additional R 4  substituent; or, 
         wherein, each instance of heterocyclyl, C 3-14 cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R 3  substituents; 
         R 2  is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; 
         wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6  substituents and optionally, with one additional R 7  substituent; 
         R a  is, in each instance, independently selected from hydrogen, halogen, C 1-8 alkyl or deuterium; 
         R b  is hydrogen, halogen, C 1-8 alkyl, C 1-8 alkoxy or deuterium; 
         R c  is hydrogen, halogen, C 1-8 alkyl or deuterium; 
         R 3  is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkoxy-carbonyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl] 2 -amino, (C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, [(C 1-4 alkyl) 2 -amino-C 1-4 alkyl](C 1-4 alkyl)amino, C 1-8 alkoxy-C 1-8 alkyl-amino, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino, C 1-8 alkyl-carbonyl-amino, C 1-8 alkoxy-carbonyl-amino, hydroxy-C 1-8 alkyl, hydroxy-C 1-8 alkoxy-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl) 2 -amino or (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino; 
         R 4  is C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, C 3-14 cycloalkyl-amino, aryl-C 1-8 alkyl, aryl-C 1-8 alkoxy-carbonyl, aryl-sulfonyloxy-C 1-8 alkyl, heterocyclyl or heterocyclyl-C 1-8 alkyl; wherein, each instance of C 3-14 cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R 5  substituents; 
         R 5  is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino or C 1-8 alkyl-thio; 
         R 6  is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, halo-C 1-8 alkyl, hydroxy-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino or C 1-8 alkyl-thio; and, R 7  is C 3-14 cycloalkyl, C 3-14 cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl. 
       
     
     
