METHODS FOR MODULATING RNA SPLICING

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

This application incorporates by reference a Sequence Listing submitted with this application as a text file entitled “10589-275-228_Sequence_Listing.txt” created on Nov. 18, 2017 and having a size of 1,112 kilobytes.

INTRODUCTION

In one aspect, described herein is a recognition element for splicing modifier (REMS) present in an intron (i.e., an “intronic REMS” or iREMS) that can be recognized as a 5′ splice site by the U1 snRNP and/or other components of the pre-mRNA splicing machinery in the presence of a small molecule splicing modifier, wherein gene expression is modulated by inducing alternative splicing of intronic exons (iExons) in the transcribed RNA. 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, a branch point and a 3′ splice site, and the methods utilize a small molecule compound described herein to induce alternative splicing of iExons. More particularly, described herein are methods for modulating the amount of an RNA transcript or protein product encoded by a gene via alternative splicing of iExons, wherein a precursor RNA transcript transcribed from the gene comprises an endogenous or non-endogenous intronic REMS, and the methods utilize a compound described herein to induce iExon alternative splicing. In another aspect, provided herein are artificial gene constructs comprising an intronic REMS (including an endogenous or non-endogenous intronic REMS), and uses of those artificial gene constructs to modulate protein production via iExon alternative splicing in the presence of a small molecule splicing modifier compound. In another aspect, provided herein are methods for altering genes to comprise an endogenous or non-endogenous intronic REMS, and the use of a small molecule compound described herein to induce alternative splicing of iExons, subsequently modulating the amount and type of protein produced from such altered endogenous or non-endogenous gene transcripts.

BACKGROUND

Diseases associated with expression of an aberrant gene product (e.g., where the production of an aberrant RNA transcript or protein causes a disease) are often treated with a focus on affecting aberrant protein expression. However, targeting components of the splicing process responsible for production of aberrant RNA before the aberrant protein is expressed by using a small molecule may affect the underlying cause of a disease or disorder, and thus more efficiently prevent or ameliorate the disease or disorder caused by expression of the aberrant gene product. Accordingly, there is a need for methods of modulating the expression of aberrant RNA transcripts encoded by certain genes using small molecules to prevent or treat diseases associated with expression of aberrant RNA transcripts or associated proteins.

SUMMARY

In one aspect, provided herein is a recognition element for splicing modifier (otherwise referred to as “REMS”) present in an intron (i.e., an “intronic REMS”) capable of being recognized by the U1 snRNP and/or other components of the pre-mRNA splicing machinery in the presence of a small molecule splicing modifier, whereby elements of the splicing reaction are affected as further described herein. In a specific embodiment, the intronic REMS comprises 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 comprises the nucleotide sequence GAguragu (SEQ ID NO: 3866) at the RNA level, wherein r is adenine or guanine. In a specific embodiment, the intronic REMS comprises 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 specific embodiment, the intronic REMS comprises 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 specific embodiments provided herein, N is adenine or guanine.

In another aspect, in addition to the intronic REMS sequence, the RNA transcript comprises an upstream branch point and a functional upstream iExon 3′ splice site. In certain embodiments including, but not limited to, iExons, an exon 5′ splice site, a branch point and the functional iExon 3′ splice site upstream from the intronic REMS are further linked to a downstream branch point and 3′ splice site of a downstream exon (see, for example, FIG. 1A). In other embodiments including, but not limited to, extended exons, the branch point and the functional 3′ splice site for an exon are downstream from the intronic REMS sequences (see, for example, FIGS. 1B and 1C). In a particular embodiment, an RNA sequence comprises two exons and an intron, wherein one exon is upstream of the intron and the other exon is downstream of the intron, and wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site (also referred to as an iExon 3′ splice site), an iREMS, a second branch point, and a second 3′ splice site. In the presence of a compound described herein, the iREMS sequence functions as a 5′ splice site, causing the NNGA (SEQ ID NO: 3863) nucleotides of the iREMS and the intronic nucleotides downstream of the first 3′ splice site to be retained and spliced as an intronic exon to provide a non-wild-type mRNA. In other words, the nucleotides between the iREMS and the first 3′ splice site are retained and form the intronic exon, which results in the expression of a non-wild-type mRNA sequence. In the presence of a compound described herein, the iREMS sequence functions as a 5′ splice site, causing the NNGA (SEQ ID NO: 3863) nucleotides of the iREMS and the intronic nucleotides between the 3′ iExon splice site to be retained and spliced as an intronic exon to provide a non-wild-type mRNA. In other aspects, in the presence of a compound described herein and a downstream branch point, the intronic REMS will undergo splicing with the 3′ splice site of a downstream exon. In this aspect, the intronic REMS is located downstream of an exon such that there is no intervening upstream branch point and iExon 3′ splice site between the exon and the REMS sequence. In the presence of a compound described herein, the exon 5′ splice site does not undergo splicing with the downstream 3′ splice site. Instead, functioning as a 5′ splice site in the presence of a compound described herein, the iREMS sequence undergoes splicing with the downstream 3′ splice site. In other embodiments, in the presence of a compound described herein, an upstream exon 5′ splice site, an upstream branch point, and a functional iExon 3′ splice site upstream from the intronic REMS, will undergo splicing. In certain embodiments, one or more sequence elements necessary to form an iExon splice junction may be present endogenously or non-endogenously. For example, one or more of the following sequence elements may be present naturally in an intron or an intron may be engineered to comprise one or more of the following sequences 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. In certain embodiments, one or more snRNPs and trans factor elements necessary for splicing may be present beyond endogenous levels as a result of the presence of a compound described herein at various splice inducing sequence combinations. Without being bound by any theory or mechanism, the small molecule compounds described herein, in conjunction with the iREMS sequence, initiate the assembly of a splicing-competent spliceosome around a weak or incompletely defined exon (i.e., a nascent iExon). Splicing modifier compounds most likely enable a functional U1 snRNP-REMS interaction and, at least, have been shown to increase the affinity of one or more snRNPs and trans factor elements necessary for splicing, including U1, U2, U4, U5 and U6, whereby 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 are enhanced. In fact, we have discovered that the interaction of the U1 snRNP, the iREMS and the small molecule splicing modifier compounds described herein serve to define nascent exons by increasing the binding affinity of the pre-mRNA splicing machinery to the iREMS sequence, stabilizing U1 binding with the iREMS sequence, activating a 3′ splice site and a branch point upstream from the iREMS and recruiting U2 snRNP and other trans-acting splicing factors such as U2AF (U2AF65 and U2AF35) and SF3A (SF3A1, SF3A2 and SF3A3) to the upstream branch point and 3′ splice site. The branch point and 3′splice site may or may not be fully occupied in the absence of the compound but have been shown to become occupied after the compound has enabled the formation of a functional U1 snRNP-REMS complex. We have elaborated on the interaction of these key splicing machinery elements, showing that, in the presence of small molecule splicing modifier compounds such as, but certainly not limited to, those described herein, the mechanism of intronic spliceosome assembly can be mediated by iREMS interaction with such compounds, such that the intronic REMS sequence functions as a U1 snRNP binding site, resulting in intronic nucleotides spliced in the mature RNA transcript as an intronic exon.

In FIG. 1A, the intronic REMS is located in Intron 1 downstream from an Exon 1 5′ splice site (i.e., a 5′ splice site at the 3′ end of Exon 1), a first branch point (BP) sequence and a first 3′ splice site sequence and upstream from a second branch point sequence and a second 3′ splice site sequence of Exon 2 in an RNA transcript (i.e., the precursor mRNA). In the presence of a small molecule splicing modifier compound described herein the intronic REMS functions as a 5′ splice site, whereby the nucleotides between the Exon 1 5′ splice site and the first 3′ splice site are removed to form a splice junction between Exon 1 and a nascent intronic exon and the nucleotides between the intronic REMS and the second 3′ splice site sequence are removed to form a splice junction between iExon 1a and Exon 2, and allowing Exon 2 and the portion of the intron comprising nucleotides from the first 3′ splice site up to and including NNGA (SEQ ID NO: 3863) of the intronic REMS to be joined, thus introducing an intron-derived iExon 1a, generating a non-wildtype mRNA. In certain embodiments of FIG. 1A, one or more elements necessary to form a splice junction may be present endogenously or introduced, wherein the one or more elements are selected from the group consisting of the first branch point, the first 3′ splice site, the intronic REMS, the second branch point and the second 3′ splice site. While illustrated for Intron 1 here, this concept is generally applicable to any other intron in a pre-mRNA transcript.

In FIG. 1B, the intronic REMS is located in an intron of an RNA transcript downstream from an Exon 1 5′ splice site (i.e., a 5′ splice site at the 3′ end of Exon 1) and upstream from an Intron 1 branch point sequence and a 3′ splice site sequence of Exon 2 (i.e., a 3′ splice site at the 5′ end of Exon 2). In the presence of a small molecule splicing modifier compound described herein, the nucleotides between the Exon 1 5′ splice site and the intronic REMS are retained and those between the intronic REMS and the Intron 1 3′ splice site sequence (except the NNGA (SEQ ID NO: 3863) nucleotides of the intronic REMS) are removed, allowing Exon 1 and the portion of the intron comprising nucleotides from those adjacent to the Exon 1 5′ splice site up to and including NNGA (SEQ ID NO: 3863) of the intronic REMS and the Exon 2 nucleotides to be joined. The scope of the invention described herein is merely illustrated in this configuration for Exon 1 but is generally applicable to any other nascent iExon in an intronic sequence. The elements necessary to induce splicing of an iExon may be present in any configuration capable of recognition by the splicing machinery as an “exon.” Accordingly, in the presence of a splicing modifier compound, the spliceosome recognizes the elements as exonic boundaries for removal of intervening intronic nucleotides between those boundaries. The configuration in this instance results in an iExon spliced between at least one upstream exon and one downstream exon of the same pre-mRNA transcript.

In FIG. 1C, the intronic REMS is located in Intron 2 downstream from an Exon 2 5′ splice site (i.e., a 5′ splice site at the 3′ end of Exon 2) and upstream from an Intron 2 branch point sequence and a 3′ splice site sequence of Exon 3 (i.e., a 3′ splice site at the 5′ end of Exon 3) in an RNA transcript. In the presence of a small molecule splicing modifier compound described herein, the nucleotides between the intronic REMS and the Exon 3 3′ splice site sequence are removed, allowing Exon 3 and the portion of the intron comprising nucleotides from those adjacent to the Exon 2 5′ splice site up to and including NNGA (SEQ ID NO: 3863) of the intronic REMS to be joined. In this example, the endogenous splicing reaction between Exon 1 and Exon 2 is unaffected by the presence of a compound described herein, resulting in the complete removal of Intron 1. While illustrated for Exon 2 here, this concept is generally applicable to any other internal nascent intronic exon, i.e., an exon that is located between at least one upstream exon and one downstream exon of the same pre-mRNA transcript.

As used herein, an “exon 5′ splice site”, a “5′ splice site of an exon” or the like refers to a 5′ splice site at the 3′ end of the exon, while an “exon 3′ splice site”, a “3′ splice site of an exon” or the like refers to a 3′ splice site at the 5′ end of the exon.

In the presence of a small molecule splicing modifier compound described herein, the iREMS nucleotides retained in the formation of an iExon are selected from the group consisting of ANGA (SEQ ID NO: 5), CNGA (SEQ ID NO: 11), GNGA (SEQ ID NO: 17), UNGA (SEQ ID NO: 23), NAGA (SEQ ID NO: 6), NCGA (SEQ ID NO: 12), NGGA (SEQ ID NO: 18), NUGA (SEQ ID NO: 24), AAGA (SEQ ID NO: 7), ACGA (SEQ ID NO: 13), AGGA (SEQ ID NO: 19), AUGA (SEQ ID NO: 25), CAGA (SEQ ID NO: 8), CCGA (SEQ ID NO: 14), CGGA (SEQ ID NO: 20), CUGA (SEQ ID NO: 26), GAGA (SEQ ID NO: 9), GCGA (SEQ ID NO: 15), GGGA (SEQ ID NO: 21), GUGA (SEQ ID NO: 27), UAGA (SEQ ID NO: 10), UCGA (SEQ ID NO: 16), UGGA (SEQ ID NO: 22) and UUGA (SEQ ID NO: 28). The formation of an iExon may result in an RNA transcript having a non-functional open reading frame due to the inclusion of a frameshift, premature stop codon or internal deletions within the open reading frame. In other embodiments, the inclusion of an iExon may result in the mature mRNA having a functional open reading frame, producing a novel protein which may or may not be functional. RNA transcripts having a non-functional open reading frame due to the inclusion of a frameshift, premature stop codon or internal deletions within the open reading frame can be substrates for nonsense-mediated decay and thus have low abundance. Any intronic REMS-mediated alternative splicing modified RNA transcripts may also have altered stability, altered intracellular transport, altered 3′ end formation efficiency and altered translation efficiency.

Accordingly, in one aspect, provided herein are methods for modulating the amount of RNA transcripts produced from precursor RNA containing an endogenous or non-endogenous intronic REMS. In another aspect, provided herein are artificial gene constructs comprising an endogenous or non-endogenous intronic REMS, which may be used in the context of, e.g., gene therapy or reporter assays. In another aspect, provided herein are methods for altering endogenous genes so that they contain an intronic REMS or an additional intronic REMS.

In another aspect, provided herein are methods for modulating the amount of one or more RNA transcripts (e.g., mRNA transcripts) or proteins thereof expressed as the product of one or more genes, wherein precursor RNA transcripts transcribed by the one or more genes comprise an intronic REMS, the methods comprising contacting a cell with a compound of Formula

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or a form thereof, wherein w₁, w₂, w₃, w₄, w₅, w₆and w₇are as defined herein. In one embodiment, provided herein is a method for modulating the amount of an RNA transcript produced from precursor RNA containing an intronic recognition element for splicing modifier (REMS), the method comprising contacting a cell containing the precursor RNA with a compound of Formula (I) or a form thereof, wherein the intronic REMS comprises the sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide, wherein the precursor RNA is a gene in Table 1. In certain embodiments, the precursor RNA is a gene in Table 7. In another embodiment, provided herein is a method for modulating the amount of an RNA transcript produced from precursor RNA containing an intronic recognition element for splicing modifier (REMS), the method comprising contacting the precursor RNA with a compound of Formula (I) or a form thereof, wherein the intronic REMS comprises the sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide, wherein the precursor RNA is a gene in Table 1. In some embodiments, the intronic REMS comprises the sequence NNGAguragu (SEQ ID NO: 3862) at the RNA level, wherein r is adenine or guanine and N is any nucleotide. In certain embodiments, the intronic REMS comprises a 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), CGGAgumgn (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), wherein r is adenine or guanine and n or N is any nucleotide. In some embodiments, the intronic REMS comprises a 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 adenine or guanine, and N is any nucleotide. In one or more embodiments provided herein, N is adenine or guanine.

In a specific embodiment, the intronic REMS referred to in a method or artificial gene construct described herein comprises, at the RNA level, a sequence presented in the following table (wherein r is adenine or guanine, and n or N is any nucleotide):

TABLE 13

Intronic REMS RNA sequence (wherein r is adenine or guanine, and n or N

is any nucleotide)

