Compounds and methods for modulating splicing

Abstract

To provide compounds and methods for regulating splicing. [Solution] This disclosure features, in particular, compounds and related compositions that regulate nucleic acid splicing, such as premRNA splicing, and methods of using the same.

Description

[Technical Field]

[0001] Claim of priority This application claims priority to U.S. Patent Application No. 62 / 983,541 filed on 28 February 2020; U.S. Patent Application No. 63 / 007,333 filed on 8 April 2020; U.S. Patent Application No. 63 / 040,484 filed on 17 June 2020; U.S. Patent Application No. 63 / 072,790 filed on 31 August 2020; and U.S. Patent Application No. 63 / 126,492 filed on 16 December 2020. The disclosures of each of the aforementioned applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Alternative splicing is a major cause of protein diversity in higher eukaryotes and is frequently regulated in tissue-specific or developmental-stage-specific ways. Disease-related alternative splicing patterns in premRNA are often mapped to changes in splice site signaling or sequence motifs and regulatory splicing factors (Faustino and Cooper (2003), Genes Dev 17(4):419-37). Current therapies that modulate RNA expression include oligonucleotide targeting and gene therapy, but each of these modalities presents its own unique challenges, as currently demonstrated. Therefore, new technologies that modulate RNA expression, including the development of small molecule compounds that target splicing, are needed. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Faustino and Cooper(2003),Genes Dev 17(4):419-37 [Overview of the project] [Means for solving the problem]

[0004] This disclosure features, in particular, compounds and related compositions that regulate nucleic acid splicing, such as premRNA splicing, and methods of using them. In one embodiment, the compounds described herein are compounds of formula (I) (e.g., formula (Ia), (Ib), (Ic), (Id), (Ie), or (If)) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof. This disclosure further provides methods for using the compounds of the present invention (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers) and compositions thereof, for example, against a target, wherein in embodiments, the compounds bind to or form complexes with nucleic acids (e.g., premRNA or small nuclear ribonucleoprotein (snRNP) or nucleic acid components of spliceosomes), proteins (e.g., snRNP or protein components of spliceosomes, e.g., members of the splicing mechanism, e.g., one or more of U1, U2, U4, U5, U6, U11, U12, U4atac, U6atac snRNP) or combinations thereof. In another embodiment, the compounds described herein can be used to modify the composition or structure of nucleic acids (e.g., premRNA or mRNA (e.g., premRNA and mRNA derived from premRNA)) by increasing or decreasing splicing, for example, at splice sites. In some embodiments, increasing or decreasing splicing regulates the level of gene products (e.g., RNA or protein) produced. In another embodiment, the compounds described herein are used to treat diseases, disorders, or conditions, such as splices. For example, they may be used for the prevention and / or treatment of diseases, disorders, or conditions related to alternative splicing. In some embodiments, the compounds described herein (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers) and compositions thereof are used for the prevention and / or treatment of proliferative disorders, disorders, or conditions in a subject (e.g., diseases, disorders, or conditions characterized by undesirable cell proliferation, such as cancer or benign neoplasms). In some embodiments, the compounds described herein (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers) and compositions thereof are used for the prevention and / or treatment of nonproliferative disorders, disorders, or conditions. In some embodiments, the compounds described herein (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers) and compositions thereof are used for the prevention and / or treatment of neurological disorders or impairments, autoimmune disorders or impairments, immunodeficiency disorders or impairments, lysosomal storage disorders or impairments, cardiovascular disorders or impairments, metabolic disorders or impairments, respiratory disorders or impairments, renal disorders or impairments, or infections in a subject.

[0005] In another embodiment, this disclosure is expressed by formula (Ia): [ka] The compound is characterized by a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of them is one or more R 1 It is optionally substituted by; W, X, Y, and Z are each independently of C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c) or O, wherein the bonds within the ring containing W, X, Y, and Z may be single bonds or double bonds when the valence allows; L 2 is absent or is C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, wherein each alkylene and heteroalkylene is optionally substituted with one or more R 5 ; each R 1 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D , wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 6 ; or two R 1 groups together with the atoms to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 6 ; each R 2 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR AAnd; R 3a and R 3b These are, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and ha Ro, Cyano, -OR A , -NR B R C , -C(O)R D , or C(O)OR D is; or R 3a and R 3b Each of them, together with the carbon atom to which they are bonded, forms an oxo group; R 3c is hydrogen or C1-C6 alkyl; each R 4 R is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 5 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and; each R 6 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D ,-NO2,-C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally one or more R 11 It may also be replaced with; each R AThese are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D , or -S(O) x R D And; R B and R C Each of these can independently be hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 7 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E R is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; each R 7 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 m is hydrogen or a C1-C6 alkyl group; m is 0, 1, or 2; x is 0, 1, or 2.

[0006] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) (e.g., a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition described herein comprises an effective amount (e.g., a therapeutically effective amount) of a compound of formula (I) (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0007] In another aspect, the Disclosure provides a method for modulating splicing, for example, the splicing of nucleic acids (e.g., DNA or RNA, e.g., premRNA), using a compound of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the Disclosure provides a composition for use in modulating splicing, for example, the splicing of nucleic acids (e.g., DNA or RNA, e.g., premRNA), using a compound of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. Modification of splicing may include influencing any step involved in splicing, and may include events upstream or downstream of the splicing phenomenon. For example, in some embodiments, the compound of formula (I) is a target, e.g., a target nucleic acid (e.g., DNA or RNA, e.g., a precursor). The compounds bind to RNA (e.g., premRNA), target proteins, or combinations thereof (e.g., snRNP and premRNA). The targets may include splice sites in premRNA or components of the splicing mechanism such as U1snRNP. In some embodiments, the compounds of formula (I) modify target nucleic acids (e.g., DNA or RNA, e.g., precursor RNA, e.g., premRNA), target proteins, or combinations thereof. In some embodiments, the compounds of formula (I) increase or decrease splicing at splice sites on target nucleic acids (e.g., RNA, e.g., precursor RNA, e.g., premRNA) by about 0.5% or more (e.g., about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, or more) compared to a reference (e.g., in the absence of the compound of formula (I), e.g., healthy or diseased cells or tissue). In some embodiments, the presence of a compound of formula (I) results in an increase or decrease of about 0.5% or more (e.g., about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, or more) in the transcription of a target nucleic acid (e.g., RNA) compared to a reference (e.g., the absence of a compound of formula (I), e.g., healthy or diseased cells or tissues).

[0008] In other embodiments, the Disclosure provides methods for preventing and / or treating a disease, disorder, or condition of interest by administering a compound of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or related compositions. In some embodiments, the disease or disorder involves undesirable or abnormal splicing. In some embodiments, the disease or disorder is a proliferative disease, disorder, or condition. Exemplary proliferative disorders include cancer, benign neoplasms, or angiogenesis. In other embodiments, the Disclosure provides methods for treating and / or preventing non-proliferative diseases, disorders, or conditions. In further embodiments, the disclosure provides methods for treating and / or preventing neurological diseases or disorders, autoimmune diseases or disorders, immunodeficiency diseases or disorders, lysosomal storage diseases or disorders, cardiovascular diseases or disorders, metabolic diseases or disorders, respiratory diseases or disorders, renal diseases or disorders, or infectious diseases.

[0009] In another aspect, the Disclosure provides a method for downregulating the expression (e.g., the level or rate of production) of a target protein in a biological sample or subject using a compound of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the Disclosure provides a method for upregulating the expression (e.g., the level or rate of production) of a target protein in a biological sample or subject using a compound of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the Disclosure provides a method for modifying isoforms of target proteins in a biological sample or subject with a compound of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. Another aspect of the Disclosure relates to a method for inhibiting the activity of target proteins in a biological sample or subject. In some embodiments, administration of a compound of formula (I) to a biological sample, cell, or subject includes inhibition of cell growth or induction of cell death.

[0010] In another embodiment, the Disclosure provides compositions for use in the prevention and / or treatment of a disease, disorder or condition of interest by administering a compound of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or related compositions. In some embodiments, the disease or disorder involves undesirable or abnormal splicing. In some embodiments, the disease or disorder involves proliferative disease. This refers to a disease, disorder, or condition. Exemplary proliferative disorders include cancer, benign neoplasms, or angiogenesis. In other embodiments, the Disclosure provides methods for treating and / or preventing nonproliferative diseases, disorders, or conditions. In yet other embodiments, the Disclosure provides methods for treating and / or preventing neurological diseases or disorders, autoimmune diseases or disorders, immunodeficiency diseases or disorders, lysosomal storage diseases or disorders, cardiovascular diseases or disorders, metabolic diseases or disorders, respiratory diseases or disorders, renal diseases or disorders, or infections.

[0011] In another aspect, the Disclosure provides compositions for use in downregulating the expression (e.g., the level or rate of production) of a target protein in a biological sample or subject, using compounds of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof. In another aspect, the Disclosure provides compositions for use in upregulating the expression (e.g., the level or rate of production) of a target protein in a biological sample or subject, using compounds of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof. In another aspect, the Disclosure provides compositions for use in modifying isoforms of target proteins in biological samples or subjects using compounds of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof. Another aspect of the Disclosure relates to compositions for use in inhibiting the activity of target proteins in biological samples or subjects. In some embodiments, administration of a compound of formula (I) to a biological sample, cell, or subject includes inhibition of cell growth or induction of cell death.

[0012] In another embodiment, the present disclosure features a kit comprising a container having a compound of formula (I) (e.g., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or pharmaceutical composition thereof. In certain embodiments, the kit described herein further comprises instructions for administering a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or pharmaceutical composition thereof.

[0013] In all aspects of this disclosure, in some embodiments, the compounds, target nucleic acids (e.g., DNA, RNA, e.g., premRNA), or target proteins described herein are referred to in U.S. Patent No. 8,729,263, U.S. Patent Application Publication No. 2015 / 0005289, International Publication No. 2014 / 028459, International Publication No. 2016 / 128343, International Publication No. 2016 / 196386, and International Publication No. 2017 / 100726. , compounds other than those described in one of the International Publications No. 2018 / 232039, International Publication No. 2018 / 098446, International Publication No. 2019 / 028440, International Publication No. 2019 / 060917 and International Publication No. 2019 / 199972, target nucleic acids (e.g., DNA, RNA, e.g., premRNA) or target proteins, target nucleic acids (e.g., DNA, RNA, e.g., premRNA) or target proteins. In some embodiments, the compounds, target nucleic acids (e.g., DNA, RNA, e.g., premRNA), or target proteins described herein are as specified in U.S. Patent No. 8,729,263, U.S. Patent Application Publication No. 2015 / 0005289, International Publication No. 2014 / 028459, International Publication No. 2016 / 128343, International Publication No. 2016 / 196386, International Publication No. 2017 / 100726, International Publication No. 2018 / 232039, International Publication No. 2018 / 098446, International Publication No. 2019 / 028440, International Publication No. 2019 / 060917, and International Publication No. 2019 / 199972. The compounds, target nucleic acids (e.g., DNA, RNA, e.g., premRNA), or target proteins described herein are incorporated herein by reference in their entirety.

[0014] Details of one or more embodiments of the present invention are described herein. Other features, purposes, and advantages of the present invention will become apparent from the detailed description, examples, and claims. [Modes for carrying out the invention]

[0015] Selected chemical definitions The definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th Ed., identified according to the inside of the cover, specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry as well as specific functional parts and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0016] The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valence known in the field of chemistry.

[0017] When a range of values ​​is listed, it is intended to include each value and subrange within that range. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0018] The following terms are intended to have the meanings set forth below and will be helpful in understanding the description and intended scope of this invention.

[0019] As used herein, "alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 24 carbon atoms ("C1-C24"). 24 This refers to an alkyl radical ("C1-C12"). In some embodiments, an alkyl group has 1 to 12 carbon atoms. 12 ("Alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each example of an alkyl group can be independently and optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C1-C 10 The alkyl group is an alkyl group (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C1-C6 alkyl group.

[0020] As used herein, "alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 24 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C"). 2に ~C 24 This refers to an alkenyl group. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C2-C10"). 10 "Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2-C6 alkenyl groups include the aforementioned C 2~4Alkenyl groups and pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. are included. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrieneyl (C8), etc. Each example of the alkenyl group can be independently optionally substituted, i.e., unsubstituted ( "unsubstituted alkenyl") or substituted with one or more substituents, for example 1 to 5 substituents, 1 to 3 substituents or 1 substituent ( "substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C1 - C 10 Alkenyl. In certain embodiments, the alkenyl group is substituted C2 - C6 alkenyl.

[0021] As used herein, the term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ( "C2 - C 24 Alkenyl"). In some embodiments, the alkynyl group has 2 to 10 carbon atoms ( "C2 - C 10 Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ( "C2 - C8 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ( "C2 - C6 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ( "C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 1-butynyl). Examples of C2 - C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. Each example of the alkynyl group can be independently optionally substituted, i.e., unsubstituted ( "unsubstituted alkynyl") or substituted with one or more substituents, for example 1 to 5 substituents, 1 to 3 substituents or 1 substituent ( "substituted alkynyl"). In certain embodiments, the alkynyl group is unsubstituted C 2~10 Alkynyl. In certain embodiments, the alkynyl group is substituted C 2~6 Alkynyl.

[0022] As used herein, the term "haloalkyl" refers to an acyclic, stable linear or branched chain, or a combination thereof, comprising at least one carbon atom and at least one halogen selected from the group consisting of F, Cl, Br, and I. Halogens F, Cl, Br, and I can be positioned at any position within the haloalkyl group. Exemplary haloalkyl groups include -CF3, -CCl3, -CH2-CF3, -CH2-CCl3, -CH2-CBr3, -CH2-CI3, -CH2-CH2-CH(CF3)-CH3, -CH2-CH2-CH(Br)-CH3, and -CH2-CH=CH-CH2-CF3, but... These are not the only examples. Each example of a haloalkyl group can be independently and optionally substituted, i.e., unsubstituted ("unsubstituted haloalkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted haloalkyl").

[0023] As used herein, the term "heteroalkyl" means an acyclic, stable linear or branched chain, or a combination thereof, comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms may be oxidized by choice, and the nitrogen heteroatom may be quaternized by choice. The heteroatoms O, N, P, S, and Si may be positioned at any position in the heteroalkyl group. Exemplary heteroalkyls include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. For example, up to two or three heteroatoms can be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The term "heteroalkyl" is often followed by -CH2O, -NR, etc. C R DWhen a specific heteroalkyl group such as is cited, heteroalkyl and -CH2O or -NR C R D The terms will be understood to be neither redundant nor mutually exclusive. Rather, specific heteroalkyl groups are listed for clarity. Thus, the term "heteroalkyl" as used herein is not to be construed as excluding specific heteroalkyl groups such as -CH2O, -NR C R D etc. Each example of a heteroalkyl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents or 1 substituent ("substituted heteroalkyl").

[0024] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and no heteroatoms provided in the aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in a cyclic array) ("C6~C 14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 aryl"; e.g., anthracyl). An aryl group may be described, for example, as a C6~C 10 member aryl, and the term "member" refers to non-hydrogen ring atoms within the moiety. Examples of aryl groups include phenyl, naphthyl, indenyl and tetrahydronaphthyl. Each example of an aryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C6~C 14 aryl. In certain embodiments, the aryl group is substituted C6~C14 It is Ariel.

[0025] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, where the valence allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. The defined heteroaryl rings also include ring systems in which the bond site is fused with one or more aryl groups located on an aryl or heteroaryl ring, in which case the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site may be located on either ring, i.e., a ring containing a heteroatom (e.g., 2-indolyl) or a ring not containing a heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 6- to 10-membered heteroaryls, where the term “member” refers to a non-hydrogen ring atom within the part. Each example of a heteroaryl group may be independently substituted by choice, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted heteroaryl").

[0026] Exemplary five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Exemplary seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiadiazolyl, indolidinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0027] As used herein, "cycloalkyl" refers to a ring of carbon atoms (3-10 C3-C3) 10This refers to a radical of a non-aromatic cyclic hydrocarbon group having a cycloalkyl group and no heteroatoms in the non-aromatic ring system. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10 Cycloalkyl groups (C3-C6 cycloalkyl groups) may be described, for example, as C4-C7 member cycloalkyl groups, where "member" refers to the non-hydrogen ring atom within the group. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). Exemplary C3-C8 cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), and cyclo This includes, but is not limited to, loheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), and bicyclo[3.1.1]heptanyl (C7). Examples of C3-C3 compounds include, but are not limited to, these. 10 Cycloalkyl groups include the aforementioned C3-C8 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C9). 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10) and others are included, but are not limited to these. As the above examples show, in certain embodiments, cycloalkyl groups may be monocyclic ("monocyclic cycloalkyl") or include fused rings such as bicyclic, bridged, or spirocyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which the cycloalkyl ring as defined above is fused with one or more aryl groups on the cycloalkyl ring, in which case the number of carbons continues to specify the number of carbons in the cycloalkyl ring system. Each example of a cycloalkyl group may be independently and optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group may be unsubstituted C3-C 10 It is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C3-C3 group. 10 It is a cycloalkyl group.

[0028] As used herein, “heterocyclyl” refers to a radical of a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 10-membered heterocyclyl”). In heterocyclyl groups containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, wherever the valence allows. Heterocyclyl groups may be monocyclic (“monocyclic heterocyclyl”) or condensed, bridging, or spirocyclic systems such as bicyclic systems (“bicyclic heterocyclyl”), and may be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. The term "heterocyclyl" includes ring systems in which the heterocyclyl ring as defined above is fused at a bond site with a cycloalkyl group or one or more cycloalkyl groups on the heterocyclyl ring, or ring systems in which the heterocyclyl ring as defined above is fused at a bond site with one or more aryl or heteroaryl groups on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members of the heterocyclyl ring system. A heterocyclyl group may be described, for example, as a 3- to 7-membered heterocyclyl, and the term "member" refers to the non-hydrogen ring atoms in the part, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each example of a heterocyclyl may be independently and optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0029] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azilidinyl, oxylanil, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, piperidi Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, nyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyrididine-2-onyl), and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridadinolyl (2-methylpyridazine-3-onyl), pyrimidinolyl (e.g., 1-methylpyrimidine-2-onyl, 3-methylpyrimidine-4-onyl), dithianyl, and dioxanyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxekanyl, and thiokanyl. Exemplary five-membered heterocyclyl groups condensed on a C6 aryl ring (also referred herein as 5,6-bicyclic heterocyclyl rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Exemplary five-membered heterocyclyl groups condensed on a heterocyclyl ring (also referred herein as 5,5-bicyclic heterocyclyl rings) include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl). Exemplary six-membered heterocyclyl groups condensed to a heterocyclyl ring (also called a 4,6-membered heterocyclyl ring) include, but are not limited to, diazaspirononanyl (e.g., 2,7-diazaspiron[3.5]nonanyl). Exemplary six-membered heterocyclyl groups condensed to an aryl ring (also referred herein as a 6,6-bicyclic heterocyclyl ring) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Exemplary six-membered heterocyclyl groups condensed to a cycloalkyl ring (also referred herein as a 6,7-bicyclic heterocyclyl ring) include, but are not limited to, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl).Examples of six-membered heterocyclyl groups condensed to a cycloalkyl ring (also referred to herein as 6,8-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0030] The terms "alkylene," "alkenylene," "alkynylene," "haloalkylene," "heteroalkylene," "cycloalkylene," or "heterocyclylene" refer to divalent radicals derived from alkyl, alkenyl, alkynyl, haloalkylene, heteroalkylene, cycloalkyl, or heterocyclyl, respectively, either alone or as part of another substituent, unless otherwise specified. For example, the term "alkenylene" means a divalent group derived from an alkene, either by itself or as part of another substituent, unless otherwise specified. Alkylene, alkenylene, alkynylene, haloalkylene, heteroalkylene, cycloalkylene, or heterocyclylene groups may be described, for example, as C1-C6 member alkylene, C2-C6 member alkenylene, C2-C6 member alkynylene, C1-C6 member haloalkylene, C1-C6 member heteroalkylene, C3-C8 member cycloalkylene, or C3-C8 member heterocyclene, with the term "member" referring to a non-hydrogen atom within the part. In the case of heteroalkylene and heterocyclylene groups, the heteroatom may occupy either or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, the orientation of the linking group formula does not indicate the orientation of the linking group. For example, the formula -C(O)2R'- can represent both -C(O)2R'- and -R'C(O)2-.

[0031] As used herein, the terms "cyano" or "-CN" refer to substituents having a carbon atom bonded to a nitrogen atom by a triple bond, such as C≡N.

[0032] As used herein, the terms "halogen" or "halo" refer to fluorine, chlorine, This refers to bromine or iodine.

[0033] As used herein, the term "hydroxy" refers to the -OH group.

[0034] As used herein, the term "nitro" refers to a substituent having two oxygen atoms bonded to a nitrogen atom, such as -NO2.

[0035] As used herein, the term “nucleic acid base” refers to nitrogen-containing biocompounds found to be linked to sugars within nucleosides, and are the basic building blocks of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The major or native nucleic acid bases are cytosine (DNA and RNA), guanine (DNA and RNA), adenine (DNA and RNA), thymine (DNA), and uracil (RNA), abbreviated as C, G, A, T, and U, respectively. A, G, C, and T appear in DNA, and therefore these molecules are called DNA bases. A, G, C, and U are called RNA bases. Adenine and guanine belong to a bicyclic class of molecules called purines (abbreviated as R). Cytosine, thymine, and uracil are all pyrimidines. Other nucleic acid bases that do not function as normal parts of the genetic code are called non-native. In one embodiment, nucleic acid bases may be chemically modified, for example, with alkyl (e.g., methyl), halo, -O-alkyl, or other modifications.

[0036] As used herein, the term “nucleic acid” refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and its polymers in single-stranded or double-stranded form. The term “nucleic acid” includes genes, cDNA, premRNA, or mRNA. In one embodiment, the nucleic acid molecule is synthetic (e.g., chemosynthesized) or recombinant. Unless otherwise specified, the term includes nucleic acids, including analogs or derivatives of native nucleotides, which have similar binding properties to the reference nucleic acid and are metabolized in a similar manner to native nucleotides. Unless otherwise indicated, a particular nucleic acid sequence implicitly includes not only the explicitly indicated sequence but also its conservatively modified variants (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences.

[0037] As used herein, "oxo" refers to the carbonyl group, i.e., -C(O)-.

[0038] The symbols used herein with respect to the compound of formula (I) [ka] This refers to a bond point to another part or functional group within the compound.

[0039] Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted. Generally, the term “substituted” means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is substituted with an acceptable substituent, such as a substituent that results in a stable compound, such as a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, or other reactions, whether preceded by the term “optionally.” Unless otherwise specified, a “substituted” group has substituents at one or more substituted positions on the group, and if two or more positions in a given structure are substituted, the substituents are either the same or different at each position. The term “substituted” is intended to include substitution with all acceptable substituents of an organic compound, such as any substituent described herein that results in the formation of a stable compound. This disclosure intends for all such combinations to arrive at a stable compound. For the purposes of the present invention, heteroatoms such as nitrogen satisfy the valence of the hydrogen substituent and / or heteroatom, and the stable part It may have any suitable substituent as described herein that results in the formation of a fraction.

[0040] Two or more substituents can optionally bond to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. Such so-called ring-forming substituents are typically, but not necessarily, found to be bonded to a cyclic base structure. In one embodiment, the ring-forming substituent is bonded to an adjacent member of the basic structure. For example, two ring-forming substituents bonded to adjacent members of a cyclic basic structure form a fused ring structure. In another embodiment, the ring-forming substituent is bonded to a single member of the basic structure. For example, two ring-forming substituents bonded to a single member of a cyclic basic structure form a spiro-ring structure. In yet another embodiment, the ring-forming substituent is bonded to a non-adjacent member of the basic structure.

[0041] The compounds provided herein may exist in one or more specific geometric isomers, optical isomers, enantiomers, diastereomers, epimers, stereoisomers, tautomers, stereoisomers, or anomeric forms, including, but not limited to, cis and trans types; E and Z types; endo and exo types; R, S and meso types; D and L types; d and l types; (+) and (-) types; keto, enol and enolate types; syn and anti types; synclinal and anticline types; α and β types; axial and equatorial types; boat, chair, twist, envelope and half-chair types; and combinations thereof, and are collectively referred to below as "isomers" (or "isomer forms").

[0042] The compounds described herein may contain one or more chiral centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of a mixture of stereoisomers, including a racemic mixture and a mixture in which one or more stereoisomers are concentrated. In one embodiment, the stereochemistry exhibited in the compound is relative rather than absolute. Isomers can be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure further encompasses the compounds described herein as individual isomers substantially free from other isomers and, instead, as mixtures of various isomers.

[0043] As used herein, a pure enantiomerized compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomerized). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore enantiomerized of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" refer to a compound that contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight of enantiomers. In certain embodiments, weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0044] In the compositions provided herein, enantiomerically pure compounds are other active ingredients Alternatively, they may be present together with inert components. For example, a pharmaceutical composition containing an enantiomerically pure R compound may, for example, comprise about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may comprise, for example, at least about 95% by weight of the R compound and up to about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may, for example, comprise about 90% excipients and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may comprise, for example, at least about 95% by weight of the S compound and up to about 5% by weight of the R compound, based on the total weight of the compound.

[0045] In some embodiments, diastereomerically pure compounds may be present together with other active or inactive components. For example, a pharmaceutical composition containing a diastereomerically pure exo compound may, for example, comprise about 90% excipients and about 10% diastereomerically pure exo compounds. In certain embodiments, the diastereomerically pure exo compound in such a composition may comprise, for example, at least about 95% by weight of the exo compound and up to about 5% by weight of the endo compound, based on the total weight of the compound. For example, a pharmaceutical composition containing a diastereomerically pure endo compound may, for example, comprise about 90% excipients and about 10% diastereomerically pure endo compounds. In certain embodiments, the diastereomerically pure endo compound in such a composition may comprise, for example, at least about 95% by weight of the endo compound and up to about 5% by weight of the exo compound, based on the total weight of the compound.

[0046] In some embodiments, isomerically pure compounds may be present together with other active or inactive components. For example, a pharmaceutical composition containing an isomerically pure exo-compound may, for example, comprise about 90% excipients and about 10% isomerically pure exo-compounds. In certain embodiments, the isomerically pure exo-compounds in such a composition may comprise, for example, at least about 95% by weight of the exo-compound and up to about 5% by weight of the endo-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an isomerically pure endo-compound may, for example, comprise about 90% excipients and about 10% isomerically pure endo-compounds. In certain embodiments, the isomerically pure endo-compounds in such a composition may comprise, for example, at least about 95% by weight of the endo-compound and up to about 5% by weight of the exo-compound, based on the total weight of the compound.

[0047] In certain embodiments, the active ingredient can be formulated with little or no excipients or carriers.

[0048] The compounds described herein may also include one or more isotopic substitutions. For example, H is 1 H,2 H (D or deuterium) and 3 It can be any isotopic form containing H (T or tritium); C is 12 C, 13 C and 14 It can be any isotopic form containing C; O is, 16 O and 18 It can be any isotopic form containing O; N is, 14 N and 15 It can be any isotopic form containing N; F is, 18 F, 19 For example, it can be any isotopic form containing F.

[0049] The term "pharmaceutically acceptable salt" means that salts of the active compound are prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. If the compounds of this disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either in its original form or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. If the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either in its original form or in a suitable inert solvent. They can be obtained by contact. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as alginates and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present invention include both basic and acidic functionalities that allow the compound to be converted into either a base addition salt or an acid addition salt. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for the present invention.

[0050] In addition to salt forms, this disclosure provides compounds in prodrug forms. The prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0051] The term "solvate" typically refers to the form of a compound associated with a solvent by solvolysis. This physical bonding may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, and diethyl ether. Compounds of formula (I) can be prepared, for example, in crystalline form and solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, solvates can be isolated, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvates" encompass both solution phases and isolateable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0052] The term "hydrate" refers to a compound that has associated with water. Typically, the number of water molecules in a compound hydrate is in a constant ratio to the number of compound molecules in the hydrate. Thus, a compound hydrate can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form two or more types of hydrates, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, e.g., hemihydrate (R·0.5H₂O)) and polyhydrate (x is a number greater than 1, e.g., dihydrate (R·2H₂O) and hexahydrate (R·6H₂O)).

[0053] The term "tautomer" refers to interchangeable forms of a particular compound structure, where the substitution of hydrogen atoms and electrons differs between the two compounds. Thus, the two structures can be in equilibrium through the transfer of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with an acid or base. Another example of tautomerism is the acidic and nitro forms of phenylnitromethane, which are similarly formed upon treatment with an acid or base. Tautomerism can be relevant to achieving the optimal chemical reactivity and biological activity of a compound of interest.

[0054] Other definitions The following definitions are more general terms used throughout this disclosure.

[0055] The articles “a” and “an” refer to one or more grammatical objects of the article (e.g., at least one). For example, “element” means one element or two or more elements. The term “and / or” means either “and” or “or” unless otherwise indicated.

[0056] The term “approximately” is used herein to mean a typical tolerance in the art. For example, “approximately” can be understood as about two standard deviations from the mean. In certain embodiments, “approximately” means ±10%. In certain embodiments, “approximately” means ±5%. When “approximately” precedes a series of numbers or ranges, it is understood that “approximately” can modify each number in the series of numbers or ranges.

[0057] As used herein, “obtain” or “to obtain” means to obtain a value, such as a number, an image, or a physical entity (e.g., a sample) by “directly obtaining” or “indirectly obtaining” the value or physical entity. “Directly obtaining” means performing a process to obtain the value or physical entity (e.g., performing an analytical method or protocol). “Indirectly obtaining” means receiving the value or physical entity from another party or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Directly obtaining a value or physical entity includes performing a process that involves a physical change of a physical substance or the use of a machine or apparatus. An example of directly obtaining a value is obtaining a sample from a human subject. Directly obtaining a value includes performing a process to obtain mass spectrometry data using a machine or device, such as a mass spectrometer.

[0058] As used herein, the terms “administer,” “give delivery,” or “dosage” refer to embedding, absorbing, ingesting, injecting, inhaling, or otherwise introducing the compounds or pharmaceutical compositions of the present invention.

[0059] As used herein, the terms “condition,” “disease,” and “disorder” are interchangeable.

[0060] The “effective dose” of a compound of formula (I) refers to an amount sufficient to induce a desired biological response, i.e., to treat a condition. As will be understood by those skilled in the art, the effective dose of a compound of formula (I) may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. Effective doses include therapeutic and prophylactic treatments. For example, in the treatment of cancer, an effective dose of the compound of the present invention may reduce tumor load or halt tumor growth or spread.

[0061] The “therapeutic dose” of a compound of formula (I) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. In some embodiments, the therapeutic dose is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. The therapeutic dose of a compound means the amount of the therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term “therapeutic dose” can include an amount that improves the overall treatment, reduces or avoids the cause of a symptom or condition, or enhances the therapeutic effect of another therapeutic agent.

[0062] The terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids it may contain. A polypeptide includes any peptide or protein containing two or more amino acids linked to each other by peptide bonds. When used in detail, this term refers to both short chains, commonly called peptides, oligopeptides, and oligomers in the art, and long chains, commonly called proteins in the art, and encompasses many types.

[0063] As used herein, “prevention,” “prevention,” and “prevention” refer to a treatment that includes administering a compound described herein (e.g., a compound of formula (I)) before the onset of a disease, disorder, or condition in order to eliminate the physical signs of the disease, disorder, or condition. In some embodiments, “prevention,” “prevention,” and “prevention” require that the signs or symptoms of the disease, disorder, or condition have not yet occurred or been observed. In some embodiments, the treatment includes prevention, while in other embodiments it does not include prevention.

[0064] The “targets” to which the drug is intended include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other non-human animals, e.g., mammals (e.g., primates (e.g., crab-eating macaques, rhesus macaques); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats and / or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese and / or turkeys). In certain embodiments, the animal is a mammal. The animal may be male or female and may be at any stage of development. The non-human animal may be a transgenic animal.

[0065] As used herein, the terms “treatment,” “to treat,” and “doing to treat” mean, for example, reversing, alleviating, delaying the onset or inhibiting the progression of one or more symptoms, signs, or underlying causes of a disease, disorder, or condition (for example, as described herein) by administering a therapy, for example, by administering a compound described herein (for example, a compound of formula (I)). In one embodiment, treatment includes reducing, reversing, alleviating, delaying the onset or inhibiting the progression of symptoms of a disease, disorder, or condition. In one embodiment, treatment includes reducing, reversing, alleviating, delaying the onset or inhibiting the progression of the disease, disorder, or condition. In one embodiment, treatment includes reducing, reversing, alleviating, delaying the onset or inhibiting the progression of the underlying cause of the disease, disorder, or condition. In some embodiments, “treatment,” “to treat,” and “doing to treat” require that signs or symptoms of a disease, disorder, or condition have occurred or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease or condition, for example, in a prophylactic treatment. For example, treatment may be administered to individuals who are susceptible to the condition before the onset of symptoms (for example, in light of their medical history and / or genetic or other susceptibility factors). For example, treatment may be continued after symptoms have subsided in order to delay or prevent relapse. For example, treatment may be continued after symptoms have subsided in order to delay or prevent relapse. In some embodiments, the treatment includes prevention, while in other embodiments, it does not include prevention.

[0066] "Proliferative disorders" refer to diseases resulting from abnormal proliferation of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders may be associated with: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, elastase); 4) pathological angiogenesis such as proliferative retinopathy and tumor metastasis; or 5) evasion of host immune surveillance and elimination of newly formed cells. Exemplary proliferative disorders include cancer (i.e., "malignant neoplasms"), benign neoplasms, and angiogenesis.

[0067] "Non-proliferative disorders" refer to diseases that do not primarily spread through abnormal cell proliferation. Nonproliferative disorders may be associated with any cell or histological type of the subject. Exemplary nonproliferative disorders include neurological disorders or conditions (e.g., recurrent and expanding disorders); autoimmune disorders or conditions; immunodeficiency disorders or conditions; lysosomal storage disorders or conditions; inflammatory disorders or conditions; cardiovascular conditions, diseases or disorders; metabolic disorders or conditions; respiratory conditions, diseases or disorders; renal diseases or disorders; and infections.

[0068] compound In one embodiment, this disclosure is given by formula (I): [ka] The present invention provides compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof. In the formula, A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of them is one or more R 1 It is optionally replaced by; W is N, C, or C(R 3a ) and X, Y, and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c), or O, where the bonds within the ring containing X, Y, and Z may be single or double bonds, wherever the valence allows; L 1 and L 2 It does not exist, or it is a C1-C6 alkylene, a C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-,-N(R 4 )C(O)-, or -C(O)N(R 4 )- where each alkylene and heteroalkylene is one or more R 5 It is optionally replaced by each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 6 Optionally replaced by; or two R 1 The groups, together with the atoms to which they are bonded, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl group, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 6 It is optionally replaced by each R 2These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A And; R 3a and R 3b These are, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, and -OR. A , -NR B R C , -C(O)R D , or C(O)OR D is; or R 3a and R 3b Each of them, together with the carbon atom to which they are bonded, forms an oxo group; R 3c is hydrogen or C1-C6 alkyl; each R 4 R is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 5 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and; each R 6 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D ,-NO2,-C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R DHere, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally one or more R 11 It may also be replaced with; each R 7 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D , or -S(O) x R D And; R B and R C Each of these can independently be hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 7 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E R is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 m is hydrogen or a C1-C6 alkyl group; m is 0, 1, or 2; x is 0, 1, or 2; and y is 0 or 1. In some embodiments, y is 1.