         2 . A method for modulating the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein one exon is upstream of the intron and the other exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous intronic recognition element for splicing modifier (iREMS), a first branch point, and a first 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from ABCA10, ABCB8, ABCC3, ACTA2, ADAL, ADAMTS1, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF3, AGPAT4, AKAP3, ANK1, ANK3, ANKRA2, ANKRD33B, ANKRD36, AP4B1-AS1, APIP, ARHGAP1, ARHGAP12, ARHGEF16, ARID5B, ARL15, ARL9, ARMCX6, ASIC1, ATG5, ATP2A3, ATXN1, B3GALT2, B3GNT6, BCL2L15, BCYRN1, BECN1, BHMT2, BIN3-IT1, BIRC3, BIRC6, BTG2, BTN3A1, C10orf54, C11orf70, C11orf94, C12orf4, C12orf56, C14orf132, C19orf47, C1orf86, C3, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, CA13, CA3, CACNA2D2, CACNB1, CADM1, CAND2, CASP7, CCDC122, CCDC79, CCER2, CCNF, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP170, CEP192, CFH, CHEK1, CIITA, CLDN23, CLTA, CMAHP, CNGA4, CNRIP1, CNTD1, COL11A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A6, COL8A1, COLEC12, COMP, CPA4, CPQ, CPSF4, CRISPLD2, CRLF1, CRYBG3, CRYL1, CSNK1E, CSNK1G1, CYB5R2, CYGB, CYP1B1, DAGLB, DCAF17, DCLK1, DCN, DDIT4L, DDX50, DEGS1, DEPTOR, DFNB59, DIRAS3, DLG5, DLGAP4, DNAH8, DNAJC13, DNAJC27, DNMBP, DOCK11, DYNC1I1, DYRK1A, DZIP1L, EFEMP1, EGR3, ELN, ELP4, EMX2OS, ENAH, ENPP1, EP300, ERCC1, ERCC8, ERGIC3, ERLIN2, ERRFI1, ESM1, EVC, EVC2, F2R, FAIM, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM20A, FAM46B, FAM65B, FAP, FARP1, FBLN2, FBN2, FBXL6, FCHO1, FGFR2, FGL2, FLT1, FRAS1, FSCN2, GAL3ST4, GALNT15, GATA6, GBGT1, GCNT1, GDF6, GGACT, GLCE, GNAQ, GPR183, GPR50, GPRC5A, GPRC5B, GRTP1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS3, HAVCR2, HDAC5, HDX, HECTD2-AS1, HEPH, HEY1, HMGA2, HMGN3-AS1, HNMT, HOOK3, HPS1, HSPA1L, HTATIP2, IFT57, IGDCC4, IGF2R, TGFBP3, TL16, INA, TNPP5K, INTU, TQCG, ITGA11, ITGA8, ITGB8, ITIH1, TTPKA, TVD, KAT6B, KCNS1, KCNS2, KDM6A, KDSR, KIAA1456, KIAA1462, KIAA1755, KIT, KLF17, KLRG1, KMT2D, KRT7, KRTAP1-1, KRTAP1-5, L3MBTL2, LAMB2P1, LETM2, LGI2, LGR4, LHX9, LINC00472, LINC00570, LINC00578, LINC00607, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LMOD1, LOC400927, LRBA, LRP4, LRRC32, LRRC39, LRRC42, LSAMP, LUM, LYPD1, LYRM1, MAFB, MAMDC2, MAN2A1, MAN2C1, MAPK13, MASP1, MB, MB21D2, MC4R, MCM10, MED13L, MEGF6, MFN2, MIAT, MIR612, MLLT10, MMP10, MMP24, MN1, MOXD1, MRPL45, MRPL55, MRPS28, MRVI1, MSH4, MTERF3, MXRA5, MYCBP2, NA, NAALADL2, NAE1, NAGS, NDNF, NGF, NGFR, NHLH1, NLN, NOTCH3, NOTUM, NOVA2, NOX4, NRROS, OCLN, OLR1, OSBPL10, OXCT1, OXCT2, PAIP2B, PBLD, PDE1C, PDE5A, PDGFD, PDGFRB, PDS5B, PEAR1, PHACTR3, PIGN, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNM3, PLEK2, PLEKHA1, PLEKHA6, PLEKHH2, PLSCR1, PNISR, PODN, POLN, POLR1A, POMT2, PPARG, PPIP5K2, PPM1E, PPP1R26, PPP3CA, PRKCA, PRKG1, PRPF31, PRPH2, PRRG4, PRUNE2, PSMD6-AS2, PTGIS, PTX3, PXK, RAB30, RAB38, RAB44, RAD9B, RAF1, RAPGEF1, RARS, RARS2, RBBP8, RBKS, RDX, RERE, RFX3-AS1, RGCC, ROR1, ROR2, RPA1, RPS10, RPS6KB2, SAMD4A, SCARNA9, SEC24A, SENP6, SERGEF, SGK3, SH3YL1, SHROOM3, SIGLEC10, SKA2, SLC12A2, SLC24A3, SLC35F3, SLC39A10, SLC44A2, SLC46A2, SLC4A11, SLC6A15, SLC7A11, SLC9A3, SLIT3, SMG1P3, SMTN, SNED1, SNX7, SORBS2, SORCS2, SOX7, SPATA18, SPATA5, SPDYA, SPEF2, SPIDR, SPRYD7, SRGAP1, SRRM1, STAC2, STAT4, STK32B, STRN4, STS, STXBP6, SULF1, SVEP1, SYNGR2, SYNPO, SYNPO2, SYNPO2L, TAGLN3, TANGO6, TASP1, TCF12, TCF4, TGFA, TGFB2, TGFB3, TGM2, THBS2, TIAM1, TMC3, TMEM102, TMEM119, TMEM134, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM50B, TNFAIP8L3, TNFRSF14, TNRC18P1, TNRC6A, TNXB, TP53AIP1, TPRG1, TRIM66, TRPC4, TSHZ2, TSPAN11, TSPAN18, TSPAN7, TSSK3, TTC7B, TUBE1, TXNIP, TYW5, URGCP, USP27X, UVRAG, VAV2, VIM-AS1, VPS41, VSTM2L, VWF, WDR27, WDR91, WISP1, WNK1, WNT10B, YDJC, ZBTB26, ZCCHC5, ZCCHC8, ZFP82, ZMIZ1-AS1, ZNF138, ZNF212, ZNF232, ZNF350, ZNF431, ZNF660, ZNF680, ZNF79, or ZNF837, and, wherein Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein: 
         w 1  and w 5  are independently C—R a  or N; 
         w 2  is C—R b  or N; 
         w 3 , w 4  and w 7  are independently C—R 1 , C—R 2 , C—R a  or N; 
         w 6  is C—R 1 , C—R 2 , C—R c  or N; 
         wherein one of w 3 , w 4 , w 6  and w 7  is C—R 1  and one other of w 3 , w 4 , w 6  and w 7  is C—R 2 , provided that, 
         when w 3  is C—R 1 , then w 6  is C—R 2  and w 4  and w 7  are independently C—R a  or N; or, 
         when w 3  is C—R 2 , then w 6  is C—R 1  and w 4  and w 7  are independently C—R a  or N; or, 
         when w 4  is C—R 1 , then w 7  is C—R 2  and w 3  is C—R a  or N and w 6  is C—R c  or N; or, 
         when w 4  is C—R 2 , then w 7  is C—R 1  and w 3  is C—R a  or N and w 6  is C—R c  or N; and, 
         wherein any one, two or three of w 1 , w 2 , w 3 , w 4 , w 5 , w 6  and w 7  may optionally be N; 
         R 1  is C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, C 1-8 alkoxy-C 1-8 alkyl-amino, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, (amino-C 1-8 alkyl) 2 -amino, (amino-C 1-8 alkyl)(C 1-8 alkyl)amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, amino-C 1-8 alkoxy, C 1-8 alkyl-amino-C 1-8 alkoxy, (C 1-8 alkyl) 2 -amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkoxy, amino-C 2-8 alkenyl, C 1-8 alkyl-amino-C 2-8 alkenyl, (C 1-8 alkyl) 2 -amino-C 2-8 alkenyl, amino-C 2-8 alkynyl, C 1-8 alkyl-amino-C 2-8 alkynyl, (C 1-8 alkyl) 2 -amino-C 2-8 alkynyl, halo-C 1-8 alkyl-amino, (halo-C 1-8 alkyl) 2 -amino, (halo-C 1-8 alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 alkyl, hydroxy-C 1-8 alkoxy-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl) 2 -amino, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino-C 1-8 