METHODS FOR MODULATING RNA SPLICING

20230272367 · 2023-08-31

Assignee

Ptc Therapeutics, Inc. (South Plainfield, NJ)

Inventors

Cpc classification

International classification

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.

Claims

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: ##STR00262## wherein: w.sub.1 and w.sub.5 are independently C—R.sub.a or N; w.sub.2 is C—R.sub.b or N; w.sub.3, w.sub.4 and w.sub.7 are independently C—R.sub.1, C—R.sub.2, C—R.sub.a or N; w.sub.6 is C—R.sub.1, C—R.sub.2, C—R.sub.c or N; wherein one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1 and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that, when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or, when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or, when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or, when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; and, wherein any one, two or three of w.sub.1, w.sub.2, w.sub.3, w.sub.4, w.sub.5, w.sub.6 and w.sub.7 may optionally be N; R.sub.1 is C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, C.sub.1-8-alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, (amino-C.sub.1-8alkyl).sub.2-amino, (amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, amino-C.sub.1-8alkoxy, C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, amino-C.sub.2-8alkenyl, C.sub.1-8alkyl-amino-C.sub.2-8alkenyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkenyl, amino-C.sub.2-8alkynyl, C.sub.1-8alkyl-amino-C.sub.2-8alkynyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkynyl, halo-C.sub.1-8alkyl-amino, (halo-C.sub.1-8alkyl).sub.2-amino, (halo-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl-amino, [(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, [(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R.sub.3 substituents and optionally, with one additional R.sub.4 substituent; or, wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R.sub.3 substituents; R.sub.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.sub.6 substituents and optionally, with one additional R.sub.7 substituent; R.sub.a is, in each instance, independently selected from hydrogen, halogen, C.sub.1-8alkyl or deuterium; R.sub.b is hydrogen, halogen, C.sub.1-8alkyl, C.sub.1-8alkoxy or deuterium; R.sub.c is hydrogen, halogen, C.sub.1-8alkyl or deuterium; R.sub.3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkyl-carbonyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, C.sub.1-8alkoxy-carbonyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl].sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, [(C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkyl](C.sub.1-4alkyl)amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-carbonyl-amino, C.sub.1-8alkoxy-carbonyl-amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino or (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino; R.sub.4 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-C.sub.1-8alkyl, C.sub.3-14cycloalkyl-amino, aryl-C.sub.1-8alkyl, aryl-C.sub.1-8alkoxy-carbonyl, aryl-sulfonyloxy-C.sub.1-8alkyl, heterocyclyl or heterocyclyl-C.sub.1-8alkyl; wherein, each instance of C.sub.3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R.sub.5 substituents; R.sub.5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; R.sub.6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, C.sub.2-8alkenyl, halo-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; and, R.sub.7 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-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: ##STR00263## wherein: w.sub.1 and w.sub.5 are independently C—R.sub.a or N; w.sub.2 is C—R.sub.b or N; w.sub.3, w.sub.4 and w.sub.7 are independently C—R.sub.1, C—R.sub.2, C—R.sub.a or N; w.sub.6 is C—R.sub.1, C—R.sub.2, C—R.sub.c or N; wherein one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1 and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that, when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or, when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or, when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or, when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; and, wherein any one, two or three of w.sub.1, w.sub.2, w.sub.3, w.sub.4, w.sub.5, w.sub.6 and w.sub.7 may optionally be N; R.sub.1 is C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, (amino-C.sub.1-8alkyl).sub.2-amino, (amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, amino-C.sub.1-8alkoxy, C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, amino-C.sub.2-8alkenyl, C.sub.1-8alkyl-amino-C.sub.2-8alkenyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkenyl, amino-C.sub.2-8alkynyl, C.sub.1-8alkyl-amino-C.sub.2-8alkynyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkynyl, halo-C.sub.1-8alkyl-amino, (halo-C.sub.1-8alkyl).sub.2-amino, (halo-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl-amino, [(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, [(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R.sub.3 substituents and optionally, with one additional R.sub.4 substituent; or, wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R.sub.3 substituents; R.sub.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.sub.6 substituents and optionally, with one additional R.sub.7 substituent; R.sub.a is, in each instance, independently selected from hydrogen, halogen, C.sub.1-8alkyl or deuterium; R.sub.b is hydrogen, halogen, C.sub.1-8alkyl, C.sub.1-8alkoxy or deuterium; R.sub.c is hydrogen, halogen, C.sub.1-8alkyl or deuterium; R.sub.3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkyl-carbonyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, C.sub.1-8alkoxy-carbonyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl].sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-carbonyl-amino, C.sub.1-8alkoxy-carbonyl-amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino or (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino; R.sub.4 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-C.sub.1-8alkyl, C.sub.3-14cycloalkyl-amino, aryl-C.sub.1-8alkyl, aryl-C.sub.1-8alkoxy-carbonyl, aryl-sulfonyloxy-C.sub.1-8alkyl, heterocyclyl or heterocyclyl-C.sub.1-8alkyl; wherein, each instance of C.sub.3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R.sub.5 substituents; R.sub.5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; R.sub.6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, C.sub.2-8alkenyl, halo-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; and, R.sub.7 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-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: ##STR00264## wherein: w.sub.1 and w.sub.5 are independently C—R.sub.a or N; w.sub.2 is C—R.sub.b or N; w.sub.3, w.sub.4 and w.sub.7 are independently C—R.sub.1, C—R.sub.2, C—R.sub.a or N; w.sub.6 is C—R.sub.1, C—R.sub.2, C—R.sub.c or N; wherein one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1 and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that, when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or, when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or, when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or, when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; and, wherein any one, two or three of w.sub.1, w.sub.2, w.sub.3, w.sub.4, w.sub.5, w.sub.6 and w.sub.7 may optionally be N; R.sub.1 is C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, (amino-C.sub.1-8alkyl).sub.2-amino, (amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, amino-C.sub.1-8alkoxy, C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, amino-C.sub.2-8alkenyl, C.sub.1-8alkyl-amino-C.sub.2-8alkenyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkenyl, amino-C.sub.2-8alkynyl, C.sub.1-8alkyl-amino-C.sub.2-8alkynyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkynyl, halo-C.sub.1-8alkyl-amino, (halo-C.sub.1-8alkyl).sub.2-amino, (halo-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl-amino, [(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, [(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R.sub.3 substituents and optionally, with one additional R.sub.4 substituent; or, wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R.sub.3 substituents; R.sub.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.sub.6 substituents and optionally, with one additional R.sub.7 substituent; R.sub.a is, in each instance, independently selected from hydrogen, halogen, C.sub.1-8alkyl or deuterium; R.sub.b is hydrogen, halogen, C.sub.1-8alkyl, C.sub.1-8alkoxy or deuterium; R.sub.c is hydrogen, halogen, C.sub.1-8alkyl or deuterium; R.sub.3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkyl-carbonyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, C.sub.1-8alkoxy-carbonyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl].sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-carbonyl-amino, C.sub.1-8alkoxy-carbonyl-amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino or (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino; R.sub.4 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-C.sub.1-8alkyl, C.sub.3-14cycloalkyl-amino, aryl-C.sub.1-8alkyl, aryl-C.sub.1-8alkoxy-carbonyl, aryl-sulfonyloxy-C.sub.1-8alkyl, heterocyclyl or heterocyclyl-C.sub.1-8alkyl; wherein, each instance of C.sub.3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R.sub.5 substituents; R.sub.5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; R.sub.6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, C.sub.2-8alkenyl, halo-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; and, R.sub.7 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-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: ##STR00265## wherein: w.sub.1 and w.sub.5 are independently C—R.sub.a or N; w.sub.2 is C—R.sub.b or N; w.sub.3, w.sub.4 and w.sub.7 are independently C—R.sub.1, C—R.sub.2, C—R.sub.a or N; w.sub.6 is C—R.sub.1, C—R.sub.2, C—R.sub.c or N; wherein one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1 and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that, when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or, when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or, when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or, when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; and, wherein any one, two or three of w.sub.1, w.sub.2, w.sub.3, w.sub.4, w.sub.5, w.sub.6 and w.sub.7 may optionally be N; R.sub.1 is C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, (amino-C.sub.1-8alkyl).sub.2-amino, (amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, amino-C.sub.1-8alkoxy, C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, amino-C.sub.2-8alkenyl, C.sub.1-8alkyl-amino-C.sub.2-8alkenyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkenyl, amino-C.sub.2-8alkynyl, C.sub.1-8alkyl-amino-C.sub.2-8alkynyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkynyl, halo-C.sub.1-8alkyl-amino, (halo-C.sub.1-8alkyl).sub.2-amino, (halo-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl-amino, [(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, [(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R.sub.3 substituents and optionally, with one additional R.sub.4 substituent; or, wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R.sub.3 substituents; R.sub.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.sub.6 substituents and optionally, with one additional R.sub.7 substituent; R.sub.a is, in each instance, independently selected from hydrogen, halogen, C.sub.1-8alkyl or deuterium; R.sub.b is hydrogen, halogen, C.sub.1-8alkyl, C.sub.1-8alkoxy or deuterium; R.sub.c is hydrogen, halogen, C.sub.1-8alkyl or deuterium; R.sub.3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkyl-carbonyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, C.sub.1-8alkoxy-carbonyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl].sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-carbonyl-amino, C.sub.1-8alkoxy-carbonyl-amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino or (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino; R.sub.4 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-C.sub.1-8alkyl, C.sub.3-14cycloalkyl-amino, aryl-C.sub.1-8alkyl, aryl-C.sub.1-8alkoxy-carbonyl, aryl-sulfonyloxy-C.sub.1-8alkyl, heterocyclyl or heterocyclyl-C.sub.1-8alkyl; wherein, each instance of C.sub.3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R.sub.5 substituents; R.sub.5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; R.sub.6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, C.sub.2-8alkenyl, halo-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; and, R.sub.7 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-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.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0457] FIGS. 1A-1C. Representative schematics of intronic exon splicing mediated by an intronic REMS, where 5′ss represents a 5′ splice site, 3′ss represents a 3′ splice site and BP represents a splicing branch point. Exon 1e and Exon 2e represent extended exons. iExon 1a represents an intronic exon. Splicing events mediated by an intronic REMS in the absence of a compound described herein are illustrated by solid lines, splicing events mediated by an intronic REMS in the presence of a compound described herein are illustrated by dashed lines.

[0458] FIGS. 2A-2D, 3, 4, 5, 6A. The dose dependent production of iExons for certain genes (as specified in the figures) in the presence of certain compounds or control (DMSO) are shown, each of which represent aspects of the operation of an intronic REMS and compounds as described herein. Compounds used in the experiments depicted in FIGS. 3, 4, 5, and 6A are described herein. Compound 774 was used for the experiments depicted in FIGS. 2A-2D.

[0459] FIGS. 6B and 6C. FIG. 6B illustrates the production of exon isoforms with control (DMSO). FIG. 6C illustrates the production of certain intronic Exon isoforms for ELMO2 in the presence of a compound described herein, each of which represent aspects of the interactions of an intronic REMS, one or more branch points, one or more 3′ splice sites and compounds as described herein.

DETAILED DESCRIPTION

Intronic Recognition Element for Splicing Modifier (Rems)

[0460] In one aspect, provided herein is an intronic recognition element for splicing modifier (otherwise referred to as “iREMS”) recognized by a small molecule splicing modifier, whereby elements of the associated iREMS complex affect interactions with the spliceosome as further described herein. In a specific embodiment, the intronic REMS has the nucleotide sequence GAgurngn (SEQ ID NO: 2) at the RNA level, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n is any nucleotide. In another specific embodiment, the intronic REMS has the nucleotide sequence GAguragu (SEQ ID NO: 3866) at the RNA level, wherein r is adenine or guanine. In one or more of such specific embodiments provided herein, n is adenine or guanine. In a more specific embodiment, the intronic REMS has the nucleotide sequence NNGAgurngn (SEQ ID NO: 1) at the RNA level, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n or N is any nucleotide. In another more specific embodiment, the intronic REMS has the nucleotide sequence NNGAguragu (SEQ ID NO: 3862) at the RNA level, wherein r is adenine or guanine and N is any nucleotide. In one or more of such more specific embodiments provided herein, N is adenine or guanine.

[0461] In another specific embodiment, the intronic REMS is downstream of an intronic branch point and a functional intronic 3′ splice site, wherein the intronic REMS comprises a nucleotide sequence 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), NUGAgurngn (SEQ ID NO: 48), AAGAgurngn (SEQ ID NO: 31), ACGAgurngn (SEQ ID NO: 37), AGGAgurngn (SEQ ID NO: 43), AUGAgurngn (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), GCGAgurngn (SEQ ID NO: 39), GGGAgurngn (SEQ ID NO: 45), GUGAgurngn (SEQ ID NO: 51), UAGAgurngn (SEQ ID NO: 34), UCGAgurngn (SEQ ID NO: 40), UGGAgurngn (SEQ ID NO: 46) and UUGAgurngn (SEQ ID NO: 52) at the RNA level, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n or N is any nucleotide, by which the intronic REMS, in the presence of a compound described herein, functions as an intronic 5′ splice site, causing the NNGA (SEQ ID NO: 3863) nucleotides of the REMS and the intronic nucleotide sequence between the intronic 3′ splice site down to and including the NNGA (SEQ ID NO: 3863) nucleotides to be spliced into the mature RNA as an intronic exon to provide a non-wild-type, nonfunctional mRNA.

[0462] In a preferred embodiment, the REMS has a nucleotide sequence 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) at the RNA level, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and N is any nucleotide. In one or more embodiments provided herein, N is A or G.

[0463] In the context of DNA, in a specific embodiment, the nucleotide sequence encoding an intronic REMS has the sequence GAgtrngn (SEQ ID NO: 4), wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n is any nucleotide. In another specific embodiment, in the context of DNA, the nucleotide sequence encoding an intronic REMS has the sequence GAgtragt (SEQ ID NO: 3865), wherein r is A or G. In a specific embodiment, in the context of DNA, the nucleotide sequence encoding an intronic REMS has the sequence NNGAgtrngn (SEQ ID NO: 3), wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n or N is any nucleotide. In another specific embodiment, in the context of DNA, the nucleotide sequence encoding an intronic REMS has the sequence NNGAgtragt (SEQ ID NO: 3864), wherein r is A or G and N is any nucleotide.

[0464] In a specific embodiment, in the context of DNA, the nucleotide sequence encoding an intronic REMS comprises a sequence selected from the group consisting of ANGAgtrngn (SEQ ID NO: 1829), CNGAgtrngn (SEQ ID NO: 1835), GNGAgtrngn (SEQ ID NO: 1841), TNGAgtrngn (SEQ ID NO: 1847), NAGAgtrngn (SEQ ID NO: 1830), NCGAgtrngn (SEQ ID NO: 1836), NGGAgtrngn (SEQ ID NO: 1842), NTGAgtrngn (SEQ ID NO: 1848), AAGAgtrngn (SEQ ID NO: 1831), ACGAgtrngn (SEQ ID NO: 1837), AGGAgtrngn (SEQ ID NO: 1843), ATGAgtrngn (SEQ ID NO: 1849), CAGAgtrngn (SEQ ID NO: 1832), CCGAgtrngn (SEQ ID NO: 1838), CGGAgtrngn (SEQ ID NO: 1844), CTGAgtrngn (SEQ ID NO: 1850), GAGAgtrngn (SEQ ID NO: 1833), GCGAgtrngn (SEQ ID NO: 1839), GGGAgtrngn (SEQ ID NO: 1845), GTGAgtrngn (SEQ ID NO: 1851), TAGAgtrngn (SEQ ID NO: 1834), TCGAgtrngn (SEQ ID NO: 1840), TGGAgtrngn (SEQ ID NO: 1846) and TTGAgtrngn (SEQ ID NO: 1852), wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n or N is any nucleotide.

[0465] In a preferred embodiment, in the context of DNA, the nucleotide sequence encoding the intronic REMS comprises a sequence selected from the group consisting of ANGAgtragt (SEQ ID NO: 2237), CNGAgtragt (SEQ ID NO: 2243), GNGAgtragt (SEQ ID NO: 2249), TNGAgtragt (SEQ ID NO: 2255), NAGAgtragt (SEQ ID NO: 2238), NCGAgtragt (SEQ ID NO: 2244), NGGAgtragt (SEQ ID NO: 2250), NTGAgtragt (SEQ ID NO: 2256), AAGAgtragt (SEQ ID NO: 2239), ACGAgtragt (SEQ ID NO: 2245), AGGAgtragt (SEQ ID NO: 2251), ATGAgtragt (SEQ ID NO: 2257), CAGAgtragt (SEQ ID NO: 2240), CCGAgtragt (SEQ ID NO: 2246), CGGAgtragt (SEQ ID NO: 2252), CTGAgtragt (SEQ ID NO: 2258), GAGAgtragt (SEQ ID NO: 2241), GCGAgtragt (SEQ ID NO: 2247), GGGAgtragt (SEQ ID NO: 2253), GTGAgtragt (SEQ ID NO: 2259), TAGAgtragt (SEQ ID NO: 2242), TCGAgtragt (SEQ ID NO: 2248), TGGAgtragt (SEQ ID NO: 2254) and TTGAgtragt (SEQ ID NO: 2260), wherein r is A or G and N is any nucleotide. In one or more embodiments provided herein, N is A or G.

[0466] An intronic REMS can be part of an endogenous RNA or can be introduced into an RNA sequence that does not naturally contain the intronic REMS sequence (in which case, the introduced intronic REMS is a non-endogenous intronic REMS, i.e., an intronic REMS not naturally present in the corresponding RNA. A nucleotide sequence encoding an intronic REMS can also be part of an endogenous DNA sequence, or a nucleotide sequence encoding the intronic REMS can be introduced into a DNA sequence that does not naturally contain the nucleotide sequence encoding an intronic REMS.

[0467] In a specific embodiment, the intronic REMS is located in an intron which further comprises is downstream of a branch point and a functional 3′ splice site which, in the presence of a small molecule splicing modifier, enables the REMS to function as a 5′ splice site. In a specific embodiment, the intronic REMS is located in an intron and is downstream of a branch point and a functional 3′ splice site which, in the presence of a small molecule splicing modifier, enables the REMS to function as a 5′ splice site. Without being bound by any theory or mechanism, the small molecule compounds described herein have been shown to increase the affinity of the interaction between the U1 snRNP, as well as other components of the pre-mRNA splicing machinery, and the nucleotides NNGA (SEQ ID NO: 3863) of the REMS whereby, in the presence of the compound, the intronic REMS functions as a U1 snRNP binding site, causing the intronic nucleotides to be spliced as an intronic exon.

Compounds

[0468] Provided herein are compounds of Formula (I) for use in the methods described herein:

##STR00016##

[0469] or a form thereof, wherein:

[0470] w.sub.1 and w.sub.5 are independently C—R.sub.a or N;

[0471] w.sub.2 is C—R.sub.b or N;

[0472] w.sub.3, w.sub.4 and w.sub.7 are independently C—R.sub.1, C—R.sub.2, C—R.sub.a or N;

[0473] w.sub.6 is C—R.sub.1, C—R.sub.2, C—R.sub.c or N;

[0474] wherein one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that,

[0475] when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0476] when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0477] when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or,

[0478] when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; and,

[0479] wherein any one, two or three of w.sub.1, w.sub.2, w.sub.3, w.sub.4, w.sub.5, w.sub.6 and w.sub.7 may optionally be N;

[0480] R.sub.1 is C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, (amino-C.sub.1-8alkyl).sub.2-amino, (amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, amino-C.sub.1-8alkoxy, C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, amino-C.sub.2-8alkenyl, C.sub.1-8alkyl-amino-C.sub.2-8alkenyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkenyl, amino-C.sub.2-8alkynyl, C.sub.1-8alkyl-amino-C.sub.2-8alkynyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkynyl, halo-C.sub.1-8alkyl-amino, (halo-C.sub.1-8alkyl).sub.2-amino, (halo-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl-amino, [(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, [(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl;

[0481] wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R.sub.3 substituents and optionally, with one additional R.sub.4 substituent; or,

[0482] wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R.sub.3 substituents;

[0483] R.sub.2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;

[0484] wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R.sub.6 substituents and optionally, with one additional R.sub.7 substituent;

[0485] R.sub.a is, in each instance, independently selected from hydrogen, halogen, C.sub.1-8alkyl or deuterium;

[0486] R.sub.b is hydrogen, halogen, C.sub.1-8alkyl, C.sub.1-8alkoxy or deuterium;

[0487] R.sub.c is hydrogen, halogen, C.sub.1-8alkyl or deuterium;

[0488] R.sub.3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkyl-carbonyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, C.sub.1-8alkoxy-carbonyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl].sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-carbonyl-amino, C.sub.1-8alkoxy-carbonyl-amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino or (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino;

[0489] R.sub.4 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-C.sub.1-8alkyl, C.sub.3-14cycloalkyl-amino, aryl-C.sub.1-8alkyl, aryl-C.sub.1-8alkoxy-carbonyl, aryl-sulfonyloxy-C.sub.1-8alkyl, heterocyclyl or heterocyclyl-C.sub.1-8alkyl;

[0490] wherein, each instance of C.sub.3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R.sub.5 substituents;

[0491] R.sub.5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio;

[0492] R.sub.6 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, C.sub.2-8alkenyl, halo-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; and,

[0493] R.sub.7 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

[0494] In one embodiment of the use of a compound of Formula (I), w.sub.1 is C—R.sub.a.

[0495] In another embodiment of the use of a compound of Formula (I), w.sub.1 is N.

[0496] In one embodiment of the use of a compound of Formula (I), w.sub.2 is C—R.sub.b.

[0497] In another embodiment of the use of a compound of Formula (I), w.sub.2 is N.

[0498] In one embodiment of the use of a compound of Formula (I), w.sub.3 is C—R.sub.a.

[0499] In another embodiment of the use of a compound of Formula (I), w.sub.3 is N.

[0500] In one embodiment of the use of a compound of Formula (I), w.sub.4 is C—R.sub.a.

[0501] In another embodiment of the use of a compound of Formula (I), w.sub.4 is N.

[0502] In one embodiment of the use of a compound of Formula (I), w.sub.5 is C—R.sub.a.

[0503] In another embodiment of the use of a compound of Formula (I), w.sub.5 is N.

[0504] In one embodiment of the use of a compound of Formula (I), w.sub.6 is C—R.sub.c.

[0505] In another embodiment of the use of a compound of Formula (I), w.sub.6 is N.

[0506] In one embodiment of the use of a compound of Formula (I), w.sub.7 is C—R.sub.a.

[0507] In another embodiment of the use of a compound of Formula (I), w.sub.7 is N.

[0508] In one embodiment of the use of a compound of Formula (I), w.sub.3 is C—R.sub.1and w.sub.6 is C—R.sub.2.

[0509] In another embodiment of the use of a compound of Formula (I), w.sub.3 is C—R.sub.2 and w.sub.6 is C—R.sub.1.

[0510] In one embodiment of the use of a compound of Formula (I), w.sub.4 is C—R.sub.1and w.sub.7 is C—R.sub.2.

[0511] In another embodiment of the use of a compound of Formula (I), w.sub.4 is C—R.sub.2 and w.sub.7 is C—R.sub.1.

[0512] In one embodiment of the use of a compound of Formula (I), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2 and w.sub.1, w.sub.4, w.sub.5 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0513] In another embodiment of the use of a compound of Formula (I), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1and w.sub.1, w.sub.4, w.sub.5 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0514] In one embodiment of the use of a compound of Formula (I), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.1, w.sub.3 and w.sub.5 are independently C—R.sub.a or N, w.sub.2 is C—R.sub.b or N and w.sub.6 is C—R.sub.c or N.

[0515] In another embodiment of the use of a compound of Formula (I), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.1, w.sub.3 and w.sub.5 are independently C—R.sub.a or N, w.sub.2 is C—R.sub.b or N and w.sub.6 is C—R.sub.c or N.

[0516] In one embodiment of the use of a compound of Formula (I), w.sub.1 and w.sub.2 are N.

[0517] In one embodiment of the use of a compound of Formula (I), w.sub.1 and w.sub.3 are N.

[0518] In one embodiment of the use of a compound of Formula (I), w.sub.1 and w.sub.4 are N.

[0519] In one embodiment of the use of a compound of Formula (I), w.sub.1 and w.sub.5 are N.

[0520] In one embodiment of the use of a compound of Formula (I), w.sub.1 and w.sub.6 are N.

[0521] In one embodiment of the use of a compound of Formula (I), w.sub.1 and w.sub.7 are N.

[0522] In one embodiment of the use of a compound of Formula (I),

[0523] R.sub.1 is C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, (amino-C.sub.1-8alkyl).sub.2-amino, (amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, amino-C.sub.1-8alkoxy, C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, amino-C.sub.2-8alkenyl, C.sub.1-8alkyl-amino-C.sub.2-8alkenyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkenyl, amino-C.sub.2-8alkynyl, C.sub.1-8alkyl-amino-C.sub.2-8alkynyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkynyl, halo-C.sub.1-8alkyl-amino, (halo-C.sub.1-8alkyl).sub.2-amino, (halo-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl-amino, [(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, [(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0524] In another embodiment of the use of a compound of Formula (I),

[0525] R.sub.1 is amino, (C.sub.1-8alkyl).sub.2-amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, (amino-C.sub.1-8alkyl).sub.2-amino, (amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, amino-C.sub.1-8alkoxy, C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, amino-C.sub.2-8alkenyl, C.sub.1-8alkyl-amino-C.sub.2-8alkenyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkenyl, amino-C.sub.2-8alkynyl, C.sub.1-8alkyl-amino-C.sub.2-8alkynyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkynyl, halo-C.sub.1-8alkyl-amino, (halo-C.sub.1-8alkyl).sub.2-amino, (halo-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl-amino, [(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, [(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0526] In another embodiment of the use of a compound of Formula (I),

[0527] R.sub.1 is C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, (amino-C.sub.1-8alkyl).sub.2-amino, (amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, amino-C.sub.1-8alkoxy, C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, amino-C.sub.2-8alkenyl, C.sub.1-8alkyl-amino-C.sub.2-8alkenyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkenyl, amino-C.sub.2-8alkynyl, C.sub.1-8alkyl-amino-C.sub.2-8alkynyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkynyl, halo-C.sub.1-8alkyl-amino, (halo-C.sub.1-8alkyl).sub.2-amino, (halo-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl-amino, [(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino or [(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino.

[0528] In another embodiment of the use of a compound of Formula (I),

[0529] R.sub.1 is heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0530] In another embodiment of the use of a compound of Formula (I),

[0531] R.sub.1 is heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl or heterocyclyl-carbonyl-oxy; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0532] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl optionally substituted with R.sub.3 and R.sub.4 substituents.

[0533] In another embodiment of the use of a compound of Formula (I), R.sub.1 is C.sub.3-14cycloalkyl optionally substituted with R.sub.3 and R.sub.4 substituents.

[0534] In another embodiment of the use of a compound of Formula (I),

[0535] R.sub.1 is aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of aryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0536] In another embodiment of the use of a compound of Formula (I), R.sub.1 is aryl-C.sub.1-8alkyl-amino optionally substituted with R.sub.3 and R.sub.4 substituents.

[0537] In another embodiment of the use of a compound of Formula (I),

[0538] R.sub.1 is heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0539] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heteroaryl optionally substituted with R.sub.3 and R.sub.4 substituents.

[0540] In one embodiment of the use of a compound of Formula (I),

[0541] R.sub.1 is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-h]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or 6,9-diazaspiro[4.5]decyl; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0542] In another embodiment of the use of a compound of Formula (I),

[0543] R.sub.1 is heterocyclyl selected from azetidin-1-yl, tetrahydrofuran-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, piperazin-1-yl, 1,4-diazepan-1-yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-4-yl, hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl, octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazin-2-yl, 3-azabicyclo[3.1.0]hex-3-yl, 8-azabicyclo[3.2.1]oct-3-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-2-en-3-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl, 9-azabicyclo[3.3.1]non-3-yl, (1R,5S)-9-azabicyclo[3.3.1]non-3-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.2]oct-2-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, (1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl, 1,4-diazabicyclo[3.2.2]non-4-yl, azaspiro[3.3]hept-2-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2,7-diazaspiro[3.5]non-7-yl, 5,8-diazaspiro[3.5]non-8-yl, 2,7-diazaspiro[4.4]non-2-yl or 6,9-diazaspiro[4.5]dec-9-yl; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0544] In another embodiment of the use of a compound of Formula (I),

[0545] R.sub.1 is substituted heterocyclyl selected from 4-methyl-1,4-diazepan-1-yl, (3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aS,6aS)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)-5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aR,7aR)-1-ethyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aR,7aR)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7aS)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl, (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl, 9-methyl-9-azabicyclo[3.3.1]non-3-yl, (3-exo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl, (1R,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl or (1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl.

[0546] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-C.sub.1-8alkyl, wherein heterocyclyl is selected from morpholinyl, piperidinyl, piperazinyl, imidazolyl or pyrrolidinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0547] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-C.sub.1-8alkyl selected from morpholin-4-yl-methyl, morpholin-4-yl-ethyl, morpholin-4-yl-propyl, piperidin-1-yl-methyl, piperazin-1-yl-methyl, piperazin-1-yl-ethyl, piperazin-1-yl-propyl, piperazin-1-yl-butyl, imidazol-1-yl-methyl, imidazol-1-yl-ethyl, imidazol-1-yl-propyl, imidazol-1-yl-butyl, pyrrolidin-1-yl-methyl, pyrrolidin-1-yl-ethyl, pyrrolidin-1-yl-propyl or pyrrolidin-1-yl-butyl; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0548] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-C.sub.1-8alkoxy, wherein heterocyclyl is selected from pyrrolidinyl, piperidinyl or morpholinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0549] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-C.sub.1-8alkoxy selected from pyrrolidin-2-yl-methoxy, pyrrolidin-2-yl-ethoxy, pyrrolidin-1-yl-methoxy, pyrrolidin-1-yl-ethoxy, piperidin-1-yl-methoxy, piperidin-1-yl-ethoxy, morpholin-4-yl-methoxy or morpholin-4-yl-ethoxy; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0550] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-amino, wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, 9-azabicyclo[3.3.1]nonyl or (1R,5S)-9-azabicyclo[3.3.1]nonyl; and, wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0551] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-amino selected from azetidin-3-yl-amino, pyrrolidin-3-yl-amino, piperidin-4-yl-amino, 9-azabicyclo[3.3.1]non-3-yl-amino, (1R,5S)-9-azabicyclo[3.3.1]non-3-yl-amino, 9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino, (3-exo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino or (1R,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0552] In one embodiment of the use of a compound of Formula (I), R.sub.1 is (heterocyclyl)(C.sub.1-8alkyl)amino, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0553] In another embodiment of the use of a compound of Formula (I), R.sub.1 is (heterocyclyl)(C.sub.1-8alkyl)amino selected from (pyrrolidin-3-yl)(methyl)amino or (piperidin-4-yl)methyl)amino; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0554] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-amino-C.sub.1-8alkyl, wherein heterocyclyl is selected from tetrahydrofuranyl; and, wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0555] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-amino-C.sub.1-8alkyl, selected from 3-(tetrahydrofuran-3-yl-amino)propyl; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0556] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, wherein heterocyclyl is selected from tetrahydrofuranyl, thienyl or pyridinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0557] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, selected from 3-[(tetrahydrofuran-2-ylmethyl)amino]propyl, 3-[(thienyl-3-ylmethyl)amino]propyl, 3-[(pyridin-2-ylmethyl)amino]propyl or 3-[(pyridin-4-ylmethyl)amino]propyl; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0558] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-oxy, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0559] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-oxy selected from pyrrolidin-3-yl-oxy or piperidin-4-yl-oxy; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0560] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-carbonyl, wherein heterocyclyl is selected from piperazinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0561] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-carbonyl selected from piperazin-1-yl-carbonyl; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0562] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-carbonyl-oxy, wherein heterocyclyl is selected from piperazinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0563] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heterocyclyl-carbonyl-oxy selected from piperazin-1-yl-carbonyl-oxy; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0564] In one embodiment of the use of a compound of Formula (I), R.sub.1 is C.sub.3-14cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl or cycloheptyl; wherein, each instance of C.sub.3-14cycloalkyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0565] In another embodiment of the use of a compound of Formula (I), R.sub.1 is C.sub.3-8cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl or cycloheptyl; wherein, each instance of C.sub.3-8cycloalkyl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0566] In one embodiment of the use of a compound of Formula (I), R.sub.1 is aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0567] In another embodiment of the use of a compound of Formula (I), R.sub.1 is aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl selected from 3-(benzylamino)propyl; wherein, each instance of aryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0568] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heteroaryl, wherein heteroaryl is selected from pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0569] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heteroaryl selected from pyridin-4-yl; wherein, each instance of heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0570] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heteroaryl-C.sub.1-8alkyl, wherein heteroaryl is selected from 1H-imidazolyl; and, wherein, each instance of heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0571] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heteroaryl-C.sub.1-8alkyl selected from 1H-imidazol-1-yl-methyl; wherein, each instance of heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0572] In one embodiment of the use of a compound of Formula (I), R.sub.1 is (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, wherein heteroaryl is selected from pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0573] In another embodiment of the use of a compound of Formula (I), R.sub.1 is (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino selected from (pyridin-3-ylmethylxmethyl)amino; wherein, each instance of heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0574] In one embodiment of the use of a compound of Formula (I), R.sub.1 is heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, wherein heteroaryl is selected from thienyl or pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0575] In another embodiment of the use of a compound of Formula (I), R.sub.1 is heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl selected from thien-3-yl-methyl-amino-propyl, pyridin-2-yl-methyl-amino-propyl, pyridin-3-yl-methyl-amino-propyl or pyridin-4-yl-methyl-amino-propyl; wherein, each instance of heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents.

[0576] In one embodiment of the use of a compound of Formula (I), R.sub.3 is selected from cyano, halogen, hydroxy, oxo, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkyl-carbonyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, C.sub.1-8alkoxy-carbonyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, C.sub.1-8alkyl-carbonyl-amino, C.sub.1-8alkoxy-carbonyl-amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino or (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino.

[0577] In another embodiment of the use of a compound of Formula (I), R.sub.3 is selected from cyano, halogen, hydroxy, oxo, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, C.sub.1-8alkoxy-carbonyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, C.sub.1-8alkoxy-carbonyl-amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino or (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino.

[0578] In one embodiment of the use of a compound of Formula (I), R.sub.3 is C.sub.1-8alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

[0579] In another embodiment of the use of a compound of Formula (I), R.sub.3 is C.sub.1-8alkyl selected from ethyl, propyl, isopropyl or tert-butyl.

[0580] In one embodiment of the use of a compound of Formula (I), R.sub.3 is halo-C.sub.1-8alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.

[0581] In another embodiment of the use of a compound of Formula (I), R.sub.3 is halo-C.sub.1-8alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, trihalo-propyl or dihalo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.

[0582] In one embodiment of the use of a compound of Formula (I), R.sub.3 is hydroxy-C.sub.1-8alkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

[0583] In another embodiment of the use of a compound of Formula (I), R.sub.3 is hydroxy-C.sub.1-8alkyl selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

[0584] In one embodiment of the use of compound of Formula (I), R.sub.3 is C.sub.1-8alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

[0585] In one embodiment of the use of a compound of Formula (I), R.sub.3 is halo-C.sub.1-8alkoxy selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro, chloro, bromo or iodo.

[0586] In one embodiment of the use of a compound of Formula (I), R.sub.3 is C.sub.1-8alkoxy-carbonyl-amino selected from methoxy-carbonyl-amino, ethoxy-carbonyl-amino, propoxy-carbonyl-amino, isopropoxy-carbonyl-amino, tert-butoxy-carbonyl-amino.

[0587] In one embodiment of the use of a compound of Formula (I), R.sub.a is, in each instance, independently selected from hydrogen, halogen, C.sub.1-8alkyl.

[0588] In one embodiment of the use of a compound of Formula (I), R.sub.a is, in each instance, optionally and independently deuterium.

[0589] In one embodiment of the use of a compound of Formula (I), R.sub.b is hydrogen, halogen, C.sub.1-8alkyl, C.sub.1-8alkoxy.

[0590] In one embodiment of the use of a compound of Formula (I), R.sub.c is, in each instance, independently selected from hydrogen, halogen, C.sub.1-8alkyl.

[0591] In one embodiment of the use of a compound of Formula (I), R.sub.c is, in each instance, optionally and independently deuterium.

[0592] In one embodiment of the use of a compound of Formula (I), R.sub.b is deuterium.

[0593] In one embodiment of the use of a compound of Formula (I), R.sub.4 is C.sub.3-14cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein, each instance of C.sub.3-14cycloalkyl is optionally substituted with R.sub.5 substituents.

[0594] In another embodiment of the use of a compound of Formula (I), R.sub.4 is C-s-cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein, each instance of C.sub.3-8cycloalkyl is optionally substituted with R.sub.5 substituents.

[0595] In one embodiment of the use of a compound of Formula (I), R.sub.4 is C.sub.3-14cycloalkyl-C.sub.1-8alkyl, wherein C.sub.3-14cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C.sub.3-14cycloalkyl is optionally substituted with R.sub.5 substituents.

[0596] In another embodiment of the use of a compound of Formula (I), R.sub.4 is C.sub.3-8cycloalkyl-C.sub.1-8alkyl, wherein C.sub.3-8cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C.sub.3-8cycloalkyl is optionally substituted with R.sub.5 substituents.

[0597] In one embodiment of the use of a compound of Formula (I), R.sub.4 is C.sub.3-14cycloalkyl-amino, wherein C.sub.3-14cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C.sub.3-14cycloalkyl is optionally substituted with R.sub.5 substituents.

[0598] In another embodiment of the use of a compound of Formula (I), R.sub.4 is C.sub.3-8cycloalkyl-amino, wherein C.sub.3-8cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C.sub.3-8cycloalkyl is optionally substituted with R.sub.5 substituents.

[0599] In one embodiment of the use of a compound of Formula (I), R.sub.4 is aryl-C.sub.1-8alkyl, aryl-C.sub.1-8alkoxy-carbonyl or aryl-sulfonyloxy-C.sub.1-8alkyl, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R.sub.5 substituents.

[0600] In another embodiment of the use of a compound of Formula (I), R.sub.4 is aryl-C.sub.1-8alkyl or aryl-C.sub.1-8alkoxy-carbonyl, wherein each instance of aryl is optionally substituted with R.sub.5 substituents.

[0601] In one embodiment of the use of a compound of Formula (I), R.sub.4 is heterocyclyl selected from oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxanyl or morpholinyl, wherein each instance of heterocyclyl is optionally substituted with R.sub.5 substituents.

[0602] In another embodiment of the use of a compound of Formula (I), R.sub.4 is heterocyclyl selected from oxetan-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 1,3-dioxan-5-yl or morpholin-4-yl, wherein each instance of heterocyclyl is optionally substituted with R.sub.5 substituents.

[0603] In one embodiment of the use of a compound of Formula (I), R.sub.4 is heterocyclyl-C.sub.1-8alkyl, wherein each instance of heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R.sub.5 substituents.

[0604] In another embodiment of the use of a compound of Formula (I), R.sub.4 is heterocyclyl-C.sub.1-8alkyl selected from pyrrolidin-1-yl-C.sub.1-8alkyl or piperidin-1-yl-C.sub.1-8alkyl, wherein each instance of heterocyclyl is optionally substituted with R.sub.5 substituents.

[0605] In one embodiment of the use of a compound of Formula (I), R.sub.5 is selected from halogen, hydroxy, cyano, nitro, halo-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; wherein, halogen and halo is selected from fluoro, chloro, bromo or iodo.

[0606] In one embodiment of the use of a compound of Formula (I), R.sub.5 is hydroxy.

[0607] In one embodiment of the use of a compound of Formula (I), R.sub.5 is C.sub.1-8alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.

[0608] In another embodiment of the use of a compound of Formula (I), R.sub.5 is C.sub.1-8alkyl selected from ethyl, propyl, isopropyl or tert-butyl.

[0609] In one embodiment of the use of a compound of Formula (I), R.sub.1 is halo-C.sub.1-8alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.

[0610] In one embodiment of the use of a compound of Formula (I), R.sub.5 is C.sub.1-8alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

[0611] In one embodiment of the use of a compound of Formula (I), R.sub.5 is halo-C.sub.1-8alkoxy selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro, chloro, bromo or iodo.

[0612] In one embodiment of the use of a compound of Formula (I), R.sub.2 is aryl selected from phenyl optionally substituted with R.sub.6 and R.sub.7 substituents.

[0613] In one embodiment of the use of a compound of Formula (I), R.sub.2 is aryl-amino, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0614] In another embodiment of the use of a compound of Formula (I), R.sub.2 is aryl-amino selected from phenyl-amino; wherein, each instance of aryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0615] In one embodiment of the use of a compound of Formula (I), R.sub.2 is aryl-amino-carbonyl, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0616] In another embodiment of the use of a compound of Formula (I), R.sub.2 is aryl-amino-carbonyl selected from phenyl-amino-carbonyl; wherein, each instance of aryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0617] In one embodiment of the use of a compound of Formula (I),

[0618] R.sub.2 is heterocyclyl selected from 1,2,3,6-tetrahydropyridinyl, 1,3-benzodioxolyl or 2,3-dihydro-1,4-benzodioxinyl; wherein, each instance of heterocyclyl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0619] In another embodiment of the use of a compound of Formula (I),

[0620] R.sub.2 is heterocyclyl selected from 1,2,3,6-tetrahydropyridin-4-yl, 1,3-benzodioxol-5-yl or 2,3-dihydro-1,4-benzodioxin-6-yl; wherein, each instance of heterocyclyl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0621] In one embodiment of the use of a compound of Formula (I),

[0622] R.sub.2 is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; wherein, each instance of heteroaryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0623] In another embodiment of the use of a compound of Formula (I),

[0624] R.sub.2 is heteroaryl selected from thien-2-yl, thien-3-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1,3-thiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indazol-5-yl, 2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl, benzofuran-5-yl, benzothien-2-yl, benzothien-3-yl, 1H-benzimidazol-2-yl, 1H-benzimidazol-6-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 9H-purin-8-yl, furo[3,2-b]pyridin-2-yl, furo[3,2-c]pyridin-2-yl, furo[2,3-c]pyridin-2-yl, thieno[3,2-c]pyridin-2-yl, thieno[2,3-d]pyrimidin-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl, pyrrolo[1,2-a]pyrimidin-7-yl, pyrrolo[1,2-a]pyrazin-7-yl, pyrrolo[1,2-b]pyridazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyrazin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[2,1-b][1,3]thiazol-6-yl, imidazo[2,1-b][1,3,4]thiadiazol-6-yl, [1,3]oxazolo[4,5-b]pyridin-2-yl or quinoxalin-2-yl; wherein, each instance of heteroaryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0625] In another embodiment of the use of a compound of Formula (I),

[0626] R.sub.2 is substituted heteroaryl selected from 4-methylthien-2-yl, 1-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl, 1-phenyl-1H-pyrazol-3-yl, 1-phenyl-1H-imidazol-4-yl, 2-methyl-1-(pyridin-2-yl)-1H-imidazol-4-yl, 4-methyl-1,3-thiazol-2-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl, 4-phenyl-1,3-thiazol-2-yl, 5-phenyl-1,2,4-oxadiazol-3-yl, 3-fluoropyridin-4-yl, 6-fluoropyridin-2-yl, 2-chloropyridin-4-yl, 4-chloropyridin-3-yl, 5-chloropyridin-2-yl, 6-methylpyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 2-methoxypyridin-4-yl, 4-methoxypyridin-3-yl, 6-methoxypyridin-2-yl, 2-ethoxypyridin-3-yl, 6-ethoxypyridin-2-yl, 6-(propan-2-yloxy)pyridin-2-yl, 6-(dimethylamino)pyridin-3-yl, 6-(methylsulfanyl)pyridin-2-yl, 6-(cyclobutyloxy)pyridin-2-yl, 6-(pyrrolidin-1-yl)pyridin-2-yl, 2-methylpyrimidin-4-yl, 2-(propan-2-yl)pyrimidin-4-yl, 2-cyclopropylpyrimidin-4-yl, 1-methyl-1H-indol-3-yl, 2-methyl-2H-indazol-5-yl, 2-methyl-1-benzofuran-5-yl, 1-methyl-1H-benzimidazol-2-yl, 4-methyl-1H-benzimidazol-2-yl 5-fluoro-1FH-benzimidazol-2-yl, 4-fluoro-1,3-benzoxazol-2-yl, 5-fluoro-1,3-benzoxazol-2-yl, 4-chloro-1,3-benzoxazol-2-yl, 4-iodo-1,3-benzoxazol-2-yl, 2-methyl-1,3-benzoxazol-6-yl, 4-methyl-1,3-benzoxazol-2-yl, 4-(trifluoromethyl)-1,3-benzoxazol-2-yl, 7-(trifluoromethyl)-1,3-benzoxazol-2-yl, 2-methyl-1,3-benzothiazol-2-yl, 2-methyl-1,3-benzothiazol-5-yl, 2-methyl-1,3-benzothiazol-6-yl, 4-chloro-1,3-benzothiazol-2-yl, 7-chloro-1,3-benzothiazol-2-yl, 4-(trifluoromethyl)-1,3-benzothiazol-2-yl, 5-methylfuro[3,2-b]pyridin-2-yl, 4,6-dimethylfuro[3,2-c]pyridin-2-yl, 5,7-dimethylfuro[2,3-c]pyridin-2-yl, 4,6-dimethylthieno[3,2-c]pyridin-2-yl, 2,4-dimethylthieno[2,3-d]pyrimidin-6-yl, 1-methylpyrrolo[1,2-a]pyrazin-7-yl, 3-methylpyrrolo[1,2-a]pyrazin-7-yl, 1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl, 2-methylpyrrolo[1,2-b]pyridazin-2-yl, 4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl, 5-methylpyrazolo[1,5-a]pyridin-2-yl, 4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl, 2-chloroimidazo[2,1-b][1,3]thiazol-6-yl, 2-methylimidazo[2,1-b][1,3]thiazol-6-yl, 3-methylimidazo[2,1-b][1,3]thiazol-6-yl, 2-ethylimidazo[2,1-b][1,3]thiazol-6-yl, 2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl, 6-cyanoimidazo[1,2-a]pyridin-2-yl (also referred to as 2-imidazo[1,2-a]pyridine-6-carbonitrile), 6-fluoroimidazo[1,2-a]pyridin-2-yl, 8-fluoroimidazo[1,2-a]pyridin-2-yl, 6,8-difluoroimidazo[1,2-a]pyridin-2-yl, 7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl, 8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl, 6-chloroimidazo[1,2-a]pyridin-2-yl, 7-chloroimidazo[1,2-a]pyridin-2-yl, 8-chloroimidazo[1,2-a]pyridin-2-yl, 8-bromoimidazo[1,2-a]pyridin-2-yl, 2-methylimidazo[1,2-a]pyridin-2-yl, 5-methylimidazo[1,2-a]pyridin-2-yl, 6-methylimidazo[1,2-a]pyridin-2-yl, 7-methylimidazo[1,2-a]pyridin-2-yl, 8-methylimidazo[1,2-a]pyridin-2-yl, 7-ethylimidazo[1,2-a]pyridin-2-yl, 8-ethylimidazo[1,2-a]pyridin-2-yl, 6,8-dimethylimidazo[1,2-a]pyridin-2-yl, 8-ethyl-6-methylimidazo[1,2-a]pyridin-2-yl, 7-methoxyimidazo[1,2-a]pyridin-2-yl, 8-methoxyimidazo[1,2-a]pyridin-2-yl, 6-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl, 8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl, 8-chloro-6-methylimidazo[1,2-a]pyridin-2-yl, 6-methyl-8-nitroimidazo[1,2-a]pyridin-2-yl, 8-cyclopropylimidazo[1,2-a]pyridin-2-yl, 2-methylimidazo[1,2-a]pyridin-6-yl, 2-ethylimidazo[1,2-a]pyridin-6-yl, 2,3-dimethylimidazo[1,2-a]pyridin-6-yl, 2,8-dimethylimidazo[1,2-a]pyridin-6-yl, 2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl, 8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl, 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl, 6-fluoroimidazo[1,2-a]pyrimidin-2-yl, 6-chloroimidazo[1,2-a]pyrimidin-2-yl, 6-methylimidazo[1,2-a]pyrimidin-2-yl, 7-methylimidazo[1,2-a]pyrimidin-2-yl, 2-methylimidazo[1,2-a]pyrimidin-6-yl, 6-methylimidazo[1,2-b]pyridazin-2-yl, 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl, 6-methylimidazo[1,2-a]pyrazin-2-yl, 8-methylimidazo[1,2-a]pyrazin-2-yl, 6,8-dimethylimidazo[1,2-a]pyrazin-2-yl, 6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl, 6-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyrazin-2-yl, 8-(methylsulfanyl)imidazo[1,2-a]pyrazin-2-yl, 2-methylimidazo[2,1-b][1,3]thiazol-6-yl, 3-methylimidazo[2,1-b][1,3]thiazol-6-yl or 2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl.

[0627] In another embodiment of the use of a compound of Formula (I),

[0628] R.sub.2 is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl; wherein, each instance of heteroaryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0629] In another embodiment of the use of a compound of Formula (I),

[0630] R.sub.2 is heteroaryl selected from furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; wherein, each instance of heteroaryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0631] In one embodiment of the use of a compound of Formula (I), R.sub.2 is heteroaryl-amino, wherein heteroaryl is selected from pyridinyl or pyrimidinyl; and, wherein, each instance of heteroaryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0632] In another embodiment of the use of a compound of Formula (I), R.sub.2 is heteroaryl-amino selected from pyridin-2-yl-amino, pyridin-3-yl-amino or pyrimidin-2-yl-amino; wherein, each instance of heteroaryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0633] In one embodiment of the use of a compound of Formula (I), R.sub.6 is selected from halogen, hydroxy, cyano, nitro, C.sub.1-8alkyl, halo-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl, C.sub.1-8alkoxy, halo-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino or C.sub.1-8alkyl-thio; wherein, halogen and halo is selected from fluoro, chloro, bromo or iodo.

[0634] In one embodiment of the use of a compound of Formula (I), R.sub.6 is C.sub.1-8alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

[0635] In another embodiment of the use of a compound of Formula (I), R.sub.6 is C.sub.1-8alkyl selected from ethyl, propyl, isopropyl or tert-butyl.

[0636] In one embodiment of the use of a compound of Formula (I), R.sub.6 is C.sub.2-8alkenyl selected from ethenyl, allyl or buta-1,3-dienyl.

[0637] In another embodiment of the use of a compound of Formula (I), R.sub.6 is C.sub.2-8alkenyl selected from ethenyl or allyl.

[0638] In one embodiment of the use of a compound of Formula (I), R.sub.6 is halo-C.sub.1-8alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.

[0639] In one embodiment of the use of a compound of Formula (I), R.sub.6 is hydroxy-C.sub.1-8alkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

[0640] In another embodiment of the use of a compound of Formula (I), R.sub.6 is hydroxy-C.sub.1-8alkyl selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

[0641] In one embodiment of the use of a compound of Formula (I), R.sub.6 is C.sub.1-8alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

[0642] In one embodiment of the use of a compound of Formula (I), R.sub.6 is halo-C.sub.1-8alkoxy selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro, chloro, bromo or iodo.