[0069] In some embodiments, the compound of formula (I) is formula (Ia): [ka] The compound, or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer, In the formula, A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of them is one or more R 1 It is optionally substituted by; W, X, Y, and Z are each independently of C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ), or O, where the bonds within the ring containing W, X, Y, and Z may be single or double bonds, wherever the valence allows; L 2 It does not exist, or it is a C1-C6 alkylene, a C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-,-N(R 4 )C(O)-, or -C(O)N(R 4 )- where each alkylene and heteroalkylene is one or more R 5 It is optionally replaced by each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R DHere, each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 6 Optionally replaced by; or two R 1 The groups, together with the atoms to which they are bonded, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl group, where each cycloalkyl, Heterocyclyls, aryls, and heteroaryls are composed of one or more R 6 It is optionally replaced by each R 2 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A And; R 3a and R 3b These are, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, and -OR. A , -NR B R C , -C(O)R D , or C(O)OR D is; or R 3a and R 3b Each of them, together with the carbon atom to which they are bonded, forms an oxo group; R 3c is hydrogen or C1-C6 alkyl; each R 4 R is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 5 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and; each R 6These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D ,-NO2,-C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally one or more R 11 It is replaced by; each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D , or -S(O) x R D And; R B and R C Each of these can independently be hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 7 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E R is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R 11These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; each R 7 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 m is hydrogen or a C1-C6 alkyl group; m is 0, 1, or 2; x is 0, 1, or 2.

[0070] As is generally described herein, A and B are each independently of one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules are optionally substituted.

[0071] In some embodiments, A and B are independently monocyclic rings, such as monocyclic cycloalkyl, monocyclic heterocyclyl, monocyclic aryl, or monocyclic heteroaryl. The monocyclic rings can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B are independently monocyclic rings containing 3 to 10 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms). In some embodiments, A is a 4-membered monocyclic ring. In some embodiments, B is a 4-membered monocyclic ring. In some embodiments, A is a 5-membered monocyclic ring. In some embodiments, B is a 5-membered monocyclic ring. In some embodiments, A is a 6-membered monocyclic ring. In some embodiments, B is a 6-membered monocyclic ring. In some embodiments, A is a 7-membered monocyclic ring. In some embodiments, B is a 7-membered monocyclic ring. In some embodiments, A is an 8-membered monocyclic ring. In some embodiments, B is an 8-membered monocyclic ring. In some embodiments, A or B independently comprises one or more R 1 Deputy This is a monocyclic ring that has been substituted by intentional selection.

[0072] In some embodiments, A or B is independently a bicyclic ring, such as a bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl. The bicyclic ring may be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B is independently a bicyclic ring containing condensation, bridging, or a spirocycle system. In some embodiments, A or B is independently a bicyclic ring containing 4 to 18 ring atoms (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms). In some embodiments, A is a 6-membered bicyclic ring. In some embodiments, B is a 6-membered bicyclic ring. In some embodiments, A is a 7-membered bicyclic ring. In some embodiments, B is a 7-membered bicyclic ring. In some embodiments, A is an 8-membered bicyclic ring. In some embodiments, B is an 8-membered biring ring. In some embodiments, A is a 9-membered biring ring. In some embodiments, B is a 9-membered biring ring. In some embodiments, A is a 10-membered biring ring. In some embodiments, B is a 10-membered biring ring. In some embodiments, A is an 11-membered biring ring. In some embodiments, B is an 11-membered biring ring. In some embodiments, A is a 12-membered biring ring. In some embodiments, B is a 12-membered biring ring. In some embodiments, A or B is independently one or more R 1 It is a biring ring that has been substituted by arbitrary choice.

[0073] In some embodiments, A or B is independently a tricyclic ring, such as a tricyclic cycloalkyl, tricyclic heterocyclyl, tricyclic aryl, or tricyclic heteroaryl. The tricyclic ring can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B is independently a tricyclic ring comprising a condensed, bridging, or spirocyclic system or a combination thereof. In some embodiments, A or B is independently a tricyclic ring comprising 6 to 24 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 ring atoms). In some embodiments, A is an 8-membered tricyclic ring. In some embodiments, B is an 8-membered tricyclic ring. In some embodiments, A is a 9-membered tricyclic ring. In some embodiments, B is a 9-membered tricyclic ring. In some embodiments, A is a 10-membered tricyclic ring. In some embodiments, B is a 10-membered tricyclic ring. In some embodiments, A or B is independently one or more R 1 This is a triring ring that has been substituted by arbitrary choice.

[0074] In some embodiments, A or B is independently a monocyclic cycloalkyl, a monocyclic heterocyclil, a monocyclic aryl, or a monocyclic heteroaryl. In some embodiments, A or B is independently a bicyclic cycloalkyl, a bicyclic heterocyclil, a bicyclic aryl, or a bicyclic heteroaryl. In some embodiments, A or B is independently a tricyclic cycloalkyl, a tricyclic heterocyclil, a tricyclic aryl, or a tricyclic heteroaryl. In some embodiments, A is a monocyclic heterocyclil. In some embodiments, B is a monocyclic heterocyclil. In some embodiments, A is a bicyclic heterocyclil. In some embodiments, B is a bicyclic heteroaryl. In some embodiments, A is a monocyclic heteroaryl. In some embodiments, B is a monocyclic heteroaryl. In some embodiments, A is a bicyclic heteroaryl. In some embodiments, B is a bicyclic heteroaryl.

[0075] In some embodiments, A or B are independently nitrogen-containing heterocyclines, for example, heterocyclines containing one or more nitrogen atoms. The one or more nitrogen atoms of the nitrogen-containing heterocycline can be located at any position in the ring. In some embodiments, the nitrogen-containing heterocycline is monocyclic, bicyclic, or tricyclic. In some embodiments, A or B are independently The heterocycline contains at least one, at least two, at least three, at least four, at least five, or at least six nitrogen atoms. In some embodiments, A is a heterocycline containing one nitrogen atom. In some embodiments, B is a heterocycline containing one nitrogen atom. In some embodiments, A is a heterocycline containing two nitrogen atoms. In some embodiments, B is a heterocycline containing two nitrogen atoms. In some embodiments, A is a heterocycline containing three nitrogen atoms. In some embodiments, B is a heterocycline containing three nitrogen atoms. In some embodiments, A is a heterocycline containing four nitrogen atoms. In some embodiments, B is a heterocycline containing four nitrogen atoms. In some embodiments, A or B is a nitrogen-containing heterocycline independently containing one or more further heteroatoms, for example, one or more oxygen, sulfur, boron, silicon, or phosphorus. In some embodiments, one or more nitrogen atoms in the nitrogen-containing heterocycline are, for example, R 1 It has been replaced with.

[0076] In some embodiments, A or B is independently a nitrogen-containing heteroaryl, for example, a heteroaryl containing one or more nitrogen atoms. The one or more nitrogen atoms of the nitrogen-containing heteroaryl may be located at any position in the ring. In some embodiments, the nitrogen-containing heteroaryl is monocyclic, bicyclic, or tricyclic. In some embodiments, A or B is independently a heteroaryl containing at least one, at least two, at least three, at least four, at least five, or at least six nitrogen atoms. In some embodiments, A is a heteroaryl containing one nitrogen atom. In some embodiments, B is a heteroaryl containing one nitrogen atom. In some embodiments, A is a heteroaryl containing two nitrogen atoms. In some embodiments, B is a heteroaryl containing two nitrogen atoms. In some embodiments, A is a heteroaryl containing three nitrogen atoms. In some embodiments, B is a heteroaryl containing three nitrogen atoms. In some embodiments, A is a heteroaryl containing four nitrogen atoms. In some embodiments, B is a heteroaryl containing four nitrogen atoms. In some embodiments, A or B is independently a nitrogen-containing heteroaryl comprising one or more further heteroatoms, for example, one or more oxygen, sulfur, boron, silicon, or phosphorus. In some embodiments, one or more nitrogen atoms of the nitrogen-containing heteroaryl are, for example, R 1 It has been replaced with.

[0077] In some embodiments, A is a six-membered nitrogen-containing heterocycline, for example, a six-membered heterocycline containing one or more nitrogen atoms. In some embodiments, A is a six-membered heterocycline containing one nitrogen atom. In some embodiments, A is a six-membered heterocycline containing two nitrogen atoms. In some embodiments, A is a six-membered heterocycline containing three nitrogen atoms. In some embodiments, A is a six-membered heterocycline containing four nitrogen atoms. One or more nitrogen atoms in the six-membered nitrogen-containing heterocycline may be located at any position in the ring. In some embodiments, A is one or more R 1It is a 6-membered nitrogen-containing heterocycline that has been optionally substituted with R. In some embodiments, one or more nitrogen atoms of the 6-membered nitrogen-containing heterocycline are, for example, R 1 It is substituted with. In some embodiments, A is a six-membered nitrogen-containing heterocycline containing one or more further heteroatoms, such as one or more oxygen, sulfur, boron, silicon, or phosphorus.

[0078] In some embodiments, B is a five-membered nitrogen-containing heterocycline or heteroaryl, for example, a five-membered heterocycline or heteroaryl containing one or more nitrogen atoms. In some embodiments, B is a five-membered heterocycline containing one nitrogen atom. In some embodiments, B is a five-membered heteroaryl containing one nitrogen atom. In some embodiments, B is a five-membered heterocycline containing two nitrogen atoms. In some embodiments, B is a five-membered heteroaryl containing two nitrogen atoms. In some embodiments, B is a five-membered heterocyclyl containing three nitrogen atoms. In some embodiments, B is a five-membered heteroaryl containing three nitrogen atoms. One or more nitrogen atoms of the five-membered nitrogen-containing heterocyclyl or heteroaryl may be located at any position in the ring. In some embodiments, B is one or more R 1 It is a five-membered nitrogen-containing heterocycline that is optionally substituted with R. In some embodiments, B is one or more R 1 It is a 5-membered nitrogen-containing heteroaryl substituted by optional choice. In some embodiments, one or more nitrogen atoms of the 5-membered nitrogen-containing heterocyclyl or heteroaryl are, for example, R 1 It is substituted with. In some embodiments, B is a five-membered nitrogen-containing heterocyclyl or heteroaryl comprising one or more further heteroatoms, such as one or more oxygen, sulfur, boron, silicon, or phosphorus.

[0079] In some embodiments, B is a nitrogen-containing bicyclic heteroaryl (e.g., a 9-membered nitrogen-containing bicyclic heteroaryl), which can optionally contain one or more R 1It may be substituted with. In some embodiments, B is a nine-membered bicyclic heteroaryl containing one nitrogen atom. In some embodiments, B is a nine-membered bicyclic heteroaryl containing two nitrogen atoms. In some embodiments, B is a nine-membered bicyclic heteroaryl containing three nitrogen atoms. In some embodiments, B is a nine-membered bicyclic heteroaryl containing four nitrogen atoms. One or more nitrogen atoms of the nine-membered bicyclic heteroaryl may be at any position in the ring. In some embodiments, B is one or more R 1 It is a nine-membered bicyclic heteroaryl substituted with [the specified compound].

[0080] In some embodiments, A and B are independently, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Selected from, in the formula, each R 1 These are as defined herein. In one embodiment, A and B are each independently a saturated, partially saturated, or unsaturated (e.g., aromatic) derivative of the aforementioned ring. In one embodiment, A and B are each independently a stereoisomer of the aforementioned ring.

[0081] In some embodiments, A and B are independently, [ka] [ka] [ka] Selected from, in the formula, each R 1 These are as defined herein. In one embodiment, A and B are each independently a saturated, partially saturated, or unsaturated (e.g., aromatic) derivative of the aforementioned ring. In one embodiment, A and B are each independently a stereoisomer of the aforementioned ring.

[0082] In some embodiments, A is [ka] Selected from, in the formula, each R 1 This is as defined herein.

[0083] In some embodiments, A is [ka] Selected from.

[0084] In some embodiments, A is [ka] Selected from.

[0085] In some embodiments, A is [ka] Selected from.

[0086] In some embodiments, A is [ka] Selected from.

[0087] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0088] In some embodiments, B is [ka] Selected from, in the formula, each R 1 This is as defined herein. In some embodiments, B is [ka] Selected from.

[0089] In some embodiments, B is [ka] Selected from.

[0090] In some embodiments, B is [ka] Selected from.

[0091] In some embodiments, B is [ka] Selected from.

[0092] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

[0093] In some embodiments, B is formula (A) or formula (B): [ka] It has the following structure: In the formula, each of J, K, and M is selected from N and C(R'); R 1 R' is as defined above; R' is hydrogen, halo (e.g., fluoro), or C1-C6 alkyl (e.g., methyl); p is 0, 1, 2, 3, or 4; where at least one of J, K, and M is N; the bonds within the ring containing J, K, and M may be single or double bonds, where the valence allows.

[0094] In some embodiments, J, K, and M are each independently N. In some embodiments, J is C(R'), and K and M are each independently M. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0095] In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

[0096] As outlined herein, L 2 It does not exist, or it is C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R4 )-,-N(R 4 )C(O)-, or -C(O)N(R 4 )- may refer to a group, where each alkylene and heteroalkylene is one or more R 5 It is being replaced by an arbitrary choice.

[0097] In some embodiments, L 2 It does not exist. In some embodiments, L 2 is a C1-C6 alkylene (e.g., C1 alkylene, C2 alkylene, C3 alkylene, C4 alkylene, C5 alkylene, or C6 alkylene). In some embodiments, L 2 L is an unsubstituted C1-C6 alkylene. In some embodiments, L 2 This refers to substituted C1-C6 alkylenes, for example, one or more R 5 These are C1-C6 alkylenes substituted with L. In some embodiments, L 2 is one R 5 It is a C1 alkylene substituted with L. In some embodiments, L 2 is -CH2- (or methylene). In some embodiments, L 2 It is -C(O)- (or carbonyl).

[0098] As outlined herein, L 2 It does not exist, or it is C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-,-N(R 4 )C(O)-, or -C(O)N(R 4 )- may refer to a group, where each alkylene and heteroalkylene is one or more R 5 It is being replaced by an arbitrary choice.

[0099] In some embodiments, L 2 It does not exist, or C1-C6 alkylene, C1-C6 heteroalkylene, -N(R 4 )C(O)-, or -C(O)N(R 4)- and each alkylene and heteroalkylene is one or more R 5 It is optionally replaced by L. In some embodiments, L 2 L is an unsubstituted C1-C6 heteroalkylene. In some embodiments, L 2 This refers to a substituted heteroalkylene, for example, one or more R 5 It is a C1-C6 heteroalkylene substituted with . In some embodiments, the heteroalkylene contains one or more heteroatoms. In some embodiments, the heteroalkylene contains one or more of oxygen, sulfur, nitrogen, boron, silicon, or phosphorus. In some embodiments, L 2 is -N(R 4 )C(O)-. In some embodiments, L 2 teeth, -C(O)N(R 4 )-. In some embodiments, L 2 It is -C(O)N(H)-.

[0100] In some embodiments, L 2 R is arbitrarily 4 It is nitrogen which may be substituted with L. In some embodiments, L 2 R 4 It is nitrogen substituted with L. In some embodiments, L 2 is -N(R 4 )-, for example, -N(CH3)-. In some embodiments, L 2 It is -NH-.

[0101] As outlined herein, W, X, Y, and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ), or O. In some embodiments, at least one of W, X, Y, and Z is N or N(R 3c ) is one of the following. In some embodiments, at least two of W, X, Y, and Z are N or N(R 3c) In some embodiments, at least two of X, Y, and Z are N(R 3c ) In some embodiments, at least one of Y and Z is N or N(R 3c ) is. In some embodiments, X is N. In some embodiments, X is N(R 3c ) In some embodiments, at least one of W, X, Y, and Z is O. In some embodiments, X is O. In some embodiments, X is C(R 3a )(for example, CH). In some embodiments, X is C(R 3a )(R 3b ) is. In some embodiments, Y is N. In some embodiments, Y is N(R 3c ) In some embodiments, Y is C(R 3a )(for example, CH). In some embodiments, Y is C(R 3a )(R 3b ) is. In some embodiments, Z is N. In some embodiments, Z is N(R 3c ) is. In some embodiments, Z is C(R 3a )(for example, CH). In some embodiments, Z is C(R 3a )(R 3b ) In some embodiments, two of X, Y, and Z are N, and the rest of X, Y, and Z are C(R 3a )(for example, CH). In some embodiments, one of X, Y, and Z is C(R 3a )(for example, CH), and the remainder of X, Y, and Z are each independently N. In some embodiments, X and Y are each independently N, and Z is C(R 3a )(for example, CH). In some embodiments, X is C(R 3a (For example, CH) and Y and Z are N independently.

[0102] In some embodiments, W is C(R 3a )(e.g., CH) or C(R 3a )(R3b )(for example, CH2). In some embodiments, W is C(R 3a )(for example, CH). In some embodiments, W is C(R 3a )(R 3b ) is. W is C(R 3a )(for example, CH), and two of X, Y, and Z are N, and the remaining X, Y, and Z are C(R 3a )(for example, CH). In some embodiments, W is C(R 3a )(for example, CH), and one of X, Y, and Z is C(R 3a )(for example, CH), and the remainder of X, Y, and Z are each independently N. In some embodiments, X and Y are each independently N, and W and Z are each independently C(R 3a )(for example, CH). In some embodiments, W and X are each independently C(R 3a (For example, CH) and Y and Z are N independently.

[0103] In some embodiments, X, Y, and Z are independently N or C(R 3a ) where at least one of X, Y, and Z is N, and the bonds within the ring containing X, Y, and Z may be single or double bonds, as the valence allows.

[0104] In some embodiments, X is C(R 3a ) and Y is C(R 3a ) and Z is O. In some embodiments, X is C(R 3a ) and Y is C(R 3a ) and Z is O and y is 0. In some embodiments, X is C(R 3 a ) and Y is C(R 3a ) and Z is O, and the bond between X and Y is a double bond. In some embodiments, X is C(R 3a ) and Y is C(R 3a) and Z is O, and the bond between X and Y is a single bond.

[0105] In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0106] In some embodiments, [ka] teeth, [ka] Selected from.

[0107] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0108] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 R is a C2-C6 alkenyl. In some embodiments, R 1 R is a C2-C6 alkynyl. In some embodiments, R 1 R is a C1-C6 heteroalkyl group. In some embodiments, R 1 teeth, It is a C1-C6 haloalkyl (e.g., -CF3). In some embodiments, R 1 is a C1 alkyl group (e.g., methyl). In some embodiments, R 1 R is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C2-C6 alkynyl, an unsubstituted C1-C6 heteroalkyl, or an unsubstituted C1-C6 haloalkyl. In some embodiments, R 1 is one or more R 6 It is a C1-C6 alkyl group substituted with R. In some embodiments, 1 is one or more R 6 It is a C2-C6 alkenyl substituted with R. In some embodiments,1 is one or more R 6 It is a C2-C6 alkynyl substituted with R. In some embodiments, 1 is one or more R 6 It is a C1-C6 heteroalkyl substituted with R. In some embodiments, 1 is one or more R 6 It is a C1-C6 haloalkyl substituted with R. In some embodiments, R 1 It is methyl.

[0109] In some embodiments, R 1 is a cycloalkyl group (e.g., a 3- to 7-membered cycloalkyl group). In some embodiments, R 1 is a heterocycline (e.g., a 3- to 7-membered heterocycline). In some embodiments, R 1 is an arrow. In some embodiments, R 1 is a C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R 1 R is a C1-C6 alkenylene-aryl. In some embodiments, R 1 R is a C1-C6 alkylene heteroaryl. In some embodiments, R 1 is a heteroaryl compound. In some embodiments, R 1 R is an unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted C1-C6 alkylene-aryl, unsubstituted C1-C6 alkenylene-aryl, unsubstituted C1-C6 alkylene-heteroaryl, or unsubstituted heteroaryl. In some embodiments, R 1 is one or more R 6 It is a cycloalkyl substituted with R. In some embodiments, R 1 is one or more R 6 It is a heterocyclyl substituted with R. In some embodiments, 1 is one or more R 6 This is an aryl that has been replaced with R. In some embodiments, R 1 is one or more R 6It is a C1-C6 alkylene-aryl substituted with R. In some embodiments, 1 is one or more R 6 It is a C1-C6 alkenylene-aryl substituted with R. In some embodiments, 1 is one or more R 6 It is a C1-C6 alkylene heteroaryl substituted with R. In some embodiments, 1 is one or more R 6 It is a heteroaryl substituted with [the specified compound].

[0110] In some embodiments, R 1 is -OR A In some embodiments, R 1 -NR B R C (For example, NH2 or NMe2). In some embodiments, R 1 -NR B C(O)R D In some embodiments, R 1 is -C(O)NR B R C In some embodiments, R 1 is -C(O)R D In some embodiments, R 1 is -C(O)OR D In some embodiments, R 1 -SR E In some embodiments, R 1 is -S(O) x R D In some embodiments, R 1 is a halo, for example, fluoro, chloro, bromo, or iodine. In some embodiments, R 1 is cyano. In some embodiments, R 1 is nitro(-NO2). In some embodiments, R 1 It is oxo.

[0111] In some embodiments, two R 1The groups, together with the atoms to which they are bonded, form a 3- to 7-membered cycloalkyl group. In some embodiments, two R groups 1 The groups, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycline. In some embodiments, two R groups 1 The groups, together with the atoms to which they are bonded, form a 5- or 6-membered aryl group. In some embodiments, two R groups 1 The groups, together with the atoms to which they are bonded, form a 5- or 6-membered heteroaryl. Cycloalkyl, heterocyclyl, aryl, or heteroaryl consists of one or more R groups. 6 It can be replaced with.

[0112] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 This is a halo (e.g., fluoro, chloro, bromo, or iodine). In some embodiments, , R 2 is cyano. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a C2-C6 alkenyl. In some embodiments, R 2 is a C2-C6 alkynyl. In some embodiments, R 2 is -OR A (For example, -OH).

[0113] In some embodiments, R 3a , R 3b , or both, independently include hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D In some embodiments, R 3a and R 3b Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R 3ais hydrogen. In some embodiments, R 3b is hydrogen. In some embodiments, R 3a is a C1-C6 alkyl group (e.g., methyl). In some embodiments, R 3b is a C1-C6 alkyl group (e.g., methyl). In some embodiments, R 3a is a halo (e.g., fluoro, chloro, bromo, or iodine). In some embodiments, R 3b is a halo (e.g., fluoro, chloro, bromo, or iodine). In some embodiments, R 3a is cyano. In some embodiments, R 3b is cyano. In some embodiments, R 3a is -OR A (For example, -OH). In some embodiments, R 3b is -OR A (For example, -OH). In some embodiments, R 3a -NR B R C In some embodiments, R 3b -NR B R C In some embodiments, R 3a is -C(O)R D In some embodiments, R 3b is -C(O)R D In some embodiments, R 3a is -C(O)OR D In some embodiments, R 3b is -C(O)OR D In some embodiments, R 3a and R 3b Each of these forms an oxo group with the carbon atom to which it is bonded.

[0114] In some embodiments, R 3c is hydrogen. In some embodiments, R 3c is a C1-C6 alkyl group. In some embodiments, R 3c It is methyl.

[0115] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 is a C1-C6 haloalkyl group (e.g., -CF3 or -CHF2). In some embodiments, R 4 It is methyl.

[0116] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a C1-C6 alkyl group. In some embodiments, R 5 R is a C1-C6 heteroalkyl group. In some embodiments, R 5 is a C1-C6 haloalkyl. In some embodiments, R 5 is a cycloalkyl group. In some embodiments, R 5 is a halo (e.g., fluoro, chloro, bromo, or iodine). In some embodiments, R 5 is cyano. In some embodiments, R 5 is an oxo. In some embodiments, R 5 is -OR A In some embodiments, R 5 -NR B R C In some embodiments, R 5 is -C(O)R D or -C(O)OR D That is the case.

[0117] In some embodiments, R 6 is a C1-C6 alkyl group. In some embodiments, R 6 R is a C2-C6 alkenyl. In some embodiments, R 6 R is a C2-C6 alkynyl. In some embodiments, R 6 R is a C1-C6 heteroalkyl group. In some embodiments, R 6is a C1-C6 haloalkyl. In some embodiments, R 6 R is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C2-C6 alkynyl, an unsubstituted C1-C6 haloalkyl, or an unsubstituted C1-C6 heteroalkyl. In some embodiments, R 6 is one or more R 11 It is a C1-C6 alkyl group substituted with R. In some embodiments, 6 is one or more R 11 C replaced by It is a 2-C6 alkenyl. In some embodiments, R 6 is one or more R 11 It is a C2-C6 alkynyl substituted with R. In some embodiments, 6 is one or more R 11 It is a C1-C6 haloalkyl substituted with R. In some embodiments, R 6 is one or more R 11 These are C1-C6 heteroalkyl groups substituted with [the specified character].

[0118] In some embodiments, R 6 is a cycloalkyl group. In some embodiments, R 6 is a heterocycline. In some embodiments, R 6 is an arrow. In some embodiments, R 6 is a heteroaryl compound. In some embodiments, R 6 is an unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments, R 6 is one or more R 11 It is a cycloalkyl substituted with R. In some embodiments, R 6 is one or more R 11 It is a heterocyclyl substituted with R. In some embodiments, 6 is one or more R 11 This is an aryl that has been replaced with R. In some embodiments, R 6 is one or more R 11 It is a heteroaryl substituted with [the specified compound].

[0119] In some embodiments, R 6 is a halo (e.g., fluoro, chloro, bromo, or iodine). In some embodiments, R 6 is cyano. In some embodiments, R 6 is an oxo. In some embodiments, R 6 is -OR A In some embodiments, R 6 -NR B R C In some embodiments, R 6 -NR B C(O)R D In some embodiments, R 6 is -NO2. In some embodiments, R 6 is -C(O)NR B R C In some embodiments, R 6 is -C(O)R D In some embodiments, R 6 is -C(O)OR D In some embodiments, R 6 -SR E In some embodiments, R 6 is -S(O) x R D That is the case.

[0120] In some embodiments, R 7 is a C1-C6 alkyl group. In some embodiments, R 7 is a halo (e.g., fluoro, chloro, bromo, or iodine). In some embodiments, R 7 is cyano. In some embodiments, R 7 is an oxo. In some embodiments, R 7 is -OR A1 (For example, -OH).

[0121] In some embodiments, R 11is a C1-C6 alkyl group. In some embodiments, R 11 R is a C1-C6 heteroalkyl group. In some embodiments, R 11 is a C1-C6 haloalkyl group (e.g., -CF3). In some embodiments, R 11 is a cycloalkyl group. In some embodiments, R 11 is a heterocycline. In some embodiments, R 11 is an arrow. In some embodiments, R 11 is a heteroaryl compound. In some embodiments, R 11 is a halo. In some embodiments, R 11 is cyano. In some embodiments, R 11 is an oxo. In some embodiments, R 11 is -OR A That is the case.

[0122] In some embodiments, R A is hydrogen. In some embodiments, R A is a C1-C6 alkyl group (e.g., methyl). In some embodiments, R A is a C1-C6 haloalkyl. In some embodiments, R A is an arrow. In some embodiments, R A is a heteroaryl compound. In some embodiments, R A is a C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R A R is a C1-C6 alkylene heteroaryl. In some embodiments, R A is -C(O)R D In some embodiments, R A is -S(O) x R D That is the case.

[0123] In some embodiments, R B , R COr both are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A dea In some embodiments, R B and R C Each of them is independently hydrogen. In some embodiments, R B and R C Each of them is independently a C1-C6 alkyl group. In some embodiments, R B and R C One of them is hydrogen, and R B and R C The other is a C1-C6 alkyl group. In some embodiments, R B and R C Along with the atoms to which they are bonded, one or more R 7 This forms a 3- to 7-membered heterocyclyl ring that is optionally substituted.

[0124] In some embodiments, R D , R E Or both are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl (e.g., benzyl), or C1-C6 alkylene-heteroaryl. In some embodiments, R D and R E Each of these is independently hydrogen. In some embodiments, R D and R E Each of these is independently a C1-C6 alkyl group. In some embodiments, R D is hydrogen. In some embodiments, R E is hydrogen. In some embodiments, R D is a C1-C6 alkyl group (e.g., methyl). In some embodiments, R E is a C1-C6 alkyl group (e.g., methyl). In some embodiments, R DR is a C1-C6 heteroalkyl group. In some embodiments, R E R is a C1-C6 heteroalkyl group. In some embodiments, R D is a C1-C6 haloalkyl. In some embodiments, R E is a C1-C6 haloalkyl. In some embodiments, R D is a cycloalkyl group. In some embodiments, R E is a cycloalkyl group. In some embodiments, R D is a heterocycline. In some embodiments, R E is a heterocycline. In some embodiments, R D is an arrow. In some embodiments, R E is an arrow. In some embodiments, R D is a heteroaryl compound. In some embodiments, R E is a heteroaryl compound. In some embodiments, R D is a C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R E is a C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R D R is a C1-C6 alkylene heteroaryl. In some embodiments, R E These are C1-C6 alkylene heteroaryl compounds.

[0125] In some embodiments, R A1 is hydrogen. In some embodiments, R A1 These are C1-C6 alkyl groups (for example, methyl groups).

[0126] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, y is 0 or 1. In some embodiments, y is 0. In some embodiments, y is 1.

[0127] In some embodiments, the compound of formula (I) is formula (Ib): [ka] Compounds thereof, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or saturates thereof. They are isomers, During the ceremony: A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of them is one or more R 1 It is optionally replaced by; X, Y, and Z are each independent of C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ), or O, where at least one of X, Y, and Z is N, N(R 3c ), or O, and the bonds within the ring containing X, Y, and Z may be single or double bonds, wherever the valence allows; L 2 It does not exist, or it is a C1-C6 alkylene, a C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-,-N(R 4 )C(O)-, or -C(O)N(R 4 )- where each alkylene and heteroalkylene is one or more R 5 It is optionally replaced by; Each R 1These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 6 It is optionally replaced by; or Two R's 1 The groups, together with the atoms to which they are bonded, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl group, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 6 It is optionally replaced by; Each R 2 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A and; R 3a and R 3b These are, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, and -OR. A , -NR B R C , -C(O)R D , or C(O)OR D is; or R 3a and R3b Each of them, together with the carbon atom to which they are bonded, forms an oxo group; R 3c is hydrogen or a C1-C6 alkyl group; Each R 4 These are independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; Each R 5 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and; Each R 6 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D ,-NO2,-C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally one or more R 11 It may also be replaced with; Each R 7 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA and; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D , or -S(O) x R D and; R B and R C Each of these can independently be hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 7 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R E These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R A1 is hydrogen or a C1-C6 alkyl group; m is 0, 1, or 2; x is 0, 1, or 2.

[0128] In some embodiments, A is one or more R 1 It is a heterocycline optionally substituted with . In some embodiments, A is a bicyclic heterocycline. In some embodiments, A is a monocyclic nitrogen-containing heterocycline. In some embodiments, A is a bicyclic nitrogen-containing heterocycline. In some embodiments, A is an optionally substituted piperidinyl. In some embodiments, A is an optionally substituted piperazinyl. In some embodiments, A is, [ka] And in the formula, each R 1 A is independently hydrogen or a C1-C6 alkyl group. In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0129] In some embodiments, A is, [ka] It is selected from the options.

[0130] In some embodiments, L 2 It does not exist. In some embodiments, L 2 This is a C1-C6 heteroalkylene, which is one or more R 5 It is optionally replaced by L. In some embodiments, L 2 is -C(O)N(R 4 )-. In some embodiments, L 2 It is -C(O)N(H)-.

[0131] In some embodiments, X is N. In some embodiments, X is C(R 3a ) is. In some embodiments, Y is N. In some embodiments, Z is C(R 3a )(for example, CH). In some embodiments, Z is N. In some embodiments, X and Y are independently N, and Z is C(R 3a )(for example, CH). In some embodiments, Y and Z are N, independently of each other, and X is C(R 3a )(For example, CH).

[0132] In some embodiments, [ka] teeth, [ka] Selected from.

[0133] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0134] In some embodiments, B is one or more R 1 It is a heteroaryl compound optionally substituted with . In some embodiments, B is a monocyclic heteroaryl compound. In some embodiments, B is a bicyclic heteroaryl compound. In some embodiments, B is a monocyclic nitrogen-containing heteroaryl compound. In some embodiments, B is a bicyclic nitrogen-containing heteroaryl compound. In some embodiments, B is an optionally substituted pyrazolyl compound. In some embodiments, B is, [ka] Selected from.

[0135] In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

[0136] In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a halo (e.g., fluoro). In some embodiments, R 2 is -OR A (For example, -OH). In some embodiments, m is 0.

[0137] In some embodiments, the compound of formula (I) is formula (Ic): [ka] The compound, or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer, During the ceremony: A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of them is one or more R 1 It is optionally replaced by; L 2 It does not exist, or it is a C1-C6 alkylene, a C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-,-N(R 4 )C(O)-, or -C(O)N(R 4 )- where each alkylene and heteroalkylene is one or more R 5 It is optionally replaced by; Each R 1These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 6 It is optionally replaced by; or Two R's 1 The groups, together with the atoms to which they are bonded, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl group, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 6 It is optionally replaced by; Each R 2 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A and; Each R 4 These are independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; Each R 5 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D, or -C(O)OR D and; Each R 6 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D Here, each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally one or more R 11 It may also be replaced with; Each R 7 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and aryl. , heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and; R B and R C Each of these can independently be hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 7 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R E These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R A1 is hydrogen or a C1-C6 alkyl group; m is 0, 1, or 2; x is 0, 1, or 2.

[0138] In some embodiments, A is one or more R 1 It is a heterocycline optionally substituted with . In some embodiments, A is a bicyclic heterocycline. In some embodiments, A is a monocyclic nitrogen-containing heterocycline. In some embodiments, A is a bicyclic nitrogen-containing heterocycline. In some embodiments, A is an optionally substituted piperidinyl. In some embodiments, A is an optionally substituted piperazinyl. In some embodiments, A is, [ka] And in the formula, each R 1 A is independently hydrogen or a C1-C6 alkyl group. In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0139] In some embodiments, A is, [ka] It is selected from the options.

[0140] In some embodiments, L 2 It does not exist. In some embodiments, L 2 This is a C1-C6 heteroalkylene, which is one or more R 5 It is optionally replaced by L. In some embodiments, L 2 is -C(O)N(R 4 )-. In some embodiments, L 2 It is -C(O)N(H)-.