SEQ ID

SEQ ID

SEQ ID

SEQ ID

NO.
Sequence
NO.
Sequence
NO.
Sequence
NO.
Sequence

29
ANGAgurngn
35
CNGAgurngn
41
GNGAgurngn
47
UNGAgurngn

30
NAGAgurngn
36
NCGAgurngn
42
NGGAgurngn
48
NUGAgurngn

31
AAGAgurngn
37
ACGAgurngn
43
AGGAgurngn
49
AUGAgurngn

32
CAGAgurngn
38
CCGAgurngn
44
CGGAgurngn
50
CUGAgurngn

33
GAGAgurngn
39
GCGAgurngn
45
GGGAgurngn
51
GUGAgurngn

34
UAGAgurngn
40
UCGAgurngn
46
UGGAgurngn
52
UUGAgurngn

53
ANGAguragn
77
ANGAgurcgn
101
ANGAgurggn
125
ANGAgurugn

54
NAGAguragn
78
NAGAgurcgn
102
NAGAgurggn
126
NAGAgurugn

55
AAGAguragn
79
AAGAgurcgn
103
AAGAgurggn
127
AAGAgurugn

56
CAGAguragn
80
CAGAgurcgn
104
CAGAgurggn
128
CAGAgurugn

57
GAGAguragn
81
GAGAgurcgn
105
GAGAgurggn
129
GAGAgurugn

58
UAGAguragn
82
UAGAgurcgn
106
UAGAgurggn
130
UAGAgurugn

59
CNGAguragn
83
CNGAgurcgn
107
CNGAgurggn
131
CNGAgurugn

60
NCGAguragn
84
NCGAgurcgn
108
NCGAgurggn
132
NCGAgurugn

61
ACGAguragn
85
ACGAgurcgn
109
ACGAgurggn
133
ACGAgurugn

62
CCGAguragn
86
CCGAgurcgn
110
CCGAgurggn
134
CCGAgurugn

63
GCGAguragn
87
GCGAgurcgn
111
GCGAgurggn
135
GCGAgurugn

64
UCGAguragn
88
UCGAgurcgn
112
UCGAgurggn
136
UCGAgurugn

65
GNGAguragn
89
GNGAgurcgn
113
GNGAgurggn
137
GNGAgurugn

66
NGGAguragn
90
NGGAgurcgn
114
NGGAgurggn
138
NGGAgurugn

67
AGGAguragn
91
AGGAgurcgn
115
AGGAgurggn
139
AGGAgurugn

68
CGGAguragn
92
CGGAgurcgn
116
CGGAgurggn
140
CGGAgurugn

69
GGGAguragn
93
GGGAgurcgn
117
GGGAgurggn
141
GGGAgurugn

70
UGGAguragn
94
UGGAgurcgn
118
UGGAgurggn
142
UGGAgurugn

71
UNGAguragn
95
UNGAgurcgn
119
UNGAgurggn
143
UNGAgurugn

72
NUGAguragn
96
NUGAgurcgn
120
NUGAgurggn
144
NUGAgurugn

73
AUGAguragn
97
AUGAgurcgn
121
AUGAgurggn
145
AUGAgurugn

74
CUGAguragn
98
CUGAgurcgn
122
CUGAgurggn
146
CUGAgurugn

75
GUGAguragn
99
GUGAgurcgn
|23
GUGAgurggn
147
GUGAgurugn

76
UUGAguragn
100
UUGAgurcgn
124
UUGAgurggn
148
UUGAgurugn

149
ANGAguraga
173
ANGAgurcga
197
ANGAgurgga
221
ANGAguruga

150
NAGAguraga
174
NAGAgurcga
198
NAGAgurgga
222
NAGAguruga

151
AAGAguraga
175
AAGAgurcga
199
AAGAgurgga
223
AAGAguruga

152
CAGAguraga
176
CAGAgurcga
200
CAGAgurgga
224
CAGAguruga

153
GAGAguraga
177
GAGAgurcga
201
GAGAgurgga
225
GAGAguruga

154
UAGAguraga
178
UAGAgurcga
202
UAGAgurgga
226
UAGAguruga

155
CNGAguraga
179
CNGAgurcga
203
CNGAgurgga
227
CNGAguruga

156
NCGAguraga
180
NCGAgurcga
204
NCGAgurgga
228
NCGAguruga

157
ACGAguraga
181
ACGAgurcga
205
ACGAgurgga
229
ACGAguruga

158
CCGAguraga
182
CCGAgurcga
206
CCGAgurgga
230
CCGAguruga

159
GCGAguraga
183
GCGAgurcga
207
GCGAgurgga
231
GCGAguruga

160
UCGAguraga
184
UCGAgurcga
208
UCGAgurgga
232
UCGAguruga

161
GNGAguraga
185
GNGAgurcga
209
GNGAgurgga
233
GNGAguruga

162
NGGAguraga
186
NGGAgurcga
210
NGGAgurgga
234
NGGAguruga

163
AGGAguraga
187
AGGAgurcga
211
AGGAgurgga
235
AGGAguruga

164
CGGAguraga
188
CGGAgurcga
212
CGGAgurgga
236
CGGAguruga

165
GGGAguraga
189
GGGAgurcga
213
GGGAgurgga
237
GGGAguruga

166
UGGAguraga
190
UGGAgurcga
214
UGGAgurgga
238
UGGAguruga

167
UNGAguraga
191
UNGAgurcga
215
UNGAgurgga
239
UNGAguruga

168
NUGAguraga
192
NUGAgurcga
216
NUGAgurgga
240
NUGAguruga

169
AUGAguraga
193
AUGAgurcga
217
AUGAgurgga
241
AUGAguruga

170
CUGAguraga
194
CUGAgurcga
218
CUGAgurgga
242
CUGAguruga

171
GUGAguraga
195
GUGAgurcga
219
GUGAgurgga
243
GUGAguruga

172
UUGAguraga
196
UUGAgurcga
220
UUGAgurgga
244
UUGAguruga

245
ANGAguragc
269
ANGAgurcgc
293
ANGAgurggc
317
ANGAgurugc

246
NAGAguragc
270
NAGAgurcgc
294
NAGAgurggc
318
NAGAgurugc

247
AAGAguragc
271
AAGAgurcgc
295
AAGAgurggo
319
AAGAgurugc

248
CAGAguragc
272
CAGAgurcgc
296
CAGAgurggc
320
CAGAgurugc

249
GAGAguragc
273
GAGAgurcgc
297
GAGAgurggc
321
GAGAgurugc

250
UAGAguragc
274
UAGAgurcgc
298
UAGAgurggc
322
UAGAgurugc

251
CNGAguragc
275
CNGAgurcgc
299
CNGAgurggc
323
CNGAgurugc

252
NCGAgurago
276
NCGAgurcgc
300
NCGAgurggc
324
NCGAgurugc

253
ACGAguragc
277
ACGAgurcgc
301
ACGAgurggc
325
ACGAgurugc

254
CCGAguragc
278
CCGAgurcgc
302
CCGAgurggc
326
CCGAgurugc

255
GCGAguragc
279
GCGAgurcgc
303
GCGAgurggc
327
GCGAgurugc

256
UCGAguragc
280
UCGAgurcgc
304
UCGAgurggc
328
UCGAgurugc

257
GNGAguragc
281
GNGAgurcgc
305
GNGAgurggc
329
GNGAgurugc

258
NGGAguragc
282
NGGAgurcgc
306
NGGAgurggc
330
NGGAgurugc

259
AGGAguragc
283
AGGAgurcgc
307
AGGAgurggc
331
AGGAgurugc

260
CGGAguragc
284
CGGAgurcgc
308
CGGAgurggc
332
CGGAgurugc

261
GGGAguragc
285
GGGAgurcgc
309
GGGAgurggc
333
GGGAgurugc

262
UGGAguragc
286
UGGAgurcgc
310
UGGAgurggc
334
UGGAgurugc

263
UNGAguragc
287
UNGAgurcgc
311
UNGAgurggc
335
UNGAgurugc

264
NUGAguragc
288
NUGAgurcgc
312
NUGAgurggc
336
NUGAgurugc

265
AUGAguragc
289
AUGAgurcgc
313
AUGAgurggc
337
AUGAgurugc

266
CUGAgurago
290
CUGAgurcgc
314
CUGAgurggc
338
CUGAgurugc

267
GUGAguragc
291
GUGAgurcgc
315
GUGAgurggc
339
GUGAgurugc

268
UUGAguragc
292
UUGAgurcgc
316
UUGAgurggc
340
UUGAgurugc

341
ANGAguragg
365
ANGAgurcgg
389
ANGAgurggg
413
ANGAgurugg

342
NAGAguragg
366
NAGAgurcgg
390
NAGAgurggg
414
NAGAgurugg

343
AAGAguragg
367
AAGAgurcgg
391
AAGAgurggg
415
AAGAgurugg

344
CAGAguragg
368
CAGAgurcgg
392
CAGAgurggg
416
CAGAgurugg

345
GAGAguragg
369
GAGAgurcgg
393
GAGAgurggg
417
GAGAgurugg

346
UAGAguragg
370
UAGAgurcgg
394
UAGAgurggg
418
UAGAgurugg

347
CNGAguragg
371
CNGAgurcgg
395
CNGAgurggg
419
CNGAgurugg

348
NCGAguragg
372
NCGAgurcgg
396
NCGAgurggg
420
NCGAgurugg

349
ACGAguragg
373
ACGAgurcgg
397
ACGAgurggg
421
ACGAgurugg

350
CCGAguragg
374
CCGAgurcgg
398
CCGAgurggg
422
CCGAgurugg

351
GCGAguragg
375
GCGAgurcgg
399
GCGAgurggg
423
GCGAgurugg

352
UCGAguragg
376
UCGAgurcgg
400
UCGAgurggg
424
UCGAgurugg

353
GNGAguragg
377
GNGAgurcgg
401
GNGAgurggg
425
GNGAgurugg

354
NGGAguragg
378
NGGAgurcgg
402
NGGAgurggg
426
NGGAgurugg

355
AGGAguragg
379
AGGAgurcgg
403
AGGAgurggg
427
AGGAgurugg

356
CGGAguragg
380
CGGAgurcgg
404
CGGAgurggg
428
CGGAgurugg

357
GGGAguragg
381
GGGAgurcgg
405
GGGAgurggg
429
GGGAgurugg

358
UGGAguragg
382
UGGAgurcgg
406
UGGAgurggg
430
UGGAgurugg

359
UNGAguragg
383
UNGAgurcgg
407
UNGAgurggg
431
UNGAgurugg

360
NUGAguragg
384
NUGAgurcgg
408
NUGAgurggg
432
NUGAgurugg

361
AUGAguragg
385
AUGAgurcgg
409
AUGAgurggg
433
AUGAgurugg

362
CUGAguragg
386
CUGAgurcgg
410
CUGAgurggg
434
CUGAgurugg

363
GUGAguragg
387
GUGAgurcgg
411
GUGAgurggg
435
GUGAgurugg

364
UUGAguragg
388
UUGAgurcgg
412
UUGAgurggg
436
UUGAgurugg

437
ANGAguragu
461
ANGAgurcgu
485
ANGAgurggu
509
ANGAgurugu

438
NAGAguragu
462
NAGAgurcgu
486
NAGAgurggu
510
NAGAgurugu

439
AAGAguragu
463
AAGAgurcgu
487
AAGAgurggu
511
AAGAgurugu

440
CAGAguragu
464
CAGAgurcgu
488
CAGAgurggu
512
CAGAgurugu

441
GAGAguragu
465
GAGAgurcgu
489
GAGAgurggu
513
GAGAgurugu

442
UAGAguragu
466
UAGAgurcgu
490
UAGAgurggu
514
UAGAgurugu

443
CNGAguragu
467
CNGAgurcgu
491
CNGAgurggu
515
CNGAgurugu

444
NCGAguragu
468
NCGAgurcgu
492
NCGAgurggu
516
NCGAgurugu

445
ACGAguragu
469
ACGAgurcgu
493
ACGAgurggu
517
ACGAgurugu

446
CCGAguragu
470
CCGAgurcgu
494
CCGAgurggu
518
CCGAgurugu

447
GCGAguragu
471
GCGAgurcgu
495
GCGAgurggu
519
GCGAgurugu

448
UCGAguragu
472
UCGAgurcgu
496
UCGAgurggu
520
UCGAgurugu

449
GNGAguragu
473
GNGAgurcgu
497
GNGAgurggu
521
GNGAgurugu

450
NGGAguragu
474
NGGAgurcgu
498
NGGAgurggu
522
NGGAgurugu

451
AGGAguragu
475
AGGAgurcgu
499
AGGAgurggu
523
AGGAgurugu

452
CGGAguragu
476
CGGAgurcgu
500
CGGAgurggu
524
CGGAgurugu

453
GGGAguragu
477
GGGAgurcgu
501
GGGAgurggu
525
GGGAgurugu

454
UGGAguragu
478
UGGAgurcgu
502
UGGAgurggu
526
UGGAgurugu

455
UNGAguragu
479
UNGAgurcgu
503
UNGAgurggu
527
UNGAgurugu

456
NUGAguragu
480
NUGAgurcgu
504
NUGAgurggu
528
NUGAgurugu

457
AUGAguragu
481
AUGAgurcgu
505
AUGAgurggu
529
AUGAgurugu

458
CUGAguragu
482
CUGAgurcgu
506
CUGAgurggu
530
CUGAgurugu

459
GUGAguragu
483
GUGAgurcgu
507
GUGAgurggu
531
GUGAgurugu

460
UUGAguragu
484
UUGAgurcgu
508
UUGAgurggu
532
UUGAgurugu

533
ANGAgurnga
557
ANGAgurngc
581
ANGAgurngg
605
ANGAgurngu

534
NAGAgurnga
558
NAGAgurngc
582
NAGAgurngg
606
NAGAgurngu

535
AAGAgurnga
559
AAGAgurngc
583
AAGAgurngg
607
AAGAgurngu

536
CAGAgurnga
560
CAGAgurngc
584
CAGAgurngg
608
CAGAgurngu

537
GAGAgurnga
561
GAGAgurngc
585
GAGAgurngg
609
GAGAgurngu

538
UAGAgurnga
562
UAGAgurngc
586
UAGAgurngg
610
UAGAgurngu

539
CNGAgurnga
563
CNGAgurngc
587
CNGAgurngg
611
CNGAgurngu

540
NCGAgurnga
564
NCGAgurngc
588
NCGAgurngg
612
NCGAgurngu

541
ACGAgurnga
565
ACGAgurngc
589
ACGAgurngg
613
ACGAgurngu

542
CCGAgurnga
566
CCGAgurngc
590
CCGAgurngg
614
CCGAgurngu

543
GCGAgurnga
567
GCGAgurngc
591
GCGAgurngg
615
GCGAgurngu

544
UCGAgurnga
568
UCGAgurngc
592
UCGAgurngg
616
UCGAgurngu

545
GNGAgurnga
569
GNGAgurngc
593
GNGAgurngg
617
GNGAgurngu

546
NGGAgurnga
570
NGGAgurngc
594
NGGAgurngg
618
NGGAgurngu

547
AGGAgurnga
571
AGGAgurngo
595
AGGAgurngg
619
AGGAgurngu

548
CGGAgurnga
572
CGGAgurngc
596
CGGAgurngg
620
CGGAgurngu

549
GGGAgurnga
573
GGGAgurngc
597
GGGAgurngg
621
GGGAgurngu

550
UGGAgurnga
574
UGGAgurngc
598
UGGAgurngg
622
UGGAgurngu

551
UNGAgurnga
575
UNGAgurngc
599
UNGAgurngg
623
UNGAgurngu

552
NUGAgurnga
576
NUGAgurngc
600
NUGAgurngg
624
NUGAgurngu

553
AUGAgurnga
577
AUGAgurngc
601
AUGAgurngg
625
AUGAgurngu

554
CUGAgurnga
578
CUGAgurngc
602
CUGAgurngg
626
CUGAgurngu

555
GUGAgurnga
579
GUGAgurngc
603
GUGAgurngg
627
GUGAgurngu

556
UUGAgurnga
580
UUGAgurngc
604
UUGAgurngg
628
UUGAgurngu

629
ANGAguangn
653
ANGAguaagr
677
ANGAguacgn
701
ANGAguaggn

630
NAGAguangn
654
NAGAguaagn
678
NAGAguacgn
702
NAGAguaggn

631
AAGAguangn
655
AAGAguaagn
679
AAGAguacgn
703
AAGAguaggn

632
CAGAguangn
656
CAGAguaagn
680
CAGAguacgn
704
CAGAguaggn

633
GAGAguangn
657
GAGAguaagn
681
GAGAguacgn
705
GAGAguaggn

634
UAGAguangn
658
UAGAguaagn
682
UAGAguacgn
706
UAGAguaggn

635
CNGAguangn
659
CNGAguaagn
683
CNGAguacgn
707
CNGAguaggn

636
NCGAguangn
660
NCGAguaagn
684
NCGAguacgn
708
NCGAguaggn

637
ACGAguangn
661
ACGAguaagn
685
ACGAguacgn
709
ACGAguaggn

638
CCGAguangn
662
CCGAguaagn
686
CCGAguacgn
710
CCGAguaggn

639
GCGAguangn
663
GCGAguaagn
687
GCGAguacgn
711
GCGAguaggn

640
UCGAguangn
664
UCGAguaagn
688
UCGAguacgn
712
UCGAguaggn

641
GNGAguangn
665
GNGAguaagn
689
GNGAguacgn
713
GNGAguaggn

642
NGGAguangn
666
NGGAguaagn
690
NGGAguacgn
714
NGGAguaggn

643
AGGAguangn
667
AGGAguaagn
691
AGGAguacgn
715
AGGAguaggn

644
CGGAguangn
668
CGGAguaagn
692
CGGAguacgn
716
CGGAguaggn

645
GGGAguangn
669
GGGAguaagn
693
GGGAguacgn
717
GGGAguaggn

646
UGGAguangn
670
UGGAguaagn
694
UGGAguacgn
718
UGGAguaggn

647
UNGAguangn
671
UNGAguaagn
695
UNGAguacgn
719
UNGAguaggn

648
NUGAguangn
672
NUGAguaagn
696
NUGAguacgn
720
NUGAguaggn

649
AUGAguangn
673
AUGAguaagn
697
AUGAguacgn
721
AUGAguaggn

650
CUGAguangn
674
CUGAguaagn
698
CUGAguacgn
722
CUGAguaggn

651
GUGAguangn
675
GUGAguaagn
699
GUGAguacgn
723
GUGAguaggn

652
UUGAguangn
676
UUGAguaagn
700
UUGAguacgn
724
UUGAguaggn

725
ANGAguaugn
749
ANGAguaaga
773
ANGAguacga
797
ANGAguagga

726
NAGAguaugn
750
NAGAguaaga
774
NAGAguacga
798
NAGAguagga

727
AAGAguaugn
751
AAGAguaaga
775
AAGAguacga
799
AAGAguagga

728
CAGAguaugn
752
CAGAguaaga
776
CAGAguacga
800
CAGAguagga

729
GAGAguaugn
753
GAGAguaaga
777
GAGAguacga
801
GAGAguagga

730
UAGAguaugn
754
UAGAguaaga
778
UAGAguacga
802
UAGAguagga

731
CNGAguaugn
755
CNGAguaaga
779
CNGAguacga
803
CNGAguagga

732
NCGAguaugn
756
NCGAguaaga
780
NCGAguacga
804
NCGAguagga

733
ACGAguaugn
757
ACGAguaaga
781
ACGAguacga
805
ACGAguagga

734
CCGAguaugn
758
CCGAguaaga
782
CCGAguacga
806
CCGAguagga

735
GCGAguaugn
759
GCGAguaaga
783
GCGAguacga
807
GCGAguagga

736
UCGAguaugr
760
UCGAguaaga
784
UCGAguacga
808
UCGAguagga

737
GNGAguaugn
761
GNGAguaaga
785
GNGAguacga
809
GNGAguagga

738
NGGAguaugn
762
NGGAguaaga
786
NGGAguacga
810
NGGAguagga

739
AGGAguaugn
763
AGGAguaaga
787
AGGAguacga
811
AGGAguagga

740
CGGAguaugn
764
CGGAguaaga
788
CGGAguacga
812
CGGAguagga

741
GGGAguaugn
765
GGGAguaaga
789
GGGAguacga
813
GGGAguagga

742
UGGAguaugn
766
UGGAguaaga
790
UGGAguacga
814
UGGAguagga

743
UNGAguaugn
767
UNGAguaaga
791
UNGAguacga
815
UNGAguagga

744
NUGAguaugn
768
NUGAguaaga
792
NUGAguacga
816
NUGAguagga

745
AUGAguaugn
769
AUGAguaaga
793
AUGAguacga
817
AUGAguagga

746
CUGAguaugn
770
CUGAguaaga
794
CUGAguacga
818
CUGAguagga

747
GUGAguaugn
771
GUGAguaaga
795
GUGAguacga
819
GUGAguagga

748
UUGAguaugn
772
UUGAguaaga
796
UUGAguacga
820
UUGAguagga

821
ANGAguauga
845
ANGAguaagc
869
ANGAguacgc
893
ANGAguaggc

822
NAGAguauga
846
NAGAguaagc
870
NAGAguacgc
894
NAGAguaggc

823
AAGAguauga
847
AAGAguaagc
871
AAGAguacgc
895
AAGAguaggc

824
CAGAguauga
848
CAGAguaagc
872
CAGAguacgc
896
CAGAguaggc

825
GAGAguauga
849
GAGAguaagc
873
GAGAguacgc
897
GAGAguaggc

826
UAGAguauga
850
UAGAguaagc
874
UAGAguacgc
898
UAGAguaggc

827
CNGAguauga
851
CNGAguaagc
875
CNGAguacgc
899
CNGAguaggc

828
NCGAguauga
852
NCGAguaagc
876
NCGAguacgc
900
NCGAguaggc

829
ACGAguauga
853
ACGAguaagc
877
ACGAguacgc
901
ACGAguaggc

830
CCGAguauga
854
CCGAguaagc
878
CCGAguacgc
902
CCGAguaggc

831
GCGAguauga
855
GCGAguaagc
879
GCGAguacgc
903
GCGAguaggc

832
UCGAguauga
856
UCGAguaagc
880
UCGAguacgc
904
UCGAguaggc

833
GNGAguauga
857
GNGAguaagc
881
GNGAguacgc
905
GNGAguaggc

834
NGGAguauga
858
NGGAguaagc
882
NGGAguacgc
906
NGGAguaggc

835
AGGAguauga
859
AGGAguaagc
883
AGGAguacgc
907
AGGAguaggc

836
CGGAguauga
860
CGGAguaagc
884
CGGAguacgc
908
CGGAguaggc

837
GGGAguauga
861
GGGAguaagc
885
GGGAguacgc
909
GGGAguaggc

838
UGGAguauga
862
UGGAguaagc
886
UGGAguacgc
910
UGGAguaggc

839
UNGAguauga
863
UNGAguaagc
887
UNGAguacgc
911
UNGAguaggc

840
NUGAguauga
864
NUGAguaagc
888
NUGAguacgc
912
NUGAguaggc

841
AUGAguauga
865
AUGAguaagc
889
AUGAguacgc
913
AUGAguaggc

842
CUGAguauga
866
CUGAguaagc
890
CUGAguacgc
914
CUGAguaggc

843
GUGAguauga
867
GUGAguaagc
891
GUGAguacgc
915
GUGAguaggc

844
UUGAguauga
868
UUGAguaagc
892
UUGAguacgc
916
UUGAguaggc

917
ANGAguaugc
941
ANGAguaagg
965
ANGAguacgg
989
ANGAguaggg

918
NAGAguaugc
942
NAGAguaagg
966
NAGAguacgg
990
NAGAguaggg

919
AAGAguaugc
943
AAGAguaagg
967
AAGAguacgg
991
AAGAguaggg

920
CAGAguaugc
944
CAGAguaagg
968
CAGAguacgg
992
CAGAguaggg

921
GAGAguaugc
945
GAGAguaagg
969
GAGAguacgg
993
GAGAguaggg

922
UAGAguaugc
946
UAGAguaagg
970
UAGAguacgg
994
UAGAguaggg

923
CNGAguaugc
947
CNGAguaagg
971
CNGAguacgg
995
CNGAguaggg

924
NCGAguaugc
948
NCGAguaagg
972
NCGAguacgg
996
NCGAguaggg

925
ACGAguaugc
949
ACGAguaagg
973
ACGAguacgg
997
ACGAguaggg

926
CCGAguaugc
950
CCGAguaagg
974
CCGAguacgg
998
CCGAguaggg

927
GCGAguaugc
951
GCGAguaagg
975
GCGAguacgg
999
GCGAguaggg

928
UCGAguaugc
952
UCGAguaagg
976
UCGAguacgg
1000
UCGAguaggg

929
GNGAguaugc
953
GNGAguaagg
977
GNGAguacgg
1001
GNGAguaggg

930
NGGAguaugc
954
NGGAguaagg
978
NGGAguacgg
1002
NGGAguaggg

931
AGGAguaugc
955
AGGAguaagg
979
AGGAguacgg
1003
AGGAguaggg

932
CGGAguaugc
956
CGGAguaagg
980
CGGAguacgg
1004
CGGAguaggg

933
GGGAguaugc
957
GGGAguaagg
981
GGGAguacgg
1005
GGGAguaggg

934
UGGAguaugc
958
UGGAguaagg
982
UGGAguacgg
1006
UGGAguaggg

935
UNGAguaugc
959
UNGAguaagg
983
UNGAguacgg
1007
UNGAguaggg

936
NUGAguaugc
960
NUGAguaagg
984
NUGAguacgg
1008
NUGAguaggg

937
AUGAguaugc
961
AUGAguaagg
985
AUGAguacgg
1009
AUGAguaggg

938
CUGAguaugc
962
CUGAguaagg
986