alkoxy, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkoxy, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkoxy, hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl-amino, [(hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, [(hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl](C 1-8 alkyl)amino, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-C 1-8 alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 alkyl, heterocyclyl-C 1-8 alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2 -amino, (heterocyclyl-C 1-8 alkyl)(C 1-8 alkyl)amino, heterocyclyl-C 1-8 alkyl-amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 cycloalkyl, aryl-C 1-8 alkyl-amino, (aryl-C 1-8 alkyl) 2 -amino, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl, (aryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-C 1-8 alkoxy, heteroaryl-amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl) 2 -amino, (heteroaryl-C 1-8 alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl, (heteroaryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl or (heteroaryl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; 
         wherein, each instance of heterocyclyl, C 3-14 cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R 3  substituents and optionally, with one additional R 4  substituent; or, 
         wherein, each instance of heterocyclyl, C 3-14 cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R 3  substituents; 
         R 2  is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; 
         wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6  substituents and optionally, with one additional R 7  substituent; 
         R a  is, in each instance, independently selected from hydrogen, halogen, C 1-8 alkyl or deuterium; 
         R b  is hydrogen, halogen, C 1-8 alkyl, C 1-8 alkoxy or deuterium; 
         R c  is hydrogen, halogen, C 1-8 alkyl or deuterium; 
         R 3  is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkoxy-carbonyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl] 2 -amino, (C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, C 1-8 alkoxy-C 1-8 alkyl-amino, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino, C 1-8 alkyl-carbonyl-amino, C 1-8 alkoxy-carbonyl-amino, hydroxy-C 1-8 alkyl, hydroxy-C 1-8 alkoxy-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl) 2 -amino or (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino; 
         R 4  is C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, C 3-14 cycloalkyl-amino, aryl-C 1-8 alkyl, aryl-C 1-8 alkoxy-carbonyl, aryl-sulfonyloxy-C 1-8 alkyl, heterocyclyl or heterocyclyl-C 1-8 alkyl; wherein, each instance of C 3-14 cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R 5  substituents; 
         R 5  is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino or C 1-8 alkyl-thio; 
         R 6  is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, halo-C 1-8 alkyl, hydroxy-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino or C 1-8 alkyl-thio; and, R 7  is C 3-14 cycloalkyl, C 3-14 cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl. 
       