[0643] In one embodiment of the use of a compound of Formula (I), R.sub.7 is C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl; wherein C.sub.3-14cycloalkyl is selected from cyclopropyl or cyclobutoxy; wherein aryl is selected from phenyl; wherein heterocyclyl is selected from oxetanyl, pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl; and, wherein heteroaryl is selected from thienyl or pyridinyl.

[0644] In another embodiment of the use of a compound of Formula (I), R.sub.7 is C.sub.3-14cycloalkyl or C.sub.3-14cycloalkyl-oxy, wherein each instance of C.sub.3-14cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0645] In another embodiment of the use of a compound of Formula (I), R.sub.7 is C.sub.3-8cycloalkyl or C.sub.3-8cycloalkyl-oxy, wherein each instance of C.sub.3-8cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0646] In one embodiment of the use of a compound of Formula (I), R.sub.7 is aryl selected from phenyl.

[0647] In one embodiment of the use of a compound of Formula (I), R.sub.7 is heterocyclyl selected from oxetanyl, pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl.

[0648] In another embodiment of the use of a compound of Formula (I), R.sub.7 is heterocyclyl selected from oxetan-3-yl, pyrrolidin-1-yl or 1,2,3,6-tetrahydropyridin-4-yl.

[0649] In one embodiment of the use of a compound of Formula (I), R.sub.7 is heteroaryl selected from thienyl or pyridinyl.

[0650] In another embodiment of the use of a compound of Formula (I), R.sub.7 is heteroaryl selected from pyridinyl.

[0651] In one embodiment of the use of a compound of Formula (I), R.sub.7 is heteroaryl selected from thien-2-yl or pyridin-2-yl.

[0652] In another embodiment of the use of a compound of Formula (I), R.sub.7 is heteroaryl selected from pyridin-2-yl.

[0653] In one embodiment of the use of a compound of Formula (I), R.sub.c is hydrogen or C.sub.1-8alkyl.

[0654] In another embodiment of the use of a compound of Formula (I),

[0655] R.sub.1 is heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents; and,

[0656] wherein, heterocyclyl is selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or 6,9-diazaspiro[4.5]decyl.

[0657] In another embodiment of the use of a compound of Formula (I),

[0658] R.sub.2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;

[0659] wherein, aryl is phenyl;

[0660] wherein, heterocyclyl is selected from 1,2,3,6-tetrahydropyridinyl, 1,3-benzodioxolyl or 2,3-dihydro-1,4-benzodioxinyl;

[0661] wherein, heteroaryl is selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; and, wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0662] In another embodiment of the use of a compound of Formula (I),

[0663] R.sub.1 is heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl;

[0664] wherein, heterocyclyl is selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or 6,9-diazaspiro[4.5]decyl; and, wherein, each instance of heterocyclyl, C3.4cycloalkyl, aryl and heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents; and

[0665] R.sub.2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;

[0666] wherein, heterocyclyl is selected from 1,2,3,6-tetrahydropyridin-4-yl, 1,3-benzodioxol-5-yl or 2,3-dihydro-1,4-benzodioxin-6-yl;

[0667] wherein, heteroaryl is selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; and, wherein, each instance of heterocyclyl and heteroaryl is optionally substituted with R.sub.6 and R.sub.7 substituents.

[0668] In another embodiment of the use of a compound of Formula (I),

[0669] R.sub.1 is C.sub.1-8alkyl, amino, C.sub.1-8alkyl-amino, (C.sub.1-8alkyl).sub.2-amino, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, amino-C.sub.1-8alkyl, C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, amino-C.sub.1-8alkyl-amino, (amino-C.sub.1-8alkyl).sub.2-amino, (amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, [(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino, amino-C.sub.1-8alkoxy, C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, amino-C.sub.2-8alkenyl, C.sub.1-8alkyl-amino-C.sub.2-8alkenyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkenyl, amino-C.sub.2-8alkynyl, C.sub.1-8alkyl-amino-C.sub.2-8alkynyl, (C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkynyl, halo-C.sub.1-8alkyl-amino, (halo-C.sub.1-8alkyl).sub.2-amino, (halo-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy, hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino, (hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino, (hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, (hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl-amino, [(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino or [(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino; and

[0670] R.sub.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 R.sub.6 and R.sub.7 substituents.

[0671] In another embodiment of the use of a compound of Formula (I),

[0672] R.sub.1 is heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C.sub.3-14cycloalkyl, aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents; and

[0673] R.sub.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 R.sub.6 and R.sub.7 substituents.

[0674] In another embodiment of the use of a compound of Formula (I),

[0675] R.sub.1 is heterocyclyl, heterocyclyl-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C.sub.1-8alkyl)amino, heterocyclyl-amino-C.sub.1-8alkyl, heterocyclyl-C.sub.1-8alkyl-amino, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl, (heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl or heterocyclyl-carbonyl-oxy; wherein, each instance of heterocyclyl is optionally substituted with R.sub.3 and R.sub.4 substituents; and

[0676] R.sub.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 R.sub.6 and R.sub.7 substituents.

[0677] In another embodiment of the use of a compound of Formula (I),

[0678] R.sub.1 is heterocyclyl optionally substituted with R.sub.3 and R.sub.4 substituents; and

[0679] R.sub.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 R.sub.6 and R.sub.7 substituents.

[0680] In another embodiment of the use of a compound of Formula (I),

[0681] R.sub.1 is C.sub.3-14cycloalkyl optionally substituted with R.sub.3 and R.sub.4 substituents; and

[0682] R.sub.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 R.sub.6 and R.sub.7 substituents.

[0683] In another embodiment of the use of a compound of Formula (I),

[0684] R.sub.1 is aryl-C.sub.1-8alkyl-amino, (aryl-C.sub.1-8alkyl).sub.2-amino, (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of aryl is optionally substituted with R.sub.3 and R.sub.4 substituents; and

[0685] R.sub.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 R.sub.6 and R.sub.7 substituents.

[0686] In another embodiment of the use of a compound of Formula (I),

[0687] R.sub.1 is aryl-C.sub.1-8alkyl-amino optionally substituted with R.sub.3 and R.sub.4 substituents; and

[0688] R.sub.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 R.sub.6 and R.sub.7 substituents.

[0689] In another embodiment of the use of a compound of Formula (I),

[0690] R.sub.1 is heteroaryl, heteroaryl-C.sub.1-8alkyl, heteroaryl-C.sub.1-8alkoxy, heteroaryl-amino, heteroaryl-C.sub.1-8alkyl-amino, (heteroaryl-C.sub.1-8alkyl).sub.2-amino, (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino, heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl, (heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl or (heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl; wherein, each instance of heterocyclyl, C.sub.3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R.sub.3 and R.sub.4 substituents; and

[0691] R.sub.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 R.sub.6 and R.sub.7 substituents.

[0692] In another embodiment of the use of a compound of Formula (I),

[0693] R.sub.1 is heteroaryl optionally substituted with R.sub.3 and R.sub.4 substituents; and

[0694] R.sub.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 R.sub.6 and R.sub.7 substituents.

[0695] In one embodiment, the compound of Formula (I), used in a method disclosed herein, is a compound selected from Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII) or Formula (XIV):

##STR00017## ##STR00018##

[0696] or a form thereof.

[0697] In an embodiment of the use of the compound of Formula (I), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2, w.sub.1, w.sub.4, w.sub.5 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0698] In another embodiment of the use of the compound of Formula (I), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1, w.sub.1, w.sub.4, w.sub.5 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0699] In another embodiment of the use of the compound of Formula (I), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.1, w.sub.3 and w.sub.5 are independently C—R.sub.a or N, w.sub.2 is C—R.sub.b or N and w.sub.6 is C—R.sub.c or N.

[0700] In another embodiment of the use of the compound of Formula (I), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.1, w.sub.3 and w.sub.5 are independently C—R.sub.a or N, w.sub.2 is C—R.sub.b or N and w.sub.6 is C—R.sub.c or N.

[0701] In an embodiment of the use of the compound of Formula (II), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2, w.sub.4, w.sub.5 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0702] In another embodiment of the use of the compound of Formula (II), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1, w.sub.4, w.sub.5 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0703] In another embodiment of the use of the compound of Formula (II), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.3 and w.sub.5 are independently C—R.sub.a or N, w.sub.2 is C—R.sub.b or N and w.sub.6 is C—R.sub.c or N.

[0704] In another embodiment of the use of the compound of Formula (II), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.3 and w.sub.5 are independently C—R.sub.a or N, w.sub.2 is C—R.sub.b or N and w.sub.6 is C—R.sub.c or N.

[0705] In an embodiment of the use of the compound of Formula (III), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2 and w.sub.1, w.sub.4, w.sub.5 and w.sub.7 are independently C—R.sub.a or N.

[0706] In another embodiment of the use of the compound of Formula (III), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1and w.sub.1, w.sub.4, w.sub.5 and w.sub.7 are independently C—R.sub.a or N.

[0707] In another embodiment of the use of the compound of Formula (III), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.1, w.sub.3 and w.sub.5 are independently C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0708] In another embodiment of the use of the compound of Formula (III), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.1, w.sub.3 and w.sub.5 are independently C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0709] In an embodiment of the use of the compound of Formula (IV), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.1 and w.sub.5 are independently C—R.sub.a or N, w.sub.2 is C—R.sub.b or N and w.sub.6 is C—R.sub.c or N.

[0710] In another embodiment of the use of the compound of Formula (IV), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.1 and w.sub.5 are independently C—R.sub.a or N, w.sub.2 is C—R.sub.b or N and w.sub.6 is C—R.sub.c or N.

[0711] In an embodiment of the use of the compound of Formula (V), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2, w.sub.1, w.sub.5 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0712] In another embodiment of the use of the compound of Formula (V), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1, w.sub.1, w.sub.5 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0713] In an embodiment of the use of the compound of Formula (VI), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2, w.sub.1, w.sub.4 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0714] In another embodiment of the use of the compound of Formula (VI), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1, w.sub.1, w.sub.4 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0715] In another embodiment of the use of the compound of Formula (VI), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.1 and w.sub.3 are independently C—R.sub.a or N, w.sub.2 is C—R.sub.b or N and w.sub.6 is C—R.sub.c or N.

[0716] In another embodiment of the use of the compound of Formula (VI), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.1 and w.sub.3 are independently C—R.sub.a or N, w.sub.2 is C—R.sub.b or N and w.sub.6 is C—R.sub.c or N.

[0717] In another embodiment of the use of the compound of Formula (VII), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.1, w.sub.3 and w.sub.5 are C—R.sub.a or N and w.sub.2 is C—R.sub.1 or N.

[0718] In another embodiment of the use of the compound of Formula (VII), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.1, w.sub.3 and w.sub.5 are C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0719] In another embodiment of the use of the compound of Formula (VIII), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2, w.sub.1, w.sub.4 and w.sub.5 are C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0720] In another embodiment of the use of the compound of Formula (VIII), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1, w.sub.1, w.sub.4 and w.sub.5 are C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0721] In an embodiment of the use of the compound of Formula (IX), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2, w.sub.4 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0722] In another embodiment of the use of the compound of Formula (IX), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1, w.sub.4 and w.sub.7 are independently C—R.sub.a or N and w.sub.2 is C—R.sub.b or N.

[0723] In another embodiment of the use of the compound of Formula (IX), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.2 is C—R.sub.b or N, w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0724] In another embodiment of the use of the compound of Formula (IX), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.2 is C—R.sub.b or N, w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0725] In an embodiment of the use of the compound of Formula (X), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2, w.sub.2 is C—R.sub.b or N and w.sub.5 and w.sub.7 are independently C—R.sub.a or N.

[0726] In another embodiment of the use of the compound of Formula (X), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1, w.sub.2 is C—R.sub.1 or N and w.sub.5 and w.sub.7 are independently C—R.sub.a or N.

[0727] In an embodiment of the use of the compound of Formula (XI), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.2 is C—R.sub.b or N, w.sub.5 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0728] In another embodiment of the use of the compound of Formula (XI), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.2 is C—R.sub.b or N, w.sub.5 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0729] In an embodiment of the use of the compound of Formula (XII), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2 and w.sub.4, w.sub.5 and w.sub.7 are independently C—R.sub.a or N.

[0730] In another embodiment of the use of the compound of Formula (XII), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1and w.sub.4, w.sub.5 and w.sub.7 are independently C—R.sub.a or N.

[0731] In another embodiment of the use of the compound of Formula (XII), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.3 and w.sub.5 are independently C—R.sub.c or N and w.sub.6 is C—R.sub.c or N.

[0732] In another embodiment of the use of the compound of Formula (XII), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.3 and w.sub.5 are independently C—R.sub.c or N and w.sub.6 is C—R.sub.c or N.

[0733] In an embodiment of the use of the compound of Formula (XIII), w.sub.3 is C—R.sub.1, w.sub.6 is C—R.sub.2, w.sub.2 is C—R.sub.b or N and w.sub.4 and w.sub.5 are independently C—R.sub.a or N.

[0734] In another embodiment of the use of the compound of Formula (XIII), w.sub.3 is C—R.sub.2, w.sub.6 is C—R.sub.1, w.sub.2 is C—R.sub.b or N and w.sub.4 and w.sub.5 are independently C—R.sub.a or N.

[0735] In an embodiment of the use of the compound of Formula (XIV), w.sub.4 is C—R.sub.1, w.sub.7 is C—R.sub.2, w.sub.2 is C—R.sub.b or N and w.sub.3 and w.sub.5 are independently C—R.sub.a or N.

[0736] In another embodiment of the use of the compound of Formula (XIV), w.sub.4 is C—R.sub.2, w.sub.7 is C—R.sub.1, w.sub.2 is C—R.sub.b or N and w.sub.3 and w.sub.5 are independently C—R.sub.a or N.

[0737] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound selected from Formula (II), Formula (III), Formula (IX), Formula (XI) or Formula (XII):

##STR00019##

[0738] or a form thereof.

[0739] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (II):

##STR00020##

[0740] or a form thereof.

[0741] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (III):

##STR00021##

[0742] or a form thereof.

[0743] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (IV):

##STR00022##

[0744] or a form thereof.

[0745] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (V):

##STR00023##

[0746] or a form thereof.

[0747] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (VI):

##STR00024##

[0748] or a form thereof.

[0749] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (VII):

##STR00025##

[0750] or a form thereof.

[0751] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (VIII):

##STR00026##

[0752] or a form thereof.

[0753] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (IX):

##STR00027##

[0754] or a form thereof.

[0755] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (X):

##STR00028##

[0756] or a form thereof.

[0757] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (XI):

##STR00029##

[0758] or a form thereof.

[0759] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (XII):

##STR00030##

[0760] or a form thereof.

[0761] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (XIII):

##STR00031##

[0762] or a form thereof.

[0763] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (XIV):

##STR00032##

[0764] or a form thereof.

[0765] In one embodiment, the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII) or Formula (XIV) used in a method disclosed herein is a compound selected from Formula (Ia), Formula (IIa), Formula (IIIa), Formula (IVa), Formula (Va), Formula (VIa), Formula (VIIa), Formula (VIIIa), Formula (IXa), Formula (Xa), Formula (XIa), Formula (XIIa), Formula (XIIIa) or Formula (XIVa), respectively:

##STR00033## ##STR00034##

[0766] or a form thereof.

[0767] In an embodiment of the use of the compound of Formula (Ia), one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that,

[0768] when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0769] when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0770] when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or,

[0771] when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0772] In an embodiment of the use of the compound of Formula (IIa), one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that,

[0773] when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0774] when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0775] when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or,

[0776] when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0777] In an embodiment of the use of the compound of Formula (IIa), one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that,

[0778] when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0779] when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0780] when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or,

[0781] when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0782] In an embodiment of the use of the compound of Formula (IVa), one of w.sub.6 and w.sub.7 is C—R.sub.1and the other is C—R.sub.2, provided that, when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2; or, when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1.

[0783] In an embodiment of the use of the compound of Formula (Va), one of w.sub.3 and w.sub.6 is C—R.sub.1and the other is C—R.sub.2, provided that, when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2; or, when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1.

[0784] In an embodiment of the use of the compound of Formula (VIa), one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that,

[0785] when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0786] when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0787] when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or,

[0788] when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0789] In an embodiment of the use of the compound of Formula (VIIa), one of w.sub.4 and w.sub.7 is C—R.sub.1and the other is C—R.sub.2, provided that, when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2; or, when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1.

[0790] In an embodiment of the use of the compound of Formula (VIIIa), one of w.sub.3 and w.sub.6 is C—R.sub.1and the other is C—R.sub.2, provided that, when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2; or, when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1.

[0791] In an embodiment of the use of the compound of Formula (IXa), one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that,

[0792] when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0793] when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0794] when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or,

[0795] when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0796] In an embodiment of the use of the compound of Formula (Xa), one of w.sub.3 and w.sub.6 is C—R.sub.1and the other is C—R.sub.2, provided that, when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2; or, when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1.

[0797] In an embodiment of the use of the compound of Formula (XIa), one of w.sub.4 and w.sub.7 is C—R.sub.1and the other is C—R.sub.2, provided that, when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2; or, when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1.

[0798] In an embodiment of the use of the compound of Formula (XIIa), one of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.1and one other of w.sub.3, w.sub.4, w.sub.6 and w.sub.7 is C—R.sub.2, provided that,

[0799] when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2 and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0800] when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1and w.sub.4 and w.sub.7 are independently C—R.sub.a or N; or,

[0801] when w.sub.4 is C—R.sub.1, then w.sub.7 is C—R.sub.2 and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N; or,

[0802] when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1and w.sub.3 is C—R.sub.a or N and w.sub.6 is C—R.sub.c or N.

[0803] In an embodiment of the use of the compound of Formula (XIIIa), one of w.sub.3 and w.sub.6 is C—R.sub.1and the other is C—R.sub.2, provided that, when w.sub.3 is C—R.sub.1, then w.sub.6 is C—R.sub.2; or, when w.sub.3 is C—R.sub.2, then w.sub.6 is C—R.sub.1.

[0804] In an embodiment of the use of the compound of Formula (XIVa), one of w.sub.4 and w.sub.7 is C—R.sub.1and the other is C—R.sub.2, provided that, when w.sub.6 is C—R.sub.1, then w.sub.7 is C—R.sub.2; or, when w.sub.4 is C—R.sub.2, then w.sub.7 is C—R.sub.1.

[0805] In another embodiment, the compound of Formula (I), Formula (II), Formula (III), Formula (IX), Formula (XI) or Formula (XII), used in a method disclosed herein, is a compound selected from Formula (Ia), Formula (IIa), Formula (IIIa), Formula (IXa), Formula (XIa) or Formula (XIIa), respectively:

##STR00035##

[0806] or a form thereof.

[0807] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound of Formula (Ia):

##STR00036##

[0808] or a form thereof.

[0809] In another embodiment, the compound of Formula (II) used in a method disclosed herein is a compound of Formula (IIa):

##STR00037##

[0810] or a form thereof.

[0811] In another embodiment, the compound of Formula (III) used in a method disclosed herein is a compound of Formula (IIa):

##STR00038##

[0812] or a form thereof.

[0813] In another embodiment, the compound of Formula (IV) used in a method disclosed herein is a compound of Formula (IVa):

##STR00039##

[0814] or a form thereof.

[0815] In another embodiment, the compound of Formula (V) used in a method disclosed herein is a compound of Formula (Va):

##STR00040##

[0816] or a form thereof.

[0817] In another embodiment, the compound of Formula (VI) used in a method disclosed herein is a compound of Formula (VIa):

##STR00041##

[0818] or a form thereof.

[0819] In another embodiment, the compound of Formula (VII) used in a method disclosed herein is a compound of Formula (VIIa):

##STR00042##

[0820] or a form thereof.

[0821] In another embodiment, the compound of Formula (VIII) used in a method disclosed herein is a compound of Formula (VIIIa):

##STR00043##

[0822] or a form thereof.

[0823] In another embodiment, the compound of Formula (IX) used in a method disclosed herein is a compound of Formula (IXa):

##STR00044##

[0824] or a form thereof.

[0825] In another embodiment, the compound of Formula (X) used in a method disclosed herein is a compound of Formula (Xa):

##STR00045##

[0826] or a form thereof.

[0827] In another embodiment, the compound of Formula (XI) used in a method disclosed herein is a compound of Formula (XIa):

##STR00046##

[0828] or a form thereof.

[0829] In another embodiment, the compound of Formula (XII) used in a method disclosed herein is a compound of Formula (XIIa):

##STR00047##

[0830] or a form thereof.

[0831] In another embodiment, the compound of Formula (XIII) used in a method disclosed herein is a compound of Formula (XIIIa):

##STR00048##

[0832] or a form thereof.

[0833] In another embodiment, the compound of Formula (XIV) used in a method disclosed herein is a compound of Formula (XIVa):

##STR00049##

[0834] or a form thereof.

[0835] In one embodiment, the compound of Formula (Ia) used in a method disclosed herein is a compound of Formula (Ia1), Formula (Ia2), Formula (Ia3) or Formula (Ia4):

##STR00050##

[0836] or a form thereof.

[0837] In one embodiment, the compound of Formula (IIa) used in a method disclosed herein is a compound of Formula (IIa1), Formula (IIa2), Formula (IIa3) or Formula (IIa4):

##STR00051##

[0838] or a form thereof.

[0839] In one embodiment, the compound of Formula (IIIa) used in a method disclosed herein is a compound of Formula (IIIa1), Formula (IIIa2), Formula (IIIa3) or Formula (IIIa4):

##STR00052##

[0840] or a form thereof.

[0841] In one embodiment, the compound of Formula (IVa) used in a method disclosed herein is a compound of Formula (IVa1) or Formula (IVa2):

##STR00053##

[0842] or a form thereof.

[0843] In one embodiment, the compound of Formula (Va) used in a method disclosed herein is a compound of Formula (Va1) or Formula (Va2):

##STR00054##

[0844] or a form thereof.

[0845] In one embodiment, the compound of Formula (VIa) used in a method disclosed herein is a compound of Formula VIa1 Formula VIa2 Formula VIa3 or Formula (VIa4):

##STR00055##

[0846] or a form thereof.

[0847] In one embodiment, the compound of Formula (VIIa) used in a method disclosed herein is a compound Formula (VIIa1) of Formula (VIIa2)

##STR00056##

[0848] or a form thereof.

[0849] In one embodiment, the compound of Formula (VIIIa) used in a method disclosed herein is a compound of Formula (VIIIa1) or Formula (VIIIa2):

##STR00057##

[0850] or a form thereof.

[0851] In one embodiment, the compound of Formula (IXa) used in a method disclosed herein is a compound of Formula (IXa1), Formula (IXa2), Formula (IXa3) or Formula (IXa4):

##STR00058##

[0852] or a form thereof.

[0853] In one embodiment, the compound of Formula (Xa) used in a method disclosed herein is a compound of Formula (Xa1) or Formula (Xa2):

##STR00059##

[0854] or a form thereof.

[0855] In one embodiment, the compound of Formula (XIa) used in a method disclosed herein is a compound of Formula (Xia1) or Formula (Xia2):

##STR00060##

[0856] or a form thereof.

[0857] In one embodiment, the compound of Formula (XIIa) used in a method disclosed herein is a compound of Formula (XIIa1), Formula (XIIa2), Formula (XIIa3) or Formula (XIIa4):

##STR00061##

[0858] or a form thereof.

[0859] In one embodiment, the compound of Formula (XIIIa) used in a method disclosed herein is a compound of Formula (XIIIa1) or Formula (XIIIa2):

##STR00062##

[0860] or a form thereof.

[0861] In one embodiment, the compound of Formula (XIVa) used in a method disclosed herein is a compound of Formula (XIVa1) or Formula (XIVa2):

##STR00063##

[0862] or a form thereof.

[0863] In one embodiment, the compound of Formula (Ia) used in a method disclosed herein is a compound of Formula (Ia1):

##STR00064##

[0864] or a form thereof.

[0865] In one embodiment, the compound of Formula (Ia) used in a method disclosed herein is a compound of Formula (Ia2):

##STR00065##

[0866] or a form thereof.

[0867] In one embodiment, the compound of Formula (Ia) used in a method disclosed herein is a compound of Formula (Ia3):

##STR00066##

[0868] or a form thereof.

[0869] In one embodiment, the compound of Formula (Ia) used in a method disclosed herein is a compound of Formula (Ia4):

##STR00067##

[0870] or a form thereof.

[0871] In one embodiment, the compound of Formula (IIa) used in a method disclosed herein is a compound of Formula (IIa1):

##STR00068##

[0872] or a form thereof.

[0873] In one embodiment, the compound of Formula (IIa) used in a method disclosed herein is a compound of Formula (IIa2):

##STR00069##

[0874] or a form thereof.

[0875] In one embodiment, the compound of Formula (IIa) used in a method disclosed herein is a compound of Formula (IIa3):

##STR00070##

[0876] or a form thereof.

[0877] In one embodiment, the compound of Formula (IIa) used in a method disclosed herein is a compound of Formula (IIa4):

##STR00071##

[0878] or a form thereof.

[0879] In one embodiment, the compound of Formula (IIIa) used in a method disclosed herein is a compound of Formula (IIIa1):

##STR00072##

[0880] or a form thereof.

[0881] In one embodiment, the compound of Formula (IIIa) used in a method disclosed herein is a compound of Formula (IIIa2):

##STR00073##

[0882] or a form thereof.

[0883] In one embodiment, the compound of Formula (IIIa) used in a method disclosed herein is a compound of Formula (IIIa3):

##STR00074##

[0884] or a form thereof.

[0885] In one embodiment, the compound of Formula (IIIa) used in a method disclosed herein is a compound of Formula (IIIa4):

##STR00075##

[0886] or a form thereof.

[0887] In one embodiment, the compound of Formula (IVa) used in a method disclosed herein is a compound of Formula (IVa1):

##STR00076##

[0888] or a form thereof.

[0889] In one embodiment, the compound of Formula (IVa) used in a method disclosed herein is a compound of Formula (IVa2):

##STR00077##

[0890] or a form thereof.

[0891] In one embodiment, the compound of Formula (Va) used in a method disclosed herein is a compound of Formula (Va1):

##STR00078##

[0892] or a form thereof.

[0893] In one embodiment, the compound of Formula (Va) used in a method disclosed herein is a compound of Formula (Va2):

##STR00079##

[0894] or a form thereof.

[0895] In one embodiment, the compound of Formula (VIa) used in a method disclosed herein is a compound of Formula (VIa1):

##STR00080##

[0896] or a form thereof.

[0897] In one embodiment, the compound of Formula (VIa) used in a method disclosed herein is a compound of Formula Formula (VIa2):

##STR00081##

[0898] or a form thereof.

[0899] In one embodiment, the compound of Formula (VIa) used in a method disclosed herein is a compound of Formula Formula (VIa3):

##STR00082##

[0900] or a form thereof.

[0901] In one embodiment, the compound of Formula (VIa) used in a method disclosed herein is a compound of Formula (VIa4):

##STR00083##

[0902] or a form thereof.

[0903] In one embodiment, the compound of Formula (VIIa) used in a method disclosed herein is a compound of Formula (VIIa1):

##STR00084##

[0904] or a form thereof.

[0905] In one embodiment, the compound of Formula (VIIa) used in a method disclosed herein is a compound of Formula (VIIa2):

##STR00085##

[0906] or a form thereof.

[0907] In one embodiment, the compound of Formula (VIIIa) used in a method disclosed herein is a compound of Formula Formula (VIIIa1):

##STR00086##

[0908] or a form thereof.

[0909] In one embodiment, the compound of Formula (VIIa) used in a method disclosed herein is a compound of Formula (VIIIa2):

##STR00087##

[0910] or a form thereof.

[0911] In one embodiment, the compound of Formula (IXa) used in a method disclosed herein is a compound of Formula (IXa1):

##STR00088##

[0912] or a form thereof.

[0913] In one embodiment, the compound of Formula (IXa) used in a method disclosed herein is a compound of Formula (IXa2):

##STR00089##

[0914] or a form thereof.

[0915] In one embodiment, the compound of Formula (IXa) used in a method disclosed herein is a compound of Formula (IXa3):

##STR00090##

[0916] or a form thereof.

[0917] In one embodiment, the compound of Formula (IXa) used in a method disclosed herein is a compound of Formula (IXa4):

##STR00091##

[0918] or a form thereof.

[0919] In one embodiment, the compound of Formula (Xa) used in a method disclosed herein is a compound of Formula (Xa1):

##STR00092##

[0920] or a form thereof.

[0921] In one embodiment, the compound of Formula (Xa) used in a method disclosed herein is a compound of Formula (Xa2):

##STR00093##

[0922] or a form thereof.

[0923] In one embodiment, the compound of Formula (XIa) used in a method disclosed herein is a compound of Formula (XIa1):

##STR00094##

[0924] or a form thereof.

[0925] In one embodiment, the compound of Formula (XIa) used in a method disclosed herein is a compound of Formula (XIa2):

##STR00095##

[0926] or a form thereof.

[0927] In one embodiment, the compound of Formula (XIIa) used in a method disclosed herein is a compound of Formula (XIIa1):

##STR00096##

[0928] or a form thereof.

[0929] In one embodiment, the compound of Formula (XIIa) used in a method disclosed herein is a compound of Formula (XIIa2):

##STR00097##

[0930] or a form thereof.

[0931] In one embodiment, the compound of Formula (XIIa) used in a method disclosed herein is a compound of Formula (XIIa3):

##STR00098##

[0932] or a form thereof.

[0933] In one embodiment, the compound of Formula (XIIa) used in a method disclosed herein is a compound of Formula (XIIa4):

##STR00099##

[0934] or a form thereof.

[0935] In one embodiment, the compound of Formula (XIIIa) used in a method disclosed herein is a compound of Formula (XIIIa1):

##STR00100##

[0936] or a form thereof.

[0937] In one embodiment, the compound of Formula (XIIIa) used in a method disclosed herein is a compound of Formula (XIIIa2):

##STR00101##

[0938] or a form thereof.

[0939] In one embodiment, the compound of Formula (XVa) used in a method disclosed herein is a compound of Formula (XIVa1):

##STR00102##

[0940] or a form thereof.

[0941] In one embodiment, the compound of Formula (XIVa) used in a method disclosed herein is a compound of Formula (XIVa2):

##STR00103##

[0942] or a form thereof.

[0943] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound selected from the group consisting of:

##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146##

##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170##

##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182## ##STR00183## ##STR00184## ##STR00185## ##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202## ##STR00203## ##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216##

##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222## ##STR00223## ##STR00224## ##STR00225## ##STR00226## ##STR00227## ##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235## ##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261##

[0944] or a form thereof.

[0945] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound selected from the group consisting of: [0946] 2-(4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0947] 2-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0948] 2-(4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0949] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [0950] 7-(1,4-diazepan-1-yl)-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [0951] 2-(3,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0952] 2-(3,4-dimethoxyphenyl)-7-(3,3-dimethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0953] 2-(3,4-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0954] 2-(3,4-dimethoxyphenyl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0955] 7-(1,4-diazepan-1-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [0956] 2-(3,4-dimethoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0957] 2-(4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0958] 2-(3,4-dimethoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0959] 2-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0960] 2-(3,4-dimethoxyphenyl)-7-(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0961] 2-(4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0962] 7-(3,3-dimethylpiperazin-1-yl)-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [0963] 2-(1,3-benzodioxol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0964] 2-(1,3-benzodioxol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0965] 2-(1,3-benzodioxol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0966] 2-(1,3-benzodioxol-5-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0967] 2-(3-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0968] 2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0969] 2-(3-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0970] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [0971] 7-(4-ethylpiperazin-1-yl)-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [0972] 7-(1,4-diazepan-1-yl)-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [0973] 2-(3-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0974] 2-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0975] 2-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0976] 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0977] 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0978] 2-phenyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0979] 7-[(3S)-3-methylpiperazin-1-yl]-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one [0980] 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0981] 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(3,3-dimethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0982] 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0983] 7-(1,4-diazepan-1-yl)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0984] 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0985] 2-(3,4-dimethoxyphenyl)-9-fluoro-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0986] 2-(3-chlorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0987] 2-(4-chlorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0988] 7-(piperazin-1-yl)-2-[3-(trifluoromethyl)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one [0989] 7-(piperazin-1-yl)-2-[4-(trifluoromethyl)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one [0990] 2-(3-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0991] 2-(4-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0992] 2-(4-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0993] 2-(3,4-dimethoxyphenyl)-9-fluoro-7-(piperidin-4-ylamino)-4H-pyrido[1,2-a]pyrimidin-4-one [0994] 2-[4-(dimethylamino)phenyl]-9-fluoro-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0995] 2-[4-(dimethylamino)phenyl]-9-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [0996] 2-(2-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0997] 3-(3,4-dimethoxyphenyl)-8-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0998] 2-[4-(dimethylamino)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [0999] 2-[4-(dimethylamino)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1000] 2-(3,4-dimethylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1001] 2-(3,4-dimethylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1002] 2-[3-(dimethylamino)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1003] 2-[3-(dimethylamino)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1004] 2-[4-(difluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1005] 2-[4-(difluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1006] 2-(3-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1007] 2-(3-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1008] 2-(4-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1009] 2-(2-fluoro-4,5-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1010] 2-(2-fluoro-4,5-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1011] 7-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1012] 2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1013] 2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1014] 2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1015] 2-(3,4-dimethoxyphenyl)-9-methoxy-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1016] 2-(3,5-difluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1017] 2-(3-fluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1018] 4-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile [1019] 2-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1020] 2-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1021] 2-[3-fluoro-5-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1022] 2-[4-fluoro-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1023] 2-[2-methoxy-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1024] 2-(3,5-difluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1025] 7-(piperazin-1-yl)-2-[3-(trifluoromethoxy)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one [1026] 2-[4-methoxy-3-(trifluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1027] 2-[4-hydroxy-3-(trifluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1028] 2-[4-methoxy-3-(trifluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1029] 2-[4-hydroxy-3-(trifluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1030] 2-(3,4-dimethoxyphenyl)-4-oxo-7-(piperazin-1-yl)-4H-quinolizine-1-carbonitrile [1031] 2-(3-fluoro-4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1032] 2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1033] 2-(6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1034] 2-(2,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1035] 2-(2,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1036] 2-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-quinolizin-4-one [1037] 2-(5-fluoropyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1038] 2-(5-fluoropyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1039] 2-(5-chloropyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1040] 2-(5-chloropyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1041] 2-(5-chloro-6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1042] 2-(1H-indol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1043] 2-(1H-indol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1044] 2-[3-(difluoromethoxy)-4-methoxyphenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1045] 2-[3-(difluoromethoxy)-4-hydroxyphenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1046] 2-[3-(difluoromethoxy)-4-methoxyphenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1047] 2-[3-(difluoromethoxy)-4-hydroxyphenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1048] 2-(3-fluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-quinolizin-4-one [1049] 2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-quinolizin-4-one [1050] 2-(3,5-difluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1051] 2-(3,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-quinolizin-4-one [1052] 2-(imidazo[1,2-a]pyridin-7-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1053] 2-(imidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1054] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1055] 2-(3-chloro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1056] 2-(3-chloro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1057] 2-(3-ethoxy-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1058] 2-(3-ethoxy-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1059] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1060] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1061] 7-(1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1062] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1063] 2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1064] 2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1065] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1066] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1067] 2-(3,4-dimethoxyphenyl)-7-(2-methylpyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1068] 7-(piperazin-1-yl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1069] 2-(2-ethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1070] 2-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1071] 2-(3,4-dimethoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1072] 7-(4-aminopiperidin-1-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1073] 7-(piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1074] 2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1075] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1076] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1077] 7-(1,4-diazepan-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1078] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1079] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1080] 2-(2-methyl-1,3-benzothiazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1081] 2-(2-methyl-1,3-benzothiazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1082] 2-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1083] 2-(2-methyl-2H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1084] 2-(3-fluoro-5-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1085] 2-(3-fluoro-5-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1086] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1087] 2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1088] 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1089] 2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1090] 2-(3-fluoro-4,5-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1091] 2-(3,4-dimethoxyphenyl)-7-(4-hydroxypiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1092] 2-(3,4-dimethoxyphenyl)-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1093] 2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1094] 2-(4-methoxy-3-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1095] 3-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile [1096] 2-methoxy-5-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile [1097] 2-(3-fluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1098] 2-(4-ethoxy-3-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1099] 2-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1100] 2-(2-methyl-1,3-benzoxazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1101] 2-(2-methyl-1,3-benzoxazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1102] 2-(3-fluoro-4-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1103] 2-(3-fluoro-4-methylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1104] 7-[(3S)-3-aminopyrrolidin-1-yl]-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1105] 2-(3,4-dimethoxyphenyl)-9-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1106] 7-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1107] 7-[(3S)-3-methylpiperazin-1-yl]-2-(4-methyl-1,3-thiazol-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1108] 2-(4-methyl-1,3-thiazol-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1109] 2-(3,4-dimethoxyphenyl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1110] 2-(3,4-dimethoxyphenyl)-7-[(3S)-3-(propan-2-ylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1111] 2-(3-fluoro-4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1112] 2-(4-methoxy-3-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1113] 2-[3-fluoro-4-(methylsulfanyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1114] 7-(4-methyl-1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1115] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1116] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1117] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1118] 2-(5-fluoro-6-methoxypyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1119] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(5-fluoro-6-methoxypyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1120] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1121] 2-(2-methyl-1,3-benzothiazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1122] 2-(2-methyl-1,3-benzothiazol-5-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1123] 7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1124] 2-(4-methyl-1H-imidazol-1-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1125] 2-(4-methyl-1H-imidazol-1-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1126] 2-(3,4-dimethoxyphenyl)-7-{[2-(methylamino)ethyl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one [1127] 2-(5-fluoro-6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1128] 2-(3,5-difluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1129] 2-(3,5-difluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1130] 7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1131] 2-(3-fluoro-4-methoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1132] 2-(3,4-dimethoxyphenyl)-7-(piperidin-4-ylamino)-4H-pyrido[1,2-a]pyrimidin-4-one [1133] 2-(3,4-dimethoxyphenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1134] 2-(3-chloro-5-fluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1135] 2-(3-chloro-5-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1136] 7-[(3S)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1137] 2-(1-methyl-1H-pyrazol-4-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1138] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1139] 7-(3,3-dimethylpiperazin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1140] 7-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1141] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1142] 7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1143] 7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1144] 2-(4,5-dimethoxypyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1145] 7-[3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-quinolizin-4-one [1146] 7-(4-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)-4H-quinolizin-4-one [1147] 7-(4-ethylpiperazin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1148] 7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-quinolizin-4-one [1149] 2-(3-fluoro-4-methoxyphenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1150] 7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1151] 7-[(3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1152] 7-(4-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1153] 2-(3-fluoro-4-methoxyphenyl)-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1154] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1155] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1156] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1157] 2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1158] 2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1159] 2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1160] 2-(4-fluoro-3-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1161] 2-(4-fluoro-3-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1162] 2-(3,4-difluoro-5-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1163] 2-(3,4-difluoro-5-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1164] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1165] 7-(3-fluoro-4-methoxyphenyl)-2-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1166] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1167] 2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-(methylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1168] 2-(3-fluoro-4-methoxyphenyl)-7-{4-[(methylamino)methyl]piperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one [1169] 7-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1170] 2-(3-fluoro-4-methoxyphenyl)-7-{[(3R)-1-methylpyrrolidin-3-yl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one [1171] 7-{4-[(dimethylamino)methyl]piperidin-1-yl}-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1172] 2-(6-methoxypyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1173] 7-(piperazin-1-yl)-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1174] 2-(5-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1175] 3-fluoro-5-{7-[(3S)-3-methylpiperazin-1-yl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}benzonitrile [1176] 3-fluoro-5-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile [1177] 2-(3-fluoro-4-methoxyphenyl)-7-[(3′S,4′S)-4′-hydroxy-1,3′-bipyrrolidin-1′-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1178] 2-(3-fluoro-4-methoxyphenyl)-7-{methyl[(3R)-pyrrolidin-3-yl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one [1179] 7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1180] 2-(3,4-dimethoxyphenyl)-7-[(1-methylpiperidin-4-yl)oxy]-4H-pyrido[1,2-a]pyrimidin-4-one [1181] 2-(3,4-dimethoxyphenyl)-7-[(3S)-pyrrolidin-3-yloxy]-4H-pyrido[1,2-a]pyrimidin-4-one [1182] 2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yloxy)-4H-pyrido[1,2-a]pyrimidin-4-one [1183] 7-(1,4-diazepan-1-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1184] 2-(3-fluoro-4-methoxyphenyl)-7-{methyl[(3R)-1-methylpyrrolidin-3-yl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one [1185] 7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1186] 7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1187] 7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1188] 7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1189] 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1190] 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-quinolizin-4-one [1191] 2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1192] 2-(3,4-dimethoxyphenyl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1193] 2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1194] 2-(3,4-dimethoxyphenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-quinolizin-4-one [1195] 2-(3,4-dimethoxyphenyl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1196] 2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1197] 2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1198] 7-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1199] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1200] 7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1201] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1202] 2-(3,4-dimethoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1203] 7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1204] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1205] 2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1206] 2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1207] 7-[(1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl]-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1208] 2-(3,4-dimethoxyphenyl)-7-(1,2,5,6-tetrahydropyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1209] 7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1210] 2-(2-ethyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1211] 2-(2-ethyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1212] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1213] 7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1214] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1215] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1216] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1217] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1218] 7-(4-aminopiperidin-1-yl)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1219] 7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1220] 7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1221] 2-(4-aminopiperidin-1-yl)-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1222] 2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1223] 2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1224] 2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1225] 2-(3-fluoro-4-methoxyphenyl)-7-[(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1226] 2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1227] 7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1228] 7-(3,3-dimethylpiperazin-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1229] 7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1230] 7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1231] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yloxy)-4H-pyrido[1,2-a]pyrimidin-4-one [1232] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1233] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1234] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1235] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1236] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1237] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1238] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1239] 7-(3-fluoro-4-methoxyphenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1240] 7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1241] 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1242] 7-[4-(dimethylamino)piperidin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1243] 2-[4-(dimethylamino)piperidin-1-yl]-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1244] 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1245] 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1246] 2-(3-fluoro-4-methoxyphenyl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1247] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1248] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1249] 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1250] 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1251] 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1252] 7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1253] 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1254] 7-(4-ethylpiperazin-1-yl)-2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1255] 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1256] 7-[(3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1257] 2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1258] 2-(3-fluoro-4-methoxyphenyl)-7-[(4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1259] 2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1260] 2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1261] 7-(3-fluoro-4-methoxyphenyl)-2-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1262] 7-(3-fluoro-4-methoxyphenyl)-2-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1263] 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1264] 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1265] 2-(3,4-dimethoxyphenyl)-7-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1266] 2-(3,4-dimethoxyphenyl)-7-[(2R)-2-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1267] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-quinolizin-4-one [1268] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one [1269] 7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-quinolizin-4-one [1270] 7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-quinolizin-4-one [1271] 7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-quinolizin-4-one [1272] 2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1273] 7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1274] 2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1275] 7-[4-(cyclopropylamino)piperidin-1-yl]-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1276] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1277] 2-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1278] 2-(3,4-dimethoxyphenyl)-7-[(3R)-3,4-dimethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1279] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1280] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1281] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1282] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1283] 2-(4,6-di methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1284] 7-[4-(dimethylamino)piperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1285] 7-(3,3-dimethylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1286] 7-(4-cyclopropylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1287] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1288] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1289] 2-(3,4-dimethoxyphenyl)-9-methyl-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1290] 2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-9-ethyl-4H-pyrido[1,2-a]pyrimidin-4-one [1291] 2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1292] 7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1293] 7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1294] 7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1295] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1296] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1297] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1298] 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one [1299] 7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1300] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1301] 7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1302] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrinmidin-4-one [1303] 2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1304] 2-(3,4-dimethoxyphenyl)-7-[4-(ethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1305] 2-(3,4-dimethoxyphenyl)-8-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1306] 2-(3,4-dimethoxyphenyl)-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1307] 7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one [1308] 2-(3,4-dimethoxyphenyl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1309] 2-(3,4-dimethoxyphenyl)-7-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1310] 2-(3,4-dimethoxyphenyl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1311] 2-(3,4-dimethoxyphenyl)-7-[4-(methylamino)cyclohex-1-en-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1312] 2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)cyclohex-1-en-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1313] 2-(3,4-dimethoxyphenyl)-7-{4-[ethyl(methyl)amino]cyclohex-1-en-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one [1314] 2-(3,4-dimethoxyphenyl)-7-{4-[methyl(propyl)amino]cyclohex-1-en-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one [1315] 2-(3,4-dimethoxyphenyl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1316] 7-(3,4-dimethoxyphenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1317] 7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1318] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1319] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1320] 7-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1321] 7-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1322] 7-(3,4-dimethoxyphenyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1323] 2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1324] 7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1325] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1326] 7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1327] 7-(3-aminopyrrolidin-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1328] 7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1329] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1330] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(2-methoxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1331] 2-(3,4-dimethoxyphenyl)-9-methyl-7-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1332] 2-(3,4-dimethoxyphenyl)-9-methyl-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1333] 2-(3,4-dimethoxyphenyl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1334] 2-(3,4-dimethoxyphenyl)-8-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1335] 7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1336] 2-(3,4-dimethoxyphenyl)-8-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1337] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1338] 7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1339] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1340] 7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1341] 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1342] 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1343] 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1344] 7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1345] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1346] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1347] 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1348] 2-(3-fluoro-4-methoxyphenyl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1349] 2-(3,4-dimethoxyphenyl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1350] 2-(3,4-dimethoxyphenyl)-7-[cis-4-(methylamino)cyclohexyl]-4H-pyrido[1,2-a]pyrimidin-4-one [1351] 2-(3,4-dimethoxyphenyl)-7-(piperidin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1352] 2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1353] 2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1354] 7-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1355] 7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1356] 7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1357] 7-(4-cyclopropylpiperazin-1-yl)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1358] 2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1359] 2-(3,4-dimethoxyphenyl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1360] 2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1361] 2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1362] 2-(3,4-dimethoxyphenyl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1363] 2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1364] 2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(morpholin-4-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1365] 2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1366] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one hydrochloride (1:1) [1367] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1368] 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1369] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1370] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1371] 7-(1,4′-bipiperidin-1′-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1372] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1373] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(morpholin-4-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1374] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1375] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1376] 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1377] 7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1378] 2-(3,4-dimethoxyphenyl)-7-{4-[(2-hydroxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1379] 2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1380] 7-[4-(diethylamino)piperidin-1-yl]-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1381] 2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1382] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1383] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1384] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1385] 7-(4-methylpiperazin-1-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1386] 7-[(3S)-3-methylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1387] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1388] 2-(1-methyl-1H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1389] 2-[6-(dimethylamino)pyridin-3-yl]-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1390] 7-[4-(diethylamino)piperidin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1391] 2-(3,4-dimethoxyphenyl)-7-{4-[(2-hydroxyethyl)(methyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1392] 2-(3,4-dimethoxyphenyl)-9-ethyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1393] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1394] 2-(1-methyl-1H-indazol-5-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1395] 2-[6-(dimethylamino)pyridin-3-yl]-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1396] 7-[4-(diethylamino)piperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1397] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1398] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1399] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1400] 2-(3,4-dimethoxyphenyl)-9-ethyl-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1401] 2-(3,4-dimethoxyphenyl)-7-{4-[(2-methoxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1402] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1403] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1404] 7-[4-(dimethylamino)piperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1405] 7-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1406] 7-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1407] 7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1408] 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1409] 2-(1-methyl-1H-indazol-5-yl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1410] 2-[6-(dimethylamino)pyridin-3-yl]-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1411] 7-(4-ethylpiperazin-1-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1412] 7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1413] 7-[4-(dimethylamino)piperidin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1414] 7-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1415] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1416] 7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1417] 7-[(3R)-3-methylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1418] 2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1419] 2-(2-methyl-2H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1420] 2-(1-methyl-1H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1421] 2-(2-methyl-2H-indazol-5-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1422] 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1423] 7-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1424] 2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one [1425] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1426] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1427] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1428] 7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1429] 2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1430] 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1431] 2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1432] 2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1433] 2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1434] 2-(1-methyl-1H-indazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1435] 2-(1-methyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1436] 7-[4-(dimethylamino)piperidin-1-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1437] 7-(4-methyl-1,4-diazepan-1-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1438] 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1439] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1440] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1441] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1442] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1443] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1444] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1445] 2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1446] 7-(1-ethylpiperidin-4-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1447] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1448] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1449] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1450] 2-(1-methyl-1H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1451] 2-(1-methyl-1H-indazol-5-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1452] 7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1453] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1454] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1455] 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1456] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1457] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1458] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1459] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1460] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1461] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1462] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1463] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1464] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1465] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1466] 2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1467] 2-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1468] 7-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1469] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1470] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1471] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrimido[1,2-b]pyridazin-4-one [1472] 2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1473] 7-[4-(dimethylamino)piperidin-1-yl]-2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1474] 2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1475] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1476] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1477] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1478] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-methoxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1479] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-{(3S)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one [1480] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-cyclopropyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1481] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1482] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1483] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-methoxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1484] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1485] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-{(3S)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one [1486] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1487] 7-[(3S)-4-cyclopropyl-3-methylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1488] 7-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1489] 7-(3,3-dimethylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1490] 2-(1-methyl-1H-indazol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1491] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1492] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1493] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1494] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1495] 7-[4-(dimethylamino)piperidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1496] 7-[4-(diethylamino)piperidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1497] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1498] 2-(1-methyl-1H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1499] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1500] 2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1501] 2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1502] 2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1503] 7-(4-ethylpiperazin-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1504] 2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1505] 7-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1506] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1507] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1508] 7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1509] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1510] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1511] 2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1512] 2-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1513] 7-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1514] 7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methyl-2H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1515] 7-{4-[(dimethylamino)methyl]piperidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1516] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1517] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(piperidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1518] 2-(3,4-dimethoxyphenyl)-7-{4-[(dimethylamino)methyl]piperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one [1519] 2-(3,4-dimethoxyphenyl)-7-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1520] 2-(3,4-dimethoxyphenyl)-7-[4-(piperidin-1-yl methyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1521] 7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1522] 7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1523] 2-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1524] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1525] 7-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1526] 7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1527] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4-[(2-hydroxyethyl)methyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1528] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1529] 7-(4-amino-4-methylpiperidin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1530] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1531] 2-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1532] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1533] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1534] 2-(2-methyl-2H-indazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1535] 7-(4-ethylpiperazin-1-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1536] 7-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(2-methyl-2H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1537] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1538] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1539] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one [1540] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one [1541] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(ethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1542] 7-{4-[bis(2-hydroxyethyl)amino]piperidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1543] 7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1544] 2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one [1545] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1546] 2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1547] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1548] 2-(1-methyl-1H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1549] 7-(1-ethylpiperidin-4-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1550] 7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1551] 2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1552] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1553] 2-(2-methyl-2H-indazol-5-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1554] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4-[(2-hydroxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1555] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1556] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1557] 7-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1558] 7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1559] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1560] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1561] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1562] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1563] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1564] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1565] 7-(4-cyclopropylpiperazin-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1566] 7-(4-cyclobutylpiperazin-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1567] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(oxetan-3-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1568] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1569] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1570] 2-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1571] 2-(4-hydroxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1572] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one [1573] 7-(1-cyclobutylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1574] 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1575] 7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1576] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-propylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1577] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1578] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1579] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1580] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1581] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1582] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1583] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1584] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1585] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1586] 7-(1-cyclopropylpiperidin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1587] 7-(1-cyclobutylpiperidin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1588] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1589] 7-[(3R)-4-cyclopropyl-3-methylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1590] 7-[(3R)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1591] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1592] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1593] 7-(4-cyclobutylpiperazin-1-yl)-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1594] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1595] 7-[(3R)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1596] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1597] 7-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1598] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1599] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1600] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1601] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1602] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1603] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1604] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1605] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1606] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1607] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-fluoroethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1608] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(3-fluoropropyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1609] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-fluoroethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1610] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(3-fluoropropyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1611] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-fluoroethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1612] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(3-fluoropropyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1613] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-fluoroethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1614] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(3-fluoropropyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1615] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{(3R)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1616] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1617] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1618] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1619] 2-[8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1620] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1621] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1622] 2-[8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl]-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1623] 7-(4-ethylpiperazin-1-yl)-2-[8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1624] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1625] 7-(1-cyclopropylpiperidin-4-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1626] 7-(1-cyclobutylpiperidin-4-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1627] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1628] 2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1629] 2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1630] 2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1631] 2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1632] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1633] 2-[4-(dimethylamino)-6-methylpyrazolo[1,5-a]pyrazin-2-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1634] 2-(2-methyl-1H-benzimidazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1635] 7-(4-ethylpiperazin-1-yl)-2-(2-methyl-1H-benzimidazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1636] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1637] 2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one [1638] 7-[1-(2,2-dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1639] 7-[1-(1,3-dihydroxypropan-2-yl)piperidin-4-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1640] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1641] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1642] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1643] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1644] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1645] 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1646] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1647] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1648] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1649] 7-(1-cyclobutylpiperidin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1650] 9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1651] 7-[4-(dimethylamino)-4-methylpiperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1652] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(ethylamino)-4-methylpiperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1653] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-methyl-4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1654] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4-[(2-hydroxyethyl)amino]-4-methylpiperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one [1655] 7-(1-cyclobutylpiperidin-4-yl)-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1656] 7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1657] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1658] 2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1659] 2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1660] 2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1661] 2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1662] 2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1663] 7-(1-cyclopropylpiperidin-4-yl)-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1664] 7-(1-ethylpiperidin-4-yl)-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1665] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1666] 9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1667] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(1-methylpiperidin-4-yl)oxy]-4H-pyrido[1,2-a]pyrimidin-4-one [1668] 2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1669] 7-(4-methylpiperazin-1-yl)-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1670] 7-(4-ethylpiperazin-1-yl)-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1671] 7-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1672] 7-[(3R)-3-methylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1673] 7-[(3S)-3-methylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1674] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1675] 2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1676] 7-(4-amino-4-methylpiperidin-1-yl)-2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1677] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-ethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1678] 2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1679] 7-[(3R)-3-methylpiperazin-1-yl]-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1680] 7-[(3S)-3-methylpiperazin-1-yl]-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1681] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1682] 7-(4-amino-4-methylpiperidin-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1683] 2-(2,7-dimethyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1684] 2-(2,7-dimethyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1685] 7-(3-aminoprop-1-yn-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1686] 2-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1687] 7-(3-aminopropyl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1688] 2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1689] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1690] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1691] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1692] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1693] 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1694] 7-(1,4-diazepan-1-yl)-2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1695] 2-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1696] 2-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1697] 2-(2,7-dimethyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1698] 2-(2,7-dimethyl-2H-indazol-5-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1699] 9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1700] 9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1701] 9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1702] 7-[3-(dimethylamino)azetidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1703] 7-[3-(diethylamino)azetidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1704] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3-(pyrrolidin-1-yl)azetidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1705] 7-(1,4-diazepan-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1706] 7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1707] 2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1708] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1709] 7-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1710] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3-(piperidin-1-yl)azetidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1711] 2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1712] 7-(2,7-diazaspiro[4.4]non-2-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1713] 2-(2,7-dimethyl-2H-indazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1714] 7-[3-(dimethylamino)propyl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1715] 7-{(3S)-3-[(dimethylamino)methyl]pyrrolidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1716] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1717] 9-methyl-2-(1-methyl-1H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1718] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1719] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1720] 2-(1,7-dimethyl-1H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1721] 2-(1,7-dimethyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1722] 2-(1,7-dimethyl-1H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1723] 7-{(3S)-3-[(diethylamino)methyl]pyrrolidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1724] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{(3S)-3-[(ethylamino)methyl]pyrrolidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one [1725] 7-{3-[(dimethylamino)methyl]azetidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1726] 7-{3-[(diethylamino)methyl]azetidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1727] 2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1728] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1729] 9-methyl-2-(1-methyl-1H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1730] 7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1731] 7-(1-ethylpiperidin-4-yl)-9-methyl-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1732] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1733] 7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1734] 7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1735] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1736] 9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1737] 7-(1-cyclobutylpiperidin-4-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1738] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1739] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1740] 2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1741] 9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one [1742] 7-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1743] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(2S,6S)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1744] 7-{(3R)-3-[(dimethylamino)methyl]pyrrolidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1745] 7-[(2S,6S)-2,6-dimethylpiperidin-4-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1746] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1747] 2-(imidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1748] 2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1749] 7-(2,7-diazaspiro[3.5]non-7-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1750] 7-(4-methylpiperazin-1-yl)-2-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1751] 7-(4-methylpiperazin-1-yl)-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1752] 2-methyl-6-[7-(4-methylpiperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl]imidazo[1,2-a]pyridine-8-carbonitrile 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1753] 7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1754] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1755] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-hydroxypiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1756] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1757] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1758] 7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1759] 7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1760] 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-8a-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1761] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1762] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1763] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1764] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one [1765] 2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(8a-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1766] 7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1767] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-{[2-(morpholin-4-yl)ethyl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one [1768] 7-{[2-(dimethylamino)ethyl]amino}-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1769] 7-{[2-(dimethylamino)ethyl](methyl)amino}-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1770] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-{methyl[2-(methylamino)ethyl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one [1771] 7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1772] 7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1773] 7-[2-(dimethylamino)ethoxy]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [1774] 7-[2-(dimethylamino)ethoxy]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [1775] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-ylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one [1776] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[2-(piperidin-1-yl)ethoxy]-4H-pyrido[1,2-a]pyrimidin-4-one [1777] 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3-(morpholin-4-yl)propoxy]-4H-pyrido[1,2-a]pyrimidin-4-one [1778] 7-[3-(dimethylamino)propoxy]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, or [1779] 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one
or a salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

[1780] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound selected from the group consisting of: [1781] 2-(3,5-difluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride [1782] 7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-quinolizin-4-one acetate [1783] 2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one trifluoroacetate (1:1), or [1784] 2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one hydrochloride (1:2)
or a free base, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

[1785] Compounds of Formula (I) can be prepared using reagents and methods known in the art, including the methods provided in International Application No. PCT/US2013/025292, filed on Feb. 8, 2013, and published as International Publication No. WO 2013/119916 on Aug. 15, 2013, the entire contents which are incorporated herein by reference (see in particular, General Synthetic Methods, Schemes A-J, at paragraphs [001126] to [001159]; and Specific Synthetic Examples, at paragraphs [001160] to [001573] and Table 1, therein).