CUGAguacgg
1010
CUGAguaggg

939
GUGAguaugc
963
GUGAguaagg
987
GUGAguacgg
1011
GUGAguaggg

940
UUGAguaugc
964
UUGAguaagg
988
UUGAguacgg
1012
UUGAguaggg

1013
ANGAguaugg
1037
ANGAguaagu
1061
ANGAguacgu
1085
ANGAguaggu

1014
NAGAguaugg
1038
NAGAguaagu
1062
NAGAguacgu
1086
NAGAguaggu

1015
AAGAguaugg
1039
AAGAguaagu
1063
AAGAguacgu
1087
AAGAguaggu

1016
CAGAguaugg
1040
CAGAguaagu
1064
CAGAguacgu
1088
CAGAguaggu

1017
GAGAguaugg
1041
GAGAguaagu
1065
GAGAguacgu
1089
GAGAguaggu

1018
UAGAguaugg
1042
UAGAguaagu
1066
UAGAguacgu
1090
UAGAguaggu

1019
CNGAguaugg
1043
CNGAguaagu
1067
CNGAguacgu
1091
CNGAguaggu

1020
NCGAguaugg
1044
NCGAguaagu
1068
NCGAguacgu
1092
NCGAguaggu

1021
ACGAguaugg
1045
ACGAguaagu
1069
ACGAguacgu
1093
ACGAguaggu

1022
CCGAguaugg
1046
CCGAguaagu
1070
CCGAguacgu
1094
CCGAguaggu

1023
GCGAguaugg
1047
GCGAguaagu
1071
GCGAguacgu
1095
GCGAguaggu

1024
UCGAguaugg
1048
UCGAguaagu
1072
UCGAguacgu
1096
UCGAguaggu

1025
GNGAguaugg
1049
GNGAguaagu
1073
GNGAguacgu
1097
GNGAguaggu

1026
NGGAguaugg
1050
NGGAguaagu
1074
NGGAguacgu
1098
NGGAguaggu

1027
AGGAguaugg
1051
AGGAguaagu
1075
AGGAguacgu
1099
AGGAguaggu

1028
CGGAguaugg
1052
CGGAguaagu
1076
CGGAguacgu
1100
CGGAguaggu

1029
GGGAguaugg
1053
GGGAguaagu
1077
GGGAguacgu
1101
GGGAguaggu

1030
UGGAguaugg
1054
UGGAguaagu
1078
UGGAguacgu
1102
UGGAguaggu

1031
UNGAguaugg
1055
UNGAguaagu
1079
UNGAguacgu
1103
UNGAguaggu

1032
NUGAguaugg
1056
NUGAguaagu
1080
NUGAguacgu
1104
NUGAguaggu

1033
AUGAguaugg
1057
AUGAguaagu
1081
AUGAguacgu
1105
AUGAguaggu

1034
CUGAguaugg
1058
CUGAguaagu
1082
CUGAguacgu
1106
CUGAguaggu

1035
GUGAguaugg
1059
GUGAguaagu
1083
GUGAguacgu
1107
GUGAguaggu

1036
UUGAguaugg
1060
UUGAguaagu
1084
UUGAguacgu
1108
UUGAguaggu

1109
ANGAguaugu
1133
ANGAguanga
1157
ANGAguangc
1181
ANGAguangg

1110
NAGAguaugu
1134
NAGAguanga
1158
NAGAguangc
1182
NAGAguangg

1111
AAGAguaugu
1135
AAGAguanga
1159
AAGAguangc
1183
AAGAguangg

1112
CAGAguaugu
1136
CAGAguanga
1160
CAGAguangc
1184
CAGAguangg

1113
GAGAguaugu
1137
GAGAguanga
1161
GAGAguangc
1185
GAGAguangg

1114
UAGAguaugu
1138
UAGAguanga
1162
UAGAguangc
1186
UAGAguangg

1115
CNGAguaugu
1139
CNGAguanga
1163
CNGAguangc
1187
CNGAguangg

1116
NCGAguaugu
1140
NCGAguanga
1164
NCGAguangc
1188
NCGAguangg

1117
ACGAguaugu
1141
ACGAguanga
1165
ACGAguang
1189
ACGAguangg

1118
CCGAguaugu
1142
CCGAguanga
1166
CCGAguangc
1190
CCGAguangg

1119
GCGAguaugu
1143
GCGAguanga
1167
GCGAguangc
1191
GCGAguangg

1120
UCGAguaugu
1144
UCGAguanga
1168
UCGAguangc
1192
UCGAguangg

1121
GNGAguaugu
1145
GNGAguanga
1169
GNGAguangc
1193
GNGAguangg

1122
NGGAguaugu
1146
NGGAguanga
1170
NGGAguangc
1194
NGGAguangg

1123
AGGAguaugu
1147
AGGAguanga
1171
AGGAguangc
1195
AGGAguangg

1124
CGGAguaugu
1148
CGGAguanga
1172
CGGAguangc
1196
CGGAguangg

1125
GGGAguaugu
1149
GGGAguanga
1173
GGGAguangc
1197
GGGAguangg

1126
UGGAguaugu
1150
UGGAguanga
1174
UGGAguangc
1198
UGGAguangg

1127
UNGAguaugu
1151
UNGAguanga
1175
UNGAguangc
1199
UNGAguangg

1128
NUGAguaugu
1152
NUGAguanga
1176
NUGAguangc
1200
NUGAguangg

1129
AUGAguaugu
1153
AUGAguanga
1177
AUGAguangc
1201
AUGAguangg

1130
CUGAguaugu
1154
CUGAguanga
1178
CUGAguangc
1202
CUGAguangg

1131
GUGAguaugu
1155
GUGAguanga
1179
GUGAguangc
1203
GUGAguangg

1132
UUGAguaugu
1156
UUGAguanga
1180
UUGAguangc
1204
UUGAguangg

1205
ANGAguangu
1229
ANGAgugngn
1253
ANGAgugagn
1277
ANGAgugcgn

1206
NAGAguangu
1230
NAGAgugngn
1254
NAGAgugagn
1278
NAGAgugcgn

1207
AAGAguangu
1231
AAGAgugngn
1255
AAGAgugagn
1279
AAGAgugcgn

1208
CAGAguangu
1232
CAGAgugngn
1256
CAGAgugagn
1280
CAGAgugcgn

1209
GAGAguangu
1233
GAGAgugngn
1257
GAGAgugagn
1281
GAGAgugcgn

1210
UAGAguangu
1234
UAGAgugngn
1258
UAGAgugagn
1282
UAGAgugcgn

1211
CNGAguangu
1235
CNGAgugngn
1259
CNGAgugagn
1283
CNGAgugcgn

1212
NCGAguangu
1236
NCGAgugngn
1260
NCGAgugagn
1284
NCGAgugcgn

1213
ACGAguangu
1237
ACGAgugngn
1261
ACGAgugagn
1285
ACGAgugcgn

1214
CCGAguangu
1238
CCGAgugngn
1262
CCGAgugagn
1286
CCGAgugcgn

1215
GCGAguangu
1239
GCGAgugngn
1263
GCGAgugagn
1287
GCGAgugcgn

1216
UCGAguangu
1240
UCGAgugngn
1264
UCGAgugagn
1288
UCGAgugcgn

1217
GNGAguangu
1241
GNGAgugngn
1265
GNGAgugagn
1289
GNGAgugcgn

1218
NGGAguangu
1242
NGGAgugngn
1266
NGGAgugagn
1290
NGGAgugcgn

1219
AGGAguangu
1243
AGGAgugngn
1267
AGGAgugagn
1291
AGGAgugcgn

1220
CGGAguangu
1244
CGGAgugngn
1268
CGGAgugagn
1292
CGGAgugcgn

1221
GGGAguangu
1245
GGGAgugngn
1269
GGGAgugagn
1293
GGGAgugegn

1222
UGGAguangu
1246
UGGAgugngn
1270
UGGAgugagn
1294
UGGAgugcgn

1223
UNGAguangu
1247
UNGAgugngn
1271
UNGAgugagn
1295
UNGAgugcgn

1224
NUGAguangu
1248
NUGAgugngn
1272
NUGAgugagn
1296
NUGAgugcgn

1225
AUGAguangu
1249
AUGAgugngn
1273
AUGAgugagn
1297
AUGAgugcgn

1226
CUGAguangu
1250
CUGAgugngn
1274
CUGAgugagn
1298
CUGAgugcgn

1227
GUGAguangu
1251
GUGAgugngn
1275
GUGAgugagn
1299
GUGAgugcgn

1228
UUGAguangu
1252
UUGAgugngn
1276
UUGAgugagn
1300
UUGAgugcgn

1301
ANGAgugggn
1325
ANGAgugugn
1349
ANGAgugaga
1373
ANGAgugcga

1302
NAGAgugggn
1326
NAGAgugugn
1350
NAGAgugaga
1374
NAGAgugcga

1303
AAGAgugggn
1327
AAGAgugugn
1351
AAGAgugaga
1375
AAGAgugcga

1304
CAGAgugggn
1328
CAGAgugugn
1352
CAGAgugaga
1376
CAGAgugcga

1305
GAGAgugggn
1329
GAGAgugugn
1353
GAGAgugaga
1377
GAGAgugcga

1306
UAGAgugggn
1330
UAGAgugugn
1354
UAGAgugaga
1378
UAGAgugcga

1307
CNGAgugggn
1331
CNGAgugugn
1355
CNGAgugaga
1379
CNGAgugcga

1308
NCGAgugggn
1332
NCGAgugugn
1356
NCGAgugaga
1380
NCGAgugcga

1309
ACGAgugggn
1333
ACGAgugugn
1357
ACGAgugaga
1381
ACGAgugcga

1310
CCGAgugggn
1334
CCGAgugugn
1358
CCGAgugaga
1382
CCGAgugcga

1311
GCGAgugggn
1335
GCGAgugugn
1359
GCGAgugaga
1383
GCGAgugcga

1312
UCGAgugggn
1336
UCGAgugugn
1360
UCGAgugaga
1384
UCGAgugcga

1313
GNGAgugggn
1337
GNGAgugugn
1361
GNGAgugaga
1385
GNGAgugcga

1314
NGGAgugggn
1338
NGGAgugugn
1362
NGGAgugaga
1386
NGGAgugcga

1315
AGGAgugggn
1339
AGGAgugugn
1363
AGGAgugaga
1387
AGGAgugcga

1316
CGGAgugggn
1340
CGGAgugugn
1364
CGGAgugaga
1388
CGGAgugcga

1317
GGGAgugggn
1341
GGGAgugugn
1365
GGGAgugaga
1389
GGGAgugcga

1318
UGGAgugggn
1342
UGGAgugugn
1366
UGGAgugaga
1390
UGGAgugcga

1319
UNGAgugggn
1343
UNGAgugugn
1367
UNGAgugaga
1391
UNGAgugcga

1320
NUGAgugggn
1344
NUGAgugugn
1368
NUGAgugaga
1392
NUGAgugcga

1321
AUGAgugggn
1345
AUGAgugugn
1369
AUGAgugaga
1393
AUGAgugcga

1322
CUGAgugggn
1346
CUGAgugugn
1370
CUGAgugaga
1394
CUGAgugcga

1323
GUGAgugggn
1347
GUGAgugugn
1371
GUGAgugaga
1395
GUGAgugcga

1324
UUGAgugggn
1348
UUGAgugugn
1372
UUGAgugaga
1396
UUGAgugcga

1397
ANGAguggga
1421
ANGAguguga
1445
ANGAgugagc
1469
ANGAgugcgc

1398
NAGAguggga
1422
NAGAguguga
1446
NAGAgugagc
1470
NAGAgugcgc

1399
AAGAguggga
1423
AAGAguguga
1447
AAGAgugagc
1471
AAGAgugcgc

1400
CAGAguggga
1424
CAGAguguga
1448
CAGAgugagc
1472
CAGAgugcgc

1401
GAGAguggga
1425
GAGAguguga
1449
GAGAgugagc
1473
GAGAgugcgc

1402
UAGAguggga
1426
UAGAguguga
1450
UAGAgugagc
1474
UAGAgugcgc

1403
CNGAguggga
1427
CNGAguguga
1451
CNGAgugagc
1475
CNGAgugcgc

1404
NCGAguggga
1428
NCGAguguga
1452
NCGAgugagc
1476
NCGAgugcgc

1405
ACGAguggga
1429
ACGAguguga
1453
ACGAgugagc
1477
ACGAgugcgc

1406
CCGAguggga
1430
CCGAguguga
1454
CCGAgugagc
1478
CCGAgugcgc

1407
GCGAguggga
1431
GCGAguguga
1455
GCGAgugagc
1479
GCGAgugcgc

1408
UCGAguggga
1432
UCGAguguga
1456
UCGAgugagc
1480
UCGAgugcgc

1409
GNGAguggga
1433
GNGAguguga
1457
GNGAgugagc
1481
GNGAgugcgc

1410
NGGAguggga
1434
NGGAguguga
1458
NGGAgugagc
1482
NGGAgugcgc

1411
AGGAguggga
1435
AGGAguguga
1459
AGGAgugagc
1483
AGGAgugcgc

1412
CGGAguggga
1436
CGGAguguga
1460
CGGAgugagc
1484
CGGAgugcgc

1413
GGGAguggga
1437
GGGAguguga
1461
GGGAgugagc
1485
GGGAgugcgc

1414
UGGAguggga
1438
UGGAguguga
1462
UGGAgugagc
1486
UGGAgugcgc

1415
UNGAguggga
1439
UNGAguguga
1463
UNGAgugagc
1487
UNGAgugcgc

1416
NUGAguggga
1440
NUGAguguga
1464
NUGAgugagc
1488
NUGAgugcgc

1417
AUGAguggga
1441
AUGAguguga
1465
AUGAgugagc
1489
AUGAgugcgc

1418
CUGAguggga
1442
CUGAguguga
1466
CUGAgugagc
1490
CUGAgugcgc

1419
GUGAguggga
1443
GUGAguguga
1467
GUGAgugagc
1491
GUGAgugcgc

1420
UUGAguggga
1444
UUGAguguga
1468
UUGAgugagc
1492
UUGAgugcgc

1493
ANGAgugggc
1517
ANGAgugugc
1541
ANGAgugagg
1565
ANGAgugcgg

1494
NAGAgugggc
1518
NAGAgugugc
1542
NAGAgugagg
1566
NAGAgugcgg

1495
AAGAgugggc
1519
AAGAgugugc
1543
AAGAgugagg
1567
AAGAgugcgg

1496
CAGAgugggc
1520
CAGAgugugc
1544
CAGAgugagg
1568
CAGAgugcgg

1497
GAGAgugggc
1521
GAGAgugugc
1545
GAGAgugagg
1569
GAGAgugcgg

1498
UAGAgugggc
1522
UAGAgugugc
1546
UAGAgugagg
1570
UAGAgugcgg

1499
CNGAgugggc
1523
CNGAgugugc
1547
CNGAgugagg
1571
CNGAgugcgg

1500
NCGAguggg
1524
NCGAgugugc
1548
NCGAgugagg
1572
NCGAgugcgg

1501
ACGAgugggc
1525
ACGAgugugc
1549
ACGAgugagg
1573
ACGAgugcgg

1502
CCGAgugggc
1526
CCGAgugugc
1550
CCGAgugagg
1574
CCGAgugcgg

1503
GCGAgugggc
1527
GCGAgugugc
1551
GCGAgugagg
1575
GCGAgugcgg

1504
UCGAgugggc
1528
UCGAgugugc
1552
UCGAgugagg
1576
UCGAgugcgg

1505
GNGAgugggc
1529
GNGAgugugc
1553
GNGAgugagg
1577
GNGAgugcgg

1506
NGGAgugggc
1530
NGGAgugugc
1554
NGGAgugagg
1578
NGGAgugcgg

1507
AGGAgugggc
1531
AGGAgugugc
1555
AGGAgugagg
1579
AGGAgugcgg

1508
CGGAgugggc
1532
CGGAgugugc
1556
CGGAgugagg
1580
CGGAgugcgg

1509
GGGAgugggc
1533
GGGAgugugc
1557
GGGAgugagg
1581
GGGAgugcgg

1510
UGGAgugggc
1534
UGGAgugugc
1558
UGGAgugagg
1582
UGGAgugcgg

1511
UNGAgugggc
1535
UNGAgugugc
1559
UNGAgugagg
1583
UNGAgugcgg

1512
NUGAgugggc
1536
NUGAgugugc
1560
NUGAgugagg
1584
NUGAgugcgg

1513
AUGAgugggc
1537
AUGAgugugc
1561
AUGAgugagg
1585
AUGAgugcgg

1514
CUGAgugggo
1538
CUGAgugugc
1562
CUGAgugagg
1586
CUGAgugcgg

1515
GUGAgugggc
1539
GUGAgugugc
1563
GUGAgugagg
1587
GUGAgugcgg

1516
UUGAgugggc
1540
UUGAgugugc
1564
UUGAgugagg
1588
UUGAgugcgg

1589
ANGAgugggg
1613
ANGAgugugg
1637
ANGAgugagu
1661
ANGAgugcgu

1590
NAGAgugggg
1614
NAGAgugugg
1638
NAGAgugagu
1662
NAGAgugcgu

1591
AAGAgugggg
1615
AAGAgugugg
1639
AAGAgugagu
1663
AAGAgugcgu

1592
CAGAgugggg
1616
CAGAgugugg
1640
CAGAgugagu
1664
CAGAgugcgu

1593
GAGAgugggg
1617
GAGAgugugg
1641
GAGAgugagu
1665
GAGAgugcgu

1594
UAGAgugggg
1618
UAGAgugugg
1642
UAGAgugagu
1666
UAGAgugcgu

1595
CNGAgugggg
1619
CNGAgugugg
1643
CNGAgugagu
1667
CNGAgugcgu

1596
NCGAgugggg
1620
NCGAgugugg
1644
NCGAgugagu
1668
NCGAgugcgu

1597
ACGAgugggg
1621
ACGAgugugg
1645
ACGAgugagu
1669
ACGAgugcgu

1598
CCGAgugggg
1622
CCGAgugugg
1646
CCGAgugagu
1670
CCGAgugcgu

1599
GCGAgugggg
1623
GCGAgugugg
1647
GCGAgugagu
1671
GCGAgugcgu

1600
UCGAgugggg
1624
UCGAgugugg
1648
UCGAgugagu
1672
UCGAgugcgu

1601
GNGAgugggg
1625
GNGAgugugg
1649
GNGAgugagu
1673
GNGAgugcgu

1602
NGGAgugggg
1626
NGGAgugugg
1650
NGGAgugagu
1674
NGGAgugcgu

1603
AGGAgugggg
1627
AGGAgugugg
1651
AGGAgugagul
1675
AGGAgugcgu

1604
CGGAgugggg
1628
CGGAgugugg
1652
CGGAgugagu
1676
CGGAgugcgu

1605
GGGAgugggg
1629
GGGAgugugg
1653
GGGAgugagu
1677
GGGAgugcgu

1606
UGGAgugggg
1630
UGGAgugugg
1654
UGGAgugagu
1678
UGGAgugcgu

1607
UNGAgugggg
1631
UNGAgugugg
1655
UNGAgugagu
1679
UNGAgugcgu

1608
NUGAgugggg
1632
NUGAgugugg
1656
NUGAgugagu
1680
NUGAgugcgu

1609
AUGAgugggg
1633
AUGAgugugg
1657
AUGAgugagu
1681
AUGAgugcgu

1610
CUGAgugggg
1634
CUGAgugugg
1658
CUGAgugagu
1682
CUGAgugcgu

1611
GUGAgugggg
1635
GUGAgugugg
1659
GUGAgugagu
1683
GUGAgugcgu

1612
UUGAgugggg
1636
UUGAgugugg
1660
UUGAgugagu
1684
UUGAgugcgu

1685
ANGAgugggu
1709
ANGAgugugu
1733
ANGAgugnga
1757
ANGAgugngc

1686
NAGAgugggu
1710
NAGAgugugu
1734
NAGAgugnga
1758
NAGAgugngc

1687
AAGAgugggu
1711
AAGAgugugu
1735
AAGAgugnga
1759
AAGAgugngc

1688
CAGAgugggu
1712
CAGAgugugu
1736
CAGAgugnga
1760
CAGAgugngc

1689
GAGAgugggu
1713
GAGAgugugu
1737
GAGAgugnga
1761
GAGAgugngc

1690
UAGAgugggu
1714
UAGAgugugu
1738
UAGAgugnga
1762
UAGAgugngc

1691
CNGAgugggu
1715
CNGAgugugu
1739
CNGAgugnga
1763
CNGAgugngc

1692
NCGAgugggu
1716
NCGAgugugu
1740
NCGAgugnga
1764
NCGAgugngc

1693
ACGAgugggu
1717
ACGAgugugu
1741
ACGAgugnga
1765
ACGAgugngc

1694
CCGAgugggu
1718
CCGAgugugu
1742
CCGAgugnga
1766
CCGAgugngc

1695
GCGAgugggu
1719
GCGAgugugu
1743
GCGAgugnga
1767
GCGAgugngc

1696
UCGAgugggu
1720
UCGAgugugu
1744
UCGAgugnga
1768
UCGAgugngc

1697
GNGAgugggu
1721
GNGAgugugu
1745
GNGAgugnga
1769
GNGAgugngc

1698
NGGAgugggu
1722
NGGAgugugu
1746
NGGAgugnga
1770
NGGAgugngc

1699
AGGAguggg?
1723
AGGAgugugu
1747
AGGAgugnga
1771
AGGAgugngc

1700
CGGAgugggu
1724
CGGAgugugu
1748
CGGAgugnga
1772
CGGAgugngc

1701
GGGAgugggu
1725
GGGAgugugu
1749
GGGAgugnga
1773
GGGAgugngc

1702
UGGAgugggu
1726
UGGAgugugu
1750
UGGAgugnga
1774
UGGAgugngc

1703
UNGAgugggu
1727
UNGAgugugu
1751
UNGAgugnga
1775
UNGAgugngc

1704
NUGAgugggu
1728
NUGAgugugu
1752
NUGAgugnga
1776
NUGAgugngc

1705
AUGAgugggu
1729
AUGAgugugu
1753
AUGAgugnga
1777
AUGAgugngc

1706
CUGAgugggu
1730
CUGAgugugu
1754
CUGAgugnga
1778
CUGAgugngc

1707
GUGAgugggu
1731
GUGAgugugu
1755
GUGAgugnga
1779
GUGAgugngc

1708
UUGAgugggu
1732
UUGAgugugu
1756
UUGAgugnga
1780
UUGAgugngc

1781
ANGAgugngg
1793
GNGAgugngg
1805
ANGAgugngu
1817
GNGAgugngu

1782
NAGAgugngg
1794
NGGAgugngg
1806
NAGAgugngu
1818
NGGAgugngu

1783
AAGAgugngg
1795
AGGAgugngg
1807
AAGAgugngu
1819
AGGAgugngu

1784
CAGAgugngg
1796
CGGAgugngg
1808
CAGAgugngu
1820
CGGAgugngu

1785
GAGAgugngg
1797
GGGAgugngg
1809
GAGAgugngu
1821
GGGAgugngu

1786
UAGAgugngg
1798
UGGAgugngg
1810
UAGAgugngu
1822
UGGAgugngu

1787
CNGAgugngg
1799
UNGAgugngg
1811
CNGAgugngu
1823
UNGAgugngu

1788
NCGAgugngg
1800
NUGAgugngg
1812
NCGAgugngu
1824
NUGAgugngu

1789
ACGAgugngg
1801
AUGAgugngg
1813
ACGAgugngu
1825
AUGAgugngu

1790
CCGAgugngg
1802
CUGAgugngg
1814
CCGAgugngu
1826
CUGAgugngu

1791
GCGAgugngg
1803
GUGAgugngg
1815
GCGAgugngu
1827
GUGAgugngu

1792
UCGAgugngg
1804
UUGAgugngg
1816
UCGAgugngu
1828
UUGAgugngu

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 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 Table 16 or 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. 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 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 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 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 infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.

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 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 thereof 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/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 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, 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 Table 1, 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 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 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 infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.

In another embodiment, provided herein is a method for modulating the amount of an RNA transcript comprising a RNA nucleotide sequence, wherein the RNA nucleotide sequence 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 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, the method comprising contacting the RNA transcript with a compound described herein (for example, a compound of Formula (I) or a form thereof or another splicing inducer).