[0141] In some embodiments, B is one or more R 1 It is a heteroaryl compound optionally substituted with . In some embodiments, B is a monocyclic heteroaryl compound. In some embodiments, B is a bicyclic heteroaryl compound. In some embodiments, B is a monocyclic nitrogen-containing heteroaryl compound. In some embodiments, B is a bicyclic nitrogen-containing heteroaryl compound. In some embodiments, B is an optionally substituted pyrazolyl compound. In some embodiments, B is, [ka] Selected from.

[0142] In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

[0143] In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a halo (e.g., fluoro). In some embodiments, R 2 is -OR A (For example, -OH). In some embodiments, m is 0.

[0144] In some embodiments, the compound of formula (I) is formula (Id): [ka] The compound, or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer, During the ceremony: A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of them is one or more R 1 It is optionally replaced by; L 2 It does not exist, or it is a C1-C6 alkylene, a C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-,-N(R 4 )C(O)-, or -C(O)N(R 4 )- where each alkylene and heteroalkylene is one or more R 5 It is optionally replaced by; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)RD , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 6 It is optionally replaced by; or Two R's 1 The groups, together with the atoms to which they are bonded, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl group, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 6 It is optionally replaced by; Each R 2 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A and; Each R 4 These are independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; Each R 5 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and; Each R 6 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)RD , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally one or more R 11 It may also be replaced with; Each R 7 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D , or -S(O) x R D and; R B and R C Each of these can independently be hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 7 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R E These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each RA1 is hydrogen or a C1-C6 alkyl group; m is 0, 1, or 2; x is 0, 1, or 2.

[0145] In some embodiments, A is one or more R 1 It is a heterocycline optionally substituted with . In some embodiments, A is a bicyclic heterocycline. In some embodiments, A is a monocyclic nitrogen-containing heterocycline. In some embodiments, A is a bicyclic nitrogen-containing heterocycline. In some embodiments, A is an optionally substituted piperidinyl. In some embodiments, A is an optionally substituted piperazinyl. In some embodiments, A is, [ka] And in the formula, each R 1 A is independently hydrogen or a C1-C6 alkyl group. In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0146] In some embodiments, A is, [ka] It is selected from the options.

[0147] In some embodiments, L 2 It does not exist. In some embodiments, L 2 This is a C1-C6 heteroalkylene, which is one or more R 5 It is optionally replaced by L. In some embodiments, L 2 is -C(O)N(R 4)-. In some embodiments, L 2 It is -C(O)N(H)-.

[0148] In some embodiments, B is one or more R 1 It is a heteroaryl compound optionally substituted with . In some embodiments, B is a monocyclic heteroaryl compound. In some embodiments, B is a bicyclic heteroaryl compound. In some embodiments, B is a monocyclic nitrogen-containing heteroaryl compound. In some embodiments, B is a bicyclic nitrogen-containing heteroaryl compound. In some embodiments, B is an optionally substituted pyrazolyl compound. In some embodiments, B is, [ka] Selected from.

[0149] In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

[0150] In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a halo (e.g., fluoro). In some embodiments, R 2 is -OR A (For example, -OH). In some embodiments, m is 0.

[0151] In some embodiments, the compound of formula (I) is formula (Ie): [ka] a compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R 1 ; W, X, Y, and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ), or O, wherein the bonds within the ring containing W, X, Y, and Z may be single or double bonds when the valency permits; each R 1 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D , wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 6 ; or two R 1 groups together with the atoms to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6 It is optionally replaced by; Each R 2 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A and; R 3a and R 3b These are, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, and -OR. A , -NR B R C , -C(O)R D , or C(O)OR D is; or R 3a and R 3b Each of them, together with the carbon atom to which they are bonded, forms an oxo group; R 3c is hydrogen or a C1-C6 alkyl group; Each R 6 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D ,-NO2,-C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally one or more R 11 It may also be replaced with; Each R 7 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, and C1-C6 alkylene-heteroaryl Reel, -C(O)R D , or -S(O) x R D and; R B and R C Each of these can independently be hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 7 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R E These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R A1 is hydrogen or a C1-C6 alkyl group; m is 0, 1, or 2; x is 0, 1, or 2; y is 1.

[0152] In some embodiments, A is one or more R 1It is a heterocycline optionally substituted with . In some embodiments, A is a bicyclic heterocycline. In some embodiments, A is a monocyclic nitrogen-containing heterocycline. In some embodiments, A is a bicyclic nitrogen-containing heterocycline. In some embodiments, A is an optionally substituted piperidinyl. In some embodiments, A is an optionally substituted piperazinyl. In some embodiments, A is, [ka] And in the formula, each R 1 A is independently hydrogen or a C1-C6 alkyl group. In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0153] In some embodiments, A is, [ka] It is selected from the options.

[0154] In some embodiments, at least one of W, X, Y, and Z is N or N(R) 3c ) is one of the following. In some embodiments, at least two of W, X, Y, and Z are N or N(R 3c ) In some embodiments, at least two of X, Y, and Z are N or N(R 3c ) In some embodiments, at least one of Y and Z is N or N(R 3c ) is. In some embodiments, X is N. In some embodiments, X is N(R 3c) It is. In some embodiments, at least one of W, X, Y, and Z is O. In some embodiments, X is O. In some embodiments, X is C(R 3a )(for example, CH). In some embodiments, X is C(R 3a )(R 3b ). In some embodiments, Y is N. In some embodiments, Y is N(R 3c ). In some embodiments, Y is C(R 3a )(for example, CH). In some embodiments, Y is C(R 3a )(R 3b ). In some embodiments, Z is N. In some embodiments, Z is N(R 3c ). In some embodiments, Z is C(R 3a )(for example, CH). In some embodiments, Z is C(R 3a )(R 3b ). In some embodiments, two of X, Y, and Z are N, and the rest of X, Y, and Z are C(R 3a )(for example, CH). In some embodiments, one of X, Y, and Z is C(R 3a )(for example, CH), and the rest of X, Y, and Z are each independently N. In some embodiments, X and Y are each independently N, and Z is C(R 3a )(for example, CH). In some embodiments, X is C(R 3a )(for example, CH), and Y and Z are each independently N.

[0155] In some embodiments, W is C(R 3a )(for example, CH) or C(R 3a )(R 3b )(for example, CH2). In some embodiments, W is C(R 3a )(for example, CH). In some embodiments, W is C(R 3a )(R 3b ). In some embodiments, W is C(R 3a)(for example, CH), and two of X, Y, and Z are N, and the remaining X, Y, and Z are C(R 3a )(for example, CH). In some embodiments, W is C(R 3a )(for example, CH), and one of X, Y, and Z is C(R 3a )(for example, CH), and the remainder of X, Y, and Z are each independently N. In some embodiments, X and Y are each independently N, and W and Z are each independently C(R 3a )(for example, CH). In some embodiments, W and X are each independently C(R 3a (For example, CH) and Y and Z are N independently.

[0156] In some embodiments, X, Y, and Z are independently N or C(R 3a ) where at least one of X, Y, and Z is N, and the bonds within the ring containing X, Y, and Z may be single or double bonds, as the valence allows.

[0157] In some embodiments, X is C(R 3a ) and Y is C(R 3a ) and Z is O. In some embodiments, X is C(R 3a ) and Y is C(R 3a ) and Z is O and y is 0. In some embodiments, X is C(R 3a ) and Y is C(R 3a ) and Z is O, and the bond between X and Y is a double bond. In some embodiments, X is Z, C(R 3a ) and Y is C(R 3a ) and Z is O, and the bond between Y and Z is a single bond.

[0158] In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0159] In some embodiments, B is optionally one or more R 1 It is a heteroaryl substituted with. In some embodiments, B is a monocyclic heteroaryl. In some embodiments, B is a bicyclic heteroaryl. In some embodiments, B is a monocyclic nitrogen-containing heteroaryl. In some embodiments, B is a bicyclic nitrogen-containing heteroaryl. In some embodiments, B is an optionally substituted pyrazolyl. In some embodiments, B is [ka] Selected from.

[0160] In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

[0161] In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a halo (e.g., fluoro). In some embodiments, R 2 is -OR A (For example, -OH). In some embodiments, m is 0.

[0162] In some embodiments, the compound of formula (I) is formula (If): [ka] The compound, or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer, During the ceremony: A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of them is one or more R 1 It is optionally replaced by; X, Y, and Z are each independent of C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ), or O, where at least one of X, Y, and Z is N, N(R 3c), or O, and the bonds within the ring containing X, Y, and Z may be single or double bonds, wherever the valence allows; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 6 It is optionally replaced by; or Two R's 1 The groups, together with the atoms to which they are bonded, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl group, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 6 It is optionally replaced by; Each R 2 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A and; R 3a and R 3b These are, independently, hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, and -OR. A , -NR B R C, -C(O)R D , or C(O)OR D is; or R 3a and R 3b Each of them, together with the carbon atom to which they are bonded, forms an oxo group. ; R 3c is hydrogen or a C1-C6 alkyl group; Each R 6 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D ,-NO2,-C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D Here, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally one or more R 11 It may also be replaced with; Each R 7 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D , or -S(O) x RD and; R B and R C Each of these can independently be hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 7 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R E These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R A1 is hydrogen or a C1-C6 alkyl group; m is 0, 1, or 2; x is 0, 1, or 2; y is 1.

[0163] In some embodiments, A is one or more R 1 It is a heterocycline optionally substituted with . In some embodiments, A is a bicyclic heterocycline. In some embodiments, A is a monocyclic nitrogen-containing heterocycline. In some embodiments, A is a bicyclic nitrogen-containing heterocycline. In some embodiments, A is an optionally substituted piperidinyl. In some embodiments, A is an optionally substituted piperazinyl. In some embodiments, A is, [ka] And in the formula, each R 1 A is independently hydrogen or a C1-C6 alkyl group. In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0164] In some embodiments, A is, [ka] It is selected from the options.

[0165] In some embodiments, X is N. In some embodiments, X is C(R 3a ) is. In some embodiments, Y is N. In some embodiments, Z is C(R 3a )(for example, CH). In some embodiments, Z is N. In some embodiments, X and Y are independently N, and Z is C(R 3a )(for example, CH). In some embodiments, Y and Z are N, independently of each other, and X is C(R 3a )(For example, CH).

[0166] In some embodiments, [ka] teeth, [ka] Selected from.

[0167] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0168] In some embodiments, B is one or more R 1 It is a heteroaryl compound optionally substituted with . In some embodiments, B is a monocyclic heteroaryl compound. In some embodiments, B is a bicyclic heteroaryl compound. In some embodiments, B is a monocyclic nitrogen-containing heteroaryl compound. In some embodiments, B is a bicyclic nitrogen-containing heteroaryl compound. In some embodiments, B is an optionally substituted pyrazolyl compound. In some embodiments, B is, [ka] Selected from.

[0169] In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

[0170] In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a halo (e.g., fluoro). In some embodiments, R 2 is -OR A (For example, -OH). In some embodiments, R 3a is hydrogen. In some embodiments, R 3cis hydrogen. In some embodiments, m is 0. In some embodiments, y is 0. In some embodiments, y is 1.

[0171] In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a halo (e.g., fluoro). In some embodiments, R 2 is -OR A (For example, -OH). In some embodiments, R 3a It is hydrogen. In one embodiment, R 3c m is hydrogen. In some embodiments, m is 0.

[0172] In some embodiments, the compound of formula (I) is selected from the compounds in Table 1, or from pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof.

[0173] [Table 1]

[0174] [Table 2]

[0175] [Table 3]

[0176] [Table 4]

[0177] [Table 5]

[0178] [Table 6]

[0179] [Table 7]

[0180] [Table 8]

[0181] [Table 9]

[0182] [Table 10]

[0183] [Table 11]

[0184] Pharmaceutical compositions, kits, and administrations The present invention provides a pharmaceutical composition comprising a compound of formula (I), for example, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer described herein, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, solvate, hydrate, tautomer or stereoisomer is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutic effective amount. In certain embodiments, the effective amount is a prophylactic effective amount.

[0185] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Generally, such preparation methods include the steps of associating a compound of formula (I) ("active ingredient") with a carrier and / or one or more other auxiliary ingredients, and, if necessary and / or desirable, then shaping and / or packaging the product into desired single or multi-dose units.

[0186] Pharmaceutical compositions may be prepared, packaged and / or sold in bulk as a single unit dose and / or as multiple single unit doses. As used herein, “unit dose” refers to a specific amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient that would be administered to a subject and / or a convenient proportion of such a dose, for example, half or one-third of such a dose.

[0187] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any further components in the pharmaceutical composition of the present invention vary depending on the identity, size, and / or condition of the target being treated, and further on the route through which the composition is administered. For example, the composition may contain 0.1% to 100% (w / w) of the active ingredient.

[0188] The term "pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not impair the pharmacological activity of the compound being formulated. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the present invention are any of those well known in the field of pharmaceutical formulations and include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. pharmaceutically acceptable excipients useful in the production of the pharmaceutical compositions of the present invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer - This includes, but is not limited to, polyethylene glycol and lanolin.

[0189] The compositions of the present invention may be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implanted reservoir. In some embodiments, the provided compounds or compositions may be administered intravenously and / or orally.

[0190] As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intraocular, intravitreous, intraarticular, intrasynovial, intrasternal, subarachnoid, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, subcutaneously, intraperitoneally, or intravenously. The sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using appropriate dispersing or wetting and suspending agents. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils have conventionally been used as solvents or suspension media.

[0191] The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For tablets for oral administration, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and suspending agent. Specific sweeteners, flavorings, or colorings may be added as needed. In some embodiments, the oral formulations provided are formulated for immediate release or sustained / delayed release. In some embodiments, the compositions are suitable for oral or sublingual administration and include tablets, lozenges, and troches. The compounds provided may be in microencapsulated form.

[0192] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. The pharmaceutically acceptable compositions of the present invention may be administered topically, particularly when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eyes, skin, or lower intestines. Appropriate topical formulations can be readily prepared for each of these areas or organs.

[0193] For use in the eyes, the pharmaceutically acceptable compositions provided may be formulated as a micronized suspension or in an ointment such as petrolatum.

[0194] To prolong the effects of a drug, it is often desirable to slow down its absorption from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low solubility in water. The absorption rate of the drug then depends on its dissolution rate, which may also depend on the crystal size and form. Alternatively, delayed absorption of parenterally administered drug dosage forms is achieved by dissolving or suspending the drug in an oil vehicle.

[0195] The descriptions of pharmaceutical compositions provided herein primarily concern pharmaceutical compositions suitable for administration to humans, but it will be understood by those skilled in the art that such compositions are generally suitable for administration to all kinds of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to various animals are well understood, and veterinary pharmacologists with ordinary skills can design and / or carry out such modifications in ordinary experiments.

[0196] The compounds provided herein are typically chosen for their ease of administration and uniformity of dosage. It is formulated in dose unit form, for example, in single-unit dosage form. However, it will be understood that the total daily dose of the composition of the present invention is to be determined by the attending physician within the bounds of sound medical judgment. A specific therapeutically effective dose level for any particular subject or organism depends on a variety of factors, including the severity of the disease and disorder being treated; the activity of the specific active ingredient used; the specific composition used; the subject's age, weight, general health, sex, and diet; the timing, route of administration, and excretion rate of the specific active ingredient used; the duration of treatment; drugs used in combination with or concurrently with the specific active ingredient used; and similar factors well known in the medical field.

[0197] The precise amount of compound required to achieve an effective dose varies from subject to subject, depending on factors such as the species, age, and overall health condition of the subject, the severity of side effects or disorders, the identity of the specific compound, and the mode of administration. The desired dose can be delivered three times a day, twice a day, once a day, every other day, every three days, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose can be delivered using multiple doses (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or more doses).

[0198] In certain embodiments, an effective amount of the compound for administration to a 70 kg adult human being once or more daily may contain, per unit dosage form, about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg of the compound.

[0199] In certain embodiments, the compound of formula (I) may be at a dose level sufficient to deliver, at least once daily, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, more preferably about 1 mg / kg to about 25 mg / kg relative to the subject's body weight per day.

[0200] It will be understood that the dose ranges described herein are intended to provide guidelines for administering the provided pharmaceutical compositions to adults. For example, the amount administered to children or adolescents may be determined by a physician or a person skilled in the art and may be lower or the same as the amount administered to adults.

[0201] It will also be understood that the compounds or compositions described herein may be administered in combination with one or more additional agents. The compounds or compositions may be administered in combination with further agents that improve their bioavailability, reduce and / or alter their metabolism, inhibit their excretion, and / or alter their distribution in the body. It will also be understood that the treatments employed may achieve the desired effect on the same disorder and / or different effects.

[0202] The compound or composition may be administered simultaneously with, or before or after, one or more additional agents that may be useful, for example, as a combination therapy. The agents may include therapeutic activators. The agents may also include prophylactic activators. Each additional agent may be administered in a dose and / or time schedule determined for that agent. The additional agents may be administered together and / or in single doses with the compound or composition described herein, or separately in different doses. The specific combination used in the regimen should take into account the compatibility of the compound of the present invention with the additional agents and / or the desired therapeutic and / or prophylactic effects to be achieved. Generally, additional agents used in combination are expected to be used at levels not exceeding those at which they would be used individually. In some embodiments, the combination The combined level when used together will be lower than the level when used individually.

[0203] Further exemplary drugs include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and analgesics. Drugs include drug compounds (e.g., compounds listed in the Code of Federal Regulations (CFR) and approved by the U.S. Food and Drug Administration), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and small organic molecules such as cells.

[0204] Kits (e.g., pharmaceutical packs) are also included in the present invention. Kits of the present invention may be useful for preventing and / or treating proliferative or nonproliferative disorders, for example, as described herein. A kit provided may comprise a pharmaceutical composition or compound of the present invention and a container (e.g., a vial, ampoule, bottle, syringe and / or dispenser package or other suitable container). In some embodiments, a kit provided may optionally further comprise a second container containing a pharmaceutical excipient for dilution or suspension of the pharmaceutical composition or compound of the present invention. In some embodiments, the container and the pharmaceutical composition or compound of the present invention provided in the second container are combined to form a single dosage form.

[0205] Accordingly, in one embodiment, a kit is provided comprising a first container containing a compound described herein or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof. In a particular embodiment, the kit of the present disclosure comprises a first container containing a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In a particular embodiment, the kit is useful for the prevention and / or treatment of a disease, disorder or condition described herein (e.g., proliferative or non-proliferative disorders) in a subject. In a particular embodiment, the kit further comprises instructions for administering the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof, to a subject for the prevention and / or treatment of a proliferative or non-proliferative disorder.

[0206] How to use Compounds useful for modulating splicing are described herein. In some embodiments, compounds of formula (I) can be used to increase or decrease splicing at splice sites, thereby altering the quantity, structure, or composition of nucleic acids (e.g., precursor RNA, e.g., premRNA or the resulting mRNA). In some embodiments, increasing or decreasing splicing modulates the level or structure of the gene product produced (e.g., RNA or protein). In some embodiments, compounds of formula (I) can modulate components of a splicing mechanism, for example, by modulating the interaction between components of the splicing mechanism and another entity (e.g., nucleic acids, proteins or combinations thereof). The splicing mechanisms referred to herein include one or more spliceosome components. Spliceosome components may include, for example, major spliceosome members (U1, U2, U4, U5, U6snRNP) or minor spliceosome members (U11, U12, U4atac, U6atacsnRNP) and one or more of their co-splicing factors.

[0207] In another embodiment, the present disclosure features a method for modifying a target (e.g., precursor RNA, e.g., premRNA) by including a splice site in the target, the method comprising providing a compound of formula (I). In some embodiments, the inclusion of a splice site in the target (e.g., precursor RNA, e.g., premRNA or the resulting mRNA) results in the addition or deletion of one or more nucleic acids to the target (e.g., a new exon, e.g., skid). (Added exons). The addition or deletion of one or more nucleic acids to a target may result in an increase in the level of the gene product (e.g., RNA, e.g., mRNA or protein).

[0208] In another embodiment, the present disclosure features a method for modifying a target (e.g., precursor RNA, e.g., premRNA or obtained mRNA) by eliminating a splice site in the target, the method comprising providing a compound of formula (I). In some embodiments, the elimination of a splice site in the target (e.g., precursor RNA, e.g., premRNA) results in the deletion or addition of one or more nucleic acids from the target (e.g., skipped exons, e.g., new exons). The deletion or addition of one or more nucleic acids to the target may result in a decrease in the level of the gene product (e.g., RNA, e.g., mRNA or protein). In other embodiments, a method for modifying a target (e.g., precursor RNA, e.g., premRNA or the resulting mRNA) includes, for example, suppressing or enhancing splicing at the splice site (e.g., more than about 0.5%, e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more) compared to a reference (e.g., the absence of the compound of formula (I) or healthy or diseased cells or tissue).

[0209] The methods described herein can be used, for example, to modulate the splicing of nucleic acids containing a specific sequence (e.g., a target sequence). Exemplary genes encoding a target sequence (e.g., DNA or RNA, including premRNA) include, in particular, ABCA4, ABCA9, ABCB1, ABCB5, ABCC9, ABCD1, ACADL, ACADM, ACADSB, ACSS2, ACTB, ACTG2, ADA, ADAL, ADAM10, ADAM15, ADAM22, ADAM32, ADAMTS12, ADAMTS13, ADAMTS20, ADAMTS6, ADAMTS9, ADAR, ADCY3, ADCY10, ADCY8, ADNP, ADRBK2, AFP, AGL, AGT, AHCTF1, AHR, AKAP10, AKAP3, AKNA, ALAS1, ALS2CL, ALB, ALDH3A2, ALG6, AMBRA1, ANK3, ANTXR2, ANXA10, ANXA11, A NGPTL3, AP2A2, AP4E1, APC, APOA1, APOB, APOC3, APOH, AR, ARID2, ARID3A, ARID3B, ARFGEF1, ARFGEF2, ARHGAP1, ARHGAP8, ARHGAP18, ARHGAP26 , ARHGEF18, ARHGEF2, ARPC3, ARS2, ASH1L, ASH1L-IT1, ASNSD1, ASPM, ATAD5, ATF1, ATG4A, ATG16L2, ATM, ATN1, ATP11C, ATP6V1G3, ATP13A5, AT P7A, ATP7B, ATR, ATXN2, ATXN3, ATXN7, ATXN10, AXIN1, B2M, B4GALNT3, BBS4, BCL2, BCL2L1, BCL2-like 11 (BIM), BCL11B, BBOX1, BCS1L, BEAN1, BHLH E40, BMPR2, BMP2K, BPTF, BRAF, BRCA1, BRCA2, BRCC3, BRSK1, BRSK2, BTAF1, BTK, C2orf55, C4orf29, C6orf118, C9orf43, C9orf72, C10orf137, C11orf30, C11orf65, C11orf70, C11οrf87, C12orf51, C13orf1, C13orf15, C14orf10l, C14orf118, C15orf29, C15orf42, C15orf60, C16orf33,C16orf38, C16orf48, C18orf8, C19orf42, C1orf107, C1orf114, C1orf130, C1orf149, C1orf27, C1orf71, C1orf94, C1R, C20orf74, C21orf70, C3orf23, C4orf18, C5orf34, C8B, C8orf33, C9orf114, C9orf86, C9orf98, C3, CA11, CAB39, CACHD1, CACNA1A, CACNA1B, CACNA1C, CACNA2D1, CACNA1G, CACNA1H, CALCA, CALCOCO2, CAMK1D, CAMKK1, C, APN3、CAPN9、CAPSL、CARD11、CARKD、CASZ1、CAT、CBLB、CBX1、CBX3、CCDC102B、CCDC11、CCDC15、CCDC18、CCDC5、CCDC81、CCDC131、CCDC146、CD4、CD274、CD1B、CDC14A、CDC16、CDC2L5、CDC42BPB、CDCA8、CDH10、CDH11、CDH24、CDH8、CDH9、CDK5RAP2、CDK6、CDK8、CDK11B、CD33、CD46、CDH1、CDH23、CDK6、CDK11B、CDK13、CEBPZ、CEL、CELSR3、CENPA、CENPI、CENPT、CENTB2、CENTG2、CEP110、CEP170、CEP192、CETP、CFB、CFTR、CFH、CGN、CGNL1、CHAF1A、CHD9、CHIC2、CHL1、CHN1、CHM、CLEC16A、CL1C2、CLCN1、CLINT1、CLK1、CLPB、CLPTM1、CMIP、CMYA5、CNGA3、CNOT1、CNOT7、CNTN6、COG3、COL11A1、COL11A2、COL12A1、COL14A1、COL15A1、COL17A1、COL19A1、COL1A1、COL1A2、COL2A1、COL3A1、COL4A1、COL4A2、COL4A5、COL4A6、COL5A2、COL6A1、COL7A1、COL9A1、COL9A2、COL22A1、COL24A1、COL25A1、COL29A1、COLQ、COMTD1、COPA、COPB2、COPS7B、COPZ2、CPSF2、CPXM2、CR1、CRBN、CRYZ、CREBBP、CRKRS、CSE1L、CSTB、CSTF3、CT45-6、CTNNB1、CUBN、CUL4B、CUL5、CXorf41、CXXC1、CYBB、CYFIP2、CYP3A4、CYP3A43、CYP3A5、CYP4F2、CYP4F3、CYP17、CYP19、CYP24A1、CYP27A1、DAB1、DAZ2、DCBLD1、DCC、DCTN3、DCUN1D4、DDA1、DDEF1、DDX1、DDX24、DDX4、DENND2D、DEPDC2、DES、DGAT2、DHFR、DHRS7、DHRS9、DHX8、DIP2A、DMD、DMTF1、DNAH3、DNAH8、DNAI1、DNAJA4、DNAJC13、DNAJC7、DNMT1、DNTTIP2、DOCK4、DOCK5、DOCK10、D OCK11、DOT1L、DPP3、DPP4、DPY19L2P2、DR1、DSCC1、DVL3、DUX4、DYNC1H1、DY SF、E2F1、E2F3、E2F8、E4F1、EBF1、EBF3、ECM2、EDEM3、EFCAB3、EFCAB4B、EFN A4、EFTUD2、EGFR、EIF3A、ELA1、ELA2A、ELF2、ELF3、ELF4、EMCN、EMD、EML5、EN O3、ENPP3、EP300、EPAS1、EPB41L5、EPHA3、EPHA4、EPHB1、EPHB2、EPHB3、EPS 15、ERBB4、ERCC1、ERCC8、ERGIC3、ERMN、ERMP1、ERN1、ERN2、ESR1、ESRRG、ET S2, ETV3, ETV4, ETV5, ETV6, EVC2, EWSR1, EXO1, EXOC4, F3, F11, F13A1, F5, F7, F8, FAH, FAM13A1, FAM13B1, FAM13C1, FAM134A, FAM161A, FAM176B, FAM184 A, FAM19A1, FAM20A, FAM23B, FAM65C, FANCA, FANCC, FANCG, FANCM, FANK1, FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGBP, FECH, FEZ2, FGA, FGD6, FGFR2, F GFR1OP、FGFR1OP2、FGFR2、FGG、FGR、FIX、FKBP3、FLI1、FLJ35848、FLJ36070 、FLNA、FN1、FNBP1L、FOLH1、FOSL1、FOSL2、FOXK1、FOXM1、FOXO1、FOXP4、FRAS 1, FUT9, FXN, FZD3, FZD6, GAB1, GABPA, GALC, GALNT3, GAPDH, GART, GAS2L3, GATA3, GATAD2A, GBA, GBGT1, GCG, GCGR, GKK, GFI1, GFM1, GH1, GHR, GHV, GJA 1、GLA、GLT8D1、GNA11、GNAQ、GNAS、GNB5、GOLGB1、GOLT1A、GOLT1B、GPATCH1 、GPR158、GPR160、GPX4、GRAMD3、GRHL1、GRHL2、GRHPR、GRIA1、GRIA3、GRIA4、GRIN2、 B, GRM3, GRM4, GRN, GSDMB, GSTCD, GSTO2, GTF2I, GTPBP4, HADHA, HAND2, HBA 2、HBB、HCK、HDAC3、HDAC5、HDX、HEPACAM2、HERC1、HES7、HEXA、HEXB、HHEX、H IPK3, HLA-DPB1, HLA-G, HLCS, HLTF, HMBS, HMGA1, HMGCL, HNF1A, HNF1B, HNF 4A、HNF4G、HNRNPH1、HOXC10、HP1BP3、HPGD、HPRT1、HPRT2、HSF1、HSF4、HSF2 BP、HSPA9、HSPG2、HTT、HXA、ICA1、IDH1、IDS、IFI44L、IKBKAP、IKZF1、IKZF3 IL1R2, IL5RA, IL7RA, IMMT, INPP5D, INSR, INTS3, INTU, IP04, IP08, IQGAP 2、IRF2、IRF4、IRF8、IRX3、ISL1、ISL2、ITFG1、ITGA6、ITGAL、ITGB1、ITGB2、 1TGB3、ITGB4、ITIH1、ITPR2、IWS1、JAK1、JAK2、JAG1、JMJD1C、JPH3、KALRN、K AT6A、KATNAL2、KCNN2、KCNT2、KDM2A、KIAA0256、KIAA0528、KIAA0564、KIAA 0586、KIAA1033、KIAA1166、KIAA1219、KIAA1409、KIAA1622、KIAA1787、KIF 3B、KIF15、KIF16B、KIF5A、KIF5B、KIF9、KIN、KIR2DL5B、KIR3DL2、KIR3DL3、 KIT, KLF3, KLF5, KLF7, KLF10, KLF12, KLF16, KLHL20, KLK12, KLKB1, KMT2A, K MT2B、KPNA5、KRAS、KREMEN1、KRIT1、KRT5、KRTCAP2、KYNU、L1CAM、L3MBTL、L 3MBTL2, LACE1, LAMA1, LAMA2, LAMA3, LAMB1, LARP7, LDLR, LEF1, LENG1, LGA LS3, LGMN, LHCGR, LHX3, LHX6, LIMCH1, LIMK2, LIN28B, LIN54, LMBRD1, LMBR D2、LMLN、LMNA、LMO2、LMO7、LOC389634、LOC390110、LPA、LPCAT2、LPL、LRP4、LRPPRC、LRRK2、LRRC19、LRRC42、LRWD1、LUM、LVRN、LYN、LYST、MADD、MAGI1、MAGT1、MALT1、MAP2K1、MAP4K4、MAPK8IP3、MAPK9、MA PT、MARC1、MARCH5、MATN2、MBD3、MCF2L2、MCM6、MDGA2、MDM4、ASXL1、FUS、SPR54、MECOM、MEF2C、MEF2D、MEGF10、MEGF11、MEMO1、ME T, MGA, MGAM, MGAT4A, MGAT5, MGC16169, MGC34774, MKKS, MIB1, MIER2, MITF, MKL2, MLANA, MLH1, MLL5, MLX, MME, MPDZ, MPI, MRAP2, MRPL11, MRPL39, MRPS28, MRPS35, MS4A13, MSH2, MSH3, MSMB, MST1R, MTDH, MTERF3, MTF1, MTF2, MTIF2, MTHFR, MUC2, MUT, MVK, MY B, MYBL2, MYC, MYCBP2, MYH2, MYRF, MYT1, MY019, MY03A, MY09B, MYOM2, MYOM3, NAG, NARG1, NARG2, NCOA1, NDC80, NDFIP2, NEB, NEDD4, NEK1, NEK5, NEK11, NF1, NF2, NFATC2, NFE2L2, NFIA, NFIB, NFIX, NFKB1, NFKB2, NFKBIL2, NFRKB, NFYA, NFYB, NIPA2, NKAIN2, N KAP, NLRC3, NLRC5, NLRP3, NLRP7, NLRP8, NLRP13, NME1, NME1-NME2, NME2, NME7, NOL10, NOP561, NOS1, NOS2A, NOTCH1, NPAS4, NPM1, NR1D1, NR1H3, NR1H4, NR4A3, NR5A1, NRXN1, NSMAF, NSMCE2, NT5C, NT5C2, NT5C3, NUBP1, NUBPL, NUDT5, NUMA1, NUP88, NUP98, N UP160、NUPL1、OAT、OAZ1、OBFC2A、OBFC2B、OLIG2、OMA1、OPA1、OPN4、OPTN 、OSBPL11、OSBPL8、OSGEPL1、OTC、OTX2、OVOL2、OXT、PA2G4、PADI4、PAH、P AN2、PAOX、PAPOLG、PARD3、PARP1、PARVB、PAWR、PAX3、PAX8、PBGD、PBRM1、PBX2、PCBP4、PCCA、PCGF2、PCNX、PCOTH、PDCD4、PDE4D、PDE8B、PDE10A、PD1A3、PDH1、PDLIM5、PDXK、PDZRN3、PELI2、PDK4、PDS5A、PDS5B、PGK1、PGM2、PHACTR4、PHEX、PHKB、PHLDB2、PHOX2B、PHTF1、PIAS1、PIEZO1、PIGF、PIGN、PIGT、PIK3C2G、PIK3CA、PIK3CD、PIK3CG、PIK3RI、PIP5K1A、PITRM1、PIWIL3、PKD1、PKHD1L1、PKD2、PKIB、PKLR、PKM1、PKM2、PLAGL2、PLCB1、PLCB4、PLCG1、PLD1、PLEKHA5、PLEKHA7、PLEKHM1、PLKR、PLXNC1、PMFBP1、POLN、POLR3D、POMT2、POSTN、POU2AF1、POU2F2、POU2F3、PPARA、PPFIA2、PPP1R12A、PPP3CB、PPP4C、PPP4R1L、PPP4R2、PRAME、PRC1、PRDM1、PREX1、PREX2、PRIM1、PRIM2、PRKAR1A、PRKCA、PRKG1、PRMT7、PROC、PROCR、PROSC、PRODH、PROX1、PRPF40B、PRPF4B、PRRG2、PRUNE2、PSD3、PSEN1、PSMAL、PTCH1、PTEN、PTK2、PTK2B、PTPN2、PTPN3、PTPN4、PTPN11、PTPN22、PTPRD、PTPRK、PTPRM、PTPRN2、PTPRT、PUS10、PVRL2、PYGM、QRSL1、RAB11FIP2、RAB23、RAF1、RALBP1、RALGDS、RB1CC1、RBL2、RBM39、RBM45、RBPJ、RBSN、REC8、RELB、RFC4、RFT1、RFTN1、RHOA、RHPN2、RIF1、RIT1、RLN3、RMND5B、RNF11、RNF32、RNFT1、RNGTT、ROCK1、ROCK2、RORA、RP1、RP6KA3、RP11-265F1、RP13-36C9、RPAP3、RPN1、RPGR、RPL22、RPL22L1、RPS6KA6、RREB1、RRM1、RRP1B、RSK2、RTEL1、RTF1、RUFY1、RUNX1、RUNX2、RXRA、RYR3、S AAL1、SAE1、SALL4、SAT1、SATB2、SBCAD、SCN1A、SCN2A、SCN3A、SCN4A、SCN5A、 SCN8A、SCNA、SCN11A、SCO1、SCYL3、SDC1、SDK1、SDK2、SEC24A、SEC24D、SEC3 1A、SEL1L、SENP3、SENP6、SENP7、SERPINA1、SETD3、SETD4、SETDB1、SEZ6、SFR S12, SGCE, SGOL2, SGPL1, SH2D1A, SH3BGRL2, SH3PXD2A, SH3PXD2B, SH3RF2, SH3TC2, SHOC2, SIPA1L2, SIPA1L3, SIVA1, SKAP1, SKIV2L2, SLC6A11, SLC6A1 3, SLC6A6, SLC7A2, SLC12A3, SLC13A1, SLC22A17, SLC25A14, SLC28A3, SLC33A1, SLC35F6, SLC38A1, SLC38A4, SLC39A10, SLC4A2, SLC6A8, SMARCA1, SMAR CA2、SMARCA5、SMARCC2、SMC5、SMN2、SMOX、SMS、SMTN、SNCAIP、SNORD86、SNR K、SNRP70、SNX5、SNX6、SOD1、SOD10、SOS、SOS2、SOX5、SOX6、SOX8、SP1、SP2、S P3、SP110、SPAG9、SPATA13、SPATA4、SPATS1、SPECC1L、SPDEF、SPI1、SPINK5 、SPP2、SPTA1、SRF、SRM、SRP72、SSX3、SSX5、SSX9、STAG1、STAG2、STAMBPLI、S TARD6、STAT1、STAT3、STAT5A、STAT5B、STAT6、STK17B、STX3、STXBP1、SUCLG 2、SULF2、SUPT6H、SUPT16H、SV2C、SYCP2、SYT6、SYCPI、SYTL3、SYTL5、TAF2、T ARDBP、TBC1D3G、TBC1D8B、TBC1D26、TBC1D29、TBCEL、TBK1、TBP、TBPL1、TBR1 、TBX、TCEB3、TCF3、TCF4、TCF7L2、TCFL5、TCF12、TCP11L2、TDRD3、TEAD1、TE、 AD3, TEAD4, TECTB, TEK, TERF1, TERF2, TET2, TFAP2A, TFAP2B, TFAP2C, TFAP4, TFDP1, TFRC, TG, TGM7, TGS1, THAP7, THAP12, THOC2, TIAL1, TIAM2, TIMM50, TLK2, TM4SF20, TM6SF1, TMEM27, TMEM77, TMEM156, TMEM194A, TMF1, TMPRSS6, TNFRSF10A, TNFRSF10B, TNFRSF8, TNK2, TNKS, TNKS2, TOM1L1, TOM1L2, TOP2B, TP53, TP53INP1, TP53BP2, TP53I3, TP63, TRAF3IP3, TRAPPC2, TRIM44, TRIM65, TRIML1, TRIML2, TRPM3, TRPM5, TRPM7, TRPS1, TSC1, TSC2, TSHB, TSPAN7, TTC17, TTF1, TTLL5, TTLL9, TTN, TTPAL, TTR, TUSC3, TXNDC10, UBE3A, UCK1, UGT1A1, UHRF1BP1, UNC45B, UNC5C, USH2A, USF2, USP1, USP6, USP18, USP38, USP39, UTP20, UTP15, UTP18, UTRN, UTX, UTY, UVRAG, UXT, VAPA, VEGFA, VPS29, VPS35, VPS39, VT11A, VT11B, VWA3B, WDFY2, WDR16, WDR17, WDR26, WDR44, WDR67, WDTC1, WRN, WRNIP1, WT1, WWC3, XBP1, XRN1, XRN2, XX-FW88277, YAP1, YARS, YBX1, YGM, YY1, ZBTB18, ZBTB20, ZC3HAV1, ZC3HC1, ZC3H7A, ZDHHC19, ZEB1, ZEB2, ZFPM1, ZFYVE1, ZFX, ZIC2, ZNF37A, ZNF91, ZNF114, ZNF155, ZNF169, ZNF205, ZNF236, ZNF317, ZNF320, ZNF326, ZNF335, ZNF365, ZNF367, ZNF407, ZNF468, ZNF506, ZNF511, ZNF511-PRAPI, ZNF519, ZNF521, ZNF592, ZNF618, ZNF763 and ZWINT are included.