Terminology

[1786] The chemical terms used above and throughout the description herein, unless specifically defined otherwise, shall be understood by one of ordinary skill in the art to have the following indicated meanings.

[1787] As used herein, the term “C.sub.1-8alkyl” generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration, including, but not limited to, methyl, ethyl, n-propyl (also referred to as propyl or propanyl), isopropyl, n-butyl (also referred to as butyl or butanyl), isobutyl, sec-butyl, tert-butyl, n-pentyl (also referred to as pentyl or pentanyl), n-hexyl (also referred to as hexyl or hexanyl), n-heptyl (also referred to as heptyl or heptanyl), n-octyl and the like. In some embodiments, C.sub.1-8alkyl includes, but is not limited to, C.sub.1-6alkyl, C.sub.1-8alkyl and the like. A C.sub.1-8alkyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

[1788] As used herein, the term “C.sub.2-8alkenyl” generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, but not limited to, ethenyl (also referred to as vinyl), allyl, propenyl and the like. In some embodiments, C.sub.2-8alkenyl includes, but is not limited to, C.sub.2-6alkenyl, C.sub.2-4alkenyl and the like. A C.sub.2-8alkenyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

[1789] As used herein, the term “C.sub.2-4alkynyl” generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon triple bonds therein, including, but not limited to, ethynyl, propynyl, butynyl and the like. In some embodiments, C.sub.2-8alkynyl includes, but is not limited to, C.sub.2-8alkynyl, C.sub.2-4alkynyl and the like. A C.sub.2-8alkynyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

[1790] As used herein, the term “C.sub.1-8alkoxy” generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the formula: —O—C.sub.1-8alkyl, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. In some embodiments, C.sub.1-8alkoxy includes, but is not limited to, C.sub.1-8alkoxy, C.sub.1-8alkoxy and the like. A C.sub.1-8alkoxy radical is optionally substituted with substituent species as described herein where allowed by available valences.

[1791] As used herein, the term “C.sub.3-14cycloalkyl” generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthalenyl and the like. In some embodiments, C.sub.3-14cycloalkyl includes, but is not limited to, C.sub.3-8cycloalkyl, C.sub.5-8cycloalkyl, C.sub.3-10cycloalkyl and the like. A C.sub.3-14cycloalkyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

[1792] As used herein, the term “aryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An aryl radical is optionally substituted with substituent species as described herein where allowed by available valences.

[1793] As used herein, the term “heteroaryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, but not limited to, furanyl (also referred to as furyl), thienyl (also referred to as thiophenyl), pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 1H-pyrazolyl, imidazolyl, 1H-imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl (such as 1H-1,2,3-triazolyl and the like), oxadiazolyl (such as 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and the like), thiadiazolyl, tetrazolyl (such as 1H-tetrazolyl, 2H-tetrazolyl and the like), pyridinyl (also referred to as pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, 1H-indolyl, indazolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl (also referred to as benzothiophenyl), benzoimidazolyl, 1H-benzoimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl (also referred to as 1,3-benzooxazolyl), purinyl, 9H-purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl, 1,4-diazanaphthalenyl, acridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl and the like. A heteroaryl radical is optionally substituted on a carbon or nitrogen atom ring member with substituent species as described herein where allowed by available valences.

[1794] As used herein, the term “heterocyclyl” generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, but not limited to, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl (also referred to as benzo[d][1,3]dioxolyl), 1,4-benzodioxanyl, 2,3-dihydro-1,4-benzodioxinyl (also referred to as 2,3-dihydrobenzo[b][1,4]dioxinyl), hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl and the like. A heterocyclyl radical is optionally substituted on a carbon or nitrogen atom ring member with substituent species as described herein where allowed by available valences.

[1795] As used herein, the term “C.sub.1-8alkoxy-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-O—C.sub.1-8alkyl.

[1796] As used herein, the term “C.sub.1-8alkoxy-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-O—C.sub.1-8alkyl.

[1797] As used herein, the term “(C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-8alkyl-O—C.sub.1-8alkyl).sub.2.

[1798] As used herein, the term “C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-NH—C.sub.1-8alkyl-O—C.sub.1-8alkyl.

[1799] As used herein, the term “(C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-N(C.sub.1-8alkyl-O—C.sub.1-8alkyl).sub.2.

[1800] As used herein, the term “(C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-N(C.sub.1-8alkyl)(C.sub.1-8alkyl-O—C.sub.1-8alkyl).

[1801] As used herein, the term “C.sub.1-8alkoxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-NH—C.sub.1-8alkyl-O—C.sub.1-8alkyl.

[1802] As used herein, the term “(C.sub.1-8alkoxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl-O—C.sub.1-8alkyl).sub.2.

[1803] As used herein, the term “(C.sub.1-8alkoxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl)(C.sub.1-8alkyl-O—C.sub.1-8alkyl).

[1804] As used herein, the term “C.sub.1-8alkoxy-carbonyl” refers to a radical of the formula: —C(O)—O—C.sub.1-8alkyl.

[1805] As used herein, the term “C.sub.1-8alkoxy-carbonyl-C.sub.2-8alkenyl” refers to a radical of the formula: —C.sub.2-8alkenyl-C(O)—O—C.sub.1-8alkyl.

[1806] As used herein, the term “C.sub.1-8alkoxy-carbonyl-amino” refers to a radical of the formula: —NH—C(O)—O—C.sub.1-8alkyl.

[1807] As used herein, the term “C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl.

[1808] As used herein, the term “(C.sub.1-8alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-8alkyl).sub.2.

[1809] As used herein, the term “C.sub.1-8alkyl-amino-C.sub.2-8alkenyl” refers to a radical of the formula: —C.sub.2-8alkenyl-NH—C.sub.1-8alkyl.

[1810] As used herein, the term “(C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkenyl” refers to a radical of the formula: —C.sub.2-8alkenyl-N(C.sub.1-8alkyl).sub.2.

[1811] As used herein, the term “C.sub.1-8alkyl-amino-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-NH—C.sub.1-8alkyl.

[1812] As used herein, the term “(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2.

[1813] As used herein, the term “C.sub.1-8alkyl-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-NH—C.sub.1-8alkyl.

[1814] As used herein, the term “(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2.

[1815] As used herein, the term “C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-NH—C.sub.1-8alkyl.

[1816] As used herein, the term “(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2.

[1817] As used herein, the term “(C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-8alkyl-NH—C.sub.1-8alkyl).sub.2.

[1818] As used herein, the term “[(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl].sub.2-amino” refers to a radical of the formula: —N[C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2].sub.2.

[1819] As used herein, the term “(C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)(C.sub.1-8alkyl-NH—C.sub.1-8alkyl).

[1820] As used herein, the term “[(C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)[C.sub.1-8alkyl-N(C.sub.1-8alkyl).sub.2].

[1821] As used herein, the term “C.sub.1-8alkyl-amino-C.sub.2-8alkynyl” refers to a radical of the formula: —C.sub.2-8alkynyl-NH—C.sub.1-8alkyl.

[1822] As used herein, the term “(C.sub.1-8alkyl).sub.2-amino-C.sub.2-8alkynyl” refers to a radical of the formula: —C.sub.2-8alkynyl-N(C.sub.1-8alkyl).sub.2.

[1823] As used herein, the term “C.sub.1-8alkyl-carbonyl” refers to a radical of the formula: —C(O)—C.sub.1-8alkyl.

[1824] As used herein, the term “C.sub.1-8alkyl-carbonyl-amino” refers to a radical of the formula: —NH—C(O)—C.sub.1-8alkyl.

[1825] As used herein, the term “C.sub.1-8alkyl-thio” refers to a radical of the formula: —S—C.sub.1-8alkyl.

[1826] As used herein, the term “amino-C.sub.2-8alkenyl” refers to a radical of the formula: —C.sub.2-8alkenyl-NH.sub.2.

[1827] As used herein, the term “amino-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-NH.sub.2.

[1828] As used herein, the term “amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-NH.sub.2.

[1829] As used herein, the term “amino-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-NH.sub.2.

[1830] As used herein, the term “(amino-C.sub.1-8alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-8alkyl-NH.sub.2).sub.2.

[1831] As used herein, the term “(amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)(C.sub.1-8alkyl-NH.sub.2).

[1832] As used herein, the term “amino-C.sub.2-8alkynyl” refers to a radical of the formula: —C.sub.2-8alkynyl-NH.sub.2.

[1833] As used herein, the term “aryl-C.sub.1-8alkoxy-carbonyl” refers to a radical of the formula: —C(O)—O—C.sub.1-8alkyl-aryl.

[1834] As used herein, the term “aryl-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-aryl.

[1835] As used herein, the term “aryl-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-aryl.

[1836] As used herein, the term “(aryl-C.sub.1-8alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-8alkyl-aryl).sub.2.

[1837] As used herein, the term “(aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)(C.sub.1-8alkyl-aryl).

[1838] As used herein, the term “aryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-NH—C.sub.1-8alkyl-aryl.

[1839] As used herein, the term “(aryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl-aryl).sub.2.

[1840] As used herein, the term “(aryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl)(C.sub.1-8alkyl-aryl).

[1841] As used herein, the term “aryl-amino” refers to a radical of the formula: —NH-aryl.

[1842] As used herein, the term “aryl-amino-carbonyl” refers to a radical of the formula: —C(O)—NH-aryl.

[1843] As used herein, the term “aryl-sulfonyloxy-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-O—SO.sub.2-aryl.

[1844] As used herein, the term “benzoxy-carbonyl” refers to a radical of the formula: —C(O)O—CH.sub.2-phenyl.

[1845] As used herein, the term “C.sub.3-14cycloalkyl-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-C.sub.3-14cycloalkyl.

[1846] As used herein, the term “C.sub.3-14cycloalkyl-amino” refers to a radical of the formula: —NH—C.sub.3-14cycloalkyl.

[1847] As used herein, the term “C.sub.3-14cycloalkyl-oxy” refers to a radical of the formula: —O—C.sub.3-14cycloalkyl.

[1848] As used herein, the term “halo” or “halogen” generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.

[1849] As used herein, the term “halo-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-halo, wherein C.sub.1-8alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.

[1850] As used herein, the term “halo-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-halo, wherein C.sub.1-8alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.

[1851] As used herein, the term “halo-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-halo.

[1852] As used herein, the term “(halo-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)(C.sub.1-8alkyl-halo).

[1853] As used herein, the term “(halo-C.sub.1-8alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-8alkyl-halo).sub.2.

[1854] As used herein, the term “heteroaryl-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-heteroaryl.

[1855] As used herein, the term “heteroaryl-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-heteroaryl.

[1856] As used herein, the term “heteroaryl-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-heteroaryl.

[1857] As used herein, the term “(heteroaryl-C.sub.1-8alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-8alkyl-heteroaryl).sub.2.

[1858] As used herein, the term “(heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)(C.sub.1-8alkyl-heteroaryl).

[1859] As used herein, the term “heteroaryl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-NH—C.sub.1-8alkyl-heteroaryl.

[1860] As used herein, the term “(heteroaryl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl-heteroaryl).sub.2.

[1861] As used herein, the term “(heteroaryl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl)(C.sub.1-8alkyl-heteroaryl).

[1862] As used herein, the term “heteroaryl-amino” refers to a radical of the formula: —NH-heteroaryl.

[1863] As used herein, the term “heterocyclyl-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-heterocyclyl.

[1864] As used herein, the term “heterocyclyl-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-heterocyclyl.

[1865] As used herein, the term “heterocyclyl-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-heterocyclyl.

[1866] As used herein, the term “(heterocyclyl-C.sub.1-8alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-8alkyl-heterocyclyl).sub.2.

[1867] As used herein, the term “(heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)(C.sub.1-8alkyl-heterocyclyl).

[1868] As used herein, the term “heterocyclyl-C.sub.1-8alkyl-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-NH—C.sub.1-8alkyl-heterocyclyl.

[1869] As used herein, the term “(heterocyclyl-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl-heterocyclyl).sub.2.

[1870] As used herein, the term “(heterocyclyl-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl)(C.sub.1-8alkyl-heterocyclyl).

[1871] As used herein, the term “heterocyclyl-amino” refers to a radical of the formula: —NH-heterocyclyl.

[1872] As used herein, the term “(heterocyclyl)(C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)(heterocyclyl).

[1873] As used herein, the term “heterocyclyl-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-NH-heterocyclyl.

[1874] As used herein, the term “heterocyclyl-carbonyl” refers to a radical of the formula: —C(O)-heterocyclyl.

[1875] As used herein, the term “heterocyclyl-carbonyl-oxy” refers to a radical of the formula: —O—C(O)-heterocyclyl.

[1876] As used herein, the term “heterocyclyl-oxy” refers to a radical of the formula: —O-heterocyclyl.

[1877] As used herein, the term “hydroxy” refers to a radical of the formula: —OH.

[1878] As used herein, the term “hydroxy-C.sub.1-8alkoxy-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-O—C.sub.1-8alkyl-OH.

[1879] As used herein, the term “hydroxy-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-OH, wherein C.sub.1-8alkyl is partially or completely substituted with one or more hydroxy radicals where allowed by available valences.

[1880] As used herein, the term “hydroxy-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-OH.

[1881] As used herein, the term “(hydroxy-C.sub.1-8alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-8alkyl-OH).sub.2.

[1882] As used herein, the term “(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)(C.sub.1-8alkyl-OH).

[1883] As used herein, the term “hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-NH—C.sub.1-8alkyl-OH.

[1884] As used herein, the term “(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl-OH).sub.2.

[1885] As used herein, the term “(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl” refers to a radical of the formula: —C.sub.1-8alkyl-N(C.sub.1-8alkyl)(C.sub.1-8alkyl-OH).

[1886] As used herein, the term “hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-NH—C.sub.1-8alkyl-OH.

[1887] As used herein, the term “(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-N(C.sub.1-8alkyl-OH).sub.2.

[1888] As used herein, the term “(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkoxy” refers to a radical of the formula: —O—C.sub.1-8alkyl-N(C.sub.1-8alkyl)(C.sub.1-8alkyl-OH).

[1889] As used herein, the term “hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-NH—C.sub.1-8alkyl-OH.

[1890] As used herein, the term “(hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-8alkyl-NH—C.sub.1-8alkyl-OH).sub.2.

[1891] As used herein, the term “(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-N(C.sub.1-8alkyl-OH).sub.2.

[1892] As used herein, the term “(hydroxy-C.sub.1-8alkyl-amino-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)(C.sub.1-8alkyl-NH—C.sub.1-8alkyl-OH).

[1893] As used herein, the term “[(hydroxy-C.sub.1-8alkyl).sub.2-amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)[C.sub.1-8alkyl-N(C.sub.1-8alkyl-OH).sub.2].

[1894] As used herein, the term “(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-8alkyl-N(C.sub.1-8alkyl,C.sub.1-8alkyl-OH).

[1895] As used herein, the term “[(hydroxy-C.sub.1-8alkyl)(C.sub.1-8alkyl)amino-C.sub.1-8alkyl](C.sub.1-8alkyl)amino” refers to a radical of the formula: —N(C.sub.1-8alkyl)[C.sub.1-8alkyl —N(C.sub.1-8alkyl)(C.sub.1-8alkyl-OH)].

[1896] As used herein, the term “substituent” means positional variables on the atoms of a core molecule that are attached at a designated atom position, replacing one or more hydrogen atoms on the designated atom, provided that the atom of attachment does not exceed the available valence or shared valences, such that the substitution results in a stable compound. Accordingly, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. It should also be noted that any carbon as well as heteroatom with a valence level that appears to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown.

[1897] For the purposes of this description, where one or more substituent variables for a compound of Formula (I) encompass functionalities incorporated into a compound of Formula (I), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.

[1898] As used herein, the terms “independently selected,” or “each selected” refer to functional variables in a substituent list that may be attached more than once on the structure of a core molecule, where the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Further, the use of a generic substituent on a core structure for a compound provided herein is understood to include the replacement of the generic substituent with specie substituents that are included within the particular genus, e.g., aryl may be independently replaced with phenyl or naphthalenyl (also referred to as naphthyl) and the like, such that the resulting compound is intended to be included within the scope of the compounds described herein.

[1899] As used herein, the term “each instance of” when used in a phrase such as “ . . . aryl, aryl-C.sub.1-8alkyl, heterocyclyl and heterocyclyl-C.sub.1-8alkyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one or two substituents . . . ” is intended to include optional, independent substitution on each of the aryl and heterocyclyl rings and on the aryl and heterocyclyl portions of aryl-C.sub.1-8alkyl and heterocyclyl-C.sub.1-8alkyl.

[1900] As used herein, the term “optionally substituted” means that the specified substituent variables, groups, radicals or moieties represent the scope of the genus and may be independently chosen as needed to replace one or more hydrogen atoms on the designated atom of attachment of a core molecule.

[1901] As used herein, the terms “stable compound” or “stable structure” mean a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture and formulations thereof into an efficacious therapeutic agent.

[1902] Compound names provided herein were obtained using ACD Labs Index Name software provided by ACD Labs and/or ChemDraw Ultra software provided by CambridgeSoft®. When the compound name disclosed herein conflicts with the structure depicted, the structure shown will supercede the use of the name to define the compound intended. Nomenclature for substituent radicals defined herein may differ slightly from the chemical name from which they are derived; one skilled in the art will recognize that the definition of the substituent radical is intended to include the radical as found in the chemical name.

[1903] As used herein the term “aberrant” refers to a deviation from the norm of, e.g., the average healthy subject or a cell(s) or tissue sample from a healthy subject. The term “aberrant expression,” as used herein, refers to abnormal expression (up-regulated or down-regulated resulting in an excessive or deficient amount thereof) of a gene product (e.g., RNA transcript or protein) by a cell, tissue sample, or subject relative to a corresponding normal, healthy cell, tissue sample or subject. In a specific embodiment, the “aberrant expression” refers to an altered level of a gene product (e.g., RNA transcript or protein) in a cell, tissue sample, or subject relative to a corresponding normal, healthy cell, tissue sample or subject. The term “aberrant amount” as used herein refers to an altered level of a gene product (e.g., RNA, protein, polypeptide, or peptide) in a cell, tissue sample, or subject relative to a corresponding normal, healthy cell, tissue sample or subject. In specific embodiments, the amount of a gene product (e.g., RNA, protein, polypeptide, or peptide) in a cell, tissue sample, or subject relative to a corresponding cell or tissue sample from a healthy subject or a healthy subject, is considered aberrant if it is 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6-fold or more above or below the amount of the gene product in the corresponding cell or tissue sample from a healthy subject or healthy subject.

[1904] The term “intronic REMS” refers to a REMS sequence present in an intron that functions as a 5′ splice site in the presence of a compound described herein. The intronic REMS, when downstream of a first branch point (BP) sequence and a first 3′ splice site (3′ ss) sequence and upstream of a second branch point (BP) sequence and a second 3′ splice site (3′ ss) sequence) (as shown in FIG. 1A) and in the presence of a compound described herein, can function as a 5′ splice site. The intronic REMS may also function as a 5′ splice site when upstream of a first branch point and a first 3′ splice site in the presence of a compound described herein (see FIG. 1B or 1C). Any one, two, three, or more or all of the following may be present endogenously or non-endogenously in the affected intron: the intronic REMS, the first BP, the second BP, the first 3′ ss, and the second 3′ss.

[1905] As used herein, a “non-endogenous” nucleotide sequence (such as a non-endogenous 5′ splice site, a non-endogenous branch point or a non-endogenous 3′ splice site) is a nucleotide sequence not naturally found to be part of a pre-RNA or a DNA sequence encoding a pre-RNA sequence. In other words, the hand of man is required to synthesize or manipulate the RNA or DNA sequence to introduce the nucleotide sequence.

[1906] As used herein, the term “non-endogenous intronic REMS” refers to a REMS sequence not naturally found to be part of an RNA sequence or naturally encoded by a DNA sequence. In other words, the hand of man is required to manipulate the RNA or DNA sequence to introduce the intronic REMS or the nucleotide sequence encoding the REMS into an intron.

[1907] As used herein, the terms “intron-derived exon,” “intronic exon,” “iExon” and “intronic exon” (collectively iExon) refers to the formation of an exon from an RNA sequence present in an intron following splicing of an RNA transcript in the presence of a compound described herein or another agent which results in an iREMS functioning as an intronic 5′ splice site. In particular, an iExon comprises the following RNA sequence as an exon when RNA splicing of an RNA transcript comprising two exons and an intron occurs in the presence of a compound described herein, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, and wherein the intron comprises 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: the RNA sequence between the first 3′ splice site and the iREMS, as shown in FIG. 1A. One or more of the iREMS sequence, branch point and 3′ splice site may be naturally present in an intron or may be introduced into the intron. When all such elements are present or introduced, in the presence of a compound described herein the elements define an exonic boundary that enables the splicing machinery to generate an iExon in RNA, a result that would not naturally occur without the addition of a splicing modulator compound.

[1908] As used herein, the term “pseudoexon” refers to a potential exon in intronic regions of pre-mRNA that is not normally spliced into mature mRNA. A subset of pseudoexons are spliced in the presence of a compound described herein or another agent resulting from an iREMS functioning as a 5′ splice site within the pseudoexon, to form an iExon. An intronic REMS-containing pseudoexon is not known to be endogenously recognized by the splicing machinery for producing an iExon, but in the presence of a splicing modulator compound as described herein, the splicing machinery produces an iExon. Accordingly, production of an iExon from a pseudoexon is intended to be included within the scope of various aspects of the collective term “iExon.”

[1909] As used herein, the term “unannotated exon” refers to endogenous sequences that are naturally present as exons in mature mRNA product according to experimental evidence but are not annotated in NCBI's RefSeq database (https://www.ncbi.nlm.nih.gov/refseq/). Some unannotated exons contain an intronic REMS at the 5′ splice site. A REMS-containing unannotated exon is not known to be endogenously recognized by the splicing machinery for producing an iExon, but in the presence of a splicing modulator compound as described herein, the splicing machinery produces an iExon. Accordingly, production of an iExon from an unannotated exon is intended to be included within the scope of various aspects of the collective term “iExon.”

[1910] As used herein, the term “substantial change” in the context of the amount of one or more RNA transcripts (e.g., rRNA, tRNA, miRNA, siRNA, piRNA, lncRNA, pre-mRNA or mRNA transcripts), an alternative splice variant thereof or an isoform thereof, or one or more proteins thereof, each expressed as the product of one or more of genes, means that the amount of such products changes by a statistically significant amount such as, in a nonlimiting example, a p value less than a value selected from 0.1, 0.01, 0.001, or 0.0001.

[1911] As used herein, the terms “subject” and “patient” are used interchangeably to refer to an animal or any living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Non-limiting examples include members of the human, equine, porcine, bovine, rattus, murine, canine and feline species. In some embodiments, the subject is a mammal or a warm-blooded vertebrate animal. In certain embodiments, the subject is a non-human animal. In specific embodiments, the subject is a human.

[1912] As used herein, the term “functional protein” refers to a form of a protein that retains a certain biological function or the functions of a full length protein or protein isoform encoded by a gene. Accordingly, inclusion of an iExon that is located in the protein coding region of an mRNA that expresses a functional protein is intended to be included within the scope of the description herein.

[1913] As used herein, the term “non-functional protein” refers to a form of a protein that does not retain any biological function compared to full length protein or a protein isoform encoded by a gene in the absence of a splicing modifier compound as described herein. Accordingly, inclusion of an iExon that is located in the protein coding region of an mRNA that expresses a non-functional protein is intended to be included within the scope of the description herein.

[1914] As used herein, in the context of a functional protein produced from an artificial construct, the term “produce substantially less” means that the amount of functional protein produced in the presence of a compound described herein is at least substantially 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% less than the amount of functional protein produced in the absence of the compound.

Compound Forms

[1915] As used herein, the terms “a compound of Formula (Ia),” “a compound of Formula (Ia1),” “a compound of Formula (Ia2),” “a compound of Formula (Ia3),” “a compound of Formula (Ia4),” “a compound of Formula (II),” “a compound of Formula (IIa),” “a compound of Formula (IIa1),” “a compound of Formula (IIa2),” “a compound of Formula (IIa3),” “a compound of Formula (IIa4),” “a compound of Formula (III),” “a compound of Formula (IIIa),” “a compound of Formula (IIIa1),” “a compound of Formula (IIIa2),” “a compound of Formula (IIIa3),” “a compound of Formula (IIIa4),” “a compound of Formula (IV),” “a compound of Formula (IVa),” “a compound of Formula (IVa1),” “a compound of Formula (IVa2),” “a compound of Formula (V),” “a compound of Formula (Va),” “a compound of Formula (Va1),” “a compound of Formula (Va2),” “a compound of Formula (VI),” “a compound of Formula (VIa),” “a compound of Formula (VIa1),” “a compound of Formula (VIa2),” “a compound of Formula (VIa3),” “a compound of Formula (VIa4),” “a compound of Formula (VII),” “a compound of Formula (VIIa),” “a compound of Formula (VIIa1),” “a compound of Formula (VIIa2),” “a compound of Formula (VIII),” “a compound of Formula (VIIIa),” “a compound of Formula (VIIIa1),” “a compound of Formula (VIIIa2),” “a compound of Formula (IX),” “a compound of Formula (IXa),” “a compound of Formula (IXa1),” “a compound of Formula (IXa2),” “a compound of Formula (IXa3),” “a compound of Formula (IXa4),” “a compound of Formula (X),” “a compound of Formula (Xa),” “a compound of Formula (Xa1),” “a compound of Formula (Xa2),” “a compound of Formula (XI),” “a compound of Formula (XIa),” “a compound of Formula (XIa1),” “a compound of Formula (XIa2),” “a compound of Formula (XII),” “a compound of Formula (XIIa),” “a compound of Formula (XIIa1),” “a compound of Formula (XIIa2),” “a compound of Formula (XIIa3),” “a compound of Formula (XIIa4),” “a compound of Formula (XIII),” “a compound of Formula (XIIIa),” “a compound of Formula (XIIIa1),” “a compound of Formula (XIIIa2),” “a compound of Formula (XIV),” “a compound of Formula (XIVa),” “a compound of Formula (XIVa1),” and “a compound of Formula (XIVa2),” each refer to subgenera of the compound of Formula (I) or a form thereof.

[1916] Rather than repeat embodiments for the various subgenera of the compound of Formula (I), in certain embodiments, the term “a compound of Formula (I) or a form thereof” is used to inclusively to refer to a compound of Formula (Ia) or a form thereof, a compound of Formula (Ia1) or a form thereof, a compound of Formula (Ia2) or a form thereof, a compound of Formula (Ia3) or a form thereof, a compound of Formula (Ia4) or a form thereof, a compound of Formula (II) or a form thereof, a compound of Formula (IIa) or a form thereof, a compound of Formula (IIa1) or a form thereof, a compound of Formula (IIa2) or a form thereof, a compound of Formula (IIa3) or a form thereof, a compound of Formula (IIa4) or a form thereof, a compound of Formula (III) or a form thereof, a compound of Formula (IIIa) or a form thereof, a compound of Formula (IIIa1) or a form thereof, a compound of Formula (IIIa2) or a form thereof, a compound of Formula (IIIa3) or a form thereof, a compound of Formula (IIIa4) or a form thereof, a compound of Formula (IV) or a form thereof, a compound of Formula (IVa) or a form thereof, a compound of Formula (IVa1) or a form thereof, a compound of Formula (IVa2) or a form thereof, a compound of Formula (V) or a form thereof, a compound of Formula (Va) or a form thereof, a compound of Formula (Va1) or a form thereof, a compound of Formula (Va2) or a form thereof, a compound of Formula (VI) or a form thereof, a compound of Formula (VIa) or a form thereof, a compound of Formula (VIa1) or a form thereof, a compound of Formula (VIa2) or a form thereof, a compound of Formula (VIa3) or a form thereof, a compound of Formula (VIa4) or a form thereof, a compound of Formula (VII) or a form thereof, a compound of Formula (VIIa) or a form thereof, a compound of Formula (VIIa1) or a form thereof, a compound of Formula (VIIa2) or a form thereof, a compound of Formula (VIII) or a form thereof, a compound of Formula (VIIIa) or a form thereof, a compound of Formula (VIIIa1) or a form thereof, a compound of Formula (VIIIa2) or a form thereof, a compound of Formula (IX) or a form thereof, a compound of Formula (IXa) or a form thereof, a compound of Formula (IXa1) or a form thereof, a compound of Formula (IXa2) or a form thereof, a compound of Formula (IXa3) or a form thereof, a compound of Formula (IXa4) or a form thereof, a compound of Formula (X) or a form thereof, a compound of Formula (Xa) or a form thereof, a compound of Formula (Xa1) or a form thereof, a compound of Formula (Xa2) or a form thereof, a compound of Formula (XI) or a form thereof, a compound of Formula (XIa) or a form thereof, a compound of Formula (XIa1) or a form thereof, a compound of Formula (XIa2) or a form thereof, a compound of Formula (XII) or a form thereof, a compound of Formula (XIIa) or a form thereof, a compound of Formula (XIIa1) or a form thereof, a compound of Formula (XIIa2) or a form thereof, a compound of Formula (XIIa3) or a form thereof, a compound of Formula (XIIa4) or a form thereof, a compound of Formula (XIII) or a form thereof, a compound of Formula (XIIIa) or a form thereof, a compound of Formula (XIIIa1) or a form thereof, a compound of Formula (XIIIa2) or a form thereof, a compound of Formula (XIV) or a form thereof, a compound of Formula (XIVa) or a form thereof, a compound of Formula (XIVa1) or a form thereof or a compound of Formula (XIVa2) or a form thereof, either separately or together.

[1917] Thus, embodiments and references to “a compound of Formula (I)” are intended to be inclusive of compounds of Formula (Ia), Formula (Ia1), Formula (Ia2), Formula (Ia3), Formula (Ia4), Formula (II), Formula (IIa), Formula (IIa1), Formula (IIa2), Formula (IIa3), Formula (IIa4), Formula (III), Formula (IIIa), Formula (IIIa1), Formula (IIIa2), Formula (IIIa3), Formula (IIIa4), Formula (IV), Formula (IVa), Formula (IVa1), Formula (IVa2), Formula (V), Formula (Va), Formula (Va1), Formula (Va2), Formula (VI), Formula (VIa), Formula (VIa1), Formula (VIa2), Formula (VIa3), Formula (VIa4), Formula (VII), Formula (VIIa), Formula (VIIa1), Formula (VIIa2), Formula (VIII), Formula (VIIIa), Formula (VIIIa1), Formula (VIIIa2), Formula (IX), Formula (IXa), Formula (IXa1), Formula (IXa2), Formula (IXa3), Formula (IXa4), Formula (X), Formula (Xa), Formula (Xa1), Formula (Xa2), Formula (XI), Formula (XIa), Formula (XIa1), Formula (XIa2), Formula (XII), Formula (XIIa), Formula (XIIa1), Formula (XIIa2), Formula (XIIa3), Formula (XIIa4), Formula (XIII), Formula (XIIIa), Formula (XIIIa1), Formula (XIIIa2), Formula (XIV), Formula (XIVa), Formula (XIVa1) and Formula (XIVa2).

[1918] As used herein, the term “form” means a compound of Formula (I) selected from a free acid, free base, salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer, or tautomer thereof.

[1919] In certain embodiments described herein, the form of the compound of Formula (I) is a selected from a salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

[1920] In certain embodiments described herein, the form of the compound of Formula (I) is a selected from a free acid, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

[1921] In certain embodiments described herein, the form of the compound of Formula (I) is a selected from a free base, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

[1922] In certain embodiments described herein, the form of the compound of Formula (I) is a free acid, free base or salt thereof.

[1923] In certain embodiments described herein, the form of the compound of Formula (I) is an isotopologue thereof.

[1924] In certain embodiments described herein, the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer or diastereomer thereof.

[1925] In certain embodiments described herein, the form of the compound of Formula (I) is a tautomer thereof.

[1926] In certain embodiments described herein, the form of the compound of Formula (I) is a pharmaceutically acceptable form.

[1927] In certain embodiments described herein, the compound of Formula (I) or a form thereof is isolated for use.

[1928] As used herein, the term “isolated” means the physical state of a compound of Formula (I) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

[1929] As used herein, the term “protected” means that a functional group on a compound of Formula (I) is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

[1930] Prodrugs of a compound of Formula (I) or a form thereof are also contemplated herein.

[1931] As used herein, the term “prodrug” means that a functional group on a compound of Formula (I) is in a form (e.g., acting as an active or inactive drug precursor) that is transformed in vivo to yield an active or more active compound of Formula (I) or a form thereof. The transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues. A discussion of the use of prodrugs is provided by V. J. Stella, et. al., “Biotechnology: Pharmaceutical Aspects, Prodrugs: Challenges and Rewards,” American Association of Pharmaceutical Scientists and Springer Press, 2007.

[1932] In one example, when a compound of Formula (I) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another example, when a compound of Formula (I) or a form thereof contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a functional group such as alkyl or substituted carbonyl and the like. In another example, when a compound of Formula (I) or a form thereof contains an amine functional group, a prodrug can be formed by the replacement of one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl. In another example, when a compound of Formula (I) or a form thereof contains a hydrogen substituent, a prodrug can be formed by the replacement of one or more hydrogen atoms with an alkyl substituent.

[1933] Pharmaceutically acceptable prodrugs of compounds of Formula (I) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters phosphonate esters, mono-, di- or triphosphate esters or alkyl substituents where appropriate. As described herein, it is understood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula (I) or a form thereof for use as a prodrug.

[1934] The compounds of Formula (I) can form salts which are intended to be included within the scope of this description. Reference to a compound of Formula (I) herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein.

[1935] The term “pharmaceutically acceptable salt(s)”, as used herein, means those salts of compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of Formula (I) may be formed, for example, by reacting a compound of Formula (I) with an amount of acid or base, such as an equivalent or stoichiometric amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[1936] Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. Embodiments of acid addition salts include, and are not limited to, acetate, acid phosphate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, hydrobromide, hydrochloride, dihydrochloride, hydroiodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. One or more embodiments of acid addition salts include a chloride, hydrochloride, dihydrochloride, trihydrochloride, hydrobromide, acetate, diacetate or trifluoroacetate salt. More particular embodiments include a chloride, hydrochloride, dihydrochloride, hydrobromide or trifluoroacetate salt.

[1937] Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (see, website for Food & Drug Administration, Washington, D.C.). These disclosures are incorporated herein by reference thereto.

[1938] Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. Certain compounds described herein can also form pharmaceutically acceptable salts with organic bases (for example, organic amines) such as, but not limited to, dicyclohexylamines, tert-butyl amines and the like, and with various amino acids such as, but not limited to, arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[1939] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the description herein and all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for the purposes described herein.

[1940] Compounds of Formula I and forms thereof may further exist in a tautomeric form. All such tautomeric forms are contemplated herein as part of the present description.

[1941] The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, may exist in different stereoisomeric forms. The present description is intended to include all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures.

[1942] The compounds of Formula (I) described herein may include one or more chiral centers, and as such may exist as racemic mixtures (R/S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In one embodiment, the compounds of Formula (I) described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another embodiment, the compounds of Formula (I) described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will recognize, when more than one chiral center is present, the compounds of Formula (I) described herein may also include portions described as an (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.

[1943] As used herein, the term “substantially pure” refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.

[1944] In one aspect, a compound of Formula (I) is a substantially pure (S) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

[1945] In one aspect, a compound of Formula (I) is a substantially pure (R) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

[1946] As used herein, a “racemate” is any mixture of isometric forms that are not “enantiomerically pure”, including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, about 80/20, about 85/15 or about 90/10.

[1947] In addition, the present description embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the description herein.

[1948] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled in the art.

[1949] Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered part of this description.

[1950] All stereoisomer forms (for example, geometric isomers, optical isomers, positional isomers and the like) of the present compounds (including salts, solvates, esters and prodrugs and transformed prodrugs thereof) which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, diastereomeric forms and regioisomeric forms are contemplated within the scope of the description herein. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures thereof, are embraced within the scope of the description herein. Also, for example, all keto-enol and imine-enamine tautomeric forms of the compounds are included in the description herein. Individual stereoisomers of the compounds of Formula (I) described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra.

[1951] The use of the terms “salt,” “prodrug” and “transformed prodrug” are intended to equally apply to the salts, prodrugs and transformed prodrugs of all contemplated isotopologues, stereoisomers, racemates or tautomers of the instant compounds.

[1952] The term “isotopologue” refers to isotopically-enriched compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as H.sup.2, H.sup.3, C.sup.3, C.sup.14, N.sup.15, O.sup.18, O.sup.17, P.sup.31, P.sup.32, S.sup.35, F.sup.18, Cl.sup.35 and Cl.sup.36, respectively, each of which is also within the scope of this description.

[1953] Certain isotopically-enriched compounds described herein (e.g., those labeled with H.sup.3 and C.sup.4) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., H.sup.3) and carbon-14 (i.e., C.sup.14) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., “deuterium enriched”) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically-enriched compounds of Formula (I) can generally be prepared using procedures known to persons of ordinary skill in the art by substituting an appropriate isotopically-enriched reagent for a non-isotopically-enriched reagent.

[1954] When the compounds are enriched with deuterium, the deuterium-to-hydrogen ratio on the deuterated atoms of the molecule substantially exceeds the naturally occurring deuterium-to-hydrogen ratio.

[1955] An embodiment described herein may include an isotopologue form of the compound of Formula (T), wherein the isotopologue is substituted on one or more atom members of the compound of Formula (I) with one or more deuterium atoms in place of one or more hydrogen atoms.

[1956] An embodiment described herein may include a compound of Formula (I) and forms thereof, wherein a carbon atom may have from 1 to 3 hydrogen atoms optionally replaced with deuterium.

[1957] One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to embrace both solvated and unsolvated forms.

[1958] As used herein, the term “solvate” means a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, “solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

[1959] One or more compounds described herein may optionally be converted to a solvate. Preparation of solvates is generally known. A typical, non-limiting process involves dissolving a compound in a desired amount of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

[1960] As used herein, the term “hydrate” means a solvate wherein the solvent molecule is water.

[1961] Polymorphic crystalline and amorphous forms of the compounds of Formula (I), and of the salts, solvates, esters and prodrugs of the compounds of Formula (I), are further intended to be included in the scope of the compounds described herein

Methods for Determining which Genes May be Modulated by the Compounds

[1962] In another aspect, provided herein are methods for determining whether the splicing of the precursor RNA of a gene is likely to be modulated by a compound of Formula (I) or a form thereof, comprising searching for the presence of an intronic REMS (i.e., a sequence functioning as a 5′ splice site) in a gene intronic sequence, wherein the presence of the intronic REMS 3′ splice site and an intronic branch point in the gene sequence indicates that the splicing of the precursor RNA of the gene is likely to be modulated by the compound of Formula (I) or a form thereof, and the absence of the intronic REMS and an intronic 3′ splice site and an intronic branch point in the gene sequence indicates that the splicing of the precursor RNA of the gene is unlikely to be modulated by the compound of Formula (I) or a form thereof. In certain embodiments, a compound of Formula (I) is a compound of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) described herein. In specific embodiments, the methods further comprise searching for the presence of the combination of an intronic REMS, an intronic 3′ splice site and an intronic branch point in the gene sequence.

[1963] In another aspect, provided herein are methods for determining whether the amount of a product (e.g., an mRNA transcript or protein) of a gene is likely to be modulated by a compound of Formula (I) or a form thereof, comprising searching for the presence of an intronic REMS in the gene sequence, wherein the presence of the combination of an intronic REMS, an intronic 3′ splice site and an intronic branch point in the gene sequence indicates that the amount of a product (e.g., an mRNA transcript or protein) of the gene is likely to be modulated by the compound of Formula (I) or a form thereof, and the absence of the combination of an intronic REMS, an intronic 3′ splice site and an intronic branch point in the gene sequence indicates that the amount of a product (e.g., an mRNA transcript or protein) of the gene is unlikely to be modulated by the compound of Formula (I) or a form thereof. In certain embodiments, a compound of Formula (I) is a compound of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) described herein. In specific embodiments, the methods further comprise searching for the presence of any of an intronic REMS, an intronic 3′ splice site, and an intronic branch point in the gene sequence.

[1964] The step of searching for the presence of an intronic REMS, an intronic 3′ splice site, and an intronic branch point in the gene sequence described herein can be performed by a computer system comprising a memory storing instructions for searching for the presence of the intronic REMS, the intronic 3′ splice site, and the intronic branch point in the gene sequence, or such a search can be performed manually.

[1965] In another aspect, provided herein are methods for determining whether the splicing of the precursor RNA of a gene is likely to be modulated via iExon inclusion by a compound of Formula (I) or a form thereof. In one particular aspect, the method comprises searching for the presence of an intronic REMS (i.e., a sequence functioning as a 5′ splice site) in combination with, in order, an upstream branch point and an upstream 3′ splice site in a gene intronic sequence. The presence of these elements with the intronic REMS and the endogenous presence of a downstream 3′ splice site and a downstream branch point in the gene sequence indicates that the splicing of the precursor RNA of the gene is likely to be modulated by the compound of Formula (I) or a form thereof. In this aspect, the presence of an upstream branch point and upstream 3′ splice site and the REMS in the intron enable the presence of the compound of Formula (I) or a form thereof to modulate iExon inclusion, i.e., splicing the iExon with the downstream endogenous exon (as shown in FIG. 1A). Otherwise, in the absence of these elements, the iREMS will be either ignored by the spliceosome or, in a limited set of circumstances, will become an extended/cryptic 5′ splice site for the upstream endogenous exon (as shown in FIGS. 1B and 1C). The absence of the intronic REMS in the gene sequence indicates that the splicing of the precursor RNA of the gene is unlikely to be modulated via iExon inclusion by the compound of Formula (I) or a form thereof. In certain embodiments, a compound of Formula (I) is a compound of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) described herein. In other specific embodiments, the methods further comprise searching for the presence of the combination of, in 5′ to 3′ order: an upstream branch point, an upstream 3′ splice site, an intronic REMS, a downstream branch point and a downstream 3′ splice site in the gene sequence.

[1966] In another aspect, provided herein are methods for determining whether the amount of a product (e.g., an mRNA transcript or protein) of a gene is likely to be modulated via iExon inclusion by a compound of Formula (T) or a form thereof, comprising searching for the presence of an intronic REMS in the gene sequence, wherein the presence of the combination of at least an upstream branch point, an upstream 3′ splice site and an intronic REMS in the gene sequence indicates that the amount of a product (e.g., an mRNA transcript or protein) of the gene is likely to be modulated via iExon inclusion by the compound of Formula (I) or a form thereof, and the absence of the combination of an upstream branch point, an upstream 3′ splice site and an intronic REMS in the gene sequence indicates that the amount of a product (e.g., an mRNA transcript or protein) of the gene is unlikely to be modulated via iExon inclusion by the compound of Formula (I) or a form thereof. In certain embodiments, a compound of Formula (I) is a compound of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) described herein. In specific embodiments, the methods further comprise searching for the presence of any of, in 5′ to 3′ order: an upstream branch point, an upstream 3′ splice site, an intronic REMS, a downstream 3′ splice site, and a downstream branch point in the gene sequence.

[1967] The step of searching for the presence of an upstream branch point, an upstream 3′ splice site and an intronic REMS in any of the gene sequences in any of the genes described herein can be performed by a computer system comprising a memory storing instructions for searching for the presence of the intronic REMS, the upstream 3′ splice site, and the upstream branch point in the gene sequence, or such a search can be performed manually.

[1968] In certain embodiments, the splicing of a precursor RNA containing an intronic REMS is assessed by contacting a compound described herein with the precursor RNA in cell culture. In some embodiments, the splicing of a precursor RNA containing an intronic REMS is assessed by contacting a compound described herein with the precursor RNA in a cell-free extract. In a specific embodiment, the compound is one known to modulate the splicing of a precursor RNA containing an exonic REMS. See, e.g., the section below relating to methods for determining whether a compound modulates the expression of certain genes, and the example below for techniques that could be used in these assessments.