In another embodiment, provided herein is a method for modulating the amount of an RNA transcript comprising a RNA nucleotide sequence, wherein the RNA nucleotide sequence 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 RNA nucleotide sequence of the intron comprises in 5′ to 3′ order: a first branch point, a first 3′ splice site, and an iREMS, wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), and wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting the RNA transcript with a compound described herein (for example, a compound of Formula (I) or a form thereof or another splicing inducer).

In another embodiment, provided herein is a method for modulating the amount of an RNA transcript comprising a RNA nucleotide sequence, wherein the RNA nucleotide sequence comprises two exons and an intron, and wherein the RNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1A, the method comprising contacting the RNA transcript with a compound described herein (for example, a compound of Formula (I) or a form thereof or another splicing inducer).

In another embodiment, provided herein is a method for modulating the amount of an RNA transcript comprising a RNA nucleotide sequence, wherein the RNA nucleotide sequence comprises two exons and an intron, and wherein the RNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1B, the method comprising contacting the RNA transcript with a compound described herein (for example, a compound of Formula (I) or a form thereof or another splicing inducer).

In another embodiment, provided herein is a method for modulating the amount of an RNA transcript comprising a RNA nucleotide sequence, wherein the RNA nucleotide sequence comprises three exons and two introns, and wherein the RNA nucleotide sequence comprises exonic and intronic elements illustrated in FIG. 1C, the method comprising contacting the RNA transcript with a compound described herein (for example, a compound of Formula (I) or a form thereof or another splicing inducer).

In a specific embodiment, the RNA transcript is the RNA transcript of a gene described in a table in this disclosure.

In another embodiment, provided herein is a method for modulating the amount of the 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, a nucleotide sequence encoding 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 or another splicing inducer) to the subject.

In another embodiment, provided herein is a method for modulating the amount of the 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: a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, and a nucleotide sequence encoding an iREMS, 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 or another splicing inducer) to the subject.

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

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 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, 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 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, 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 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), disclosed in Table 1, 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 preventing and/or treating a disease associated with aberrant expression of a product of a gene disclosed in Table 7, infra, (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 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 infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.

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 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, infra, 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 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, infra, 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, disclosed in Table 1, infra, 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 Table 1, infra, 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, infra, 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 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 infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.

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 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, infra, 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 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, infra, 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/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 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, infra, 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 Table 1, infra, 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, infra, 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 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 infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.

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, a nucleotide sequence encoding 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 or another splicing inducer) to the subject.

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 of the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, and a nucleotide sequence encoding an iREMS, 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 or another splicing inducer) to the subject.

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

In another aspect, provided herein are artificial gene constructs. In one embodiment, provided herein is an artificial gene construct comprising endogenous DNA is modified to introduce a non-endogenous nucleotide sequence encoding an intron comprising a 3′ splice site(s) and a branch point(s) and an intronic REMS. In another embodiment, provided herein is an artificial gene construct comprising DNA encoding exons and one, two or more introns, wherein a nucleotide sequence encoding an intronic REMS, functioning as a 5′ splice site in the presence of a compound described herein, which may be upstream of an endogenous nucleotide sequence encoding a branch point and an endogenous nucleotide sequence encoding a 3′ splice site, is modified to introduce a nucleotide sequence encoding a non-endogenous branch point and a non-endogenous 3′ splice site further upstream from the endogenous intronic REMS. In another embodiment, provided herein is an artificial gene construct comprising DNA encoding exons and one, two or more introns, wherein a nucleotide sequence encoding an intronic REMS 5′ splice site, which may be downstream of an endogenous nucleotide sequence encoding a branch point and an endogenous nucleotide sequence encoding a 3′ splice site, is modified to introduce a nucleotide sequence encoding a non-endogenous branch point and a non-endogenous 3′ splice site further downstream from the endogenous intronic REMS. In another embodiment, provided herein is an artificial gene construct comprising DNA encoding an intronic REMS, comprising nucleotides encoding an intronic REMS having one or more 5′ splice site(s), 3′ splice site(s) and branch point(s). In certain embodiments, the artificial gene construct encodes a frameshift or premature stop codon or internal insertions or deletions within the open reading frame. In other embodiments, the artificial gene construct encodes a mature mRNA having a functional open reading frame, producing a novel protein which may or may not be functional. In some embodiments, the artificial gene construct encodes a detectable reporter protein. RNA transcripts having a non-functional open reading frame due to the inclusion of a frameshift, premature stop codon or internal insertions or deletions within the open reading frame can be substrates for nonsense-mediated decay and thus have low abundance. Any intronic REMS-mediated alternative splicing modified RNA transcripts may also have altered stability, altered intracellular transport, altered 3′ end formation efficiency and altered translation efficiency.

In a specific embodiment, the nucleotide sequence of the intronic REMS introduced into the nucleotide sequence of the artificial gene construct comprises the sequence NNGAgtrngn (SEQ ID NO: 3), wherein r is adenine or guanine and n or N is any nucleotide. In a specific embodiment, in the context of DNA, the nucleotide sequence encoding the 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 adenine or guanine and n or N is any nucleotide.

In a further specific 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 adenine or guanine and N is any nucleotide. In one or more embodiments provided herein, N is adenine or guanine. In various specific embodiments, the nucleotide sequence encoding the intronic REMS is a nucleotide sequence encoding a non-endogenous intronic REMS, i.e., a precursor RNA transcript comprising the non-endogenous intronic REMS not naturally found in the DNA sequence of the artificial construct.

In a specific embodiment, the intronic REMS referred to in a method or artificial gene construct described herein comprises, at the DNA level, a sequence presented in the following table (wherein r is adenine or guanine, and n or N is any nucleotide):

TABLE 14

Intronic REMS DNA sequence (wherein r is adenine or guanine, and n or N

is any nucleotide)