[0210] Note: There seems to be a typo in the original text where "ZNF511-PRAP1" should probably be "ZNF511-PRAPI". This has been corrected in the translation as "ZNF511-PRAPI". Further exemplary genes encoding target sequences (e.g., DNA or RNA, including premRNA) include A1CF, A4GALT, AAR2, ABAT, ABCA11P, ZNF721, ABCA5, ABHD10, ABHD13, ABHD2, ABHD6, AC000120.3, KRIT1, AC004076.1, ZNF772, AC004076.9, ZNF772, AC004223.3, RAD51D, AC004381.6, AC006486.1, ERF, AC007390.5, and AC00778. 0.1, PRKAR1A, AC007998.2, INO80C, AC009070.1, CMC2, AC009879.2, AC009879.3, ADHFE1, AC010487.3, ZNF816-ZNF321P, ZNF816, AC010328.3, A C010522.1, ZNF587B, AC010547.4, ZNF19, AC012313.3, ZNF497, AC012651.1, CAPN3, AC013489.1, DET1, AC016747.4, C2orf74, AC020907.6, FXYD 3, AC021087.5, PDCD6, AHRR, AC022137.3, ZNF761, AC025283.3, NAA60, AC027644.4, RABGEF1, AC055811.2, FLCN, AC069368.3, ANKDD1A, AC07361 0.3, ARF3, AC074091.1, GPN1, AC079447.1, LIPT1, AC092587.1, AC079594.2, TRIM59, AC091060.1, C18orf21, AC092143.3, MC1R, AC093227.2, ZN F607, AC093512.2, ALDOA, AC098588.1, ANAPC10, AC107871.1, CALML4, AC114490.2, ZMYM6, AC138649.1, NIPA1, AC138894.1, CLN3, AC139768.1, AC242426.2, CHD1L, ACADM, ACAP3, ACKR2, RP11-141M3.5, KRBOX1, ACMSD, ACOT9, ACP5, ACPL2, ACSBG1, ACSF2, ACSF3, ACSL1, ACSL3, ACVR1, ADAL, ADAM29, ADAMTS10, ADAMTSL5, ADARB1, ADAT2, ADCK3, ADD3, ADGRG1, ADGRG2, ADH1B, ADIPOR1, ADNP, ADPRH, AGBL5, AGPAT1, AGPAT3, AGR2, AGTR1, AHDC1, AHI1, AHNAK, AIFM1, AIFM3, AIMP2, AK4, AKAP1, AKNAD1, CLCC1, AKR1A1, AKT1 、AKT1S1、AKT2、AL139011.2、PEX19、AL157935.2、ST6GALNAC6、AL358113.1、TJP2、AL441992.2、KYAT1、AL449266. 1,CLCC1、AL590556.3、LINC00339、CDC42、ALAS1、ALB、ALDH16A1、ALDH1B1、ALDH3A1、ALDH3B2、ALDOA、ALKBH2、ALP L、AMD1、AMICA1、AMN1、AMOTL2、AMY1B、AMY2B、ANAPC10、ANAPC11、ANAPC15、ANG、RNASE4、AL163636.2、ANGEL2、ANG PTL1、ANKMY1、ANKRD11、ANKRD28、ANKRD46、ANKRD9、ANKS3、ANKS3、RP11-127I20.7、ANKS6、ANKZF1、ANPEP、ANXA11 、ANXA2、ANXA8L2、AL603965.1、AOC3、AP000304.12、CRYZL1、AP000311.1、CRYZL1、AP000893.2、RAB30、AP001267. 5、ATP5MG、AP002495.2、AP003175.1、OR2AT4、AP003419.1、CLCF1、AP005263.1、ANKRD12、AP006621.5、AP006621.1, AP1G1, AP3M1, AP3M2, APBA2, APBB1, APLP2, APOA2, APOL1, APOL3, APTX, ARAP1, STARD10, ARF4, ARFIP1, ARFIP2, ARFRP1, AHRGAP11A, AHRGAP33, AHRGAP4, AHRGEF10, AHRGEF3, AHRGEF35, OR2A1-AS1, AHRGEF35, OR2A1-AS1, AHRGEF34P, ARID1B, AHRGEF35, OR2A20P, OR2A1-AS1, AHRGEF9, AR L1, ARL13B, ARL16, ARL6, ARMC6, ARMC8, ARMCX2, ARMCX5, RP4-769N13.6, ARMCX5-GPRASP2, BHLHB9, ARMCX5-GPRASP2, GPRASP1, ARMCX5-GPRASP2, GPRASP2, ARMCX6, ARNT2, ARPP19, ARRB2, ARSA, ART3, ASB3, GPR75-ASB3, ASCC2, ASNS, AC079781.5, ASPSCRI1, ASS1, ASUN, ATE1, ATF1, ATF 7IP2、ATG13、ATG4D、ATG7、ATG9A、ATM、ATOX1、ATP1B3、ATP2C1、ATP5F1A 、ATP5G2、ATP5J、ATP5MD、ATP5PF、ATP6AP2、ATP6V0B、ATP6V1C1、ATP6V1D 、ATP7B、ATXN1、ATXN1L,IST1、ATXN3、ATXN7L1、AURKA、AURKB、AXDND1、B 3GALNT1、B3GALT5,AF064860.1、B3GALT5,AF064860.5、B3GNT5、B4GALT3 、B4GALT4、B9D1、BACH1、BAIAP2、BANF1、BANF2、BAX、BAZ2A、BBIP1、BCHE 、BCL2L14、BCL6、BCL9L、BCS1L、BDH1、BDKRB2,AL355102.2、BEST1、BEST3 、BEX4、BHLHB9、BID、BIN3、BIRC2、BIVM、BIVM-ERCC5、BIVM、BLCAP、BLK、 BLOC1S1、RP11-644F5.10、BLOC1S6、AC090527.2、BLOC1S6、RP11-96O20.4、BLVRA、BMF、BOLA1、BORCS8-MEF2B、BORCS8、BRCA1、BRD1、BRDT、BRINP3、BROX、BTBD10、BTBD3、BTBD9、BTD、BTF3L4、BTNL9、BUB1B-PAK6、PAK6、BUB3、C10orf68、C11orf1、C11orf48、C11orf54、C11orf54,AP001273.2、C11orf57、C11orf63、C11orf82、C12orf23、C12orf4、C12orf65、C12orf79、C14orf159、C14orf93、C17orf62、C18orf21、C19orf12、C19orf40、C1. 9orf47、C19orf48、C19orf54、C1D、C1GALT1、C1QB、C1QTNF1、C1S、C1orf101、C1orf112、C1orf116、C1orf159、C1orf63、C2、C2,CFB、C20orf27、C21orf58、C2CD4D、C2orf15、LIPT1、MRPL30、C2orf80、C2orf81、C3orf14、C3orf17、C3orf18、C3orf22、C3orf33,AC104472.3、C4orf33、C5orf28、C5orf34、C6orf118、C6orf203、C6orf211、C6orf48、C7orf50、C7orf55、C7orf55-LUC7L2、LUC7L2、C8orf44-SGK3、C8orf44、C8orf59、C9,DAB2、C9orf153、C9orf9、CA5BP1,CA5B、CABYR、CALCA、CALCOCO1、CALCOCO2、CALM1、CALM3、CALML4、RP11-315D16.2、CALN1、CALU、CANT1、CANX、CAP1、CAPN12、CAPS2、CARD8、CARHSP1、CARNS1、CASC1、CASP3、CASP7、CBFA2T2、CBS、CBY1、CCBL1、CCBL2、RBMXL1、CCDC12、CCDC126、CCDC14、CCDC149、CCDC150、CCDC169-SOHLH2、CCDC169、CCDC171、CCDC37、CCDC41、CCDC57、CCDC63、CCDC7、CCDC74B、CCDC77、CCDC82、CCDC90B、CCDC91、CCDC92、CCNE1、CCHCR1、CCL28、CCNB1IP1、CCNC、CCND3、CCNG1、CCP110、CCR9、CCT7、CCT8、CD151、CD1D、CD200、CD22、CD226、CD276、CD36、CD59、CDC26、CDC42、CDC42SE1、CDC42SE2、CDHR3、CDK10、CDK16、CDK4、CDKAL1、CDKL3,CTD-2410N18.4、CDKN1A、CDKN2A、CDNF、CEBPZOS、CELF1、CEMIP、CENPK、CEP170B、CEP250、CEP57、CEP57L1、CEP63、CERS4、CFL1、CFL2、CFLAR、CGNL1、CHCHD7、CHD1L、CHD8、CHFR,ZNF605、CHIA、CHID1、CHL1、CHM、CHMP1A、CHMP3、RNF103-CHMP3、CHRNA2、CIDEC、CIRBP、CITED1、CKLF-CMTM1、CMTM1、CKMT1B、CLDN12,CTB-13L3.1、CLDND1,AC021660.3、CLDND1,CPOX、CLHC1、CLIP1、CLUL1、CMC4、MTCP1、CNDP2、CNFN、CNOT1、CNOT6、CNOT7、CNOT8、CNR1、CNR2、CNTFR、CNTRL、COA1、COASY、COCH、COL8A1、COLCA1、COLEC11、COMMD3-BMI1、BMI1、COPS5、COPS7B、COQ8A、CORO6、COTL1、COX14,RP4-605O3.4、COX7A2、COX7A2L、COX7B2、CPA4、CPA5、CPEB1、CPNE1、AL109827.1、RBM12、CPNE1、RP1-309K20.6、RBM12、CPNE3、CPSF3L、CPT1C、CREB3L2、CREM、CRP、CRYZ、CS,AC073896.1、CS、RP11-977G19.10、CSAD、CSDE1、CSF2RA、CSGALNACT1、CSK、CSNK2A1、CSRNP2、CT45A4、CT45A4、CT45A5、CT45A6、CTBP2、CTCFL、CTD-2116N17.1、KIAA0101、CTD-2349B8.1、SYT17、CTD-2528L19.4、ZNF607、CTD-2619J13.8、ZNF497、CTNNA1、CTNNBIP1、CTNND1、CTPS2、CTSB、CTSL、CTTN、CUL2、CUL9、CWC15、CXorf40B 、CYB561A3、CYBC1、CYLD、CYP11A1、CYP2R1、CYP4B1、CYP4F22、DAG1、DAGLB,KDELR2、DARS、DBN L、DCAF11、DCAF8,PEX19、DCLRE1C、DCTD、DCTN1、DCTN4、DCUN1D2、DDR1、DDX11、DDX19B、AC012 184.2、DDX19B、RP11-529K1.3、DDX25、DDX39B、ATP6V1G2-DDX39B、SNORD84、DDX42、DDX60L、. DEDD, DEDD2, DEFA1, DEFA1B, DEFA1B, DEFA3, DENND1C, DENND2A, DENND4B, DET1, DGKA, DGKZ, DGLUCY, DHRS4L2, DHRS9, DHX40, DIABLO, AC048338.1, DIAPH1, DICER1, DKKL1, DLG1, DLG3, DLST, DMC1 DMKN、DMTF1、DMTN、DNAJC14、DNAJC19、DNAL1、DNASE1L1、DNMT3A、DOC2A、DOCK8、DOK1、DOPEY1、DPAGT1、DPP8、DRAM2、DRD2、DROSHA、DSN1、DTNA、DTX2 、DTX3、DUOX1、DUOXA1、DUS2、DUSP10、DUSP13、DUSP18、DUSP22、DYDC1、DYDC2、DYNLL1、DYNLT1、DYRK1A、DYRK2、DYRK4、RP11-500M8.7、DZIP1L、E2F6、E CHDC1, ECSIT, ECT2, EDC3, EDEM1, EDEM2, MMP24-AS1, RP4-614O4.11, EEF1AKNMT, EEF1D, EFEMP1, EFHC1, EGFL7, EHF, EI24, EIF1AD, EIF2B5, EIF4G1, EIF2B5, POLR2H, EIF3E, EIF3K, EIF4E3, EIF4G1, ELF1, ELMO2, ELMOD1, AP000889.3, ELMOD3, ELOC, ELOF1, ELOVL1, ELOVL7, ELP1, ELP6, EML3, EMP3, ENC 1、ENDOV、ENO1、ENPP5、ENTHD2、ENTPD6、EP400NL、EPB41L1、EPDR1、NME8、EPHX1、EPM2A、EPN1、EPN2、EPN3、EPS8L2、ERBB3、ERC1、ERCC1、ERG、ERI2、ER I2、DCUN1D3、ERLIN2、ERMARD、ERRFI1、ESR2、RP11-544I20.2、ESRRA、ESRRB、ESRRG、ETFA、ETFRF1、ETV1、ETV4、ETV7、EVA1A、EVC2、EVX1、EXD2、EXO5、E XOC1、EXOC2、FAAP24、FABP6、FADS1、FADS2、FAHD2B、FAM107B、FAM111A、FAM111B、FAM114A1、FAM114A2、FAM115C、FAM115C、FAM115D、FAM120B、FAM133 B、FAM135A、FAM153A、FAM153B、FAM154B、FAM156A、FAM156B、FAM168B、FAM172A、FAM182B、FAM192A、FAM19A2、FAM200B、FAM220A、FAM220A、AC009412.1、FAM222B、FAM227B、FAM234A、AC004754.1、FAM3C、FAM45A、FAM49B、FAM60A、FAM63A、FAM81A、FAM86B1、FAM86B2、FANCI、FA NK1、FAR2、FAXC、FAXDC2、FBF1、FBH1、FBXL4、FBXO18、FBXO22、FBXO31、FBXO41、FBXO44、FBXO45、FBXW9、FCHO1、FCHSD2、FDFT 1、FDPS、FER、FETUB、FGD4、FGF1、FGFR1、FGFRL1、FGL1、FHL2、FIBCD1、FIGNL1、FIGNL1,DDC、FKBP5、FKRP、FLRT2、FLRT3、FMC1 、LUC7L2、FMC1-LUC7L2、FNDC3B、FOLH1、FOLR1、FOXP1、FOXK1、FOXM1、FOXO1、FOXP4、AC097634.4、FOXRED1、FPR1、FPR2、FRG1B 、FRS2、FTO、FTSJ1、FUK、FUT10、FUT3、FUT6、FXYD3、FZD3、G2E3、GAA、GABARAPL1、GABPB1、GABRA5、GAL3ST1、GALE、GALNT11、G ALNT14、GALNT6、GAPVD1、GARNL3、GAS2L3、GAS8、GATA1、GATA2、GATA4、GBA、GCNT1、GDPD2、GDPD5、GEMIN7,MARK4、GEMIN8、GGA 3, GGACT, AL356966.1, GGPS1, GHRL, GID8, GIGYF2, GIMAP8, GIPC1, GJB1, GJB6, GLB1L, GLI1, GLT8D1, GMFG, GMPR2, GNAI2, GNAQ, GNB1, GNB2, GNE, GNG2, GNGT2, GNPDA1, GNPDA2, GOLGA3, CHFR, GOLGA4, GOLPH3L, GOLT1B, GPBP1L1, GPER1, GPR116, GPR14. 1,EPDR1,GPR155,GPR161,GPR56,GPR63,GPR75-ASB3,ASB3,GPR85,GPSM2,GRAMD1B,GRB10,GRB7,GREM2,GRIA2,GSDMB,GSE1,GSN,GSTA4,GSTZ1,GTDC1,GTF2H1,GTF2H4,VARS2,GTF3C2,GUCY1A3,GUCY1B3,GUK1,GULP1,GYPC,GYS1,GZF1,HAGH,HAO2,HAPLN3 、HAVCR1、HAX1、HBG2、AC104389.4、HBG2、AC104389.4、HBE1、HBG2、AC104389.4、HBE1、OR51B5、HBG2、HBE1、AC104389.28、HBS1L 、HCFC1R1、HCK、HDAC2、HDAC6、HDAC7、HDLBP、HEATR4、HECTD4、HEXIM2、HHAT、HHATL、CCDC13、HINFP、HIRA、C22orf39、HIVEP3、HJV 、HKR1、HLF、HMBOX1、HMGA1、HMGB3、HMGCR、HMGN4、HMOX2、HNRNPC、HNRNPD、HNRNPH1、HNRNPH3、HNRNPR、HOMER3、HOPX、HOXA3、HOX B3、HOXB3、HOXB4、HOXC4、HOXD3、HOXD3、HOXD4、HPCAL1、HPS4、HPS5、HRH1、HS3ST3A1、HSH2D、HSP90AA1、HSPD1、HTT、HUWE1、HYOU1 、IAH1、ICA1L、ICAM2、ICE2、ICK、IDH2、IDH3G、IDS、IFI27、IFI44、IFT20、IFT22、IFT88、IGF2、INS-IGF2、IGF2BP3、IGFBP6、IKBKA P、IKBKB、IL11、IL18BP、IL18RAP、IL1RAP、IL1RL1、IL18R1、IL1RN、IL32、IL4I1,NUP62,AC011452.1、IL4I1,NUP62,CTC-326K19.6, IL6ST, ILVBL, IMMP1L, IMPDH1, INCA1, ING1, INIP, INPP1, INPP5J, INP P5K、INSIG2、INTS11、INTS12、INTS14、IP6K2、IP6K3、IPO11、LRRC70、IQCE 、IQGAP3、IRAK4、IRF3、IRF5、IRF6、ISG20、IST1、ISYNA1、ITFG2、ITGB1BP1 ITGB7, ITIH4, RP5-966M1.6, ITPRIPL1, JADE1, JAK2, JARID2, JDP2, KANK 1. KANK1,RP11-31F19.1, KANK2, KANSL1L, KAT6A, KBTBD2, KBTBD3, KCNAB 2. KCNE3, KCNG1, KCNJ16, KCNJ9, KCNMB2, AC117457.1, LINC01014, KCTD20 KCTD7, RABGEF1, KDM1B, KDM4A, AL451062.3, KHNYN, KIAA0040, KIAA0 KIAA0196, KIAA0226L, PPP1R2P4, KIAA0391, KIAA0391, AL121594.1, KIA A0391, PSMA6, KIAA0753, KIAA0895, KIAA0895L, KIAA1191, KIAA1407, KI AA1841, C2orf74, KIF12, KIF14, KIF27, KIF9, KIFC3, KIN, KIRREL1, KITLG KLC1, APOPT1, AL139300.1, KLC4, KLHDC4, KLHDC8A, KLHL13, KLHL18, KLH L2, KLHL24, KLHL7, KLK11, KLK2, KLK5, KLK6, KLK7, KNOP1, KRBA2, AC13517 8.2、KRBA2、RP11-849F2.7、KRIT1、KRT15、KRT8、KTN1、KXD1、KYAT3、RBMXL 1, KYNU, L3MBTL1, LACC1, LARGE, LARP4, LARP7, LAT2, LBHD1, LCA5, LCA5L. LCTL, LEPROTL1, LGALS8, LGALS9C, LGMN, LHFPL2, LIG4, LIMCH1, LIMK2, LI MS2, LINC00921, ZNF263, LIPF, LLGL2, LMAN2L, LMCD1, LMF1, RP11-161M6.2、LMO1、LMO3、LOXHD1、LPAR1、LPAR2、LPAR4、LPAR5、LPAR6、LPHN1、LPIN2、LPIN3、LPP、LRFN5、LRIF1、LRMP、LRRC14、LRRC20、LRRC24、C8orf82、LRRC39、LRRC42、LRRC48、LRRC4C、LRRC8A、LRRC8B、LRRD1、LRTOMT、LRTOMT、AP0. 00812.5、LSM7、LTB4R、LTBP3、LUC7L2、FMC1-LUC7L2、LUC7L3、LUZP1、LYG 1、LYL1、LYPD4、LYPD6B、LYRM1、LYRM5、LYSMD4、MACC1、MAD1L1、MAD1L1、A C069288.1、MAEA、MAFF、MAFG、MAFK、MAGEA12,CSAG4、MAGEA2、MAGEA2B、MAGEA4、MAGEB1、MAGOHB、MAN2A2、MANBAL、MAOB、MAP2K3、MAP3K7CL、MAP3K 8, MAP7, MAP9, MAPK6, MAPK7, MAPK8, MAPKAP1, 10-Mar, 7-Mar, 8-Mar, MARK2, MASP1, MATK, MATR3, MATR3, SNHG4, MB, MBD5, MBNL1, MBOAT7, MCC, MCF D2, MCM9, MCONL3, MCRS1, MDC1, MDGA2, MDH2, MDM2, ME1, MEAK7, MECR, MED4, MEF2A, MEF2B, BORCS8-MEF2B, MEF2BNB-MEF2B, MEF2B, MEF2BNB, MEF2C 、MEF2D、MEGF10、MEI1、MEIS2、MELK、MET、METTL13、METTL23、MFF、MFN2、M FSD2A、MGST3、MIB2、MICAL1、MICAL3、MICOS10、NBL1,MICOS10-NBL1、MID 1、MINA、MINOS1-NBL1,MINOS1、MIOS、MIPOL1、MIS12、MKLN1、MKNK1、MKNK 1,MOB3C、MLF2、MLH1、MMP17、MOBP、MOCS1、MOGS、MOK、MORF4L1、MPC1、MPC 2、MPG、MPI、MPP1、MPP2、MPPE1、MPST、MRAS、MRO、MROH1、MROH7-TTC4、MRO H7、MRPL14、MRPL24、MRPL33,BABAM2、MRPL33、BRE、MRPL47、MRPL48、MRPL 55、MRRF、MRTFA、MRTFB、MRVI1、MS4A1、MS4A15、MS4A3、MS4A6E、MS4A7、MS 4A14、MSANTD3、MSANTD4、MSH5、MSH5-SAPCD1、MSL2、MSRB3、MSS51、MTCP1,CMC4、MTERF、MTERF1、MTERF3、MTERFD2、MTERFD3、MTF2、MTG2、MTHFD2、MTHFD2L、MTIF2、MTIF3、MTMR10、MTRF1 、MTRR、MTUS2、MUTYH、MVK、MX1、MX2、MYH10、MYL12A、MYB、MYD88、MYL5、MYLIP、MYNN、MYO15A、MYO1B、MYOM2、MZ F1、N4BP2L2、NAA60、NAB1、NAE1、NAGK、NAP1L1、NAP1L4、NAPG、NARFL、NARG2、NAT1、NAT10、NBPF11、WI2-3658N 16.1、NBPF12、NBPF15、NBPF24、NBPF6、NBPF9、NBR1、NCAPG2、NCBP2、NCEH1、NCOA1、NCOA4、NDC1、NDRG1、NDRG2, 、NDRG4、NDST1、NDUFAF6、NDUFB2、NDUFC1、NDUFS1、NDUFS8、NDUFV1、NEDD1、NEIL1、NEIL2、NEK10、NEK11、NEK6、NEK9、NELFA、NEU4、NFAT5、NFE2、NFE2L2、AC019080.1、NFRKB、NFYA、NFYC、NIF3L1、N IPA2、NKIRAS1、NKX2-1、NLRC3、NME1、NME1-NME2、NME2、NME1-NME2、NME2、NME4、NME6、NME9、NOD1 、NOL10、NOL8、NONO、NPAS1、NPIPA8、RP11-1212A22.1、NPIPB3、NPIPB4、NPIPB9、NPL、NPM1、NPPA、 NQO2、NR1H3、NR2C2、NR2F2、NR4A1、NRDC、NREP、NRF1、NRG4、NRIP1、NSD2、NSDHL、NSG1、NSMCE2、NSRP1、NT5C2、NTF4、NTMT1、NTNG2、NUBP2、NUCB2、NUDT1、NUDT2、NUDT4、NUF2、NUMBL、NUP50、NUP54 NUP85、NVL、NXF1、NXPE1、NXPE3、OARD1、OAT、OAZ2、OCIAD1、OCLN、ODF2、OGDHL、OGFOD2、AC026362.1、OGFOD2、RP11-197N18.2、OLA1、OPRL1、OPTN、OR2H1、ORAI2、ORMDL1、ORMDL3、OSBPL2 OSBPL3、OSBPL5、OSBPL9、OSER1、OSGIN1、OSR2、P2RX4、P2RY2、P2RY6、P4HA2、PABPC1、PACRGL、PACSIN3、PADI1、PAIP2、PAK1、PAK3、PAK4、PAK7、PALB2、PANK2、PAQR6、PARP11、PARVG、PASK、PAX6、PBRM1、PBXIP1、PCBP3、PCBP4,AC115284.1、PCBP4、RP11-155D18.14、RP11-155D18.12、PCGF3、PCGF5、PCNP、PCSK9、PDCD10、PDCD6、AHRR、PDDC1、PDGFRB、PDIA6、PDIK1L、PDLIM7、PDP1、PDPK1、PDPN、PDZD11、PEA15、PEX2、PEX5、PEX5L、PFKM、PFN4、PGAP2、PGAP2、AC090587.2、PGAP3、PGM3、PGPEP1、PHB、PHC2、PHF20、PHF21A、PHF23、PHKB、PHLDB1、PHOSPHO1、PHOSPHO2、KLHL23、PI4KB、PIAS2、PICALM、PIF1、PIGN、PIGO、PIGT、PIK3CD、PILRB、STAG3L5P-PVRIG2P-PILRB、PIP5K1B、PIR、PISD、PIWIL4,FUT4、PKD2、PKIA、PKIG、PKM、PKN2、PLA1A、PLA2G2A、PLA2G5、PLA2G7、PLAC8、PLAGL1、PLD1、PLD3、PLEKHA1、PLEKHA2、PLEKHA6、PLEKHG5、PLIN1、PLS1、PLS3、PLSCR1、PLSCR2、PLSCR4、PLXNB1、PLXNB2、PMP22、PMS1、PNISR、PNKP,AKT1S1、PNMT、PNPLA4、PNPLA8、PNPO、PNRC1、POC1B、POFUT1、POLB、POLD1、POLH、POLI、POLL、POLR1B、POM121、POM121C,AC006014.7、POM121C、AC211429.1、POMC、POMT1、POP1、PORCN、POU5F1、PSORS1C3、PPARD、PPARG、PPHLN1、PPIL3、PPIL4、PPM1A、PPM1B,AC013717.1, PPP1CB, PPP1R11, PPP1R13L, PPP1R26, PPP1R9A, PPP2R2B, PPP3CA, PPP6R 1, PPP6R3, PPT2, PPT2-EGFL8, EGFL8, PPWD1, PRDM2, PRDM8, PRELID3A, PREP L, PRICKLE1, PRKAG1, PRMT2, PRMT5, PRMT7, PROM1, PRPS1, PRPSAP2, PRR14L PRR15L, PRR5, PRR5-ARHGAP8, PRR5L, PRR7, PRRC2B, PRRT4, PRSS50, PRSS4 5. PRSS44, PRUNE, PRUNE1, PSEN1, PSMA2, PSMF1, PSORS1C1, PSPH, PSRC1, PT BP3, PTHLH, PTK2, PTPDC1, PTPRM, PUF60, PUM2, PUS1, PUS10, PXN, PXYLP1 YCR1, QRICH1, R3HCC1L, R3HDM2, RAB17, RAB23, RAB3A, RAB3D,TMEM205, RAB 4B-EGLN2, EGLN2, AC008537.1, RAB5B, RAB7L1, RABL2A, RABL2B, RABL5, RAC GAP1, RAD17, RAD51L3-RFFL, RAD51D, RAD52, RAE1, RAI14, RAI2, RALBP1, RA N, RANGAP1, RAP1A, RAP1B, RAP1GAP, RAPGEF4, RAPGEFL1, RASGRP2, RASSF1 RBCK1, RBM12B, RBM14, RBM4, RBM14-RBM4, RBM23, RBM4, RBM14-RBM4, RBM47 RBM7,AP002373.1, RBM7, RP11-212D19.4, RBMS2, RBMY1E, RBPJ, RBPMS, RB SN, RCBTB2, RCC1, RCC1, SNHG3, RCCD1, RECQL, RELL2, REPIN1, AC073111.3. REPIN1, ZNF775, RER1, RERE, RFWD3, RFX3, RGL2, RGMB, RGS11, RGS3, RGS5, A L592435.1 RHBDD1 RHNO1 TULP3 RHOC AL603832.3 RHOC,RP11-426L16. 10. RHOH, RIC8B, RIMKLB, RIN1, RIPK2, RIT1, RLIM, RNASE4, ANG, AL16、RNASEK、RNASEK-C17orf49、RNF111、RNF123、RN. F13、RNF14、RNF185、RNF216、RNF24、RNF32、RNF34、RNF38、RNF4、RNF44、RNH1、RNMT、RNPS1、RO60、ROPN1、ROPN1B、ROR2、RP1-102H19.8、C6orf163、RP1-283E3.8,CDK11A、RP11-120M18.2,PRKAR1A、RP11-133K1.2、PAK6、RP11-164J13.1,CAPN3、RP11-21J18.1、ANKRD12、RP11-322E11.6,INO80C、RP11-337C18.10,CHD1L、RP11-432B6.3、TRIM59、RP11-468E2.4,IRF9、RP11-484M3.5,UPK1B、RP11-517H2.6、CCR6、RP11-613M10.9、SLC25A51、RP11-659G9.3、RAB30、RP11-691N7.6,CTNND1、RP11-849H4.2、RP11-896J10.3、NKX2-1、RP11-96O20.4,SQRDL、RP11-986E7.7、SERPINA3、RP4-769N13.6、GPRASP1、RP4-769N13.6,GPRASP2、RP4-798P15.3、SEC16B、RP5-1021I20.4、ZNF410、RP6-109B7.3、FLJ27365、RPE、RPH3AL、RPL15、RPL17、RPL17-C18orf32,RPL17、RPL23A、RPL36,HSD11B1L、RPP38、RPS20、RPS27A、RPS3A、RPS6KA3、RPS6KC1、RPS6KL1、RPUSD1、RRAGD、RRAS2、RRBP1、RSL1D1、RSRC2、RSRP1、RUBCNL、RUNX1T1、RUVBL2、RWDD1、RWDD4、S100A13,AL162258.1、S100A13,RP1-178F15.5、S100A16、S100A4、S100A3、S100A6、S100PBP、SAA1、SACM1L、SAMD4B、SAR1A、SARAF、SARNP,RP11-762I7.5、SCAMP5、SCAP、SCAPER、SCFD1、SCGB3A2、SCIN、SCML1、SCNN1D、SCO2、S COC、SCRN1、SDC2、SDC4、SEC13、SEC14L1、SEC14L2、SEC22C、SEC23B、SEC2 4C、SEC61G、SEMA4A、SEMA4C、SEMA4D、SEMA6C、SENP7、SEPP1、11-Sep、2-S ep、SERGEF、AC055860.1、SERP1、SERPINA1、SERPINA5、SERPINB6、SERPIN G1、SERPINH1、SERTAD3、SETD5、SFMBT1、AC096887.1、SFTPA1、SFTPA2、S FXN2、SGCD、SGCE、SGK3、SGK3,C8orf44、SH2B1、SH2D6、SH3BP1,Z83844.3 、SH3BP2、SH3BP5、SH3D19、SH3YL1、SHC1、SHISA5、SHMT1、SHMT2、SHOC2、S HROOM1、SIGLEC5,SIGLEC14、SIL1、SIN3A、SIRT2、SIRT6、SKP1、STAT4、AC 104109.3, SLAIN1, SLC10A3, SLC12A9, SLC14A1, SLC16A6, SLC1A2, SLC1A6, SLC20A2, SLC25A18, SLC25A19, SLC25A22, SLC25A25, SLC25A29, SLC2 5A30, SLC25A32, SLC25A39, SLC25A44, SLC25A45, SLC25A53, SLC26A11, SLC26A4, SLC28A1, SLC29A1, SLC2A14, SLC2A5, SLC2A8, SLC35B2, SLC35B3 SLC35C2, SLC37A1, SLC38A1, SLC38A11, SLC39A13, SLC39A14, SLC41A3, SLC44A3, SLC4A7, SLC4A8, SLC5A10, SLC5A11, SLC6A1, SLC6A12, SLC6A9 、SLC7A2、SLC7A6、SLC7A7、SLCO1A2、SLCO1C1、SLCO2B1、SLFN11、SLFN12、 SLFNL1、SLMO1、SLTM、SLU7、SMAD2、SMAP2、SMARCA2、SMARCE1、AC073508.2、SMARCE1、KRT222、SMC6、SMG7、SMIM22、SMOX、SMPDL3A、SMTN、SMU1、SMUG1、SNAP25、SNCA、SNRK、SNRPC、SNRPD1、SNRPD2、SNRPN、SNRPN,SNURF、SNUPN、SNX11、SNX16、SNX17、SOAT1、. SOHLH2,CCDC169-SOHLH2,CCDC169、SORBS1、SORBS2、SOX5、SP2、SPART、SPATA20、SPATA21、SPATS2、SPATS2L、SPDYE2、SPECC1、SPECC1L、SPECC1L- ADORA2A, SPECC1L-ADORA2A, ADORA2A, SPEG, SPG20, SPG21, SPIDR, SPIN1, SPOCD1, SPOP, SPRR2A, SPRR2B, SPRR2E, SPRR2B, SPRR2F, SPRR2D, SPRR3 、SPRY1、SPRY4、SPTBN2、SRC、SRGAP1、SRP68、SRSF11、SSX1、SSX2IP、ST3GAL4、ST3GAL6、ST5、ST6GALNAC6、ST7L、STAC3、STAG1、STAG2、STAMBP、STA MBPL1、STARD3NL、STAT6、STAU1、STAU2、AC022826.2、STAU2、RP11-463D19.2、STEAP2、STEAP3、STIL、STK25、STK33、STK38L、STK40、STMN1、STON1、S TON1-GTF2A1L、STRAP、STRBP、STRC、AC011330.5、STRC、CATSPER2、STRC、CATSPER2、AC011330.5、STRC、STRCP1、STT3A、STX16-NPEPL1、NPEP L1、STX5、STX6、STX8、STXBP6、STYK1、SULT1A1、SULT1A2、SUMF2、SUN1、 SUN2、SUN2、DNAL4、SUOX、SUPT6H、SUV39H2、SV2B、SYBU、SYNCRIP、SYNJ 2、SYT1、SYTL4、TAB2、TACC1、TADA2B、TAF1C、TAF6,AC073842.2、TAF6 、RP11-506M12.1、TAF9、TAGLN、TANK、TAPSAR1,PSMB9、TAPT1、TATDN1、 TAZ、TBC1D1、TBC1D12、HELLS、TBC1D15、TBC1D3H、TBC1D3G、TBC1D5、TB C1D5,SATB1、TBCA、TBCEL、TBCEL、AP000646.1、TBL1XR1、TBP、TBX5、TB XAS1、TCAF1、TCEA2、TCEAL4、TCEAL8、TCEAL9、TCEANC、TCEB1"TCF19、 TCF25、TCF4、TCP1、TCP10L、AP000275.65、TCP11、TCP11L2、TCTN1、TDG 、TDP1、TDRD7、TEAD2、TECR、TENC1、TENT4A、TEX264、TEX30、TEX37、TFD P1、TFDP2、TFEB、TFG、TFP1,TF、TFPI、TGIF1、THAP6、THBS3、THOC5、THR AP3、THUMPD3、TIAL1、TIMM9、TIMP1、TIRAP、TJAP1、TJP2、TK2、TLDC1、T LE3、TLE6、TLN1、TLR10、TM9SF1、TMBIM1、TMBIM4、TMBIM6、TMC6、TMCC1 、TMCO4、TMEM126A、TMEM139、TMEM150B、TMEM155、TMEM161B、TMEM164、TMEM168、TMEM169、TMEM175、TMEM176B、TMEM182、TMEM199,CTB-96E2.3、TMEM216、TMEM218、TMEM230、TMEM263、TMEM45A、TMEM45B、TMEM62、TMEM63B、TMEM66、TMEM68、TMEM98、TMEM9B、TMPRSS11D、TMPRSS5、TMSB15B、TMTC4、TMUB2、TMX2-CTN ND1、RP11-691N7.6,CTNND1、TNFAIP2、TNFAIP8L2、SCNM1、TNFRSF10C、TNFRSF19、TNFRSF8、TNFSF12-TNFSF13、TNFSF12、TNFSF13、TNFSF13、TNFSF13、TNFSF13 K2, TNNT1, TNRC18, TNS3, TOB2, TOM1L1, TOP1MT, TOP3B, TOX2, TP53, RP11-199F11.2, TP53I11, TP53INP2, TPCN1, TPM3P9, AC022137.3, TPT1, TRA2B, TRAF2, TRAF3, TRAPPC12, TRAPPC3, TREH, TREX1, TREX2, TRIB2, TRIM3, TRIM36, TRIM39, TRIM46, TRIM6, TRIM6-TRIM34, TRIM6-TRIM34, TRIM34, TRIM66, TRIM73, TRIT1, TRMT10B, TRMT2B, TR. MT2B-AS1、TRNT1、TRO、TROVE2、TRPS1、TRPT1、TSC2、TSGA10、TSPAN14、 TSPAN3、TSPAN4、TSPAN5、TSPAN6、TSPAN9、TSPO、TTC12、TTC23、TTC3、T TC39A, TTC39C, TTLL1, TTLL7, TTPAL, TUBD1, TWNK, TXNL4A, TXNL4B, TXNRD1, TYK2, U2AF1, UBA2, UBA52, UBAP2, UBE2D2, UBE2D3, UBE2E3, UBE2 I、UBE2J2、UBE3A、UBL7、UBXN11、UBXN7、UGDH、UGGT1、UGP2、UMAD1,AC0 07161.3、UNC45A、UQCC1、URGCP-MRPS24,URGCP、USMG5、USP16、USP21、 USP28、USP3、USP33、USP35、USP54、USP9Y、USPL1、UTP15、VARS2、VASH2 、VAV3、VDAC1、VDAC2、VDR、VEZT、VGF、VIL1、VILL、VIPR1、VPS29、VPS37C 、VPS8、VPS9D1、VRK2、VWA1、VWA5A、WARS、WASF1、WASHC5、WBP5、WDHD1、 WDPCP、WDR37、WDR53、WDR6、WDR72、WDR74、WDR81、WDR86、WDYHV1、WFDC 3、WHSC1、WIPF1、WSCD2、WWP2、XAGE1A、XAGE1B、XKR9、XPNPEP1、XRCC3、 XRN2, XXYLT1, YIF1A, YIF1B, YIPF1, YIPF5, YPEL5, YWHAB, YWHAZ, YY1A P1、ZBTB1、ZBTB14、ZBTB18、ZBTB20、ZBTB21、ZBTB25、ZBTB33、ZBTB34、 ZBTB38、ZBTB43、ZBTB49、ZBTB7B、ZBTB7C、ZBTB8OS、ZC3H11A、ZBED6、Z C3H13、ZCCHC17、ZCCHC7、ZDHHC11、ZDHHC13、ZEB2、ZFAND5、ZFAND6、ZF P1、ZFP62、ZFX、ZFYVE16、ZFYVE19、ZFYVE20、ZFYVE27、ZHX2、AC016405.1、ZHX3、ZIK1、ZIM2,PEG3、ZKSCAN1、ZKSCAN3、ZKSCAN8、ZMAT3、ZMAT5、ZMIZ2、ZMYM6、ZMYND11、ZNF10,AC026786.1、ZNF133、ZNF146、ZNF16、ZNF177、ZNF18、ZNF200、ZNF202、ZNF211、ZNF219、ZNF226、ZNF227、ZNF23、AC010547.4、ZNF23、AC010547.9、ZNF239、ZNF248、ZNF25、ZNF253、ZNF254、ZNF254、AC092279.1、ZNF263、ZNF274、ZNF275、ZNF28、ZNF468、ZNF283、ZNF287、ZNF3、ZNF320、ZNF322、ZNF324B、ZNF331、ZNF334、ZNF34、ZNF350、ZNF385A、ZNF395、FBXO16、ZNF415、ZNF418、ZNF43、ZNF433-AS1、AC008770.4、ZNF438、ZNF444、ZNF445、ZNF467、ZNF480、ZNF493、ZNF493,CTD-2561J22.3、ZNF502、ZNF507、ZNF512、AC074091.1、ZNF512,RP11-158I13.2、ZNF512B、ZNF512B、SAMD10、ZNF521、ZNF532、ZNF544、AC020915.5、ZNF544、CTD-3138B18.4、ZNF559,ZNF177、ZNF562、ZNF567、ZNF569、ZNF570、ZNF571-AS1,ZNF540、ZNF577、ZNF580,ZNF581、ZNF580、ZNF581,CCDC106、ZNF600、ZNF611、ZNF613、ZNF615、ZNF619,ZNF620、ZNF639、ZNF652、ZNF665、ZNF667、ZNF668、ZNF671、ZNF682、ZNF687、ZNF691、ZNF696、ZNF701、ZNF706、ZNF707、ZNF714、ZNF717、ZNF718、ZNF720、ZNF721、ZNF730、ZNF763、ZNF780B,AC005614.This includes genes such as 5, ZNF782, ZNF786, ZNF79, ZNF791, ZNF81, ZNF83, ZNF837, ZNF839, ZNF84, ZNF845, ZNF846, ZNF865, ZNF91, ZNF92, ZNHIT3, ZSCAN21, ZSCAN25, ZSCAN30, and ZSCAN32.