Methods for Determining which Compounds of Formula (I) Modulate the Expression of Certain Genes

[1969] Provided herein are methods for determining whether a compound of Formula (I) or a form thereof modulates the amount of one, two, three or more RNA transcripts (e.g., pre-mRNA or mRNA transcripts or isoforms thereof) of one, two, three or more genes. In some embodiments, the gene is any one of the genes disclosed in Tables 2-7 or any one of the genes disclosed in Table 1. In certain embodiments, the gene is a gene disclosed in Tables 2-6. In some embodiments, the gene is a gene disclosed in Table 7. In other embodiments, the gene is a gene disclosed in Table 1. In certain embodiments, the gene is a gene not disclosed in either International Publication No. WO 2015/105657, International Publication No. WO 2016/196386, or both.

[1970] In one embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript, comprising: (a) contacting a cell(s) with a compound of Formula (I) or a form thereof, and (b) determining the amount of the RNA transcript produced by the cell(s), wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first cell(s) with a compound of Formula (I) or a form thereof, (b) contacting a second cell(s) with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of the RNA transcript produced by the first cell(s) and the second cell(s); and (d) comparing the amount of the RNA transcript produced by the first cell(s) to the amount of the RNA transcript expressed by the second cell(s), wherein an alteration in the amount of the RNA transcript produced by the first cell(s) relative to the amount of the RNA transcript produced by the second cell(s) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In certain embodiments, the contacting of the cell(s) with the compound occurs in cell culture. In other embodiments, the contacting of the cell(s) with the compound occurs in a subject, such as a non-human animal subject.

[1971] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof; and (b) determining the amount of the two or more RNA transcript splice variants produced by the cell(s), wherein an alteration in the amount of the two or more RNA transcript in the presence of the compound relative to the amount of the two or more RNA transcript splice variants in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript.

[1972] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof; (b) isolating two or more RNA transcript splice variants from the cell(s) after a certain period of time; and (c) determining the amount of the two or more RNA transcript splice variants produced by the cell(s), wherein an alteration in the amount of the two or more RNA transcript in the presence of the compound relative to the amount of the two or more RNA transcript splice variants in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising (a) culturing a first cell(s) in the presence of a compound of Formula (I) or a form thereof; (b) culturing a second cell(s) in the presence of a negative control (e.g., a vehicle control, such as PBS or DMSO); (c) isolating two or more RNA transcript splice variants produced by the first cell(s) and isolating two or more RNA transcript splice variants produced by the second cell(s); (d) determining the amount of the two or more RNA transcript splice variants produced by the first cell(s) and the second cell(s); and (e) comparing the amount of the two or more RNA transcript splice variants produced by the first cell(s) to the amount of the two or more RNA transcript splice variants produced by the second cell(s), wherein an alteration in the amount of the two or more RNA transcript splice variants produced by the first cell(s) relative to the amount of the two or more RNA transcript splice variants produced by the second cell(s) indicates that the compound of Formula (I) or a form thereof modulates the aplicing of the RNA transcript.

[1973] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a cell-free system with a compound of Formula (I) or a form thereof, and (b) determining the amount of the RNA transcript produced by the cell-free system, wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first cell-free system with a compound of Formula (I) or a form thereof, (b) contacting a second cell-free system with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of the RNA transcript produced by the first cell-free system and the second cell-free system; and (d) comparing the amount of the RNA transcript produced by the first cell-free system to the amount of the RNA transcript expressed by the second cell-free system, wherein an alteration in the amount of the RNA transcript produced by the first cell-free system relative to the amount of the RNA transcript produced by the second cell-free system indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In certain embodiments, the cell-free system comprises purely synthetic RNA, synthetic or recombinant (purified) enzymes, and protein factors. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template, synthetic or recombinant (purified) enzymes, and protein factors. In other embodiments, the cell-free system comprises purely synthetic RNA and nuclear extract. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template and nuclear extract. In other embodiments, the cell-free system comprises purely synthetic RNA and whole cell extract. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template and whole cell extract. In certain embodiments, the cell-free system additionally comprises regulatory RNAs (e.g., microRNAs).

[1974] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a cell-free system with a compound of Formula (I) or a form thereof; and (b) determining the amount of two or more RNA transcript splice variants produced by the cell-free system, wherein an alteration in the amount of the two or more RNA transcript splice variants in the presence of the compound relative to the amount of the two or more RNA transcript splice variants in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first cell-free system with a compound of Formula (I) or a form thereof; (b) contacting a second cell-free system with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of two or more RNA transcript splice variants produced by the first cell-free system and the second cell-free system; and (d) comparing the amount of the two or more RNA transcript splice variants produced by the first cell-free system to the amount of the RNA transcript expressed by the second cell-free system, wherein an alteration in the amount of the two or more RNA transcript splice variants produced by the first cell-free system relative to the amount of the two or more RNA transcript splice variants produced by the second cell-free system indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript. In certain embodiments, the cell-free system comprises purely synthetic RNA, synthetic or recombinant (purified) enzymes, and protein factors. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template, synthetic or recombinant (purified) enzymes, and protein factors. In other embodiments, the cell-free system comprises purely synthetic RNA and nuclear extract. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template and nuclear extract. In other embodiments, the cell-free system comprises purely synthetic RNA and whole cell extract. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template and whole cell extract. In certain embodiments, the cell-free system additionally comprises regulatory RNAs (e.g., microRNAs).

[1975] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof, (b) isolating the RNA transcript from the cell(s) after a certain period of time; and (c) determining the amount of the RNA transcript produced by the cell(s), wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising (a) culturing a first cell(s) in the presence of a compound of Formula (I) or a form thereof, (b) culturing a second cell(s) in the presence of a negative control (e.g., a vehicle control, such as PBS or DMSO); (c) isolating the RNA transcript produced by the first cell(s) and isolating the RNA transcript produced by the second cell(s); (d) determining the amount of the RNA transcript produced by the first cell(s) and the second cell(s); and (e) comparing the amount of the RNA transcript produced by the first cell(s) to the amount of the RNA transcript produced by the second cell(s), wherein an alteration in the amount of the RNA transcript produced by the first cell(s) relative to the amount of the RNA transcript produced by the second cell(s) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript.

[1976] In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject. In some embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject with a disease. In specific embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject with a disease associated with an aberrant amount of an RNA transcript(s) for a particular gene(s). In some specific embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject with a disease associated with an aberrant amount of an isoform(s) of a particular gene(s). In some embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a fibroblast (e.g., GM03813 or PNN 1-46 fibroblasts), an immune cell (e.g., a T cell, B cell, natural killer cell, macrophage), or a muscle cell. In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell.

[1977] In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is from a cell line. In some embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cell line derived from a subject with a disease. In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is from a cell line known to have aberrant RNA transcript levels for a particular gene(s). In specific embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is from a cell line derived from a subject with a disease known to have aberrant RNA transcript levels for a particular gene(s). In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell line. In some specific embodiments, the cell(s) contacted or cultured with the compound of Formula (I) or a form thereof is from a cell line derived from a subject with a disease known to have an aberrant amount of an RNA isoform(s) and/or protein isoform(s) of a particular gene(s). Non-limiting examples of cell lines include 3T3, 4T1, 721, 9L, A2780, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1, BEAS-2B, bEnd.3, BHK, BR 293, BT2O, BT483, BxPC3, C2Cl2, C3H-10T1/2, C6/36, C6, Cal-27, CHO, COR-L23, COS, COV-434, CML T1, CMT, CRL7O3O, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299, H69, HB54, HB55, HCA2, HDF (human dermal fibroblasts), HEK-293, HeLa, Hepa1c1c7, HL-60, HMEC, Hs578T, HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22, KG1, KYO1, LNCap, Ma-Mel, MC-38, MCF-7, MCF-10A, MDA-MB-231, MDA-MB-468, MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69, NIH-3T3, NALM-1, NS0, NW-145, OPCN, OPCT, PNT-1A, PNT-2, Raji, RBL, RenCa, RIN-5F, RMA, Saos-2, Sf21, Sf9, SH-SY5Y, SiHa, SKBR3, SKOV-3, T2, T-47D, T84, THP1, U373, U87, U937, VCaP, Vero, VERY, W138, WM39, WT-49, X63, YAC-1, and YAR cells. In one embodiment, the cells are from a patient. In another embodiment, the patient cells are GM03813 cells.

[1978] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a tissue sample with a compound of Formula (I) or a form thereof; and (b) determining the amount of the RNA transcript produced by the tissue sample, wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first tissue sample with a compound of Formula (I) or a form thereof, (b) contacting a second tissue sample with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of the RNA transcript produced by the first tissue sample and the second tissue sample; and (d) comparing the amount of the RNA transcript produced by the first tissue sample to the amount of the RNA transcript produced by the second tissue sample, wherein an alteration in the amount of the RNA transcript produced by the first tissue sample relative to the amount of the RNA transcript produced by the second tissue sample indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. Any tissue sample containing cells may be used in the accordance with these methods. In certain embodiments, the tissue sample is a blood sample, a skin sample, a muscle sample, or a tumor sample. Techniques known to one skilled in the art may be used to obtain a tissue sample from a subject.

[1979] In some embodiments, a dose-response assay is performed. In one embodiment, the dose response assay comprises: (a) contacting a cell(s) with a concentration of a compound of Formula (I) or a form thereof; (b) determining the amount of the RNA transcript produced by the cell(s), wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript; (c) repeating steps (a) and (b), wherein the only experimental variable changed is the concentration of the compound or a form thereof; and (d) comparing the amount of the RNA transcript produced at the different concentrations of the compound or a form thereof. In another embodiment, the dose response assay comprises: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof, (b) isolating the RNA transcript from the cell(s) after a certain period of time; (c) determining the amount of the RNA transcript produced by the cell(s), wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript; (d) repeating steps (a), (b), and (c), wherein the only experimental variable changed is the concentration of the compound or a form thereof; and (e) comparing the amount of the RNA transcript produced at the different concentrations of the compound or a form thereof. In another embodiment, the dose-response assay comprises: (a) contacting each well of a microtiter plate containing cells with a different concentration of a compound of Formula (I) or a form thereof; (b) determining the amount of an RNA transcript produced by cells in each well; and (c) assessing the change of the amount of the RNA transcript at the different concentrations of the compound or form thereof.

[1980] In one embodiment, the dose response assay comprises: (a) contacting a cell(s) with a concentration of a compound of Formula (I) or a form thereof, wherein the cells are within the wells of a tissue culture container (e.g., a 96-well plate) at about the same density within each well, and wherein the cells are contacted with different concentrations of compound in different wells; (b) isolating the RNA from said cells in each well; (c) determining the amount of the RNA transcript produced by the cell(s) in each well; and (d) assessing change in the amount of the RNA transcript in the presence of one or more concentrations of compound relative to the amount of the RNA transcript in the presence of a different concentration of the compound or the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO).

[1981] In certain embodiments, the contacting of the cell(s) with the compound occurs in cell culture. In other embodiments, the contacting of the cell(s) with the compound occurs in a subject, such as a non-human animal subject.

[1982] In certain embodiments described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a compound of Formula (I) or a form thereof, or a negative control for a period of 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72 hours or more. In other embodiments described herein, the cell(s) is contacted or cultured with a compound of Formula (T) or a form thereof, or a tissue sample is contacted with a compound of Formula (I) or a form thereof, or a negative control for a period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12 hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24 to 48 hours, 48 to 72 hours.

[1983] In certain embodiments described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 0.0001 μM, 0.0003 μM, 0.001 μM, 0.003 μM, 0.01 μM, 0.05 μM, 1 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 50 μM, 75 μM, 100 μM, or 150 μM. In other embodiments described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 0.0001 μM, 0.0003 μM, 0.0005 μM, 0.001 μM, 0.003 μM, 0.005 μM, 0.01 μM, 0.03 μM, 0.05 μM, 0.1 μM, 0.3 μM, 0.5 μM or 1 μM. In other embodiments described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 175 μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 μM, 450 μM, 500 μM, 550 μM 600 μM, 650 μM, 700 μM, 750 μM, 800 μM, 850 μM, 900 μM, 950 μM or 1 mM. In some embodiments described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, or 950 nM. In certain embodiments described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is between 0.0001 μM to 0.001 μM, 0.0001 μM to 0.01 μM, 0.0003 μM to 0.001 μM, 0.0003 μM to 0.01 μM, 0.001 μM to 0.01 μM, 0.003 μM to 0.01 μM, 0.01 μM to 0.1 μM, 0.1 μM to 1 μM, 1 μM to 50 μM, 50 μM to 100 μM, 100 μM to 500 μM, 500 μM to 1 nM, 1 nM to 10 nM, 10 nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM.

[1984] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a subject (in certain embodiments, a non-human animal); and (b) determining the amount of the RNA transcript in a sample obtained from the subject, wherein an alteration in the amount of the RNA transcript measured in the sample from the subject administered the compound or form thereof relative to the amount of the RNA transcript in a sample from the subject prior to administration of the compound or form thereof or a sample from a different subject from the same species not administered the compound or form thereof indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a first subject (in certain embodiments, a non-human animal); (b) administering a negative control (e.g., a pharmaceutical carrier) to a second subject (in certain embodiments, a non-human animal) of the same species as the first subject; and (c) determining the amount of the RNA transcript in a first tissue sample from the first subject and the amount of the RNA transcript in the second tissue sample from the second subject; and (d) comparing the amount of the RNA transcript in the first tissue sample to the amount of the RNA transcript in the second tissue sample, wherein an alteration in the amount of the RNA transcript in the first tissue sample relative to the amount of the RNA transcript in the second tissue sample indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In certain embodiments, a compound of Formula (I) or form thereof is administered to a subject at a dose of about 0.001 mg/kg/day to about 500 mg/kg/day. In some embodiments, a single dose of a compound of Formula (I) or a form thereof is administered to a subject in accordance with the methods described herein. In other embodiments, 2, 3, 4, 5 or more doses of a compound of Formula (I) is administered to a subject in accordance with the methods described herein. In specific embodiments, the compound of Formula (I) or a form thereof is administered in a subject in a pharmaceutically acceptable carrier, excipient or diluent.

[1985] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a subject (in certain embodiments, a non-human animal); and (b) determining the amount of two or more RNA transcript splice variants in a sample obtained from the subject, wherein an alteration in the amount of the two or more RNA transcript splice variants measured in the sample from the subject administered the compound or form thereof relative to the amount of the two or more RNA transcript splice variants in a sample from the subject prior to administration of the compound or form thereof or a sample from a different subject from the same species not administered the compound or form thereof indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a first subject (in certain embodiments, a non-human animal); (b) administering a negative control (e.g., a pharmaceutical carrier) to a second subject (in certain embodiments, a non-human animal) of the same species as the first subject; and (c) determining the amount of two or more RNA transcript splice variants in a first tissue sample from the first subject and the amount of two or more RNA transcript splice variants in the second tissue sample from the second subject; and (d) comparing the amount of the two or more RNA transcript splice variants in the first tissue sample to the amount of the two or more RNA transcript splice variants in the second tissue sample, wherein an alteration in the amount of the two or more RNA transcript splice variants in the first tissue sample relative to the amount of the two or more RNA transcript splice variants in the second tissue sample indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript. In certain embodiments, a compound of Formula (I) or form thereof is administered to a subject at a dose of about 0.001 mg/kg/day to about 500 mg/kg/day. In some embodiments, a single dose of a compound of Formula (I) or a form thereof is administered to a subject in accordance with the methods described herein. In other embodiments, 2, 3, 4, 5 or more doses of a compound of Formula (I) is administered to a subject in accordance with the methods described herein. In specific embodiments, the compound of Formula (I) or a form thereof is administered in a subject in a pharmaceutically acceptable carrier, excipient or diluent.

[1986] In some embodiments, the compound of Formula (I) or a form thereof that is contacted or cultured with a cell(s) or a tissue sample, or administered to a subject is a compound of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV). In some embodiments, the compound of Formula (I) or a form thereof that is contacted or cultured with a cell(s) or a tissue sample, or administered to a subject is a compound described herein.

[1987] Techniques known to one skilled in the art may be used to determine the amount of an RNA transcript(s). In some embodiments, the amount of one, two, three or more RNA transcripts is measured using deep sequencing, such as ILLUMINA® RNASeq, ILLUMINA® next generation sequencing (NGS), ION TORRENT™ RNA next generation sequencing, 454™ pyrosequencing, or Sequencing by Oligo Ligation Detection (SOLID™). In other embodiments, the amount of multiple RNA transcripts is measured using an exon array, such as the GENECHIP® human exon array. In certain embodiments, the amount of one, two, three or more RNA transcripts is determined by RT-PCR. In other embodiments, the amount of one, two, three or more RNA transcripts is measured by RT-qPCR or digital color-coded barcode technology. Techniques for conducting these assays are known to one skilled in the art.

[1988] In some embodiments, analysis is performed on data derived from the assay to measure the magnitude of splicing to determine the amount of exons spliced into an mRNA transcript that is produced in the presence of the compound relative to the amount in the absence of the compound or presence of a negative control. In a preferred embodiment, the method utilized is calculation of change in Percent Spliced In (APSI). The method utilizes read data from RNAseq (or any other method that can distinguish mRNA splice isoforms) to calculate the ratio (percentage) between reads that either demonstrate inclusion (junctions between the upstream exon and the exon of interest) or exclusion (junction between the upstream and downstream exons, excluding the exon of interest), to demonstrate whether the presence of the compound affects the amount of exon inclusion relative to the amount of inclusion in the absence of the compound or the presence of a negative control.

[1989] The APSI value is derived from the formula:

ΔPSI (%)={(a+b)/2/[(a+b)/2+c]}.sup.C−{(a+b)/2/[(a+b)/2+c]}.sup.U×100

[1990] Where “U” represents the value for probability of iExon inclusion (a+b)/2/[(a+b)/2+c].sup.U in the absence of the compound; and, where “C” represents the value for probability of iExon inclusion (a+b)/2/[(a+b)/2+c].sup.C in the presence of the compound. The values for “a” and “b” represent the number of reads supporting inclusion of an iExon in an RNA transcript. In other words, the “a” value is derived from the amount of reads for a first intronic nucleotide sequence comprising, in 5′ to 3′ order: a first exon having a 5′ splice site operably linked and upstream from a first intronic nucleotide sequence comprising a first branch point further operably linked and upstream from a first intronic 3′ splice site (upstream of the nascent iExon). The “b” value is derived from the amount of reads for a second intronic nucleotide sequence comprising, in 5′ to 3′ order: an iREMS sequence operably linked downstream from the first intronic 3′ splice site and upstream from a second intronic nucleotide sequence comprising a second branch point further operably linked and upstream from a second intronic 3′ splice site of a second exon. The value for “c” represents the number of reads supporting exclusion of an iExon. Accordingly, when a compound enables the splicing machinery to recognize a nascent iExon, the value for (a+b)/2/[(a+b)/2+c].sup.C in the presence of the splicing modifier compound will differ from the value for (a+b)/2/[(a+b)/2+c].sup.U in the absence of the compound. The statistically significant value for the likelihood of iExon inclusion may be obtained according to statistical analysis methods or other probability analysis methods known to those of ordinary skill in the art.

[1991] In some embodiments, a statistical analysis or other probability analysis is performed on data from the assay utilized to measure an RNA transcript. In certain embodiments, for example, a Fisher's Exact Test statistical analysis is performed by comparing the total number of reads for the inclusion and exclusion of an iExon (or region) based on data from one or more assays used to measure whether the amount of an RNA transcript is altered in the presence of the compound relative to the amount in the absence of the compound or presence of a negative control. In specific embodiments, the statistical analysis results in a confidence value for those RNA transcripts with the alternation of 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001%. In some specific embodiments, the confidence value is a p value of those altered RNA transcripts of is 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001%. In certain specific embodiments, an exact test, student t-test or p value of those RNA transcripts with the alteration is 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% and 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001%, respectively.

[1992] In certain embodiments, a further analysis is performed to determine how the compound of Formula (I) or a form thereof is changing the amount of an RNA transcript(s). In specific embodiments, a further analysis is performed to determine if an alternation in the amount of an RNA transcript(s) in the presence of a compound of Formula (I) or a form thereof relative the amount of the RNA transcript(s) in the absence of the compound or a form thereof, or the presence of a negative control is due to changes in transcription, splicing, and/or stability of the RNA transcript(s). Techniques known to one skilled in the art may be used to determine whether a compound of Formula (I) or a form thereof changes, e.g., the transcription, splicing and/or stability of an RNA transcript(s).

[1993] In certain embodiments, the stability of one or more RNA transcripts is determined by serial analysis of gene expression (SAGE), differential display analysis (DD), RNA arbitrary primer (RAP)-PCR, restriction endonuclease-lytic analysis of differentially expressed sequences (READS), amplified restriction fragment-length polymorphism (ALFP), total gene expression analysis (TOGA), RT-PCR, RT-qPCR, RNA-Seq, digital color-coded barcode technology, high-density cDNA filter hybridization analysis (HDFCA), suppression subtractive hybridization (SSH), differential screening (DS), cDNA arrays, oligonucleotide chips, or tissue microarrays. In other embodiments, the stability of one or more RNA transcripts is determined by Northern blot, RNase protection, or slot blot.

[1994] In some embodiments, the transcription in a cell(s) or tissue sample is inhibited before (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours before) or after (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours after) the cell or the tissue sample is contacted or cultured with an inhibitor of transcription, such as α-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D. In other embodiments, the transcription in a cell(s) or tissue sample is inhibited with an inhibitor of transcription, such as α-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D, while the cell(s) or tissue sample is contacted or cultured with a compound of Formula (I) or a form thereof.

[1995] In certain embodiments, the level of transcription of one or more RNA transcripts is determined by nuclear run-on assay or an in vitro transcription initiation and elongation assay. In some embodiments, the detection of transcription is based on measuring radioactivity or fluorescence. In some embodiments, a PCR-based amplification step is used. In specific embodiments, the amount of alternatively spliced forms of the RNA transcripts of a particular gene are measured to see if there is an alteration in the amount of one, two or more alternatively spliced forms of the RNA transcripts of the gene. In some embodiments, the amount of an isoform(s) encoded by a particular gene is measured to see if there is an alteration in the amount of the isoform(s). In certain embodiments, the levels of spliced forms of RNA are quantified by RT-PCR, RT-qPCR, RNA-Seq, digital color-coded barcode technology, or Northern blot. In other embodiments, sequence-specific techniques may be used to detect the levels of an individual splice form. In certain embodiments, splicing is measured in vitro using nuclear extracts. In some embodiments, detection is based on measuring radioactivity or fluorescence. Techniques known to one skilled in the art may be used to measure alterations in the amount of alternatively spliced forms of an RNA transcript of a gene and alterations in the amount of an isoform encoded by a gene. In a specific embodiment, modulation of RNA transcripts is assessed as described in the Examples described herein.

[1996] Also provided herein are methods of screening for new compounds that can be used to modulate the amount of a product (e.g., a precursor RNA, an mRNA, or protein) of a gene comprising an intronic REMS in its DNA or RNA sequence. The methods described above in this section with respect to determining whether the amount of a product (e.g., a precursor RNA, an mRNA, or protein) of a gene is likely to be modulated by a compound of Formula (I) or a form thereof can be also used in the methods of screening for new compounds. In a specific embodiment, the method comprises contacting a candidate compound with an RNA transcript, wherein the RNA transcript comprises exons and one or more introns, wherein at least one intron comprises, in 5′ to 3′ order, a branch point, a 3′ splice site, and an intronic REMS. In another specific embodiment, the method comprises contacting a candidate compound with an RNA transcript, wherein the RNA transcript comprises exons and one or more introns, wherein at least one intron comprises an intronic REMS downstream of a branch point and a 3′ splice site. The RNA transcript may be present in a cell or cell lysate. The methods described above regarding the techniques of contacting a compound with an RNA transcript, the dosage, etc., may be used in the methods of screening. The candidate compounds to be screened can be provided by any source. For example, the candidate compounds to be screened can be from a compound library, such as a commercial compound library.

Pharmaceutical Compositions and Modes of Administration

[1997] When administered to a patient, a compound of Formula (I) or a form thereof is preferably administered as a component of a composition that optionally comprises a pharmaceutically acceptable carrier, excipient or diluent. The composition can be administered orally, or by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa) and may be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, and can be used to administer the compound.

[1998] Methods of administration include, but are not limited to, parenteral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intraocular, intratumoral, intracerebral, intravaginal, transdermal, ocularly, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of a compound into the bloodstream, tissue or cell(s). In a specific embodiment, a compound is administered orally.

[1999] The amount of a compound of Formula (I) or a form thereof that will be effective in the treatment of a disease resulting from an aberrant amount of mRNA transcripts depends, e.g., on the route of administration, the disease being treated, the general health of the subject, ethnicity, age, weight, and gender of the subject, diet, time, and the severity of disease progress, and should be decided according to the judgment of the practitioner and each patient's or subject's circumstances.

[2000] In specific embodiments, an “effective amount” in the context of the administration of a compound of Formula (I) or a form thereof, or composition or medicament thereof refers to an amount of a compound of Formula (I) or a form thereof to a patient which has a therapeutic effect and/or beneficial effect. In certain specific embodiments, an “effective amount” in the context of the administration of a compound of Formula (I) or a form thereof, or composition or medicament thereof to a patient results in one, two or more of the following effects: (i) reduces or ameliorates the severity of a disease; (ii) delays onset of a disease; (iii) inhibits the progression of a disease; (iv) reduces hospitalization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the quality of life of a subject; (viii) reduces the number of symptoms associated with a disease; (ix) reduces or ameliorates the severity of a symptom(s) associated with a disease; (x) reduces the duration of a symptom associated with a disease associated; (xi) prevents the recurrence of a symptom associated with a disease; (xii) inhibits the development or onset of a symptom of a disease; and/or (xiii) inhibits of the progression of a symptom associated with a disease. In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to restore the amount of a RNA transcript of a gene to the amount of the RNA transcript detectable in healthy patients or cells from healthy patients. In other embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to restore the amount an RNA isoform and/or protein isoform of gene to the amount of the RNA isoform and/or protein isoform detectable in healthy patients or cells from healthy patients.

[2001] In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to decrease the aberrant amount of an RNA transcript of a gene which associated with a disease. In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to decrease the amount of the aberrant expression of an isoform of a gene. In some embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to result in a substantial change in the amount of an RNA transcript (e.g., mRNA transcript), alternative splice variant or isoform.

[2002] In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to increase or decrease the amount of an RNA transcript (e.g., an mRNA transcript) of gene which is beneficial for the prevention and/or treatment of a disease. In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to increase or decrease the amount of an alternative splice variant of an RNA transcript of gene which is beneficial for the prevention and/or treatment of a disease. In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to increase or decrease the amount of an isoform of gene which is beneficial for the prevention and/or treatment of a disease. Non-limiting examples of effective amounts of a compound of Formula (I) or a form thereof are described herein.

[2003] For example, the effective amount may be the amount required to prevent and/or treat a disease associated with the aberrant amount of an mRNA transcript of gene in a human subject.

[2004] In general, the effective amount will be in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day for a patient having a weight in a range of between about 1 kg to about 200 kg. The typical adult subject is expected to have a median weight in a range of between about 70 and about 100 kg.

[2005] Within the scope of the present description, the “effective amount” of a compound of Formula (I) or a form thereof for use in the manufacture of a medicament, the preparation of a pharmaceutical kit or in a method for preventing and/or treating a disease in a human subject in need thereof, is intended to include an amount in a range of from about 0.001 mg to about 35,000 mg.

[2006] The compositions described herein are formulated for administration to the subject via any drug delivery route known in the art. Non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.

[2007] Embodiments described herein include the use of a compound of Formula (I) or a form thereof in a pharmaceutical composition. In a specific embodiment, described herein is the use of a compound of Formula (I) or a form thereof in a pharmaceutical composition for preventing and/or treating a disease in a human subject in need thereof comprising administering an effective amount of a compound of Formula (I) or a form thereof in admixture with a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the human subject is a patient with a disease associated with the aberrant amount of an mRNA transcript(s).

[2008] A compound of Formula (I) or a form thereof may optionally be in the form of a composition comprising the compound or a form thereof and an optional carrier, excipient or diluent. Other embodiments provided herein include pharmaceutical compositions comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent. In a specific embodiment, the pharmaceutical compositions are suitable for veterinary and/or human administration. The pharmaceutical compositions provided herein can be in any form that allows for the composition to be administered to a subject.

[2009] In a specific embodiment and in this context, the term “pharmaceutically acceptable carrier, excipient or diluent” means a carrier, excipient or diluent approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a specific carrier for intravenously administered pharmaceutical compositions. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.

[2010] Typical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and non limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient and the specific active ingredients in the dosage form. Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising one or more compounds of Formula (I) or a form thereof as described herein. The compositions and single unit dosage forms can take the form of solutions or syrups (optionally with a flavoring agent), suspensions (optionally with a flavoring agent), emulsions, tablets (e.g., chewable tablets), pills, capsules, granules, powder (optionally for reconstitution), taste-masked or sustained-release formulations and the like.

[2011] Pharmaceutical compositions provided herein that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets, caplets, capsules, granules, powder, and liquids. Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art.

[2012] Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.

Methods of Modulating the Amount of RNA Transcripts Encoded by Certain Genes

[2013] In one 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 utilize a compound described herein. In certain embodiments, the gene contains a nucleotide sequence encoding an endogenous intronic REMS. In a specific embodiment, the precursor RNA transcript further contains a branch point and a 3′ splice site upstream from the intronic REMS. In certain embodiments, the gene is any one of the genes disclosed in Tables 2-7 or 1. In certain embodiments, the gene contains a nucleotide sequence encoding a non-endogenous intronic REMS. In one embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, by way of nonlimiting example, disclosed in Tables 2-7 or 1, infra, the method comprising contacting a cell with a compound of Formula (I) or a form thereof.

[2014] In another embodiment, provided herein is a method for modulating the amount of a product of a gene (such as an RNA transcript or a protein), wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first 5′ splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, an iREMS, a nucleotide sequence encoding a second branch point and a nucleotide sequence encoding a second 3′ splice site, wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), and wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting a cell with a compound described herein (for example, a compound of Formula (I) or a form thereof).

[2015] In another embodiment, provided herein is a method for modulating the amount of a product of a gene (such as an RNA transcript or protein), wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence of the intron comprises in 5′ to 3′ order: an iREMS, a nucleotide sequence encoding a first branch point and a nucleotide sequence encoding a first 3′ splice site, wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), and wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting a cell with a compound described herein (for example, a compound of Formula (I) or a form thereof).

[2016] In another embodiment, provided herein is a method for modulating the amount of a product of a gene (such as an RNA transcript or protein), wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1A, the method comprising contacting a cell with a compound described herein.

[2017] In another embodiment, provided herein is a method for modulating the amount of a product of a gene (such as an RNA transcript or protein), wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1B, the method comprising contacting a cell with a compound described herein.

[2018] In another embodiment, provided herein is a method for modulating the amount of a product of a gene (such as an RNA transcript or protein), wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1C, the method comprising contacting a cell with a compound described herein.

[2019] In a specific embodiment, the gene is a gene described in a table in this disclosure.

[2020] In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in Tables 2-7, infra, wherein the precursor transcript transcribed from the gene comprises an intronic REMS, the method comprising contacting a cell with a compound of Formula (I) or a form thereof.

[2021] In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in International Patent Application No. PCT/US2014/071252 (International Publication No. WO 2015/105657), wherein the precursor transcript transcribed from the gene comprises an intronic REMS, the method comprising contacting a cell with a compound of Formula (I) or a form thereof. In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in International Patent Application No. PCT/US2016/034864 (International Publication No. WO 2016/196386), wherein the precursor transcript transcribed from the gene comprises an intronic REMS, the method comprising contacting a cell with a compound of Formula (I) or a form thereof. In a specific embodiment, the precursor RNA transcript further contains a branch point and a 3′ splice site upstream from the intronic REMS.

[2022] In certain embodiments, the gene is a gene not disclosed in either International Publication No. WO 2015/105657, International Publication No. WO 2016/196386, or both.

[2023] In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in Table 1, infra, wherein the precursor transcript transcribed from the gene comprises an intronic REMS, the method comprising contacting a cell with a compound of Formula (I) or a form thereof. In a specific embodiment, the precursor RNA transcript further contains a branch point and a 3′ splice site upstream from the intronic REMS.

[2024] In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in Table 7, infra, comprising contacting a cell with a compound of Formula (I) or a form thereof. See the example section for additional information regarding the genes in Table 7. In certain embodiments, the cell is contacted with the compound of Formula (I) or a form thereof in a cell culture. In other embodiments, the cell is contacted with the compound of Formula (I) or a form thereof in a subject (e.g., a non-human animal subject or a human subject). In a specific embodiment, the RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2025] In one aspect, provided herein is a method for producing a mature mRNA transcript comprising iExon from a pre-mRNA transcript, 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 or 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. In one embodiment, provided herein is a method for producing a mature mRNA transcript comprising an iExon, the method comprising contacting a pre-mRNA transcript with a compound described herein (e.g., 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 or 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. In another embodiment, provided herein is a method for producing a mature mRNA transcript comprising an iExon, the method comprising contacting a cell or cell lysate containing a pre-mRNA transcript with a compound described herein (e.g., 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 or 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. In some embodiments, the pre-mRNA transcript is encoded by a gene disclosed herein (e.g., in a table herein).

[2026] In a particular embodiment, provided herein is a method for producing a mature mRNA transcript comprising an iExon, the method comprising contacting a pre-mRNA transcript with a compound described herein (e.g., 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, DTAPH3, 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, SARIA, 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. In another particular embodiment, provided herein is a method for producing a mature mRNA transcript comprising an iExon, the method comprising contacting a cell or cell lysate containing a pre-mRNA transcript with a compound described herein (e.g., 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, ERLTN2, ERRFT1, 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.

[2027] In another aspect, provided herein is a method modulating the amount of a mature mRNA transcript produced by a pre-mRNA transcript, 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 or 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. In one embodiment, provided herein is 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 described herein (e.g., 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 or 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. In another embodiment, provided herein is a method for modulating the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting a cell or cell lysate containing the pre-mRNA transcript with a compound described herein (e.g., 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 or 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. In some embodiments, the intron further comprises a first 5′ splice site, a second branch point, and a second 3′ splice site upstream of the iREMS. In some embodiments, the pre-mRNA transcript is encoded by a gene disclosed herein (e.g., in a table herein).

[2028] In a particular embodiment, provided herein is 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 described herein (e.g., 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, IGFBP3, IL16, INA, INPP5K, INTU, IQCG, ITGA11, ITGA8, ITGB8, ITIH1, ITPKA, IVD, KAT6B, KCNS1, KCNS2, KDM6A, KDSR, KIAA1456, K1AA1462, K1AA1755, KIT, KLF17, KLRG1, KMT2D, KRT7, KRTAP1-1, KRTAP1-5, L3MBTL2, LAMB2P1, LETM2, LGI2, LGR4, LHX9, LINC00472, LINC00570, LINC00578, LINC00607, LINC00678, LINC00702, LINC00886, LTNC00961, 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. In a particular embodiment, provided herein is a method for modulating the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting a cell or cell lysate containing the pre-mRNA transcript with a compound described herein (e.g., 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, IGFBP3, IL16, INA, INPP5K, INTU, IQCG, ITGA11, ITGA8, ITGB8, ITIH1, ITPKA, IVD, 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. In some embodiments, the intron further comprises a first 5′ splice site, a second branch point, and a second 3′ splice site upstream of the iREMS.

[2029] In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is primary cell(s) or cell(s) from a cell line. In some embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a fibroblast(s), an immune cell(s), or a muscle cell(s). In some embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell. Non-limiting examples of cell lines include 3T3, 4T1, 721, 9L, A2780, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1, BEAS-2B, bEnd.3, BHK, BR 293, BT20, BT483, BxPC3, C2C12, C3H-10T1/2, C6/36, C6, Cal-27, CHO, COR-L23, COS, COV-434, CML T1, CMT, CRL7030, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299, H69, HB54, HB55, HCA2, HDF, HEK-293, HeLa, Hepa1c1c7, HL-60, HMEC, Hs578T, HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22, KG1, KYO1, LNCap, Ma-Mel, MC-38, MCF-7, MCF-1OA, MDA-MB-231, MDA-MB-468, MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69, NIH-3T3, NALM-1, NS0, NW-145, OPCN, OPCT, PNT-1A, PNT-2, Raji, RBL, RenCa, RIN-5F, RMA, Saos-2, Sf21, Sf9, SH-SY5Y, SiHa, SKBR3, SKOV-3, T2, T-47D, T84, THP1, U373, U87, U937, VCaP, Vero, VERY, W138, WM39, WT-49, X63, YAC-1, and YAR cells. In one embodiment, the cells are from a patient. In another embodiment, the patient cells are GM03813 cells.

[2030] In certain embodiments described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof with a compound of Formula (I) or a form thereof for a period of 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72 hours or more. In other embodiments described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof with a compound of Formula (I) or a form thereof for a period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12 hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24 to 48 hours, 48 to 72 hours.

[2031] In certain embodiments described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 0.01 μM, 0.05 μM, 1 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 50 μM, 75 μM, 100 μM, or 150 μM. In other embodiments described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 175 μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 μM, 450 μM, 500 μM, 550 μM 600 μM, 650 μM, 700 μM, 750 μM, 800 μM, 850 μM, 900 μM, 950 μM or 1 mM. In some embodiments described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, or 950 nM. In certain embodiments described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is between 0.01 μM to 0.1 μM, 0.1 μM to 1 μM, 1 μM to 50 μM, 50 μM to 100 μM, 100 μM to 500 μM, 500 μM to 1 nM, 1 nM to 10 nM, 10 nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM. In certain embodiments described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof that results in a substantial change in the amount of an RNA transcript (e.g., an mRNA transcript), an alternatively spliced variant, or an isoform of a gene (e.g., a gene in Table 1, infra).

[2032] In another aspect, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the precursor RNA transcript further contains a branch point and a 3′ splice site upstream from the intronic REMS.

[2033] In one embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, by way of nonlimiting example, disclosed in Table 1, infra, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2034] In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in Tables 2-7, infra, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene in a subject, disclosed in International Patent Application No. PCT/US2014/071252 (International Publication No. WO 2015/105657), wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to the subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene in a subject, disclosed in International Patent Application No. PCT/US2016/034864 (International Publication No. WO 2016/196386), wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to the subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2035] In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in International Patent Application No. PCT/US2014/071252 (International Publication No. WO 2015/105657), wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in International Patent Application No. PCT/US2016/034864 (International Publication No. WO 2016/196386), wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2036] In a particular aspect, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene in a subject, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS (for example, an endogenous intronic REMS or a non-endogenous intronic REMS), the methods comprising administering to the subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the precursor RNA transcript contains in 5′ to 3′ order a branch point, a 3′ splice site and an intronic REMS. In specific embodiments of the foregoing aspects, as listed in Table 1, the gene is ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM12, ADAM15, ADAM17, ADAM33, ADAMTS1, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APLP2, APP, APPL2, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARMCX3, ARMCX6, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF71P, ATG5, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, AXIN1, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3-IT1, BIRC3, BIRC6, BNC1, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1orf86, C10orf54, C11orf30, C11orf70, C11orf73, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CADM1, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDK11B, CDK16, CDKAL1, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP170, CEP192, CEP68, CFH, CFLAR, CHD8, CHEK1, CIITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND5A, DEPTOR, DFNB59, DGCR2, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DLGAP4, DNAH8, DNAJC13, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEF1A1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELN, ELP4, EMX2OS, ENAH, ENG, ENPP1, ENPP2, ENSA, EP300, EPN1, EPT1, ERC1, ERCC1, ERCC8, ERGIC3, ERLIN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM198B, FAM20A, FAM219A, FAM219B, FAM3C, FAM46B, FAM65A, FAM65B, FAP, FARP1, FBLN2, FBN2, FBXO9, FBXL6, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GCFC2, GCNT1, GDF6, GGACT, GGCT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HOOK3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSD17B4, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IL16, IL6ST, INA, INHBA, INPP5K, INSIG1, INTU, IQCE, IQCG, ITGA11, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIF14, KIF2A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LARP7, LATS2, LDLR, LEMD3, LETM2, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, L1NC00578, LINC00607, L1NC00657, L1NC00678, LINC00702, L1NC00886, LINC00961, LINC01011, LINC01118, LINC01204, LMAN2L, LMO7, LMOD1, LOC400927, LONP1, LOX, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC32, LRRC39, LRRC42, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MADD, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MAP4K4, MAPK13, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYCBP2, MYLK, MYO1D, MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NELFA, NEO1, NEURLIB, NF2, NFE2L1, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PBLD, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PEAR1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPHLN1, PPIP5K1, PPIP5K2, PPM1E, PPP1R12A, PPP1R26, PPP3CA, PPP6R1, PPP6R2, PRKACB, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB23, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAPlA, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASSF8, RBBP8, RBCK1, RBFOX2, RBKS, RBM10, RCC1, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF38, RNFT1, ROR1, ROR2, RPA1, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A1, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SGK3, SGOL2, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SLC12A2, SLC24A3, SLC25A17, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMN2, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SOCS2, SON, SORBS2, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRGAP1, SRRM1, SRSF3, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRIP1, STRN3, STRN4, STS, STX16, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBL2, TCF12, TCF4, TCF7L2, TENC1, TENM2, TEP1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFB1, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJP2, TLE3, TLK1, TMC3, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNRC6A, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2G2, UBE2V1, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC5B, URGCP, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR91, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF431, ZNF583, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF74, ZNF764, ZNF778, ZNF780A, ZNF79, ZNF827, ZNF837, ZNF839 or ZNF91.

[2037] In a specific embodiment of the foregoing aspect, as listed in Table 2, the gene is: ABCA1, ABCB7, ABCC1, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ADAM12, ADAM15, ADAM17, ADAM33, AFF2, AGK, AGPAT3, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK2, ANKFY1, ANKHD1-EIF4EBP3, ANKRD17, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, APAF1, APLP2, APP, APPL2, APTX, ARHGAP22, ARID1A, ARID2, ARMCX3, ASAP1, ASL, ASNS, ASPH, ATAD2B, ATF7IP, ATG9A, ATMIN, ATP2C1, ATXN3, AURKA, AXIN1, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BEND6, BICD1, BIN1, BNC1, BRD2, BRPF1, BSCL2, BTBD10, BZW1, C11orf30, C11orf73, C17orf76-AS1, C4orf27, C5orf24, C6orf48, C9orf69, CAB39, CALU, CAMKK1, CAPNS1, CASC3, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC88A, CCDC92, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDK11B, CDK16, CDKAL1, CEP68, CFLAR, CHD8, CIZ1, CLIC1, CLK4, CNOT1, COG1, COL12A1, COL1A1, COL6A1, COPS7B, CPEB2, CREB5, CRLS1, CRTAP, CSDE1, CSNK1A1, CTDSP2, CTNND1, CUL2, CUL4A, CUX1, CYB5B, CYBRD1, CYP51A1, DAB2, DACT1, DARS, DAXX, DCAF10, DCAF11, DCBLD2, DCUN1D4, DDAH1, DDAH2, DDHD2, DDR1, DDX39B, DDX42, DENND1A, DENND1B, DENND5A, DGCR2, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIS3L, DKFZp434M1735, DKK3, DLC1, DNM2, DOCK1, DPP8, DSEL, DST, DSTN, EBF1, EEA1, EEF1A1, EFCAB14, EGR1, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ENG, ENPP2, ENSA, EPN1, EPT1, ERC1, ERGIC3, ETV5, EXO1, EXTL2, EYA3, FADS1, FADS2, FAF1, FAM111A, FAM198B, FAM219A, FAM219B, FAM3C, FAM65A, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FDFT1, FDPS, FER, FEZ1, FGD5-AS1, FGFRL1, FHOD3, FLII, FLNB, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FUS, FYN, GABPB1, GALC, GALNT1, GAS7, GBA2, GCFC2, GGCT, GHDC, GIGYF2, GJC1, GMIP, GNA13, GNAS, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR89A, GPSM2, GREM1, GRK6, GSE1, GTF2H2B, HAS2, HAT1, HAUS3, HAUS6, HDAC7, HEG1, HLA-A, HLA-E, HLTF, HMGA1, HMGB1, HMGCR, HMGCS1, HMOX1, HNRNPR, HNRNPUL1, HP1BP3, HRH1, HSD17B12, HSD17B4, HTT, IARS, IDH1, 1DI1, IGF2BP2, IL6ST, INHBA, INSIG1, IQCE, ITGAV, ITGB5, ITM2C, ITSN1, KANSL3, KCNK2, KIAA1033, KIAA1143, KIAA1199, KIAA1522, KIAA1524, KIAA1549, KTAA1715, KIF14, KIF2A, KIF3A, KLC1, KLC2, KLF6, KLHL7, KRT18, KRT19, KRT34, KRTAP2-3, LAMA2, LAMB1, LARP4, LARP7, LATS2, LDLR, LEMD3, LGALS8, LIMS1, LINC00341, LINC00657, LMAN2L, LMO7, LONP1, LOX, LRCH4, LRIG1, LRP8, LRRC8A, LSS, LTBR, LUC7L2, LZTS2, MADD, MAGED4, MAGED4B, MAN1A2, MAP4K4, MBD1, MBOAT7, MDM2, MED1, MEDAG, MEF2D, MEIS2, MEMO1, MEPCE, MFGE8, MICAL2, MINPP1, MKL1, MKLN1, MKNK2, MLLT4, MLST8, MMAB, MMS19, MMS22L, MPPE1, MPZL1, MRPL3, MSANTD3, MSC, MSH2, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERFD1, MTHFD1L, MTMR9, MTRR, MUM1, MVD, MVK, MYADM, MYLK, MYO1D, MYO9B, MYOF, NAA35, NADK, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NELFA, NEO1, NEURLIB, NF2, NFE2L1, NFX1, NID1, NID2, NIPA1, NKX3-1, NOL10, NOMO3, NPEPPS, NRD1, NREP, NRG1, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, ODF2, OS9, OSBPL6, OSMR, P4HA1, P4HB, PABPC1, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE4A, PDE7A, PDLIM7, PDXDC1, PEPD, PEX5, PFKP, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGU, PIK3C2B, PITPNA, PITPNB, PITPNM1, PLAU, PLEC, PLEKHB2, PLSCR3, PLXNB2, PLXNC1, PMS1, POLE3, POLR3D, POSTN, POU2F1, PPAPDC1A, PPARA, PPHLN1, PPIP5K1, PPP1R12A, PPP6R1, PPP6R2, PRKACB, PRKDC, PRMT1, PRNP, PRSS23, PSMA4, PSMC1, PSMD6, PTK2B, PTPN14, PUF60, PUS7, PVR, PXN, QKI, RAB23, RAB2B, RAB34, RAD1, RAD23B, RALB, RAPlA, RAP1GDS1, RARG, RASSF8, RBCK1, RBFOX2, RBM10, RCC1, RFTN1, RFWD2, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF38, RNFT1, RPL10, RPS6KC1, RRBP1, RWDD4, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24B, SEC61A1, SEPT9, SERPINE2, SF1, SGOL2, SH3RF1, SKIL, SLC25A17, SLC39A3, SLC41A1, SLC4A4, SLC7A6, SLC7A8, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMN2, SMPD4, SMYD3, SMYD5, SNAP23, SNHG16, SNX14, SOCS2, SON, SOS2, SPATA20, SPATS2, SPG20, SPRED2, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRSF3, STARD4, STAT1, STAT3, STAU1, STC2, STEAP2, STRIP1, STRN3, STX16, SUPT20H, SYNE1, SYNE2, SYT15, SYTL2, TACC1, TAF2, TANC2, TARBP1, TARS, TBC1D15, TBL2, TCF7L2, TENC1, TENM2, TEP1, TET3, TFCP2, TGFB1, TGFBR1, TGFBRAP1, THADA, THAP4, THRB, TIMP2, TJP2, TLE3, TLK1, TMEM154, TMEM47, TMEM63A, TNC, TNFAIP3, TNFRSF12A, TNIP1, TNKS1BP1, TNPO3, TNS1, TNS3, TOE1, TOMM40, TOMM5, TOPORS, TP531NP1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRMT1L, TRPS1, TSC2, TSHZ1, TSPAN2, TTC7A, TUBB2C, TUBB3, TXNL1, TXNRD1, U2SURP, UBAP2L, UBE2G2, UBE2V1, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC5B, USP19, USP7, VANGL1, VARS2, VCL, VIPAS39, VPS13A, VPS29, VPS51, VWA8, WDR19, WDR37, WDR48, WIPF1, WNT5B, WSB1, WWTR1, XIAP, XRN2, YAP1, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZHX3, ZMIZ1, ZMYM2, ZNF12, ZNF148, ZNF219, ZNF227, ZNF24, ZNF268, ZNF28, ZNF281, ZNF335, ZNF37A, ZNF37BP, ZNF395, ZNF583, ZNF621, ZNF652, ZNF655, ZNF674, ZNF74, ZNF764, ZNF778, ZNF780A, ZNF827, ZNF839 or ZNF91.

[2038] In a specific embodiment of the foregoing aspect, the gene is: ABCB8, ANKRD36, APLP2, ARHGAP12, ARMCX6, ASAP1, ATG5, AXIN1, BIRC6, C1orf86, CDC42BPA, CLTA, DYRK1A, ERGIC3, FBXL6, FOXM1, GGCT, KAT6B, KDM6A, KIF3A, KMT2D, LARP7, LYRM1, MADD, MAN2C1, MRPL55, MYCBP2, MYO9B, PNISR, RAP1A, RAPGEF1, SENP6, SH3YL1, SLC25A17, SMN2, SREK1, STRN3, TAF2, TMEM134, VPS29, ZFAND1 or ZNF431.

[2039] In another specific embodiment of the foregoing aspect, the gene is: ABCB8, ANKRD36, ARHGAP12, ARMCX6, ATG5, BIRC6, C1orf86, CLTA, DYRK1A, FBXL6, KAT6B, KDM6A, KMT2D, LYRM1, MAN2C1, MRPL55, MYCBP2, PNISR, RAPGEF1, SENP6, SH3YL1, TMEM134 or ZNF431.