SEQ ID

SEQ ID

SEQ ID

SEQ ID

NO.
Sequence
NO.
Sequence
NO.
Sequence
NO.
Sequence

1829
ANGAgtrngn
1835
CNGAgtrngn
1841
GNGAgtrngn
1847
TNGAgtrngn

1830
NAGAgtrngn
1836
NCGAgtrngn
1842
NGGAgtrngn
1848
NTGAgtrngn

1831
AAGAgtrngn
1837
ACGAgtrngn
1843
AGGAgtrngn
1849
ATGAgtrngn

1832
CAGAgtrngn
1838
CCGAgtrngn
1844
CGGAgtrngn
1850
CTGAgtrngn

1833
GAGAgtrngn
1839
GCGAgtrngn
1845
GGGAgtrngn
1851
GTGAgtrngn

1834
TAGAgtrngn
1840
TCGAgtrngn
1846
TGGAgtrngn
1852
TTGAgtrngn

1853
ANGAgtragn
1877
ANGAgtrcgn
1901
ANGAgtrggn
1925
ANGAgtrtgn

1854
NAGAgtragn
1878
NAGAgtrcgn
1902
NAGAgtrggn
1926
NAGAgtrtgn

1855
AAGAgtragn
1879
AAGAgtrcgn
1903
AAGAgtrggn
1927
AAGAgtrtgn

1856
CAGAgtragn
1880
CAGAgtrcgn
1904
CAGAgtrggn
1928
CAGAgtrtgn

1857
GAGAgtragn
1881
GAGAgtrcgn
1905
GAGAgtrggn
1929
GAGAgtrtgn

1858
TAGAgtragn
1882
TAGAgtregn
1906
TAGAgtrggn
1930
TAGAgtrtgn

1859
CNGAgtragn
1883
CNGAgtrcgn
1907
CNGAgtrggn
1931
CNGAgtrtgn

1860
NCGAgtragn
1884
NCGAgtrcgn
1908
NCGAgtrggn
1932
NCGAgtrtgn

1861
ACGAgtragn
1885
ACGAgtrcgn
1909
ACGAgtrggn
1933
ACGAgtrtgn

1862
CCGAgtragn
1886
CCGAgtrcgn
1910
CCGAgtrggn
1934
CCGAgtrtgn

1863
GCGAgtragn
1887
GCGAgtrcgn
1911
GCGAgtrggn
1935
GCGAgtrtgn

1864
TCGAgtragn
1888
TCGAgtrcgn
1912
TCGAgtrggn
1936
TCGAgtrtgn

1865
GNGAgtragn
1889
GNGAgtrcgn
1913
GNGAgtrggn
1937
GNGAgtrtgn

1866
NGGAgtragn
1890
NGGAgtrcgn
1914
NGGAgtrggn
1938
NGGAgtrtgn

1867
AGGAgtragn
1891
AGGAgtrcgn
1915
AGGAgtrggn
1939
AGGAgtrtgn

1868
CGGAgtragn
1892
CGGAgtrcgn
1916
CGGAgtrggn
1940
CGGAgtrtgn

1869
GGGAgtragn
1893
GGGAgtrcgn
1917
GGGAgtrggn
1941
GGGAgtrtgn

1870
TGGAgtragn
1894
TGGAgtrcgn
1918
TGGAgtrggn
1942
TGGAgtrtgn

1871
TNGAgtragn
1895
TNGAgtrcgn
1919
TNGAgtrggn
1943
TNGAgtrtgn

1872
NTGAgtragn
1896
NTGAgtrcgn
1920
NTGAgtrggn
1944
NTGAgtrtgn

1873
ATGAgtragn
1897
ATGAgtrcgn
1921
ATGAgtrggn
1945
ATGAgtrtgn

1874
CTGAgtragn
1898
CTGAgtregn
1922
CTGAgtrggn
1946
CTGAgtrtgn

1875
GTGAgtragn
1899
GTGAgtrcgn
1923
GTGAgtrggn
1947
GTGAgtrtgn

1876
TTGAgtragn
1900
TTGAgtrcgn
1924
TTGAgtrggn
1948
TTGAgtrtgn

1949
ANGAgtraga
1973
ANGAgtrcga
1997
ANGAgtrgga
2021
ANGAgtrtga

1950
NAGAgtraga
1974
NAGAgtrcga
1998
NAGAgtrgga
2022
NAGAgtrtga

1951
AAGAgtraga
1975
AAGAgtrcga
1999
AAGAgtrgga
2023
AAGAgtrtga

1952
CAGAgtraga
1976
CAGAgtrcga
2000
CAGAgtrgga
2024
CAGAgtrtga

1953
GAGAgtraga
1977
GAGAgtrcga
2001
GAGAgtrgga
2025
GAGAgtrtga

1954
TAGAgtraga
1978
TAGAgtrcga
2002
TAGAgtrgga
2026
TAGAgtrtga

1955
CNGAgtraga
1979
CNGAgtrcga
2003
CNGAgtrgga
2027
CNGAgtrtga

1956
NCGAgtraga
1980
NCGAgtrcga
2004
NCGAgtrgga
2028
NCGAgtrtga

1957
ACGAgtraga
1981
ACGAgtrcga
2005
ACGAgtrgga
2029
ACGAgtrtga

1958
CCGAgtraga
1982
CCGAgtrcga
2006
CCGAgtrgga
2030
CCGAgtrtga

1959
GCGAgtraga
1983
GCGAgtrcga
2007
GCGAgtrgga
2031
GCGAgtrtga

1960
TCGAgtraga
1984
TCGAgtrcga
2008
TCGAgtrgga
2032
TCGAgtrtga

1961
GNGAgtraga
1985
GNGAgtrcga
2009
GNGAgtrgga
2033
GNGAgtrtga

1962
NGGAgtraga
1986
NGGAgtrcga
2010
NGGAgtrgga
2034
NGGAgtrtga

1963
AGGAgtraga
1987
AGGAgtrcga
2011
AGGAgtrgga
2035
AGGAgtrtga

1964
CGGAgtraga
1988
CGGAgtrcga
2012
CGGAgtrgga
2036
CGGAgtrtga

1965
GGGAgtraga
1989
GGGAgtrcga
2013
GGGAgtrgga
2037
GGGAgtrtga

1966
TGGAgtraga
1990
TGGAgtrcga
2014
TGGAgtrgga
2038
TGGAgtrtga

1967
TNGAgtraga
1991
TNGAgtrcga
2015
TNGAgtrgga
2039
TNGAgtrtga

1968
NTGAgtraga
1992
NTGAgtrcga
2016
NTGAgtrgga
2040
NTGAgtrtga

1969
ATGAgtraga
1993
ATGAgtrcga
2017
ATGAgtrgga
2041
ATGAgtrtga

1970
CTGAgtraga
1994
CTGAgtrcga
2018
CTGAgtrgga
2042
CTGAgtrtga

1971
GTGAgtraga
1995
GTGAgtrcga
2019
GTGAgtrgga
2043
GTGAgtrtga

1972
TTGAgtraga
1996
TTGAgtrcga
2020
TTGAgtrgga
2044
TTGAgtrtga

2045
ANGAgtragc
2069
ANGAgtrcgc
2093
ANGAgtrggc
2117
ANGAgtrtgc

2046
NAGAgtragc
2070
NAGAgtrcgc
2094
NAGAgtrggc
2118
NAGAgtrtgc

2047
AAGAgtragc
2071
AAGAgtrcgc
2095
AAGAgtrggc
2119
AAGAgtrtgc

2048
CAGAgtragc
2072
CAGAgtrcgc
2096
CAGAgtrggc
2120
CAGAgtrtgc

2049
GAGAgtragc
2073
GAGAgtrcgc
2097
GAGAgtrggc
2121
GAGAgtrtgc

2050
TAGAgtragc
2074
TAGAgtrcgc
2098
TAGAgtrggc
2122
TAGAgtrtgc

2051
CNGAgtragc
2075
CNGAgtrcgc
2099
CNGAgtrggc
2123
CNGAgtrtgc

2052
NCGAgtragc
2076
NCGAgtrcgc
2100
NCGAgtrggc
2124
NCGAgtrtgc

2053
ACGAgtragc
2077
ACGAgtrcgc
2101
ACGAgtrggc
2125
ACGAgtrtgc

2054
CCGAgtragc
2078
CCGAgtrcgc
2102
CCGAgtrggc
2126
CCGAgtrtgc

2055
GCGAgtragc
2079
GCGAgtrcgc
2103
GCGAgtrggc
2127
GCGAgtrtgc

2056
TCGAgtragc
2080
TCGAgtrcgc
2104
TCGAgtrggc
2128
TCGAgtrtgc

2057
GNGAgtragc
2081
GNGAgtrcgc
2105
GNGAgtrggc
2129
GNGAgtrtgc

2058
NGGAgtragc
2082
NGGAgtrcgc
2106
NGGAgtrggc
2130
NGGAgtrtgc

2059
AGGAgtragc
2083
AGGAgtrcgc
2107
AGGAgtrggc
2131
AGGAgtrtgc

2060
CGGAgtragc
2084
CGGAgtrcgc
2108
CGGAgtrggc
2132
CGGAgtrtgc

2061
GGGAgtragc
2085
GGGAgtrcgc
2109
GGGAgtrggc
2133
GGGAgtrtgc

2062
TGGAgtragc
2086
TGGAgtrcgc
2110
TGGAgtrggc
2134
TGGAgtrtgc

2063
TNGAgtragc
2087
TNGAgtrcgc
2111
TNGAgtrggc
2135
TNGAgtrtgc

2064
NTGAgtragc
2088
NTGAgtrcgc
2112
NTGAgtrggc
2136
NTGAgtrtgc

2065
ATGAgtragc
2089
ATGAgtrcgc
2113
ATGAgtrggc
2137
ATGAgtrtgc

2066
CTGAgtragc
2090
CTGAgtrcgc
2114
CTGAgtrggc
2138
CTGAgtrtgc

2067
GTGAgtragc
2091
GTGAgtrcgc
2115
GTGAgtrggc
2139
GTGAgtrtgc

2068
TTGAgtragc
2092
TTGAgtrcgc
2116
TTGAgtrggc
2140
TTGAgtrtgc

2141
ANGAgtragg
2165
ANGAgtrcgg
2189
ANGAgtrggg
2213
ANGAgtrtgg

2142
NAGAgtragg
2166
NAGAgtrcgg
2190
NAGAgtrggg
2214
NAGAgtrtgg

2143
AAGAgtragg
2167
AAGAgtrcgg
2191
AAGAgtrggg
2215
AAGAgtrtgg

2144
CAGAgtragg
2168
CAGAgtrcgg
2192
CAGAgtrggg
2216
CAGAgtrtgg

2145
GAGAgtragg
2169
GAGAgtrcgg
2193
GAGAgtrggg
2217
GAGAgtrtgg

2146
TAGAgtragg
2170
TAGAgtrcgg
2194
TAGAgtrggg
2218
TAGAgtrtgg

2147
CNGAgtragg
2171
CNGAgtrcgg
2195
CNGAgtrggg
2219
CNGAgtrtgg

2148
NCGAgtragg
2172
NCGAgtrcgg
2196
NCGAgtrggg
2220
NCGAgtrtgg

2149
ACGAgtragg
2173
ACGAgtrcgg
2197
ACGAgtrggg
2221
ACGAgtrtgg

2150
CCGAgtragg
2174
CCGAgtrcgg
2198
CCGAgtrggg
2222
CCGAgtrtgg

2151
GCGAgtragg
2175
GCGAgtrcgg
2199
GCGAgtrggg
2223
GCGAgtrtgg

2152
TCGAgtragg
2176
TCGAgtrcgg
2200
TCGAgtrggg
2224
TCGAgtrtgg

2153
GNGAgtragg
2177
GNGAgtrcgg
2201
GNGAgtrggg
2225
GNGAgtrtgg

2154
NGGAgtragg
2178
NGGAgtrcgg
2202
NGGAgtrggg
2226
NGGAgtrtgg

2155
AGGAgtragg
2179
AGGAgtrcgg
2203
AGGAgtrggg
2227
AGGAgtrtgg

2156
CGGAgtragg
2180
CGGAgtrcgg
2204
CGGAgtrggg
2228
CGGAgtrtgg

2157
GGGAgtragg
2181
GGGAgtrcgg
2205
GGGAgtrggg
2229
GGGAgtrtgg

2158
TGGAgtragg
2182
TGGAgtrcgg
2206
TGGAgtrggg
2230
TGGAgtrtgg

2159
TNGAgtragg
2183
TNGAgtrcgg
2207
TNGAgtrggg
2231
TNGAgtrtgg

2160
NTGAgtragg
2184
NTGAgtrcgg
2208
NTGAgtrggg
2232
NTGAgtrtgg

2161
ATGAgtragg
2185
ATGAgtrcgg
2209
ATGAgtrggg
2233
ATGAgtrtgg

2162
CTGAgtragg
2186
CTGAgtrcgg
2210
CTGAgtrggg
2234
CTGAgtrtgg

2163
GTGAgtragg
2187
GTGAgtrcgg
2211
GTGAgtrggg
2235
GTGAgtrtgg

2164
TTGAgtragg
2188
TTGAgtrcgg
2212
TTGAgtrggg
2236
TTGAgtrtgg

2237
ANGAgtragt
2261
ANGAgtrcgt
2285
ANGAgtrggt
2309
ANGAgtrtgt

2238
NAGAgtragt
2262
NAGAgtrcgt
2286
NAGAgtrggt
2310
NAGAgtrtgt

2239
AAGAgtragt
2263
AAGAgtrcgt
2287
AAGAgtrggt
2311
AAGAgtrtgt

2240
CAGAgtragt
2264
CAGAgtrcgt
2288
CAGAgtrggt
2312
CAGAgtrtgt

2241
GAGAgtragt
2265
GAGAgtrcgt
2289
GAGAgtrggt
2313
GAGAgtrtgt

2242
TAGAgtragt
2266
TAGAgtrcgt
2290
TAGAgtrggt
2314
TAGAgtrtgt

2243
CNGAgtragt
2267
CNGAgtrcgt
2291
CNGAgtrggt
2315
CNGAgtrtgt

2244
NCGAgtragt
2268
NCGAgtrcgt
2292
NCGAgtrggt
2316
NCGAgtrtgt

2245
ACGAgtragt
2269
ACGAgtrcgt
2293
ACGAgtrggt
2317
ACGAgtrtgt

2246
CCGAgtragt
2270
CCGAgtrcgt
2294
CCGAgtrggt
2318
CCGAgtrtgt

2247
GCGAgtragt
2271
GCGAgtrcgt
2295
GCGAgtrggt
2319
GCGAgtrtgt

2248
TCGAgtragt
2272
TCGAgtrcgt
2296
TCGAgtrggt
2320
TCGAgtrtgt

2249
GNGAgtragt
2273
GNGAgtrcgt
2297
GNGAgtrggt
2321
GNGAgtrtgt

2250
NGGAgtragt
2274
NGGAgtregt
2298
NGGAgtrggt
2322
NGGAgtrtgt

2251
AGGAgtragt
2275
AGGAgtrcgt
2299
AGGAgtrggt
2323
AGGAgtrtgt

2252
CGGAgtragt
2276
CGGAgtrcgt
2300
CGGAgtrggt
2324
CGGAgtrtgt

2253
GGGAgtragt
2277
GGGAgtrcgt
2301
GGGAgtrggt
2325
GGGAgtrtgt

2254
TGGAgtragt
2278
TGGAgtrcgt
2302
TGGAgtrggt
2326
TGGAgtrtgt

2255
TNGAgtragt
2279
TNGAgtrcgt
2303
TNGAgtrggt
2327
TNGAgtrtgt

2256
NTGAgtragt
2280
NTGAgtrcgt
2304
NTGAgtrggt
2328
NTGAgtrtgt

2257
ATGAgtragt
2281
ATGAgtrcgt
2305
ATGAgtrggt
2329
ATGAgtrtgt

2258
CTGAgtragt
2282
CTGAgtrcgt
2306
CTGAgtrggt
2330
CTGAgtrtgt

2259
GTGAgtragt
2283
GTGAgtrcgt
2307
GTGAgtrggt
2331
GTGAgtrtgt

2260
TTGAgtragt
2284
TTGAgtrcgt
2308
TTGAgtrggt
2332
TTGAgtrtgt

2333
ANGAgtrnga
2357
ANGAgtrngc
2381
ANGAgtrngg
2405
ANGAgtrngt

2334
NAGAgtrnga
2358
NAGAgtrngc
2382
NAGAgtrngg
2406
NAGAgtrngt

2335
AAGAgtrnga
2359
AAGAgtrngc
2383
AAGAgtrngg
2407
AAGAgtrngt

2336
CAGAgtrnga
2360
CAGAgtrngc
2384
CAGAgtrngg
2408
CAGAgtrngt

2337
GAGAgtrnga
2361
GAGAgtrngc
2385
GAGAgtrngg
2409
GAGAgtrngt

2338
TAGAgtrnga
2362
TAGAgtrngc
2386
TAGAgtrngg
2410
TAGAgtrngt

2339
CNGAgtrnga
2363
CNGAgtrngc
2387
CNGAgtrngg
2411
CNGAgtrngt

2340
NCGAgtrnga
2364
NCGAgtrngc
2388
NCGAgtrngg
2412
NCGAgtrngt

2341
ACGAgtrnga
2365
ACGAgtrngc
2389
ACGAgtrngg
2413
ACGAgtrngt

2342
CCGAgtrnga
2366
CCGAgtrngc
2390
CCGAgtrngg
2414
CCGAgtrngt

2343
GCGAgtrnga
2367
GCGAgtrngc
2391
GCGAgtrngg
2415
GCGAgtrngt

2344
TCGAgtrnga
2368
TCGAgtrngc
2392
TCGAgtrngg
2416
TCGAgtrngt

2345
GNGAgtrnga
2369
GNGAgtrngc
2393
GNGAgtrngg
2417
GNGAgtrngt

2346
NGGAgtrnga
2370
NGGAgtrngc
2394
NGGAgtrngg
2418
NGGAgtrngt

2347
AGGAgtrnga
2371
AGGAgtrngc
2395
AGGAgtrngg
2419
AGGAgtrngt

2348
CGGAgtrnga
2372
CGGAgtrngc
2396
CGGAgtrngg
2420
CGGAgtrngt

2349
GGGAgtrnga
2373
GGGAgtrngc
2397
GGGAgtrngg
2421
GGGAgtrngt

2350
TGGAgtrnga
2374
TGGAgtrngc
2398
TGGAgtrngg
2422
TGGAgtrngt

2351
TNGAgtrnga
2375
TNGAgtrngc
2399
TNGAgtrngg
2423
TNGAgtrngt

2352
NTGAgtrnga
2376
NTGAgtrngc
2400
NTGAgtrngg
2424
NTGAgtrngt

2353
ATGAgtrnga
2377
ATGAgtrngc
2401
ATGAgtrngg
2425
ATGAgtrngt

2354
CTGAgtrnga
2378
CTGAgtrngc
2402
CTGAgtrngg
2426
CTGAgtrngt

2355
GTGAgtrnga
2379
GTGAgtrngc
2403
GTGAgtrngg
2427
GTGAgtrngt

2356
TTGAgtrnga
2380
TTGAgtrngc
2404
TTGAgtrngg
2428
TTGAgtrngt

2429
ANGAgtangn
2453
ANGAgtaagn
2477
ANGAgtacgn
2501
ANGAgtaggn

2430
NAGAglangn
2454
NAGAgtaagn
2478
NAGAgtacgn
2502
NAGAgtaggn

2431
AAGAgtangn
2455
AAGAgtaagn
2479
AAGAgtacgn
2503
AAGAgtaggn

2432
CAGAgtangn
2456
CAGAgtaagn
2480
CAGAgtacgn
2504
CAGAgtaggn

2433
GAGAgtangn
2457
GAGAgtaagn
2481
GAGAgtacgn
2505
GAGAgtaggn

2434
TAGAgtangn
2458
TAGAgtaagn
2482
TAGAgtacgn
2506
TAGAgtaggn

2435
CNGAgtangn
2459
CNGAgtaagn
2483
CNGAgtacgn
2507
CNGAgtaggn

2436
NCGAgtangn
2460
NCGAgtaagn
2484
NCGAgtacgn
2508
NCGAgtaggn

2437
ACGAgtangn
2461
ACGAgtaagn
2485
ACGAgtacgn
2509
ACGAgtaggn

2438
CCGAgtangn
2462
CCGAgtaagn
2486
CCGAgtacgn
2510
CCGAgtaggn

2439
GCGAgtangn
2463
GCGAgtaagn
2487
GCGAgtacgn
2511
GCGAgtaggn

2440
TCGAgtangn
2464
TCGAgtaagn
2488
TCGAgtacgn
2512
TCGAgtaggn

2441
GNGAgtangn
2465
GNGAgtaagn
2489
GNGAgtacgn
2513
GNGAgtaggn

2442
NGGAgtangn
2466
NGGAgtaagn
2490
NGGAgtacgn
2514
NGGAgtaggn

2443
AGGAgtangn
2467
AGGAgtaagn
2491
AGGAgtacgn
2515
AGGAgtaggn

2444
CGGAgtangn
2468
CGGAgtaagn
2492
CGGAgtacgn
2516
CGGAgtaggn

2445
GGGAgtangn
2469
GGGAgtaagn
2493
GGGAgtacgn
2517
GGGAgtaggn

2446
TGGAgtangn
2470
TGGAgtaagn
2494
TGGAgtacgn
2518
TGGAgtaggn

2447
TNGAgtangn
2471
TNGAgtaagn
2495
TNGAgtacgn
2519
TNGAgtaggn

2448
NTGAgtangn
2472
NTGAgtaagn
2496
NTGAgtacgn
2520
NTGAgtaggn

2449
ATGAgtangn
2473
ATGAgtaagn
2497
ATGAgtacgn
2521
ATGAgtaggn

2450
CTGAgtangn
2474
CTGAgtaagn
2498
CTGAgtacgn
2522
CTGAgtaggn

2451
GTGAgtangn
2475
GTGAgtaagn
2499
GTGAgtacgn
2523
GTGAgtaggn

2452
TTGAgtangn
2476
TTGAgtaagn
2500
TTGAgtacgn
2524
TTGAgtaggn

2525
ANGAgtatgn
2549
ANGAgtaaga
2573
ANGAgtacga
2597
ANGAgtagga

2526
NAGAgtatgn
2550
NAGAgtaaga
2574
NAGAgtacga
2598
NAGAgtagga

2527
AAGAgtatgn
2551
AAGAgtaaga
2575
AAGAgtacga
2599
AAGAgtagga

2528
CAGAgtatgn
2552
CAGAgtaaga
2576
CAGAgtacga
2600
CAGAgtagga

2529
GAGAgtatgn
2553
GAGAgtaaga
2577
GAGAgtacga
2601
GAGAgtagga

2530
TAGAgtatgn
2554
TAGAgtaaga
2578
TAGAgtacga
2602
TAGAgtagga

2531
CNGAgtatgn
2555
CNGAgtaaga
2579
CNGAgtacga
2603
CNGAgtagga

2532
NCGAgtatgn
2556
NCGAgtaaga
2580
NCGAgtacga
2604
NCGAgtagga

2533
ACGAgtatgn
2557
ACGAgtaaga
2581
ACGAgtacga
2605
ACGAgtagga

2534
CCGAgtatgn
2558
CCGAgtaaga
2582
CCGAgtacga
2606
CCGAgtagga

2535
GCGAgtatgn
2559
GCGAgtaaga
2583
GCGAgtacga
2607
GCGAgtagga

2536
TCGAgtatgn
2560
TCGAgtaaga
2584
TCGAgtacga
2608
TCGAgtagga

2537
GNGAgtatgn
2561
GNGAgtaaga
2585
GNGAgtacga
2609
GNGAgtagga

2538
NGGAgtatgn
2562
NGGAgtaaga
2586
NGGAgtacga
2610
NGGAgtagga

2539
AGGAgtatgn
2563
AGGAgtaaga
2587
AGGAgtacga
2611
AGGAgtagga

2540
CGGAgtatgn
2564
CGGAgtaaga
2588
CGGAgtacga
2612
CGGAgtagga

2541
GGGAgtatgn
2565
GGGAgtaaga
2589
GGGAgtacga
2613
GGGAgtagga

2542
TGGAgtatgn
2566
TGGAgtaaga
2590
TGGAgtacga
2614
TGGAgtagga

2543
TNGAgtatgn
2567
TNGAgtaaga
2591
TNGAgtacga
2615
TNGAgtagga

2544
NTGAgtatgn
2568
NTGAgtaaga
2592
NTGAgtacga
2616
NTGAgtagga

2545
ATGAgtatgn
2569
ATGAgtaaga
2593
ATGAgtacga
2617
ATGAgtagga

2546
CTGAgtatgn
2570
CTGAgtaaga
2594
CTGAgtacga
2618
CTGAgtagga

2547
GTGAgtatgn
2571
GTGAgtaaga
2595
GTGAgtacga
2619
GTGAgtagga

2548
TTGAgtatgn
2572
TTGAgtaaga
2596
TTGAgtacga
2620
TTGAgtagga

2621
ANGAgtatga
2645
ANGAgtaagc
2669
ANGAgtacgc
2693
ANGAgtaggc

2622
NAGAgtatga
2646
NAGAgtaagc
2670
NAGAgtacgc
2694
NAGAgtaggc

2623
AAGAgtatga
2647
AAGAgtaagc
2671
AAGAgtacgc
2695
AAGAgtaggc

2624
CAGAgtatga
2648
CAGAgtaagc
2672
CAGAgtacgc
2696
CAGAgtaggc

2625
GAGAgtatga
2649
GAGAgtaagc
2673
GAGAgtacgc
2697
GAGAgtaggc

2626
TAGAgtatga
2650
TAGAgtaagc
2674
TAGAgtacgc
2698
TAGAgtaggc

2627
CNGAgtatga
2651
CNGAgtaagc
2675
CNGAgtacgc
2699
CNGAgtaggc

2628
NCGAgtatga
2652
NCGAgtaagc
2676
NCGAgtacgc
2700
NCGAgtaggc

2629
ACGAgtatga
2653
ACGAgtaagc
2677
ACGAgtacgc
2701
ACGAgtaggc

2630
CCGAgtatga
2654
CCGAgtaagc
2678
CCGAgtacgc
2702
CCGAgtaggc

2631
GCGAgtatga
2655
GCGAgtaagc
2679
GCGAgtacgc
2703
GCGAgtaggc

2632
TCGAgtatga
2656
TCGAgtaagc
2680
TCGAgtacgc
2704
TCGAgtaggc

2633
GNGAgtatga
2657
GNGAgtaagc
2681
GNGAgtacgc
2705
GNGAgtaggc

2634
NGGAgtatga
2658
NGGAgtaagc
2682
NGGAgtacgc
2706
NGGAgtaggc

2635
AGGAgtatga
2659
AGGAgtaagc
2683
AGGAgtacgc
2707
AGGAgtaggc

2636
CGGAgtatga
2660
CGGAgtaagc
2684
CGGAgtacgc
2708
CGGAgtaggc

2637
GGGAgtatga
2661
GGGAgtaagc
2685
GGGAgtacgc
2709
GGGAgtaggc

2638
TGGAgtatga
2662
TGGAgtaagc
2686
TGGAgtacgc
2710
TGGAgtaggc

2639
TNGAgtatga
2663
TNGAgtaagc
2687
TNGAgtacgc
2711
TNGAgtaggc

2640
NTGAgtatga
2664
NTGAgtaagc
2688
NTGAgtacgc
2712
NTGAgtaggc

2641
ATGAgtatga
2665
ATGAgtaagc
2689
ATGAgtacgc
2713
ATGAgtaggc

2642
CTGAgtatga
2666
CTGAgtaagc
2690
CTGAgtacgc
2714
CTGAgtaggc

2643
GTGAgtatga
2667
GTGAgtaagc
2691
GTGAgtacgc
2715
GTGAgtaggc

2644
TTGAgtatga
2668
TTGAgtaagc
2692
TTGAgtacgc
2716
TTGAgtaggc

2717
ANGAgtatgc
2741
ANGAgtaagg
2765
ANGAgtacgg
2789
ANGAgtaggg

2718
NAGAgtatgc
2742
NAGAgtaagg
2766
NAGAgtacgg
2790
NAGAgtaggg

2719
AAGAgtatgc
2743
AAGAgtaagg
2767
AAGAgtacgg
2791
AAGAgtaggg

2720
CAGAgtatgc
2744
CAGAgtaagg
2768
CAGAgtacgg
2792
CAGAgtaggg

2721
GAGAgtatgc
2745
GAGAgtaagg
2769
GAGAgtacgg
2793
GAGAgtaggg

2722
TAGAgtatgc
2746
TAGAgtaagg
2770
TAGAgtacgg
2794
TAGAgtaggg

2723
CNGAgtatgc
2747
CNGAgtaagg
2771
CNGAgtacgg
2795
CNGAgtaggg

2724
NCGAgtatgc
2748
NCGAgtaagg
2772
NCGAgtacgg
2796
NCGAgtaggg

2725
ACGAgtatgc
2749
ACGAgtaagg
2773
ACGAgtacgg
2797
ACGAgtaggg

2726
CCGAgtatgc
2750
CCGAgtaagg
2774
CCGAgtacgg
2798
CCGAgtaggg

2727
GCGAgtatgc
2751
GCGAgtaagg
2775
GCGAgtacgg
2799
GCGAgtaggg

2728
TCGAgtatgc
2752
TCGAgtaagg
2776
TCGAgtacgg
2800
TCGAgtaggg

2729
GNGAgtatgc
2753
GNGAgtaagg
2777
GNGAgtacgg
2801
GNGAgtaggg

2730
NGGAgtatgc
2754
NGGAgtaagg
2778
NGGAgtacgg
2802
NGGAgtaggg

2731
AGGAgtatgc
2755
AGGAgtaagg
2779
AGGAgtacgg
2803
AGGAgtaggg

2732
CGGAgtatgc
2756
CGGAgtaagg
2780
CGGAgtacgg
2804
CGGAgtaggg

2733
GGGAgtatgc
2757
GGGAgtaagg
2781
GGGAgtacgg
2805
GGGAgtaggg

2734
TGGAgtatgc
2758
TGGAgtaagg
2782
TGGAgtacgg
2806
TGGAgtaggg

2735
TNGAgtatgc
2759
TNGAgtaagg
2783
TNGAgtacgg
2807
TNGAgtaggg

2736
NTGAgtatgc
2760
NTGAgtaagg
2784
NTGAgtacgg
2808
NTGAgtaggg

2737
ATGAgtatgc
2761
ATGAgtaagg
2785
ATGAgtacgg
2809
ATGAgtaggg

2738
CTGAgtatgc
2762
CTGAgtaagg
2786
CTGAgtacgg
2810
CTGAgtaggg

2739
GTGAgtatgc
2763
GTGAgtaagg
2787
GTGAgtacgg
2811
GTGAgtaggg

2740
TTGAgtatgc
2764
TTGAgtaagg
2788
TTGAgtacgg
2812
TTGAgtaggg

2813
ANGAgtatgg
2837
ANGAgtaagt
2861
ANGAgtacgt
2885
ANGAgtaggt

2814
NAGAgtatgg
2838
NAGAgtaagt
2862
NAGAgtacgt
2886
NAGAgtaggt

2815
AAGAgtatgg
2839
AAGAgtaagt
2863
AAGAgtacgt
2887
AAGAgtaggt

2816
CAGAgtatgg
2840
CAGAgtaagt
2864
CAGAgtacgt
2888
CAGAgtaggt

2817
GAGAgtatgg
2841
GAGAgtaagt
2865
GAGAgtacgt
2889
GAGAgtaggt

2818
TAGAgtatgg
2842
TAGAgtaagt
2866
TAGAgtacgt
2890
TAGAgtaggt

2819
CNGAgtatgg
2843
CNGAgtaagt
2867
CNGAgtacgt
2891
CNGAgtaggt

2820
NCGAgtatgg
2844
NCGAgtaagt
2868
NCGAgtacgt
2892
NCGAgtaggt

2821
ACGAgtatgg
2845
ACGAgtaagt
2869
ACGAgtacgt
2893
ACGAgtaggt

2822
CCGAgtatgg
2846
CCGAgtaagt
2870
CCGAgtacgt
2894
CCGAgtaggt

2823
GCGAgtatgg
2847
GCGAgtaagt
2871
GCGAgtacgt
2895
GCGAgtaggt

2824
TCGAgtatgg
2848
TCGAgtaagt
2872
TCGAgtacgt
2896
TCGAgtaggt

2825
GNGAgtatgg
2849
GNGAgtaagt
2873
GNGAgtacgt
2897
GNGAgtaggt

2826
NGGAgtatgg
2850
NGGAgtaagt
2874
NGGAgtacgt
2898
NGGAgtaggt

2827
AGGAgtatgg
2851
AGGAgtaagt
2875
AGGAgtacgt
2899
AGGAgtaggt

2828
CGGAgtatgg
2852
CGGAgtaagt
2876
CGGAgtacgt
2900
CGGAgtaggt

2829
GGGAgtatgg
2853
GGGAgtaagt
2877
GGGAgtacgt
2901
GGGAgtaggt

2830
TGGAgtatgg
2854
TGGAgtaagt
2878
TGGAgtacgt
2902
TGGAgtaggt

2831
TNGAgtatgg
2855
TNGAgtaagt
2879
TNGAgtacgt
2903
TNGAgtaggt

2832
NTGAgtatgg
2856
NTGAgtaagt
2880