     
     
         3 . The method of  claim 2 , wherein the intron further comprises a first 5′ splice site, a second branch point, and a second 3′ splice site upstream of the iREMS. 
     
     
         4 . A method for producing a mature mRNA transcript comprising an iExon, the method comprising contacting a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein one exon is upstream of the intron and the other exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, a non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, and wherein wherein Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein: 
         w 1  and w 5  are independently C—R a  or N; 
         w 2  is C—R b  or N; 
         w 3 , w 4  and w 7  are independently C—R 1 , C—R 2 , C—R a  or N; 
         w 6  is C—R 1 , C—R 2 , C—R c  or N; 
         wherein one of w 3 , w 4 , w 6  and w 7  is C—R 1  and one other of w 3 , w 4 , w 6  and w 7  is C—R 2 , provided that, 
         when w 3  is C—R 1 , then w 6  is C—R 2  and w 4  and w 7  are independently C—R a  or N; or, 
         when w 3  is C—R 2 , then w 6  is C—R 1  and w 4  and w 7  are independently C—R a  or N; or, 
         when w 4  is C—R 1 , then w 7  is C—R 2  and w 3  is C—R a  or N and w 6  is C—R c  or N; or, 
         when w 4  is C—R 2 , then w 7  is C—R 1  and w 3  is C—R a  or N and w 6  is C—R c  or N; and, 
         wherein any one, two or three of w 1 , w 2 , w 3 , w 4 , w 5 , w 6  and w 7  may optionally be N; 
         R 1  is C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, C 1-8 alkoxy-C 1-8 alkyl-amino, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, (amino-C 1-8 alkyl) 2 -amino, (amino-C 1-8 alkyl)(C 1-8 alkyl)amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, amino-C 1-8 alkoxy, C 1-8 alkyl-amino-C 1-8 alkoxy, (C 1-8 alkyl) 2 -amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkoxy, amino-C 2-8 alkenyl, C 1-8 alkyl-amino-C 2-8 alkenyl, (C 1-8 alkyl) 2 -amino-C 2-8 alkenyl, amino-C 2-8 alkynyl, C 1-8 alkyl-amino-C 2-8 alkynyl, (C 1-8 alkyl) 2 -amino-C 2-8 alkynyl, halo-C 1-8 alkyl-amino, (halo-C 1-8 alkyl) 2 -amino, (halo-C 1-8 alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 alkyl, hydroxy-C 1-8 alkoxy-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl) 2 -amino, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino-C 1-8 alkoxy, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkoxy, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkoxy, hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl-amino, [(hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, [(hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl](C 1-8 alkyl)amino, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-C 1-8 alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 alkyl, heterocyclyl-C 1-8 alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2 -amino, (heterocyclyl-C 1-8 alkyl)(C 1-8 alkyl)amino, heterocyclyl-C 1-8 alkyl-amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 cycloalkyl, aryl-C 1-8 alkyl-amino, (aryl-C 1-8 alkyl) 2 -amino, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl, (aryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-C 1-8 alkoxy, heteroaryl-amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl) 2 -amino, (heteroaryl-C 1-8 alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl, (heteroaryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl or (heteroaryl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; 
         wherein, each instance of heterocyclyl, C 3-14 cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R 3  substituents and optionally, with one additional R 4  substituent; or, 
         wherein, each instance of heterocyclyl, C 3-14 cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R 3  substituents; 
         R 2  is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; 
         wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6  substituents and optionally, with one additional R 7  substituent; 
         R a  is, in each instance, independently selected from hydrogen, halogen, C 1-8 alkyl or deuterium; 
         R b  is hydrogen, halogen, C 1-8 alkyl, C 1-8 alkoxy or deuterium; 
         R c  is hydrogen, halogen, C 1-8 alkyl or deuterium; 
         R 3  is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkoxy-carbonyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl] 2 -amino, (C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, C 1-8 alkoxy-C 1-8 alkyl-amino, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino, C 1-8 alkyl-carbonyl-amino, C 1-8 alkoxy-carbonyl-amino, hydroxy-C 1-8 alkyl, hydroxy-C 1-8 alkoxy-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl) 2 -amino or (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino; 
         R 4  is C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, C 3-14 cycloalkyl-amino, aryl-C 1-8 alkyl, aryl-C 1-8 alkoxy-carbonyl, aryl-sulfonyloxy-C 1-8 alkyl, heterocyclyl or heterocyclyl-C 1-8 alkyl; wherein, each instance of C 3-14 cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R 5  substituents; 
         R 5  is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino or C 1-8 alkyl-thio; 
         R 6  is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, halo-C 1-8 alkyl, hydroxy-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino or C 1-8 alkyl-thio; and, 
         R 7  is C 3-14 cycloalkyl, C 3-14 cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl. 
       