[2040] In another specific embodiment of the foregoing aspect, the gene is: ABCA10, ABCC1, ACTA2, ADAL, ADAM12, ADAMTS1, ADAMTS5, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPS, AKAP3, ANK1, ANK2, ANK3, ANKRD33B, ANXA11, ANXA6, AP4B1-AS1, ARHGEF16, ARID5B, ARL9, ARMCX3, ASAP1, ASIC1, ATP2A3, B3GALT2, B3GNT6, BCL2L15, BCYRN1, BIN3-IT1, BIRC3, BTG2, C10orf54, C11orf70, C11orf73, C11orf94, C12orf56, C19orf47, C3, C4orf27, C7orf31, C8orf34, CA13, CA3, CACNA2D2, CACNB1, CADM1, CAND2, CCDC79, CCER2, CCNF, CDCA7, CDKAL1, CELSR1, CEMIP, CEP170, CFH, CIITA, CLDN23, CMAHP, CNGA4, CNTD1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A6, COL8A1, COLEC12, COMP, CPA4, CPQ, CRISPLD2, CRLF1, CRYL1, CUX1, CYB5B, CYB5R2, CYGB, CYP1B1, DCLK1, DCN, DDTT4L, DDX42, DDX50, DEGS1, DENND1A, DENND5A, DEPTOR, DFNB59, DGKA, DHFR, DIAPH3, DIRAS3, DIS3L, DLG5, DNAH8, DNAJC27, DOCK1, DOCK11, DYNC1I1, DZIP1L, EBF1, EFEMP1, EGR3, EIF2B3, ELN, ELP4, EMX2OS, ENPP1, ERCC8, ESM1, EVC2, F2R, FAM160A1, FAM198B, FAM20A, FAM46B, FAM65B, FAP, FARP1, FBLN2, FBN2, FBXO9, FCHO1, FER, FGFR2, FGL2, FLT1, FRAS1, FSCN2, GAL3ST4, GALC, GALNT15, GATA6, GBGT1, GCNT1, GDF6, GNAQ, GOLGB1, GPR183, GPR50, GPRC5A, GPRC5B, GRTP1, GUCA1B, GXYLT1, HAPLN1, HAPLN2, HAS3, HAVCR2, HDAC5, HECTD2-AS1, HEPH, HEY1, HLTF, HMGN3-AS1, HMOX1, HOOK3, HSD17B12, HSPA1L, HTATIP2, HTT, IGDCC4, IGF2R, IGFBP3, IL16, INA, INTU, IQCG, ITGA11, ITGA8, ITGB8, ITIH1, ITPKA, KCNS1, KCNS2, KDM6A, KDSR, KIAA1456, KIAA1462, KIAA1524, KIAA1715, KIAA1755, KIT, KLF17, KLRG1, KRT7, KRTAP1-1, KRTAP1-5, L3MBTL2, LAMB2P1, LGI2, LGR4, LHX9, LINC00472, LINC00570, LINC00578, LINC00607, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LMOD1, LRBA, LRP4, LRRC32, LRRC39, LSAMP, LUM, LYPD1, LYRM1, MAFB, MAMDC2, MAN1 A2, MAN2A1, MAPK13, MASP1, MB, MC4R, MEDAG, MEGF6, MEMO1, MIAT, MIR612, MLLT10, MMP10, MMP24, MMS19, MN1, MOXD1, MRVI1, MSH4, MTERF3, MXRA5, MYO1D, NA, NAALADL2, NAE1, NAGS, NDNF, NEURLIB, NGFR, NHLH1, NLN, NOTCH3, NOTUM, NOVA2, NOX4, NRROS, NTNG1, OCLN, OLR1, OSBPL10, OXCT2, PAIP2B, PAPD4, PBLD, PCM1, PDE1C, PDE5A, PDGFD, PDGFRB, PDS5B, PDXDC1, PEAR1, PEPD, PHACTR3, PI4K2B, PIK3R1, PIM2, PITPNB, PITPNM3, PLAU, PLEK2, PLEKHA6, PLEKHH2, PLXNC1, PMS1, PODN, POLN, POLR1AA, POSTN, PPM1E, PPP3CA, PRKCA, PRKDC, PRKG1, PRPH2, PRRG4, PRUNE2, PSMD6-AS2, PTGIS, PTX3, RAB30, RAB38, RAB44, RAD9B, RARS, RBBP8, RBKS, RCC1, RDX, RFWD2, RFX3-AS1, RGCC, RNFT1, ROR1, ROR2, RWDD4, SCARNA9, SCO1, SEC22A, SHROOM3, SIGLEC10, SLC24A3, SLC35F3, SLC39A10, SLC46A2, SLC4A11, SLC6A15, SLC7A11, SLC9A3, SLIT3, SMG1P3, SMTN, SMYD3, SNED1, SORBS2, SORCS2, SOX7, SPDYA, SPEF2, SQRDL, STAC2, STAT1, STAT4, STEAP2, STK32B, STRN4, STS, STXBP6, SULF1, SVEP1, SYNGR2, SYNPO, SYNPO2, SYNPO2L, TAGLN3, TANGO6, TARBP1, TEX21P, TGFA, TGFB2, TGFB3, TGM2, THADA, THBS2, THRB, TMEM102, TMEM119, TMEM256-PLSCR3, TMEM50B, TNC, TNFAIP8L3, TNFRSF14, TNRC18P1, TNS3, TNXB, TP53AIP1, TPRG1, TRAF3, TRIM66, TRPC4, TSHZ2, TSPAN11, TSPAN18, TSPAN7, TSSK3, TXNIP, UNC5B, USP27X, UVRAG, VIM-AS1, VPS41, VSTM2L, VWA8, VWF, WDR91, WISP1, WNT10B, XRN2, YDJC, ZBTB26, ZCCHC5, ZFP82, ZMIZ1-AS1, ZNF212, ZNF350, ZNF660, ZNF79 or ZNF837.

[2041] In another specific embodiment of the foregoing aspect, the gene is: ABCA10, ACTA2, ADAL, ADAMTS1, ADAMTS5, ADD1, ADGRG6, ADH6, ADHFE1, AFF3, AKAP3, ANK1, ANK3, ANKRD33B, AP4B1-AS1, ARHGEF16, ARID5B, ARL9, ASIC1, ATP2A3, B3GALT2, B3GNT6, BCL2L15, BCYRN1, BIN3-IT1, BIRC3, BTG2, C10orf54, C11orf70, C11orf94, C12orf56, C19orf47, C3, C7orf31, C8orf34, CA13, CA3, CACNA2D2, CACNB1, CADM1, CAND2, CCDC79, CCER2, CCNF, CELSR1, CEMIP, CEP170, CFH, CIITA, CLDN23, CMAHP, CNGA4, CNTD1, COL11A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A6, COL8A1, COLEC12, COMP, CPA4, CPQ, CRISPLD2, CRLF1, CRYL1, CYB5R2, CYGB, CYP1B1, DCLK1, DCN, DDIT4L, DDX50, DEGS1, DEPTOR, DFNB59, DIRAS3, DLG5, DNAH8, DNAJC27, DOCK11, DYNC1I1, DZIP1L, EFEMP1, EGR3, ELN, ELP4, EMX2OS, ENPP1, ERCC8, ESM1, EVC2, F2R, FAM160A1, FAM20A, FAM46B, FAM65B, FAP, FARP1, FBLN2, FBN2, FBXO9, FCHO1, FGFR2, FGL2, FLT1, FRAS1, FSCN2, GAL3ST4, GALNT15, GATA6, GBGT1, GCNT1, GDF6, GNAQ, GPR183, GPR50, GPRC5A, GPRC5B, GRTP1, GUCA1B, GXYLT1, HAPLN1, HAPLN2, HA S3, HAVCR2, HDAC5, HECTD2-AS1, HEPH, HEY1, HMGN3-AS1, HOOK3, HSPA1L, HTATIP2, IGDCC4, IGF2R, IGFBP3, IL16, INA, INTU, IQCG, ITGA11, ITGA8, ITGB8, ITIH1, ITPKA, KCNS1, KCNS2, KDM6A, KDSR, KIAA1456, KIAA1462, KIAA1755, KIT, KLF17, KLRG1, KRT7, KRTAP1-1, KRTAP1-5, L3MBTL2, LAMB2P1, LGI2, LGR4, LHX9, LINC00472, LINC00570, LINC00578, LINC00607, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LMOD1, LRBA, LRP4, LRRC32, LRRC39, LSAMP, LUM, LYPD1, MAFB, MAMDC2, MAN2A1, MAPK13, MASP1, MB, MC4R, MEGF6, MIAT, MIR612, MLLT10, MMP10, MMP24, MN1, MOXD1, MRVI1, MSH4, MTERF3, MXRA5, NA, NAALADL2, NAE1, NAGS, NDNF, NGFR, NHLH1, NLN, NOTCH3, NOTUM, NOVA2, NOX4, NRROS, OCLN, OLR1, OSBPL10, OXCT2, PAIP2B, PBLD, PDE1C, PDE5A, PDGFD, PDGFRB, PDS5B, PEAR1, PHACTR3, PI4K2B, PIK3R1, PIM2, PITPNM3, PLEK2, PLEKHA6, PLEKHH2, PODN, POLN, POLR1A, PPM1E, PPP3CA, PRKCA, PRKG1, PRPH2, PRRG4, PRUNE2, PSMD6-AS2, PTGIS, PTX3, RAB30, RAB38, RAB44, RAD9B, RARS, RBBP8, RBKS, RDX, RFX3-AS1, RGCC, ROR1, ROR2, SCARNA9, SHROOM3, SIGLEC10, SLC24A3, SLC35F3, SLC39A10, SLC46A2, SLC4A11, SLC6A15, SLC7A11, SLC9A3, SLIT3, SMG1P3, SMTN, SNED1, SORBS2, SORCS2, SOX7, SPDYA, SPEF2, STAC2, STAT4, STK32B, STRN4, STS, STXBP6, SULF1, SVEP1, SYNGR2, SYNPO, SYNPO2, SYNPO2L, TAGLN3, TANGO6, TEX21P, TGFA, TGFB2, TGFB3, TGM2, THBS2, TMEM102, TMEM119, TMEM256-PLSCR3, TMEM50B, TNFAIP8L3, TNFRSF14, TNRC18P1, TNXB, TP53AIP1, TPRG1, TRIM66, TRPC4, TSHZ2, TSPAN11, TSPAN18, TSPAN7, TSSK3, TXNIP, USP27X, UVRAG, VIM-AS1, VPS41, VSTM2L, VWF, WDR91, WISP1, WNT10B, YDJC, ZBTB26, ZCCHC5, ZFP82, ZMIZ1-AS1, ZNF212, ZNF350, ZNF660, ZNF79 or ZNF837.

[2042] In another specific embodiment of the foregoing aspect, as listed in Table 7, the gene is ABCB8, ABCC3, ADAM17, ADCY3, AGPAT4, ANKRA2, ANXA11, APIP, APLP2, APLP2, ARHGAP1, ARL15, ASAP1, ASPH, ATAD2B, ATXN1, AXIN1, BECN1, BHMT2, BICD1, BTN3A1, C11orf30, C11orf73, C12orf4, C14orf132, C8orf44, C8orf44-SGK3, C8orf8, CASC3, CASP7, CCDC122, CDH13, CECR7, CENPI, CEP112, CEP192, CHEK1, CMAHP, CNRIP1, COPS7B, CPSF4, CRISPLD2, CRYBG3, CSNK1E, CSNK1G1, DAGLB, DCAF17, DCUN1D4, DDX42, DENND1A, DENND5A, DGKA, DHFR, DIAPH3, DLGAP4, DNAJC13, DNMBP, DOCK1, DYRK1A, EIF2B3, ENAH, ENOX1, EP300, ERC1, ERCC1, ERGIC3, ERLIN2, ERRFI1, EVC, FAF1, FAIM, FAM126A, FAM13A, FAM162A, FAM174A, FAM198B, FBN2, FER, FHOD3, FOCAD, GALC, GCFC2, GGACT, GGCT, GLCE, GOLGA4, GOLGB1, GPSM2, GULP1, GXYLT1, HAT1, HDX, HLTF, HMGA2, HNMT, HPS1, HSD17B12, HSD17B4, HTT, IFT57, INPP5K, IVD, KDM6A, KIAA1524, KIAA1715, LETM2, LOC400927, LRRC42, LUC7L3, LYRM1, MADD, 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, PPHLN1, PPIP5K2, PPP1R26, PRPF31, PRSS23, PRUNE2, PSMA4, PXK, RAF1, RAPlA, RAPGEF1, RARS2, RBKS, RERE, RFWD2, RNFT1, RPA1, RPS10, RPS6KB2, SAMD4A, SAR1A, SCO1, SEC24A, SENP6, SERGEF, SGK3, SH3YL1, SKA2, SLC12A2, SLC25A17, SLC44A2, SMYD3, SNAP23, SNHG16, SNX7, SOS2, SPATA18, SPATA5, SP1DR, SPRYD7, SRGAP1, SRRM1, STAT1, STRN3, STXBP6, SUPT20H, TAF2, TASP1, TBC1D15, TCF12, TCF4, TIAM1, TJP2, TMC3, TMEM189-UBE2V1, TMEM214, TNRC6A, TNS3, TOE1, TRAF3, TRIM65, TSPAN2, TTC7B, TUBE1, TYW5, UBAP2L, UBE2V1, URGCP, VAV2, VPS29, WDR27, WDR37, WDR91, WNK1, XRN2, ZCCHC8, ZFP82, ZNF138, ZNF232, ZNF37BP or ZNF680.

[2043] In another specific embodiment of the foregoing aspect, the gene is 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, 1FT57, 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.

[2044] In another specific embodiment of the foregoing aspect, the gene is APLP2, AXIN1, CECR7, DAGLB, DLGAP4, ERCC1, ERGIC3, FAM198B, GGCT, HAT1, HPS1, INPP5K, MADD, PPHLN1, PRUNE2, RAPlA, RNFT1, RPS6KB2, SH3YL1, SKA2, SPATA18, STRN3, TMEM189-UBE2V1, TRIM65, TUBE1, UBE2V1, VPS29 or ZNF680.

[2045] In another specific embodiment of the foregoing aspect, the gene is ABCB8, ABCC3, ADCY3, AGPAT4, ANKRA2, APIP, ARHGAP1, ARL15, ATXN1, BECN1, BHMT2, BTN3A1, C12orf4, C14orf132, C8orf44, C8orf44-SGK3, C8orf88, CASP7, CCDC122, CECR7, CENPI, CEP112, CEP192, CHEK1, CMAHP, CNRIP1, CPSF4, CRISPLD2, CRYBG3, CSNK1E, CSNK1G1, DAGLB, DCAF17, DLGAP4, DNAJC13, DNMBP, DYRK1A, ENAH, EP300, ERCC1, ERLIN2, ERRFI1, EVC, FAIM, FAM126A, FAM13A, FAM162A, FAM174A, FBN2, GGACT, GLCE, GULP1, GXYLT1, HDX, HMGA2, HNMT, HPS1, IFT57, INPP5K, IVD, KDM6A, LETM2, LOC400927, LRRC42, LYRM1, MB21D2, MCM10, MED13L, MFN2, MRPL45, MRPS28, MTERF3, MYCBP2, NGF, OXCT1, PDS5B, PIGN, PIK3CD, PIK3R1, PIKFYVE, PLEKHA1, PLSCR1, POMT2, PPARG, PPIP5K2, PPP1R26, PRPF31, PRUNE2, PXK, RAF1, RAPGEF1, RARS2, RBKS, RERE, RPA1, RPS10, RPS6KB2, SAMD4A, SEC24A, SENP6, SERGEF, SGK3, SH3YL1, SKA2, SLC12A2, SLC44A2, SNX7, SPATA18, SPATA5, SPIDR, SPRYD7, SRGAP1, SRRM1, STXBP6, TASP1, TCF12, TCF4, TIAM1, TMC3, TMEM189-UBE2V1, TMEM214, TNRC6A, TTC7B, TUBE1, TYW5, URGCP, VAV2, WDR27, WDR91, WNK1, ZCCHC8, ZFP82, ZNF138, ZNF232 or ZNF680.

[2046] In another particular aspect, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene in a subject, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS (for example, an endogenous intronic REMS or a non-endogenous intronic REMS), the methods comprising administering to the subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2047] In another particular aspect, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene in a subject, wherein the precursor RNA transcript transcribed from the gene comprises a non-endogenous intronic REMS, the methods comprising administering to the subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2048] In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2049] In another embodiment, provided herein is a method for modulating the amount of a product of a gene (such as an RNA transcript or a protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first 5′ splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, an iREMS, a nucleotide sequence encoding a second branch point and a nucleotide sequence encoding a second 3′ splice site, wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), and wherein r is adenine or guanine and n is any nucleotide, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.

[2050] In another embodiment, provided herein is a method for modulating the amount of a product of a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence of the intron comprises in 5′ to 3′ order: an iREMS, a nucleotide sequence encoding a first branch point and a nucleotide sequence encoding a first 3′ splice site, wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), and wherein r is adenine or guanine and n is any nucleotide, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.

[2051] In another embodiment, provided herein is a method for modulating the amount of a product of a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1A, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.

[2052] In another embodiment, provided herein is a method for modulating the amount of a product of a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1B, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.

[2053] In another embodiment, provided herein is a method for modulating the amount of a product of a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1C, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.

[2054] In a specific embodiment, the gene is a gene described in a table in this disclosure.

[2055] In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, disclosed in Table 7, infra, comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes in Table 7. In a specific embodiment, the RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In a specific embodiment, the method for modulating the amount of one or more RNA transcripts of a gene using a compound of Formula (I) or a form thereof is as described in the Examples described herein.

[2056] In certain embodiments, a compound of Formula (I) or a form thereof contacted or cultured with a cell(s), or administered to a subject is a compound of Formula (II), Formula (11), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV). In some embodiments, a compound of Formula (I) or a form thereof contacted or cultured with a cell(s), or administered to a subject is a compound described herein.

[2057] Table 1 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon with a corresponding change in isoform abundance as a result of iExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.

TABLE-US-00003 TABLE 1 Table 1 ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM12, ADAM15, ADAM17, ADAM33, ADAMTS1, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APLP2, APP, APPL2, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARMCX3, ARMCX6, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF7IP, ATG5, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, AXIN1, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3-IT1, BIRC3, BIRC6, BNC1, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1orf86, C10orf54, C11orf30, C11orf70, C11orf73, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CADM1, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDK11B, CDK16, CDKAL1, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP170, CEP192, CEP68, CFH, CFLAR, CHD8, CHEK1, CIITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND5A, DEPTOR, DFNB59, DGCR2, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DLGAP4, DNAH8, DNAJC13, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEF1A1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELN, ELP4, EMX2OS, ENAH, ENG, ENPP1, ENPP2, ENSA, EP300, EPN1, EPT1, ERC1, ERCC1, ERCC8, ERGIC3, ERLIN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM198B, FAM20A, FAM219A, FAM219B, FAM3C, FAM46B, FAM65A, FAM65B, FAP, FARP1, FBLN2, FBN2, FBXO9, FBXL6, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GCFC2, GCNT1, GDF6, GGACT, GGCT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HOOK3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSD17B4, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IL16, IL6ST, INA, INHBA, INPP5K, INSIG1, INTU, IQCE, IQCG, ITGA11, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIF14, KIF2A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LARP7, LATS2, LDLR, LEMD3, LETM2, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, LINC00578, LINC00607, LINC00657, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LMAN2L, LMO7, LMOD1, LOC400927, LONP1, LOX, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC32, LRRC39, LRRC42, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MADD, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MAP4K4, MAPK13, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYCBP2, MYLK, MYO1D, MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NELFA, NEO1, NEURL1B, NF2, NFE2L1, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PBLD, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PEAR1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPHLN1, PPIP5K1, PPIP5K2, PPM1E, PPP1R12A, PPP1R26, PPP3CA, PPP6R1, PPP6R2, PRKACB, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB23, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAP1A, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASSF8, RBBP8, RBCK1, RBFOX2, RBKS, RBM10, RCC1, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF38, RNFT1, ROR1, ROR2, RPA1, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A1, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SGK3, SGOL2, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SLC12A2, SLC24A3, SLC25A17, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMN2, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SOCS2, SON, SORBS2, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRGAP1, SRRM1, SRSF3, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRIP1, STRN3, STRN4, STS, STX16, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBL2, TCF12, TCF4, TCF7L2, TENC1, TENM2, TEP1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFBI, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJP2, TLE3, TLK1, TMC3, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNRC6A, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2G2, UBE2V1, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC5B, URGCP, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR91, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF431, ZNF583, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF74, ZNF764, ZNF778, ZNF780A, ZNF79, ZNF827, ZNF837, ZNF839 or ZNF91

[2058] Table 2 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon with a corresponding change in isoform abundance as a result of iExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.

TABLE-US-00004 TABLE 2 ABCA1, ABCB7, ABCC1, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ADAM12, ADAM15, ADAM17, ADAM33, AFF2, AGK, AGPAT3, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK2, ANKFY1, ANKHD1-EIF4EBP3, ANKRD17, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, APAF1, APLP2, APP, APPL2, APTX, ARHGAP22, ARID1A, ARID2, ARMCX3, ASAP1, ASL, ASNS, ASPH, ATAD2B, ATF7IP, ATG9A, ATMIN, ATP2C1, ATXN3, AURKA, AXIN1, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BEND6, BICD1, BIN1, BNC1, BRD2, BRPF1, BSCL2, BTBD10, BZW1, C11orf30, C11orf73, C17orf76-AS1, C4orf27, C5orf24, C6orf48, C9orf69, CAB39, CALU, CAMKK1, CAPNS1, CASC3, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC88A, CCDC92, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDK11B, CDK16, CDKAL1, CEP68, CFLAR, CHD8, CIZ1, CLIC1, CLK4, CNOT1, COG1, COL12A1, COL1A1, COL6A1, COPS7B, CPEB2, CREB5, CRLS1, CRTAP, CSDE1, CSNK1A1, CTDSP2, CTNND1, CUL2, CUL4A, CUX1, CYB5B, CYBRD1, CYP51A1, DAB2, DACT1, DARS, DAXX, DCAF10, DCAF11, DCBLD2, DCUN1D4, DDAH1, DDAH2, DDHD2, DDR1, DDX39B, DDX42, DENND1A, DENND1B, DENND5A, DGCR2, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIS3L, DKFZp434M1735, DKK3, DLC1, DNM2, DOCK1, DPP8, DSEL, DST, DSTN, EBF1, EEA1, EEF1A1, EFCAB14, EGR1, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ENG, ENPP2, ENSA, EPN1, EPT1, ERC1, ERGIC3, ETV5, EXO1, EXTL2, EYA3, FADS1, FADS2, FAF1, FAM111A, FAM198B, FAM219A, FAM219B, FAM3C, FAM65A, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FDFT1, FDPS, FER, FEZ1, FGD5-AS1, FGFRL1, FHOD3, FLII, FLNB, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FUS, FYN, GABPB1, GALC, GALNT1, GAS7, GBA2, GCFC2, GGCT, GHDC, GIGYF2, GJC1, GMIP, GNA13, GNAS, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR89A, GPSM2, GREM1, GRK6, GSE1, GTF2H2B, HAS2, HAT1, HAUS3, HAUS6, HDAC7, HEG1, HLA-A, HLA-E, HLTF, HMGA1, HMGB1, HMGCR, HMGCS1, HMOX1, HNRNPR, HNRNPUL1, HP1BP3, HRH1, HSD17B12, HSD17B4, HTT, IARS, IDH1, IDI1, IGF2BP2, IL6ST, INHBA, INSIG1, IQCE, ITGAV, ITGB5, ITM2C, ITSN1, KANSL3, KCNK2, KIAA1033, KIAA1143, KIAA1199, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIF14, KIF2A, KIF3A, KLC1, KLC2, KLF6, KLHL7, KRT18, KRT19, KRT34, KRTAP2-3, LAMA2, LAMB1, LARP4, LARP7, LATS2, LDLR, LEMD3, LGALS8, LIMS1, LINC00341, LINC00657, LMAN2L, LMO7, LONP1, LOX, LRCH4, LRIG1, LRP8, LRRC8A, LSS, LTBR, LUC7L2, LZTS2, MADD, MAGED4, MAGED4B, MAN1A2, MAP4K4, MBD1, MBOAT7, MDM2, MED1, MEDAG, MEF2D, MEIS2, MEMO1, MEPCE, MFGE8, MICAL2, MINPP1, MKL1, MKLN1, MKNK2, MLLT4, MLST8, MMAB, MMS19, MMS22L, MPPE1, MPZL1, MRPL3, MSANTD3, MSC, MSH2, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERFD1, MTHFD1L, MTMR9, MTRR, MUM1, MVD, MVK, MYADM, MYLK, MYO1D, MYO9B, MYOF, NAA35, NADK, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NELFA, NEO1, NEURL1B, NF2, NFE2L1, NFX1, NID1, NID2, NIPA1, NKX3-1, NOL10, NOMO3, NPEPPS, NRD1, NREP, NRG1, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, ODF2, OS9, OSBPL6, OSMR, P4HA1, P4HB, PABPC1, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE4A, PDE7A, PDLIM7, PDXDC1, PEPD, PEX5, PFKP, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGU, PIK3C2B, PITPNA, PITPNB, PITPNM1, PLAU, PLEC, PLEKHB2, PLSCR3, PLXNB2, PLXNC1, PMS1, POLE3, POLR3D, POSTN, POU2F1, PPAPDC1A, PPARA, PPHLN1, PPIP5K1, PPP1R12A, PPP6R1, PPP6R2, PRKACB, PRKDC, PRMT1, PRNP, PRSS23, PSMA4, PSMC1, PSMD6, PTK2B, PTPN14, PUF60, PUS7, PVR, PXN, QKI, RAB23, RAB2B, RAB34, RAD1, RAD23B, RALB, RAP1A, RAP1GDS1, RARG, RASSF8, RBCK1, RBFOX2, RBM10, RCC1, RFTN1, RFWD2, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF38, RNFT1, RPL10, RPS6KC1, RRBP1, RWDD4, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24B, SEC61A1, SEPT9, SERPINE2, SF1, SGOL2, SH3RF1, SKIL, SLC25A17, SLC39A3, SLC41A1, SLC4A4, SLC7A6, SLC7A8, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMN2, SMPD4, SMYD3, SMYD5, SNAP23, SNHG16, SNX14, SOCS2, SON, SOS2, SPATA20, SPATS2, SPG20, SPRED2, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRSF3, STARD4, STAT1, STAT3, STAU1, STC2, STEAP2, STRIP1, STRN3, STX16, SUPT20H, SYNE1, SYNE2, SYT15, SYTL2, TACC1, TAF2, TANC2, TARBP1, TARS, TBC1D15, TBL2, TCF7L2, TENC1, TENM2, TEP1, TET3, TFCP2, TGFBI, TGFBR1, TGFBRAP1, THADA, THAP4, THRB, TIMP2, TJP2, TLE3, TLK1, TMEM154, TMEM47, TMEM63A, TNC, TNFAIP3, TNFRSF12A, TNIP1, TNKS1BP1, TNPO3, TNS1, TNS3, TOE1, TOMM40, TOMM5, TOPORS, TP53INP1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRMT1L, TRPS1, TSC2, TSHZ1, TSPAN2, TTC7A, TUBB2C, TUBB3, TXNL1, TXNRD1, U2SURP, UBAP2L, UBE2G2, UBE2V1, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC5B, USP19, USP7, VANGL1, VARS2, VCL, VIPAS39, VPS13A, VPS29, VPS51, VWA8, WDR19, WDR37, WDR48, WIPF1, WNT5B, WSB1, WWTR1, XIAP, XRN2, YAP1, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZHX3, ZMIZ1, ZMYM2, ZNF12, ZNF148, ZNF219, ZNF227, ZNF24, ZNF268, ZNF28, ZNF281, ZNF335, ZNF37A, ZNF37BP, ZNF395, ZNF583, ZNF621, ZNF652, ZNF655, ZNF674, ZNF74, ZNF764, ZNF778, ZNF780A, ZNF827, ZNF839 or ZNF91

[2059] Table 3 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon with a corresponding change in isoform abundance as a result of iExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.

TABLE-US-00005 TABLE 3 ABCA1, ABCC1, ABL2, ACACA, ACAT2, AFF2, AHRR, AK021888, AK310472, AKAP1, ANK2, ANKHD1-EIF4EBP3, AP2B1, APAF1, APLP2, ARID1A, ARMCX3, ASAP1, ASPH, ATAD2B, ATF7IP, ATG9A, AXIN1, BACE1, BIN1, BNC1, BRPF1, BZW1, C11orf30, C11orf73, C17orf76-AS1, C4orf27, C6orf48, CAB39, CAMKK1, CCDC88A, CCDC92, CDC25B, CDC42BPA, CDCA7, CDH11, CDH13, CEP68, CFLAR, COPS7B, CREB5, CUL2, CUL4A, CUX1, CYP51A1, DCUN1D4, DDR1, DDX39B, DDX42, DENND1A, DENND5A, DGKA, DHCR24, DHCR7, DIAPH1, DIAPH3, DNM2, DOCK1, EFCAB14, EIF2B3, EPN1, EPT1, ERC1, ETV5, FADS1, FADS2, FAF1, FAM198B, FAM219B, FBXO10, FBXO9, FDFT1, FDPS, FER, FEZ1, FHOD3, FLII, FLNB, FNBP1, FOS, FOSB, FOXM1, FYN, GABPB1, GALC, GAS7, GGCT, GJC1, GPSM2, GRK6, HAS2, HAT1, HLTF, HMGA1, HMGB1, HMGCR, HMGCS1, HMOX1, HP1BP3, HSD17B12, HTT, IDI1, INHBA, INSIG1, KANSL3, KIAA1199, KIAA1524, KIAA1715, KIF3A, KLF6, KRT19, KRT34, KRTAP2-3, LAMA2, LARP7, LDLR, LEMD3, LMAN2L, LRCH4, LRP8, LSS, MAGED4, MAGED4B, MAN1A2, MEDAG, MEF2D, MEMO1, MFGE8, MICAL2, MMAB, MMS19, MMS22L, MSL3, MSMO1, MTAP, MTERFD1, MVD, MVK, NASP, NAV2, NEURL1B, NFE2L1, NID1, NPEPPS, NREP, NRG1, NSUN4, NT5C2, NUP153, P4HA1, PABPC1, PAPD4, PCBP2, PCM1, PCSK9, PDXDC1, PEPD, PHF19, PHF8, PHTF2, PIK3C2B, PITPNB, PLEC, PMS1, POU2F1, PPHLN1, PRKDC, PRSS23, PSMC1, PTPN14, PUF60, PVR, RAB23, RAD23B, RAP1A, RASSF8, RBM10, RCC1, RFWD2, RNFT1, RWDD4, SAMD9L, SART3, SCAF4, SCD, SEC22A, SEC61A1, SERPINE2, SF1, SLC25A17, SLC7A6, SLC7A8, SMN2, SMYD3, SMYD5, SNAP23, SNHG16, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, STARD4, STAT1, STAU1, STEAP2, STRN3, SYNE1, TACC1, TAF2, TANC2, TARBP1, TBC1D15, TEP1, TFCP2, TGFBRAP1, THADA, TIMP2, TLK1, TMEM154, TNS3, TOMM5, TRAF3, TRAK1, TRAPPC12, TRIM2, TRIM26, TRIM65, TSPAN2, U2SURP, UBAP2L, UBE2V1, UCHL5, UHRF1BPIL, VANGL1, VARS2, VPS13A, VPS29, VWA8, WSB1, XIAP, XRN2, YPEL5, ZAK, ZC3H18, ZFAND5, ZMIZ1, ZMYM2, ZNF219, ZNF227, ZNF24, ZNF37A, ZNF37BP, ZNF395, ZNF652, ZNF674, ZNF74 or ZNF778

[2060] Table 4 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon with a corresponding change in isoform abundance as a result of iExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.

TABLE-US-00006 TABLE 4 ABCC1, ACADVL, ADAM15, AGPAT3, AHRR, AJUBA, AKAP1, AKAP9, ALCAM, ALDH4A1, ANKFY1, AP2B1, APLP2, APP, ARID1A, ARID2, ASPH, ATMIN, BASP1, BC033281, BCAR3, C11orf73, C17orf76-AS1, C5orf24, C6orf48, CAB39, CASP8AP2, CAV1, CCAR1, CCT6A, CD276, CD46, CDC25B, CDK16, CEP68, CHD8, CLIC1, COL12A1, CPEB2, CREB5, CRLS1, CRTAP, CTNND1, CUX1, CYBRD1, DACT1, DCAF10, DCAF11, DDHD2, DDX39B, DIAPH3, DKK3, DLC1, DSTN, EBF1, EGR1, EIF4G1, EIF4G3, ENG, ERC1, ETV5, FAM198B, FAM219A, FAM3C, FEZ1, FGD5-AS1, FLII, FN1, FNBP1, FOS, FOSB, FOXK1, FOXM1, FYN, GABPB1, GALC, GALNT1, GBA2, GGCT, GHDC, GMIP, GNA13, GNAS, GNL3L, GOLGA2, GORASP1, GREM1, GSE1, HAUS6, HDAC7, HEG1, HLA-A, HLA-E, HMGA1, HP1BP3, IL6ST, ITGAV, KIAA1549, KIF14, KLC1, KLF6, KLHL7, KRT18, LAMA2, LAMB1, LARP7, LATS2, LGALS8, LIMS1, LINC00341, LONP1, LOX, MDM2, MEPCE, MINPP1, MLLT4, MPPE1, MRPL3, MSH2, MSH6, MSL3, MTMR9, MTRR, MUM1, MYADM, MYLK, NADK, NAV2, NCSTN, NFE2L1, NID1, NIPA1, NPEPPS, NRD1, NUDT4, NUSAP1, P4HB, PABPC1, PAK4, PAPD4, PCNXL2, PDE4A, PDXDC1, PHRF1, PHTF2, PI4K2A, PIK3C2B, PLAU, PLEKHB2, PLSCR3, PLXNB2, POSTN, POU2F1, PPARA, PPP1R12A, PRKACB, PSMD6, PTPN14, PUS7, QKI, RAB34, RAD1, RAD23B, RASSF8, RBCK1, RBFOX2, RFTN1, RNF19A, RNF38, RPS6KC1, RWDD4, SEC14L1, SEC24B, SERPINE2, SF1, SLC39A3, SLC41A1, SLC4A4, SLC7A6, SMARCA4, SMN2, SNHG16, SNX14, SON, SPRED2, STAU1, STEAP2, STRIP1, STRN3, TBL2, TGFBI, TGFBR1, THAP4, TLE3, TMEM47, TNKS1BP1, TOMM40, TOPORS, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM65, TRMT1L, TRPS1, TXNL1, TXNRD1, U2SURP, UBE2G2, UBE2V1, UHMK1, USP7, VPS29, VWA8, WDR19, WDR37, WIPF1, YPEL5, YTHDF3, Z24749, ZBTB10, ZBTB7A, ZFAND5, ZMIZ1, ZNF12, ZNF148, ZNF335, ZNF395, ZNF583, ZNF621, ZNF655, ZNF74 or ZNF780A

[2061] Table 5 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon with a corresponding change in isoform abundance as a result of iExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.

TABLE-US-00007 TABLE 5 ABCB7, ABHD10, ABLIM3, ACACA, ADAM12, ADAM17, ADAM33, AGK, AGPS, AHCYL2, AHDC1, AHRR, AK021888, AK310472, AKAP1, AKAP9, AKNA, AMPD2, ANKRD17, ANKS6, ANP32A, ANXA11, ANXA6, APLP2, APP, APPL2, APTX, ARHGAP22, ARMCX3, ASAP1, ASNS, ASPH, ATG9A, ATP2C1, AURKA, AXIN1, B4GALT2, BACE1, BASP1, BEND6, BICD1, BIN1, BRD2, BRPF1, BTBD10, C11orf30, C11orf73, C17orf76-AS1, C4orf27, C6orf48, CAB39, CAPNS1, CASC3, CCDC77, CCDC88A, CD46, CDC40, CDC42BPA, CDCA7, CDH13, CDK11B, CEP68, CIZ1, CLK4, CNOT1, COG1, COL12A1, COL1A1, COL6A1, COPS7B, CSDE1, CSNK1A1, CUX1, CYB5B, CYBRD1, DAB2, DARS, DCBLD2, DCUN1D4, DDAH2, DDR1, DDX39B, DDX42, DENND1A, DENND1B, DENND5A, DGKA, DHFR, DHX9, DIAPH1, DIAPH3, DIS3L, DNM2, DOCK1, DPP8, DSEL, EEA1, EFCAB14, EIF2B3, EIF4G1, EIF4G3, ELF2, ENG, ENPP2, EPN1, EXTL2, EYA3, FAF1, FAM198B, FAM3C, FBXO10, FBXO18, FBXO31, FBXO9, FER, FEZ1, FHOD3, FLII, FN1, FNBP1, FOCAD, FOSL1, FOXM1, GABPB1, GALC, GALNT1, GCFC2, GGCT, GIGYF2, GMIP, GNAS, GNL3L, GOLGB1, GPR89A, GPSM2, GREM1, GRK6, GTF2H2B, HAT1, HAUS3, HEG1, HLA-A, HLTF, HP1BP3, HRH1, HSD17B12, HSD17B4, HTT, IARS, IDH1, IGF2BP2, ITM2C, KCNK2, KIAA1033, KIAA1143, KIAA1522, KIAA1524, KIAA1715, KIF3A, KLHL7, LAMA2, LARP4, LARP7, LATS2, LIMS1, LINC00341, LINC00657, LMAN2L, LMO7, LRCH4, LRIG1, LRRC8A, LTBR, LUC7L2, LZTS2, MADD, MAGED4B, MAN1A2, MAP4K4, MED1, MEDAG, MEF2D, MEIS2, MEMO1, MICAL2, MKLN1, MLLT4, MMS19, MPZL1, MSANTD3, MSC, MSL3, MTAP, MTERFD1, MTHFD1L, MYADM, MYLK, MYO9B, MYOF, NASP, NAV2, NCOA3, NCOA4, NELFA, NEO1, NEURL1B, NF2, NID2, NOL10, NPEPPS, NRG1, NSUN4, NT5C2, NT5E, NTNG1, NUP153, NUP35, NUP50, NUSAP1, ODF2, OS9, OSBPL6, P4HA1, P4HB, PABPC1, PAPD4, PARN, PARP4, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PDE7A, PDXDC1, PEPD, PFKP, PHF19, PHRF1, PHTF2, PIEZO1, PIGU, PITPNA, PITPNB, PITPNM1, PLAU, PLSCR3, PLXNC1, PMS1, POU2F1, PPAPDC1A, PPHLN1, PPIP5K1, PPP1R12A, PRKDC, PRMT1, PRSS23, PSMA4, PTK2B, PUF60, PVR, RAB23, RAB2B, RAD1, RAD23B, RAP1A, RAP1GDS1, RARG, RASSF8, RBCK1, RCC1, RFWD2, RGS3, RNF14, RNFT1, RPL10, RRBP1, RWDD4, SAR1A, SCAF4, SCAF8, SCLT1, SCO1, SDCBP, SEC22A, SEPT9, SF1, SGOL2, SLC25A17, SLC4A4, SLC7A6, SMARCC2, SMC4, SMC6, SMCHD1, SMN2, SMPD4, SMYD3, SNAP23, SNHG16, SOCS2, SOS2, SPATA20, SPATS2, SPG20, SQRDL, SREBF1, SREK1, SRSF3, STAT1, STAU1, STEAP2, STRN3, STX16, SUPT20H, SYNE1, SYNE2, SYT15, SYTL2, TAF2, TARBP1, TARS, TBL2, TCF7L2, TENC1, TENM2, TEP1, TET3, TGFBR1, THADA, THRB, TJP2, TLE3, TMEM47, TMEM63A, TNFAIP3, TNIP1, TNPO3, TNS1, TNS3, TOE1, TOMM5, TP53INP1, TRAF3, TRAPPC12, TRIM2, TRIM23, TRIM65, TSC2, TSPAN2, TUBB2C, TXNRD1, UBAP2L, UBE2V1, UCHL5, USP19, VANGL1, VIPAS39, VPS29, VPS51, VWA8, WDR48, WNT5B, WSB1, WWTR1, XRN2, YAP1, YES1, YPEL5, YTHDF3, Z24749, ZBTB24, ZC3H14, ZFAND1, ZFAND5, ZHX3, ZMIZ1, ZMYM2, ZNF219, ZNF268, ZNF395, ZNF827 or ZNF91

[2062] Table 6 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon with a corresponding change in isoform abundance as a result of iExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.

TABLE-US-00008 TABLE 6 ACACA, ACADVL, AFF2, AHCYL2, AHRR, AKAP1, ALDH4A1, ANKRD17, AP2B1, APLP2, ASL, ASPH, ATG9A, ATMIN, ATXN3, BAG2, BASP1, BRPF1, BSCL2, C11orf30, C11orf73, C17orf76-AS1, C6orf48, C9orf69, CAB39, CALU, CDC25B, CDC42BPA, CDKAL1, CLIC1, COL12A1, COL1A1, COL6A1, CSNK1A1, CTDSP2, CUL2, CUL4A, DAXX, DCAF10, DDAH1, DDR1, DDX39B, DENND1A, DGCR2, DKFZp434M1735, DKK3, DNM2, DST, EEF1A1, EFCAB14, EHMT2, EIF4G1, EIF4G2, EIF4G3, ENSA, EXO1, FAM111A, FAM198B, FAM65A, FBXO34, FEZ1, FGD5-AS1, FGFRL1, FLII, FN1, FOXK1, FOXM1, FUS, GALC, GALNT1, GAS7, GCFC2, GGCT, GJC1, GNA13, GNL3L, GOLGA4, GPR1, GREM1, HEG1, HLA-A, HLA-E, HLTF, HNRNPR, HNRNPUL1, IQCE, ITGB5, ITSN1, KIAA1033, KIF2A, KIF3A, KLC2, LATS2, LIMS1, LINC00341, LINC00657, LONP1, LOX, LUC7L2, MBD1, MBOAT7, MEF2D, MEIS2, MICAL2, MKL1, MKNK2, MLST8, MPPE1, MSL3, MSRB3, MTRR, MYADM, MYLK, MYO1D, NAA35, NAV1, NAV2, NCOA1, NFX1, NKX3-1, NOMO3, NRG1, NUDT4, NUPL1, NUSAP1, OSMR, P4HA1, P4HB, PAPD4, PARD3, PARN, PARP14, PARVB, PCBP2, PCBP4, PCGF3, PDLIM7, PDXDC1, PEX5, PFKP, PHRF1, PI4K2A, POLE3, POLR3D, POSTN, PPARA, PPP6R1, PPP6R2, PRNP, PXN, RAB34, RAD23B, RALB, RAP1A, RASSF8, RBCK1, RBFOX2, RGS10, RIF1, RNF14, RNF19A, SAMD9, SCAF4, SDCBP, SERPINE2, SF1, SH3RF1, SKIL, SLC25A17, SLC4A4, SMG1, SMN2, SNHG16, SREBF1, STAT3, STC2, STEAP2, STRN3, SYNE1, SYNE2, TACC1, TARS, TGFBI, TMEM47, TNC, TNFRSF12A, TNS1, TRAF3, TRIM28, TSC2, TSHZ1, TTC7A, TUBB2C, TUBB3, TXNL1, TXNRD1, UBE2G2, UBE2V1, UBQLN4, UNC5B, USP19, VARS2, VCL, VPS29, WDR37, WIPF1, WWTR1, ZC3H12C, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZMIZ1, ZNF28, ZNF281, ZNF655, ZNF764 or ZNF839

[2063] Table 7 shows genes that demonstrate an effect on change in isoform abundance as a result of having intronic REMS elements in the presence of Compound 774 (at doses ranging from 0.3 μM to 3 μM), having statistically significant adjusted Fisher's Exact Test p value.

TABLE-US-00009 TABLE 7 ABCB8, ABCC3, ADAM17, ADCY3, AGPAT4, ANKRA2, ANXA11, APIP, APLP2, APPL2, ARHGAP1, ARL15, ASAP1, ASPH, ATAD2B, ATXN1, AXIN1, 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, DAGLB, DCAF17, DCUN1D4, DDX42, DENND1A, DENND5A, DGKA, DHFR, DIAPH3, DLGAP4, DNAJC13, DNMBP, DOCK1, DYRK1A, EIF2B3, ENAH, ENOX1, EP300, ERC1, ERCC1, ERGIC3, ERLIN2, ERRFI1, EVC, FAF1, FAIM, FAM126A, FAM13A, FAM162A, FAM174A, FAM198B, FBN2, FER, FHOD3, FOCAD, GALC, GCFC2, GGACT, GGCT, GLCE, GOLGA4, GOLGB1, GPSM2, GULP1, GXYLT1, HAT1, HDX, HLTF, HMGA2, HNMT, HPS1, HSD17B12, HSD17B4, HTT, IFT57, INPP5K, IVD, KDM6A, KIAA1524, KIAA1715, LETM2, LOC400927, LRRC42, LUC7L3, LYRM1, MADD, 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, PPHLN1, PPIP5K2, PPP1R26, PRPF31, PRSS23, PRUNE2, PSMA4, PXK, RAF1, RAP1A, RAPGEF1, RARS2, RBKS, RERE, RFWD2, RNFT1, RPA1, RPS10, RPS6KB2, SAMD4A, SAR1A, SCO1, SEC24A, SENP6, SERGEF, SGK3, SH3YL1, SKA2, SLC12A2, SLC25A17, SLC44A2, SMYD3, SNAP23, SNHG16, SNX7, SOS2, SPATA18, SPATA5, SPIDR, SPRYD7, SRGAP1, SRRM1, STAT1, STRN3, STXBP6, SUPT20H, TAF2, TASP1, TBC1D15, TCF12, TCF4, TIAM1, TJP2, TMC3, TMEM189-UBE2V1, TMEM214, TNRC6A, TNS3, TOE1, TRAF3, TRIM65, TSPAN2, TTC7B, TUBE1, TYW5, UBAP2L, UBE2V1, URGCP, VAV2, VPS29, WDR27, WDR37, WDR91, WNK1, XRN2, ZCCHC8, ZFP82, ZNF138, ZNF232, ZNF37BP or ZNF680

[2064] Table 7a shows genes that demonstrate an effect on inclusion of an iExon with a corresponding change in isoform abundance as a result of having intronic REMS elements in the presence of Compound 774 (at doses ranging from 0.3 μM to 3 μM), having statistically significant adjusted Fisher's Exact Test p value.

TABLE-US-00010 TABLE 7a 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

[2065] Table 7b shows genes that demonstrate an effect on inclusion of an exon with a corresponding change in isoform abundance as a result of having iREMS elements in the presence of Compound 774 (at doses ranging from 0.3 μM to 3 μM), having statistically significant adjusted Fisher's Exact Test value.

TABLE-US-00011 TABLE 7b APLP2, AXIN1, CECR7, DAGLB, DLGAP4, ERCC1, ERGIC3, FAM198B, GGCT, HAT1, HPS1, INPP5K, MADD, PPHLN1, PRUNE2, RAP1A, RNFT1, RPS6KB2, SH3YL1, SKA2, SPATA18, STRN3, TMEM189-UBE2V1, TRIM65, TUBE1, UBE2V1, VPS29 or ZNF680
Methods of Preventing and/or Treating Diseases

[2066] In another aspect, provided herein are methods for preventing and/or treating a disease associated with the aberrant expression of a product of a gene (e.g., an mRNA transcript or protein), wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2067] In certain embodiments, the gene is any one of the genes disclosed in Tables 2-7 or 1. In certain embodiments, the gene contains a nucleotide sequence encoding a non-endogenous intronic REMS. In certain embodiments, the gene contains a nucleotide sequence encoding an endogenous intronic REMS. In one embodiment, provided herein are methods for preventing and/or treating a disease associated with aberrant expression of a product of a gene (e.g., an mRNA, RNA transcript or protein), by way of nonlimiting example, disclosed in Table 1, supra, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one of the introns comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2068] In another embodiment, provided herein are methods for preventing and/or treating a disease associated with aberrant expression of a product of a gene (e.g., an mRNA, RNA transcript or protein), disclosed in Tables 2-7, supra, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2069] In another embodiment, provided herein are methods for preventing and/or treating a disease associated with aberrant expression of a product of a gene (e.g., an mRNA, RNA transcript or protein), by way of nonlimiting example, disclosed in International Patent Application No. PCT/US2014/071252 (International Publication No. WO 2015/105657), wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease associated with aberrant expression of a product of a gene (e.g., an mRNA, RNA transcript or protein), by way of nonlimiting example, disclosed in International Patent Application No. PCT/US2016/034864 (International Publication No. WO 2016/196386), wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease associated with aberrant expression of a product of a gene (e.g., an mRNA, RNA transcript or protein), by way of nonlimiting example, not disclosed in either International Publication No. WO 2015/105657, International Publication No. WO 2016/196386, or both, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2070] In another embodiment, provided herein are methods for preventing and/or treating a disease associated with aberrant expression of a product of a gene (e.g., an mRNA, RNA transcript or protein), disclosed in Table 1, supra, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2071] In another embodiment, provided herein are methods for preventing and/or treating a disease associated with aberrant expression of a product of a gene, disclosed in Table 7, supra, (e.g., an mRNA, RNA transcript or protein), comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes in Table 7. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2072] In another aspect, provided herein are methods for preventing and/or treating a disease in which a change in the level of expression of one, two, three or more RNA isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2073] In certain embodiments, the gene is any one of the genes disclosed in Tables 2-7 or 1. In certain embodiments, the gene contains a nucleotide sequence encoding ae non-endogenous intronic REMS. In certain embodiments, the gene contains a nucleotide sequence encoding an endogenous intronic REMS. In one embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 1, supra, is beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2074] In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene, disclosed in Tables 2-7, supra, is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene, disclosed in International Patent Application No. PCT/US2014/071252 (International Publication No. WO 2015/105657), is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene, disclosed in International Patent Application No. PCT/US2016/034864 (International Publication No. WO 2016/196386), is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene, not disclosed in either International Publication No. WO 2015/105657, International Publication No. WO 2016/196386, or both, is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2075] In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene, disclosed in Table 1, supra, is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2076] In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene, disclosed in Table 1, supra, is beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, one, two, three or more RNA isoforms encoded by a gene, disclosed in Table 7, supra, are decreased following administration of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes in Table 7. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2077] In another aspect, provided herein are methods for preventing and/or treating a disease in which a change in the level of expression of one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2078] In certain embodiments, the gene is any one of the genes disclosed in Tables 2-7 or 1. In certain embodiments, the gene contains a nucleotide sequence encoding a non-endogenous intronic REMS. In certain embodiments, the gene contains a nucleotide sequence encoding an endogenous intronic REMS. In one embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 1, supra, is beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2079] In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene, disclosed in Tables 2-7, supra, is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2080] In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene, disclosed in International Patent Application No. PCT/US2014/071252 (International Publication No. WO 2015/105657), is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene, disclosed in International Patent Application No. PCT/US2016/034864 (International Publication No. WO 2016/196386), is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2081] In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene, disclosed in Table 1, supra, is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2082] In another embodiment, provided herein are methods for preventing and/or treating a disease in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene, disclosed in Table 1, supra, is beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, one, two, three or more RNA isoforms encoded by a gene, disclosed in Table 7, supra, are decreased following administration of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes in Table 7. In a specific embodiment, the gene comprises one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS.

[2083] In another embodiment, provided herein is a method for either preventing, treating or preventing and treating a disease in a subject in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first 5′ splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, an IREMS, a nucleotide sequence encoding a second branch point and a nucleotide sequence encoding a second 3′ splice site, wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), and wherein r is adenine or guanine and n is any nucleotide, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.

[2084] In another embodiment, provided herein is a method for either preventing, treating and preventing and treating a disease in a subject in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence of the intron comprises in 5′ to 3′ order: an iREMS, a nucleotide sequence encoding a first branch point and a nucleotide sequence encoding a first 3′ splice site, wherein the IREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), and wherein r is adenine or guanine and n is any nucleotide, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.

[2085] In another embodiment, provided herein is a method for either preventing, treating and preventing and treating a disease in a subject in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1A, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.

[2086] In another embodiment, provided herein is a method for either preventing, treating or preventing and treating a disease in a subject in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1B, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.

[2087] In another embodiment, provided herein is a method for either preventing, treating or preventing and treating a disease in a subject in which the alteration (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron and wherein the DNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1C, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.

[2088] In a specific embodiment, the gene is a gene described in a table in this disclosure.

[2089] In some embodiments, the compound of Formula (I) or a form thereof that is administered to a subject is a compound of Formula (11), Formula (111), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV). In some embodiments, the compound of Formula (I) or a form thereof that is administered to a subject is a compound described herein.