NTGAgtacgt
2904
NTGAgtaggt

2833
ATGAgtatgg
2857
ATGAgtaagt
2881
ATGAgtacgt
2905
ATGAgtaggt

2834
CTGAgtatgg
2858
CTGAgtaagt
2882
CTGAgtacgt
2906
CTGAgtaggt

2835
GTGAgtatgg
2859
GTGAgtaagt
2883
GTGAgtacgt
2907
GTGAgtaggt

2836
TTGAgtatgg
2860
TTGAgtaagt
2884
TTGAgtacgt
2908
TTGAgtaggt

2909
ANGAgtatgt
2933
ANGAgtanga
2957
ANGAgtangc
2981
ANGAgtangg

2910
NAGAgtatgt
2934
NAGAgtanga
2958
NAGAgtangc
2982
NAGAgtangg

2911
AAGAgtatgt
2935
AAGAgtanga
2959
AAGAgtangc
2983
AAGAgtangg

2912
CAGAgtatgt
2936
CAGAgtanga
2960
CAGAgtangc
2984
CAGAgtangg

2913
GAGAgtatgt
2937
GAGAgtanga
2961
GAGAgtangc
2985
GAGAgtangg

2914
TAGAgtatgt
2938
TAGAgtanga
2962
TAGAgtangc
2986
TAGAgtangg

2915
CNGAgtatgt
2939
CNGAgtanga
2963
CNGAgtangc
2987
CNGAgtangg

2916
NCGAgtatgt
2940
NCGAgtanga
2964
NCGAgtangc
2988
NCGAgtangg

2917
ACGAgtatgt
2941
ACGAgtanga
2965
ACGAgtangc
2989
ACGAgtangg

2918
CCGAgtatgt
2942
CCGAgtanga
2966
CCGAgtangc
2990
CCGAgtangg

2919
GCGAgtatgt
2943
GCGAgtanga
2967
GCGAgtangc
2991
GCGAgtangg

2920
TCGAgtatgt
2944
TCGAgtanga
2968
TCGAgtangc
2992
TCGAgtangg

2921
GNGAgtatgt
2945
GNGAgtanga
2969
GNGAgtangc
2993
GNGAgtangg

2922
NGGAgtatgt
2946
NGGAgtanga
2970
NGGAgtangc
2994
NGGAgtangg

2923
AGGAgtatgt
2947
AGGAgtanga
2971
AGGAgtangc
2995
AGGAgtangg

2924
CGGAgtatgt
2948
CGGAgtanga
2972
CGGAgtangc
2996
CGGAgtangg

2925
GGGAgtatgt
2949
GGGAgtanga
2973
GGGAgtangc
2997
GGGAgtangg

2926
TGGAgtatgt
2950
TGGAgtanga
2974
TGGAgtangc
2998
TGGAgtangg

2927
TNGAgtatgt
2951
TNGAgtanga
2975
TNGAgtangc
2999
TNGAgtangg

2928
NTGAgtatgt
2952
NTGAgtanga
2976
NTGAgtangc
3000
NTGAgtangg

2929
ATGAgtatgt
2953
ATGAgtanga
2977
ATGAgtangc
3001
ATGAgtangg

2930
CTGAgtatgt
2954
CTGAgtanga
2978
CTGAgtangc
3002
CTGAgtangg

2931
GTGAgtatgt
2955
GTGAgtanga
2979
GTGAgtangc
3003
GTGAgtangg

2932
TTGAgtatgt
2956
TTGAgtanga
2980
TTGAgtangc
3004
TTGAgtangg

3005
ANGAgtangt
3029
ANGAgtgngn
3053
ANGAgtgagn
3077
ANGAgtgcgn

3006
NAGAgtangt
3030
NAGAgtgngn
3054
NAGAgtgagn
3078
NAGAgtgcgn

3007
AAGAglangt
3031
AAGAgtgngn
3055
AAGAgtgagn
3079
AAGAgtgcgn

3008
CAGAgtangt
3032
CAGAgtgngn
3056
CAGAgtgagn
3080
CAGAgtgcgn

3009
GAGAgtangt
3033
GAGAgtgngn
3057
GAGAgtgagn
3081
GAGAgtgcgn

3010
TAGAgtangt
3034
TAGAgtgngn
3058
TAGAgtgagn
3082
TAGAgtgcgn

3011
CNGAgtangt
3035
CNGAgtgngn
3059
CNGAgtgagn
3083
CNGAgtgcgn

3012
NCGAgtangt
3036
NCGAgtgngn
3060
NCGAgtgagn
3084
NCGAgtgcgn

3013
ACGAgtangt
3037
ACGAgtgngn
3061
ACGAgtgagn
3085
ACGAgtgcgn

3014
CCGAgtangt
3038
CCGAgtgngn
3062
CCGAgtgagn
3086
CCGAgtgcgn

3015
GCGAgtangt
3039
GCGAgtgngn
3063
GCGAgtgagn
3087
GCGAgtgcgn

3016
TCGAgtangt
3040
TCGAgtgngn
3064
TCGAgtgagn
3088
TCGAgtgcgn

3017
GNGAgtangt
3041
GNGAgtgngn
3065
GNGAgtgagn
3089
GNGAgtgcgn

3018
NGGAgtangt
3042
NGGAgtgngn
3066
NGGAgtgagn
3090
NGGAgtgcgn

3019
AGGAgtangt
3043
AGGAgtgngn
3067
AGGAgtgagn
3091
AGGAgtgcgn

3020
CGGAgtangt
3044
CGGAgtgngn
3068
CGGAgtgagn
3092
CGGAgtgcgn

3021
GGGAgtangt
3045
GGGAgtgngn
3069
GGGAgtgagn
3093
GGGAgtgcgn

3022
TGGAgtangt
3046
TGGAgtgngn
3070
TGGAgtgagn
3094
TGGAgtgcgn

3023
INGAgtangt
3047
TNGAgtgngn
3071
TNGAgtgagn
3095
TNGAgtgcgn

3024
NTGAgtangt
3048
NTGAgtgngn
3072
NTGAgtgagn
3096
NTGAgtgcgn

3025
ATGAgtangt
3049
ATGAgtgngn
3073
ATGAgtgagn
3097
ATGAgtgcgn

3026
CTGAgtangt
3050
CTGAgtgngn
3074
CTGAgtgagn
3098
CTGAgtgcgn

3027
GTGAgtangt
3051
GTGAgtgngn
3075
GTGAgtgagn
3099
GTGAgtgcgn

3028
TTGAgtangt
3052
TTGAgtgngn
3076
TTGAgtgagn
3100
TTGAgtgcgn

3101
ANGAgtgggn
3125
ANGAgtgtgn
3149
ANGAgtgaga
3173
ANGAgtgcga

3102
NAGAgtgggn
3126
NAGAgtgtgn
3150
NAGAgtgaga
3174
NAGAgtgcga

3103
AAGAgtgggn
3127
AAGAgtgtgn
3151
AAGAgtgaga
3175
AAGAgtgcga

3104
CAGAgtgggn
3128
CAGAgtgtgn
3152
CAGAgtgaga
3176
CAGAgtgcga

3105
GAGAgtgggn
3129
GAGAgtgtgn
3153
GAGAgtgaga
3177
GAGAgtgcga

3106
TAGAgtgggn
3130
TAGAgtgtgn
3154
TAGAgtgaga
3178
TAGAgtgcga

3107
CNGAgtgggn
3131
CNGAgtgtgn
3155
CNGAgtgaga
3179
CNGAgtgcga

3108
NCGAgtgggn
3132
NCGAgtgtgn
3156
NCGAgtgaga
3180
NCGAgtgcga

3109
ACGAgtgggn
3133
ACGAgtgtgn
3157
ACGAgtgaga
3181
ACGAgtgcga

3110
CCGAgtgggn
3134
CCGAgtgtgn
3158
CCGAgtgaga
3182
CCGAgtgcga

3111
GCGAgtgggn
3135
GCGAgtgtgn
3159
GCGAgtgaga
3183
GCGAgtgcga

3112
TCGAgtgggn
3136
TCGAgtgtgn
3160
TCGAgtgaga
3184
TCGAgtgcga

3113
GNGAgtgggn
3137
GNGAgtgtgn
3161
GNGAgtgaga
3185
GNGAgtgcga

3114
NGGAgtgggn
3138
NGGAgtgtgn
3162
NGGAgtgaga
3186
NGGAgtgcga

3115
AGGAgtgggn
3139
AGGAgtgtgn
3163
AGGAgtgaga
3187
AGGAgtgcga

3116
CGGAgtgggn
3140
CGGAgtgtgn
3164
CGGAgtgaga
3188
CGGAgtgcga

3117
GGGAgtgggn
3141
GGGAgtgtgn
3165
GGGAgtgaga
3189
GGGAgtgcga

3118
TGGAgtgggn
3142
TGGAgtgtgn
3166
TGGAgtgaga
3190
TGGAgtgcga

3119
TNGAgtgggn
3143
TNGAgtgtgn
3167
TNGAgtgaga
3191
TNGAgtgcga

3120
NTGAgtgggn
3144
NTGAgtgtgn
3168
NTGAgtgaga
3192
NTGAgtgcga

3121
ATGAgtgggn
3145
ATGAgtgtgn
3169
ATGAgtgaga
3193
ATGAgtgcga

3122
CTGAgtgggn
3146
CTGAgtgtgn
3170
CTGAgtgaga
3194
CTGAgtgcga

3123
GTGAgtgggn
3147
GTGAgtgtgn
3171
GTGAgtgaga
3195
GTGAgtgcga

3124
TTGAgtgggn
3148
TTGAgtgtgn
3172
TTGAgtgaga
3196
TTGAgtgcga

3197
ANGAgtggga
3221
ANGAgtgtga
3245
ANGAgtgagc
3269
ANGAgtgcgc

3198
NAGAgtggga
3222
NAGAgtgtga
3246
NAGAgtgagc
3270
NAGAgtgcgc

3199
AAGAgtggga
3223
AAGAgtgtga
3247
AAGAgtgagc
3271
AAGAgtgcgc

3200
CAGAgtggga
3224
CAGAgtgtga
3248
CAGAgtgagc
3272
CAGAgtgcgc

3201
GAGAgtggga
3225
GAGAgtgtga
3249
GAGAgtgagc
3273
GAGAgtgcgc

3202
TAGAgtggga
3226
TAGAgtgtga
3250
TAGAgtgagc
3274
TAGAgtgcgc

3203
CNGAgtggga
3227
CNGAgtgtga
3251
CNGAgtgagc
3275
CNGAgtgcgc

3204
NCGAgtggga
3228
NCGAgtgtga
3252
NCGAgtgagc
3276
NCGAgtgcgc

3205
ACGAgtggga
3229
ACGAgtgtga
3253
ACGAgtgagc
3277
ACGAgtgcgc

3206
CCGAgtggga
3230
CCGAgtgtga
3254
CCGAgtgagc
3278
CCGAgtgcgc

3207
GCGAgtggga
3231
GCGAgtgtga
3255
GCGAgtgagc
3279
GCGAgtgcgc

3208
TCGAgtggga
3232
TCGAgtgtga
3256
TCGAgtgagc
3280
TCGAgtgcgc

3209
GNGAgtggga
3233
GNGAgtgtga
3257
GNGAgtgagc
3281
GNGAgtgcgc

3210
NGGAgtggga
3234
NGGAgtgtga
3258
NGGAgtgagc
3282
NGGAgtgcgc

3211
AGGAgtggga
3235
AGGAgtgtga
3259
AGGAgtgagc
3283
AGGAgtgcgc

3212
CGGAgtggga
3236
CGGAgtgtga
3260
CGGAgtgagc
3284
CGGAgtgcgc

3213
GGGAgtggga
3237
GGGAgtgtga
3261
GGGAgtgagc
3285
GGGAgtgcgc

3214
TGGAgtggga
3238
TGGAgtgtga
3262
TGGAgtgagc
3286
TGGAgtgcgc

3215
TNGAgtggga
3239
TNGAgtgtga
3263
TNGAgtgagc
3287
TNGAgtgcgc

3216
NTGAgtggga
3240
NTGAgtgtga
3264
NTGAgtgagc
3288
NTGAgtgcgc

3217
ATGAgtggga
3241
ATGAgtgtga
3265
ATGAgtgagc
3289
ATGAgtgcgc

3218
CTGAgtggga
3242
CTGAgtgtga
3266
CTGAgtgagc
3290
CTGAgtgcgc

3219
GTGAgtggga
3243
GTGAgtgtga
3267
GTGAgtgagc
3291
GTGAgtgcgc

3220
TTGAgtggga
3244
TTGAgtgtga
3268
TTGAgtgagc
3292
TTGAgtgcgc

3293
ANGAgtgggc
3317
ANGAgtgtgc
3341
ANGAgtgagg
3365
ANGAgtgcgg

3294
NAGAgtgggc
3318
NAGAgtgtgc
3342
NAGAgtgagg
3366
NAGAgtgcgg

3295
AAGAgtgggc
3319
AAGAgtgtgc
3343
AAGAgtgagg
3367
AAGAgtgcgg

3296
CAGAgtgggc
3320
CAGAgtgtgc
3344
CAGAgtgagg
3368
CAGAgtgcgg

3297
GAGAgtgggc
3321
GAGAgtgtgc
3345
GAGAgtgagg
3369
GAGAgtgcgg

3298
TAGAgtgggc
3322
TAGAgtgtgc
3346
TAGAgtgagg
3370
TAGAgtgcgg

3299
CNGAgtgggc
3323
CNGAgtgtgc
3347
CNGAgtgagg
3371
CNGAgtgcgg

3300
NCGAgtgggc
3324
NCGAgtgtgc
3348
NCGAgtgagg
3372
NCGAgtgcgg

3301
ACGAgtgggc
3325
ACGAgtgtgc
3349
ACGAgtgagg
3373
ACGAgtgcgg

3302
CCGAgtgggc
3326
CCGAgtgtgc
3350
CCGAgtgagg
3374
CCGAgtgcgg

3303
GCGAgtgggc
3327
GCGAgtgtgc
3351
GCGAgtgagg
3375
GCGAgtgcgg

3304
TCGAgtgggc
3328
TCGAgtgtgc
3352
TCGAgtgagg
3376
TCGAgtgcgg

3305
GNGAgtgggc
3329
GNGAgtgtgc
3353
GNGAgtgagg
3377
GNGAgtgcgg

3306
NGGAgtgggc
3330
NGGAgtgtgc
3354
NGGAgtgagg
3378
NGGAgtgcgg

3307
AGGAgtgggc
3331
AGGAgtgtgc
3355
AGGAgtgagg
3379
AGGAgtgcgg

3308
CGGAgtgggc
3332
CGGAgtgtgc
3356
CGGAgtgagg
3380
CGGAgtgcgg

3309
GGGAgtgggc
3333
GGGAgtgtgc
3357
GGGAgtgagg
3381
GGGAgtgcgg

3310
TGGAgtgggc
3334
TGGAgtgtgc
3358
TGGAgtgagg
3382
TGGAgtgcgg

3311
TNGAgtgggc
3335
TNGAgtgtgc
3359
TNGAgtgagg
3383
TNGAgtgcgg

3312
NTGAgtgggc
3336
NTGAgtgtgc
3360
NTGAgtgagg
3384
NTGAgtgcgg

3313
ATGAgtgggc
3337
ATGAgtgtgc
3361
ATGAgtgagg
3385
ATGAgtgcgg

3314
CTGAgtgggc
3338
CTGAgtgtgc
3362
CTGAgtgagg
3386
CTGAgtgcgg

3315
GTGAgtgggc
3339
GTGAgtgtgc
3363
GTGAgtgagg
3387
GTGAgtgcgg

3316
TTGAgtgggc
3340
TTGAgtgtgc
3364
TTGAgtgagg
3388
TTGAgtgcgg

3389
ANGAgtgggg
3413
ANGAgtgtgg
3437
ANGAgtgagt
3461
ANGAgtgcgt

3390
NAGAgtgggg
3414
NAGAgtgtgg
3438
NAGAgtgagt
3462
NAGAgtgcgt

3391
AAGAgtgggg
3415
AAGAgtgtgg
3439
AAGAgtgagt
3463
AAGAgtgcgt

3392
CAGAgtgggg
3416
CAGAgtgtgg
3440
CAGAgtgagt
3464
CAGAgtgcgt

3393
GAGAgtgggg
3417
GAGAgtgtgg
3441
GAGAgtgagt
3465
GAGAgtgcgt

3394
TAGAgtgggg
3418
TAGAgtgtgg
3442
TAGAgtgagt
3466
TAGAgtgcgt

3395
CNGAgtgggg
3419
CNGAgtgtgg
3443
CNGAgtgagt
3467
CNGAgtgcgt

3396
NCGAgtgggg
3420
NCGAgtgtgg
3444
NCGAgtgagt
3468
NCGAgtgcgt

3397
ACGAgtgggg
3421
ACGAgtgtgg
3445
ACGAgtgagt
3469
ACGAgtgcgt

3398
CCGAgtgggg
3422
CCGAgtgtgg
3446
CCGAgtgagt
3470
CCGAgtgcgt

3399
GCGAgtgggg
3423
GCGAgtgtgg
3447
GCGAgtgagt
3471
GCGAgtgcgt

3400
TCGAgtgggg
3424
TCGAgtgtgg
3448
TCGAgtgagt
3472
TCGAgtgcgt

3401
GNGAgtgggg
3425
GNGAgtgtgg
3449
GNGAgtgagt
3473
GNGAgtgcgt

3402
NGGAgtgggg
3426
NGGAgtgtgg
3450
NGGAgtgagt
3474
NGGAgtgcgt

3403
AGGAgtgggg
3427
AGGAgtgtgg
3451
AGGAgtgagt
3475
AGGAgtgcgt

3404
CGGAgtgggg
3428
CGGAgtgtgg
3452
CGGAgtgagt
3476
CGGAgtgcgt

3405
GGGAgtgggg
3429
GGGAgtgtgg
3453
GGGAgtgagt
3477
GGGAgtgcgt

3406
TGGAgtgggg
3430
TGGAgtgtgg
3454
TGGAgtgagt
3478
TGGAgtgcgt

3407
TNGAgtgggg
3431
TNGAgtgtgg
3455
TNGAgtgagt
3479
TNGAgtgcgt

3408
NTGAgtgggg
3432
NTGAgtgtgg
3456
NTGAgtgagt
3480
NTGAgtgcgt

3409
ATGAgtgggg
3433
ATGAgtgtgg
3457
ATGAgtgagt
3481
ATGAgtgcgt

3410
CTGAgtgggg
3434
CTGAgtgtgg
3458
CTGAgtgagt
3482
CTGAgtgcgt

3411
GTGAgtgggg
3435
GTGAgtgtgg
3459
GTGAgtgagt
3483
GTGAgtgcgt

3412
TTGAgtgggg
3436
TTGAgtgtgg
3460
TTGAgtgagt
3484
TTGAgtgcgt

3485
ANGAgtgggt
3509
ANGAgtgtgt
3533
ANGAgtgnga
3557
ANGAgtgngc

3486
NAGAgtgggt
3510
NAGAgtgtgt
3534
NAGAgtgnga
3558
NAGAgtgngc

3487
AAGAgtgggt
3511
AAGAgtgtgt
3535
AAGAgtgnga
3559
AAGAgtgngc

3488
CAGAgtgggt
3512
CAGAgtgtgt
3536
CAGAgtgnga
3560
CAGAgtgngc

3489
GAGAgtgggt
3513
GAGAgtgtgt
3537
GAGAgtgnga
3561
GAGAgtgngc

3490
TAGAgtgggt
3514
TAGAgtgtgt
3538
TAGAgtgnga
3562
TAGAgtgngc

3491
CNGAgtgggt
3515
CNGAgtgtgt
3539
CNGAgtgnga
3563
CNGAgtgngc

3492
NCGAgtgggt
3516
NCGAgtgtgt
3540
NCGAgtgnga
3564
NCGAgtgngc

3493
ACGAgtgggt
3517
ACGAgtgtgt
3541
ACGAgtgnga
3565
ACGAgtgngc

3494
CCGAgtgggt
3518
CCGAgtgtgt
3542
CCGAgtgnga
3566
CCGAgtgngc

3495
GCGAgtgggt
3519
GCGAgtgtgt
3543
GCGAgtgnga
3567
GCGAgtgngc

3496
TCGAgtgggt
3520
TCGAgtgtgt
3544
TCGAgtgnga
3568
TCGAgtgngc

3497
GNGAgtgggt
3521
GNGAgtgtgt
3545
GNGAgtgnga
3569
GNGAgtgngc

3498
NGGAgtgggt
3522
NGGAgtgtgt
3546
NGGAgtgnga
3570
NGGAgtgngc

3499
AGGAgtgggt
3523
AGGAgtgtgt
3547
AGGAgtgnga
3571
AGGAgtgngc

3500
CGGAgtgggt
3524
CGGAgtgtgt
3548
CGGAgtgnga
3572
CGGAgtgngc

3501
GGGAgtgggt
3525
GGGAgtgtgt
3549
GGGAgtgnga
3573
GGGAgtgngc

3502
TGGAgtgggt
3526
TGGAgtgtgt
3550
TGGAgtgnga
3574
TGGAgtgngc

3503
TNGAgtgggt
3527
TNGAgtgtgt
3551
TNGAgtgnga
3575
TNGAgtgngc

3504
NTGAgtgggt
3528
NTGAgtgtgt
3552
NTGAgtgnga
3576
NTGAgtgngc

3505
ATGAgtgggt
3529
ATGAgtgtgt
3553
ATGAgtgnga
3577
ATGAgtgngc

3506
CTGAgtgggt
3530
CTGAgtgtgt
3554
CTGAgtgnga
3578
CTGAgtgngc

3507
GTGAgtgggt
3531
GTGAgtgtgt
3555
GTGAgtgnga
3579
GTGAgtgngc

3508
TTGAgtgggt
3532
TTGAgtgtgt
3556
TTGAgtgnga
3580
TTGAgtgngc

3581
ANGAgtgngg
3593
GNGAgtgngg
3605
ANGAgtgngt
3617
GNGAgtgngt

3582
NAGAgtgngg
3594
NGGAgtgngg
3606
NAGAgtgngt
3618
NGGAgtgngt

3583
AAGAgtgngg
3595
AGGAgtgngg
3607
AAGAgtgngt
3619
AGGAgtgngt

3584
CAGAgtgngg
3596
CGGAgtgngg
3608
CAGAgtgngt
3620
CGGAgtgngt

3585
GAGAgtgngg
3597
GGGAgtgngg
3609
GAGAgtgngt
3621
GGGAgtgngt

3586
TAGAgtgngg
3598
TGGAgtgngg
3610
TAGAgtgngt
3622
TGGAgtgngt

3587
CNGAgtgngg
3599
TNGAgtgngg
3611
CNGAgtgngt
3623
TNGAgtgngt

3588
NCGAgtgngg
3600
NTGAgtgngg
3612
NCGAgtgngt
3624
NTGAgtgngt

3589
ACGAgtgngg
3601
ATGAgtgngg
3613
ACGAgtgngt
3625
ATGAgtgngt

3590
CCGAgtgngg
3602
CTGAgtgngg
3614
CCGAgtgngt
3626
CTGAgtgngt

3591
GCGAgtgngg
3603
GTGAgtgngg
3615
GCGAgtgngt
3627
GTGAgtgngt

3592
TCGAgtgngg
3604
TTGAgtgngg
3616
TCGAgtgngt
3628
TTGAgtgngt

In certain embodiments, provided herein is a vector comprising the artificial gene construct described herein. In some embodiments, provided herein is a cell comprising an artificial gene construct described herein or a vector comprising an artificial gene construct described herein.

In another aspect, provided herein is a method of modulating the amount and type of a protein produced by a cell containing an artificial gene construct described herein. In one embodiment, provided herein is a method of modulating the amount and type of a protein produced by a cell containing an artificial gene construct described herein, the method comprising contacting the cell with a compound of Formula (I) or a form thereof. In certain embodiments, the artificial gene construct encodes a therapeutic protein. In certain embodiments, the artificial gene construct encodes a non-functional protein. In some embodiments producing a therapeutic protein, the artificial gene construct may also encode a detectable reporter protein. In some embodiments producing a non-functional protein, the artificial gene construct may also encode a detectable reporter protein.

In another aspect, provided herein is a method of modulating the amount of a protein produced by a subject, wherein the subject is or was administered an artificial gene construct described herein. In one embodiment, provided herein is method of regulating the amount of a protein produced by a subject, the method comprising: (a) administering an artificial gene construct or a vector comprising the artificial gene construct described herein to the subject; and (b) administering a compound of Formula (I) or a form thereof to the subject. In another embodiment, provided herein is a method of regulating the amount of a protein produced by a subject, the method comprising administering a compound of Formula (I) or a form thereof to a subject carrying a gene containing a nucleotide sequence encoding an intronic REMS. In another embodiment, provided herein is a method of regulating the amount of a protein produced by a subject, the method comprising administering a compound of Formula (I) to the subject, wherein the subject was previously administered an artificial gene construct described herein. In certain embodiments, the artificial gene construct may encode a therapeutic or a non-functional protein. In some embodiments, the artificial gene construct encodes a detectable reporter protein. In certain embodiments, the subject is a non-human. In specific embodiments, the subject is a human.

In another aspect, provided herein is a method for modulating the amount of an RNA transcript produced from precursor RNA containing an endogenous or non-endogenous intronic recognition element for splicing modifier (REMS), the method comprising contacting the precursor RNA with a compound of Formula (I) or a form thereof, wherein the endogenous or non-endogenous intronic REMS comprises the sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, and wherein Formula (I) is

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In another aspect, provided herein is a method for modulating the amount of an RNA transcript produced from precursor RNA containing an endogenous or non-endogenous intronic recognition element for splicing modifier (REMS), the method comprising contacting the precursor RNA with a compound of Formula (I) or a form thereof, wherein the endogenous or non-endogenous intronic REMS comprises the sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide, and wherein Formula (I) is

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In another aspect, provided herein is a method of regulating the amount and type of a protein produced by a gene comprising a nucleotide sequence encoding an endogenous or non-endogenous intronic REMS in a subject, wherein the nucleotide sequence encoding the endogenous or non-endogenous intronic REMS comprises the sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide, the method comprising administering a compound of Formula (I) to the subject, wherein Formula (I) is

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₁is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In another aspect, provided herein is a method of regulating the amount and type of a protein produced by a gene comprising a nucleotide sequence encoding an endogenous or non-endogenous intronic REMS in a subject, wherein the nucleotide sequence encoding the endogenous or non-endogenous intronic REMS comprises the sequence NNGAgtrngn (SEQ ID NO: 3), wherein r is adenine or guanine and n or N is any nucleotide, the method comprising administering a compound of Formula (I) to the subject, wherein Formula (I) is

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In specific embodiments of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is selected from: 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, CYPIB1, 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, TARS, IDH1, IDI1, IFT57, TGDCC4, TGF2BP2, TGF2R, TGFBP3, 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, 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, P14K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PTTPNM3, 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, TP531NP1, 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.