[0211] In some embodiments, the gene encoding the target sequence includes the HTT gene.

[0212] Exemplary genes that can be regulated by compounds of formula (I) described herein include, in particular, AC005258.1, AC005943.1, AC007849.1, AC008770.2, AC010487.3, AC011477.4, AC012651.1, AC012531.3, AC034102.2, AC073896.4, AC 104472.3, AL109811.3, AL133342.1, AL137782.1, AL157871.5, AF241726.2, AL355336.1, AL358113.1, AL360181.3, AL445423.2, AL691482.3, AP001267.5, RF01169 and RF02271 may also be included.

[0213] The compounds described herein may be further used to modulate sequences including specific splice site sequences, such as RNA sequences (e.g., premRNA sequences). In some embodiments, the splice site sequence includes a 5' splice site sequence. In some embodiments, the splice site sequence includes a 3' splice site sequence. Examples of gene sequences and splice site sequences (e.g., 5' splice site sequences) include AAAgcaaguu, AAAguaaaaa, AAAguaaaau, AAAguaaagu, AAAguaaaua, AAAguaaaug, AAAguaaauu, AAAguaacac, AAAguaacca, AAAguaacuu, AAAguaagaa, AAAguaagac, AAAguaagag, AAAguaagau, AAAguaagca, AAAguaagcc, AAAguaagcu, AAAguaagga, AAAguaaggg, AAAguaaggu, AAAguaagua, AAAguaaguc, AAAguaagug, AAAguaaguu, AAAguaaucu, AAAguaauua, AAAguacaaa, AAAguaccgg, AAAguacuag, AAAguacugg, AAAguacuuc, AAAguacuug, AAAguagcuu, AAAguaggag, AAAguaggau, AA Aguagggg, AAAguaggua, AAAguaguaa, AAAguauauu, AAAguauccu, AAAguaucuc, AAAguaugga, AAAguaugua, AAAguaugug, AAAguauguu, AAAguauugg, AAAguauuuu, AAAgucagau, AAAgucugag, AAAgugaaua, AAAgugagaa, AAAgugagac, AAAgugag, AAAgugagau, AAAgug agca, AAAgugagcu, AAAgugagg, AAAgugagua, AAAgugaguc, AAAgugagu, AAAgugaguu, AAAgugcguc, AAAgugcuga, AAAguggguc, AAAguggguu, AAAgugguaa, AAAguguaug, AAAgugugu, AAAguguguu, AAAguuaagu, AAAguuacuu, AAAguuagug, AAAguuaugu, AAAguugagu,AAAguuugua、AACguaaaac、AACguaaagc、AACguaaagg、AACguaagca、AACguaaggg、AACguaaguc、AACguaagug、AACguaaugg、AACguaguga、AACguaugua、AACguauguu、AACgugagca、AACgugagga、AACgugauuu、AACgugggau、AACgugggua、AACguguguu、AACguuggua、AAGgcaaauu、AAGgcaagag、AAGgcaagau、AAGgcaagcc、AAGgca agga、AAGgcaaggg、AAGgcaagug、AAGgcaaugu、AAGgcacugc、AAGgcagaa、AAGgcaggau、AAGgcaggca、AAGgcaggga、AAGgcagggg、AAGgcaggua、AAGgcaggug、AAGg caucuc、AAGgcaugcu、AAGgcaugga、AAGgcauguu、AAGgcauuau、AAGgcgagcu、AAGgcgaguc、AAGgcgaguu、AAGgcuagcc、AAGguaaaaa、AAGguaaaac、AAGguaaaag、A、 AGguaaaau、AAGguaaaca、AAGguaaacc、AAGguaaacu、AAGguaaaga、AAGguaaagc、AAGguaaagg、AAGguaaagu、AAGguaaaua、AAGguaaauc、AAGguaaaug、AAGgu aaauu、AAGguaacaa、AAGguaacau、AAGguaaccc、AAGguaacua、AAGguaacuc、AAGguaacug、AAGguaacuu、AAGguaagaa、AAGguaagac、AAGguaagag、AAGguaaga u、AAGguaagca、AAGguaagcc、AAGguaagcg、AAGguaagcu、AAGguaagga、AAGguaaggc、AAGguaaggg、AAGguaaggu、AAGguaagua、AAGguaaguc、AAGguaagug、AA Gguaaguu、AAGguaauaa、AAGguaauac、AAGguaauag、AAGguaauau、AAGguauca、AAGguaaucc、AAGguaaucu、AAGguauga、AAGguaaugc、AAGguaaugg、AAGgua augu、AAGguaauua、AAGguaauuc、AAGguaauug、AAGguaauuu、AAGguacaaa、AAGguacaag、AAGguacaau、AAGguacacc、AAGguacacu、AAGguacagg、AAGguacagu 、AAGguacaua、AAGguacau、AAGguacau、AAGguaccaa、AAGguaccag、AAGguacca、AAGguaccu、AAGguaccuc、AAGguaccug、AAGguaccuu、AAGguaccaa、AAG guacggg、AAGguacggu、AAGguacguc、AAGguacguu、AAGguacuaa、AAGguacuau、AAGguacucu、AAGguacuga、AAGguacugc、AAGguacugu、AAGguacuuc、AAGguac uug、AAGguacuuu、AAGguagaaa、AAGguagaac、AAGguagaca、AAGguagacc、AAGguagacu、AAGguagagu、AAGguagaua、AAGguagcaa、AAGguagcag、AAGguagcca、AAGguagccu, AAGguagcua, AAGguagcug, AAGguagcuu, AAGguaggaa, AAGguaggag, AAGguaggau, AAGguaggca, AAGguaggcc, AAGguaggcu, AAGguaggga, AAGguagggc, AAGguagggg, AAGguagggu, AAGguaggua, AAGguagguc, AAGguaggug, AAGguagguu, AAGguaguaa, AAGguaguag, AAGguagucu, AAGguagugc, AAGguagugg, AAGguaguuc, AAGguaguuu, AAGguauaaa, AAGguauaau, AAGguauaca, AAGguauacu, AAGguauaua, AAGguauauc, AAGguauaug, AAGguauauu, AAGguaucac, AAGguaucag, AAGguauccc, AAGguauccu, AAGguaucuc, AAGguaucug, AAGguaucuu, AAGguaugaa, AAGguaugac, AAGguaugag, AAGguaugau, AAGguaugca, AAGgu augcc, AAGguaugcu, AAGguaugga, AAGguauggc, AAGguauggg, AAGguaugug, AAGguauguu, AAGguauuaa, AAGguauuac, AAGguauuag, AAGguauuau, AAGguauucc, AAGguauuga, AAGguauugu, AAGguauuua, AAGguauuuc, AAGguauuug, AAGguauuuu, AAGgucaaau, AAGgucaaga, AAGgucaagu, AAGgucacag, AAGgucagaa, AAGgucagac, AAGgucagag, AAGgucagca, AAGgucagcc, AAGgucagcg, AAGgucagcu, AAGgucagga, AAGgucagg, AAGgucaggu, AAGgucagua, AAGgucagu,AAGguccuuc, AAGgucgagg, AAGgucuaau, AAGgucuacc, AAGgucuaua, AAGgucucucu, AAGgucucug, AAGgucucuu, AAGgucugaa, AAGgucugag, AAGgucugga, AAGgucuggg, AAGgucugua, AAGgucuguu, AAGgucuuu, AAGgucuuuu, AAGgugaaac, AAGgugaaag, AAGgugaaau, AAGgugaacu, AAGgugaagc, AAGgugaagg, AAGg ugaagu、AAGgugaaua、AAGgugaaug、AAGgugaauu、AAGgugacaa、AAGgugacag、AAGgugacau、AAGgugacug、AAGgugacuu、AAGgugagaa、AAGgugagac、AAGgugagag、AAGgugagau、AAGgugagca、AAGgugagcc、AAGgugagcg、AAGgugagcu、AAGgugaga、AAGgugaggc、AAGgugaggg、AAGgugagagu、AAGgugagua、AAGgugaguc ,AAGgugagug, AAGgugaguu, AAGgugauaa, AAGgugauca, AAGgugaucc, AAGgugauga, AAGgugaugc, AAGgugaugu, AAGgugauua, AAGgugauug, AAGgugauuu, AAGgugcaca, AAGgugcauc, AAGgugcccu, AAGgugccug, AAGgugcgug, AAGgugcguu, AAGgugcucc, AAGgugcuga, AAGgugcugcugg, AAGgugcuua, AAGgu gcuuu, AAGguggaua, AAGguggcua, AAGguggcug, AAGguggcuu, AAGgugggaa, AAGgugggag, AAGgugggau, AAGgugggca, AAGguggcc, AAGguggcg, AAGguggga, AAGguggggu, AAGgugggua, AAGgugggug, AAGguggguu, AAGguggguaa, AAGgugguac, AAGgugguggau, AAGguggugg, AAGgugguaa, AAGgugguuc, AAGgugguu,AAGguguaag、AAGgugucaa、AAGgugucag、AAGgugucug、AAGgugugaa、AAGgugugag、AAGgugugca、AAGgugugga、AAGguguggu、AAGgugugua、AAGguguguc、AAGgugugug、AAGguguguu、AAGguguucu、AAGguguugc、AAGguguugg、AAGguguuug、AAGguuaaaa、AAGguuaaca、AAGguuaagc、AAGguuaauu、AAGguuacau、AAGguuagaa、AAGguuagau、AAGguuagca、AAGguuagcc、AAGguuagga、AAGguuagga、AAGguag gc, AAGguuagua, AAGguuaguc, AAGguuagug, AAGguuaguu, AAGguuauag, AAGguuauga, AAGguucaaa, AAGguucaag, AAGguuccuu, AAGguuccgg, AAGguucgu, AAGguucuaa, AAGguucuga, AAGgucuua, AAGguugaau, AAGguugacu, AAGguugagg, AAGguugagu, AAGguugaua, AAGguugcac, AAGguugcug, AAGguuggaa, AAGguuggca, AAGguuggga, AAGguuggg, AAGguuggua, AAGguugguc, AAGgu, uggug, AAGguugguu, AAGguuguaa, AAGguugucc, AAGguugugc, AAGguuguua, AAGguuuuacc, AAGguuuaua, AAGguuuuccu, AAGguuucgu, AAGguuugag, AAGguuugca, AAGguuugcc, AAGguuugcu, AAGguuugga, AAGguuugga, AAGguuugugua, AAGguuuguc, AAGguuugug, AAGguuuuaa, AAGguuuuca, AAGguuuucg, AAGguuuugc, AAGguuuug, AAGguuuuuaa, AAGguuuuca, AAGguuuucg, AAGguuuugc, 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,CAGguaugca,CAGguaugcc,CAGguaugcg,CAGguaugcu,CAGguaugga,CAGguauggg,CAGguaugggu,CAGguaugua,CAGguauguc,CAGguaugug,CAGguauguu,CAGguauuau,CAGguauuca,CAGguauucu,CAGguauuga,CAGguauugg,CAGguauugu,CAGguauuua,CAGguauuuc,CAGguauuug,CAGguauuuu,CAGgucaaca,CAGgucaaug,CAGgucacgu,CAGgucagaa,CAGgucagac,CAGgucagca,CAGgucagcc,CAGgucagcg,CAGgucagga,CAGgucagua,CAGgucagucu,CAGgucagu,CAGgucagu,CAGgucaucc,CAGgucaugc,CAGgucauua,CAGgucauuu,CAGguccacc,CAGguccacu,CAGguccagu,CAGguccau,CAGguccauc,CAGguccauu,CAGgucccag,CAGguccug,CAGguccuga、CAGguccugc、CAGguccugg、CAGgucggcc、CAGgucggug、CAGgucguug、CAGgucucuc、CAGgucucuu、CAGgucugag、CAGgucugcc、CAGguc ugcg、CAGgucugga、CAGgucuggu、CAGgucugua、CAGgucuguc、CAGgucugug、CAGgucuguu、CAGgucuucc、CAGgucuuuc、CAGgugaaag、CAGgugaaau、C AGgugaaca、CAGgugaaga、CAGgugaagg、CAGgugaaua、CAGgugaauc、CAGgugaauu、CAGgugacaa、CAGgugacau、CAGgugacca、CAGgugaccc、CAGgugaccg、CAGgugaccu、CAGgugacgg、CAGgugacua、CAGgugacuc、CAGgugacug、CAGgugagaa、CAGgugagac、CAGgugagag、CAGgugagau、CAGgugagca、CAG 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CAGgugucag, CAGgugucca, CAGguguccu, CAGgugucua, CAGgugucu, CAGgugucu, CAGgug ucug, CAGGugugaa, CAGGugugac, CAGGugugag, CAGGugugau, CAGGugugca, CAGGugugcc, CAGGugugcg, CAGGugugcu, CAGGugugga, CAGGuguggc, CAGGugugua, CAGGuguguc, CAGGugugug, CAGGuguguu, CAGGuguuua, CAGguuaaaa, CAGguuaaua, CAGguuaauc, CAGguuaccu, CAGguuagaa, CAGguuagag, CAGguuagau, CAGguuagcc, CAGguuaggg, CAGguuaggu, CAGguuagua, CAGguuaguc, CAGguuagug, CAGguuaguu, CAGguuauca, CAGguuaugu, CAGguuaauua, CAGguuauug, CAGguucaaa, CAGguucaac, CAGguucaag, CAGguucaca, CAGguucacg, CAGguucagg, CAGguucaug, CAGguuccag, CAGguuccca, CAGguucccg, CAGguucgaa, CAGguucgag,CAGguucuau, CAGguucugc, CAGguucuua, CAGguucuuc, CAGguucuuu, CAGguugaac, CAGguugaag, CAGguugagu, CAGguugaua, CAGguuggag, CAGguuggca, CAGguuggcc, CAGguugguc, CAGguuggug, CAGguugguu, CAGguuguaa, CAGguuguac, CAGguuguau, CAGguuguca, CAGguuguga, CAGguuguug, CAGguuuuaag, CAGguuuua C AGguuuuu、CAGguuuuu、CAGguuuucu、CAGguuuugg、CAGguuuuuc、CAGguuuuu、CAUgcaggu、CAUguaaaac、CAUguaacua、CAUguaagaa、CAUguaagag、CAUgu aagau、CAUguaagcc、CAUguaagua、CAUguaagug、CAUguaaguu、CAUguaauua、CAUguacaua、CAUguaccac、CAUguacgu、CAUguaggua、CAUguaggug、CAUguaggu CA Ugugcgua、CAUgugggaa、CAUGuggguu、CAUguguguu、CAUguguguu、CAUguuaaua、CAUguuagcc、CCAguaagau、CCAguaagca、CCAguaagcc、CCAguaagcu、CCAgua agga、CCAguaagua、CCAguaaguc、CCAguaagug、CCAguaaguu、CCAguaauug、CCAguacggg、CCAguagguc、CCAguauugu、CCAgugaggc、CCAgugagua、CCAgugagug、CCAGuggguc, CCAGUUAGUU, CCAGUUGAGU, CCCGUAGAU, CCCGUAGUUGUC, CCCGUAGUU, CCCGUCCUGC, CCCGUGAGUG, CCGGUAGAUG, CCGGUAGAUG, CCGGUAGAUG, CCGGUAGAUGC, CCGGUAUGG, CCGGUAGUCAUG, CCGGUAGUCAUG, CCGGUAUGG, CCGGUCAGU, CCGGUAUGG, CCGGUCAGU, CCGGUAUGG, CCGGUCAGUG, CCGGUGAGAA, CCGGUGAGGG, CCGGUGAGG, CCGGUGAGG uu, CCGgugcgcg, CCGguggcg, CCGguugguc, CCUguaaaug, CCUguaaauu, CCUguaagaa, CCUguaagac, CCUguaagag, CCUguaagca, CCUguaagcg, CCUguaagga, CCUguaaguu, CCUguaggua, CCUguaggug, CCUguaucuu, CCUguauggu, CCUguaugug, CCUgugagaa, CCUgugagca, CCUgugaggg, CCUgugagug, CCUgu gaguu, CCUguggcuc, CCUgugggua, CCUgugugua, CCUguuagaa, CGAguaaggg, CGAguaaggu, CGAguagcug, CGAguaggug, CGAguagguu, CGAgugagca, CGCguaagag, CGGgcaggca, CGGguaagcc, CGGguaagcu, CGGguaaguu, CGGguaauuc, CGGguaauuu, CGGguacagu, CGGguacggg, CGGguaggag, CGGguaggcc, CGGguaggug, CG Gguauuua、CGGgucugag、CGGgugaccg、CGGgugacuc、CGGgugagaa、CGGgugaggg、CGGgugaggu、CGGgugagua、CGGgugagug、CGGgugaguu、CGGgugauuu、CGGgugccuu、CGGguggag、CGGguggug、CGGgugggu、CGGgugguu、CGGguguguc、CGGgugugug、CGGguguguu、CGGguucaag、CGGguucaug、CGGguuugcu、CGUguagggu、CGUguaugca、CGUguaugua、CGUgucugua、CGUgugagug、CGUguuuucu、CUAguaaaug、CUAguaagcg、CUAguaagcu、CUAguaagua、CUAguaaguc、CUAguaagug、CUAguaaguu、CUAg uaauuu、CUAguaggua、CUAguagguu、CUAguaugua、CUAguauguu、CUAgugagua、CUCguaagca、CUCguaagug、CUCguaaguu、CUCguaucug、CUCgucugu、CUCgugaa ua、CUCgugagua、CUCgugauua、CUGguaaaaa、CUGguaaaau、CUGguaaacc、CUGguaaacg、CUGguaaagc、CUGguaaaua、CUGguaaauc、CUGguaaaug、CUGguaaauu、C UGguaacac、CUGguaacag、CUGguaaccc、CUGguaaccg、CUGguaacug、CUGguaacuu、CUGguaagaa、CUGguaagag、CUGguaagau、CUGguaagca、CUGguaagcc、CUGgu aagcu、CUGguaagga、CUGguaaggc、CUGguaaggg、CUGguaaggu、CUGguaagua、CUGguaagg、CUGguaaugu、CUGguaauga、CUGguaaugc、CUGguaauuc、CUGguaauu CU Gguagaua, CUGguagcgu, CUGguaggau, CUGguaggca, CUGguaggua, CUGguagguc, CUGguaggug, CUGguaucaa, CUGguaugau, CUGguauggc, CUGguaugggu, CUGguauguga, CUGguaugug, CUGguauguu, CUGguauuga, CUGguauuuc, CUGguauuuu, CUGgucaaca, CUGgucagag, CUGgucccgc, CUGgucggua, CUGgucuggg, CUGgugaag,C UGgugagua、CUGgugaguc、CUGgugagug、CUGgugaguu、CUGgugauua、CUGgugauuu、CUGgugcaga、CUGgugcgcu、CUGgugcgug、CUGgugcuga、CUGgugggag、CUGg uggggga、CUGgugggua、CUGguggguc、CUGgugggug、CUGgugguu、CUGgugugaa、CUGgugugca、CUGgugugcu、CUGguguggu、CUGgugugug、CUGguguguu、CUGguuagcu、CUGguuagug、CUGguucgug、CUGguuggcu、CUGguuguuu、CUGguuugua、CUGguuuguc、CUGguuugug、CUUguaaaug、CUUguaagcu、CUUguaagga、CUUguaaggc ,CUUguaagua, CUUguaagug, CUUguaaguu, CUUguacguc, CUUguacgug, CUUguaggua, CUUguagugc, CUUguauagg, CUUgucagua, CUUgugagua, CUUgugaguc, CUUgugaguu, CUUgugguguu, CUUgugugua, CUUguuagug, CUUguuugag, GAAguaaaac, GAAguaaagc, GAAguaaagu, GAAguaaaua, GAAguaaauu, GAAguaagaa, GAAgu aagcc、GAAaguaagcu、GAAguaagga、GAAguaagua、GAAguaagug、GAAguaaugu、GAAguaua、GAAguaaugc、GAAguaauua、GAAguaauuu、GAAguaccau、GAAguacgua、GAAguacguc、GAAguaggca、GAAguagguc、GAAguauaa、GAAguaugcu、GAAguaugug、GAAguauguu、GAAguauuaa、GAAgucagu、GAAgugag、GAAgugagcg、GAAgugaggu、GAAgugaguc、GAAgugagug、GAAgugaguu、GAAgugauaa、GAAgugauuc、GAAgugcgug、GAAguguggg、G、 AAguguguc、GAAguuggug、GACguaaagu、GACguaagcu、GACguaagua、GACguaaugg、GACguaugcc、GACguauguu、GACgugagcc、GACgugagug、GAGgcaaaug、GAGgcaagag、GAGgcaagua、GAGgcaagug、GAGgcaaggu、GAGgcaggga、GAGgcaggga、GAGgcaagg、GAGgcaagga AGguaaaac、GAGguaaaag、GAGguaaaau、GAGguaaacc、GAGguaaaga、GAGguaaagc、GAGguaaagu、GAGguaaaua、GAGguaaauc、GAGguaaaug、GAGguaaauu、GAGguaacaa、GAGguaacag、GAGguaacca、GAGguaaccu、GAGguaacuu、GAGguaagaa、GAGguaagag、GAGguaagau、GAGguaagca AGguaagcc、GAGguaagcg、GAGguaagcu、GAGguaagga、GAGguaaggc、GAGguaaggg、GAGguaaggu、GAGguaagua、GAGguaaguc、GAGguaauaa、GAGguaauac、GAGguaauao、GAGguaauca、GAGguaaucu、GAGguaaugg、GAGguaaugu、GAGguaauug、GAGguaauuu、GAGguacaaa、GAGguaaac AGguacaga、GAGguacagc、GAGguacagu、GAGguacaua、GAGguacauu、GAGguaccag、GAGguaccga、GAGguaaccug、GAGguaccuu、GAGguacuag、GAGguacuau、GAGguacucc、GAGguacugc、GAGguacugg、GAGguacugu、GAGguacuug、GAGguacuuu、GAGguaag、GAGguagaga、GAGguagagg AGguagagu、GAGguagauc、GAGguagcua、GAGguagcug、GAGguaggaa、GAGguaggag、GAGguaggca、GAGguaggcu、GAGguaggga、GAGguagggc、GAGguagggg、GAGguaggua、GAGguaggug、GAGguagguu、GAGguaguaa、GAGguaguag、GAGguaguau、GAGguagucu、GAGguagugc、GAGguaguggc、GAGguaguua、GAGguaguug、GAGguauaa g. uugu、GAGguauuua、GAGguauuuc、GAGguauuug、GAGguauuuu、GAGgucaaca、GAGgucaagg、GAGgucaaug、GAGgucacug、GAGgucagaa、GAGgucagag、GAGgucagcu 、GAGgucagga、GAGgucaggc、GAGgucagg、GAGgucaggu、GAGgucagua、GAGgucauau、GAGgucaugu、GAGgucauuu、GAGguccaua、GAGguccauc、GAGguccggg、GAG guccggu、GAGguccuug、GAGgucgggg、GAGgucucgu、GAGgucugag、GAGgucuggu、GAGgucuguc、GAGgucuguu、GAGgucuuuu、GAGgugaaaa、GAGgugaaau、GAGguga aca、GAGgugaagg、GAGgugaaua、GAGgugaauu、GAGgugacau、GAGgugacca、GAGgugaccu、GAGgugacua、GAGgugacuu、GAGgugagaa、GAGgugagac、GAGgugagag、GAGgugagau, GAGgugagca, GAGgugagcc, GAGgugagcg, GAGgugagcu, GAGgugagga, GAGgugaggc, GAGgugaggg, GAGgugagua, GAGgugagug, GAGgugaguu, GAGgugauau, GAGgugaucc, GAGgugaucu, GAGgugauga, GAGgugaugg, GAGgugaugu, GAGgugauuc, GAGgugcaca, GAGgugcaga, GAGgugcagc, GAGgugcagg, GAGgugcc ag、GAGgugccca、GAGgugccuu、GAGgugcggg、GAGgugccug、GAGgugcucc、GAGgucugg、GAGgugcuua、GAGgugcuug、GAGguggaaa、GAGguggaau、GAGguggacc、G AGguggacg、GAGguggagg、GAGguggcug、GAGgugggaa、GAGgugggag、GAGgugggau、GAGgugggca、GAGgugggcg、GAGgugggcu、GAGguggga、GAGguggggc、GAGgu ggggg、GAGgugggua、GAGguggguc、GAGguggug、GAGguggguu、GAGguguau、GAGgugguuc、GAGgugucau、GAGgugug、GAGgugugau、GAGgugugca、GAGgugugcu、GAGgugguga、GAGguggugg、GAGgugugu、GAGgugugua、GAGgugug、GAGguuaaau、GAGguuaaga、GAGguuaua、GAGguuaccg、GAGguagaa、GAGguuagac、GA Gguuagag, GAGguuaggu, GAGguuagua, GAGguuaguc, GAGguuagug, GAGguuaguu, GAGguuaugu, GAGguuauuc, GAGguucaaa, GAGguucaua, GAGguucuga, GAGguugaag, GAGguugcag, GAGguugcug, GAGguuggaa, GAGguuggag, GAGguuggau, GAGguuggua, GAGguugguc, GAGguugguu, GAGguuguag, GAGguuucug, GAGguugaga,、GAGguuuuga、GAGguuuugg、GAGguuugua、GAGguuuuu、GAGguuuuca、GAGguuuuga、GAGguuuugg、GAGguuuuu、GAGguuuuuc、GAUguaaaau、GAUguaagca、G AUguaagcc、GAUguaaggu、GAUguaagua、GAUguaagug、GAUguaaguu、GAUguacauc、GAUguaggua、GAUguauggc、GAUguaugua、GAUguauguu、GAUgucagug、GAUg ugagag、GAUgugagcc、GAUgugagcu、GAUgugagga、GAUgugaguc、GAUgugagug、GAUgugaguu、GAUgugggua、GAUgugggug、GAUguguguu、GAUguuagcu、GAUguucagu、GAUguucgug、GAUguuuguu、GCAguaaagg、GCAguaagaa、GCAguaagga、GCAguaagua、GCAguaaguc、GCAguaaguu、GCAguagaug、GCAguaggua、GCAguaugug GC Agugggua、GCAguuaagu、GCAguugagu、GCCguaaguc、GCCgugagua、GCGguaaagc、GCGguaaaua、GCGguaagcu、GCGguaaggg、GCGguaagug、GCGguaauca、GCGgu acgua、GCGguacuug、GCGguagggu、GCGguagugu、GCGgugagca、GCGgugagcu、GCGgugaguu、GCGguggcuc、GCGgugugca、GCGguguguu、GCGguuaagu、GCGguuug ca、GCUgcuguaa、GCUguaaaua、GCUguaagac、GCUguaagag、GCUguaagca、GCUguaagga、GCUguaagua、GCUguaaguc、GCUguaagug、GCUguaaguu、GCUguaggug、GCUguauggu, GCUgucagug, GCUguccuug, GCUgugagaa, GCUgugagcc, GCUgugagag, GCUgugagua, GCUgugaguc, GCUgugagug, GCUgugaguu, GCUgugguu, GGAguaagag, GGAguaagca, GGAguaagcc, GGAguaagcu, GGAguaagga, GGAguaagug, GGAguaaguu, GGAguaauuu, GGAguacugu, GGAguaggaa, GGAguaggua, GGAguagg uu、GGAguaguau、GGAguaugac、GGAguauggu、GGAgucaagu、GGAgugaggg、GGAgugagua、GGAgugaguc、GGAgugagug、GGAgugaguu、GGAgugcuuu、GGAgugggca、G GAguggug、GGAguuaagg、GGAguugaga、GGCguaagcc、GGCguaggua、GGCguaggug、GGCgugagcc、GGCgugaguc、GGGguaaaca、GGGguaaacc、GGGguaaacu、GGGgu aagaa、GGGguaagag、GGGguaagau、GGGguaagca、GGGguaagcc、GGGguaagcu、GGGguaagga、GGGguaaggg、GGGguaagua、GGGguaagug、GGGguaaguu、GGGguagaca、GGGguaggag、GGGguaggcc、GGGguaggga、GGGguaggua、GGGguaggug、GGGguagguu、GGGguaguc、GGGguaucug、GGGguaugac、GGGguaugga、GGGUaguag、GG Gguauguc、GGGguaugug、GGGguauguu、GGGgucagua、GGGguccgug、GGGgucggag、GGGgucugug、GGGgugaaca、GGGgugaaga、GGGgugagaa、GGGgugagau、GGGgug agcc、GGGgugagcg、GGGgugagcu、GGGgugagga、GGGgugaggc、GGGgugagg、GGGgugaguc、GGGgugagu、GGGgugaguu、GGGgugcgua、GGGgugggu、GGGgugggua、GGGguggg, ug、GGGgugguu、GGGgugugcg、GGGgugugua、GGGguguguc、GGGgugugug、GGGguuacag、GGGguuggac、GGGguuggga、GGGguuugcc、GGGguuugua、GGUguaagaa、GGUguaagau、GGUguaagca、GGUguaagcc、GGUguaagcg、GGUguaaguc、GGUguaagug、GGUguagguc、GGUguagguu、GGUguccgua、GGUUguga gag、GGUgugagcc、GGUgugagcu、GGUgugagua、GGUgugaguc、GGUgugcuuc、GGUguggcug、GGUguggcug、GGUgugugcug、GGUgugaaa、GGUguugcug、GUUGUUAG 、GUAGUAGUAGUA、GUAGUAGUAGUA、GUAGUAGUAGUAGUA、GUAGUAGUAGUAGUA、GUAGUAGUAGUA、GUAGUAGUAGUAUM、GUAGUAGUAGUAUM、GUAGUAAUGUG、GUGUGAGU、GUAGUGA Cgugaguu、GUGgcaagua、GUGguaaaau、GUGguaaaau、GUGguaaaau、GUGguaaacau、GUGguaaaacau、GUGguaagaa、GUGguaagac、GUGGAG、GUGgua aagau、GUGguaagca、GUGguaagcg、GUGguaagcu、GUGguaaggc、GUGguaagc、GUGguaagua、GUGguaaguc、GUGguaagug、GUGguaagua、GUGGUAGUAAU、GUGGUAAUGAUS c. UGguauaaa、GUGguaucuc、GUGguaugaa、GUGguaugau、GUGguaugca、GUGguaugua、GUGguaugua、GUGguccgug、GUGgucuggc、GUGgugaaac、GUGgugagaa、GUGgugagaa ugagau、GUGgugagca、GUGgugagcu、GUGgugagga、GUGgugaggc、GUGgugagug、GUGgugaguu、GUGgugauua、GUGgugauuc、GUGgugcgau、GUGGGUGGUGUUA gaa、GUGgugggua、GUGguggguc、GUGguguccg、GUGguuagca、GUGguuaggu、GUGguuagug、GUGguuugca、GUGguuugua、GUUguaaggua、GUUguaagua、GUUagua、GUGUUguaaguu, GUUguaccac, GUUguagcgu, GUUguaugug, GUUguauguu, GUUgucugug, GUUgugagcu, GUUgugagug, GUUgugaguu, GUUgugggua, GUUguggguu, UAAguaaaug, UAAguaacua, UAAguaagaa, UAAguaagag, UAAguaagau, UAAguaagca, UAAguaagcu, UAAguaagga, UAAguaaggu, UAAguaagua, UAAguaaguc, UAAguaagug, UAAguaaguu, UAAguaauaa, UAAguacuag, UAAguaguuu, UAAguauaaa, UAAguacuag, UAAguaguuu, UAAguauaca, UAAguaugua, UAAguaugua, UAAguauuau, UAAguauuuu, UAAgugagac, UAAgugagagga, UAAgugaggg, UAAgugagua, UAAgugaguc, UAAgugagug, UAAgugaguu, UAAgugagaucc, UAAgugauuc, UAAgugcgug, UAAguuaagu, UAAguuccag, UAAguucuuu, UAAguuguaa, UAAguuguau, UAAguuuguu, UACguaacug, UACguaagaa, UACguaagau, UACguaagua, UACguaagug, UACguauccu, UACgucuggc, UACgugacca, UAGgcaagac, UAGgcaaguc, UAGgcagguc, UAGgcgugug, UAGguaaaaa, UAGguaaaac, UAGguaaaag, UAGguaaaau, UAGguaaaca, UAGguaaaga、UAGguaaaua、UAGguaaauc、UAGguaaaug、UAGguaaauu、UAGguaacac、UAGguaacag、UAGguaacau、UAGguaacca、UAGguaacgg、UAGguaacua、UAGguaacuc、UAGguaacug、UAGguaacuu、UAGguaagac、UAGguaagag、UAGguaagau、UAGguaagca、UAGguaagcc、UAGguaagcu、UAGguaagga、UAGguaaggc、UAGguaaggg、UAGguaagua、UAGguaaguc、UAGguaagug、UAGguaaguu、UAGguaauag、UAGguaauau、UAGguaaucu、UAGguaauga、UAGguaaugg、UAGguaaugu、UAGguaauua、UAGguaauuc、UAGguaauuu、UAGguacagc、UAGguacagu、UAGguacauu、UAGguaccag、UAGguaccua、UAGguaccuu、UAGguacgag、UAGguacgua、UAGguacguu、UAGguacuau、UAGguacuga、UAGguacugg、UAGguacuuc、UAGguacuuu、UAGguagcgg、UAGguaggaa、UAGguaggac、UAGguaggau、UAGguaggga、UAGguagggg、UAGguaggua、UAGguagguc、UAGguaggug、UAGguagguu、UAGguaguaa、UAGguagucu、UAGguagugg、UAGguagugu、UAGguaguuu、UAGguauaaa、UAGguauaac、UAGguauaag、UAGguauaau、UAGguauaca、UAGguauacu、UAGguauaua、UAGguauauc、UAGguauauu、UAGguaucag、UAGguaucua、UAGguaucuc、UAGguaugaa、UAGguaugag、UAGguaugca、UAGguaugga、UAGguauggc、UAGguauggu、UAGguaugua、UAGguauguc、UAGguaugug、UAGguauguu、UAGguauuaa、UAGguauuac、UAGguauuau、UAGguauuca、UAGguauucc, UAGguauucu, UAGguauuga, UAGguauuua, UAGguauuuc, UAGguauuuu, UAGgucacuc, UAGgucagcu, UAGgucaggu, UAGgucagua, UAGgucagug, UAGgucaguu, UAGgucaucu, UAGgucauug, UAGguccaau, UAGguccugu, UAGgucucaa, UAGgucucgc, UAGgucuggc, UAGgucuguc, UAGgucugug, UAGgugaagu, UAGgugaaua, UAGgugaaug, UAGgugaauu, UAGgugacau, UAGgugacca, UAGgugacua, UAGgugagaa, UAGgugagac, UAGgugagag, UAGgugagau, UAGgugagcc, UAGgugagcu, UAGgugagga, UAGgugaggc, UAGgugaggu, UAGgugaggu, UAGgugagcu, UAGgugaggu, UAGgugaggu, UAGgugaggu, UAGgugaggu, UAGgugauca, UAGgugauuc, UAGgugauuu, UAGgugacaua, UAGgu gccgu, UAGgugccug, UAGgugcgca, UAGgugcgua, UAGgugcgug, UAGgugcuga, UAGguggaua, UAGgugggaa, UAGgugggac, UAGgugggag, UAGgugggau, UAGguggcc, UAGguggcu, UAGgugguu, UAGguggugu, UAGguguuaa, UAGgugugaa, UAGgugugag, UAGgugugca, UAGgugugcc, UAGgugugcg, UAGguguggu, UAGgugugua, UAGgugugug, UAGguguugg, UAGguguugg, UAGguuga, UAGguguugg, UAGguuga, UAGguugagc, UAGguugagc, UAGguugagua, UAGguugac, UAGguugagu, UAGguucccc, UAGgucuac, UAGguuggua, UAGguugguu, UAGguugucc, UAGguuuau, UAGguuugcc, UAGguuuuga、UAUguaagau、UAUguaagca、UAUguaagcc、UAUguaagua、UAUguaaguc、UAUguaagug、UAUguaaguu、UAUguacgug、UAUguacguu、UAUguagguc、UAUguagguu、UAUguauccu、UAUguaucuc、UAUguaugua、UAUguauguc、UAUguaugug、UAUguauuau、UAUgucagaa、UAUgucugua、UAUgugaaua、UAUgugacag、UAUgugagua、UAUgugagug、UAUgugaguu、UAUgugggca、UAUgugugua、UAUguguuua、UAUguuuugu、UCAgcgacau、UCAguaaaau、UCAguaaaua、UCAguaacug、UCAguaagaa、UCAguaagag、UCAguaagau、UCAguaagca、UCAguaagcc、UCAguaagcu、UCAguaaggg、UCAguaagua、UCAguaaguc、UCAguaagug、UCAguaaguu、UCAguaucuu、UCAguaugga、UCAguauggu、UCAgucccca、UCAgugagca、UCAgugagcu、UCAgugagua、UCAgugagug、UCAgugaguu、UCAgugauug、UCAgugggug、UCAguugagc、UCAguugauu、UCAguuuagu、UCCguaagca、UCCguaagcu、UCCguaaguc、UCCguaagug、UCCguaauag、UCCguacuua、UCCguaugua、UCCguauguu、UCCgugagau、UCCgugaguc、UCGguaaauu、UCGguaagag、UCGguaagcu、UCGguacauc、UCGguacucc、UCGguagacc、UCGguagguu、UCGguaguaa、UCGguaugug、UCGguauguu、UCGguauuga、UCGgucagua、UCGgucuuag、UCGgugaagu、UCGgugagaa、UCGgugagca、UCGgugaggc、UCGgugagua、UCGgugcgcu、UCGgugcuuu、UCGgugguuu、UCGguuagcu、UCUguaaaag、UCUguaagaa, UCUguaagau, UCUguaagca, UCUguaagcu, UCUguaagua, UCUguaaguc, UCUguaagug, UCUguaaguu, UCUguaauaa, UCUguaauga, UCUguaaugu, UCUguaggua, UCUguagguu, UCUguauaua, UCUguaugac, UCUguaugua, UCUguccucg, UCUgugagag, UCUgugagcu, UCUgugagag, UCUgugagua, UCUgugaguc, UCUgugaguu, UCUgugcgua, UCUgugugag, UGUguaacuu, UGUguaagau, UGUguaagca, UGUguaagcu, UGUguaaggc, UGUguaaggu, UGUguaaguag, UGUguaaguc, UGUguaagug, UGUguaaguu, UGUguaaucc, UG, Aguaauua, UGAguacagu, UGAguacgua, UGAguacguu, UGAguacugu, UGAguagcug, UGAguaggua, UGAguauaaa, UGAguaugcu, UGAguaugga, UGAguaugua, UGAguauguc, UGAguauguu, UGAgucagag, UGAgucuacg, UGAgugaaua, UGAgugaauu, UGAgugagaa, UGAgugagau, UGAgugagca, UGAgugagcc, UGAgugagga, UGAgugagua, UGAgugagu, UGAgugagu, UGAgugg gaa、UGAguuaaga、UGAguuaaug、UGAguuacgg、UGAguuaggu、UGAguucuau、UGAguugguu、UGAguuguag、UGAguuuauc、UGCguaaguc、UGCguaagug、UGCguacggc、UGCguacggg、UGCg uaugua、UGGcaaguc、UGGgcaagug、UGGcacauc、UGGgccacgu、UGGgccccgg、UGGguaaau、UGGguaaagc、UGGguaaagg、UGGguaaagu、UGGguaaaua、UGGguaaaug、UGGguaaauu、U GGguaacag、UGGguaacau、UGGguaacua、UGGguaacuu、UGGguaagaa、UGGguaagac、UGGguaagag、UGGguaagau、UGGguaagca、UGGguaagcc、UGGguaagcu、UGGguaaggg、UGGguaaggu、UGGguaagua、UGGguaaguc、UGGguaagug、UGGguaaguu、UGGguaaugu、UGGguaauua、UGGguaauuu、UGGguacaaa、UGGguacagu、UGGguacua c. Gguaugug、UGGguauguu、UGGguauuug、UGGcuuug、UGGgugaccu、UGGgugacua、UGGgugagac、UGGgugagag、UGGgugagca、UGGgugagcc、UGGgugagga、UGGgug uggc 、UGGGuggug、UGGGugguu、UGGGugguga、UGGGuggugu、UGGGuggugu、UGGGuggugu、UGGGuguuua、UGGGuuaaug、UGGGuguaguc、UGGGuguugauu、UGGGuguugauu、UGGGuggugu guucaag, UGGguucgua, UGGguuggug, UGGguuuaag, UGGguuuaag, UGGguuugua, UGUgcaagua, UGUguaaaua, UGUguaagaa, UGUguaagac, UGUguaagag, UGUguaaggu, UGUguaagua, UGUguaaguc, UGUguaaguu, UGUguacuuc, UGUguaggcg, UGUguaggua, UGUguaguua, UGUguaugug, UGUgucagua, UGUgucugua, UGUgucuguc, UGUgugaccc,UGUgugagau、UGUgugagca、UGUgugagcc、UGUgugagua、UGUgugaguc、UGUgugagu、UGUggcgug、UGUguggug、UGUguggguu、UGUgugugaku、UGUgugugu、UGUg uuuaga、UUAguaaaua、UUAguaagaa、UUAguaagua、UUAguaagug、UUAguaaguu、UUAguaggug、UUAgugagca、UUAgugaguu、UUAguuaagu、UUguaaguc、UUguaag uu, UUCguaauua, UUCgugagua, UUCgugaguu, UUGgcaagug, UUGgccgagu, UUGguaaaaa, UUGguaaaau, UUGguaaaga, UUGguaaagg, UUGguaaagu, UUGguaaauc, UUGguaaaug, UUGguaaauu, UUGguaacug, UUGguaacuu, UUGguaagaa, UUGguaagag, UUGguaagcu, UUGguaagga, UUGguaaggg, UUGguaagua, UUGguaagug, UUGgu aaguu, UUGguaauac, UUGguaauca, UUGguaaugc, UUGguaaugu, UUGguaauug, UUGguaauuu, UUGguacaua, UUGguacgug, UUGguagagg, UUGguaggac, UUGguaggcg, UUGguaggcu, UUGguaggga, UUGguaggua, UUGguagguc, UUGguaggug, UUGguauaaa, UUGguauaca, UUGguauauu, UUGguaucua, UUGguaucuc, UUGguaugca, UU Gguaugua、UUGguaugug、UUGguauguu、UUGguauugu、UUGguauuua、UUGguauuuu、UUGgucaagaa、UUGgucagua、UUGgucucug、UUGgucucaca、UUGgugaaaa、UUGgug acug、UUGgugagac、UUGgugagau、UGGugagca、UGGugagga、UGGugaggg、UGGugagua、UUGgugaguc、UUGgugagu、UUGgugaguu、UUGgugaugg、UUGgugauua、 , UUGgugauug, UUGgugcaca, UUGgugggaa, UUGguggggc, UUGgugggua, UUGguggguc, UUGgugggug, UUGguggguu, UUGgugugu, UUGguggugc, UUGguggug, UUG guguguu, UUGguuaagu, UUGguuagca, UUGguuagu, UUGguuaguu, UUGguugga, UUGguugguu, UUGguuugua, UUGguuuguc, UUUgcaagug, UUUguaaaua, UUUguaaa This includes ug, UUUguaagaa, UUUguaagac, UUUguaagag, UUUguaagca, UUUguaaggu, UUUguaagua, UUUguaaguc, UUUguaagug, UUUguaaguu, UUUguaauuu, UUUguacagg, UUUguacgug, UUUguacuog, UUUguacugu, UUUguagguu, UUUguauccu, UUUguauguuu, UUUgugagca, UUUgugagug, UUUgugcguc, UUUguguguc, and uGGguaccug.