[2090] In a specific embodiment, the methods for preventing a disease described herein prevent the onset or development of one or symptoms of the disease. In another embodiment, the methods for preventing a disease described herein prevent the recurrence of the disease or delays the recurrence of the disease. In another embodiment, the methods for treating a disease described herein has one, two or more of the effects: (i) reduce or ameliorate the severity of the disease; (ii) inhibit the progression of the disease; (iii) reduce hospitalization of a subject; (iv) reduce hospitalization length for a subject; (v) increase the survival of a subject; (vi) improve the quality of life of a subject; (vii) reduce the number of symptoms associated with the disease; (viii) reduce or ameliorates the severity of a symptom(s) associated with the disease; (ix) reduce the duration of a symptom(s) associated with the disease; (x) prevent the recurrence of a symptom associated with the disease; (xi) inhibit the development or onset of a symptom of the disease; and/or (xii) inhibit of the progression of a symptom associated with the disease.

[2091] In certain embodiments, the disease or disorder prevented and/or treated in accordance with a method described herein is a disease or disorder associated with a gene listed in Table 1 or Table 7. In specific embodiments, the disease or disorder prevented and/or treated in accordance with a method described herein is leukemia, acute myeloid leukemia, colon cancer, gastric cancer, macular degeneration, acute monocytic leukemia, breast cancer, combined methylmalonic aciduria and homocystinuria, cblC type, hepatocellular carcinoma, cone-rod dystrophy, alveolar soft part sarcoma, myeloma, skin melanoma, prostatitis, pancreatitis, pancreatic cancer, retinitis, adenocarcinoma, adenoiditis, adenoid cystic carcinoma, cataract, retinal degeneration, gastrointestinal stromal tumor, Wegener's granulomatosis, sarcoma, myopathy, prostate adenocarcinoma, Alzheimer's disease, hyperprolinemia, acne, tuberculosis, succinic semialdehyde dehydrogenase deficiency, esophagitis, mental retardation, esophageal adenocarcinoma, glycine encephalopathy, Crohn's disease, spina bifida, tuberculosis, autosomal recessive disease, schizophrenia, neural tube defects, lung cancer, myelodysplastic syndromes, amyotropic lateral sclerosis, neuronitis, germ cell tumors, Parkinson's disease, talipes equinovarus, dystrophinopathies, Hodgkin's lymphoma, ovarian cancer, non-Hodgkin's lymphoma, multiple myeloma, chronic myeloid leukemia, ischemia, acute lymphoblastic leukemia, renal cell carcinoma, transitional cell carcinoma, colorectal cancer, chronic lymphocytic leukemia, anaplastic large cell lymphoma, kidney cancer, cerebritis, bladder related disorders, breast cancer, cervical cancer, cleft lip, cleft palate, cervicitis, spasticity, lipoma, scleroderma, Gitelman syndrome, poliomyelitis, paralysis, Aagenaes syndrome, or oculomotor nerve paralysis.

[2092] In specific embodiments, the disease or disorder prevented and/or treated in accordance with a method described herein is basal cell carcinoma, goblet cell metaplasia, or a malignant glioma. In other specific embodiments, the disease or disorder prevented and/or treated in accordance with a method described herein is a cancer of the liver, breast, lung, prostate, cervix, uterus, colon, pancreas, kidney, stomach, bladder, ovary, or brain.

[2093] In other specific embodiments, the disease or disorder prevented and/or treated in accordance with a method described herein is Duchenne muscular dystrophy, Beckers muscular dystrophy, Facioscapulohumeral muscular dystrophy, Limb-girdle muscular dystrophy, Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy, Huntington's disease, amyotrophic lateral sclerosis, cystic fibrosis, congenital myopathies, muscle dystrophies, Alzheimer's disease, Parkinson's disease, schizophrenia, bipolar disorders, cognitive impairment, hereditary sensory and autonomic neuropathies, diseases of chronic inflammation, immune check point-dependent diseases, retinitis pigmentosa, aniridia, Dravet disease, or an epilepsy.

[2094] In certain embodiments, the disease prevented and/or treated in accordance with a method described herein is a disease caused by expression of one or more aberrant RNA transcripts, including a cancer amenable to treatment by downregulation of a gene or isoform thereof as described herein. In specific embodiments, cancers that can be prevented and/or treated in accordance with a method described herein include, but are not limited to, cancer of the head, neck, eye, mouth, throat, esophagus, esophagus, chest, bone, lung, kidney, colon, rectum or other gastrointestinal tract organs, stomach, spleen, skeletal muscle, subcutaneous tissue, prostate, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain or central nervous system.

[2095] Specific examples of cancers that can be prevented and/or treated in accordance with the methods provided herein include, but are not limited to, the following: renal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast carcinoma; breast sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma; carcinomas of the epidermis; leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myclodysplastic syndrome, chronic leukemias such as but not limited to, chronic myclocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin's disease, non-Hodgkin's disease; multiple myelomas such as but not limited to smoldering multiple mycloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcomas such as but not limited to bone sarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced bone osteosarcoma, Paget's disease of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease (including juvenile Paget's disease) and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; cervical carcinoma; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; KRAS-mutated colorectal cancer; PD-1-dependent cancers; PD-1L-dependent cancers; colon carcinoma; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to papillary, nodular, and diffuse; lung cancers such as KRAS-mutated non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; lung carcinoma; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, androgen-independent prostate cancer, androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma; kidney cancers such as but not limited to renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer); renal carcinoma; Wilms' tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesotheliorna, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas.

[2096] In certain embodiments cancers that can be prevented and/or treated in accordance with the methods provided herein include, the following: pediatric solid tumor, Ewing's sarcoma, Wilms tumor, neuroblastoma, neurofibroma, carcinoma of the epidermis, malignant melanoma, cervical carcinoma, colon carcinoma, lung carcinoma, renal carcinoma, breast carcinoma, breast sarcoma, metastatic breast cancer, HIV-related Kaposi's sarcoma, prostate cancer, androgen-independent prostate cancer, androgen-dependent prostate cancer, neurofibromatosis, lung cancer, non-small cell lung cancer, KRAS-mutated non-small cell lung cancer, malignant melanoma, melanoma, colon cancer, KRAS-mutated colorectal cancer, glioblastoma multiforme, renal cancer, kidney cancer, bladder cancer, ovarian cancer, hepatocellular carcinoma, thyroid carcinoma, rhabdomyosarcoma, acute myeloid leukemia, and multiple myeloma.

[2097] In certain embodiments, cancers and conditions associated therewith that are prevented and/or treated in accordance with the methods provided herein are breast carcinomas, lung carcinomas, gastric carcinomas, esophageal carcinomas, colorectal carcinomas, liver carcinomas, ovarian carcinomas, thecomas, arrhenoblastomas, cervical carcinomas, endometrial carcinoma, endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma, head and neck cancer, nasopharyngeal carcinoma, laryngeal carcinomas, hepatoblastoma, Kaposi's sarcoma, melanoma, skin carcinomas, hemangioma, cavernous hemangioma, hemangioblastoma, pancreas carcinomas, retinoblastoma, astrocytoma, glioblastoma, Schwannoma, oligodendroglioma, medulloblastoma, neuroblastomas, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, thyroid carcinomas, Wilm's tumor, renal cell carcinoma, prostate carcinoma, abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), or Meigs' syndrome. In specific embodiment, the cancer astrocytoma, an oligodendroglioma, a mixture of oligodendroglioma and an astrocytoma elements, an ependymoma, a meningioma, a pituitary adenoma, a primitive neuroectodermal tumor, a medullblastoma, a primary central nervous system (CNS) lymphoma, or a CNS germ cell tumor. In specific embodiments, the cancer treated in accordance with the methods provided herein is an acoustic neuroma, an anaplastic astrocytoma, a glioblastoma multiforme, or a meningioma. In other specific embodiments, the cancer treated in accordance with the methods provided herein is a brain stem glioma, a craniopharyngioma, an ependyoma, a juvenile pilocytic astrocytoma, a medulloblastoma, an optic nerve glioma, primitive neuroectodermal tumor, or a rhabdoid tumor.

[2098] Specific examples of conditions caused by expression of one or more aberrant RNA transcripts that can be prevented and/or treated in accordance with the methods described herein include cystic fibrosis, muscular dystrophy, polycystic autosomal-dominant kidney disease, cancer-induced cachexia, benign prostatic hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, retinopathies (including diabetic retinopathy and retinopathy of prematurity), retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, exudative macular degeneration, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, and pterygium keratitis sicca, viral infections, inflammation associated with viral infections, chronic inflammation, lung inflammation, nephrotic syndrome, preeclampsia, ascites, pericardial effusion (such as that associated with pericarditis), pleural effusion, Sjogren's syndrome, acne rosacea, phylectenulosis, syphilis, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infection, Herpes zoster infections, protozoan infections, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, systemic lupus, polyarteritis, trauma, Wegener's sarcoidosis, Paget's disease, scleritis, Stevens-Johnson's disease, pemphigoid, radial keratotomy, Eales' disease, Behcet's disease, sickle cell anemia, pseudoxanthoma elasticum, Stargardt's disease, pars planitis, chronic retinal detachment, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, ocular histoplasmosis, Mycobacteria infections, Lyme's disease, Best's disease, myopia, optic pits, hyperviscosity syndromes, toxoplasmosis, sarcoidosis, trauma, post-laser complications, diseases associated with rubeosis (neovascularization of the iris and of the angle), and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue, including all forms of prolific vitreoretinopathy. Certain examples of non-neoplastic conditions that can be prevented and/or treated in accordance with the methods described herein include viral infections, including but not limited to, those associated with viruses belonging to Flaviviridae, flavivirus, pestivirus, hepacivirus, West Nile virus, hepatitis C virus (HCV) or human papilloma virus (HPV).

[2099] Particular examples of conditions caused by expression of one or more of aberrant RNA transcripts that can be prevented and/or treated in accordance with the methods described herein include Duchenne muscular dystrophy, Beckers muscular dystrophy, Facioscapulohumeral muscular dystrophy, Limb-girdle muscular dystrophy, Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy, Huntington's disease, amyotrophic lateral sclerosis, cystic fibrosis, congenital myopathies, muscle dystrophies, Alzheimer's disease, Parkinson's disease, schizophrenia, bipolar disorders, cognitive impairment, hereditary sensory and autonomic neuropathies, diseases of chronic inflammation, immune check point-dependent diseases, retinitis pigmentosa, aniridia, Dravet disease, or an epilepsy.

Artificial Gene Constructs

[2100] Also provided herein are artificial gene constructs comprising a DNA sequence encoding exons and one or more introns, wherein the nucleotide sequence of at least one intron encodes an intronic REMS downstream of the nucleotide sequence encoding a branch point and the nucleotide sequence encoding a 3′ splice site in 5′ to 3′ order, and artificial gene constructs comprising an RNA sequence that comprises exons and one or more introns, wherein at least one intron comprises a branch point, a 3′ splice site and an intronic REMS in 5′ to 3′ order. The DNA sequence described herein can be or derived from, for example, a genomic DNA sequence or a DNA analog thereof. The RNA sequence described herein can be or derived from, for example, a precursor RNA transcript or an RNA analog thereof. As used herein, the term “artificial gene construct” refers to a DNA or RNA gene construct that comprises a nucleotide sequence not found in nature.

[2101] In another aspect, provided herein is 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), and wherein r is adenine or guanine and n is any nucleotide.

[2102] In another aspect, provide herein is 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), and wherein r is adenine or guanine and n is any nucleotide.

[2103] In another aspect, provided herein is an artificial gene construct comprising an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in FIG. 1A.

[2104] In another aspect, provided herein is an artificial gene construct comprising an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in FIG. 1B.

[2105] In another aspect, provided herein is an artificial gene construct comprising an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in FIG. 1C.

[2106] In another aspect, provided herein is an artificial gene construct comprising a DNA sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first 5′ splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, an iREMS, a nucleotide sequence encoding a second branch point and a nucleotide sequence encoding a second 3′ splice site, wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), and wherein r is adenine or guanine and n is any nucleotide.

[2107] In another aspect, provide herein is an artificial gene construct comprising a DNA sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the nucleotide sequence encoding the intron comprises in 5′ to 3′ order: an iREMS, a nucleotide sequence encoding a first branch point and a nucleotide sequence encoding a first 3′ splice site, wherein the iREMS comprises an DNA sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide.

[2108] In another aspect, provide herein is an artificial gene construct comprising a DNA sequence encoding two exons and an intron, wherein the DNA sequence comprises exonic and intronic elements illustrated in FIG. 1A.

[2109] In another aspect, provide herein is an artificial gene construct comprising a DNA sequence encoding two exons and an intron, wherein the DNA sequence comprises exonic and intronic elements illustrated in FIG. 1B.

[2110] In another aspect, provide herein is an artificial gene construct comprising a DNA sequence encoding two exons and an intron, wherein the DNA sequence comprises exonic and intronic elements illustrated in FIG. 1C.

[2111] In one aspect, provided herein are artificial gene constructs comprising an intronic REMS. In one embodiment, an artificial gene construct comprises genomic DNA or DNA encoding exons and one, two or more introns, wherein a nucleotide sequence encoding an intronic REMS, which may be upstream or downstream of a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site, is modified to introduce a nucleotide sequence encoding the intronic REMS. In another embodiment, an artificial gene construct comprises DNA encoding exons, an intronic REMS, a 3′ splice site(s) and a branch point(s) sequence, wherein a nucleotide sequence encoding an intronic REMS, which may be upstream or downstream of at least one nucleotide sequence encoding a branch point and at least one nucleotide sequence encoding a 3′ splice site, is modified to introduce a nucleotide sequence encoding an intronic REMS. In another embodiment, an artificial gene construct comprises genomic DNA or DNA encoding exons and one, two or more introns, wherein a nucleotide sequence encoding an intronic REMS, which may be upstream or downstream of a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site, is introduced into an intron by genetic engineering. In another embodiment, an artificial gene construct comprises genomic DNA or DNA encoding exons and one, two or more introns, wherein a nucleotide sequence encoding an intronic REMS, which may be upstream or downstream of a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site, is endogenously present in an intron. In some embodiments, an artificial gene construct comprises a DNA sequence that is genetically engineered to introduce a nucleotide sequence encoding an intronic REMS, wherein the location of the intronic REMS is as illustrated in any of FIGS. 1A-1C. In some embodiments, an artificial gene construct comprises a DNA sequence that is genetically engineered to comprise one, two, or all of the following: intronic REMS, branch point, and 3′ splice site. In some embodiments, an artificial gene construct comprises a DNA sequence that is genetically engineered to comprise a branch point, a 3′ splice site and an intronic REMS, in 5′ to 3′ order. In certain embodiments, the DNA sequence chosen to be used in the production of an artificial gene construct may contain a nucleotide sequence encoding an intronic REMS and an additional nucleotide sequence encoding an intronic REMS or a branch point or a 3′ splice site sequence is introduced. In specific embodiments, the nucleotide sequence encoding an intronic REMS or a branch point or a 3′ splice site is a non-endogenous sequence, i.e., a sequence not naturally found in the DNA sequence of the artificial gene construct. In certain embodiments, the artificial gene construct comprises other elements, such as a promoter (e.g., a constitutive, inducible or tissue specific promoter), a Poly(A) site, a transcription termination site, and a transcription binding site(s). In certain embodiments, the artificial gene construct comprises at least the sequences to encode a therapeutic protein. In some embodiments, the artificial gene construct comprises at least an intronic REMS for a gene listed in Table 1-7. In a specific embodiment, the artificial gene construct further comprises exons of a gene listed in Table 1-7. In certain embodiments, the artificial gene construct comprises at least the exons of a detectable reporter gene, such as green fluorescent protein (GFP), yellow fluorescent protein (YFP), red fluorescent protein, beta galactosidase, renilla luciferase, firefly luciferase, etc.

[2112] In certain embodiments, an artificial gene construct is produced as follows: a nucleotide sequence encoding an intronic REMS is introduced into a nucleotide sequence encoding an existing intronic branch point and intronic 3′ splice site of genomic DNA or DNA, wherein the DNA encodes two or more exons and one or more introns, and wherein the nucleotide sequence encoding the intronic REMS is downstream (in a preferred embodiment) or upstream of a nucleotide sequence encoding a branch point and a 3′ splice site. In some embodiments, an artificial gene construct is produced as follows: a nucleotide sequence encoding an intronic REMS is introduced downstream (in a preferred embodiment) or upstream of a nucleotide sequence encoding a branch point and a 3′ splice site of genomic DNA or DNA, wherein the DNA encodes two or more exons and an intron(s). In a specific embodiment, the nucleotide sequence encoding the intronic REMS is introduced internally within a nucleotide sequence encoding an intron. In certain embodiments, an artificial gene construct is produced as follows: a nucleotide sequence encoding an intronic REMS, a nucleotide sequence encoding a branch point, and a nucleotide sequence encoding a 3′ splice site are introduced into a cDNA, wherein the nucleotide sequence encoding the intronic REMS may be upstream of the branch point and 3′ splice site, respectively; or may be downstream (in a preferred embodiment) of the 3′ splice site and branch point, respectively. The nucleotide sequence encoding the intronic REMS functions as a 5′ splice site. In certain embodiments, the nucleotide sequence encoding the intronic REMS is internally within an intron. In a specific embodiment, the genomic DNA or DNA chosen for use in the production of an artificial gene construct does not contain one or more of a nucleotide sequence encoding an intronic REMS or a nucleotide sequence encoding a branch point or a nucleotide sequence encoding a 3′ splice site. In certain embodiments, the genomic DNA or DNA chosen for use in the production of an artificial gene construct contains an intronic REMS and an additional intronic REMS is introduced. In some embodiments, in introducing a nucleotide sequence encoding an intronic REMS into a DNA sequence, care should be taken so as not to disrupt an open reading frame or introduce a stop codon. The introduction of a nucleotide sequence encoding an intronic REMS into a DNA sequence may or may not result in an amino acid change at the protein level. In certain embodiments, the introduction of a nucleotide sequence encoding an intronic REMS into a DNA sequence results in an amino acid change at the protein level. In some embodiments, this amino acid change is a conservative amino acid substitution. In other embodiments, the introduction of a nucleotide sequence encoding an intronic REMS into a DNA sequence does not result in an amino acid change at the protein level. Techniques known to one of skill in the art may be used to introduce an intronic REMS and other elements, such as a branch point sequence or 3′ splice site sequence into a DNA sequence, e.g., gene editing techniques such as the CRISPR-Cas approach, Transcription Activator-Like Effector Nucleases (TALENs), or Zinc finger nucleases (ZFNs) may be used.

[2113] In certain embodiments, an artificial gene construct comprises an RNA sequence comprising exons and one, two or more introns, wherein an intronic REMS 5′ splice site, which is downstream of a 3′ splice site, is introduced into an intron by genetic engineering. In another embodiment, an artificial gene construct comprises an RNA sequence comprising exons, one, two or more introns, a 5′ splice site(s), a 3′ splice site(s) and a branch point(s), wherein an intronic REMS, which is downstream of a 3′ splice site, is introduced into an intron by genetic engineering. In some embodiments, an artificial gene construct comprises a DNA sequence that is genetically engineered to comprise one, two, or all of the following: branch point, 3′ splice site and/or intronic REMS. In some embodiments, an artificial gene construct comprises a DNA sequence that is genetically engineered to comprise a branch point, a 3′ splice site and an intronic REMS, in 5′ to 3′ order. In another embodiment, an artificial gene construct comprises an RNA sequence comprising exons and one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS, wherein the intronic REMS is endogenously present in an intron. In another embodiment, an artificial gene construct comprises an RNA sequence comprising exons, endogenously having a 5′ splice site(s), a 3′ splice site(s) and a branch point(s), wherein an intron, which is upstream of a 3′ splice site, is modified to introduce a non-endogenous branch point, a non-endogenous 3′ splice site and a non-endogenous intronic REMS. In specific embodiments, the intronic REMS is non-endogenous, i.e., not naturally found in the RNA sequence of the artificial gene construct. In certain embodiments, the artificial gene construct comprises other elements, such as a promoter (e.g., a tissue-specific promoter or constitutively expressed promoter), 5′ untranslated region, 3′ untranslated region, a binding site(s) for RNA binding proteins, a small molecule RNA sensor(s), e.g., riboswitches, stem-loop structures, and/or internal ribosome entry sites (IRES), etc. In certain embodiments, the artificial gene construct comprises at least the introns of a gene encoding a therapeutic protein. In some embodiments, the artificial gene construct comprises at least the introns of a gene listed in Tables 1-7. In a specific embodiment, the artificial gene construct further comprises exons of a gene listed in Table 1-7. In a specific embodiment, the RNA transcript chosen to be used in the production of an artificial gene construct does not contain an intronic REMS. In certain embodiments, the RNA transcript chosen to use in the production of an artificial gene construct contains an intronic REMS and an additional exonic or intronic REMS is introduced. In certain embodiments, the RNA transcript chosen to use in the production of an artificial gene construct contains an intronic REMS and an additional intronic REMS is introduced. In other embodiments, the artificial gene construct comprises at least one intron and two exons of a detectable reporter gene, such as green fluorescent protein (GFP), yellow fluorescent protein (YFP), red fluorescent protein, beta galactosidase, renilla luciferase, firefly luciferase, etc.

[2114] In certain embodiments, an artificial gene construct is produced as follows: an intronic REMS is introduced into an existing 5′ splice site of precursor RNA, wherein the RNA comprises two or more exons and one or more introns, and wherein an intronic REMS is upstream of a branch point sequence and a 3′ splice site sequence. In some embodiments, an artificial gene construct is produced as follows: an intronic REMS is introduced upstream of a 3′ splice site of a precursor RNA, wherein the RNA comprises two or more exons and an intron(s). In a specific embodiment, the intronic REMS is introduced internally within an intron. In certain embodiments, an artificial gene construct is produced as follows: a branch point, a 3′ splice site and an intronic REMS are introduced into a precursor RNA, wherein the REMS may be either downstream or upstream of the branch point and 3′ splice site. In certain embodiments, an artificial gene construct is produced as follows: a branch point, a 3′ splice site and an intronic REMS are introduced into an mRNA, wherein the REMS may be either downstream or upstream of the branch point and 3′ splice site. The intronic REMS functions as a 5′ splice site. In some embodiments, in introducing an intronic REMS into an RNA sequence, care should be taken so as not to disrupt an open reading frame or introduce a stop codon. The introduction of an intronic REMS into an RNA transcript may or may not result in an amino acid change at the protein level. In certain embodiments, the introduction of an intronic REMS into an RNA transcript results in an amino acid change at the protein level. In some embodiments, this amino acid change is a conservative amino acid substitution. In other embodiments, the introduction of an intronic REMS into an RNA transcript does not result in an amino acid change at the protein level. Techniques known to one of skill in the art may be used to introduce an intronic REMS and other elements, such as a branch point or 3′ splice site into an RNA transcript.

[2115] In some embodiments, an artificial gene construct is present in a viral vector (e.g., an adeno-associated virus (AAV), self-complimentary adeno-associated virus, adenovirus, retrovirus, lentivirus (e.g., Simian immunodeficiency virus, human immunodeficiency virus, or modified human immunodeficiency virus), Newcastle disease virus (NDV), herpes virus (e.g., herpes simplex virus), alphavirus, vaccina virus, etc.), a plasmid, or other vector (e.g., non-viral vectors, such as lipoplexes, liposomes, polymerosomes, or nanoparticles).

[2116] In some embodiments, the artificial gene construct is an RNA molecule modified to enable cellular uptake. In certain embodiments, the artificial gene construct is an RNA molecule containing pseudouridine or other modified/artificial nucleotides for enhanced cellular uptake and gene expression.

[2117] The use of an artificial gene construct described herein in gene therapy allows one to regulate the amount and type of a protein produced from the construct depending on whether or not a compound described herein is present. The compound is essentially a tunable switch that, depending on the amount and duration of the dose of the compound, regulates the amount and type of protein produced.

[2118] In certain embodiments, an RNA transcript transcribed from an artificial gene construct that is DNA would not produce or produce substantially less functional protein in the presence of a compound described herein than the amount of functional protein produced in the absence of a compound described herein. For example, if the artificial gene construct comprises a nucleotide sequence encoding an intronic REMS, which is downstream of an intronic nucleotide sequence encoding a branch point and a 3′ splice site, then the creation of an intronic exon would ultimately result in less amount of the original protein (i.e., without amino acid sequence derived from the intronic exon) being produced in the presence of a compound described herein. Alternatively, in certain embodiments, an RNA transcript transcribed from an artificial gene construct that is DNA would produce or would produce substantially less functional protein in the presence of a compound described herein than the amount of functional protein produced in the absence of a compound described herein.

[2119] In certain embodiments, an artificial gene construct or vector comprising an artificial gene construct is used in cell culture. For example, in a cell(s) transfected with an artificial gene construct or transduced with a vector comprising an artificial gene construct, the amount and type of a protein produced from the artificial gene construct can be altered depending upon whether or not a compound described herein is contacted with the transfected cell(s). For example, if the artificial gene construct comprises a nucleotide sequence encoding an intronic REMS, which is downstream of a nucleotide sequence encoding a branch point and a 3′ splice site, then the likelihood of producing an intronic exon would be less in the absence of the compound. Thus, the use of an artificial gene construct described herein allows one to regulate the amount and type of a protein produced from the construct depending on whether or not a compound described herein is present. In other words, a compound described herein is essentially a switch that regulates the amount and type of protein produced. This regulation of the production of protein could be useful, e.g., when trying to assess the role of certain genes or the effects of certain agents on pathways. The amount of the protein produced can be modified based on the amount of a compound described herein that is contacted with the transfected cell and/or how long the compound is contacted with the transfected cell.

[2120] In certain embodiments, an animal (e.g., a non-human animal, such as a mouse, rat, fly, etc.) is engineered to contain an artificial gene construct or a vector comprising an artificial gene construct. Techniques known to one of skill in the art may be used to engineer such animals. The amount of protein produced by this engineered animal can be regulated by whether or not a compound described herein is administered to the animal. The amount of the protein produced can be titrated based on the dose and/or the duration of administration of a compound described herein to the engineered animal. In certain embodiments, the artificial gene construct encodes a detectable reporter gene, such as green fluorescent protein (GFP), yellow fluorescent protein (YFP), red fluorescent protein, beta galactosidase, renilla luciferase, firefly luciferase, etc. In accordance with this embodiment, the engineered animal may be used to monitor development at different stages, visualize tissue function, etc. In other embodiments, the artificial gene construct encodes a therapeutic gene product, such as described the gene product of a gene in Tables 2-7 and 1. In accordance with this embodiment, the engineered animal may be used to monitor development at different stages or in functional biological studies where a certain protein or protein isoform needs to be expressed only for a period of time and not constitutively, etc.

[2121] In certain embodiments, an artificial gene construct or a vector comprising an artificial gene construct are used in gene therapy. Non-limiting examples of vectors include, but are not limited to, plasmids and viral vectors, such as vectors derived from replication defective retroviruses, adenoviruses, adeno-associated viruses and baculoviruses. The vector can be an RNA vector or preferably a DNA vector.

Gene Therapy

[2122] In another aspect, provided herein are artificial gene constructs or vectors comprising an artificial gene construct for use in gene therapy. The use of an artificial gene construct described herein in gene therapy allows one to regulate the amount and type of a protein produced from the construct depending on whether or not a compound described herein is present. The compound is essentially a switch that regulates the amount and type of protein produced.

[2123] In certain embodiments, an RNA transcript transcribed from an artificial gene construct that is DNA would not produce or would produce substantially more protein in the absence of a compound described herein than the amount of protein produced in the presence of a compound described herein. In certain embodiments, an RNA transcript transcribed from an artificial gene construct would not produce or would produce substantially more protein in the absence of a compound described herein than the amount of protein produced in the presence of a compound described herein. For example, if the artificial gene construct comprises a nucleotide sequence encoding an intronic REMS, which is downstream of a nucleotide sequence encoding a branch point and a 3′ splice site, then the likelihood of producing an intronic exon would be less in the absence of a compound described herein, which would ultimately result in more amount of the original protein (i.e., without amino acid sequence derived from the intronic exon) being produced. Thus, the use of an artificial gene construct or a vector comprising an artificial gene construct may be useful in treating and/or preventing certain conditions or diseases associated with genes. The conditions or diseases may include those described herein. Alternatively, in certain embodiments, an RNA transcript transcribed from an artificial gene construct that is DNA would produce substantially less functional protein in the presence of a compound described herein than the amount of functional protein produced in the absence of a compound described herein. For example, in certain embodiments, if the artificial gene construct comprises a nucleotide sequence encoding an intronic REMS, the production of the original protein (i.e., without amino acid sequence derived from the intronic exon), which is a functional protein, would be reduced in the presence of a compound described herein. However, in the absence of a compound described herein, normal splicing would occur, and the production of the functional protein will not be reduced. The amount and type of the protein produced can be titrated based on dose and duration of dosing of the compound.

[2124] In a specific embodiment, the artificial gene construct used in gene therapy comprises 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), and wherein r is adenine or guanine and n is any nucleotide.

[2125] In another specific embodiment, the artificial gene construct used in gene therapy comprises 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), and wherein r is adenine or guanine and n is any nucleotide.

[2126] In another specific embodiment, the artificial gene construct used in gene therapy comprises an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in FIG. 1A.

[2127] In another specific embodiment, the artificial gene construct used in gene therapy comprises an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in FIG. 1B.

[2128] In another specific embodiment, the artificial gene construct used in gene therapy comprises an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in FIG. 1C.

[2129] In another specific embodiment, the artificial gene construct used in gene therapy comprises a DNA sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first 5′ splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, an iREMS, a nucleotide sequence encoding a second branch point and a nucleotide sequence encoding a second 3′ splice site, wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide.

[2130] In another specific embodiment, the artificial gene construct used in gene therapy comprises a DNA sequence encoding two exons and an intron, wherein the nucleotide sequence encoding one exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding the other exon is downstream of the nucleotide sequence encoding the intron, wherein the nucleotide sequence encoding the intron comprises in 5′ to 3′ order: an iREMS, a nucleotide sequence encoding a first branch point and a nucleotide sequence encoding a first 3′ splice site, wherein the iREMS comprises an DNA sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide.

[2131] In another specific embodiment, the artificial gene construct used in gene therapy comprises a DNA sequence encoding two exons and an intron, wherein the DNA sequence comprises exonic and intronic elements illustrated in FIG. 1A.

[2132] In another specific embodiment, the artificial gene construct used in gene therapy comprises a DNA sequence encoding two exons and an intron, wherein the DNA sequence comprises exonic and intronic elements illustrated in FIG. 1B.

[2133] In another specific embodiment, the artificial gene construct used in gene therapy comprises a DNA sequence encoding two exons and an intron, wherein the DNA sequence comprises exonic and intronic elements illustrated in FIG. 1C.

[2134] An artificial gene construct, a vector comprising the artificial gene construct, or an RNA molecule comprising an artificial gene construct modified to enable cellular uptake may be introduced into cells or administered directly to patients. In one embodiment, an artificial gene construct or a vector comprising the artificial gene construct is introduced into cells ex vivo or in vivo. In a specific embodiment, an artificial gene construct or vector is introduced into a cell(s) ex vivo and the cell(s) may be administered to a subject. Various techniques known to one of skill in the art may be used to introduce an artificial gene construct or vector comprising the artificial gene construct into a cell(s), such as electroporation, transfection, transformation, etc. In another embodiment, an artificial gene construct or vector comprising the artificial gene construct is administered to a subject. The artificial gene construct or vector comprising the artificial gene construct may be administered to a subject by any technique known to one skilled in the art, e.g., intramuscularly, intravenously, subcutaneously, intradermally, topically, intrathecally, intraperitoneally, intratumorally, etc. In some embodiments, the artificial gene construct or vector comprising the artificial gene construct is administered to a subject systemically. In other embodiments, the artificial gene construct or vector comprising the artificial gene construct is administered to a subject locally.

Altering Endogenous Genes

[2135] In another aspect, provided herein are method for altering an endogenous gene such that it contains a nucleotide sequence encoding an intronic REMS, or contains an additional nucleotide sequence encoding an intronic REMS (in other words, an intronic REMS not naturally found in the endogenous gene, i.e., a non-endogenous intronic REMS). In a specific embodiment, provided herein are method for altering an endogenous gene such that it contains a nucleotide sequence encoding an intronic REMS and contains a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site upstream of the nucleotide sequence encoding the intronic REMS. As used herein, the term “endogenous gene” refers to a gene naturally found in a cell or living subject. Techniques known to one of skill in the art can be used to introduce any one, two, or all of the following: a branch point, a 3′ splice site, and an intronic REMS into an endogenous gene, e.g., the CRISPR-Cas approach, TALEN, or ZFN may be used. In certain embodiments, a nucleotide sequence encoding an existing 5′ splice site can be replaced with an intronic REMS or an intronic REMS may be inserted internally within an intron. In certain embodiments, in introducing a nucleotide sequence encoding an intronic REMS into an endogenous gene, care should be taken so as not to disrupt an open reading frame or introduce a stop codon. The introduction of a nucleotide sequence encoding an intronic REMS into an endogenous gene may or may not result in an amino acid change at the protein level. In certain embodiments, the introduction of a nucleotide sequence encoding an intronic REMS into an endogenous gene results in an amino acid change at the protein level. In some embodiments, this amino acid change is a conservative amino acid substitution. In other embodiments, the introduction of a nucleotide sequence encoding an intronic REMS into an endogenous gene does not result in an amino acid change at the protein level.

[2136] In one aspect, provided herein are kits comprising, in a container, an artificial gene construct or a vector comprising an artificial construct. In certain embodiments, the kits further comprise a compound described herein, in a separate container, and/or a negative control, such as phosphate buffered saline or a compound that does not recognize an intronic REMS, in a separate container. In a specific embodiment, the kits further comprise a positive control, such as a compound described herein as a positive control. In some embodiments, the kits further comprise primers and/or antibodies, in one or more separate containers, for assessing the production of an mRNA transcript from an artificial gene construct and/or protein production therefrom.

[2137] In another aspect, provided herein are kits comprising, in one or more containers, the components and/or reagents necessary to produce an artificial gene construct and/or a vector comprising an artificial gene construct. In another aspect, provided herein are kits comprising, in one or more containers, the components and/or reagents necessary to alter an endogenous gene so that it contains a nucleotide sequence encoding an intronic REMS or an additional nucleotide sequence encoding an intronic REMS (in other words, a REMS not naturally found in the endogenous gene, i.e., a non-endogenous REMS). In another aspect, provided herein are kits comprising, in one or more containers, the components and/or reagents necessary to alter an endogenous gene so that it contains a nucleotide sequence encoding an intronic REMS and contains a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site upstream of the nucleotide sequence encoding the intronic REMS. In some embodiments, the kits further comprise primers and/or antibodies, in one or more separate containers, for assessing the production of an mRNA transcript from altered endogenous gene and/or protein production therefrom.

[2138] In another aspect, provided herein are kits comprising, in a container, a compound described herein, and instructions for use. In some embodiments, the kits further comprise a negative control, such as phosphate buffered saline or a compound that does not recognize an intronic REMS, in a separate container.

Examples

[2139] To describe in more detail and assist in understanding the present description, the following non-limiting biological examples are offered to more fully illustrate the scope of the description and are not to be construed as specifically limiting the scope thereof. Such variations of the present description that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are considered to fall within the scope of the present description and as hereinafter claimed. The example below illustrates the existence of an intronic recognition element for splicing modifier (REMS) that is important for the recognition of a compound described herein, and the binding of such a compound to the intronic REMS on a precursor RNA permits or enhances the splicing of the precursor RNA, and suggests the usefulness of the intronic REMS in combination with a compound described herein for modulating RNA splicing, and for modulating the amount of a gene product.

[2140] Materials and Methods

[2141] Cell treatment: GM04856 lymphocyte cells were diluted in a medium composed of DMEM, 10% FBS and 1x Pen/Strep to a concentration of 2.5e5 cells/mL. 2 mL (500K cells) were seeded in 6-well plates and recovered for 4 h at 37° C., 5% CO.sub.2. Compound dilutions were prepared as 2× compound stock in medium (e.g. for final 100 nM, make a 200 nM stock). After 4 h recovery, 2 mL of the 2× compound stock were added to each well, resulting in 4 mL/well with 1× final compound concentration. The cells were incubated for ˜20 h at 37° C., 5% CO.sub.2. After incubation, the cells were pelleted for 5 min at 1000 rpm. The supernatant was vacuum-removed and the cells were resuspended in 350 μl of RLT buffer (w/10 μl/mL beta-mercapto-ethanol, RNeasy kit). Total RNA was isolated using the RNeasy Mini Kit from Qiagen according to the manufacturer's instructions. The concentration of the resulting total RNA was determined using Nanodrop and diluted with water to a final concentration of 25 ng/μL.

[2142] Endpoint PCR: 20 μL endpoint RT-PCRs were set up in 96-well plates using the AgPath-ID One-Step RT-PCR Reagents (Applied Biosystems) according to the manufacturer. Each reaction contained 200 nM forward primer, 200 nM reverse primer, and 50 ng total RNA. The following RT-PCR protocol was used: reverse transcription at 48° C. for 15 min, denaturation at 95° C. for 10 min, 35 PCR cycles with denaturation at 95° C. for 30 sec, annealing at 58° C. for 30 sec, and elongation at 68° C. for 1 min, final hold at 4° C. 10 μL of each RT-PCR reactions were analyzed on 2% 48-well E-Gels (Invitrogen) (pre-run 1 min, run 14 min) and imaged using an BioRad Gel Doc EZ Imager. The following size markers were used: TrackIt 1 Kb Plus DNA ladder and TrackIt 100 bp DNA ladder (10 μL/well, both Invitrogen).

[2143] Results: Oligonucleotides corresponding to exons that flank the intron where an iExon is located were used to amplify total RNA purified from untreated (DMSO) or cells treated with Compound 774 (at dose levels 10 nM, 1 μM or 10 μM). The resulting products were run on an agarose gel and the resulting bands of interest are demarcated by arrowheads, as shown in FIGS. 2A-D and 3-6A. In all cases, the increase of compound concentration results in appearance of a slower migrating PCR product containing the intronic-derived exon. In all cases, additional bands seen are intermediate spliced products.

[2144] Endpoint RT-PCR: Analysis of alternatively spliced mRNAs in cultured cells

[2145] GM03813 cells (Coriell Institute) derived from a patient with SMA type I (Coriell Institute) were plated at 5,000 cells/well in 200 μL DMEM with 10% FBS in 96-well plates, and incubated for 6 hours in a cell culture incubator (37° C., 5% CO.sub.2, 100% relative humidity). Cells were then treated with certain representative compounds (e.g., Compound 774, Compound 702 and Compound 170) at different concentrations (in 0.5% DMSO) in duplicate for 24 hours. After removal of the supernatant, cells were lysed in Cells-To-Ct lysis buffer (Life Technologies, Inc.). Reverse transcription was performed using 5 μL of cell lysate and the iScript RT enzyme kit (Bio-Rad Laboratories, Inc). PCR was performed using 5 &L of cDNA and Platinum Taq HMFi DNA Polymerase (Life Technologies, Inc.) under the following PCR conditions: Step1: 94° C. (2 min), Step 2: 94° C. (30 sec), Step 3: 55° C. (30 sec), Step 4: 68° C. (1 min), then repeat Steps 2 to 4 for 33 cycles, then hold at 4° C. Alternatively spliced mRNAs were identified using primers listed in Tables 8 and 9. PCR products were separated on 2% agarose E-gels, stained with ethidium bromide and visualized using a gel imager (UVP). Results for genes affected by intronic exons generated by treatment with Compound 774 are shown in Table 10.

TABLE-US-00012 TABLE 8 SEQ ID Gene Forward Primer Sequence 5′-3′ NO. ABCB8 ABCB_54-73 GCCGGCGGCTCCTGTTTTAC 3629 ANXA11 ANXA_101-120 AGTCGCTGTACCACGACATC 3630 ARL15 ARL1_87-106-1a-KE GCTGCCGGATGTCTGATCTC 3631 DCAF17 DECA_23-43-KE TGCTGTACCTTGCAGTGTTCC 3632 DHFR DHFR_5-24 CCATGAATCACCCAGGCCAT 3633 FAIM FAIM_197-217-KE GTGAAACCTACCCCAGAGCCT 3634 GXYLT1 GXYL_57-77 GGAAGCAATTGCCAAGAAGCA 3635 HTT HTT_E49_For TGCCCAGTCATTTGCACCTT 3636 MADD MADD_137-156-KE TGCCACAGGAAAGGGTCCTA 3637 MEMO1 MEMO_37-56 TGGAGCTCTGAGTGAGTCAA 3638 OXCT1 OXCT_55-75-KE GGCCTGACAGTGGATGACGTA 3639 PAPD4 PAPD_46-65-KE CCCGGAGCAGTGATGGTGAT 3640 PDXDC1 *PDXD_23-42 TGTGCCGTGTACCCTGTAAC 3641 PMS1 PMS1_104-127-KE TCTCCTCATGAGCTTTGGTATCCT 3642 PPIP5K2 PPIP_34-57-KE TCAGTTGACCTATCTCCCTCATGG 3643 PPP1R26 PPP1R26e3F1 CGTGTGGGAACACTGGCTG 3644 PRPF31 RPRF_50-69-KE GCCAACCGTATGAGCTTCGG 3645 RARS2 RARS_30-53-KE TTGGACATTTGCGTTCTACCATCA 3646 TNS3 TNS3_6-29-KE CCAGGTGATAAACTTGTGATCGTG 3647 WNK1 Wnk1_45-67 GCTGGTGTTTTTAAGATGGGACG 3648 SF3B SF3B_107-127-2a GGCATCAGCTTTGCCATTCAT 3649 SF3B SF3B_134-153-9a TTGGACAGCCTCTCTCCCAT 3650 MEMO1 MEMO_37-56 TGGAGCTCTGAGTGAGTCAA 3651 DHFR DHFR_5-24 CCATGAATCACCCAGGCCAT 3652 GCFC2 GCFC2e2F1 GGAGAAAAAGAACTTTCATCAACAG 3653 FAM174A FAM174Ae2F1 CAGGATGATGAGGATGATGACAAc 3654 SOS2 SOS2e19F1 CTGAAAAAGAGTTTACAGATTATTTGTTC 3655 COPS7B COPS7Be2F1 CGGAGTGTATGTCTTTGGAGAACTT 3656 LMBRD2 LMBRD2e16R1 GGAATCTTCTCTATTGTGTCCATAACG 3657 ASAP1 ASAP1e11F1 TACCCCTTCTTTTCACTGCCAT 3658 PPP1R26 PPP1R26e3F1 CGTGTGGGAACACTGGCTG 3659 NT5C2 NT5C2e12F1 AAACCACTCTTTTTTGGAGAAGGC 3660 ELMO2 ELMO2e2F1 AGGTGTAGAAAGAGGTACATGGAGAA 3661

TABLE-US-00013 TABLE 9 SEQ ID Gene Reverse Primer Sequence 5'-3' NO. ABCB8 ABCB_235-254 AGGAGCTGCGGTAGCCATCA 3662 ANXA11 ANXA_302-321 GAGCCACCAGTCACTGTTCA 3663 ARL15 ARL1_392-411-1a-KE TGAGGCCTATGCAAACCAGG 3664 DCAF17 DECA_168-190-KE CCATGAGACAAGGTAGCATCTGT 3665 DHFR DHFR_209-228 TGCCTTTCTCCTCCTGGACA 3666 FAIM FAIM_367-388-KE AGCAACATCCCAAACAGCTACG 3667 GXYLT1 GXYL_246-268 AGGAACGGATGTTGTCATCTTCA 3668 HTT HTT_E51_Rev GGGTATTTGTCCTTCTTTCT 3669 MADD MADD_288-309-KE TCTCCTCTGTCTCACCAAGGTC 3670 MEMO1 MEMO_218-239 TCCCCCTGGGATTCATCATAGT 3671 OXCT1 OXCT_236-256-KE AATGAAAAACACGCAGCCTGG 3672 PAPD4 PAPD_183-205-KE AAGGTGAGTATATGCCGTGCTTC 3673 PDXDC1 *PDXD_179-199 CAAGCAACAGGGGCAGTCTTC 3674 PMS1 PMS1_285-308-KE ACATGAGAGCCATCTTGTGATCTG 3675 PPIP5K2 PPIP_149-172-KE TTCACCTCCCCATTTTAGAACCAA 3676 PPP1R26 PPP1R26e4R1 GCGATGCTTTATTTCTCTACCG 3677 PRPF31 RPRF_218-237-KE TCGTTTACCTGTGTCTGCCG 3678 RARS2 RARS_251-270-KE ATGCCCCAATCGCCAAGGTA 3679 TNS3 TNS3_96-116-KE CGGCTCCTTGTCCTTCAACAT 3680 WNK1 Wnk1_187-207 CTGAGGACTCTGAGGTGCTGG 3681 SF3B SF3B_256-275-2a GTACTTTGCCAGTGTTGGGG 3682 SF3B SF3B_304-324-9a ACTCTCAGAGATGATCGGGGT 3683 MEMO1 MEMO_218-239 TCCCCCTGGGATTCATCATAGT 3684 DHFR DHFR_209-228 TGCCTTTCTCCTCCTGGACA 3685 GCFC2 GCFC2e3R1 GAATAAAAGCTGCATCTGGGATC 3686 FAM174A FAM174Ae3R1 CAACATTGATATAGTGGCTTCTTATTC 3687 SOS2 SOS2e20R1 CTGAAGAAGCAGATACTGGTGGAG 3688 COPS7B COPS7Be3R1 GTATGTCCCATAGGCAAACAGGTT 3689 LMBRD2 LMBRD2e15F1 AAAGGCAAGAAGAAGGTGAAAATC 3690 ASAP1 ASAP1e12R1 GCTAACTGCACTCCGAGACTTAAT 3691 PPP1R26 PPP1R26e4R1 GCGATGCTTTATTTCTCTACCG 3692 NT5C2 NT5C2e13R1 TAGACGATACCATGCTGTAGGGG 3693 ELMO2 ELMO 232-252 TTGATAATGGATGCCAGGGGC 3694

[2146] Results: The statistically significant value for the likelihood of iExon production (APSI) according to the Fisher's Exact Test (FET) for PNN and HDF cell lines treated with Compound 774 at 3 μM and Fold Decrease (FD) for certain genes tested, where NR represents “Not Reported,” is shown in Table 10.

[2147] The APSI for inclusion of an iExon and resulting modulated expression of RNA transcripts identified is represented by stars, where one star (*) represents ≤25% change in expression, where two stars (**) represent change in expression in a range from <26% to HD 50 change, where three stars (***) represent change in expression in a range from <51% to ≤75% change, and, where four stars (****) represent change in expression in a range from <75% to ≤100% change.