     
     
         5 . A method for modulating the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting the pre-mRNA transcript with the a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein one exon is upstream of the intron and the other exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: a non-endogenous intronic recognition element for splicing modifier (iREMS), a first branch point, and a first 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, and wherein wherein Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein: 
         w 1  and w 5  are independently C—R a  or N; 
         w 2  is C—R b  or N; 
         w 3 , w 4  and w 7  are independently C—R 1 , C—R 2 , C—R a  or N; 
         w 6  is C—R 1 , C—R 2 , C—R c  or N; 
         wherein one of w 3 , w 4 , w 6  and w 7  is C—R 1  and one other of w 3 , w 4 , w 6  and w 7  is C—R 2 , provided that, 
         when w 3  is C—R 1 , then w 6  is C—R 2  and w 4  and w 7  are independently C—R a  or N; or, 
         when w 3  is C—R 2 , then w 6  is C—R 1  and w 4  and w 7  are independently C—R a  or N; or, 
         when w 4  is C—R 1 , then w 7  is C—R 2  and w 3  is C—R a  or N and w 6  is C—R c  or N; or, 
         when w 4  is C—R 2 , then w 7  is C—R 1  and w 3  is C—R a  or N and w 6  is C—R c  or N; and, 
         wherein any one, two or three of w 1 , w 2 , w 3 , w 4 , w 5 , w 6  and w 7  may optionally be N; 
         R 1  is C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, C 1-8 alkoxy-C 1-8 alkyl-amino, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, (amino-C 1-8 alkyl) 2 -amino, (amino-C 1-8 alkyl)(C 1-8 alkyl)amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, amino-C 1-8 alkoxy, C 1-8 alkyl-amino-C 1-8 alkoxy, (C 1-8 alkyl) 2 -amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkoxy, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkoxy, amino-C 2-8 alkenyl, C 1-8 alkyl-amino-C 2-8 alkenyl, (C 1-8 alkyl) 2 -amino-C 2-8 alkenyl, amino-C 2-8 alkynyl, C 1-8 alkyl-amino-C 2-8 alkynyl, (C 1-8 alkyl) 2 -amino-C 2-8 alkynyl, halo-C 1-8 alkyl-amino, (halo-C 1-8 alkyl) 2 -amino, (halo-C 1-8 alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 alkyl, hydroxy-C 1-8 alkoxy-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl) 2 -amino, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino-C 1-8 alkoxy, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkoxy, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkoxy, hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl-amino, [(hydroxy-C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, [(hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl](C 1-8 alkyl)amino, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-C 1-8 alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 alkyl, heterocyclyl-C 1-8 alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2 -amino, (heterocyclyl-C 1-8 alkyl)(C 1-8 alkyl)amino, heterocyclyl-C 1-8 alkyl-amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (heterocyclyl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 cycloalkyl, aryl-C 1-8 alkyl-amino, (aryl-C 1-8 alkyl) 2 -amino, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl, (aryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, (aryl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-C 1-8 alkoxy, heteroaryl-amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl) 2 -amino, (heteroaryl-C 1-8 alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl, (heteroaryl-C 1-8 alkyl) 2 -amino-C 1-8 alkyl or (heteroaryl-C 1-8 alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; 
         wherein, each instance of heterocyclyl, C 3-14 cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R 3  substituents and optionally, with one additional R 4  substituent; or, 
         wherein, each instance of heterocyclyl, C 3-14 cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R 3  substituents; 
         R 2  is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; 
         wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R 6  substituents and optionally, with one additional R 7  substituent; 
         R a  is, in each instance, independently selected from hydrogen, halogen, C 1-8 alkyl or deuterium; 
         R b  is hydrogen, halogen, C 1-8 alkyl, C 1-8 alkoxy or deuterium; 
         R c  is hydrogen, halogen, C 1-8 alkyl or deuterium; 
         R 3  is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkoxy-carbonyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl-amino-C 1-8 alkyl) 2 -amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl] 2 -amino, (C 1-8 alkyl-amino-C 1-8 alkyl)(C 1-8 alkyl)amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl](C 1-8 alkyl)amino, C 1-8 alkoxy-C 1-8 alkyl-amino, (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino, (C 1-8 alkoxy-C 1-8 alkyl)(C 1-8 alkyl)amino, C 1-8 alkyl-carbonyl-amino, C 1-8 alkoxy-carbonyl-amino, hydroxy-C 1-8 alkyl, hydroxy-C 1-8 alkoxy-C 1-8 alkyl, hydroxy-C 1-8 alkyl-amino, (hydroxy-C 1-8 alkyl) 2 -amino or (hydroxy-C 1-8 alkyl)(C 1-8 alkyl)amino; 
         R 4  is C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, C 3-14 cycloalkyl-amino, aryl-C 1-8 alkyl, aryl-C 1-8 alkoxy-carbonyl, aryl-sulfonyloxy-C 1-8 alkyl, heterocyclyl or heterocyclyl-C 1-8 alkyl; wherein, each instance of C 3-14 cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R 5  substituents; 
         R 5  is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino or C 1-8 alkyl-thio; 
         R 6  is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, halo-C 1-8 alkyl, hydroxy-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino or C 1-8 alkyl-thio; and, 
         R 7  is C 3-14 cycloalkyl, C 3-14 cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl. 
       
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the iREMS comprises an RNA sequence GAguragu, and wherein r is adenine or guanine. 
     
     
         7 . The method of any one of  claims 1 - 5 , wherein the iREMS comprises an RNA sequence NNGAgurngn (SEQ ID NO: 1), and wherein r is adenine or guanine and n or N is any nucleotide. 
     