[0214] Further exemplary gene sequences and splice site sequences (e.g., 5' splice site sequences) include AAGgcaagau, AUGguaugug, GGGgugaggc, CAGguaggug, AAGgucagua, AAGguuagag, AUGgcacuua, UAAguaaguc, UGGgugagcu, CGAgcugggc, AAAgcacccc, UAGguggggg, AGAguaacgu, UCGgugaugu, AAUgucaguu, AGGgucugag, GAGgugacug, AUGguagguu, GAGgucug uc, CAGguaugu, CAAguacugc, CACgugcgua, CCGgugagcu, CAGguacuuc, CAGgcgagag, GAAgcaagua, AGGgugagca, CAGgcaaguc, AAGgugaggc, CAGguaagua, C CAguugggu, AAGgugugg, CAGguuggag, CCGguaugaa, UGGguaaugu, CAGgugaggu, AGAguaauag, CAGguaugag, AUGguaaguu, UUGguggguc, UUUguaagca, CUCgu augcc, UAGguaagag, UAGgcaaguu, GGAguuaagu, GAGguaugcc, AAGgugugu, CAGgugggug, UUAguaagua, AAGguuggcu, UGAguaugug, CCAgccuucc, CCUguacgu g, CCUguaggua, CAGguacgcu, GAGguucuuc, AAGguugccu, CGUguucacu, CGGguggga, UAGgugggau, CGGguaagga, AAGguacuau, GGGguaagcu, ACGguagagc, CA Ggugaaga, GCGguaagag, CAGguguugu, GAAguuugug, AUGgugagca, CGGguucgug, AUUguccggc, GAUgugugug, AUGgucuguu, AAGguaggau, CCGguaagau, AAGgua aaga, GGGgugaguu, AGGguuggug, GGAgugagug, AGUguaagga, UAGguaacug, AAGgugaaga, UGGguaagug, CAGguaagag, UAGgugagcg, GAGguaaaaa, GCCguaaguu,AAGguuuugu、CAGgugagga、ACAgcccaug、GCGgugagcc、CAGguaugca、AUGguaccua、CAAguaugua、AUGguggugc、UAAguggcag、UAGguauagu、CUGguauuua、AGGguaaacg、AUAguaagug、UUGguacuga、GGUguaagcc、GAGguggaua、GAUguaagaa、ACGgucaguu、UAAguaaaca、AAGguaucug、AGGguauuug、AAGgugaaug、CUGgugaauu、CAGguuuuuu、CAUguaugug、UUGguagagg、AAGguaugcc、CAGgugccac、UCGguauuga、AAGguuugug、AAUguacagg、CAUguggguu、CAUgugaguu、UUGguaaugu、AGUguaggug、GAGguaacuc、GAGguggcgc、CUGguaauug、GAGguuugcu、UGUguacgu、 g、UAGguaaaga、CUAguaggca、UCUgugaguc、UCUguaaggc、CAGguuugug、GAGguagggc、AAGguaacca、ACUgugaguu、UAGguaauag、AAAguaagcu、AUGgugagug、U AGguuugug、AACguaggac、GUAgcaggua、GAGgucagac、AGGguaugaa、GAGguuagug、CAGgcacgug、GGGgcaagac、CAGguguguc、CAGguauuga、CAGguauguc、AAGg caaggu、UUGgugagaa、AAGguaaaau、GGGguaagua、AAGguaucuu、GACgugaguc、UAUguaugcu、AAGguacugu、CAGgugaacu、CACguaaaug、AAGgugugau、GAAguau uug, AAGgucugug, AAGguggagg, AAGguauaug, CAGguucuua, AGGguaacca, CAGgugucac, AAAguucugu, UUGgugaguu, CAAgugaguc, UAGguagguc, GCGgugagcu 、AUUgugagga、CAGgugcaca、CAGguuggaa、CUGgucacuu、GGAguaagug、GAGgugggcu、AAGguacuug、AGGguaggau、AAUguguguu、ACAguuaagu、GAGgugugug、AA Ggcgggcu, AUAgcaagua, AAGguuguua, CAAgcaaggc, GUGguaauua, UCUguucagu, AGGguaggcc, AAGguaucau, UAGguaccuu, AAGguaugac, GGAguaggua, UAAgu uggca、AGUgugaggc、GAGguuugug、UGGgucugcu、CAGgugaucc、CAGgucagug、AAGguaaggg、CAGgugcagu、GAGguggguc、GCUgugagug、AAGguggagu、GGGgucag uu、AGCguaagug、AGAguaugaa、GGGguagggu、AAGgccagca、CGAguaugcc、GUGgugagcg、AAUguaaauu、CAGgugcgca、GGUguaugaa、CUUgugaguu、AAGguaucuc、AGAguaagga uucgcg, CAGgugaucu, ACUguaagua, AAGguaaauc, CAGgcaaaua, GUGguaagca, CAGguuaaau, UUGguaauaa, UAUguaggua, CAGguaguau, AAGgugugcc, UGGguaag ag、CAGgcaagca、UUGguaaggg、AAGgcaggug、ACGguaaaug、GCUgugagca、AUGguacaca、GUAguguguu、ACUguaagag、CCCgcagguc、GAGgugagcc、GAGgugcugu、U AAguaugcu、GAGgccaucu、UCAgugagug、CAGgugcuac、AAUgugggug、GAGgugugaa、CUGguagguc、GUGgcgcgcg、CAGgugcaaa、UAAguggagg、CAUgugggua、GAGgu agggu、AAAgugaguu、AGGguucuag、UGUgugagcu、AGGgugaauc、CAGgucaggg、AAGgucccug、CUGguagagu、UAGgucaguu、AAAguaaggg、CAAguaugug、CAGgugcuu u、AAGguaauuc、GGGgugcacg、ACUgugcuac、CAGguaccua、CAGguagcuu、UGGgugaggc、CUGguacauu、AGGguaaucu、CAGguacaag、CAGguaauuc、AGGgcacuug、UA Ggugagaa, GGguaaugc, CCAgugaguu, AAAguaugug, CUGgugaauc, UAUguaugua, CCUgcaggug, CAGguaucug, GGgugaggu, CUGguaaaac, UGUgugugcu, CAGguu aagu、CAGguaaucc、UAGguauuug、UGGguagguc、CAGguaacag、AGCgugcgug、AAGgucagga、GGUgugagcc、CUGguaagua、GGGgugggca、AAGgugggaa、CAGgugagug、CUGguug, uua, CAGguaauag, UAGgugaguu, AGAguaaguu, UAGguaaucc, CCGgugacug, GUCgugauua, CUUguaagug, UAGguaguca, CUGguaaguc, AGGgugagcg, CAGguaugga AUUgugacca, GUUgugggua, AAGguacaag, CUAgcaagug, CUGgugagau, CAGgugggca, AUGgcucgag, CUGguacguu, UUGgugugua, GG Ggugggag, GCAgcgugag, GGguaaaga, GAGguaugua, AAGgugagac, AAGguacaau, CUGguaugag, AACguaaaau, GUGguaggga, CUGguaugug, CUUguaagca, AAGgu aggga、AUUguaagcc、AUGguaagcu、CAGgugaauu、UAGgugaaua、CAAguaugga、AUGguauggc、GAGgucaugc、CAGguacccu、ACAgugagac、CAGgucugau、GAAguuggg u、CUGgugcgug、CAGguacgag、ACAgugagcc、AAGguaagua、GGAguaaggc、GAGgugugua、AAGgucauuu、CAGguagucu、AUGguaucug、AAGguaaacu、GAGguaggugC UGguaagca、AGGguaagag、AAAguaaagc、CAGguuugag、GAGgcgggua、CGAguacgau、CAGguuguug、AAAguauggg、UAGgcugguc、AAGguaagga、AAGguuuccu、UUGg uaaaac、GAGguaagua、CAGguucaag、UGGguuaugu、GAGgugaguu、ACGgugaaac、GAUguaacca、AAGgugcggg、CCGguacgug、GAUgugagaa、GUGgcgguga、CAGguau uag、GAGguuggga、AAGgcuagua、AAGgugggcg、CAGgcaggga、AAUguuaguu、GAGguaaagg、CAGgugugcu、CUGguaugau、AUGguuaguc、CUGgugagaa、CAGgccggcg、CAGgugacug, AAAguaaggu, UAAguacuug, AAGguaaagc, UCGguagggg, CAGguagga, AGUguaagca, CCCgugaga u、GUGguuguuu、CAGguuugcc、AGGguauggg、UAAguaagug、GAGguaagac、GAUguagguc、CAAguaggug、AUAguaa aua, GAGguugggg, GAGgcgagua, CAGguagugu, GUGguaggug, CAAgugagug, AAGgugacaa, CCAgcguaau, ACGgu gaggu、GGGguauauu、CAGgugagua、AAGgugcgug、UAUguaaauu、CAGgucagua、ACGguacuua、GAGgucagca、UAA G. GGGgucagac, AAUgugugag, UCCgucagua, CAGgugcuuc, CCAguuagug, CCGgugggcg, AGGgugcaug, G GGguaggau、UAGgugggcc、GAGguguucg、UUGgcaagaa、UCCguaagua、CAGguguaag、CUCgugagua、GAGguguuuu 、GAGgugagca、GAGguaaagu、AAGguacguu、CAGguccagu、AUGgugaaac、GUAgugagcu、CAGgugaaaa、AGGguaca gg、AAGguaacgc、AAGguauacc、CCUgugagau、GGGguacgug、GAGguauggu、UAGguauuau、GAAguaggag、UCGgu、 aaggg、CCGguaagcg、GAAguaauua、CAGgugaguc、AAGgucaaga、AUGguaaguc、CAGgugagcu、CCAguuuuug、CAGgugggag、AAGguauuau、AAGguaaaua、AAGgugcugu、AAAguacacc、CU Gguucgug, UCAguaaguc, GAAguacgug, CAGgugacaa, UGGguaagaa, UGUguagggg, GAGguaggca, UUGgugaggc, AUGgugugua, CAGguccucc, UUGguaaaug, GCUgugaguu, AUGgucugua 、CAUgcaggug、CUGguacacc、CAGguccuua、CAAguaaucu、AUGgcagccu、AAGgucagaa、AACgugaggc、CAGgcacgca、ACGguccagg、UCUguacaua、GAGgugauua、ACGguaaaua、AUGguaacug、CAGgcgcguu、CAGguauaga、AAGguuuguu、CAGguaugaa、UAGguuggua、CUGgugagac、CAGguuagga、AUGgugacug、UUGguauccc、CUUguaggac、AAAguguguu、CAGguuucuu、GGGguauggc、GGGguaggac、ACUguaaguc、AUCguaagcu、UAGguucccc、GGUgugagca、CUGguuggua、GGGguuaggg、UGAguaagaa、GAGguauucc、UGGguuaguc、CAGgcucgug、UAGguagagu、UAGgugcccu、AAAgugagua、GAGguucaua、UUGguaagag、ACCgugugua、UAUguaguau、UGGguaauag、CAGgucugaa、AAAguauaaa、GUGgugaguc、AGUgugauua、UUGgugugug、CAGgugaugg、GCUgugagua、CAGguacaug、AAGguacagu、GAAguuguag、CAGgugauua、UAGgugaauu、GGUguuaaua、CAGguauuua、CAAguacucg、CAAguaagaa、AAGguaccuu、ACGgugaggg、UGAgcaggca、GGGgugaccg、GAGguaaaug、CGGguuugug、AAGgugagcg、GUGguaugga、CUGguaagga、GAGguaccag、CCGgugagug、AAGguuagaa、GAGguacuug、AGAguaaaac、UCUgugagua、AAGgcgggaa、CAGguaugcg、AGGguaaaac、AAGgugacug、AGGguauguu、AAGguaugua、CAGgucucuc、CAGgcaugua、CUGguaggua、AAGgucaugc、CAGguacaca、GAUguacguu、ACAguacgug、ACGguaccca、CAGguagugc、ACAguaagag、GGUgcacacc、GAGguguaac、AAGgugugua、UAGguacuua、GCGguacugc、UGGguaaguc、CAUguaggua、CAGguaggau、CAGgucuggc、GUGg uuuuaa, CAGgugggaa, UGGgugagua, CGAgugagcc, AAGguauggc, AGUguuguca, CAGgugauuu, UAGguaucuc, UAAguauguu, AAGguugagc, AGAguaaaga, GGUguaag ua、GGGgugagcu、CAGguauaau、GAGguacaaa、AUGguaccaa、UAGguagggg、UGAgucagaa、AAGgcaauua、UUGguaagau、CAGguacaga、AGAguuagag、CAGgugcguc、G AGguauuac, ACGguacaga, CAGgucuucc, AAGguaaggu, GGguaauuu, AGUguaggcu, AAAguaagcg, CCUguaagcc, AGGgugauuu, UGUguaugaa, CUGguacaca, AGGgu agaga, AUAguaagca, AGAguaugua, UUGgucagca, CAGgcaaguu, AAGguauaua, AAGgucugga, CAGguacgca, AGGgugcggg, AUGguaagug, AAAgugauga, UGCgugagu a、AGAguaggga、UGUguaggua、UAGguaggau、UAAgugagug、GCUguaagua、GAAguaagaa、UCGgugaggc、UAGguauuuu、AAGguacaca、AAGguaggua、UGGguagguu、AC Agcaagua, GAGguaggag, UGGgugaguu, GCGgugagau, CCUguagguu, CAGgugugua, CUGguaagcc, AAGgugauuc, CAGguagcua, GUUguaagug, AUGguaagca, AUAgua ggga, GGGguucgcu, CCGgucagag, GUAguaugag, CGUguaagau, UGAguaggca, UCAguaugua, GGguaucug, AGAguauuuu, AAGguuguag, AGUguaaguu, CGGguaaguu.UCGgugcg, ga、UAGguaagua、GAAguuagau、GCUgugagac、CAGgcaggua、CAGguagggg、UAAguuaaga、AUGguggguu、UAGguaaguu、CUGguaaauu、CCGguaagga、GAGgcaggca、 CAUguaagug, AAGgugccua, UUGguaggga, AAGguaaaca, CGGgugugag, GGGgugugag, UCCguggguc, ACGguaaauc, UCAguaggua, CAGgucagcc, CAGgcggugg, CGA guaagcu, CCCgugagca, AAAguaauga, CUGguaagcu, CGGguaacca, CAGgucgcac, GGguaggcc, UAGgugagcc, UAGguaggca, GCGgugcgug, AUGgugagua, GGGgug aggg、GAGgucacac、CAGguaggcc、CAAgugcuga、GUCgucuuca、CAUguaagaa、GUAguaagga、UAGguuugua、CAAguuagag、AAGguagagu、AAGgugagau、AAAguaggu a、ACAgugaauc、CAGgugugcg、CAGgucggcc、AAGguaguau、ACUgucaguc、UCUgcagccu、CGAguaagug、AGAguaauua、AGUgugagug、CCGgugagcg、AAGguaaccu、A AGguugugg、AAGgcauggg、AAGgucagag、ACGguaaggu、GGGgugagca、GAGguugcuu、AAGguaucgc、CCGguaaagg、AAAguuaaug、UAGguacgag、ACCguaauua、GGGg uaagga、CCGguaacgc、CAGgucagaa、AAGguacuga、GAGgugacca、GGGgugagcc、AAGguacagg、AUGguaauua、CAGgugagag、AAGgugacuc、AUAguaagua、GAGguaa acc, CAGgugggau, CAGgugagaa, AGGguaaaaa, GAGgugugac, CACguaagcu, CAGguccccc, CAGgucaggu, CGGguaaguc, ACGguauggg, GAUguaaguu, CAAguaauau.CAGguuggg、CCUGUGCUG、AAGGUAUGAUGAUG、AGGGUGGGUU、CAGGUGUGUAA、UUGGUAUCUC、GGGGUGAGUGUG、CUGGUGUGUG、AGGGUGGGC、GUGGUGUA、CAGGUAUGUA、AAGGUACAUU、UUAGUAGUG、AAUGUAUAUC、CUUGUAGUA、GAGGUUAGUA、CAGGUAGGU、CAGGUAGU、CAGGUAGU、CAGGUAGU、CAGGUAGG、CAGGUAGG、CAGGUAGG、CAGGUAGG、CAGGUAGG、CAGGUAUGAUUC、CAGGUCUG ga、GGGGugugcu、UAGgugagug、AAUguaaccu、UAAgugaguc、CAGgugcacu、ACGguaagua、GAGguauccu、UCUguaaguc、CAGguauuca、UGUguaagg、CCAgcaaggc、G AGgugaagg、AAUgugggu、UCGgugcgug、UUGguaaggc、GAGguaagug、AAAguaagau、UAGgucuuu、GAGgucugau、CCAguuagag、UGGgugaaaa、AGaguaagau、CAGgu aauug、CAGgccgguc、CCGguaagag、GAGGugagcu、CUGguaagac、CAGgugagau、CUGguuuuu、UGGguaggua、CAGguuagug、CAGguguucg、CGGguagguc、GUGguacau a. Ggcaagua、CGCgugagcc、AGUGugcgu、GAUguaagca、AAGguaauag、GGAgcaguug、AGCguaagau、AAGgucaggc、GAGguauuca、AAUguaaagu、CAGguaacaa、UCGgua ggug、AAAguaaguc、CGGgugcagu、GGUgugugca、UGagugagaa、CACguguaag、GUGguuggua、GCAgccuuga、CGAgugugau、CAGguauaua、UAUguaugug、CCCgugguca、AUGgua, agac, GAGgugugga, AGUguauccu, UGAguguguc, UGGguaaucu, AUGgcagguu, GAGguaagau, UCAgcagcgu, AAGgugggau, CGGgugcgcu, CAGgugucug, AGCgugguaa, AAUgugaaug, UCGugagac, UAGguaaagc, CUGguaaaag, CCGgugcgga, CAGguacuca, CAGguagcaa, GAAguugagu, GAGguggagg, AGGguaugag, UAGguaugcu, UAGgugagac, CAGguaauua, CGUguaagcc, CUUguaaguu, AAGguaacuu, UCGgcaaggc, GAGgucucg, GAGguggcg, AAGgcaugug, CUGguauguu, UAAgucauuu, CAUguaauua, AAUguaaaga, UAGgugcuca, AAGguaaugg, GAGguacu ga、UGGguaagua、UGGguaaaaa、AAGgugagcu、UACgugagagu、AGGgugagcc、CGGgugagga、UGGgugagag、GGUguaagcu、CGGguggguu、CCAgcuaagu、AAGguuguc、GAGguuagac、GAGguaccuc、UUUuguagu、GAGguuagga、CAGguaggga、AGGguaauac、UGCgugugua、CCAguaacc a. AGAguaaggu、CCGguggguc、CAGguauucu、UGGguaacgu、UUGgugagag、UAGguacccu、GGGgugcguc、AAGgcaggag、ACGguacauu、GAGguaguua、CAGguauggg、UUUguguguc、CAGguacuua、AUGguauacu、AGUgugagcc、ACAguaacga、CUGguaccca、CAGguaaccc、GGAguaagua、GAGgugggug、ACUguauguc、ACGgugagua、CUGguaaugu、AAGguaucag、CAGgugcccc、AGUgucagug、AAGguaggag、GGAguaugug、UUGguauuuu、CCUguuguga、UUUguaagaa、UAGguaacau、CAGguaagca、CAGgucacag、CAGgugugag、UAGguuugcg、CUGguaagaa、ACGguuguau、AAGguugggg、AAGgugaauu、GGGguuaguu、ACGguaaggc、CAGguuuaag、CUGguaaguu、GGGgugagag、UGGguggguu、GAGguuuguu、UGGguaaaug、CAGgcaggcc、CACgugcagg、AAGgugagcc、CAAguaagug、CAGgucaguc、GCGguauaau、UAGguaaagu、UAGguggauu、GAGgucugga、UCGgucaguu、UGGguaacug、AAGguuugau、UGUgcuggug、UGUguaccuc、UGGguacagu、AUCgucagcg、CAGgucuugg、GAAguuggua、GAAguaaaga、UUGguaagcu、UAGguaccag、AGGguaucau、CAGguaaaaa、ACGguaauuu、AUUguaaguu、GAGguacagu、CAGgugaaag、UGGguuguuu、GGGguaggug、CAGgugccca、AGCgugagau、CCAgugagug、AGGguagaug、UGGguguguc、AUCgcgugag、AGGguaagcc、AGGguagcag、UUCguuuccg、AAGguaagcg、UGGguaagcc、CAGguauggc、UGUguaagua、AAGguagaga、ACGguaauaa、CUGguacggu、GAGgucacag、UAUguaaguu、CUGguacgcc、CAAguaagau、CUAgugagua、CCGguaaccg、CUUguaaguc、GUGgugagaa、ACCguaugu、 a、GUAguaagug、UUGgugggua、CGGguacuuu、UGGguaaaua、AGAgugagua、AAGguagguu、AAGguaugcg、CCUguaggcu、ACAguagaaa、CCGguagua、CGGguaggcg、G CAgugagug, GAGgugaguc, CUGguagccu, CAUguaugua, GAAguaacuu, GAAguaagau, AAGguaauca, AAUguaugua, UGAguaagau, AGAgugagca, GUAg uucuau、GAGguaauca、UAGguaugga、UAGgugggac、GAGguacaug、UGGguaaggc、CAGguacgcc、CCAguuacgc、ACUgugguga、GAGguaaguc、AUUguaggug、ACCguca gug、AAUgugaggg、ACUgugagug、UGGguguggu、AAGguuggga、AAGguuugga、UCCgugagug、CGGgugagug、AGAguaagcu、CAGgcaagcu、UAGguauauu、AAAguagcag 、GAGguaaccu、AAGgugggca、AGGgugagua、UGGguaaggu、CUUgucagug、UAGgugcgcu、GAGgcaaauu、AGGguaccuc、CAAgugcgua、AGAguaagac、GUGguaaaua、GA Uguaagcg, GGguaaagc, UAGgugagua, CAGguaacau, CCUguacggc, UAGguauguc, UAGguccaua, GAGgugaaaa, AAAguacuga, UUGguaagcg, CAGgcaagcg, UUUgc agguu、CAGguuuaua、CUGguaaagc、AUGgugagcu、CAGgugguug、GUAguaaguu、CAGguaauac、CAGgcaaggc、AAGguaauuu、UUUguccgug、GAGguagguu、ACCgugag ug、CAAguaagcu、ACAgugagua、UUGgugagau、AAGguagucu、CAGguaaagg、GGGguaugga、UUUguaagug、GUGguaagag、AGUgugaguu、AAGgcaagcg、UAAgugagua、AGGgugagug、AGUguacgug、AGGgugcgua、GGCgugagcc、CGAguuauga、CAGguaaaga、UUGgugaaga、AGGguaaugg、AAGguccaga、AGUgugaguc、CAGguaauuu、CAGguaacgc、CUGguacacu、CUGguuagug、CAGguacuug、CACguaagua、GUGgugcggc、GAGgucaguu、AUGguaugcc、AAGgugugug、CUGguggguc、CAGgugaggc、AAGguuaguc、AAGguagcug、GAGgucagga、GUUguaggua、UGGguacaag、AUGguaggug、GAGguaagcc、AUGgcaagua、AAGguauauu、GCGgugagag、AAGgugcuuc、UAGguacauc、ACUgugguaa、GAGguaggcu、GAGguaugca、AGGguaguuc、CAGguauccu、AGGguaaguc、AGGgucaguu、CAGguuggga、CAGguggaua、GGAguagguu、GAGguaggau、GGGguuugug、UAGguaauug、AAGguaaccc、ACGguaagaa、GAGguagggg、CGAguaggug、UCCguaagug、UCGguacagg、CAAguaagcg、AAGguccgcg、AAUgugagua、CAGgugaaug、GUGguaaggc、AGAgugagug、UCUguauguc、UGGgugaguc、UCGguuagua、GAUguaugca、GAGguuggug、GAGguggggc、UGGgucaguc、GCAgugagua、CAGguugcuu、AGGguagagu、UAGgucaggu、CGCguaugua、GAGguauuaa、CAGguaaacu、AAAguaaguu、GGGgucuggc、GCUguggggu、UUGguaaguc、AAGguagaag、AAUgugaguc、AAGgucagcu、AAGguaagag、AUGgugagga、AAGguacuuc、AAGguaagaa、CCGguacagc、GCGgugcgga、CAGguacaua、CUGgugagga、CUGguaggug、AACguagguu、AUGgugugug、UUGguac、 uau, CAGgucggug, CAGgcauggg, AUGguaucuu, AAGguaacua, CAGgugggcg, CACgugagga, AAGgugguuc, UGGgcauucu, AUGguaagcc, AGGgucagug, AGAguacgua 、AAGguaggca、AAGguauuca、CAGguagauu、GAGguauuua、GAGgucuaca、GUUguagguc、CAGguacucg、GUCguauguu、AAGguacuuu、AGAgugagau、AGUguuggua、AA Ugugagug, AAGguagauu, AUGguuugua, GAGgccccag, AUGgucaguu, UCUguaagga, CAGgucgggc, CAGguaagcc, UAGgucagug, AGAguagga, CUGguacuuc, CUCgu aagca, CAGguaacua, CAGguggcug, UGGguccgua, GAGguugugc, CAGgugcgcg, AAAguauggc, UGAguacgua, CUGguacgga, CAAgugaccu, AAGgugaugu, AAGgucugc a、AAAguuugua、AAGgugagca、GAUguaagcc、CAAguaauuu、CAGgugugug、UGGgugaggg、AAGgugaccu、UAGgugugag、CAGgcagguc、UCAguaaguu、UCAgcaguga、A AGguaccac, UAAguaggug, AAGgucagcc, CAGguaacuc, AAAguaagag, AAGguagaua, AAGgcaaggg, CAGgugucgg, CAGguggcua, GGguugcca, CAGgccgugg, UUGg uauaug、GAGguugagu、GAGguagguc、GUGguaagac、UAGguccuuc、GAGgcaaguc、GAGguaacau、CAGguauauc、UCGguugguu、CAGgugaacc、CAGgucuuuuu、CAGgcau ggc、AAAguacuug、CAGgugauuc、UUGguagguu、UAUgugagca、CAGgugagcg、AAUguauaaa、AAAguaaggc、UAGguuuguc、UAGgugggag、GAGguaaguu、AAGguagccg、CAGguggugc, UGAgucaguu, CUGguaggcc, CAAguaagga, CGGguaaggc, AAGgcgagga, CAGguaguuc, CAGguaagga, CCUgugagug, AAGguaaaug, CCGguaauua, CAGg uaaguu, AAGgugguca, CAGguaccuc, AUCguaagua, CCGguacaua, GCGgugagug, GAGgugguau, CUGgugugga, GAGguaauuc, CAAguacgua, UCUguaagug, AAUguaag ug、AGGgucuguu、GAGguacugc、AGGguaaggc、AAGgcaagag、CAGguggguu、UAGguuagga、UGAguaagcu、AGAguaagag、AUGgcaggug、UAGgcaagua、AUGguaggua、G CAgcccgca、ACGguaaacu、AGGgugaguu、GUAguagucu、GUGgcugaaa、CAGguuaguc、CUGgugagca、UCAguaagug、AAAgugauug、UAGgucugga、GAGguguuuc、AAGgu aaauu、CAUguacauc、AAGguuugaa、CCAgcaagug、UAGguaauaa、GAGgcaagug、CAAgugauuc、CAGgucgugg、GAAguaugcc、UCGgugcccu、GAGgucaguc、CAGgugaga c、UUUgucugua、CAGguagaua、UGGguaucag、UAGgugggcu、AUGgugagau、CAGguaacac、CCGguauccu、UAGguaagcu、UCAguacauc、UAGguuugcc、AUGguaagaa、UU Gguaagac, CCGguuaguc, GGguaagaa, UGGguaaguu, CCGgugagaa, CCUgugaggg, ACGguaggag, ACAguauguc, CAGguauuaa, CAGguggauc, AGAgugcgua, AAGgug accg, AGAguaggug, ACUguaugua, UAGgucaauu, AGUguguaag, CGGguaccuu, CUAgugaguu, CUAguaagug, CAGguacaac, UAGgugugug, CAUguacggc, AUGgugugag.AGGgu g gaag、CAGgugcgag、UAGgugcucc、AAGguggugg、AAGgucuguu、CAGgugggcc、AAGgucaguc、CAGguuuuua、AACgugaggu、CGGguaagag、UUUgucggua、UAGguuaag u、GUGguaagaa、CAGguauugg、GCUguaaguu、CUAguaagua、UCGguaaaua、CAGguaacuu、CCUgugagua、CAGguuauau、CUGgugaaca、AAGguauaaa、GAGguaagca、A AGgugaagc、CAGgugaguu、UUUgugagua、CUUguacgcc、AGAguaagug、UGGguaggug、UGAgcccugc、UGUguaugua、AAGguagagg、GAGguggggg、UAGguaauuc、AAGg cauggu、AGAguaagca、AAGguaggaa、CAAguaagua、ACUguaauug、CAGgucugug、UCGguaccga、CUGgugagag、AAGguuugcu、AUGguaccac、UAAguuaguu、CAGguagg ac、AGAgugaggc、CGAgucagua、CAGgucugag、GAGguggugg、ACGguauugg、GCUgcgagua、CUGguaagug、GUGgugagau、GGGguuugau、UCUgugagug、CUUgucagua、 GAGguaaaac, UCUguaagau, CCAguaaguu, CAGguaaagu, GCGgugagca, UAAguaagag, CUGgcaggug, GAGguaaggg, UGAguaaguu, GAGgugagac, GCUgucuguu, AAGg uaacaa、GAGguaacgg、CUGguauucu、CAAguaacug、AAGguggggu、UAGguauggc、CAGguauuuu、GUGguaaacu、GAGgucugag、CUGguaaggu、CAAguaaguu、AAGguag acc、GAGgcgagcg、CUGguaaaua、UGUguaagcg、CAGguuaggg、GGGgugagga、ACAguaugug、CCGgugggga、GAGgucagug、AGGguaaggu、ACAguaagua、GGUguaaggu、GAGguaauaa、CAGguauucc、CUGguauaaa、CCGgucugug、CAGguaacug、GCAguaagua、AAGguagggg、CAAguccacc、CAAguuggug、CAGgugcggu、CAGguaaaau、ACGguaagga、UGGguaauaa、UAGguaagug、CCGguagguu、AGAguaugga、CUCgugaguc、AAAgccggug、UUGguaauuu、GAGguaaaag、CCUgugugag、AAAguaagga、UGAgugagug、AAGguacaug、CCGguaaaug、CAGgugaagc、CAGguacccg、GAGguaaggc、UUUguauguu、CAGgugcucc、UCGguagguc、CGGgugaggc、AAGguaauua、ACUgugaguc、AAGgucagca、GUGgugagug、CAUguccacc、AAGgugaccc、CGGguuagua、GCGguaguaa、GCUguaggua、CCUguugagu、UAGgucuggc、GAUgugagcc、CUUgugagua、CUGguguguu、GAGgcaugug、CAGgcaagag、UUGguaagaa、GAGguguggg、GAGguauuuu、CAGguaguaa、AGGguaagac、UUUguaggca、AGGgugagau、GAGguuugua、AAGgugagug、GAGgugggag、AAGgugagaa、CUGguaagag、AUAguaaaga、GAUgugaguc、AAGgugcagg、CAGgucuguc、GAGgugauuu、CAGguuggcu、CGGguauggg、AUGguccauc、CCGguuggug、GGAguaaguc、AAUguaagga、CAGguuuguu、UAGgugugua、UAUgucuuug、ACGguacuuc、AAGgcacgcg、CUGguaaacc、CUUgugggua、UGAguaaguc、CUGgugggug、GAGguggaga、GUGguggcug、GUGguaagug、AACgugagua、GAAgcuguaa、CGGguaucuu、CAGgugucag、AAUguacg、 ca、CCGgugggua、UGGgugaggu、AAGguauguu、CAGguauguu、CAGguuugcu、UUGguaaguu、CAGguaguug、CCUgugaaua、GCUgugugug、CAAguaauuc、AGGguaaugu、 GCUgugaguc, ACCguaaguu, CGUguaagua, GGGguaaguc, AAUguaugau, AAUgugauua, UCAguaaga, CAGguccguc, GAAguauuga, UUGguaagga, CAGgucgguu, UAG guagug, ACGguaaaac, AAGguagguc, UACgugagua, UUGguaagca, GCGgugaguc, GAAguaaggg, CGCgugaguu, CAGguacccc, UCUguaagac, GAGgugggca, AAUgua agac, CAGgcaaggg, CAAguaacua, AAAguuuguc, CAGguacugu, AAGgucccuc, UCGguaaguc, UGGgugagug, CUUgugagau, AGAgugagcu, UAAgugggga, UAGguaggg a、CAGguuagcc、AGGguaauca、AAGguucagc、UGGgugggug、CAGguuguga、AAGguaagug、CAUgugcgua、CCGguauauu、ACCguaugug、CAGguauagu、CAGguauuac、C AGgugcagg, GUGgugagcu, AAGguaacau, CUGgugaugg, AUGguaaaug, CCGgugagca, AAGguaaacc, AAGguacugg, GCGgucagga, CUGgucaggg, AAAguacguu, AGAg uagguu、AGGguaagcu、AUUgugagua、CCGgccacca、GAGguaacuu、GAGguaugaa、CAGgucagac、UAGgcgugug、AGGguaaguu、CAGgcaugag、CAGguaacgu、CAGgcga gca, UAGguauggu, AGAguaggau, CUGguuucaa, GGguaaacu, CAGgcaugca, UUGguaaucu, AGGgcagaau, AUGguaaaac, GCUgcaggug, GAAgcacgug, CAUguaaaca.UGGguaagau、AGGguagcua、AGGguggggu、CCUguaaguu、UGAgugaguu、GGAguaugua、CAGgugaccu、AAAguacgga、GAGguacaga、GAUguaggua、GGGguaauug、UAGguggguu、GUGguacgua、AAGguacagc、GAGgugaaga、GGGguaagca、UGAguagguc、GGGguaaguu、AUUgugaguu、UCAguaagac、AGUgugagcu、AAGgcaaaac、CUGgugaguc、AAGgucucug、GAGgcugugc、AGAgugagac、GAGgugaugu、AGAguauggu、UGGguggguc、GCUgcugagc、CAGguagcug、UAGgucagaa、CCGguaggug、GCAguaugau、CAGguuucag、GAGguuugcc、GGGguggggg、AAGguacaua、UGGguguguu、AGAguaaggc、GCGguuagug、AAGgugacuu、AUGguaagau、AUGguaguug、CAUguaagac、CUGguaugua、UUCguaagga、GAAguaugac、CGGguaauuc、UGGguaacuu、CAGgugccua、CAUguagggc、ACCgucagga、CGUguucgau、GAGgcaggac、UAGguaauau、UCGguauacu、UAGguugugc、CCGgugaguc、CAGgugccaa、CAGgugaugc、AAGgugagga、GUGgugaggg、UGGgucagua、GAGgucaggg、UAGguacgua、GAGgcaagag、CCUguuggua、GAGguaucca、UAAguaagcu、AAGgucaguu、AAAguuaaag、GAGgugcuau、ACGguaaguu、CUGgugaggg、GAGguuaugu、CUUgugugca、UGAgcugggg、AAGguauagu、UAGguaaaac、GGGgugaggu、GAGgcaagca、GGAguaacgu、AGAguaagua、AAAguaagua、GAGgcaacca、UGUguaaguu、UAGgugaggc、ACAguaagaa、UGAguaagug、CAAgucagua、AGGgua、 aaug、AAGguaugca、GCUgugcgug、GAGguucgcc、AAGgcuugca、CAGgcaagug、AUAguaaguc、UUGguaggua、GCAgcaggua、AAGguauauc、AGCguaagcc、CUGguucga a、ACGgugggug、CUGgucauug、CAGgucagga、CAAgugagac、GAGguacugg、GAGguguagu、GAGguguccu、CAGgugcgua、AGUgcccuga、AUGgugaguc、UGUgugugua、C AGguaugcu, CUGguacagu, UUGguacgua, UCUguacgua, UAAguaauuc, CACguaugug, CAGgcaagua, UCGgugagug, GGUgugaguc, UCUguaagcu, AAGguucaga, AGGg uacuuc、GCGgcagguu、GAGgcccgug、CAGguauaaa、AUGgucaagu、AAGgugagua、GUGguuuguu、AGAgugagga、GAGguaugac、UAGgcgugag、AAGguacucc、UGAgugag ga、GAGguaugau、GGGgucggua、ACGguaugca、CAGguaccac、UAAguaccug、AGGgugggcu、CUGgucuguu、UAGgucagag、AAGguguguu、CUGgucagug、AAGgugggac、 GUGguaguag、CUAguuuagg、CCCgccccau、GCUguacugc、GAGguaauau、UAGguuggug、AAGguccaac、UAGgugagga、GUGguaaguu、AGUgugagag、AAUguacaug、UUGg caggug, UAGguuauug, CAGguacuga, GCGguggguc, UGUguaagau, GAGgugagua, GCAgccccgg, CAGgugcuaa, AGUguaagag, CAGguacauc, CAGgugggac, AGGguaa aua, UAAguaauua, CAGguaaccg, AAGguuugca, UAGgugguuu, CAGgugaccg, UGUguaagcu, GGAgugaguc, AGGguaggag, AGGgugggug, AAGgucugag, GAUguaauau.GGGguaauua, UAGguaggua, GGgcaagua, GGguaagga, UAGguacuac, UCGgugggug, AAGgugugga, CAGguc ugcc, UAAgugagcc, GAAguaaguu, GAAguaagcc, UAGgugcgac, GGguauggc, GCAguaagaa, CAGgugugga, U. UGguaacgu, GCUguaaaaa, UUGguuagua, AUAguaaggg, UUGguacuag, CGGgcagccg, CAGgugcugg, UAUgugaguu, CAGgucuggg, UA Aguaagaa、AAGguuauua、AGAguaaagc、AGAgugugag、UAGgugcgag、CAAguaaacg、AAGguacgua、CUGgugagua、CCAguaugua、UUG gugagug, UGAguaagua, GAGguuagca, GUGguaagcc, CUGguauggc, AAAguaacac, CAGguacuaa, UCUguaaguu, GAGgugaggg, ACUg ugggua、GAUguuugug、CAGgugucaa、CAGgucacca、CCGgugagua、UUGguaaaua、CAGguggggg、ACUgcaggug、UAGguauguu、GGAgc aagug、UCGgugccuc、CAAguaacuu、GAGguaacca、CAGguaauau、GGAguaagaa、GAGguaccuu、AGGguaagga、CCUgugaguc、GAGgua augg、AUGguguguc、GGGgugagua、AGGgucaggu、UGGguaaggg、AGGguagguu、AUAgugaguu、CCCguaggcu、ACAguaugua、GACgugu gua、GCGgugagga、CAGgugaccc、UAAguuuagu、ACAguugagu、CGGgugaggg、CAGguggauu、CGGguagagg、UAGgugcgug、GGGguaag aa、GAGguggggu、CACguggguu、ACGguaauug、AGAgugaguc、UUGgcuccaa、AAGgugaugc、AAGguugguc、AGCguaaguu、AUUguaugu a、UCAguaagu、CAAguacgug、CAGgugcgug、CAGguaggua、AUGguggggu、AUGguagguu、CAGguaauca、AAGguagggu、CAGgccaagg、GUGgugagag、AGguggu AGguacucu、UAGgcaugug、UUGguaccuu、CUGgugugcc、ACAguugcca、UUGguaauau、GAGgugcaug、UUGguaagua、UGUguguguGga、GUGgugug、GUGgugugu uacaca、AGAguaugcu、UUUguaagua、UCUgugcggg、AAGgucagug、GAGguaggaa、GCGguuagca、AGGgugagggg gcc、GAGguaagua、UAGguauuac、CAUaguaagag、CUGguaggc、GAGuaagua、CGGguaagua、CAGguaagua、GUGguaggua、CAGguaugua、AAGgccaguga、AAAguga 、ACGguaggaa、AUGguaggaa、CGGgugagac、GAGguaggaa、UGGgugagcc、CCAgugagua、CUAguacgag、CAGguaugac、GCUgugaggu、CUGguaugaa、gagu、GUG Ugugagug、GUGgugagca、CUGguacuu、CAGguacuau、AGGguaaggg、UUGguaaaca、GGUaagca、UCGgugagga、UGGguaaca、UCGguacgug、UAGguagca aaggc. gg、GCGguagggg、GUUguuuccc、AAAgcaucca、GUGguagguu、AAGgugugaa、CAGguaaug、AAGguaccaa、UUGguaauug、AAGgugcuca、AAGguucau、caGucaac、CAGCUguaagug、AGGguauguc、GAGgucgggg、AAGgugccug、AAGguaaaaa、GUGgugaguu、UAGguaagaa、AGGguauccu、GUGguaauau、UCUguaagua、UGGguaugga、AUGg uaugga、GACgugagcc、CUGguuuggc、AUGguauauc、AAAguaaacu、AGCgugagug、CUGguauaga、CAGgugggga、AGAguauguu、UAGguacuug、GCAguaggug、AGUguaug uc、AAGguuaagc、CUGguggccu、GAAgugaguc、UUGguguaag、CAGguaagaa、CGGgucucgg、GAGgugcaca、CUCguaaguu、AAGgugauca、UAUguaagaa、GAGgugcuug、C AGgugguca, ACGguaaguc, ACAguaaugu, CCUguaaggu, GAGguuaagu, UCGguaugug, UGGguauguu, AAGguauuac, CAGgugaggg, UUGguaaaca, AAGguagugu, GAGgu guggc, CAGguacgga, AAGgucauca, CAAguaggca, CAGgugaaac, CAGguacugc, AAUgcaagug, CAUguaauuc, AAGguaugcu, CUGgugaguu, CAGgugguuu, UGUgugagu a、AAGgucggug、AUGguaaauu、AGGguauuac、AGUguaugga、AACguaagau、GUGguaaggu、ACUguuagua、CAGguaucag、AAGguuaguu、CUGgugagcu、UUGgugagcu、UG Uguacgua, GAGgucagcc, GAGguagaau, AAGguaugag, UAGguauuuc, UGUguaacac, AGUguaaggc, GGgucugcu, AAGguuagca, CAGguaaaug, AACguaagcu, CAGguc ugca, CAGguauugu, GUGguaauuc, GCCgugagcc, GGguaagag, UGAguaugua, CAGguaaggg, GGguaaauu, CAGgcaacuu, UGUguaaguc, CAGgugcgcu.CGGguaa, acc、CCGgucaguc、UAGgugggcg、GCGgucaguu、GGGguggguc、AGCguaauag、ACGgugaguc、CUGguacuug、CAGguuggua、AGAguaugug、CUGgugggua、GAGguggcuu 、AUAguauuga、UGAgucgucc、CAGgugcucu、UACguaauau、GCUguccuga、CAGgcugcac、CUGgugcgcu、GCGguaagaa、UAAguuacuu、GAAgugagug、UAGgcaagu、UAA Aguaaua、ACGgugagug、CAGguagguu、GGGguauaac、GUUgugaguu、CAUgugagua、GAGgugcauu、AAGguuugua、UCGguaaugu、CGAguaaggg、GAGgcacgga、AGGgu gugga、CAGguauggu、AAGguagaaa、CAGgugccug、UGGguauaug、UGAgugagac、UGGguaauuu、AUGguaaaua、AAGgcaaagg、AGUuuguu、AUGguauugg、CUGguugg c、UUGguaaaau、ACAgugaguu、CAGgugcugu、GAGguuaaga、AGAguaagaa、GAGguccgcg、GUGgugagga、CAGgugagcc、CAGgugacau、AUGgcaagcu、UCGguau、UCGguau AGgcaacaa、GGGguaggga、CUGgucucgc、UAGguaacga、CGGguaaggu、UAGguaaugc、CAGgcaagaa、ACAguaggua、CAAguaugag、GCUguucgaa、AAGguuaugc、GAUgc ugaguu、CAGguggaga、AGAguuaguu、UGAgugugcg、GAGguacagc、CAGguaagac、CAUgugcuuu、AGGguguguu、ACAguuaagg、ACAgugaggg、GAUguauacc、UUAguaa gcu、CAGguaagau、AGAgcugcgu、GAGgcaaguu、GAAguaagug、AAGgugaaaa、AAGguaccua、GAGguaucag、AUGguaugua、AAGguaugaa、UUGgugagcc、AAGguaggaAGGguaugua, CAGguaccga, AGAguaaacu, AAGgugcaua, AAGguaaugu, CCGgugugug, AGGguaaauu, GGGguuuggc, CAGguacacg, UUGguaacca, GAGgucaggu, UCUg uuggua、CAGguuaguu、UUGguauguc、AAGgugcguc、AGGguaagaa、UUUguaagcc、AAGgucaggu、CUGguaaacu、UCGguaauuu、CUGguaggcu、GAGgucugua、GAGguacu uu、CUGguaaagg、CGGgugugug、CAGguguggu、UCGguacguc、CAGgugccag、GGGgugagaa、ACAgcuagua、AAGguauagc、CUGguaggag、GCUguacgua、AAGguaaaggC AAgcacgag、CUAguaagac、CCCguaagcg、CAAgugugag、AUGguaaggg、AAGgugaggg、CAAguaggua、GGUguugcug、GAGguacugu、UAGguaagau、CAGgugcgaa、GAGgu ccagg、UUGguauaca、GGAgugagua、GAGgugagau、AAGguggggc、CAGguaaacg、UCGguaacuu、CAGguaaauu、GAGgugcgca、ACUgugagua、ACGgugugac、GUGguaagu c CAGguaggca, CAGgucagca, GUGguaugug, AAAguaucug, CGGguaugua, AAGguauaaa, GAGgugggga, GCUguaggug, GAAgugaguu, AAAguauuua, UAUguaagua, AC Gguaugag, CUGgugagug, AGAguaaaau, GCUguauggc, AUGguaaacc, GCAguaauaa, UAAguauuua, AAUgucagug, AUUgcaggag, CCGguaagaa, AAGgcaaguu, GAGguu uguc, AAGguaacug, AAAguaugag, GAUguuagua, CAGguggguc, AAGguaccga, CCAguaauua, GUGguaugcg, AUGgugcgcu, CAGgucuaug, AAGguauuua, CUAguaagau.AGAgu、 aauuu、GAGguaacgu、AAGguagcca、CUGgucccgg、GAGguccuuc、ACGgucaccc、AAGguaauac、CAGgugca ug、AUGguaauag、UUUguaacac、UGGguaugau、CAGgcccccc、AGAguaguaa、AGUguaagaa、GAAguauguu、 CAGgugugca、UUGgugagggg、UGGguugguu、CAGguacgua、GAGgugcggc、UCUguacggg、CGGgugcgug、UAC guaagug、CAUguaagga、CAGgugacgg、GAUguaugcu、UCUgcaauuc、UGAguaaggc、GAGguauauu、AGAguga guu、AAGguaagcu、UAGgugaagu、CAGguuagua、UAUguaagug、UUGguggggg、UGAgcucaaa、UCGguaugua、UAAguaugcc、AAUguaagua、CAGguuugca、ACGgugagag 、CAGguguuuu、GUGgugagcc、AGGguacaua、UAGguaaccc、GUGgucagua、CUGgugagcc、CAGgugcuua、AUAgucguga、AUAgugagug、GAGgucaaaa、CGUguagcuu、CA Gguguuug、CAGguuggac、CAGguaagcu、AGGgucagaa、CACguauguc、CACgugagug、GGGguacgga、AAGgcaggac、GAGgugaagc、GAGguuugaa、CAGguaagug、CAGgu aacca、CAGguacucc、AAGgugcuuu、GAGguaaaua、GAGgcaggug、GAGguucgga、CAGguauuug、CAGguaaaua、CAGgugaugu、CAGgugauac、GAGgugaggc、AGGgugggg g、UAAguaaguu、UGGgugaaca、UAGguacugc、CAGgcuccug、AGGguaggca、CAGgugcccg、GAGguacauc、AGGgugugug、AAGguaguaa、UGGguaugag、GGGguguCguC UAguaggug、GAGgcaagga、AAGgcaagac、AAAgugcggu、AAGguugguu、GAGguuaaug、UUGgugaguc、UCGguuagcu、GCAguaagca、AAGgcaagca、ACAguaaggcu、GAGAGgcu uaacag、AAAguacgua、GAGguaauac、UUGguaggug、CUGguuaguc、GAGgugacgc、ACAguaagga、AAUguacuua、GGGguacagu、CGUguaugug、UCCguagguu、GAGgugg ucg、UCAgugaguc、AAAguaagca、GAGgucuggu、GAGguaauua、GUAguaagua、AAGgugggga、UCUgugagca、GAAguucgug、ACGgugaggc、UCAgugagua、UAGguaguug、GGUgucuggg、GGGguaagug、GAGguggguu、UGUgugaguu、CAUguaagua、AAGguaggug、AAUguaggag、GAGgcacguc、CAAguacauu、UUGguacaga、GAGguaguag、AAAgugaggg、UUGgucagug、AGGgugaguc、CAGgugaaca、GGUgugggcc、CGGgugagcu、GGGgugaguc、ACAgugagag、AGGgugaggu、GCUguaaguc、AUAguagguu、CAGgcaugug、AAGguaaguu、CAGguccgug、GAGgcaggua、AUGguggaag、AUGgugggcg、GAGgugagaa、AGUgugagca、UUGguaagua、CAAguaagca、GGUgugagcu、CCCgugggua、CAGguagaau、CAGgcugagc、CUGguggccc、UGAguaagag、CACguuagcu、AAGgugaguc、AAGguagcuc、UCGgugaguu、GAGgcccuuc、CAGguuaugc、CCUguaagcu、CAGgucuccu、UAGguaggcu、GGGguagggg、AAGguaguga、GAGguuguug、CAGguugguu、AAAguaagcc、ACAgugagug、UGGgugugau、CCCguaacua、AAGguguugc、AAAgcuggug、GAGguauagu、ACGguaag、 ag、AUGguacggu、GAGgccaguu、GAGguaugcg、UCGgugggag、AAGguggaua、CCAguguggc、AGGguaagug、UCUguagguc、CAGgcaagga、CGGguaauuu、AUUgugaguc、 CAGguaaacc、AAGgucaauu、AAGgugaaua、GUCguaagaa、GCGguaaguc、CUGguagagc、GAGgucgguc、CAGguaaaca、AAGgcaagga、CAGgucgucu、GGGguagggc、CUG guacuaa、GAGguagcug、CUUgucagcu、UAGguaaggc、CUGguauuac、UAAguacguc、AAGguaagcc、ACGgugaaag、CCAgccaaua、CAGguuuguc、AAGguauaau、AAGguc uuag、AGGgugagcu、AAGguuaggg、CGGguaaauu、CAGguaacgg、AGAgugugua、ACAguaaguu、GAUguaauuu、GAGguaggga、UUGgcaagug、AAAgugagga、AAGguagug c AGAguaauuc, GGAguaaaua, GUGguaccca, CAGguauugc, GAUgugaggg, CAAguaaauc, CAGgugucuc, AAGguaacag, UUGguaaaag, CAGguaucau, ACGgugagac, C UGguaugac, CAGguucacu, GAGgugauca, AGUguaaguc, AACguaagua, AAAgugagug, GAGguacagg, CAAuga, GAUguaagga, UCAguucccc, GCGguaagga, UAGg uacuaa、AAGgugaaag、ACUguaagug、UGGguaugug、AUGguaacag、CAGguagggu、ACAguaagug、AAGgugcucc、AAGgugugcu、AAGgugguga、ACGgugcgcc、AAGguau ugc, GGGguaugug, CAGgugggcu, GGguauguu, AACgugaaua, CAGguaaugg, UAGguaugau, CAGgcaggug, GGGguugguc, AAGguauggg, UAAgugaggc, CAAgugaucg.AAAguacggg、AGAgcuacag、GAGgugggaa、CAGguacuuu、GAGGugagagag、CAGguagguc、UGGguacagc、AAGgugucag、AAGgcaagaa、GAGguaaaca、AAGguaaagu、AAGguaguca、CUGguauguc、GAGguauggg、AAGguauugu、CUGguacuga、GAGguaagcu、UGGgugggua、CAGguucgug、AAGguauggu、CAGgugagca、UGGguaaauu、UGUguagg ug、UGUGugagcc、CUGguauau、AAAguauguu、UGUguaagaa、CUAgugagaa、AGGguagguc、AAGguggug、UCGguaagug、AGUguaaaua、GAUguaagug、AAGguuagu、UAGguaagca、CAAgugagaa、AGUguaagua、CAGgugaauc、UGGgugagac、AAGguagggc、CUGguuugug、GCGguagggc、GAGguaaucc、AUUguaauaa、CUGgugaaua、AAGgu uuaaa、CCUguacugu、GCGgugagcg、AAGguaaucc、UAUgugagua、CCCgugagug、CAGgugcaga、CAGgucagu、CAGguaggcu、AAAguaagug、UAGguugguc、CAGguugcc u、AAGguauggu、GGUgguggacg、AAAguggagaa、AGGGugagag、GAUguggcau、UCGguaaggu、GAGgugcguc、CGGgugaguc、AAGguggggg、GAGguucuug、AAGgugcuug、UA Gguaugua, AUGgucagca, CGGguacuca, AGGgugagga, AUCgugagua, UCAguaagua, UAGguaaaua, AAGguaauug, GAAgucagug, CAGguacaaa, AAAguuaauc, AGCgugagcg, CCGgcuggug, AGUguaauuu, UGAgccacuc, GGGgucugua, AUGgcauguc, CGGguaaaga, AGGguagcau, CGGguaggag, GAGguucgug, UAAguuauuc, UAUguaagau,AAGgua、 guuu、CAGgugguau、GUGguaauga、AAGgugauuu、CAGgugaagu、GUAguaauua、AUGguuggug、CCAguaagug、UAGgugagag、AUGgugaggc、AAAguuagug、AAGgugccu u、UAGguaugag、CAGgugugac、CUGguggguu、AUGguaagga、UCUguaagaa、UCCgugaguu、AAAgcaggua、UAUgugagug、CAGguggagg、CAGguuagac、AUAguaagac、A AGguguugu、GAGgucugug、AAGguaagau、CAUguaaguu、CUGguaauua、CAGguaggcg、AGAguaaguc、UGGgugagga、AAUguaggua、UAGguuagca、GGGguaggua、GAGg uauugc、AUUguacaca、GAAguaggua、GGAguaagcu、UAGguaugug、GAGgugaaua、GAGgugggau、AAGguaaucu、GGUgugaguu、AACgugaguu、GAGguaaccg、UAGguaag ga、AUUguaagaa、UGGgugagca、AAGguaaggc、CCAguaucgu、CCGgugggug、GAGguagugu、ACGgugggaa、GAGgugaccu、CACguaugua、AGGgugggga、AAUguaaguc、 AAAguuaagu、CAUgugagug、AGAguauguc、GCGguaugac、CGGgugaguu、CCGguauuuu、GAGguagaac、UAGguaugaa、CAGgcgcgug、CAAguaaguc、AGUguaagau、AAGg uucuac, CCAguaagua, GAGguagcag, CAGgucuguu, CAGguacaau, CCGguaaaga, UAAgugcugu, AGGgugagaa, CUCguaaggu, CAGgucagcu, CAGguaaggc, AGGgugc agg、GAGgugaaac、AGGguaagua、AAUguaugcc、AAGguaagca、ACGguacggu、AAGguaauga、UCUgcucaau、ACGguaaugu、AAGguaguug、ACGguaagug、CAGgugauga、This includes GAGguaacac, GAGguaggua, CAGguaccuu, CAGguaauaa, UUGgugggug, CUGguaauga, UAGguaaguc, AGGgugugac, GAGgcaauaa, GUGguaaagc, CUGgugggcg, GAUguauguu, AGGgugagac, UCGgucagca, AUGgugauua, CGAgugugua, CAGguuggug, AGCgcaagua, UGGguacguu, GAGguauuug, AGUguacaua, AUGguaagua, ACAguagguu, AAGgugagag, UUGgugaagu, AAAguaugua, UGGguaagga, UAGgugccuu, and CCUgugggug.