TABLE-US-00014 TABLE 10 FET FET Inclusion ΔPSI ΔPSI FD ΔPSI ΔPSI FD Gene Symbol Position (PNN) (PNN) PNN (HDF) (HDF) HDF ABCB8 i1 ** 9.42E−16 NR ** 3.66E−09 NR ABCC3 i30 ** 6.00E−07 −0.25 * 1 −1.03 ADAM17 i1 ** 7.83E−11 VR * 4.87E−08 NR ADCY3 i6 * 0.003 NR * 0.656286 NR AGPAT4 i1 * 1.13E−05 NR ** 1.21E−06 NR ANKRA2 i5 * 0.28 −1.05 * 0.001 0.73 ANXA11 i16 * 9.07E−56 NR * 2.24E−20 NR APIP i1 * 2.52E−11 NR * 1.42E−19 NR APPL2 i1 * 4.28E−06 NR * 0.47 NR ARHGAP1 i1 * 0.34 −0.11 * 0.01 −1.02 ARL15 i4 ** 1.77E−08 NR * 1.94E−05 NR ARL15 i1 **** 1.20E−17 NR *** 2.25E−18 NR ASAP1 i12 * 0 −0.79 * 0 −1.40 ASAP1 i19 * 0 −0.79 * 0 −1.40 ASAP1 i19 * 0.0003 −0.79 * 0.22 −1.40 ASAP1 i12 * 0.004 −0.79 * 1 −1.40 ASPH i24 * 1 NR * 0.19 NR ATAD2B i27 * 0.51 NR * 0.47 NR ATXN1 i7 * 0.08 NR * 1 NR BECN1 i11 * 3.01E−18 NR * 5.27E−06 NR BHMT2 i2 * 0.05 NR * 1 NR BICD1 i5 * 2.64E−05 NR * 0.06 NR BTN3A1 i1 * 0.02 NR * 0.0001 NR C11orf30 i20 *** 3.45E−12 −0.82 *** 3.57E−10 −1.06 C11orf73 i2 ** 1.10E−47 −1.44 * 2.53E−40 0.52 C12orf4 i1 **** 2.07E−43 NR **** 1.91E−66 NR C14orf132 i1 * 0.16 NR * 0.04 NR C8orf44 i1 *** 0.004 NR * 1 NR C8orf44-SGK3 i1 *** 1.17E−08 NR ** 0.06 NR C8orf88 i3 * 0.13 NR * 4.31E−05 NR CASC3 i3 * 0.04 −0.48 * 0.08 −1.14 CASP7 i2 * 0.001 NR * 1.99E−06 NR CCDC122 i6 * 0.29 −1.07 * 1 0.41 CDH13 i7 * 0.0003 −2.06 * 1.32E−05 −0.76 CECR7 i3 **** 3.06E−07 NR **** 0.14 NR CENPI i19 **** 1.62E−50 NR *** 1.78E−58 NR CEP112 i24 * 0.11 −0.96 * 0.02 −0.62 CEP192 i13 * 0.03 NR * 0.34 NR CHEK1 i13 ** 3.38E−05 NR * 0.0002 NR CMAHP i6 * 1 −1.59 *** 0.002 −0.47 CNRIP1 i2 * 3.10E−22 NR * 1.70E−42 NR CNRIP1 i15 * 1.62E−17 NR * 2.06E−34 NR COPS7B i2 * 1.45E−22 NR * 4.58E−14 NR CPSF4 i2 * 0.009 NR * 0.40 NR CRISPLD2 i1 *** 0.009 −0.25 *** 0.001 −1.29 CRYBG3 i17 * 1 −0.33 * 1 −1.08 CSNK1E i3 **** 1.50E−07 NR *** 0.004 NR CSNK1G1 i2 * 0.004 NR * 1 NR DCAF17 i2 * 0.06 NR * 1 NR DCAF17 i6 **** 1.01E−17 NR ** 9.85E−15 NR DCUN1D4 i8 * 0.05 −1.16 * 3.90E−17 −0.01 DDX42 i8 * 9.24E−17 −1.26 * 0.0002 −1.62 DENND1A i10 ** 0.0005 −2.20 *** 8.97E−07 −2.09 DENND5A i3 * 0 −2.48 * 0 −2.09 DENND5A i8 * 0 −2.48 * 0 −2.09 DGKA i10 * 0.02 NR * 0.22 NR DHFR i5 **** 2.99E−06 NR *** 0.0006 NR DHFR i5 **** 5.92E−08 NR *** 0.0004 NR DIAPH3 i27 * 8.17E−12 −2.51 * 4.97E−12 −2.14 DIAPH3 i15 ** 8.33E−15 −2.51 * 1.10E−08 −2.14 DNAJC13 i43 * 0.05 −0.23 * 0.33 −1.05 DNMBP i1 * 0.66 −0.32 * 0.62 −0.99 DNMBP i11 * 0.001 −0.32 * 0.11 −0.99 DOCK1 i23 * 2.18E−13 −1.29 * 0.0006 −1.28 DYRK1A i3 * 0.01 NR * 0.33 NR EIF2B3 i6 * 0.0005 −1.86 * 1.49E−06 −0.82 ENAH i1 ** 9.79E−34 NR ** 7.69E−23 NR ENOX1 i5 * 0 −1.28 * 0 −0.68 EP300 i1 * 0.0006 0.13 * 1 −1.19 ERC1 i18 ** 4.96E−20 −0.53 * 0.0002 −1.49 ERLIN2 i1 * 4.62E−06 NR * 0.12 NR ERRFI1 i1 **** 0.004 NR * 1 NR EVC i5 * 1.62E−12 −0.53 * 0.23 −0.96 FAF1 i14 * 0.21 −1.32 * 0.009 −0.83 FAIM i2 * 0.08 NR * 0.30 NR FAM126A i7 * 5.38E−10 NR * 1.31E−05 NR FAM13A i4 * 0.49 NR * 0.04 NR FAM162A i1 **** 2.03E−84 NR *** 6.15E−83 NR FAM174A i2 * 0.001 NR * 0.0006 NR FBN2 i5 ** 5.89E−26 −0.69 ** 9.15E−22 −1.75 FER i13 ** 0.02 −1.81 * 0.001 −1.26 FHOD3 i21 * 2.20E−06 −0.60 * 2.48E−05 −1.23 FOCAD i6 * 0.01 NR * 1 NR GALC i6 *** 2.48E−07 −2.21 *** 2.31E−06 −2.14 GCFC2 i11 * 1 −1.34 * 0.18 −0.27 GGACT i2 * 0.24 NR * 0.49 NR GLCE i2 * 0.01 NR * 0.01 NR GOLGA4 i1 * 1 −0.24 * 0.31 −0.98 GOLGB1 i14 * 1 −1.32 * 1.24E−05 −1.24 GPSM2 i1 ** 0.0004 NR * 0.14 NR GULP1 i1 *** 0.001 NR ** 0.0006 NR GXYLT1 i7 * 4.54E−05 NR * 0.02 NR HDX i1 **** 1.66E−05 NR *** 1.11E−05 NR HLTF i14 * 1 −1.76 * 0.19 −1.75 HMGA2 i3 * 2.99E−06 NR * 0.003 NR HNMT i1 * 0.03 NR * 0.89 NR HSD17B12 i6 *** 3.41E−16 −2.92 ** 1.16E−39 −2.39 HSD17B4 i2 * 5.71E−06 NR * 0.002 NR HTT i49 ** 6.23E−08 −1.21 *** 2.98E−05 −1.86 IFT57 i5 * 2.26E−15 NR * 1.31E−18 NR IVD i7 * 6.58E−13 NR * 4.50E−12 NR KDM6A i26 ** 4.61E−14 NR ** 1.87E−11 NR KIAA1524 i11 * 0 −1.43 * 0 −0.62 KIAA1715 i6 * 0 −1.41 * 0 0.05 LETM2 i8 ** 5.73E−05 NR * 1 NR LOC400927 i3 **** 1.50E−07 NR * 0.004 NR LRRC42 i2 ** 8.25E−09 NR * 0.01 NR LUC7L3 i1 * 4.59E−06 NR * 0.003 NR LYRM1 i2 * 3.63E−06 NR * 4.98E−14 NR MB21D2 i * 0.007 NR * 0.002 NR MCM10 i15 * 0.0009 NR * 1 NR MED13L i3 * 1 −0.17 * 1 −1.11 MED13L i22 * 0.07 −0.17 * 1 −1.11 MEDAG i2 ** 0.0004 −2.40 * 0.01 −1.60 MEMO1 i6 ** 2.42E−35 −1.30 * 5.11E−40 −0.56 MFN2 i1 **** 1.08E−90 NR *** 8.82E−42 NR MMS19 i2 * 0 −1.36 * 0 −1.75 MRPL45 i4 * 4.39E−11 NR * 1.75E−10 NR MRPS28 i2 * 1.43E−09 NR * 0.003 NR MTERF3 i3 * 1.38E−07 −1.63 * 1.74E−18 −0.19 MYCBP2 i80 * 2.71E−06 −0.36 * 0.04 −1.12 MYCBP2 i55 *** 1.44E−05 −0.36 ** 0.03 −1.12 MYLK i5 * 5.54E−09 0.23 * 3.75E−06 −1.10 MYOF i29 * 0.01 −0.82 * 0.003 −1.75 NGF i1 **** 1.75E−69 NR *** 2.47E−53 NR NREP i3 * 0.0002 −1.31 * 0.46 −0.10 NSUN4 i5 ** 1.90E−09 −1.48 * 1.80E−08 −0.67 NT5C2 i11 * 2.32E−11 −1.26 * 4.54E−07 −0.05 OSMR i3 * 0.004 −0.14 * 0.03 −0.97 OXCT1 i16 * 0.0005 NR * 0.46 NR PAPD4 i7 **** 2.37E−32 −2.33 **** 3.72E−52 −1.40 PCM1 i15 * 0.06 −1.30 * 0.10 −0.86 PDE7A i2 *** 1.46E−10 NR *** 3.25E−09 NR PDS5B i13 * 0.03 −0.42 * 0.03 −1.02 PDXDC1 i7 *** 1.09E−13 NR *** 4.13E−18 NR PIGN i22 ** 1.35E−20 NR * 1.27E−26 NR PIK3CD i3 ** 3.02E−06 NR * 0.32 NR PIK3R1 i2 * 0.02 −0.83 ** 6.81E−10 −1.06 PIKFYVE i12 * 0.02 NR * 0.002 NR PITPNB i7 * 1 −1.45 * 0.03 −1.17 PITPNB i7 * 4.52E−05 −1.45 * 2.70E−07 −1.17 PLEKHA1 i1 ** 0.006 NR ** 0.002 NR PLSCR1 i1 * 0.0008 NR * 1 NR PMS1 i5 **** 1.49E−07 −2.57 *** 3.56E−24 −1.02 POMT2 i13 **** 2.02E−40 NR **** 5.83E−53 NR PPARG i4 * 0.04 NR * 1 NR PPIP5K2 i13 * 4.52E−11 NR * 1.70E−05 NR PPP1R26 i3 ** 3.54E−09 NR * 0.0007 NR PRPF31 i11 ** 2.66E−39 NR * 8.15E−18 NR PRSS23 i3 * 9.82E−07 NR * 0.10 NR PSMA4 i4 * 1.45E−09 NR * 1.80E−20 NR PXK i1 * 8.38E−05 NR * 2.07E−06 NR RAF1 i7 * 4.10E−37 NR * 3.85E−24 NR RAPGEF1 i11 *** 1.30E−07 NR **** 5.56E−05 NR RARS2 i6 * 2.50E−20 NR * 5.90E−08 NR RBKS i1 ** 0.0004 NR ** 0.002 NR RERE i13 ** 3.04E−07 0.02 ** 3.70E−05 −1.06 RFWD2 i11 * 1.50E−13 −2.40 * 3.95E−16 −0.90 RPA1 i1 * 3.28E−12 NR * 0.006 NR RPS10 i5 * 9.72E−28 NR * 3.15E−20 NR SAMD4A i1 * 0.003 NR * 0.001 NR SAR1A i1 * 1.85E−48 NR * 8.33E−65 NR SCO1 i4 * 5.88E−07 NR * 6.67E−08 NR SEC24A i7 * 0.003 NR * 0.008 NR SENP6 i2 **** 5.51E−84 NR **** 3.10E−77 NR SERGEF i1 **** 0.14 −1.02 * 1 −0.81 SGK3 i1 *** 1.17E−08 NR ** 0.06 NR SLC12A2 i10 *** 7.56E−18 NR * 0.0008 NR SLC25A17 i2 *** 7.32E−38 NR *** 3.49E−74 NR SLC44A2 i21 * 1.56E−06 0.06 * 0.002 −0.99 SMYD3 i5 * 0.0001 −1.40 * 9.36E−06 0.33 SNAP23 i3 **** 6.29E−112 −2.82 *** 1.22E−150 −0.89 SNHG16 i1 * 1.92E−18 −1.68 * 5.75E−14 −0.99 SNX7 i7 * 3.44E−26 NR * 8.14E−24 NR SOS2 i19 ** 1.39E−10 NR * 2.76E−05 NR SPATA5 i10 * 1 NR * 0.27 NR SPIDR i1 * 3.23E−08 NR * 0.007 NR SPRYD7 i4 * 2.80E−05 NR * 7.62E−07 NR SRGAP1 i1 * 0.001 −0.16 * 0.0002 −0.99 SRRM1 i3 * 1 0.14 * 1 −1.05 STAT1 i21 * 7.01E−09 −3.06 * 7.52E−31 −1.86 STXBP6 i2 * 9.26E−08 NR * 1 NR STXBP6 i1 **** 6.15E−14 NR *** 2.75E−05 NR SUPT20H i24 * 5.05E−07 NR * 0.22 NR TAF2 i20 * 0 −1.03 * 0 −0.57 TAF2 i23 *** 6.92E−18 −1.02754 ** 3.95E−12 −0.57 TASP1 i13 *** 7.02E−08 NR ** 6.32E−05 NR TBC1D15 i5 * 0.12 NR * 1 NR TCF12 i3 * 1.21E−22 NR * 3.63E−15 NR TCF4 i4 * 3.51E−22 NR * 7.89E−07 NR TIAM1 i4 *** 0.05 NR * 1 NR TJP2 i1 * 0.02 NR * 0.25 NR TMC3 i2 ** 0.18 NR * 0.45 NR TMEM214 i8 * 1.97E−56 NR * 4.75E−07 NR TNRC6A i4 *** 1.38E−21 NR * 1.08E−10 NR TNS3 i23 ** 0.0007 −2.76 * 0.007 −2.74 TOE1 i4 * 3.34E−05 NR * 0.002 NR TRAF3 i8 * 0.0004 −0.54 * 0.14 −0.97 TSPAN2 i4 *** 1.12E−18 −1.06 ** 1.81E−08 −0.58 TTC7B i5 * 3.09E−06 NR * 8.95E−05 NR TYW5 i1 * 0.0009 NR * 0.10 NR UBAP2L i24 ** 5.24E−52 NR * 1.43E−35 NR URGCP i1 * 0.15 NR * 0.32 NR VAV2 i4 ** 2.55E−08 NR ** 1.65E−07 NR WDR27 i2 ** 0.003 NR * 1 NR WDR27 i9 ** 0.008 NR ** 0.09 NR WDR37 i9 ** 0.0009 NR ** 0.03 NR WDR91 i5 *** 7.69E−06 NR ** 0.0006 NR WNK1 i23 * 0.01 0.071985 * 1 −1.26 XRN2 i3 * 1 −1.29088 * 1 −0.55 XRN2 i16 * 3.25E−07 −1.29088 * 1.05E−08 −0.55 ZCCHC8 i11 * 5.24E−10 NR * 4.65E−08 NR ZFP82 i4 ** 9.95E−06 NR ** 1.56E−08 NR ZNF138 i3 *** 0.025 NR * 0.07 NR ZNF232 i4 * 0.23 NR * 0.02 NR ZNF37BP i4 **** 0.003 NR *** 0.03 NR

[2148] Results: The statistically significant value for the likelihood of exon inclusion (APSI) according to the Fisher's Exact Test (FET) for PNN and HDF cell lines treated with Compound 774 at 3 μM and Fold Decrease (FD) for certain genes tested, where NR represents “Not Reported,” is shown in Table 10a.

[2149] The APSI for inclusion of an exon and resulting modulated expression of RNA transcripts identified is represented by stars, where one star (*) represents ≤25% change in expression, where two stars (**) represent change in expression in a range from <26% to ≤50% change, where three stars (***) represent change in expression in a range from <51% to ≤75% change, and, where four stars (****) represent change in expression in a range from <75% to ≤100% change.

TABLE-US-00015 TABLE 10a FET FET Inclusion ΔPSI ΔPSI FD ΔPSI ΔPSI FD Gene Symbol Position (PNN) (PNN) PNN (HDF) (HDF) HDF APLP2 e7 ** 0 NR ** 2.69E−271 NR AXIN1 e9 ** 0.004 NR * 1 NR CECR7 e5 * 0.02 NR * 1 NR DAGLB c4 * 0.74 NR * 0.43 NR DLGAP4 e8 * 1.12E−13 NR * 1.12E−07 NR ERCC1 e8 * 0.0009 NR * 0.20 NR ERGIC3 e8 * 1.44E−220 NR * 2.39E−209 NR FAM198B e3 * 0.003 −1.81 * 0.20 −0.35 GGCT e2 ** 1.36E−30 NR ** 5.86E−45 NR HAT1 e3 * 6.50E−11 NR * 1.34E−10 NR HPS1 e5 * 0.01 NR * 0.34 NR INPP5K e2 * 0.53 NR * 0.14 NR MADD e21 * 2.28E−08 NR * 7.00E−07 NR PPHLN1 e3 *** 8.22E−83 NR ** 8.90E−66 NR PRUNE2 e18 * 0.52 −0.52 ** 0.05 −1.74 RAP1A e2 * 3.80E−15 NR * 4.27E−07 NR RNFT1 e3 * 0.02 NR * 6.02E−07 NR RPS6KB2 e2 * 0.14 NR * 1 NR SH3YL1 e9 * 0.009 NR * 0.08 NR SKA2 e3 * 0.0001 NR * 0.05 NR SPATA18 e4 ** 1.50E−05 NR * 0.29 NR STRN3 e8 **** 4.13E−54 NR *** 4.39E−44 NR TMEM189- e6 * 2.19E−30 NR * 4.66E−20 NR UBE2V1 TRIM65 e5 *** 2.49E−11 NR ** 0.0002 NR TUBE1 e4 * 7.36E−05 NR * 2.05E−10 NR UBE2V1 e3 * 2.19E−30 NR * 4.66E−20 NR VPS29 e2 ** 3.05E−17 NR ** 2.61E−38 NR ZNF680 e3 * 0.13 NR * 0.32 NR

[2150] Details on the location of the iExon produced in affected genes from Table 10 are shown in Table 11.

TABLE-US-00016 TABLE 11 Gene Symbol Ref SeqID Coordinates Description ABCB8 NM_007188 chr7: 150728328- ATP-binding cassette, sub-family B 150728378 (MDR/TAP), member 8 ABCC3 NM_003786 chr17: 48767318- ATP-binding cassette, sub-family C 48767437 (CFTR/MRP), member 3 ADAM17 NM_003183 chr2: 9683889- ADAM metallopeptidase domain 17 9683825 ADCY3 NM_004036 chr2: 25061781- adenylate cyclase 3 25061716 AGPAT4 NM_020133 chr6: 161687802- 1-acylglycerol-3-phosphate O-acyltransferase 4 161687740 ANKRA2 NM_023039 chr5: 72851082- ankyrin repeat, family A (RFXANK-like), 2 72850950 ANXA11 NM_001278407 chr10: 81916254- annexin A11 81916134 APIP NM_015957 chr11: 34933660- APAF1 interacting protein 34933520 APLP2 NM_001642 chr11: 129993507- amyloid beta (A4) precursor-like protein 2 129993674 APPL2 NM_018171 chr12: 105625422- adaptor protein, phosphotyrosine interaction, PH 105625147 domain and leucine zipper containing 2 ARHGAP1 NM_004308 chr11: 46718619- Rho GTPasc activating protein 1 46718571 ARL15 NM_019087 chr5: 53212951- ADP-ribosylation factor-like 15 53212826 ASAP1 NM_001247996 chr8: 131173039- ArfGAP with SH3 domain, ankyrin repeat and 131173031 PH domain 1 ASAP1 NM_001247996 chr8: 131135828- ArfGAP with SH3 domain, ankyrin repeat and 131135650 PH domain 1 ASAP1 NM_001247996 chr8: 131135731- ArfGAP with SH3 domain, ankyrin repeat and 131135650 PH domain 1 ASAP1 NM_001247996 chr8: 131173046- ArfGAP with SH3 domain, ankyrin repeat and 131173031 PH domain 1 ASPH NM_004318 chr8: 62,421,470- aspartate beta-hydroxylase 62,421,527 ATAD2B NM_001242338 chr2: 23976387- ATPase family, AAA domain containing 2B 23976214 ATXN1 NM_000332 chr6: 16409524- ataxin 1 16409426 AXIN1 NM_003502 chr16: 341297- axin 1 341190 BECN1 NM_003766 chr17: 40963348- beclin 1, autophagy related 40963310 BHMT2 NM_017614 chr5: 78374568- betaine--homocysteine S-methyltransferase 2 78374655 BICD1 NM_001714 chr12: 32486172- bicaudal D homolog 1 (Drosophila) 32486263 BTN3A1 NM_001145008 chr6: 26404363- butyrophilin, subfamily 3, member Al 26404455 C11orf30 NM_020193 chr11: 76259972- chromosome 11 open reading frame 30 76260061 C11orf73 NR 024596 chr11: 86037555- chromosome 11 open reading frame 73 86037718 C12orf4 NM_020374 chr12: 4646680- chromosome 12 open reading framc 4 4646546 C14orf132 NM_001252507 chr14: 96506612- chromosome 14 open reading frame 132 96506704 C8orf44 NM_019607 chr8: 67588980- chromosome 8 open reading frame 44 67589137 C8orf44-SGK3 NM_001204173 chr8: 67697924- C8orf44-SGK3 readthrough 67698031 C8orf88 NM_001190972 chr8: 91990874- chromosome 8 open reading frame 88 91990807 CASC3 NM_007359 chr17: 38298307- cancer susceptibility candidate 3 38298353 CASP7 NM_033340 chr10: 115477382- caspase 7, apoptosis-related cysteine peptidase 115477512 CCDC122 NM_144974 chr13: 44431087- coiled-coil domain containing 122 44431054 CDH13 NM_001220488 chr16: 83402146- cadherin 13 83402179 CECR7 NM_014339 chr22: 17,535,915- cat eye syndrome chromosome region, candidate 17,535,996 7 (non-protein coding) CECR7 NR 015352 chr22: 17535855- cat eye syndrome chromosome region, candidate 17535996 7 (non-protein coding) CENPI NM_006733 chrX: 100411511- centromere protein I 100411544 CEP112 NM_001199165 chr17: 63684725- centrosomal protein 112kDa 63684629 CEP192 NM_032142 chr18: 13038514- centrosomal protein 192kDa 13038578 CHEK1 NM_001114121 chr11: 125526101- checkpoint kinase 1 125526230 CMAHP NR 002174 chr6: 25107418- cytidine monophospho-N-acetylneuraminic acid 25107336 hydroxylase, pseudogene CNRIP1 NM_001111101 chr2: 68542975- cannabinoid receptor interacting protein 1 68542840 CNRIP1 NM_000945 chr2: 68,542,833- cannabinoid receptor interacting protein 1 68,542,986 COPS7B NM_001282950 chr2: 232655806- COP9 signalosome subunit 7B 232655883 CPSF4 NM_006693 chr7: 99045396- cleavage and polyadenylation specific factor 4, 99045536 30kDa CRISPLD2 NM_031476 chr16: 84869783- cysteine-rich secretory protein LCCL domain 84870041 containing 2 CRYBG3 NM_153605 chr3: 97635177- beta-gamma crystallin domain containing 3 97635237 CSNK1E NM_001289912 chr22: 38766050- casein kinase 1, epsilon 38765991 CSNK1G1 NM_022048 chr15: 64575350- casein kinase 1, gamma 1 64575317 DAGLB NM_139179 chr7: 6474651- diacylglycerol lipasc, beta 6474425 DCAF17 NM_025000 chr2: 172298369- DDB1 and CUL4 associated factor 17 172298546 DCAF17 NM_025000 chr2: 172309926- DDB1 and CUL4 associated factor 17 172309987 DCUN1D4 NM_001040402 chr4: 52775086- DCN1, defective in cullin neddylation 1, 52775141 domain containing 4 DDX42 NM_007372 chr17: 61883354- DEAD (Asp-Glu-Ala-Asp) box helicase 42 61883511 DENND1A NM_020946 chr9: 126385380- DENN/MADD domain containing 1A 126385322 DENND5A NM_015213 chr11: 9227781- DENN/MADD domain containing 5A 9227736 DENND5A NM_015213 chr11: 9198449- DENN/MADD domain containing 5A 9198319 DGKA NM_201445 chr12: 56333603- diacylglycerol kinasc, alpha 80kDa 56333699 DHFR NM_000791 chr5: 79929807- dihydrofolate reductase 79929696 DHFR NM_000791 chr5: 79928121- dihydrofolate reductase 79928051 DIAPH3 NM_001042517 chr13: 60266972- diaphanous-related formin 3 60266851 DIAPH3 NM_001042517 chr13: 60548266- diaphanous-related formin 3 60548219 DLGAP4 NM_014902 chr20: 35127645- discs, large (Drosophila) homolog-associated 35127724 protein 4 DNAJC13 NM_015268 chr3: 132227720- DnaJ (Hsp40) homolog, subfamily C, member 132227883 13 DNM_BP NM_015221 chr10: 101762780- dynamin binding protein 101762699 DNM_BP NM_015221 chr10: 101654399- dynamin binding protein 101654318 DOCK1 NM_001380 chr10: 128901890- dedicator of cytokinesis 1 128901944 DYRK1A NM_101395 chr21: 38794884- dual-specificity tyrosine-(Y)-phosphorylation 38794954 regulated kinase 1A EIF2B3 NM_020365 chr1: 45350395- eukaryotic translation initiation factor 2B, 45350311 subunit 3 gamma, 58kDa ENAH NM_001008493 chr1: 225788060- enabled homolog (Drosophila) 225787910 ENOX1 NM_017993 chr13: 43,984,307- ecto-NOX disulfide-thiol exchanger 1 43,984,398 EP300 NM_001429 chr22: 41496302- E1A binding protein p300 41496407 ERC1 NR 027948 chr12: 1536281- ELKS/RAB6-interacting/CAST family member 1536343 1 ERCC1 NM_001983 chr19: 45917292- excision repair cross-complementation group 1 45917221 ERGIC3 NM_198398 chr20: 34142143- ERGIC and golgi 3 34142157 ERLIN2 NM_007175 chr8: 37594849- ER lipid raft associated 2 37594946 ERRFI1 NM_018948 chr1: 8,080,640- ERBB receptor feedback inhibitor 1 8,080,926 EVC NM_153717 chr4: 5743061- Ellis van Creveld protein 5743168 FAF1 NM_007051 chr1: 51003153- Fas (TNFRSF6) associated factor 1 51003085 FAIM NM_001033030 chr3: 138335412- Fas apoptotic inhibitory molecule 138335506 FAM126A NM_032581 chr7: 23011932- family with sequence similarity 126, member A 23011871 FAM13A NM_014883 chr4: 89890343- family with scquence similarity 13, member A 89890310 FAM162A NM_014367 chr3: 122120223- family with sequence similarity 162, member A 122120382 FAM174A NM_198507 chr5: 99917051- family with sequence similarity 174, member A 99917108 FAM198B NM_001031700 chr4: 159091499- family with sequence similarity 198, member B 159091399 FBN2 NM_001999 chr5: 127850450- fibrillin 2 127850370 FER NM_005246 chr5: 108321155- fer (fps/fes related) tyrosine kinase 108321188 FHOD3 NM_001281740 chr18: 34322340- formin homology 2 domain containing 3 34322431 FOCAD NM_017794 chr9: 20737106- focadhesin 20737152 GALC NM_001201402 chr14: 88447791- galactosylceramidase 88447758 GCFC2 NM_003203 chr2: 75913102- GC-rich sequence DNA-binding factor 2 75913000 GGACT NM_001195087 chr13: 101194723- gamma-glutamylamine cyclotransferase 101194628 GGCT NM_001199815 chr7: 30540297- gamma-glutamylcyclotransferase 30540152 GLCE NM_015554 chr15: 69517534- glucuronic acid epimerase 69517591 GOLGA4 NM_002078 chr3: 37285619- golgin A4 37285734 GOLGB1 NM_001256486 chr3: 121401810- golgin B1 121401764 GPSM2 NM_013296 chr1: 109420153- G-protein signaling modulator 2 109420396 GULP1 NM_001252668 chr2: 189164835- GULP, engulfment adaptor PTB domain 189164866 containing 1 GXYLT1 NM_173601 chr12: 42489016- glucoside xylosyltransferase 1 42488953 HAT1 NM_003642 chr2: 172803228- histone acetyltransferase 1 172803303 HDX NM_001177479 chrX: 83756519- highly divergent homeobox 83756437 HLTF NM_139048 chr3: 148769931- helicase-like transcription factor 148769832 HMGA2 NM_003483 chr12: 66267911- high mobility group AT-hook 2 66267926 HNM_T NM_006895 chr2: 138724667- histamine N-methyltransferase 138724956 HPS1 NM_000195 chr10: 100195171- Hermansky-Pudlak syndrome 1 100195029 HSD17B12 NM_016142 chr11: 43838189- hydroxystcroid (17-bcta) dchydrogenasc 12 43838222 HSD 17B4 NM_001199291 chr5: 118792986- hydroxysteroid (17-beta) dehydrogenase 4 118793063 HTT NM_002111 chr4: 3215349- huntingtin 3215463 IFT57 NM_018010 chr3: 107911373- intraflagellar transport 57 107911323 INPP5K NM_001135642 chr17: 1419412- inositol polyphosphate-5-phosphatase K 1419182 IVD NM_002225 chr15: 40706629- isovaleryl-CoA dehydrogenase 40706723 KDM6A NM_021140 chrX: 44965787- lysine (K)-specific demethylase 6A 44965894 KIAA1524 NM_020890 chr3: 108284925- KIAA1524 108284745 KIAA1715 NM_030650 chr2: 176835145- KIAA1715 176834927 LETM2 NM_001286787 chr8: 38262801- leucine zipper-EF-hand containing 38262912 transmembrane protein 2 LOC400927 NR 002821 chr22: 38766050- TPTE and PTEN homologous inositol lipid 38765991 phosphatase pseudogene LRRC42 NM_001256409 chr1: 54413535- leucine rich repeat containing 42 54413654 LUC7L3 NM_006107 chr17: 48798190- LUC7-like 3 pre-mRNA splicing factor 48798241 LYRM1 NM_001128301 chr16: 20922505- LYR motif containing 1 20922586 MADD NM_003682 chr11: 47314094- MAP-kinase activating death domain 47314147 MB21D2 NM_178496 chr3: 192555098- Mab-21 domain containing 2 192555020 MCM10 NM_182751 chr10: 13239941- minichromosome maintenance complex 13240039 component 10 MED13L NM_015335 chr12: 116547674- mediator complex subunit 13-like 116547579 MED13L NM_015335 chr12: 116419435- mediator complex subunit 13-like 116419344 MEDAG NM_032849 chr13: 31492953- mesenteric estrogen-dependent adipogenesis 31493127 MEMO1 NM_015955 chr2: 32112156- Methylation modifier for class I HLA 32112104 MFN2 NM_014874 chr1: 12041867- mitofusin 2 12041910 MMS19 NM_022362 chr10: 99241240- MMS19 homolog, cytosolic iron-sulfur 99241106 assembly component MRPL45 NM_032351 chr17: 36468550- mitochondrial ribosomal protein L45 36468624 MRPS28 NM_014018 chr8: 80915355- mitochondrial ribosomal protein S28 80915234 MTERF3 NM_001286643 chr8: 97263851- mitochondrial transcription termination factor 3 97263810 MYCBP2 NM_015057 chr13: 77628142- MYC binding protein 2, E3 ubiquitin protein 77628054 ligase MYCBP2 NM_015057 chr13: 77692630- MYC binding protein 2, E3 ubiquitin protein 77692475 ligase MYLK NM_053025 chr3: 123459382- myosin light chain kinase 123459323 MYOF NM_013451 chr10: 95117679- myoferlin 95117562 NGF NM_002506 chr1: 115843104- nerve growth factor (beta polypeptide) 115843018 NREP NM_001142476 chr5: 111086122- neuronal regeneration related protein 111086049 NSUN4 NR 045789 chr1: 46823248- NOP2/Sun domain family, member 4 46823331 NT5C2 NM_012229 chr10: 104853974- 5′-nucleotidase, cytosolic II 104853926 OSMR NM_003999 chr5: 38876877- oncostatin M receptor 38876923 OXCT1 NM_000436 chr5: 41734751- 3-oxoacid CoA transferase 1 41734677 PAPD4 NM_173797 chr5: 78937278- PAP associated domain containing 4 78937340 PCM1 NM_006197 chr8: 17818551- pericentriolar material 1 17818653 PDE7A NM_001242318 chr8: 66693182- phosphodiesterase 7A 66693079 PDS5B NM_015032 chr13: 33263018- PDS5 cohesin associated factor B 33263158 PDXDC1 NM_001285447 chr16: 15103356- pyridoxal-dependent decarboxylase domain 15103418 containing 1 PIGN NM_176787 chr18: 59764997- phosphatidylinositol glycan anchor biosynthesis, 59764914 class N PIK3CD NM_005026 chr1: 9774095- phosphatidylinositol-4,5-bisphosphate 3-kinase, 9774189 catalytic subunit delta PIK3R1 NM_181523 chr5: 67538784- phosphoinositide-3-kinase, regulatory subunit 1 67538973 (alpha) PIKFYVE NM_015040 chr2: 209176229- phosphoinositide kinase, FYVE finger 209176294 containing PITPNB NM_012399 chr22: 28288318- phosphatidylinositol transfer protein, beta 28288117 PITPNB NM_012399 chr22: 28290410- phosphatidylinositol transfer protein, beta 28290364 PLEKHA1 NM_001195608 chr10: 124148798- pleckstrin homology domain containing, family 124148900 A (phosphoinositide binding specific) member 1 PLSCR1 NM_021105 chr3: 146255831- phospholipid scramblasc 1 146255783 PMS1 NM_000534 chr2: 190683464- PMS1 homolog 1, mismatch repair system 190683555 component POMT2 NM_013382 chr14: 77753614- protein-O-mannosyltransferase 2 77753576 PPARG NM_138712 chr3: 12427535- peroxisome proliferator-activated receptor 12427591 gamma PPHLN1 NM_016488 chr12: 42745687- periphilin 1 42745851 PPIP5K2 NM_015216 chr5: 102492916- diphosphoinositol pentakisphosphate kinase 2 102492948 PPP1R26 NM_014811 chr9: 138376071- protein phosphatase 1, regulatory subunit 26 138376135 PRPF31 NM_015629 chr19: 54632112- pre-mRNA processing factor 31 54632180 PRSS23 NR 120591 chr11: 86651889- protease, serine, 23 86652069 PRUNE2 NM_015225 chr9: 79234303- prune homolog 2 (Drosophila) 79234256 PSMA4 NM_001102667 chr15: 78834921- proteasome subunit alpha 4 78834987 PXK NM_017771 chr3: 58321084- PX domain containing serine/threonine kinase 58321179 RAF1 NM_002880 chr3: 12645036- Raf-1 proto-oncogene, serine/threonine kinase 12644977 RAP1A NM_001010935 chr1: 112170092- RAP1A, member of RAS oncogene family 112170148 RAPGEF1 NM_005312 chr9: 134479440- Rap guanine nucleotide exchange factor 134479348 (GEF) 1 RARS2 NM_020320 chr6: 88257102- arginyl-tRNA synthetase 2, mitochondrial 88256965 RBKS NM_001287580 chr2: 28111807- ribokinasc 28111741 RERE NM_012102 chr1: 8456591- arginine-glutamic acid dipeptide (RE) repeats 8456504 RFWD2 NM_022457 chr1: 176044514- ring finger and WD repeat domain 2, E3 176044399 ubiquitin protein ligase RNFT1 NM_016125 chr17: 58039977- ring finger protein, transmembrane 1 58039901 RPA1 NM_002945 chr17: 1745069- replication protein A1, 70kDa 1745127 RPS10 NM_001204091 chr6: 34385627- ribosomal protein S10 34385575 RPS6KB2 NM_003952 chr11: 67196453- ribosomal protein S6 kinase, 70kDa, polypeptide 67196493 2 SAMD4A NM_015589 chr14: 55115465- sterile alpha motif domain containing 4A 55115566 SAR1A NM_001142648 chr10: 71926149- secretion associated, Ras related GTPasc 1A 71926032 SCO1 NM_004589 chr17: 10594966- SCO1 cytochrome c oxidase assembly protein 10594907 SEC24A NM_021982 chr5: 134013731- SEC24 homolog A, COPII coat complex 134013842 component SENP6 NM_015571 chr6: 76331643- SUMO1/sentrin specific peptidase 6 76331687 SERGEF NR 104040 chr11: 18031686- secretion regulating guanine nucleotide 18031622 exchange factor SGK3 NM_001033578 chr8: 67697924- serum/glucocorticoid regulated kinase family, 67698031 member 3 SH3YL1 NM_015677 chr2: 224920- SH3 and SYLF domain containing 1 224868 SKA2 NM_182620 chr17: 57196856- spindle and kinetochore associated complex 57196757 subunit 2 SLC12A2 NM_001046 chr5: 127478818- solute carrier family 12 127478874 (sodium/potassium/chloride transporter), member 2 SLC25A17 NM_006358 chr22: 41193340- solute carrier family 25 (mitochondrial carrier; 41193288 peroxisomal membrane protein, 34kDa), member 17 SLC44A2 NM_001145056 chr19: 10753573- solute carrier family 44 (choline transporter), 10753697 member 2 SMYD3 NM_001167740 chr1: 246394576- SET and MYND domain containing 3 246394501 SNAP23 NM_003825 chr15: 42805372- synaptosomal-associated protein, 23kDa 42805407 SNHG16 NR 038109 chr17: 74554456- small nucleolar RNA host gene 16 74554545 SNX7 NR 033716 chr1: 99204216- sorting nexin 7 99204359 SOS2 NM_006939 chr14: 50600608- son of sevenless homolog 2 (Drosophila) 50600526 SPATA18 NM_145263 chr4: 52928386- spermatogenesis associated 18 52928498 SPATA5 NM_145207 chr4: 123901321- spermatogenesis associated 5 123901384 SPIDR NM_001080394 chr8: 48185929- scaffolding protein involved in DNA repair 48186042 SPRYD7 NM_020456 chr13: 50492357- SPRY domain containing 7 50492229 SRGAP1 NM_020762 chr12: 64319388- SLIT-ROBO Rho GTPasc activating protein 1 64319457 SRRM1 NM_005839 chr1: 24973570- serine/arginine repetitive matrix 1 24973640 STAT1 NM_007315 chr2: 191843332- signal transducer and activator of 191843254 transcription 1, 91kDa STRN3 NM_001083893 chr14: 31398517- striatin, calmodulin binding protein 3 31398407 STXBP6 NM_014178 chr14: 25411028- syntaxin binding protein 6 (amisyn) 25410930 STXBP6 NM_014178 chr14: 25457178- syntaxin binding protein 6 (amisyn) 25457092 SUPT20H NM_001014286 chr13: 37585794- suppressor of Ty 20 homolog (S. cerevisiae) 37585696 TAF2 NM_003184 chr8: 120771346- TAF2 RNA polymerase II, TATA box binding 120771264 protein (TBP)-associated factor, 150kDa TAF2 NM_003184 chr8: 120757276- TAF2 RNA polymerase II, TATA box binding 120757121 protein (TBP)-associated factor, 150kDa TASP1 NM_017714 chr20: 13395909- taspase, threonine aspartase, 1 13395770 TBC1D15 NM_022771 chr12: 72278640- TBC1 domain family, member 15 72278801 TCF12 NM_207037 chr15: 57227695- transcription factor 12 57227728 TCF4 NM_001243226 chr18: 53202868- transcription factor 4 53202790 TIAM1 NM_003253 chr21: 32641011- T-cell lymphoma invasion and metastasis 1 32640727 TJP2 NM_004817 chr9: 71792959- tight junction protein 2 71793045 TMEM189- NM_199203 chr20: 48713357- TMEM189-UBE2V1 readthrough UBE2V1 48713209 TMEM214 NM_017727 chr2: 27260130- transmembrane protein 214 27260168 TNRC6A NM_014494 chr16: 24769760- trinucleotide repeat containing 6A 24769920 TMC3 NR 120365 chr15: 81633491- transmembrane channel like 3 81633560 TNS3 NM_022748 chr7: 47337036- tensin 3 47336903 TOE1 NM_025077 chr1: 45807382- target of EGR1, member 1 (nuclear) 45807415 TRAF3 NM_145725 chr14: 103356688- TNF receptor-associated factor 3 103356763 TRIM65 NM_173547 chr17: 73887959- tripartite motif containing 65 73887894 TSPAN2 NM_005725 chr1: 115601892- tetraspanin 2 115601858 TTC7B NM_001010854 chr14: 91171677- tetratricopeptide repcat domain 7B 91171544 TUBE1 NM_016262 chr6: 112405449- tubulin, epsilon 1 112405392 TYW5 NR 004862 chr2: 200813345- tRNA-yW synthesizing protein 5 200813295 UBAP2L NM_001287816 chr1: 154234649- ubiquitin associated protein 2-like 154234678 UBE2V1 NM_199144 chr20: 48713357- ubiquitin-conjugating enzyme E2 variant 1 48713209 URGCP NM_001077664 chr7: 43945050- upregulator of cell proliferation 43944971 VAV2 NM_001134398 chr9: 136698500- vav 2 guanine nucleotide exchange factor 136698469 VPS29 NM_057180 chr12: 110937351- VPS29 retromer complex component 110937340 WDR27 NM_182552 chr6: 170087077- WD repeat domain 27 170087013 WDR27 NM_182552 chr6: 170061846- WD repeat domain 27 170061799 WDR37 NM_014023 chr10: 1148398- WD repeat domain 37 1148517 WDR91 NM_014149 chr7: 134890341- WD repeat domain 91 134890209 WNK1 NM_018979 chr12: 1004327- WNK lysine deficient protein kinase 1 1004362 XRN2 NM_012255 chr20: 21307793- 5′-3′ exoribonuclease 2 21307903 XRN2 NM_012255 chr20: 21326472- 5′-3′ exoribonuclease 2 21326525 ZCCHC8 NM_017612 chr12: 122963343- zinc finger, CCHC domain containing 8 122963211 ZFP82 NM_133466 chr19: 36891305- ZFP82 zinc finger protein 36891187 ZNF138 NM_001160183 chr7: 64277652- zinc finger protein 138 64277713 ZNF232 NM_014519 chr17: 5012080- zinc finger protein 232 5012041 ZNF37BP NR 026777 chr10: 43046910- zinc finger protein 37B, pscudogene 43046848 ZNF680 NM_178558 chr7: 64002295- zinc finger protein 680 64002108

[2151] The sequences for iExons produced in certain affected genes at the indicated coordinates from Table 11 are shown in Table 12. In certain instances, detection and analysis of the amount and type of iExon sequences are useful biomarkers produced as a result of contacting a cell with a compound as described herein or administering to a subject in need thereof a compound as described herein.