In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from 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 another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is not described in International Publication No. WO 2015/105657. In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is not described in International Publication No. WO 2016/196386. In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is not described in International Publication No. WO 2015/105657 and not described in International Publication No. WO 2016/196386.

In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is selected from: 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, ARTD2, 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, ERGTC3, 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, ML ST8, 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, PPPIR12A, 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, SEC61 A1, 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, 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.

In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is selected from: 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, RAPlA, RAPGEF1, SENP6, SH3YL1, SLC25A17, SMN2, SREK1, STRN3, TAF2, TMEM134, VPS29, ZFAND1 or ZNF431.

In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is selected from: ABCB8, ANKRD36, ARHGAP12, ARMCX6, ATG5, BIRC6, C1orf86, CLTA, DYRK1A, FBXL6, KAT6B, KDM6A, KMT2D, LYRM1, MAN2C1, MRPL55, MYCBP2, PNISR, RAPGEF1, SENP6, SH3YL1, TMEM134 or ZNF431.

In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is selected from: 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, CYPIB1, DCLK1, DCN, DDIT4L, 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, MAN1A2, 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, P14K2B, PIK3R1, PIM2, PITPNB, PITPNM3, PLAU, PLEK2, PLEKHA6, PLEKHH2, PLXNC1, PMS1, PODN, POLN, POLR1A, 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.

In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is selected from: 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, 1L16, 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.

In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is selected from: 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, 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, 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, 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.

In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from 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, K1AA1524, K1AA1715, 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.

In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is selected from: 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.

In another specific embodiment of the aspects and embodiments described herein, the gene is, or the RNA transcript is transcribed from a gene that is selected from: 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.

In another aspect, provide herein is a method of modulating the amount and type of a protein produced by a cell containing the artificial gene construct as described above, the method comprising contacting the cell with a compound of Formula (I) or a form thereof, wherein Formula (I) is

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy,
- C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In a specific embodiment, in the context of DNA, the nucleotide sequence encoding the 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 adenine or guanine and n or N is any nucleotide.

In various specific embodiments, the nucleotide sequence encoding the intronic REMS is a nucleotide sequence encoding a non-endogenous intronic REMS, i.e., a precursor RNA transcript comprising the non-endogenous intronic REMS not naturally found in the DNA sequence of the artificial construct.

In one aspect, provided herein is a method for modulating the amount of an RNA transcript comprising a RNA nucleotide sequence comprising in 5′ to 3′ order: a branch point, a 3′ splice site and an endogenous intronic recognition element for splicing modifier (iREMS), 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 RNA transcript is an RNA 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; the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

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- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C3.14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

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- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In certain embodiments, the iREMS comprises an RNA sequence GAguragu (SEQ ID NO: 3866), wherein r is adenine or guanine and n is any nucleotide. In some embodiments, the iREMS comprises an RNA sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide. In a specific embodiment, 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), 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), wherein r is adenine or guanine and n or N is any nucleotide. In certain embodiments, n is adenine or guanine.

In certain embodiments, the iREMS comprises an RNA sequence NNGAguragu (SEQ ID NO: 3862), wherein r is adenine or guanine and N is any nucleotide. In a specific embodiment, 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. the iREMS comprises an RNA sequence presented in Table 13. In certain embodiments, n is adenine or guanine.

In another aspect, provided herein is a method for modulating the amount of an RNA transcript produced from a DNA sequence comprising a DNA nucleotide sequence encoding exons and one or more introns, comprising in 5′ to 3′ order: a branch point, a 3′ splice site and an endogenous iREMS; wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:

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- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-4alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In a specific embodiment, the DNA sequence is in a gene 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-TT1, 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, P1K3CD, P1K3R₁, 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 another specific embodiment, the DNA sequence is a gene not disclosed in either International Publication No. WO 2015/105657, International Publication No. WO 2016/196386, or both.

In another aspect, provided herein is a method for modulating the amount of an RNA transcript produced from a DNA sequence comprising a DNA nucleotide sequence encoding exons and one or more introns, comprising in 5′ to 3′ order: a branch point, a 3′ splice site and a non-endogenous iREMS; wherein the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In certain embodiments, the iREMS comprises a DNA sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide. In certain embodiments, n is adenine or guanine. In certain embodiments, the iREMS comprises a DNA sequence NNGAgtrngn (SEQ ID NO: 3), wherein r is adenine or guanine and n or N is any nucleotide. In a specific embodiment, the DNA sequence NNGAgtrngn (SEQ ID NO: 3) is 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). In certain embodiments, n is adenine or guanine.

In certain embodiments, the iREMS comprises a DNA sequence NNGAgtragt (SEQ ID NO: 3864), wherein r is adenine or guanine and N is any nucleotide. In a specific embodiment, the DNA sequence NNGAgtragt (SEQ ID NO: 3864) is 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 adenine or guanine, and N is any nucleotide. In a specific embodiment, the iREMS comprises a DNA sequence presented in Table 14. In certain embodiments, n is adenine or guanine. In certain embodiments of the aspects and embodiments described herein, n is adenine or guanine.

In certain embodiments of a method for modulating the amount of an RNA transcript described herein, modulation of the amount of the RNA transcript is modulation of the amount of the RNA transcript in a cell or a lysate of the cell, the method comprising contacting the compound of Formula (I) or a form thereof with the cell or the cell lysate. In a specific embodiment of a method for modulating the amount of an RNA transcript described herein, modulation of the amount of the RNA transcript is modulation of the amount of the RNA transcript in a cell, the method comprising contacting the compound of Formula (I) or a form thereof with the cell. In certain embodiments of a method of modulating the amount of an RNA transcript described herein, the modulation modulates the amount and/or type of a protein translated from the RNA transcript and produced in the cell or lysate of the cell.

In certain embodiments of a method for modulating the amount of an RNA transcript described herein, modulation of the amount of the RNA transcript is modulation of the amount of the RNA transcript in a subject, the method comprising administering the compound of Formula (I) or a form thereof to the subject. In certain embodiments of a method for modulating the amount of an RNA transcript described herein, the modulation modulates the amount and/or type of a protein translated from the RNA transcript and produced in the subject. In a specific embodiment, the subject is a non-human subject. In another specific embodiment, the subject is a human subject.

In certain embodiments, the RNA transcript encodes a detectable reporter protein.

In another aspect, provided herein is 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. In certain embodiments, n is adenine or guanine. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3′ splice site are non-endogenous. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3′ splice site are endogenous.

In another aspect, provided herein is an artificial gene construct comprising a DNA sequence encoding exons and one or more introns, wherein the nucleotide sequence encoding at least one intron comprises an iREMS that is downstream of the nucleotide sequence encoding a branch point and the nucleotide sequence encoding a 3′ splice site, and wherein the iREMS comprises the sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide. In certain embodiments, n is adenine or guanine. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3′ splice site are non-endogenous. In certain embodiments, one, two, or all of the IREMS, the branch point, and the 3′ splice site are endogenous.

In another aspect, provided herein is a cell 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. In certain embodiments, n is adenine or guanine. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3′ splice site are non-endogenous. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3′ splice site are endogenous.

In another aspect, provided herein is a cell comprising a DNA sequence encoding exons and one or more introns, wherein the nucleotide sequence encoding at least one intron comprises an iREMS that is downstream of the nucleotide sequence encoding a branch point and the nucleotide sequence encoding a 3′ splice site, and wherein the iREMS comprises the sequence GAgtrngn (SEQ ID NO: 4), wherein r is adenine or guanine and n is any nucleotide. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3′ splice site are non-endogenous. In certain embodiments, one, two, or all of the iREMS, the branch point, and the 3′ splice site are endogenous.

In another aspect, provided herein is a cell comprising an artificial gene construct described herein.

In another aspect, provided herein is a cell comprising a vector comprising an artificial gene construct described herein.

In another aspect, provided herein is a method for modulating the amount of an RNA transcript comprising a RNA nucleotide sequence comprising in 5′ to 3′ order: a branch point, a 3′ splice site, and an endogenous intronic recognition element for splicing modifier (iREMS), 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 RNA transcript is an RNA 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; the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In another aspect provided herein is a method for modulating the amount of an RNA transcript comprising a RNA nucleotide sequence comprising in 5′ to 3′ order: a branch point, a 3′ splice site and an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS); wherein the iREMS comprises an RNA sequence GAgurngn (SEQ ID NO: 2), wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In certain embodiments, the RNA transcript is an RNA transcript of a gene that is selected from 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, DTAPH3, 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, TVD, KDM6A, KTAA1524, 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, 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.

In another aspect, provided herein is a method for modulating the amount of an RNA transcript comprising a RNA nucleotide sequence, wherein the RNA nucleotide sequence 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 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, the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-4alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In another aspect, provided herein is a method for modulating the amount of an RNA transcript comprising a RNA nucleotide sequence, wherein the RNA nucleotide sequence 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 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, the method comprising contacting the RNA transcript with a compound of Formula (I) or a form thereof, wherein Formula (I) is:

embedded image

- wherein:
- w₁and w₅are independently C—R_aor N;
- w₂is C—R_bor N;
- w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;
- w₆is C—R₁, C—R₂, C—R_cor N;
- wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,
- when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,
- when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,
- when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,
- when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,
- wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;
- R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,
- wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;
- R₂is 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 R₆substituents and optionally, with one additional R₇substituent;
- R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;
- R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;
- R_cis hydrogen, halogen, C_1-8alkyl or deuterium;
- R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;
- R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl; wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;
- R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;
- R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,
- R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In certain embodiments, the iREMS is an endogenous iREMS, and the RNA transcript is an RNA 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, LTNC00702, LINC00886, LTNC00961, LINC01011, LTNC01118, 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 certain embodiments, the iREMS is an endogenous iREMS, and the RNA transcript is an RNA transcript of a gene that is selected from 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, C8orf38, 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, SPIDR, SPRYD7, SRGAP1, SRRM1, STAT1, STRN3, STXBP6, SUPT20H, TAF2, TASP1, TBCID15, 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.

In certain embodiments, the iREMS is a non-endogenous IREMS. In a specific embodiment, the iREMS is a non-endogenous iREMS and the RNA transcript is an RNA transcript of a gene that is selected from 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, K1AA1524, 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, 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.

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).

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, 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. 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, 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.

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).

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, 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 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, C1orfB6, 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, TQCG, TTGA11, ITGA8, TTGB8, ITIH1, TTPKA, 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-A S1, 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.

In one aspect, provided herein is a method for preventing, treating or preventing and treating a disease or disorder 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, the method comprising administering a compound described herein to a subject in need thereof, wherein the one, two, three or more RNA isoforms are produced from a pre-mRNA transcript 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 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.

In one aspect, provided herein is a method for preventing, treating or preventing and treating a disease or disorder 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, the method comprising administering a compound described herein to a subject in need thereof, wherein the one, two, three or more RNA isoforms are produced from a pre-mRNA transcript 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 intron comprises 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.

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), wherein r is adenine or guanine and n is any nucleotide.

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), wherein r is adenine or guanine and n is any nucleotide.

In various embodiments of the aspects and embodiments described herein, the iREMS comprises an RNA sequence GAguragu, wherein r is adenine or guanine.

In various embodiments of the aspects and embodiments described herein, the iREMS comprises an RNA sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide. In a specific embodiment, 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), 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), wherein r is adenine or guanine and n or N is any nucleotide.

In various embodiments of the aspects and embodiments described herein, the iREMS comprises an RNA sequence NNGAguragu (SEQ ID NO: 3862), wherein r is adenine or guanine and N is any nucleotide. In a specific embodiment, 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.

In various embodiments of the method for modulating the amount of an RNA transcript described herein, modulation of the amount of the RNA transcript is modulation of the amount of the RNA transcript in a cell or a lysate of the cell, and the method comprises contacting the compound of Formula (I) or a form thereof with the cell or cell lysate. In a specific embodiment, modulation of the amount of the RNA transcript is modulation of the amount of the RNA transcript in a cell, and the method comprises contacting the compound of Formula (I) or a form thereof with the cell. In a specific embodiment, the modulation modulates the amount and/or type of a protein translated from the RNA transcript and produced in the cell or lysate of the cell.

In various embodiments of the method for modulating the amount of an RNA transcript described herein, the RNA transcript encodes a detectable reporter protein.

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: the nucleotide sequence encoding a first 5′ splice site, the nucleotide sequence encoding a first branch point, the nucleotide sequence encoding a first 3′ splice site, an iREMS, the nucleotide sequence encoding a second branch point and the 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.

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, the nucleotide sequence encoding a first branch point and the 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.

In various embodiments of the aspects and embodiments described herein, the iREMS comprises a DNA sequence GAgtragt, wherein r is adenine or guanine.

In various embodiments of the aspects and embodiments described herein, the iREMS comprises a DNA sequence NNGAgtrngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide. In a specific embodiment, the DNA sequence NNGAgtrngn (SEQ ID NO: 1) is selected from the group consisting of ANGAgtrngn (SEQ ID NO: 29), CNGAgtrngn (SEQ ID NO: 35), GNGAgtrngn (SEQ ID NO: 41), TNGAgtrngn (SEQ ID NO: 47), NAGAgtrngn (SEQ ID NO: 30), NCGAgtrngn (SEQ ID NO: 36), NGGAgtrngn (SEQ ID NO: 42), NTGAgtrngn (SEQ ID NO: 48), AAGAgtrngn (SEQ ID NO: 31), ACGAgtrngn (SEQ ID NO: 37), AGGAgtrngn (SEQ ID NO: 43), ATGAgtrngn (SEQ ID NO: 49), CAGAgtrngn (SEQ ID NO: 32), CCGAgtrngn (SEQ ID NO: 38), CGGAgtrngn (SEQ ID NO: 44), CTGAgtrngn (SEQ ID NO: 50), GAGAgtrngn (SEQ ID NO: 33), GCGAgtrngn (SEQ ID NO: 39), GGGAgtrngn (SEQ ID NO: 45), GTGAgtrngn (SEQ ID NO: 51), TAGAgtrngn (SEQ ID NO: 34), TCGAgtrngn (SEQ ID NO: 40), TGGAgtrngn (SEQ ID NO: 46) and TTGAgtrngn (SEQ ID NO: 52), wherein r is adenine or guanine and n or N is any nucleotide.

In various embodiments of the aspects and embodiments described herein, the iREMS comprises a DNA sequence NNGAgtragt (SEQ ID NO: 3862), wherein r is adenine or guanine and N is any nucleotide. In a specific embodiment, the DNA sequence NNGAgtragt (SEQ ID NO: 3862) is selected from the group consisting of ANGAgtragt (SEQ ID NO: 437), CNGAgtragt (SEQ ID NO: 443), GNGAgtragt (SEQ ID NO: 449), TNGAgtragt (SEQ ID NO: 455), NAGAgtragt (SEQ ID NO: 438), NCGAgtragt (SEQ ID NO: 444), NGGAgtragt (SEQ ID NO: 450), NTGAgtragt (SEQ ID NO: 456), AAGAgtragt (SEQ ID NO: 439), ACGAgtragt (SEQ ID NO: 445), AGGAgtragt (SEQ ID NO: 451), ATGAgtragt (SEQ ID NO: 457), CAGAgtragt (SEQ ID NO: 440), CCGAgtragt (SEQ ID NO: 446), CGGAgtragt (SEQ ID NO: 452), CTGAgtragt (SEQ ID NO: 458), GAGAgtragt (SEQ ID NO: 441), GCGAgtragt (SEQ ID NO: 447), GGGAgtragt (SEQ ID NO: 453), GTGAgtragt (SEQ ID NO: 459), TAGAgtragt (SEQ ID NO: 442), TCGAgtragt (SEQ ID NO: 448), TGGAgtragt (SEQ ID NO: 454) and TTGAgtragt (SEQ ID NO: 460), wherein r is adenine or guanine, and N is any nucleotide.

BRIEF DESCRIPTION OF THE DRAWINGS

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.

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.

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)

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.

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.

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.

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.

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.

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.

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.

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

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

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or a form thereof, wherein:

w₁and w₅are independently C—R_aor N;

w₂is C—R_bor N;

w₃, w₄and w₇are independently C—R₁, C—R₂, C—R_aor N;

w₆is C—R₁, C—R₂, C—R_cor N;

wherein one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,

when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,

when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,

when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,

when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N; and,

wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆and w₇may optionally be N;

R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl;

wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two or three R₃substituents and optionally, with one additional R₄substituent; or,

wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with one, two, three or four R₃substituents;

R₂is 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 R₆substituents and optionally, with one additional R₇substituent;

R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl or deuterium;

R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy or deuterium;

R_cis hydrogen, halogen, C_1-8alkyl or deuterium;

R₃is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl]₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino;

R₄is C_3-14cycloalkyl, C_3-14cycloalkyl-C_1-8alkyl, C_3-14cycloalkyl-amino, aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl, aryl-sulfonyloxy-C_1-8alkyl, heterocyclyl or heterocyclyl-C_1-8alkyl;

wherein, each instance of C_3-14cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R₅substituents;

R₅is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio;

R₆is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, C_2-8alkenyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; and,

R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

In one embodiment of the use of a compound of Formula (I), w₁is C—R_a.

In another embodiment of the use of a compound of Formula (I), w₁is N.

In one embodiment of the use of a compound of Formula (I), w₂is C—R_b.

In another embodiment of the use of a compound of Formula (I), w₂is N.

In one embodiment of the use of a compound of Formula (I), w₃is C—R_a.

In another embodiment of the use of a compound of Formula (I), w₃is N.

In one embodiment of the use of a compound of Formula (I), w₄is C—R_a.

In another embodiment of the use of a compound of Formula (I), w₄is N.

In one embodiment of the use of a compound of Formula (I), w₅is C—R_a.

In another embodiment of the use of a compound of Formula (I), w₅is N.

In one embodiment of the use of a compound of Formula (I), w₆is C—R_c.

In another embodiment of the use of a compound of Formula (I), w₆is N.

In one embodiment of the use of a compound of Formula (I), w₇is C—R_a.

In another embodiment of the use of a compound of Formula (I), w₇is N.

In one embodiment of the use of a compound of Formula (I), w₃is C—R₁and w₆is C—R₂.

In another embodiment of the use of a compound of Formula (I), w₃is C—R₂and w₆is C—R₁.

In one embodiment of the use of a compound of Formula (I), w₄is C—R₁and w₇is C—R₂.

In another embodiment of the use of a compound of Formula (I), w₄is C—R₂and w₇is C—R₁.

In one embodiment of the use of a compound of Formula (I), w₃is C—R₁, w₆is C—R₂and w₁, w₄, w₅and w₇are independently C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of a compound of Formula (I), w₃is C—R₂, w₆is C—R₁and w₁, w₄, w₅and w₇are independently C—R_aor N and w₂is C—R_bor N.

In one embodiment of the use of a compound of Formula (I), w₄is C—R₁, w₇is C—R₂, w₁, w₃and w₅are independently C—R_aor N, w₂is C—R_bor N and w₆is C—R_cor N.

In another embodiment of the use of a compound of Formula (I), w₄is C—R₂, w₇is C—R₁, w₁, w₃and w₅are independently C—R_aor N, w₂is C—R_bor N and w₆is C—R_cor N.

In one embodiment of the use of a compound of Formula (I), w₁and w₂are N.

In one embodiment of the use of a compound of Formula (I), w₁and w₃are N.

In one embodiment of the use of a compound of Formula (I), w₁and w₄are N.

In one embodiment of the use of a compound of Formula (I), w₁and w₅are N.

In one embodiment of the use of a compound of Formula (I), w₁and w₆are N.

In one embodiment of the use of a compound of Formula (I), w₁and w₇are N.

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

R₁is C_1-8alkyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl; wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R₃and R₄substituents.

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

R₁is amino, (C_1-8alkyl)₂-amino, C_1-8alkoxy-C_1-8alkyl-amino, (C_1-8alkoxy-C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, amino-C_1-8alkyl-amino, (amino-C_1-8alkyl)₂-amino, (amino-C_1-8alkyl)(C_1-8alkyl)amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, [(C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, amino-C_1-8alkoxy, C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkyl)₂-amino-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (C_1-8alkoxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, amino-C_2-8alkenyl, C_1-8alkyl-amino-C_2-8alkenyl, (C_1-8alkyl)₂-amino-C_2-8alkenyl, amino-C_2-8alkynyl, C_1-8alkyl-amino-C_2-8alkynyl, (C_1-8alkyl)₂-amino-C_2-8alkynyl, halo-C_1-8alkyl-amino, (halo-C_1-8alkyl)₂-amino, (halo-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino, hydroxy-C_1-8alkyl-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, hydroxy-C_1-8alkyl-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkoxy, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkoxy, hydroxy-C_1-8alkyl-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)₂-amino, (hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl-amino-C_1-8alkyl)(C_1-8alkyl)amino, (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl-amino, [(hydroxy-C_1-8alkyl)₂-amino-C_1-8alkyl](C_1-8alkyl)amino, [(hydroxy-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl](C_1-8alkyl)amino, heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl; wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R₃and R₄substituents.