[0215] Further exemplary gene sequences and splice site sequences (e.g., 5' splice site sequences) include UCCguaaguu, GUGguaaacg, CGGgugcggu, CAUguacuuc, AGAguaaagg, CGCgugagua, AGAgugggca, AGAguaagcc, AGAguaaaca, GUGguuauga, AGGguaauaa, UGAguaagac, AGAguuuguu, CGGgucugca, CAGguaaguc, AAGguagaau, CAGgucccuc, AGAguaaugg, GAGgucuaag, AGAguagagu, AUGgucagua, GAGgccuggg, AAGguguggc, AGAgugaucu, AAGguaucca, UUCguaagua, UAAgugggug, GCCgugaacg, GAGguugugg, UAUguaugca, UGUguaaca, AGGguauuag, UGAguauauc, AGAguuugug, GAGgucgcug, GAGgucaucg, ACGguaaagc, UGAguacuug, CGAgucgccg, CUGgua cguc, AGGguauugc, GAAgugaaug, CAGaugaguc, UGGguauugg, UGAguaaaga, GUGguuccug, UGAgcaagua, UAUguaagag, AAGgucuugc, AAAgcaugg, AGAguacagu, GUGguaaucc, CAGguagagg, AAGguacaac, U GGgcagcau, CCGgucauca, CCGguuugua, UGAguaaggg, GAAguaugua, GGGguagcuc, GCUguacaua, CUGgucucuu, GUGguaaaug, AUCguaagug, GAGgcaugua, AAGgu cuccc、UGGgugcguu、UGUguagguu、GAAgugagca、GGUguaauuu、CUGgugaaau、AUCguaaguc、AGAguaaucc、GGAguagguc、GAGguaccaa、CUUguaggug、AAGguauaa g、AGAguuggua、AUGguuugug、UGGgucagau、AGAguaggac、AGAguagugu、AGAguaggag、CAGgucucua、AAGguggaug、UGGguaucaa、GAUguaugga、AAGguguuuc、GC There are 100+ videos in all formats from Youtube using Genius search engine cgac, UCGguaagaa, AGGguuggca, AAAguacagu, UAAguuaagg, AUGguaaugu, GUGguuuuac, AGAguaacaa, AAGguagccc, GCGgugaggc, AUGguucagc, AAGguacuua 、AAGguccgug、UAGguaagcg、AUGguaccuu、GCCguggugg、CUGgugcguc、CAGguggaaa、AAAgucugua、GAGguaaccc、AGAguauggg、UAUgccccug、AAGgugccag、ACG gugcggc、AGGguacuga、AGAguaagcg、CUGgcaaggg、CCAgugugug、GAGguagacg、CGGgugcggg、GAUguaagcu、AUUguauuua、UGCgugagug、CUGgucuaua、GAGgugc uag, GAGgugccau, CAGguacguc, GAGguucagc, AACguaagaa, AGAguaguac, AAGguaacgg, UAGgugugac, CCGguaauag, CAGguaccag, UUUguaauug, AAUguacgaa.CAGguaauga、AUCgucaagg、CUGguagaug、GGGgugcagu、AGUgagaa、GGGguuuuau、CCUguccccu、AUUgugaagu、AAGguaaacg、UACgucgugg、AAGgugccau、GGGg ucccag, UAUguauggu, CGGguaauua, CGGguacucc, CAGgugacuu, AGUguggguu, AGAguauggc, AAGgccaaca, AAAgcaagua, UCAguagguc, GUGguggcgg, CAUguauc cu、UCGgugagcc、AUAguugggu、AAUguuagcu、AUGgugaaug、CGGguaaugu、UCUguaggug、CCGgugaggc、UGAguccacu、CUAguaagag、CGGguggggc、CGAguaagca、U GUgccaauu、UCGguaagcc、UAUguaggug、UUGgugggcc、GAGgcugggc、AGAguaacuu、ACGguagguc、CAGgcccaga、CCGguggguu、AAGgugacgg、GGGguacagc、CAUgu aaguc、AUUgugagaa、UGUguaagga、UUUguaagau、AGGgucauuu、UGGguuuguu、CGAguaagcc、GUGgugugua、AUGguauaac、UGGguacgua、AAAguagagu、UCGguaacu g、AGAguaauga、AUGguggguc、AGAguaauau、CAGguacugg、UAAgucaguu、GCGguagaga、AAGgugaugg、ACAguauguu、GAUguacguc、UAGguuucuc、GAGgcauggg、AU Agcuaagu、GUAgucugua、AAGgugaacg、GUGguggucg、GAGguugauc、UGAguggguu、ACUguacgug、CUGgugacug、CAAguuaagc、GAGguaccca、AACguaacuu、CAGguu acua、AGAguuaguc、UGGgcacguc、AGUguauggu、AAGguugcaa、CAGguuguua、AAGgcauccc、GAUguaaggc、AGGguacggg、GAGgucaaag、CAAgugagcg、AGAguaaucu、UCGguagcug, AAAguaguag, CAGguucguc, CGUguaugaa, AGUguaaaaa, AAGgucucac, UAGguggagc, UGAguaggug, AGAguaugcc, GAGguugcau, CAAguaagag, U CUgugugcc, GAGgugaugc, GGGgugauaa, CCCgugagcc, AGAguaacug, GCGguaagua, AGAguacauc, UCGgucuggg, UAAguaucuc, GGCguagguu, AGAguacgcc, GAUg ucuucu、AGGgcaaggu、CGAguaugau、AUGguagagu、CAAguacgag、UCGguaugau、CCGguguguu、AGGgucugug、GGAguaggcu、AAGgucuaug、GCAgugcgug、UGGguga gaa、AGGguaaagu、GAGguaggac、CUAguaagca、UUAguaggcu、CUGgugggau、CUGguuagua、AAGguacgug、CGGgugagau、AAGgugcaug、AAUgugggcu、CAGguugacu CAGguuacag, GCGguaacau, AUUgucaguc, CAAguauaca, GAUguccgcc, AAGgugcgga, AACguaagag, UGGguuggua, CAAguguaag, GUGguaacgu, CUGgugauca, AG Gguggggc, UCGguaaaga, CAGguacacc, CGGguaaggg, CAAguuugcu, ACAgugcgug, UUGguauggg, GAGgcucauc, CUGguaauag, AUGguggaua, UCAgugaauu, AAUgu aauua, GCAgucuaaa, AAGguauucu, GAGgucauca, UGGguccaug, AGAguuugua, AGGguagacu, AAGguaggac, UGUguguuga, UCAguacgug, AUGgucucuc, UGAguuag ua、UGAguaaagu、GAGgugaccg、GAGguauauc、CAGgugccau、AGAgugguga、GUUguaagaa、AGAguaaaua、AGGgugaagg、CUGguagauu、GAGguucagg、AGGgucuuca、CUGguaaccu, ACAguacuga, AGAguggguc, AUGguaugg, AAGguuauau, AGAguaugaa, AAAguaugaa, UAGguggcua, ACCguauggg, AAAguauaau, UUUguauggc, GGGg ucgcgu、GUGgugguuu、CAGguuugac、GGAguaggcg、GAGguacccu、AUGgugugca、GUGguuggug、AAAguaugcu、UAaguacau、ACAguaugag、GGAguauguu、UUUgugag aa、AAUgugcguu、CAGguagagu、AUGguguuaa、CAUgugcguc、AUAguuggau、GAGguacgua、GUUgugagaa、CAAguacauc、GAGguaguuu、ACUguacaga、CCGguuguga、U GGgucagug、GUAguaagaa、GACguacuuu、AGAgucaguc、UAGguuaguu、AGGgcagcag、AAGguccuac、AAUguaauug、CAGgugcggg、CUGguaaugg、CAAguagccc、GAAgu caguu、ACAguaauug、UUAguuagua、CCUguauuuu、AUCguaagaa、CCAgugagca、GAAguaaggc、UGAgugggua、UCAgugguag、UCUguacagg、CGAgugagug、UCCguaugu g、CAUgccguuu、AAAgugacuu、AGAguaggca、GAAguaagag、CAGgcagguu、UUGguagagc、AAGguggaaa、GAGgcagguc、AUGguacgac、AGGguaggaa、AGGguaggua、UU Gguaaggu, AUGguacaga, CAGguagagc, UAGguaaggu, GGGguuagag, AAGguaucaa, GGguagccc, CAGgugccuc, GCAguaagag, ACGguagagu, UGGguaaugg, CUGguc aguu, GUGguacauu, AAAguagguu, AAGgccaaga, CGGgugggca, ACGguccggg, CGAguaugag, CUGguaugcc, GAGguggaug, CAGgccuuuc, AAAguacauc, AAAguaauca,GAGguaac、 ug, CUGguaaaga, CGUguaagca, UGGgcaagua, GCGguggcga, GAGguggccg, AUUgcaugca, ACGgugacug, CAGgucagau, AGAguaacuc, UGAguaacag, AAGguac ccg, AGGguaggcu, GGGgcaggac, CCUguaagug, AUUguaagug, ACUguacgag, GGGgua aaga, AGGguuacuu, CAUguaaaug, GGAguaguaa, CAGgucaauc, CGGguuagug, UAGguacaug, UAGguuaaga, UGGguaccuu, CGGguggaca, CAGgucuuac, AAGgu ggagc, AUGguaacca, UCGguaaguu, UAUguacaaa, AAUguagauu, GUAgcuagua, AAGguauugg, GAGgucuuug, GAAguucagg, UGGguaucac, AGAguacugg, CAGgu uaaug、AGGguacgug、AGGgcacagg、CUGguuaguu、UUGguacgag、ACGgugauca、CCUgugagag、GAGgugaagu、AAGguacauc、UCUguaugug、UUGguggaag、UGGgcagguu、GAAguggagc、ACAguaagac、CGGguaccaa、CAAguacguc、AGAgugaggg、CGGguaagaa、AAUguaggug、AUCgugugcu、UAGgucaugg、CAGguuuuga、AAGgcaugca、GAGgugcugc、AAGguuaaua、CAGguucauc、GCGguaggug、GACgugagua、CAGgucuacu、UUGguaugag、AGCgugggca、AUGguaaggu、AUGguaccuc、UUGguauggu、UAUguaugaa、UGGguauggg、GAUguaaaua、CCGguaaguu、GAGgucugaa、GAGgugcgag、CUGgucagcc、CAGguuuugu、CGGguggugu、UAAguuagua、UUUgugugug、CAGguuaacc、UUGguacuuu、GCUguaaggc、AGGguggcug、GAUguaaaaa、AAGgucaaaa、CAGguagcgc、CAGguuuggc、GAGgugguuu、CGGguaaaua、CUGguucggu、GGAgugagcc、AAGgugcgcg、GAAguacauc、AGUgucugua、CCCgugagcu、GAGguucaca、CUAgugggua、GAGguaacua、UCGguauguc、UAAguauuug、CAGguaagcg、GAGgugguaa、CGAguaagag、CCGguaagcu、GAGgucuugu、AAGguggguc、CACguaagug、AGUguaauga、AAAgugugua、GGAgugccaa、CACgugaguu、AAGguuggau、UAUguaaaua、CUGguaggaa、UAUguaaacu、AAUguauuuu、CUGgcaagug、UGUgugguau、UAUguauguu、UUGgugacuc、GGAguaaggu、AAGguagaug、UGGguagggu、AAUguaauuc、GUGguauggc、GGAguggguu、AGGguaccac、UAGgugacag、ACAguaggca、AUGguuugaa、GCAguaacua、CCGguaggua、AGAguaggcc、AAGguugaca、CUGgugugua、GAAgucuguc、UGGgcucgga、CAGguagccu、AGAguaggua、UAAguauguc、CUGguauauc、GAGguguguu、AUGgugcaug、AAGguacgcc、UGAguaacua、GAGgugacag、GUUguccugu、UUGgugucuu、AAUgugaagg、UUGguggaua、UAGguguguu、CUGgcaaguu、GCAguaagau、GCGguggaaa、UGCguccagc、AAAguggagu、CGUgugagcc、AGAguacugu、CAGguauagc、UACguaagga、AAGgucuuua、AAGguggucu、GGGguaaauu、UCAgugagga、AGAguacguu、GAGgucguca、UAGguuugau、CAUguaaacc、AAGguggcac、 CAGguagaug、AACguaaaag、UAGgucucug、AUAguaggug、UAGgcaagag、UAGgcacggc、AAGgucuuca、CCAguaugcu、CAAgugaguu、CAGgucucaa、CAGguuacau、GGAgugagca、AGAguacgca、CUGguguugg、AAGguacuca、CUAguaaggg、AGAguaaaag、AAGguaacga、CUGguccccg、UAAguauggg、GAGgucgagc、UUGguauaua、AAAgucaagg、AAGgucuagg、CGAguagguc、AGGguucguu、GAGgcaggcc、CUAguauuac、ACGguaugug、UAGgugguuc、AGAguauaac、UUGgugcguc、ACCguuaucu、CCAgugauga、GAAguaugca、GAAguauggc、CCGguaggac、AAUguaagca、AGAguaauug、AGGguugguu、GUGguaggag、AAGgcaguuu、CAAguaagcc、CUGgcaagua、CAGgcaugau、AGGguaauug、GGGguaaccu、AAAguaacua、UAGgucugcc、ACGguaugaa、AGUguauggg、UGGguuggca、UAGguaaacu、AGAgugggua、AGAguauuug、AGUguaggaa、CUUguacgua、GAUgugagau、CAGgcagcca、AAGgucacug、AAGgucugac、UAGguuccuu、CUGgugcuuu、UGAguuggug、UUGgugggau、UGAguagggu、UCGgugaggu、AAAguaaaga、AAGgcaaguc、CGGguaaagc、AAAguuaguu、UUAguaagca、GAGgucacau、UAAgugguau、UAGgugcuuu、GGAguaggca、UGAguaagga、CAGguggagc、GAUguagaag、AAUgccugcc、AUGguaaggc、UGGguaauau、CUGguaccuc、CACgugagcc、UGAguuugug、CCGguagugu、AAAgugacaa、GAAguggguu、CAGgugcagc、GAGgugggcc、UAUgugcguc、GGGguacugg、CUGguagguu、UUGgcauguu、AAUguaauac、UAGgccggug、AGAgucagua、UAAguaaauc、CAGguuccuc、UAGguacgau、AGAguuagug、GCAguaagug、AGGgug ugguag、GGAguaaugu、GAUguaaguc、CCAguuucgu、AAGguucgggg、AUGguggagu、AAGguaccgg、GAAgugcgaa、UGGgucaguu、AAGguguaga、UGGguaggcc、CCAguga uc、AAGgucacuu、AGCgugaggc、UCCgugguaa、AGAguacuua、GGGgucagau、AAGguggacc、AGAgugagcg、AGAgucagau、UAAguauuac、AGAguauuuc、AGAgucag、AGAguuca UGgugaagu、UAGgugaucc、GGAguaagau、UAGguaccaa、AGAguugguc、GAAgugagac、AUCguagguu、GAGguacgcu、ACGguaaggg、CAGgcauguc、UUAguaagau、UGAgu agguu、AGGguacgaa、ACGguauguu、AGGguacugu、UUGguaugga、UAAguaacug、GCGgucagcc、UUUgugaguc、GUGgucagug、CUGgucugua、GAGguucuua、AUGguacuua a、AAUgugcuuu、AGGguggcgu、CCGgcaggaa、CAUguggguc、UUGguuuguu、CAGguucugu、ACGguaagcg、CUGgucagua、UCAguaggcu、UGAguaggac、CAGguuuuaa Gguguccc、AGGguggguu、GUGgugagac、CACguaggga、GUGguauuuu、GAGauauccu、AAGgugaaca、UAAguagggc、CUGgugcggg、CUGgucaaua、AGAguaaaaaaaaaaa cagu、CGGguaagca、AAAgugagcc、AUGguaauca、GCAguacgug、AUGguacaug、AAGguuaaga、CGGguaaaug、GAGguucgca、GAGgcucugg、AUGgugggac、AACgugguag、AAGgugauag、GGGguuugca、CAUguaaggg、UCAguugagu、AAAgugcggc、AGAgugagcc、AUGgcaagaa、ACAguaaggu、AAGgucucua、GUGguaaaaaaa、AAAUggug AGgugcacu、GUCgugguau、CAGguauagg、UGAgugagag、ACUgugagcc、AUCguuaguu、UUUguaccaa、UGGgugagau、AGAgugagaa、AGAguagggg、AGGgcaagua、CGGagua ucagua、UUGguaugcc、CGGguuagau、GGGgugaagu、CCCgugugaa、GCAguuugga、UGCguaagac、AGAgucugua、CACgugagca、AGGguaaaag、CAGgcugggu、GAAgucu uca、AAGgcaaaaa、GUAguaaaua、CUAgugagag、GAAguuucug、CCUguacgua、GAGgugcgcg、AAGguguaaa、CCAguauguu、CCGgucagcu、AUGguuccug、CAAguaau 、AGAguaggcu、AUGgugggca、GGAguaagac、AGGgucacga、UAGgugauau、GAAguaaguc、CGGguaagau、CAAguagcua、UGAguaaaau、GUCguacgug、AUGguacgua、CAgua Ggucucgg、GAGgcauguc、AGAgugggau、GUGguuagag、UGGgugguga、AAGguuaaac、CUUguuagcu、AAAguaggaa、UAGguuguau、AGGgugcgcc、AAGgugggcu aucug、AAGguaacgu、AUGguggggc、CAAguacacg、GGCguaagug、AUAguaggac、AGAgugaggu、UUUguaaaaa、GAAguuugua、CUAguaaucu、AAGguuuuua、GAGgugg uu、UAGgcgagua、ACCgugagua、CAGgucccga、AUGguacugg、UGAguucagu、AAUguguggu、UCCguugguu、CAGgucagag、CAGgucccua、UAGguagacu、CAAguuaagg、GAGgugugcg、GAAgcugccc、CGAguacgug、CGGguaggua、UUGguauuga、AUUguaugau、UUGguaugaa、GAGg ugguca、GCUguaugaa、CAGguguugc、CAGguaaaac、AUAguaaggu、CUGguuagag、AGCgugugag、AAGguuau with、CACgugagua、AGGgucagua、GAGguauaau、CAGguuauuu、AGGguggacu、AUUguaauuc、UUUguggguu、A UGguacgug、AAGguguucc、CAGgugacgc、GAGguacuaa、ACAguucagu、GAGgucacgg、CAAguaaggc、AAGgu uuggg、AAAgugggcu、GCGguucuug、GAGguggagc、UGAgucagug、CAGgucaagg、AGUguaagcu、GAGgcagaa a、AAGgucacac、GAAguagguu、GUCguaaguu、AGAguaugca、CCUgugcaaa、ACGgugaaaa、CAGguacgaa、CA Ugugagga、AGCgugagua、GGUguguagg、AACgugagcu、GAGgugaacu、AGAguucagu、AACgugugua、CAGguu gugg、AAGguacuag、UCAgugaaaa、AAUgucuggu、ACGguaaaau、CUGguguaag、GAGgugcgaa、AGGguuucuc、 CAGguagccc、AUUguauugg、AUGguacuua、GAGgcccgac、UCGguaagac、CGGgcuguag、UAUgugugug、UAG guagaaa、GUGgucauua、UAGgugaaag、ACUguaauuc、GCAguacagg、UCGgugaguc、UAUguaggga、AUGgua uguc、GUGgugugug、CUGgugaccu、AAUgugaaua、UAGgucucac、GAGguuauug、UGAguaggcu、CGGgcacgu a、GCAguaaaua、CCGgugagag、UAAguugguc、CCGgugagcc、AAGguuguca、CUGguauuau、GGGguauggg、A This includes AAgucagua, UUUguaugua, UAAguacugc, CAGguaccaa, GAAguucaga, AUGgugcggu, GUGgugaggu, UGAguaagcc, UAUguaaggg, GUGguggaaa, GAGgugauug, GGAguuugua, AAGgucacga, GUGguagagg, UAAguauauc, AAGgugucca, UAUgugguau, GAGguacaau, AAGguggggg, GGAguaggug, and UAGgugacuu.