TABLE-US-00017 TABLE 12 Gene Symbol Coordinates Sequence ABCC3 chr17:48767318- GGCCCATAGGAAGGACGCAAAGGCCTGTGTGTGCAGGCC 48767437 AGAAAAAGGCTATCCACACAGGGTGGCCAGGACACTTTCT CCTGTAAGGAAGGGATGCACCAGCCAGGCCTGAAAGAAT GA (SEQ ID NO: 3695) ADCY3 chr2:25061781- CGGATCAAAGATTGAAGAAAGATTGTACTCCTGTGTCGTG 25061716 GCTCCAACACTGAGGCTGAGATGGGA (SEQ ID NO: 3696) AGPAT4 chr6:161687802- GATACTGCAGCCATCAGCAGACAATCAATGCAATCATCTC 161687740 AGACTGTGTCCTGCGTCCCAGGA (SEQ ID NO: 3697) ANKRA2 chr5:72851082- AAGTACTGTCAGCTTTGAAGGAGAAGGCTTCATGGAGGAG 72850950 CTGTGACTTGACTCCAGAGTGAAAGGATAATTAGGATTGA TACAGGACGGAGGAAGGAAGGCATCCAGGCAATCTCAAT AAAAGCATCCATGA (SEQ ID NO: 3698) ANXA11 chr10:81916254- AGTATCTCCTGCATGCCAGCAAGCTATGGACATCTGGAAG 81916134 AAGCCACATGCCTTGCCCTCAAGTTGCTTAGGGTGGAAGG AAATGATTAGAAATGAGCCAAGCCGAGCCTGCACTCTTAG A (SEQ ID NO: 3699) APIP chr11:34933660- CTCTGAAATTAAATCCCTACTGACTGGCCCTTGAACTGATT 34933520 TTTTCTAACATCAGCAAAAGTCAAGGAGTGTTTCCCTAAA AAAGAAAGCATTTACTCAGAAACCGTATATTGAAGTCCAG GCTGAAAAATGCAAACATGA (SEQ ID NO: 3700) APPL2 chr12:105625422- TCAGGGCTGTACGCTGTGGACCAAAGATCATGCTCGCTGA 105625147 TGAGAGCCACCCTGCTGGTGACCTCAGTGCTGCCGACCCA TTTACATCCCAGCCCTGCCACATTCCTACAGTGGGAGGTT GAACACATTTCTTAACCTTGATGAGCCTCAGTTTCATCATC AGTAAAATGAAGTTAATGGAACCATGGAATCTACCTTGGA GAGTTGCTAGAAGAATTAAATGAAGTCACATATGTTTAGT GCCCAGCACAGCGTCCAGCACATAGGTGGTACAGA (SEQ ID NO: 3701) ARHGAP1 chr11:46718619- GGCCGTCAACCTTTCCACCTTGAAACTGGTGTCAGGAGCA 46718571 CCCTGCAGA (SEQ ID NO: 3702) ASAP1 chr8:131173039- GTTGTTGCAGCTGCGCACCTGCTCTGTGAAGCACAGATTG 131173031 TCATGGGGGCAGTTCTCTCAAAAACATGGCATATTGTGAT GA (SEQ ID NO: 3703) ASAP1 chr8:131135828- AGCAAACCCCATTGTCAGGGGAAAGCAGAACAAAGAAAA 131135650 GTATTTAGAAATGTATTTCCGGGATGCACAGATTCTTTTCA CCCTCACCTTCCCCTAGGTTGTTGCAGCTGCGCACCTGCTC TGTGAAGCACAGATTGTCATGGGGGCAGTTCTCTCAAAAA CATGGCATATTGTGATGA (SEQ ID NO: 3704) ASAP1 chr8:131135731- TCTAGGAGA (SEQ ID NO: 3705) 131135650 ASAP1 chr8:131173046- ATCGAAGTCTAGGAGA (SEQ ID NO: 3706) 131173031 ASPH chr8:62,421,470- TCATTCTGATCTACTGAAATTCCCCAGTTCAGACTCCATTG 62,421,527 AAAGCCCTGGGATGGCA (SEQ ID NO: 3707) ATAD2B chr2:23976387- GTCATCTGAGCAAATGTAATCACTCATCTACCCACAAAAT 23976214 GGCTAAATGACTTAATTCAACTCCCTTTGTTGATTTGCCTG TTAGTTTGTTTATCTGGTGGTCTATCTATTAAATGTTTATTG AGTACCTGCAGTGCCAGATGCTGTGCTGGGTGTTTGGAAT GCAAAAAATGA (SEQ ID NO: 3708) ATXN1 chr6:16409524- TTTCATAAAGAGGACAGACGCTAAGGCAATTGTGTGGAAC 16409426 AGAGCAGCTTCTCGGGGTAACCATCTCCTGCTGATGTATA AATATCGGGGCAAAACTGA (SEQ ID NO: 3709) BECN1 chr17:40963348- GATCCCATTGATGGATGGAAACTCTAGTTTTTACTTAGA 40963310 (SEQ ID NO: 3710) BHMT2 chr5:78374568- GATGTTTTCATCTGGCCCAAGAAGAACTTGTTCTTAATGTT 78374655 AAAAGACCTTTTTGCTAAACTGGGAAGAAAGTGCTGGAAT AACAAGA (SEQ ID NO: 3711) BICD1 chr12:32486172- GTCAATTTCTGCCTTGTGGATAATTTTCTGAATCTGTAATA 32486263 TTTCTGAAGATTCCTCCAAGTATTTACAGAACATACAGAA GTATTTTATGA (SEQ ID NO: 3712) BTN3A1 chr6:26404363- ATCTTGTTCTCAGAGGCCATTCCCAGACCCACAGCAAGAG 26404455 GGATTATGGCTGCAGGCCTCATGCTCCTTTGTTTTGGAAGA AACTGTTGAGGA (SEQ ID NO: 3713) C11orf30 chr11:76259972- GCCTTGTTCAAAGCTCTGGGCATCTAGCAATGAGTAAGAT 76260061 AGTCAAGATCTGTGCTCTGTCCACGTTCTCTTGGAGCTTAC ATTTTAAGA (SEQ ID NO: 3714) C11orf73 chr11:86037555- GTAATTATTGAACATCTACTTGCTGCCTACTTTCAACATCT 86037718 GCATGTGTGTGTGAATATTAAATATCACACCAAGACATTG TTCAGAGGAGACAGAATAGTGAGCTGAGATAAATGAGAA TCTCTCTATGGAAGATTAGACTGGAGCATGAACTTGAAAT ATGA (SEQ ID NO: 3715) C14orf132 chr14:96506612- AACAAAGACAAATCCCGGATTTCTCCATCAGTCTGTGACC 96506704 CTAGAGAAGACCCAGAGCTGGCTCCAGGGAAGGGCTGCG TTTGGCCTGGGAGA (SEQ ID NO: 3716) C8orf88 chr8:91990874- TGTTCCCTTTCAACTTTCAAAACGAATATCCATGCAACACT 91990807 CAGTGCATACAAAGTGGAGTTAGCAGA (SEQ ID NO: 3717) CASC3 chr17:38298307- GAGAAAGTTTCCTGTCTTTTGGATAAACTACTAGAGATGC 38298353 CATCAGA (SEQ ID NO: 3718) CASP7 chr10:115477382- GGTTGCAGAGAGCACTGGTTGAAGCCTATCCTGAAGCTAC 115477512 CTTGGTAGAGGAGTTAATTGCACCAGGAGACCTAATTTCA GAAAGGTCACAGATTATATTCCACCCTCCACAAAAGTAAC CTGGAAGATGA (SEQ ID NO: 3719) CCDC122 chr13:44431087- TAACATATTTTATTGAGGTATAATTGTCATAAGA (SEQ ID 44431054 NO: 3720) CDH13 chr16:83402146- GTTTTTTGGGAACAGGTGGTGTTTGGTTACATGA (SEQ ID 83402179 NO: 3721) CECR7 chr22:17,535,915- CGAGAGGAAGAGGAGAAGCATGCAGGAGTGTACATGAAA 17,535,996 CAAGATTGGCCACGAGATGACAAATATCTGAATCCGCTGA TGA (SEQ ID NO: 3722) CEP112 chr17:63684725- AACCAACTTCAAGATGGCTGCAGCAGTGCCAGGCATTCTG 63684629 CCCAGATCTGCACTATTCGGAGGCAGAAAAGGGCTGCCAG TTTCTAGGGCCTAATGA (SEQ ID NO: 3723) CMAHP chr6:25107418- AATGAACACTCCATGAGAGCAGGGACCTGCTTTGCCTTGT 25107336 TCACCACTTTATTCCCAGTGGCTAGAACCACGTCTGACAC AGA (SEQ ID NO: 3724) CNRIP1 chr2:68,542,833- GTCTTACTCTTGTCACCGAGGCTGGAGTGCAGTGGTGTGA 68,542,986 TCATAGCTCACTGCAGCCTCAACCTCCTGGATCCAAGTGA TCCTCCTGCCTCAGCCTCCCAAGTTGCTGGCACTACAGGTG TGGTATCACCACACCCGGTTAACTAAAAAAAAT (SEQ ID NO: 3725) CNRIP1 chr2:68542975- TTAACCGGGTGTGGTGATACCACACCTGTAGTGCCAGCAA 68542840 CTTGGGAGGCTGAGGCAGGAGGATCACTTGGATCCAGGA GGTTGAGGCTGCAGTGAGCTATGATCACACCACTGCACTC CAGCCTCGGTGACAAGA (SEQ ID NO: 3726) CPSF4 chr7:99045396- AAGAGACAGGATTTCACCGTGACAGCCAGGATGGTCTCCG 99045536 TGCCAGCCAGGATGGTCTCGATCTCCTGACCTTGTGATCC GCCCACCTCGGCCTTCCAAAGTGCTGGGATTACCAGCGTG ATCCACTGCGCCCGGCCATGA (SEQ ID NO: 3727) CRISPLD2 chr16:84869783- ATTGGGTCTTATCCCCAAGATATCTCATTATGTACATGCAA 84870041 ATCAGCGGAGCATCGTCATGACACCAGGAGGACACCCCGT GACGCCGATTACCGCACTCTCAACCTCAACCCAGCGTCAG AGTTTTCTGGCATCTCTTCTTTGAGCCTGGCCGCCTGCAGC TGGAAATGCTCATATATGGTGGTGTGACTAACCTGAGAGA GAGAGATCAGGGATCCTGAGAAGTTCTGCATTCTTGGTCT GCTTCCCAGTGGGACGA (SEQ ID NO: 3728) CRYBG3 chr3:97635177- GGCCTTTCTGTCTGGTGTGTGCAGAATGATCTGGGTCACCT 97635237 CTGAGGCCCATATTTATAGA (SEQ ID NO: 3729) CSNK1G1 chr15:64575350- GTTATTGGGGTACAGATGGTGTTTGGTTACATGA (SEQ ID 64575317 NO: 3730) DAGLB chr7:6474651- TTGGATCATCATCGCTGCCACAGTGGTTTCCATTATCATTG 6474425 TCTTTGACCCTCTTGGGGGGAAAATGGCTCCATATTCCTCT GCCGGCCCCAGCCACCTGGATAGTCATGATTCAAGCCAGT TACTTAATGGCCTCAAGACAGCAGCTACAAGCGTGTGGGA AACCAGAATCAAGCTCTTGTGCTGTTGCATTGGGAAAGAC GACCATACTCGGGTTGCTTTTTCGA (SEQ ID NO: 3731) DCAF17 chr2: 172298369- TTTTGCCAAGGAGTTTGTCCACAGAGCTCTTCATGCCCTCA 172298546 TGCTGGAAGTGGAAATCTGGACATGTTATCTTATCATGTC ATTATCACACCTAGGAAAATGAGCAACAATTCTTCAGGAT CATTTAATGTCAAGTTTATAACTTCCTGCTTTAACTTAAAA AAAAAATTAAATTAGA (SEQ ID NO: 3732) DCUNID4 chr4:52775086- GCCGAAGATGGTGTTAGTGATTGCGAGCTGCTGGCTGGCA 52775141 CCCTTGCAGAGCAGGA (SEQ ID NO: 3733) DDX42 chr17:61883354- GTGCAGTTTGAACAGGGCTTGACAGTGGCTGGACCATCAC 61883511 TAAGTGAGACTTTAATTCATCAAGCATAACTGAAAATGGA GGCAGTAGATTATATCTTGGTAGCCAGCATGTGTAGACTT GTCTTATTTGGAGCCCACTTGGAATTTTCATTTCAAGA (SEQ ID NO: 3734) DENND1A chr9:126385380- CTGTGGCATAAGAATGAAAAGAAAAGAAACAAAAGCAGA 126385322 TGGCAGAGAAAACGAAAGGA (SEQ ID NO: 3735) DENND5A chr11:9227781- GCCAAAATCATATTATATGATCAACCTCAAGTGCATGGGA 9227736 AGCTGTGAAAGTGAACATTGAACTGGGTATAATGTTACCC TGAACAGTATGAAGGTCTATGAGCAAGAAAGAAGGGGTG AATGAATTATGA (SEQ ID NO: 3736) DENND5A chr11:9198449- ATAGGACAGCATTTAAAAATCTCATGTGGAAGAATATACC 9198319 ACTAGA (SEQ ID NO: 3737) DGKA chr12:56333603- ACCTGGGCCTCCCAAGCATTATCCAGCTCAGTTCCTGCCTG 56333699 GCACATGGATGGTGTGGGGCAGGCATGCAGTAGCAGCTG ATCTTTTAGGAGGAAGA (SEQ ID NO: 3738) DIAPH3 chr13:60266972- GTAAATTAGACCCAAAATAACTCCCAGGGAGCAATACAC 60266851 AGCCTGGAAAACATGAAACAAGGAGCGGCTGTTTGGTGT AATAAAGGAGGAGCACCAGGCTGAATTTTCAGAGGCCTA ATAGA (SEQ ID NO: 3739) DIAPH3 chr13:60548266- GGTTTTGTTCCTAATGTCACATGTTTCCTAAGTAATTCAGC 60548219 ATAAAGA (SEQ ID NO: 3740) DLGAP4 chr20:35127645- GAGAGGACTAGAAGGAACGGTTCCCACCTCTCGGAGGAC 35127724 AACGGACCCAAAGCGATCGATGTGATGGCACCCTCCTCAG A (SEQ ID NO: 3741) DNAJC13 chr3:132227720- CCCACTGTGGAGACCTACTGCTCAGGAAAAAAAGAGCTTT 132227883 CAAAATACTACTGCTCGTTGGCAATGCACCTGGTCACCCA AGAGCTCCGATGGAGATGTACAAGGAGATTAATGTTTTCA TGCCTGCTAATACAGCATCCATTTTGCAGCCCATGGATCA AGGA (SEQ ID NO: 3742) DNMBP chr10:101762780- TTTGAAAATCAAATATTGAATGCAAAAGCTAGGAAGCTGT 101762699 AAACAGGAAACGTAAACGAGAAAGAACAAGCAGTGAATA CGA (SEQ ID NO: 3743) DNMBP chr10:101654399- CATTGGCCAGGACTACTAGAACTGTGTCAAAACAGCTGCT 101654318 ACACTAACGGGCATCTTTGTCTTGTTCTCAGTCTTAAAAAG A (SEQ ID NO: 3744) DOCK1 chr10:128901890- GAACGTTGGGGATGCAGATGACCAGTATCTAGTGCTGCGT 128901944 GACTTTGGATTACGA (SEQ ID NO: 3745) DYRK1A chr21:38794884- GTTCAGGGATGCTGGAAAGGACACTGAAGTAGGCCTTGGC 38794954 TGATGGGCCTTTCAGAAGTGAACACTTAAGA (SEQ ID NO: 3746) EIF2B3 chr1:45350395- GGAACTGACTTGTTTTCCAATGGAGGAGGAACATTTGCTG 45350311 CCTACACTGGTTTGAAGCATTAAAAGGGGAGAAAAAGAG CTAAGA (SEQ ID NO: 3747) ENOX1 chr13:43,984,307- TTACTCTAGAAGTCGTACTACATTTTCTGAGAGAAGTAGG 43,984,398 AGGTGAGACGAGAGTAAGTAACTTCTGCTCTCTGAATATT TCAATTAGGCAG (SEQ ID NO: 3748) ERC1 chr12:1536281- ACAGACCCTTCCAGAACCAGATGACCATCAAGACAAAAG 1536343 CATACTCAAGCAGACAAGAAAGGA (SEQ ID NO: 3749) ERCC1 chr19:45917292- GTGACTGAATGTCTGACCACCGTGAAGTCAGTCAACAAAA 45917221 CGGACAGTCAGACCCTCCTGACCACATTTGGA (SEQ ID NO: 3750) ERGIC3 chr20:34142143- TACATGCTGTGGAGA (SEQ ID NO: 3751) 34142157 ERLIN2 chr8:37594849- GGCCAAAGGAATAACTGGGAAGGTGGATGCGAGGCCAAC 37594946 GAATCCTACCTTGAAACTCTGCTCGCCTGCTGGCTCTGCCA CTCCAGCATCTGAAAGGA (SEQ ID NO: 3752) EVC chr4:5743061- TTCCATACAACTATCCCGCTGATTCTTTCTTCAAAGAAGCA 5743168 AACCCTCCTTTGCTTTTTATATTTTCTTCACACATGGAAAT GGGGGATGTGGAGGGCCTTGCACAGA (SEQ ID NO: 3753) FAF1 chr1:51003153- TAATTTTTAACAGTGTAAAGGGGTCCTGAGACCAAAAAGT 51003085 TTGAGAACTGCTGCAATCAACTATAAAGA (SEQ ID NO: 3754) FAIM chr3:138335412- GCTGGTCTCGAGTTCCTGGCTTCAAATGATTCTCCTGTCTC 138335506 AGCCTCTCAAAGTGCGGGGATTACAGGGATGAGCCACCAT GCACACTCCAAGGA (SEQ ID NO: 3755) FAM126A chr7:23011932- GTCAATTTTTCTGACCACCTGAACAGATTGTTTTCTGTCAA 23011871 TTAAGGGCAGCTTTGTTACGA (SEQ ID NO: 3756) FAM13A chr4:89890343- GTTTTGGGGAAACAGATGGTGTTTGCTTACATGA (SEQ ID 89890310 NO: 3757) FAM174A chr5:99917051- ACTGCTGTGGAATTCCTGAGAAAGAGCAACTGAGGGATA 99917108 GCAACATGGATTTCACTGA (SEQ ID NO: 3758) FAM198B chr4:159091499- CAGCAGCAGCAGCGTGTCTTTCCATGCGCTTGGCATTCTTT 159091399 ATTTTCCCAGCCTGGGAGGATATGAGAGTTCCAGGGAAAT GCTGTATTGGACATGCAAGA (SEQ ID NO: 3759) FBN2 chr5:127850450- GATTAATTACCGTTAATGTCTTGGAGACTATAACGTACAC 127850370 TGCACGTTGTAATAACACAAAAGGACAAGCAAGATGTAA GA (SEQ ID NO: 3760) FER chr5:108321155- GTTTCTGGGGAGCAGGTGGTGTTTGCTTACATGA (SEQ ID 108321188 NO: 3761) FHOD3 chr18:34322340- GACAAAAAGCAAAGAAGAAGACTGTGGTCTAGAAGCCGA 34322431 AGGAAGATGAGAAGGAAGAGTGTCCGAGGAGTCAGCCAC AGCCAGAAAGGAGA (SEQ ID NO: 3762) FOCAD chr9:20737106- CATTGACTCCGTTATCTACACAATAAAATCTGGATCCACA 20737152 GATAAGA (SEQ ID NO: 3763) GALC chr14:88447791- GTTTTTGGAGAATAGGTGGTATTTGGTTACATGA (SEQ ID 88447758 NO: 3764) GCFC2 chr2:75913102- CAAGAGAGAAAGAGAGGAATCAAGAATGGGTCCATTGAG 75913000 GAATTGGCCTGAGCAACTGGAAGGACAGAGGTGCCATTTC CTGAAATGAAAAAGTCTGACAGGA (SEQ ID NO: 3765) GGACT chr13:101194723- TAAGATGCTATGAGGAAATCCGTGCACGAGGGATGACAG 101194628 CGTGGCAGGCTGGAACACGCTTTTTAGATTTACTTTCGTGG ACTGGATCTGTTAAGA (SEQ ID NO: 3766) GLCE chr15:69517534- GGCAGAGGTGGAGAGGGGTTAGATTATTTCATCTGCCCTA 69517591 CAGTTGGCATAATAAAGA (SEQ ID NO: 3767) GOLGA4 chr3:37285619- GTCCAGGGATTGAAGGCTGGGGAGTAGAGCCATCCTGGGT 37285734 CAGGCTGCTGGTAGGAGCGGTGGGACCTGAAAGACGTGG CGGCGTGGCCGGCGTCCAGCGCCCGAGGCTGTCACGA (SEQ ID NO: 3768) GOLGB1 chr3:121401810- AGGTGCCTGATGCTGTTAATTCCTGAGCCTTTTGAAGATTC 121401764 TGCAGA (SEQ ID NO: 3769) GXYLT1 chr12:42489016- GGATTGTTTGTATTCCTGCCAATGATTTGTGAGACAGTCTG 42488953 TTCCCCACATCCTCGTCAACAGA (SEQ ID NO: 3770) HAT1 chr2:172803228- TTCGTTTTCCTGAAGATCTTGAAAATGACATTAGAACTTTC 172803303 TTTCCTGAGTATACCCATCAACTCTTTGGGGATGA (SEQ ID NO: 3771) HLTF chr3:148769931- TCTTGCTCTGTCGCCCAGGCTGGAGTGCAATGGCGCGATC 148769832 TCAGCTCACTGCAACCTCCACCTCCCAGGTTCAAGTGATC CTGCTGCCTCAGCCTCTTGA (SEQ ID NO: 3772) HMGA2 chr12:66267911- CTTGTTGGGAATAAGA (SEQ ID NO: 3773) 66267926 HNMT chr2:138724667- ATACCAGAATTGCTGTTAACAAATAAAATACTGGCCAGAT 138724956 GTGTTGGTTCACGCCTGTAATCCTAGCACTTCGGGAGGCT GAGGCGGGAGGATTACTTGAGCCTAGGAGTTTGAGACCA GCCTGGGCAACATAGCAAGATCCCATCTCTACAAAAAAGT GAAAAAGTTAGCTGAACAAGGCGGCATGCACATGCTACTC CAGACGCTGAAGTGGGAAGATCACTTAAGTCCGAGAGAT CGAGGCTTCAGTGAGATATGGCTGAGACACTGCTCTCAGC CTGGATGACAGA (SEQ ID NO: 3774) HPS1 chr10:100195171- TTTGGAGAATGCCTGTTCATTGCCATCAATGGTGACCACA 100195029 CCGAGAGCGAGGGGGACCTGCGGCGGAAGCTGTATGTGC TCAAGTACCTGTTTGAAGTGCACTTTGGGCTGGTGACTGT GGACGGTCATCTTATCCGAAAGGA (SEQ ID NO: 3775) HSD17B12 chr11:43838189- GTTATTGGGGAACAGGTGGTGTTTGGTTACATGA (SEQ ID 43838222 NO: 3776) HSD17B4 chr5:118792986- CTTTCTGACATCTTAACGAGGCAATACAGAGAGACGAATT 118793063 TTCATCAGTTTGTTCAGGGAGACACATATAACAAAAGA (SEQ ID NO: 3777) HTT chr4:3215349- AGGCAAGCCCTGGTGCTGTGGGAGCCCCAAGGAAGAGCC 3215463 TCTGGCCTGGTGGCCACGTAGCCCAGGAGAGATTTCTACA GGAGCCCACAGCGCTGAAGGAGAGAGAGGCAGCAGA (SEQ ID NO: 3778) IFT57 chr3:107911373- ATCCATACATACTTAATGCTGAAATGTGAAGGGCTGAGAA 107911323 AAAAGAAAAGA (SEQ ID NO: 3779) INPP5K chr17:1419412- CACATACATCAGGAGGTCTGCCTGATCCCATGGTGAACCC 1419182 CGGGAATCCGAAATCAGATTGAGATAAGATCCTTTAGGGA AGTGACTTAGCCTGGTCTCTTGCCTGCTCTTTCACGGGGAA CAACGCTAATCGCCCACTTAGTCTAAGTCACGATGCTTGG ATTTGCTGCTAATCGTCGGATTTGAGAGTGGGAACAAGAA ATCCGGACTTTTGCTCTCCATCCTCTTAGA (SEQ ID NO: 3780) IVD chr15:40706629- CTCTGAATGGCCTGTCTCCTGGACAAAGAAGCTTTCACGG 40706723 ACTACTCTGCAGGGAGGTGACATTGGACCAGAGCTGACTC CACCTGGGGGAAAGA (SEQ ID NO: 3781) KIAA1524 chr3:108284925- GTCAGGAATTATGGTTAAAGGTGGATTTTCACTGATGGTA 108284745 ATAAGATATTACTTTATACCCCTTCCCTCCTCATGAATTAA GTCCATCTAATCTTTACTGAGGACCTGCTGAGTGGTAGAC ACTATGATTTGTTTCTGTTTCCACAGATGTCACAATTGTCA GTAATTGTGGACCTTTAGA (SEQ ID NO: 3782) KIAA1715 chr2:176835145- TTCTCAGGTTTTCTTGACACCAAGAAAGAGAGGGAATCAA 176834927 GAAGATCGGTTGTAAGAGAGCAATTCAACATGAAAATACT GAAGAAGAGATGGGAGAGAGAGAGAGATAATTGTTTTCT TCAGAGTTTTCCACTTTCTATCAGTAACTCTGATCACATGG ATATCTATTGTGGGGCTAGTTGATGCATCCCTTCAGATGTG TTGGAAAGAGGACCAAGA (SEQ ID NO: 3783) LUC7L3 chr17:48798190- TGTAGGAAAGCAAGTTGGTGCTAGATGACTCCTTTTAGGA 48798241 CTTTAAGAAAGA (SEQ ID NO: 3784) LYRM1 chr16:20922505- GTGAAGTAGTATTTGAAGCTTTTCATCAGTTGGCTCATTCT 20922586 TTACTCAAGAATAAACCTCAAGAAACGTCATCAGGGTCAG A (SEQ ID NO: 3785) MADD chr11:47314094- AATTGTGGAACAAGCACCAGGAAGTGAAAAAGCAAAAAG 47314147 CTTTGGAAAAACAGA (SEQ ID NO: 3786) MB21D2 chr3:192555098- GCATGTTTATGTGGGAATGTCTCTCCATGTTTACAAACTTC 192555020 AGAAGGCCCCTTTGGGAAAGAAAACCTCTCAGAGAAGA (SEQ ID NO: 3787) MCM10 chr10:13239941- TCTTGCTCTGTTGCCAGGCTAGAGTGCAGTGGCGCAGTCTT 13240039 GGCTCGCTACAGCCTCTGCCTCCTGGGTTCAAGCGATCCTC CTGCCTCAGCCTCACGA (SEQ ID NO: 3788) MED13L chr12:116547674- GTCATTTTTAACATGGATTCTTAGATGCTGACAAATATTGC 116547579 CAAATTCCATTCCAAAAGAGGTTACACTTATTTCCTTTCAT CAGTGAATGA (SEQ ID NO: 3789) MED13L chr12:116419435- CTCCTCTGAGTGTTCCTCCAAATCTGTCTTTTGGAGTAGAC 116419344 CTAGAAATCATCTGTTACTAAGGTGTACTATGCATGTGGA ACCATTGATTTAAGA (SEQ ID NO: 3790) MEDAG chr13:31492953- GAGAGGCCAGGAACAGAATGCCCAGTAACAAGAAGTGCT 31493127 CATTAGAACATCTGAAGCCCACGTGTTCTTTGGCTTGATTA TAACCAGAAAGCCAGATAGTTCTTTAGGAATGTAATTCAC AGCTGTATCAAGTACACCTCCTGCACCGATCACTCAGGAG GAATCTAAAAAAAGA (SEQ ID NO: 3791) MEMO1 chr2:32112156- AAAGCGTGCTCTGGAATGGATTCACAAATGAGCTACCCTC 32112104 CTTCCCTCAAAGA (SEQ ID NO: 3792) MMS19 chr10:99241240- CATTAATTTACAGAAATACACGTATTCTCCTTGTTTTGGTG 99241106 GAAGCTGCAGCTGCCAATCATCTCTCAAACCCTGTGGGTA GCTGCTAAGCTGTATTTCAGAGGAATGTCACAATCATACC ACTGGGGAGAAAGA (SEQ ID NO: 3793) MRPL45 chr17:36468550- GTCTGGGTGGTGGCTCATACCCGTAATCCAGCACTTTTGG 36468624 AGGCCGAAGTGGGAGGATTGTTTCTGGGCAGCAGA (SEQ ID NO: 3794) MRPS28 chr8:80915355- ATGGGACCTGCAAAGGATAAACTGGTCATTGGACGGATCT 80915234 TTCATATTGTGGAGAATGATCTGTACATAGATTTTGGTGG AAAGTTTCATTGTGTATGTAGAAGACCAGAAGTGGATGGA GA (SEQ ID NO: 3795) MTERF3 chr8:97263851- GGACGTGTCTCCGTGCTAAAGACCTAGAGATTACAACGAT 97263810 GA (SEQ ID NO: 3796) MYCBP2 chr13:77628142- GCATCTAGCATAGAACTCCCTATTCTGCATTATGACTACTG 77628054 GACCACTTATCTCTCTGCCCTACTTGATAAGTTCCATGAGG ACAAAGA (SEQ ID NO: 3797) MYCBP2 chr13:77692630- GTGACCAACTGAGTGCCATATTGAATTCCATTCAGTCACG 77692475 ACCCAATCTCCCAGCTCCTTCCATCTTTGATCAAGCTGCAA AACCTCCCTCTTCCCTAGTACACAGCCCATTTGTGTTCGGA CAGCCCCTTTCCTTCCAGCAGCCTCAGCTTCAGA (SEQ ID NO: 3798) MYOF chr10:95117679- GGTGAGAAGTTTCTGAAGGTGCTTGAACGCTCTTCTTCCA 95117562 CACGAGGGCACCAAGTTGAAGCGGGAAGAACACTGAGCC ATCAGTTAGAAGGCTCAGGATATGGTCCAGTTCTAACGA (SEQ ID NO: 3799) NREP chr5:111086122- TGTTCCAGGGCGCCATTAACGATTGGAGTTGGCACAAAAT 111086049 TTGAAACTAGAAGTGGACTATTTGCTCCTTGAGA (SEQ ID NO: 3800) NSUN4 chr1:46823248- GGGCTCAGGAGTCCAGCGGTCCTAAGTATACCTTGCAGCC 46823331 ATCTTCCTAAAAGTTCTGACCATGACTGAGGACACTGAGA AGGA (SEQ ID NO: 3801) NT5C2 chr10:104853974- AGTTTTGGTCTTAACTGAAACAGTCAAACAAACCCACTAA 104853926 TTGAAAAGA (SEQ ID NO: 3802) OSMR chr5:38876877- CTTCCTGAGAGTTTCTTGGCCTATACCCAGCTGAAGTGCA 38876923 GGGAAGA (SEQ ID NO: 3803) OXCT1 chr5:41734751- ATTTTGAAAGAAGTCTGTCTCTCAAATATTTAAAGAATCA 41734677 AAATGATGTCGTATTAAAGCTTGACAAGCTAATGA (SEQ ID NO: 3804) PAPD4 chr5:78937278- AGCTCTACCTCTGTTTTGAAATGTCATTAGTTTGGATATGT 78937340 TACCAGGATGCAGCAAAGAAGA (SEQ ID NO: 3805) PCM1 chr8:17818551- TTATGGACCAGCATTTCCATCTTTTACTGGCCTGAAATAAT 17818653 ATAATAAAATCTTTAAGCCACCATAAGATATCTAAGGAAA ATAACTGTATGTGGTTTAAAGA (SEQ ID NO: 3806) PDS5B chr13:33263018- GCATTAGAAACATTCATATTATGAAAATACTACCTTTTTAT 33263158 TCTCACTTGGTGTACTGATGTGCATTACGGTGGAGAGCAG TAGGCTGCAGATTTTGTGCTGCATAGCCTGAGCAGCACCG TGTTATAGTTTGACATAAGA (SEQ ID NO: 3807) PIK3R1 chr5:67538784- TGCTCTACAAGTATAGAAAGAAGCCTTCCTCTTCCCACCG 67538973 TCCCCAGACACCACATAATGGAAAAAGCAAGAATTTTCTG CATAAGCAAGGCCTTAAAAAAAAAAAAGCCAGCCTCTGA TGGGACTTCTTTCCTGCCAGAAATCCCACTGGTCCACTGTC GCAATTTTTACAAAAGGCCACGATGAAAGA (SEQ ID NO: 3808) PIKFYVE chr2:209176229- TGGAAAGAACCTCATTTGAGCTATGCTTGGTCACAGACCT 209176294 AGAGAAAGTTCACGGGGAAGTAAAGA (SEQ ID NO: 3809) PITPNB chr22:28288318- GCGAAAATGGGCAGTGTTTACAGGCATGAATGCTGGTGGA 28288117 AAGAGCAGAGTAAGGGCAGATTGCACAAGAACCGTGGAG GCCCTGGTTCCCATCACCTCCACCTCAGCACAGACTTCAG AGAGGAGAGGAGGCACTGGATGCATGACAGCAGCACTTG AGATAGGTGCTCCAGGTGGAAGGCACTGCACATGCAAAG GCTGA (SEQ ID NO: 3810) PITPNB chr22:28290410- TGAGCTTGGAGTGAAGTCTAGTACGTCTGTGCAGCAAAGA 28290364 GACCAGA (SEQ ID NO: 3811) PLSCR1 chr3:146255831- GACCACATAAACCCATTTTGAATTATTCAACCATTGCTGA 146255783 ACTTCTTGA (SEQ ID NO: 3812) PMS1 chr2:190683464- GGATTCCCCCAGCAGACGTTTTTCATCTAAGAAATGGCTT 190683555 GAGTGCTTCCTTTTATCGGGTGCTGTGATAGATTCTCAAAA TATGAAAATGA (SEQ ID NO: 3813) PPIP5K2 chr5:102492916- AACCCAACACAGATCTTAATACCATGAAAAGGA (SEQ ID 102492948 NO: 3814) PRSS23 chr11:86651889- AGCAATCTCTTTGTATTTATACAATTATGACAACAGTAGTA 86652069 AGAGAAGAAGGTTCAGAGGATACAAGGTAACACACCTAC ATAAACGACCTACTGGGTACAAATATTGTAAATCAACATA GGCCTAGAAAAGGTGGTCAGATGCTGAATTTTGACTAAAT ACCTCCGATGGCACATAATGA (SEQ ID NO: 3815) PRUNE2 chr9:79234303- AACTAGCTGCCTTTACAATGATCCAGAAATGTCTTCTATG 79234256 GAGAAGGA (SEQ ID NO: 3816) PSMA4 chr15:78834921- AGAGACGCAACATCCACAAGCTTCTTGATGAAGTCTTTTT 78834987 TTCTGAAAAAATTTATAAACTCAATGA (SEQ ID NO: 3817) PXK chr3:58321084- CTGTAAAGTTTGACTGAGAAATGTTGCATCAGCCCTGAAG 58321179 TTTATTGAGAAAATCTTACGCTGATGCAAACTTTTTGGACT GTTAGTGTCTTATGA (SEQ ID NO: 3818) RAF1 chr3:12645036- AATAACAACCTGAGTGCTTCTCCCAGGGCGTGGTCCAGAC 12644977 GATTTTGTTTGAGGGGAAGA (SEQ ID NO: 3819) RARS2 chr6:88257102- AATTGGAGAAATTAGTACTTGTGGCATAGATTGTTGTGCG 88256965 GTCAGCTCTTACTGTTCTTGAGCAGCATTTTAAGAGAAGA AATGACAGGACTTGATGAAAAAGTATAAGAAATATACAG TATAAAAAAAGCTATATGA (SEQ ID NO: 3820) RFWD2 chr1:176044514- GACTAAGATTTGAATTTATTATGTATATGAAGATCTTAAA 176044399 ATTTAAGCCATTAGCTAAAGAAACTATTGGAGGAGATCTT TTATTGTATTCTGTCAGCTGTTTAACTCAGTAATGA (SEQ ID NO: 3821) RNFT1 chr17:58039977- GAATTTCTCTTGGAATTGGGCTGCTAACAACTTTTATGTAT 58039901 GCAAACAAAAGCATTGTAAATCAGGTTTTTCTAAGA (SEQ ID NO: 3822) RPA1 chr17:1745069- ACGTCAGCTATCAGTTTAAGCATTACTTCTATGCCTAGTTT 1745127 GCTGAGACTTTATAATGA (SEQ ID NO: 3823) RPS6KB2 chr11:67196453- GACGCATGTCCCCTTGCCGAGTTGAGGGCAGCTGGCCTAG 67196493 A (SEQ ID NO: 3824) SAMD4A chr14:55115465- ATGTGATGGGAAGTCTCTGGAAGAGTTGAGAAGGAGAAT 55115566 GAAGGCGCTTCATTGACCCTTGAAAATGACCACTCTGAAT GCGGCACAGAGAGTAATGAAAGA (SEQ ID NO: 3825) SAR1A chr10:71926149- TGCATCTAAGTGGCATTCTGATTCACATTATTGATAAGACT 71926032 GATTTCCTAGAGTIGTTCTTCACTGGATGACAGCAGTCGTA TGTCTAGGGAATGTGAATGAACCGCTGCCTGGAGGA (SEQ ID NO: 3826) SCO1 chr17:10594966- AGAAAGGATTTGAACTTGGCCTTCATGTATCAACTAAGTT 10594907 AATCGAGCCTTGAATTGAGA (SEQ ID NO: 3827) SEC24A chr5:134013731- AGACCGGGTCTCTCGTTGTCACCCAGGTTAGAGTGCAGTT 134013842 CCATGATCATAGCTCACTGCAGCCTTGAACTCTTGGGCTC AAGCAGTCCTCCTGCCTCAGCCTCCAGACAGA (SEQ ID NO: 3828) SERGEF chr11:18031686- GTGTCTTCAAAAACAAACATATTTAAAAGATTTTACTTCTC 18031622 ATCTCCAGGAAGAACCAGCTAGGA (SEQ ID NO: 3829) SH3YL1 chr2:224920-224868 GTAACAGAAATGAATATAAGCTCTATCCTGGACTTTCCAG CTATCATGAGAGA (SEQ ID NO: 3830) SKA2 chr17:57196856- AAAAATCCAGTTACACTCTTAAAGGAATTGTCAGTGATAA 57196757 AGTCTCGATATCAAACTTTGTATGCCCGCTTTAAACCAGTT GCTGTTGAGCAGAAAGAGA (SEQ ID NO: 3831) SMYD3 chr1:246394576- CTATATCAGAAAAGCAGGAAACCAGAGAAAATATACCTA 246394501 TTTGAAAGTGGCATGTCAGCTGGGATGAGAGAGAAGA (SEQ ID NO: 3832) SNAP23 chr15:42805372- TATTGGAATATGACAGGGAAGATGAATTCACTATGA (SEQ 42805407 ID NO: 3833) SNHG16 chr17:74554456- AGGCCTTTCTTTGTTTGGCATCTGCAGAGACGGTGAAAAG 74554545 CAGAGCTCCAGGTTGAAGGATCAGAGTAATAGATGGAGC CCTTAACATGA (SEQ ID NO: 3834) SNX7 chr1:99204216- AGTTTGCAAAGGAAGGAAAGGAGCAGAGACTTGAATGAG 99204359 CAGAAAATCATTTCAGGGCCTGTTCTCTATGTCCTTGCTAT CCCTGTCTTCTGTAGCTATTCTGAAACCATCAACAAAGGA GCACACCATTCCATCAGCAAAAGA (SEQ ID NO: 3835) SPATA5 chr4:123901321- AACCTTTATATAAATGGAATCATACTGTATACAACCTTTTG 123901384 GAATTAGCTTTTTTCACATATGA (SEQ ID NO: 3836) SPIDR chr8:48185929- GTATTCAGTAGAAGCAGATGAACAGCCAGATGAAGAGAT 48186042 GGATAGAGCAAGACATGGACATTATAAAGGAATTCAATA GAAGCACATGAACGGCCAGATGAAGAGATGGATAGA (SEQ ID NO: 3837) SPRYD7 chr13:50492357- GTGTGGTTGTACGTGCCTGTAGTCCCAGCTACTTGAGAGG 50492229 CTGAGCTGAGAGGATCTCTTGAGCCGGGGAGGTCAAGTCT CCTGTGAGCAGTGATCATCGTGCCGCTGCACTCCAGCCTT GGCACCAGA (SEQ ID NO: 3838) SRGAP1 chr12:64319388- TCACAGATACCACGTGTTAATATCTAAAGTAGAAAAAGGA 64319457 ATAAAGCAAAGGAGGACAAAAAGAAAAGGA (SEQ ID NO: 3839) STAT1 chr2:191843332- GTTTGTTATCTGCAGATCAAGGATGTGAGTCAATGTAATC 191843254 TGCAACCCGTTCTTGGAAGGAATCACATTTCCCACAGGA (SEQ ID NO: 3840) STXBP6 chr14:25411028- GTGGTCCCTGAGTTAAGAACATGCAATGGCACTCTCTCAA 25410930 GGAGAGGAAGGAGCCAAAGAAGAAAGAGGTCCAAAGCA GAAAAGAGCAGACAGCTAAGA (SEQ ID NO: 3841) SUPT20H chr13:37585794- TTGAAGACGATAATTCTAACTTCCTGTCAGTTGAAGACGA 37585696 TAATTCTAACTTCCTGTCAGTTGAAGACGATAATTCTAACT TCACACTTAATTAAAAGA (SEQ ID NO: 3842) TAF2 chr8: 120771346- GAAGATGATCACCTTGCCAAGGAAGCATCATGTAATATAT 120771264 CAGCTCATCAGCAGGGAGTGAAGAGGAAGTCTGATACAC CACTGGGGTCCCCACTAGAACCTGGTCAAATACTGGAGAA GAATGAGGATAGCAGTAAAGTCAAACTCAAAATCAGA (SEQ ID NO: 3843) TAF2 chr8:120757276- TTTTGAGATCCACCAAATATGTCATTGTTGCCAGTCTTCTT 120757121 TCCCAAGATGTATGGATAGTTTTTAATGTCTCATAAATATG A (SEQ ID NO: 3844) TBCID15 chr12:72278640- TTTGACAGACCTGAAATCAATCAAGCAAAACAAAGAGGG 72278801 TATGGGCTGGTCCTATTTGGTATTCTGTCTAAAGGATGACG TCGTTCTCCCTGCTCTACACTTTCATCAAGGAGATAGCAAA CTACTGATTGAATCTCTTGAAAAATATGTGGTATTGTGTGA (SEQ ID NO: 3845) TCF12 chr15:57227695- GTTTTTGGGGAACAGGTGGTATTTGGTGACATGA (SEQ ID 57227728 NO: 3846) TJP2 chr9:71792959- GGATTGGTGTCTCTATCATCCAGCTGGCCATTAAACAACC 71793045 AAAGCTTCATCATCCTAGATAACCTGTGAGCTCTCAGAGG AGACAGA (SEQ ID NO: 3847) TMEM189- chr20:48713357- GAGTAAAAGTCCCTCGCAATTTCCGACTGTTGGAAGAACT UBE2V1 48713209 CGAAGAAGGCCAGAAAGGAGTAGGAGATGGCACAGTTAG CTGGGGTCTAGAAGATGACGAAGACATGACACTTACAAG ATGGACAGGGATGATAATTGGGCCTCCAAGA (SEQ ID NO: 3848) TMEM214 chr2:27260130- CCATCCTAGATCTGAGATTTGCAACCTGGAAGTTCAAGA 27260168 (SEQ ID NO: 3849) TNS3 chr7:47337036- GCAGGCCCACCCATGAAACATACACGACACCACAGAGAC 47336903 CTCCCTGAAGGTCCCTCAACTGCATGGACATGTAGTTCTTC CAGCCAAGCAGAGGGATCCCGGCCAGGTCCCCACTGATCC AGTTTGCAAAAAGA (SEQ ID NO: 3850) TOE1 chr1:45807382- GTTTATGGGGAACAGGTGGTGTTTGGTTAAATGA (SEQ ID 45807415 NO: 3851) TRAF3 chr14:103356688- CACCAATACATTATTATGAAGTCAGTACAGAGAGATTGGC 103356763 ATCTTAGTATTTTCTGAGGAAGAGAACAGCCAAAGA (SEQ ID NO: 3852) TSPAN2 chr1:115601892- GTTTTGTGGGGAACAGGTGGTGTTTGGTTACATGA (SEQ ID 115601858 NO: 3853) TUBE1 chr6:112405449- AGTGGTTGGTGATGGTGGAAGTATTTCCAAGGGAAAAATA 112405392 TGTTCTTTAAAAGCACGA (SEQ ID NO: 3854) TYW5 chr2:200813345- TGACAGCATGAACTGTCAGAAGCTTTGAGTTCAAGCATCT 200813295 TGGGAGCAAGA (SEQ ID NO: 3855) UBE2V1 chr20:48713357- GAGTAAAAGTCCCTCGCAATTTCCGACTGTTGGAAGAACT 48713209 CGAAGAAGGCCAGAAAGGAGTAGGAGATGGCACAGTTAG CTGGGGTCTAGAAGATGACGAAGACATGACACTTACAAG ATGGACAGGGATGATAATTGGGCCTCCAAGA (SEQ ID NO: 3856) URGCP chr7:43945050- GCTTTGGGGCAGTGGTCATTTCCGGGACCAGGCCTTTTCAT 43944971 TGCCAGCTGACTACCCAGCACTTTGAGCTCATGAATAGA (SEQ ID NO: 3857) XRN2 chr20:21307793- GTGGTTTGAATTGAGAAGGGAAGTATAGCAAAAGCTTGA 21307903 GAAAGCCTTACCGTCTGGAGTTTGGACTGTATCCTATAGG CAATGAGTAGTCATGAAAATGATTTGAGAGGA (SEQ ID NO: 3858) XRN2 chr20:21326472- CCATCAACAACTCTTAGCTGAAAGAGGGATAAGGCCCAA 21326525 GCAAGGATAGAGAGA (SEQ ID NO: 3859) ZNF232 chr17:5012080- GTGAGAGACTTTGCCTGTTTCATCACTCATAAAATTAGGA 5012041 (SEQ ID NO: 3860) ZNF680 chr7:64002295- GCAGAACTGGCCGTGAACTGTGGCTCAGGGAGCTGGAACT 64002108 GAGTCATCGAACTGCTTCAGAAACCACAGTAAAGGACAA GGTCTGCAGGCCTGCCTGCGTGGCTATAAATGGCTGTCTT CCTCCAGGCCTCTGGAAGGGCACGGTCTCTCCCAGACTGT GGCTGGGAGGAGTTTGGGATGATTAGAGA (SEQ ID NO: 3861)

[2152] Diseases or disorders associated with expression of an aberrant gene product for certain genes described herein are listed in Table 15, wherein contacting a patient cell with a compound described herein or administering to a subject in need thereof a compound described herein has been demonstrated to modulate the expression of associated RNA transcripts and are thus expected to be useful in preventing or ameliorating a disease or disorder caused by expression of an aberrant gene product.

TABLE-US-00018 TABLE 15 Diseases or disorders associated with expression of an aberrant gene product for certain genes. Gene GeneID Example(s) of Associated Disease or Disorder ABCC3 8714 Cholestasis, Colorectal Neoplasms, Peripheral Nervous System Diseases ADAM17 6868 Blister, Inflammatory Skin and Bowel Disease, Neonatal ANXA11 311 Sarcoidosis APLP2 334 Nerve Degeneration, Myocardial Ischemia ASPH 444 Ectopia Lentis, Spontaneous Filtering Blebs, and Craniofacial Dysmorphism ATXN1 6310 Spinocerebellar Ataxia 1, Spinocerebellar Ataxias AXIN1 8312 Carcinoma, Hepatocellular, Caudal Duplication Anomaly BECN1 8678 Status Epilepticus, Colonic Neoplasms, Lewy Body Disease, Myocardial Infarction, Lung Neoplasms BHMT2 23743 Cleft Lip, Cleft Palate C11orf30 56946 Dermatitis, Atopic, Breast Neoplasms, Polycystic Ovary Syndrome C11orf73 51501 Stomach Neoplasms, Melanoma, Disease Progression CASP7 840 Myocardial Reperfusion Injury, Vitiligo, Breast Neoplasms, Leukemia, Myeloid, Acute CDH13 1012 Lung Neoplasms, Carcinoma, Hepatocellular, Prostatic Neoplasms, Carcinoma, Non-Small-Cell Lung, Esophageal Neoplasms, Amphetamine-Related Disorders, Substance-Related Disorders, Barrett Esophagus CHEK1 1111 Glomerulonephritis, IGA, Peripheral Nervous System Diseases CRISPLD2 83716 Neurotoxicity Syndromes, Lung Diseases, Liver Diseases DCAF17 80067 Woodhouse Sakati syndrome DHFR 1719 Megaloblastic Anemia due to Dihydrofolate Reductase Deficiency, Osteosarcoma, Autistic Disorder, Folic Acid Deficiency, Neoplasm Metastasis, Colorectal Neoplasms, Nervous System Diseases, Anemia, Megaloblastic, Drug-Related Side Effects and Adverse Reactions, Metabolism, Inborn Errors, Infertility, Female, Abortion, Spontaneous, Pancytopenia DIAPH3 81624 Neuropathy, auditory neuropathy, benign epilepsy with centrotemporal spikes, prostate cancer, pancreatitis, prostatitis, sensorineural hearing loss DENND5A 23258 Stomatitis DNAJC13 23317 Parkinson Disease DOCK1 1793 Substance-Related Disorders DYRK1A 1859 Mental Retardation, Autosomal Dominant 7 EIF2B3 8891 Leukoencephalopathy with Vanishing White Matter, Vanishing White Matter Leukodystrophy with Ovarian Failure ENAH 55740 Glomerulonephritis, IGA EP300 2033 Rubinstein-Taybi Syndrome, Endometrial Neoplasms, Carcinoma, Transitional Cell, Esophageal Squamous Cell Carcinoma, Urinary Bladder Neoplasms, Colorectal Neoplasms, Carcinoma, Adenoid Cystic, Small Cell Lung Carcinoma, Colon Carcinoma, Rubinstein-Taybi Syndrome 2 ERCC1 2067 Cerebrooculofacioskeletal Syndrome 4, Carcinoma, Non-Small-Cell Lung, Stomach Neoplasms, Neoplasms, Neoplasm Metastasis, Melanoma, Testicular Neoplasms, Peripheral Nervous System Diseases, Adenocarcinoma of lung. Nasopharyngeal carcinoma, Uterine Cervical Ncoplasms, Arsenic Poisoning, Neoplasms, Germ Cell and Embryonal ERLIN2 11160 Intellectual Disability, Spastic Paraplegia 18, Autosomal Recessive ERRFI1 54206 Endometriosis, Polycystic Ovary Syndrome EVC 2121 Ellis-Van Creveld Syndrome, Weyers acrofacial dysostosis FAM126A 84668 Leukodystrophy, Hypomyelinating, 5, Substance-Related Disorders, Intellectual Disability, Peripheral Nervous System Discases FAM13A 10144 Pulmonary Disease, Chronic Obstructive, Idiopathic Pulmonary Fibrosis FAM198B 51313 Glomerulonephritis, IGA FBN2 2201 Congenital contractural arachnodactyly, Colorectal Neoplasms FHOD3 80206 Substance-Related Disorders GALC 2581 Krabbe discasc, leukodystrophy, metachromatic leukodystrophy, lipid storage disease, infantile krabbe disease, chron's disease, neuropathy, neuronitis, motor neuron disease, hereditary spastic paraplegia, cerebritis, peripheral neuropathy, paraplegia, spasticity, Gaucher's disease, blindness, lysosomal storage disease, gangliosidosis, farber lipogranulomatosis, lipogranulomatosis, open-angle glaucoma, primary open angle glaucoma, glaucoma, multiple sclerosis, hepatitis, squamous cell carcinoma, hematopoietic stem cell transplantation, late-infantile or juvenile krabbe disease, adult krabbe disease GGCT 79017 Meningioma, osteosarcoma, tuberculosis, gestational diabetes, leukemia, eczema, eczema herpeticum, myoblastoma GOLGA4 2803 Arsenic Poisoning, Prostatic Neoplasms, Skin Diseases GPSM2 29899 Chudley-Mccullough syndrome GULP1 51454 Thyroid Diseases HLTF 6596 Colon cancer, adenocarcinoma, colorectal cancer, adenoma, gastric cancer, squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, endometrial adenocarcinoma, cervicitis, gastric cardia adenocarcinoma, cervical cancer, esophagitis, laryngeal squamous cell carcinoma, laryngitis, esophageal squamous cell carcinoma HMGA2 8091 Neoplasms, Lipomatosis, Multiple, Birth Weight HNMT 3176 Asthma, Urticaria, Rhinitis, Drug Hypersensitivity, Susceptibility to Asthma HPS1 3257 Albinism with hemorrhagic diathesis and pigmented reticuloendothelial cells HSD17B4 3295 Bifunctional peroxisomal enzyme deficiency, Gonadal dysgenesis XX type deafness, Zellweger Syndrome, Peroxisomal Disorders, Spasms, Infantile HTT 3064 Huntington Disease, Movement Disorders, Manganese Poisoning, Cadmium Poisoning IVD 3712 Acidemia, isovaleric KDM6A 7403 Esophageal Squamous Cell Carcinoma, Urinary Bladder Neoplasms, Neoplasms, Carcinoma, Adenoid Cystic, Carcinoma, Transitional Cell, KABUKI SYNDROME 2 MED13L 23389 Transposition of the Great Arteries, Dextro-Looped 1, Intellectual Disability MFN2 9927 Charcot-Marie-Tooth Disease, Axonal, Type 2A2, Hereditary Motor And Sensory Neuropathy VI, Charcot-Marie-Tooth Disease, Cardiomegaly MRPS28 28957 Breast Neoplasms MYLK 4638 Aortic Aneurysm, Familial Thoracic 7, Acute Lung Injury, Pneumonia, Neoplasm Metastasis, Glaucoma, Gastrointestinal Diseases, Vascular Diseases, Hypersensitivity, Brain Edema, Neoplasm Invasiveness, Glioma, Hypercholesterolemia NGF 4803 Neuropathy, Hereditary Sensory And Autonomic, Type V, Inflammation, Cystitis, Hyperalgesia, Urinary Bladder, Overactive, Hereditary Sensory and Autonomic Neuropathies, Glomerulonephritis, Heroin Dependence, Peripheral Nervous System Diseases, Epilepsy, Tonic-Clonic, Hyperkinesis, Neurogenic Inflammation, Lewy Body Discasc, Kidney Failure, Chronic, Nerve Degeneration, Lung Injury, Seizures, Bronchial Hyperreactivity, Nervous System Diseases, Renal Insufficiency, Chronic, Skin Ulcer, Corneal Ulcer, Parkinsonian Disorders, Neurodegenerative Diseases, Amnesia, Status Epilepticus, Parkinson Disease, Cocaine-Related Disorders, Neurobehavioral Manifestations, Nephritis, Interstitial NT5C2 22978 Precursor Cell Lymphoblastic Leukemia-Lymphoma, Recurrence, Spastic Paraplegia 45, Autosomal Recessive OSMR 9180 Amyloidosis IX, Glomerulonephritis, IGA, Carcinoma, Non-Small-Cell Lung, Amyloidosis, Primary Cutaneous OXCT1 5019 Succinyl-CoA: 3-oxoacid CoA transferase deficiency, Osteoporosis PAPD4 167153 Sleeping sickness PCM1 5108 Schizophrenia, Thyroid cancer, papillary PDXDC1 23042 Carcinoma, Renal Cell, Glomerulonephritis, IGA, Carboxy-lyase activity, pyridoxal phosphate binding PIGN 23556 Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 1 PIK3CD 5293 Activated PI3K-delta Syndrome, Lymphoma, Large B-Cell, Diffuse, Prostatic Neoplasms PIK3R1 5295 Short Syndrome, Insulin Resistance, Carcinoma, Mammary Neoplasms, Experimental, Burkitt Lymphoma, Mammary Neoplasms, Animal, Autosomal Recessive Agammaglobulinemia 7 PIKFYVE 200576 Corneal Dystrophy, Fleck PITPNB 23760 Obesity PLEKHA1 59338 Macular Degeneration, Age-Related, 1 PLSCR1 5359 Influenza, Human POMT2 29954 Muscular Dystrophy-Dystroglycanopathy (Limb-Girdle), Type C, 2, Muscular Dystrophy-Dystroglycanopathy (Congenital with Mental Retardation), Type B, 2, Muscular Dystrophy-Dystroglycanopathy (Congenital with Brain and Eye Anomalies), Type A, 2, Walker-Warburg Syndrome, Congenital muscular dystrophy PPARG 5468 Obesity, Familial Partial Lipodystrophy Type 3, Hypertension, Diabetes Mellitus, Type 2, Inflammation, Acute Lung Injury, Acute Kidney Injury, Diabetes Mellitus, Experimental, Insulin Resistance, Diabetes Mellitus, Atherosclerosis, Colonic Neoplasms, Colorectal Neoplasms, Thyroid Neoplasms, Alzheimer Disease, Adenocarcinoma, Stomach Neoplasms, Dyslipidemias, Pancreatic Neoplasms, Melanoma, Lipodystrophy, Familial Partial, Crohn Disease, Metabolic Diseases, Carcinoma, Hepatocellular, Colon Carcinoma, Psoriasis, Ischemia, Reperfusion Injury, Ostcoarthritis, Glioma, Liver Neoplasms, Polycystic Kidney, Autosomal Dominant, Leukostasis, Thyroid cancer, follicular, Lipidoses, Glomerulonephritis, Nerve Degeneration, Pituitary ACTH Hypersecretion, Carotid Intimal Medial Thickness 1, Barrett Esophagus, Lymphoma, T-Cell, Chronobiology Disorders, Obesity, Morbid PPHLN1 51535 Nervous system disorders, for example, interacts with synphilin-1, mutations of which are implicated in Parkinson's disease, gastric cancer, ichthyosis PRPF31 26121 Retinitis Pigmentosa 11, Retinitis Pigmentosa PRSS23 11098 Melanoma PSMA4 5685 Carcinoma, Mammary Neoplasms, Experimental, HIV Infections, Mammary Neoplasms, Animal, Liver Neoplasms PXK 54899 Lupus Erythematosus, Systemic, Arthritis, Rheumatoid RAF1 5894 Noonan Syndrome 5, Noonan Syndrome, Leopard syndrome, 2, Leopard Syndrome, Glioma, Cardiomyopathy, Hypertrophic, Carcinoma, Non-Small- Cell Lung, Lung Neoplasms, Breast Neoplasms, Liver Neoplasms, Kidney Neoplasms, Cardiomyopathy, Dilated, Hyperalgesia RARS2 57038 Pontocerebellar Hypoplasia Type 6 RFWD2 64326 Autistic Disorder RPA1 6117 Chloracne RPS10 6204 Diamond-Blackfan Anemia 9 RPS6KB2 6199 Breast Neoplasms SAMD4A 23034 Substance-Related Disorders SCO1 6341 Cytochrome-c Oxidase Deficiency, Mitochondrial Discascs SLC12A2 6558 Hypertension, Epilepsy, Epilepsy, Temporal Lobe, Carcinoma, Mammary Neoplasms, Experimental, Glucose Intolerance, Prostatic Neoplasms, Movement Disorders, Cardiovascular Diseases, Mammary Neoplasms, Animal SMYD3 64754 Amphetamine-Related Disorders SNAP23 8773 Myocardial Ischemia SPATA5 166378 Schizophrenia STAT1 6772 Susceptibility ToMycobacterial and Viral Infections, Autosomal Recessive, Candidiasis, Familial, 7, Arthritis, Experimental, Carcinoma, Hepatocellular, Mycobacterium Infections, Candidiasis, Chronic Mucocutaneous, Liver Cirrhosis, Arthritis, Rheumatoid, Cytomegalovirus Infections, Hearing Loss, Disease Progression, Mycobacterium Infections, Nontuberculous, Influenza, Human STRN3 29966 Cerebritis, cerebral cavernous malformation, cavernous malformation, cerebral cavernous malformations 3, neuronitis STXBP6 29091 Autistic Disorder TAF2 6873 Mental Retardation, Autosomal Recessive 40, Intellectual Disability TCF12 6938 Craniosynostosis 3, Craniosynostoses TCF4 6925 Pitt-Hopkins syndrome, Seizures, Peripheral Nervous System Diseases, Craniofacial Abnormalities, Heart Diseases, Microcephaly, Liver Neoplasms TIAM1 7074 Amyotrophic lateral sclerosis 1 TJP2 9414 Hypercholanemia, Familial, Hearing Loss, Cholestasis, Intrahepatic TRAF3 7187 Susceptibility to Herpes Simplex Encephalitis, 3 VPS29 51699 Down syndrome, paraplegia WNK1 65125 Neuropathy, Hereditary Sensory and Autonomic, Type IIA, Pseudohypoaldosteronism, Type IIc, Hypertension, Kidney Diseases, Pseudohypoaldosteronism, Peripheral Nervous System Diseases ZCCHC8 55596 Intellectual Disability

[2153] It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, the invention described herein is not to be limited in scope by the specific embodiments herein disclosed. These embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description, which modification also intended to be within the scope of this invention.

[2154] All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

METHODS FOR MODULATING RNA SPLICING

Assignee

Inventors

Cpc classification

Classification Explorer

A61P25/08

HUMAN NECESSITIES

Classification Explorer

A61P1/04

HUMAN NECESSITIES

Classification Explorer

A61P29/00

HUMAN NECESSITIES

Classification Explorer

A61P31/12

HUMAN NECESSITIES

Classification Explorer

A61P9/00

HUMAN NECESSITIES

Classification Explorer

A61P25/18

HUMAN NECESSITIES

Classification Explorer

A61P1/02

HUMAN NECESSITIES

Classification Explorer

A61P13/10

HUMAN NECESSITIES

Classification Explorer

A61P27/12

HUMAN NECESSITIES

Classification Explorer

A61P17/02

HUMAN NECESSITIES

Classification Explorer

A61P7/00

HUMAN NECESSITIES

Classification Explorer

A61P31/22

HUMAN NECESSITIES

Classification Explorer

A61P31/10

HUMAN NECESSITIES

Classification Explorer

A61P37/08

HUMAN NECESSITIES

Classification Explorer

A61P9/10

HUMAN NECESSITIES

Classification Explorer

C07C291/00

CHEMISTRY; METALLURGY

Classification Explorer

A61P25/00

HUMAN NECESSITIES

Classification Explorer

A61P31/04

HUMAN NECESSITIES

Classification Explorer

C12N15/102

CHEMISTRY; METALLURGY

Classification Explorer

A61P1/18

HUMAN NECESSITIES

Classification Explorer

A61P27/04

HUMAN NECESSITIES

Classification Explorer

A61P13/02

HUMAN NECESSITIES

Classification Explorer

A61P17/06

HUMAN NECESSITIES

Classification Explorer

A61P31/14

HUMAN NECESSITIES

Classification Explorer

A61P11/02

HUMAN NECESSITIES

Classification Explorer