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

R₁is heterocyclyl, heterocyclyl-C_1-8alkyl, heterocyclyl-C_1-8alkoxy, heterocyclyl-amino, (heterocyclyl)(C_1-8alkyl)amino, heterocyclyl-amino-C_1-8alkyl, heterocyclyl-C_1-8alkyl-amino, (heterocyclyl-C_1-8alkyl)₂-amino, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino, heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)₂-amino-C_1-8alkyl, (heterocyclyl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C_3-14cycloalkyl, aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl, (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl, heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl; wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R₃and R₄substituents.

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

In another embodiment of the use of a compound of Formula (I), R₁is heterocyclyl optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is C_3-14cycloalkyl optionally substituted with R₃and R₄substituents.

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

R₁is aryl-C_1-8alkyl-amino, (aryl-C_1-8alkyl)₂-amino, (aryl-C_1-8alkyl)(C_1-8alkyl)amino, aryl-C_1-8alkyl-amino-C_1-8alkyl, (aryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (aryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl; wherein, each instance of aryl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is aryl-C_1-8alkyl-amino optionally substituted with R₃and R₄substituents.

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

R₁is heteroaryl, heteroaryl-C_1-8alkyl, heteroaryl-C_1-8alkoxy, heteroaryl-amino, heteroaryl-C_1-8alkyl-amino, (heteroaryl-C_1-8alkyl)₂-amino, (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, (heteroaryl-C_1-8alkyl)₂-amino-C_1-8alkyl or (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino-C_1-8alkyl; wherein, each instance of heterocyclyl, C_3-14cycloalkyl, aryl and heteroaryl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heteroaryl optionally substituted with R₃and R₄substituents.

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

R₁is 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 R₃and R₄substituents.

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

R₁is 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 R₃and R₄substituents.

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

R₁is 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.

In one embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-C_1-8alkyl, wherein heterocyclyl is selected from morpholinyl, piperidinyl, piperazinyl, imidazolyl or pyrrolidinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-C_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 R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-C_1-8alkoxy, wherein heterocyclyl is selected from pyrrolidinyl, piperidinyl or morpholinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-C_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 R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is 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 R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is 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 R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is (heterocyclyl)(C_1-8alkyl)amino, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is (heterocyclyl)(C_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 R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-amino-C_1-8alkyl, wherein heterocyclyl is selected from tetrahydrofuranyl; and, wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-amino-C_1-8alkyl, selected from 3-(tetrahydrofuran-3-yl-amino)propyl; wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-C_1-8alkyl-amino-C_1-8alkyl, wherein heterocyclyl is selected from tetrahydrofuranyl, thienyl or pyridinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-C_1-8alkyl-amino-C_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 R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-oxy, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-oxy selected from pyrrolidin-3-yl-oxy or piperidin-4-yl-oxy; wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-carbonyl, wherein heterocyclyl is selected from piperazinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-carbonyl selected from piperazin-1-yl-carbonyl; wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-carbonyl-oxy, wherein heterocyclyl is selected from piperazinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heterocyclyl-carbonyl-oxy selected from piperazin-1-yl-carbonyl-oxy; wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is C_3-14cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl or cycloheptyl; wherein, each instance of C_3-14cycloalkyl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is C_3-8cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl or cycloheptyl; wherein, each instance of C_3-8cycloalkyl is optionally substituted with R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is aryl-C_1-8alkyl-amino-C_1-8alkyl, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is aryl-C_1-8alkyl-amino-C_1-8alkyl selected from 3-(benzylamino)propyl; wherein, each instance of aryl is optionally substituted with R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is heteroaryl, wherein heteroaryl is selected from pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heteroaryl selected from pyridin-4-yl; wherein, each instance of heteroaryl is optionally substituted with R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is heteroaryl-C_1-8alkyl, wherein heteroaryl is selected from 1H-imidazolyl; and, wherein, each instance of heteroaryl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heteroaryl-C_1-8alkyl selected from 1H-imidazol-1-yl-methyl; wherein, each instance of heteroaryl is optionally substituted with R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino, wherein heteroaryl is selected from pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is (heteroaryl-C_1-8alkyl)(C_1-8alkyl)amino selected from (pyridin-3-ylmethylxmethyl)amino; wherein, each instance of heteroaryl is optionally substituted with R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁is heteroaryl-C_1-8alkyl-amino-C_1-8alkyl, wherein heteroaryl is selected from thienyl or pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted with R₃and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁is heteroaryl-C_1-8alkyl-amino-C_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 R₃and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₃is selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkyl-carbonyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, amino-C_1-8alkyl-amino, C_1-8alkyl-amino-C_1-8alkyl-amino, (C_1-8alkyl)₂-amino-C_1-8alkyl-amino, C_1-8alkoxy-C_1-8alkyl-amino, C_1-8alkyl-carbonyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino.

In another embodiment of the use of a compound of Formula (I), R₃is selected from cyano, halogen, hydroxy, oxo, C_1-8alkyl, halo-C_1-8alkyl, C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, C_1-8alkoxy-carbonyl, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl, (C_1-8alkyl)₂-amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl-amino, C_1-8alkoxy-C_1-8alkyl-amino, C_1-8alkoxy-carbonyl-amino, hydroxy-C_1-8alkyl, hydroxy-C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl-amino, (hydroxy-C_1-8alkyl)₂-amino or (hydroxy-C_1-8alkyl)(C_1-8alkyl)amino.

In one embodiment of the use of a compound of Formula (I), R₃is C_1-8alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

In another embodiment of the use of a compound of Formula (I), R₃is C_1-8alkyl selected from ethyl, propyl, isopropyl or tert-butyl.

In one embodiment of the use of a compound of Formula (I), R₃is halo-C_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.

In another embodiment of the use of a compound of Formula (I), R₃is halo-C_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.

In one embodiment of the use of a compound of Formula (I), R₃is hydroxy-C_1-8alkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

In another embodiment of the use of a compound of Formula (I), R₃is hydroxy-C_1-8alkyl selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

In one embodiment of the use of compound of Formula (I), R₃is C_1-8alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

In one embodiment of the use of a compound of Formula (I), R₃is halo-C_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.

In one embodiment of the use of a compound of Formula (I), R₃is C_1-8alkoxy-carbonyl-amino selected from methoxy-carbonyl-amino, ethoxy-carbonyl-amino, propoxy-carbonyl-amino, isopropoxy-carbonyl-amino, tert-butoxy-carbonyl-amino.

In one embodiment of the use of a compound of Formula (I), R_ais, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl.

In one embodiment of the use of a compound of Formula (I), R_ais, in each instance, optionally and independently deuterium.

In one embodiment of the use of a compound of Formula (I), R_bis hydrogen, halogen, C_1-8alkyl, C_1-8alkoxy.

In one embodiment of the use of a compound of Formula (I), R_cis, in each instance, independently selected from hydrogen, halogen, C_1-8alkyl.

In one embodiment of the use of a compound of Formula (I), R_cis, in each instance, optionally and independently deuterium.

In one embodiment of the use of a compound of Formula (I), R_bis deuterium.

In one embodiment of the use of a compound of Formula (I), R₄is C_3-14cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein, each instance of C_3-14cycloalkyl is optionally substituted with R₅substituents.

In another embodiment of the use of a compound of Formula (I), R₄is C-s-cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein, each instance of C_3-8cycloalkyl is optionally substituted with R₅substituents.

In one embodiment of the use of a compound of Formula (I), R₄is C_3-14cycloalkyl-C_1-8alkyl, wherein C_3-14cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C_3-14cycloalkyl is optionally substituted with R₅substituents.

In another embodiment of the use of a compound of Formula (I), R₄is C_3-8cycloalkyl-C_1-8alkyl, wherein C_3-8cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C_3-8cycloalkyl is optionally substituted with R₅substituents.

In one embodiment of the use of a compound of Formula (I), R₄is C_3-14cycloalkyl-amino, wherein C_3-14cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C_3-14cycloalkyl is optionally substituted with R₅substituents.

In another embodiment of the use of a compound of Formula (I), R₄is C_3-8cycloalkyl-amino, wherein C_3-8cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C_3-8cycloalkyl is optionally substituted with R₅substituents.

In one embodiment of the use of a compound of Formula (I), R₄is aryl-C_1-8alkyl, aryl-C_1-8alkoxy-carbonyl or aryl-sulfonyloxy-C_1-8alkyl, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R₅substituents.

In another embodiment of the use of a compound of Formula (I), R₄is aryl-C_1-8alkyl or aryl-C_1-8alkoxy-carbonyl, wherein each instance of aryl is optionally substituted with R₅substituents.

In one embodiment of the use of a compound of Formula (I), R₄is heterocyclyl selected from oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxanyl or morpholinyl, wherein each instance of heterocyclyl is optionally substituted with R₅substituents.

In another embodiment of the use of a compound of Formula (I), R₄is 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 R₅substituents.

In one embodiment of the use of a compound of Formula (I), R₄is heterocyclyl-C_1-8alkyl, wherein each instance of heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R₅substituents.

In another embodiment of the use of a compound of Formula (I), R₄is heterocyclyl-C_1-8alkyl selected from pyrrolidin-1-yl-C_1-8alkyl or piperidin-1-yl-C_1-8alkyl, wherein each instance of heterocyclyl is optionally substituted with R₅substituents.

In one embodiment of the use of a compound of Formula (I), R₅is selected from halogen, hydroxy, cyano, nitro, halo-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, amino, C_1-8alkyl-amino, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; wherein, halogen and halo is selected from fluoro, chloro, bromo or iodo.

In one embodiment of the use of a compound of Formula (I), R₅is hydroxy.

In one embodiment of the use of a compound of Formula (I), R₅is C_1-8alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.

In another embodiment of the use of a compound of Formula (I), R₅is C_1-8alkyl selected from ethyl, propyl, isopropyl or tert-butyl.

In one embodiment of the use of a compound of Formula (I), R₁is halo-C_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.

In one embodiment of the use of a compound of Formula (I), R₅is C_1-8alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

In one embodiment of the use of a compound of Formula (I), R₅is halo-C_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.

In one embodiment of the use of a compound of Formula (I), R₂is aryl selected from phenyl optionally substituted with R₆and R₇substituents.

In one embodiment of the use of a compound of Formula (I), R₂is aryl-amino, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R₆and R₇substituents.

In another embodiment of the use of a compound of Formula (I), R₂is aryl-amino selected from phenyl-amino; wherein, each instance of aryl is optionally substituted with R₆and R₇substituents.

In one embodiment of the use of a compound of Formula (I), R₂is aryl-amino-carbonyl, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R₆and R₇substituents.

In another embodiment of the use of a compound of Formula (I), R₂is aryl-amino-carbonyl selected from phenyl-amino-carbonyl; wherein, each instance of aryl is optionally substituted with R₆and R₇substituents.

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

R₂is 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 R₆and R₇substituents.

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

R₂is 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 R₆and R₇substituents.

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

R₂is 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 R₆and R₇substituents.

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

R₂is 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 R₆and R₇substituents.

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

R₂is 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.

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

R₂is 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 R₆and R₇substituents.

In one embodiment of the use of a compound of Formula (I), R₂is heteroaryl-amino, wherein heteroaryl is selected from pyridinyl or pyrimidinyl; and, wherein, each instance of heteroaryl is optionally substituted with R₆and R₇substituents.

In another embodiment of the use of a compound of Formula (I), R₂is 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 R₆and R₇substituents.

In one embodiment of the use of a compound of Formula (I), R₆is selected from halogen, hydroxy, cyano, nitro, C_1-8alkyl, halo-C_1-8alkyl, hydroxy-C_1-8alkyl, C_1-8alkoxy, halo-C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl, (C_1-8alkyl)₂-amino or C_1-8alkyl-thio; wherein, halogen and halo is selected from fluoro, chloro, bromo or iodo.

In one embodiment of the use of a compound of Formula (I), R₆is C_1-8alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

In another embodiment of the use of a compound of Formula (I), R₆is C_1-8alkyl selected from ethyl, propyl, isopropyl or tert-butyl.

In one embodiment of the use of a compound of Formula (I), R₆is C_2-8alkenyl selected from ethenyl, allyl or buta-1,3-dienyl.

In another embodiment of the use of a compound of Formula (I), R₆is C_2-8alkenyl selected from ethenyl or allyl.

In one embodiment of the use of a compound of Formula (I), R₆is halo-C_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.

In one embodiment of the use of a compound of Formula (I), R₆is hydroxy-C_1-8alkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

In another embodiment of the use of a compound of Formula (I), R₆is hydroxy-C_1-8alkyl selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

In one embodiment of the use of a compound of Formula (I), R₆is C_1-8alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

In one embodiment of the use of a compound of Formula (I), R₆is halo-C_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.

In one embodiment of the use of a compound of Formula (I), R₇is C_3-14cycloalkyl, C_3-14cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl; wherein C_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.

In another embodiment of the use of a compound of Formula (I), R₇is C_3-14cycloalkyl or C_3-14cycloalkyl-oxy, wherein each instance of C_3-14cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In another embodiment of the use of a compound of Formula (I), R₇is C_3-8cycloalkyl or C_3-8cycloalkyl-oxy, wherein each instance of C_3-8cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In one embodiment of the use of a compound of Formula (I), R₇is aryl selected from phenyl.

In one embodiment of the use of a compound of Formula (I), R₇is heterocyclyl selected from oxetanyl, pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl.

In another embodiment of the use of a compound of Formula (I), R₇is heterocyclyl selected from oxetan-3-yl, pyrrolidin-1-yl or 1,2,3,6-tetrahydropyridin-4-yl.

In one embodiment of the use of a compound of Formula (I), R₇is heteroaryl selected from thienyl or pyridinyl.

In another embodiment of the use of a compound of Formula (I), R₇is heteroaryl selected from pyridinyl.

In one embodiment of the use of a compound of Formula (I), R₇is heteroaryl selected from thien-2-yl or pyridin-2-yl.

In another embodiment of the use of a compound of Formula (I), R₇is heteroaryl selected from pyridin-2-yl.

In one embodiment of the use of a compound of Formula (I), R_cis hydrogen or C_1-8alkyl.

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

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.

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

R₂is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;

wherein, aryl is phenyl;

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

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 R₆and R₇substituents.

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

R₂is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;

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;

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 R₆and R₇substituents.

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

R₂is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino, wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with R₆and R₇substituents.

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

R₁is heterocyclyl optionally substituted with R₃and R₄substituents; and

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

R₁is C_3-14cycloalkyl optionally substituted with R₃and R₄substituents; and

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

R₁is aryl-C_1-8alkyl-amino optionally substituted with R₃and R₄substituents; and

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

R₁is heteroaryl optionally substituted with R₃and R₄substituents; and

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):

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or a form thereof.

In an embodiment of the use of the compound of Formula (I), w₃is C—R₁, w₆is C—R₂, w₁, w₄, w₅and w₇are independently C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (I), w₃is C—R₂, w₆is C—R₁, w₁, w₄, w₅and w₇are independently C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (I), w₄is C—R₁, w₇is C—R₂, w₁, w₃and w₅are independently C—R_aor N, w₂is C—R_bor N and w₆is C—R_cor N.

In another embodiment of the use of the compound of Formula (I), w₄is C—R₂, w₇is C—R₁, w₁, w₃and w₅are independently C—R_aor N, w₂is C—R_bor N and w₆is C—R_cor N.

In an embodiment of the use of the compound of Formula (II), w₃is C—R₁, w₆is C—R₂, w₄, w₅and w₇are independently C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (II), w₃is C—R₂, w₆is C—R₁, w₄, w₅and w₇are independently C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (II), w₄is C—R₁, w₇is C—R₂, w₃and w₅are independently C—R_aor N, w₂is C—R_bor N and w₆is C—R_cor N.

In another embodiment of the use of the compound of Formula (II), w₄is C—R₂, w₇is C—R₁, w₃and w₅are independently C—R_aor N, w₂is C—R_bor N and w₆is C—R_cor N.

In an embodiment of the use of the compound of Formula (III), w₃is C—R₁, w₆is C—R₂and w₁, w₄, w₅and w₇are independently C—R_aor N.

In another embodiment of the use of the compound of Formula (III), w₃is C—R₂, w₆is C—R₁and w₁, w₄, w₅and w₇are independently C—R_aor N.

In another embodiment of the use of the compound of Formula (III), w₄is C—R₁, w₇is C—R₂, w₁, w₃and w₅are independently C—R_aor N and w₆is C—R_cor N.

In another embodiment of the use of the compound of Formula (III), w₄is C—R₂, w₇is C—R₁, w₁, w₃and w₅are independently C—R_aor N and w₆is C—R_cor N.

In an embodiment of the use of the compound of Formula (IV), w₄is C—R₁, w₇is C—R₂, w₁and w₅are independently C—R_aor N, w₂is C—R_bor N and w₆is C—R_cor N.

In another embodiment of the use of the compound of Formula (IV), w₄is C—R₂, w₇is C—R₁, w₁and w₅are independently C—R_aor N, w₂is C—R_bor N and w₆is C—R_cor N.

In an embodiment of the use of the compound of Formula (V), w₃is C—R₁, w₆is C—R₂, w₁, w₅and w₇are independently C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (V), w₃is C—R₂, w₆is C—R₁, w₁, w₅and w₇are independently C—R_aor N and w₂is C—R_bor N.

In an embodiment of the use of the compound of Formula (VI), w₃is C—R₁, w₆is C—R₂, w₁, w₄and w₇are independently C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (VI), w₃is C—R₂, w₆is C—R₁, w₁, w₄and w₇are independently C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (VI), w₄is C—R₁, w₇is C—R₂, w₁and w₃are independently C—R_aor N, w₂is C—R_bor N and w₆is C—R_cor N.

In another embodiment of the use of the compound of Formula (VI), w₄is C—R₂, w₇is C—R₁, w₁and w₃are independently C—R_aor N, w₂is C—R_bor N and w₆is C—R_cor N.

In another embodiment of the use of the compound of Formula (VII), w₄is C—R₁, w₇is C—R₂, w₁, w₃and w₅are C—R_aor N and w₂is C—R₁or N.

In another embodiment of the use of the compound of Formula (VII), w₄is C—R₂, w₇is C—R₁, w₁, w₃and w₅are C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (VIII), w₃is C—R₁, w₆is C—R₂, w₁, w₄and w₅are C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (VIII), w₃is C—R₂, w₆is C—R₁, w₁, w₄and w₅are C—R_aor N and w₂is C—R_bor N.

In an embodiment of the use of the compound of Formula (IX), w₃is C—R₁, w₆is C—R₂, w₄and w₇are independently C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (IX), w₃is C—R₂, w₆is C—R₁, w₄and w₇are independently C—R_aor N and w₂is C—R_bor N.

In another embodiment of the use of the compound of Formula (IX), w₄is C—R₁, w₇is C—R₂, w₂is C—R_bor N, w₃is C—R_aor N and w₆is C—R_cor N.

In another embodiment of the use of the compound of Formula (IX), w₄is C—R₂, w₇is C—R₁, w₂is C—R_bor N, w₃is C—R_aor N and w₆is C—R_cor N.

In an embodiment of the use of the compound of Formula (X), w₃is C—R₁, w₆is C—R₂, w₂is C—R_bor N and w₅and w₇are independently C—R_aor N.

In another embodiment of the use of the compound of Formula (X), w₃is C—R₂, w₆is C—R₁, w₂is C—R₁or N and w₅and w₇are independently C—R_aor N.

In an embodiment of the use of the compound of Formula (XI), w₄is C—R₁, w₇is C—R₂, w₂is C—R_bor N, w₅is C—R_aor N and w₆is C—R_cor N.

In another embodiment of the use of the compound of Formula (XI), w₄is C—R₂, w₇is C—R₁, w₂is C—R_bor N, w₅is C—R_aor N and w₆is C—R_cor N.

In an embodiment of the use of the compound of Formula (XII), w₃is C—R₁, w₆is C—R₂and w₄, w₅and w₇are independently C—R_aor N.

In another embodiment of the use of the compound of Formula (XII), w₃is C—R₂, w₆is C—R₁and w₄, w₅and w₇are independently C—R_aor N.

In another embodiment of the use of the compound of Formula (XII), w₄is C—R₁, w₇is C—R₂, w₃and w₅are independently C—R_cor N and w₆is C—R_cor N.

In another embodiment of the use of the compound of Formula (XII), w₄is C—R₂, w₇is C—R₁, w₃and w₅are independently C—R_cor N and w₆is C—R_cor N.

In an embodiment of the use of the compound of Formula (XIII), w₃is C—R₁, w₆is C—R₂, w₂is C—R_bor N and w₄and w₅are independently C—R_aor N.

In another embodiment of the use of the compound of Formula (XIII), w₃is C—R₂, w₆is C—R₁, w₂is C—R_bor N and w₄and w₅are independently C—R_aor N.

In an embodiment of the use of the compound of Formula (XIV), w₄is C—R₁, w₇is C—R₂, w₂is C—R_bor N and w₃and w₅are independently C—R_aor N.

In another embodiment of the use of the compound of Formula (XIV), w₄is C—R₂, w₇is C—R₁, w₂is C—R_bor N and w₃and w₅are independently C—R_aor N.

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):

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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

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or a form thereof.

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:

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or a form thereof.

In an embodiment of the use of the compound of Formula (Ia), one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,

when w₃is C—R₁, then w₆is C—R₂and w₄and w₇are independently C—R_aor N; or,

when w₃is C—R₂, then w₆is C—R₁and w₄and w₇are independently C—R_aor N; or,

when w₄is C—R₁, then w₇is C—R₂and w₃is C—R_aor N and w₆is C—R_cor N; or,

when w₄is C—R₂, then w₇is C—R₁and w₃is C—R_aor N and w₆is C—R_cor N.

In an embodiment of the use of the compound of Formula (IIa), one of w₃, w₄, w₆and w₇is C—R₁and one other of w₃, w₄, w₆and w₇is C—R₂, provided that,