     
         8 . The method of  claim 7 , wherein the RNA sequence NNGAgurngn (SEQ ID NO: 1) is selected from the group consisting of ANGAgurngn (SEQ ID NO: 29), CNGAgurngn (SEQ ID NO: 35), GNGAgurngn (SEQ ID NO: 41), UNGAgurngn (SEQ ID NO: 47), NAGAgurngn (SEQ ID NO: 30), NCGAgurngn (SEQ ID NO: 36), NGGAgurngn (SEQ ID NO: 42), NUGAgumgn (SEQ ID NO: 48), AAGAgurngn (SEQ ID NO: 31), ACGAgurngn (SEQ ID NO: 37), AGGAgurngn (SEQ ID NO: 43), AUGAgumgn (SEQ ID NO: 49), CAGAgurngn (SEQ ID NO: 32), CCGAgurngn (SEQ ID NO: 38), CGGAgurngn (SEQ ID NO: 44), CUGAgurngn (SEQ ID NO: 50), GAGAgurngn (SEQ ID NO: 33), GCGAgumgn (SEQ ID NO: 39), GGGAgurngn (SEQ ID NO: 45), GUGAgumgn (SEQ ID NO: 51), UAGAgurngn (SEQ ID NO: 34), UCGAgumgn (SEQ ID NO: 40), UGGAgurngn (SEQ ID NO: 46) and UUGAgumgn (SEQ ID NO: 52), wherein r is adenine or guanine and n or N is any nucleotide. 
     
     
         9 . The method of any one of  claims 1 - 5 , wherein the iREMS comprises an RNA sequence NNGAguragu (SEQ ID NO: 3862), wherein r is adenine or guanine and N is any nucleotide. 
     
     
         10 . The method of  claim 9 , wherein the RNA sequence NNGAguragu (SEQ ID NO: 3862) is selected from the group consisting of ANGAguragu (SEQ ID NO: 437), CNGAguragu (SEQ ID NO: 443), GNGAguragu (SEQ ID NO: 449), UNGAguragu (SEQ ID NO: 455), NAGAguragu (SEQ ID NO: 438), NCGAguragu (SEQ ID NO: 444), NGGAguragu (SEQ ID NO: 450), NUGAguragu (SEQ ID NO: 456), AAGAguragu (SEQ ID NO: 439), ACGAguragu (SEQ ID NO: 445), AGGAguragu (SEQ ID NO: 451), AUGAguragu (SEQ ID NO: 457), CAGAguragu (SEQ ID NO: 440), CCGAguragu (SEQ ID NO: 446), CGGAguragu (SEQ ID NO: 452), CUGAguragu (SEQ ID NO: 458), GAGAguragu (SEQ ID NO: 441), GCGAguragu (SEQ ID NO: 447), GGGAguragu (SEQ ID NO: 453), GUGAguragu (SEQ ID NO: 459), UAGAguragu (SEQ ID NO: 442), UCGAguragu (SEQ ID NO: 448), UGGAguragu (SEQ ID NO: 454) and UUGAguragu (SEQ ID NO: 460), wherein r is adenine or guanine, and N is any nucleotide. 
     
     
         11 . An artificial gene construct comprising an RNA sequence comprising exons and one or more introns, wherein at least one intron comprises an iREMS that is downstream of a branch point and a 3′ splice site, and wherein the iREMS comprises the sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide. 
     
     
         12 . An artificial gene construct comprising an RNA sequence comprising two exons and an intron, wherein one exon is upstream of the intron and the other exon is downstream of the intron, wherein the RNA nucleotide sequence of the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an iREMS, a second branch point and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide. 
     
     
         13 . An artificial gene construct comprising an RNA sequence comprising two exons and an intron, wherein one exon is upstream of the intron and the other exon is downstream of the intron, wherein the RNA nucleotide sequence of the intron comprises in 5′ to 3′ order: an iREMS, a first branch point and a first 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide. 
     
     
         14 . The method of any one of  claims 1 - 10 , wherein the pre-mRNA transcript is in a cell or a lysate of the cell and the method comprises contacting the cell or cell lysate with the compound. 
     
     
         15 . The method of  claim 14 , wherein the modulation of the production of the mature mRNA transcript modulates the amount and/or type of a protein translated from the mature mRNA transcript and produced in the cell or lysate of the cell. 
     
     
         16 . The method of any one of  claims 1 - 10 ,  14  and  15 , wherein the pre-mRNA transcript encodes a detectable reporter protein.