[0216] In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes AGA. In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes AAA. In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes AAC. In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes AAU. In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes AAG. In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes ACA. In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes AUA. In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes AUU. In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes AUG. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes AUC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CAA. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CAU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CAC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CAG. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GAA. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GAC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GAU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GAG. In some embodiments, the splice region sequence (e.g., the 5' splice region sequence) includes GGA. In some embodiments, the splice region sequence (e.g., the 5' splice region sequence) includes GCA. In some embodiments, the splice region sequence (e.g., the 5' splice region sequence) includes GGG.In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GGC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GUU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GGU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GUC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GUA. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GUG. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes UCU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes UCC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes UCA. In some embodiments, the splice sequence (e.g., 5' splice sequence) includes UCG. In some embodiments, the splice sequence (e.g., 5' splice sequence) includes UUU. In some embodiments, the splice sequence (e.g., 5' splice sequence) includes UUC. In some embodiments, the splice sequence (e.g., 5' splice sequence) includes UUA. In some embodiments, the splice sequence (e.g., 5' splice sequence) includes UUG. In some embodiments, the splice sequence (e.g., 5' splice sequence) includes UGU. In some embodiments, the splice sequence (e.g., 5' splice sequence) includes UUA. In some embodiments, the splice sequence (e.g., 5' splice sequence) includes UUG. In some embodiments, the splice sequence (e.g., 5' splice sequence) includes UGU. The splice region sequence (e.g., 5' splice region sequence) includes UAU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes GGA. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CUU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CUC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CUA. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CUG. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CCU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CCC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CCA. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CCG. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes ACU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes ACC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes ACG. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes AGC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes AGU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes AGG. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes CGU. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes UAC. In some embodiments, the splice region sequence (e.g., 5' splice region sequence) includes UAA. In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes UAG. In some embodiments, the splice site sequence (e.g., 5' splice site sequence) includes CGC.In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) includes CGA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) includes CGG. In some embodiments, the splice site sequence includes AGAguaaggg.

[0217] In one embodiment, the gene sequence or splice site sequence provided herein relates to a proliferative disorder, disorder, or condition (e.g., cancer, benign neoplasm, or inflammatory disease). In one embodiment, the gene sequence or splice site sequence provided herein relates to a nonproliferative disorder, disorder, or condition. In one embodiment, the gene sequence or splice site sequence provided herein relates to a neurological disorder or disorder; an autoimmune disorder or disorder; an immunodeficiency disorder or disorder; a lysosomal storage disorder or disorder; a cardiovascular condition, disease, or disorder; a metabolic disorder or disorder; a respiratory condition, disease, or disorder; a renal disease or disorder; or an infectious disease. In one embodiment, the gene sequence or splice site sequence provided herein relates to a neurological disorder or disorder (e.g., Huntington's disease). In one embodiment, the gene sequence or splice site sequence provided herein relates to an immunodeficiency disorder or disorder. In one embodiment, the gene sequence or splice site sequence provided herein relates to a lysosomal storage disorder or disorder. In one embodiment, the gene sequence or splice site sequence provided herein relates to a cardiovascular condition, disease, or disorder. In one embodiment, the gene sequence or splice site sequence provided herein is related to metabolic disease or disorder. In one embodiment, the gene sequence or splice site sequence provided herein is related to respiratory condition, disease, or disorder. In one embodiment, the gene sequence or splice site sequence provided herein is related to renal disease or disorder. In one embodiment, the gene sequence or splice site sequence provided herein is related to infectious disease.

[0218] In one embodiment, the gene sequence or splice site sequence provided herein is related to intellectual disability. The splice sequence is associated with a mutation in the SETD5 gene. In one embodiment, the gene sequence or splice site sequence provided herein is associated with an immunodeficiency disorder. In one embodiment, the gene sequence and splice site sequence provided herein are associated with a mutation in the GATA2 gene.

[0219] In some embodiments, the compounds of formula (I) described herein interact with (e.g., bind to) splicing complex components (e.g., nucleic acids (e.g., RNA) or proteins). In some embodiments, the splicing complex components are 9G8, Al hnRNP, A2 hnRNP, ASD-1, ASD-2b, ASF, BRR2, B1 hnRNP, C1 hnRNP, C2 hnRNP, CBP20, CBP80, CELF, F hnRNP, FBP11, Fox-1, Fox-2, G hnRN, H hnRNP, hnRNP1, hnRNP3, hnRNP C, hnRNP G, hnRNP K, hnRNP M, hnRNP U, Hu, HUR, I hnRNP, K hnRNP, KH-type splicing regulatory protein (KSRP), L hnRNP, LUC7L, M hnRNP, mBBP, muscle-blind-like protein (MBNL), NF45, NFAR, Nova-1, Nova-2, nPTB, P54 / SFRS11, polypyrimidine tract-binding protein (PTB), PRP proteins (e.g., PRP8, PRP6, PRP31, PRP4, PRP3, PRP28, PRP5, PRP2, PRP19), PRP19 complex protein, RBM42, R hnRNP, RNPC1, SAD1, SAM68, SC35, SF, SF1 / BBP, SF2, SF3A complex, SF3B complex, SFRS10, Sm proteins (B, D1, D2, D3, F, E, G, etc.), SNU17, SNU66, SNU114, SR protein quality, SRm300, SRp20, SRp30c, SRP35C, SRP36, SRP38, SRp40, SRp55, SRp75, SRSF, STAR, GSG, SUP-12, TASR-1, TASR-2, TIA, TIAR, TRA2, TRA2a / b, U hnRNP, U1 snRNP, U11 snRNP, U12 snRNP, U1-70K, U1-A, U1-C, U2 Selected from snRNP, U2AF1-RS2, U2AF35, U2AF65, U4 snRNP, U5 snRNP, U6 snRNP, Urp, and YB1.

[0220] In some embodiments, the splicing complex component includes RNA (e.g., snRNA). In some embodiments, the compounds described herein bind to the splicing complex component containing snRNA. The snRNA may be selected from, for example, U1snRNA, U2snRNA, U4snRNA, U5snRNA, U6snRNA, U11snRNA, U12snRNA, U4atacsnRNA, and any combination thereof.

[0221] In some embodiments, the splicing complex components include proteins, such as snRNA-related proteins. In some embodiments, the proteins include SC35, SRp55, SRp40, SRm300, SFRS10, TASR-1, TASR-2, SF2 / ASF, 9G8, SRp75, SRp30c, SRp20, and P54 / SFRS11. In some embodiments, the splicing complex components include U2 snRNA cofactors (e.g., U2AF65, U2AF35), Urp / U2AF1-RS2, SF1 / BBP, CBP80, CBP20, SF1, or PTB / hnRNP1. In some embodiments, the splicing complex components include heterologous ribonucleoprotein particles (hnRNPs), such as hnRNP proteins. In some embodiments, the hnRNP proteins include A1, A2 / B1, L, M, K, U, F, H, G, R, I, or C1 / C2. The human genes encoding hnRNP are HNRNPA0, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3, HNRNPA2B1, HNRNPAB, HNRNPB1, HNRNPC, HNRNPCL1, HNRNPD, HNRPDL, HNRNPF, HNRNPH1, HNRNPH2, HNRNPH3, HNRNPK, HNRNPL, HNRPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1, Includes HNRNPUL2, HNRNPUL3, and FMR1.

[0222] In one embodiment, compounds of formula (I) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and compositions can modulate (e.g., increase or decrease) the splicing phenomenon of a target nucleic acid sequence (e.g., DNA, RNA, or premRNA), such as a nucleic acid encoding a gene described herein or a nucleic acid encoding a protein described herein or a nucleic acid containing a splice site described herein. In one embodiment, the splicing event is alternative splicing.

[0223] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, and composition thereof increases splicing at splice sites on a target nucleic acid (e.g., RNA, e.g., premRNA) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, as determined by a method known in the art, e.g., qPCR. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, and composition thereof reduces splicing at splice sites on a target nucleic acid (e.g., RNA, e.g., premRNA) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, as determined by a method known in the art, e.g., qPCR.

[0224] In another embodiment, the Disclosure provides a method for forming a complex comprising a spliceosome component (e.g., a major spliceosome component or a small amount of a spliceosome component), a nucleic acid (e.g., DNA, RNA, e.g., premRNA), and a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or composition thereof, characterized by a method comprising contacting the nucleic acid (e.g., DNA, RNA, e.g., premRNA) with the compound of formula (I). In one embodiment, the spliceosome component is selected from U1, U2, U4, U5, U6, U11, U12, U4atac, U6atac micronuclear ribonucleoprotein (snRNP) or related cofactors. In one embodiment, the spliceosome component is recruited to the nucleic acid in the presence of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or composition thereof.

[0225] In another embodiment, the present disclosure provides a method for modifying the three-dimensional structure of a nucleic acid (e.g., DNA, RNA, e.g., premRNA) comprising contacting the nucleic acid with a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or composition thereof. In one embodiment, the modification includes forming a bulge or kink in the nucleic acid. In one embodiment, the modification includes stabilizing the bulge or kink in the nucleic acid. In one embodiment, the modification includes reducing the bulge or kink in the nucleic acid. In one embodiment, the nucleic acid includes a splice site. In one embodiment, the compound of formula (I) interacts with the nucleic acid base, ribose, or phosphate moiety of the nucleic acid (e.g., DNA, RNA, e.g., premRNA).

[0226] This disclosure also provides methods for treating or preventing diseases, disorders, or conditions. In one embodiment, the disease, disorder, or condition is related to (e.g., caused by) a splicing phenomenon such as an undesirable, abnormal, or alternative splicing phenomenon. In one embodiment, the disease, disorder, or condition includes proliferative disorders (e.g., cancer, benign neoplasms, or inflammatory diseases) or nonproliferative disorders. In one embodiment, the disease, disorder, or condition is a neurological disorder, autoimmune disorder, immunodeficiency disorder, cardiovascular condition, metabolic disorder, lysosomal storage disorder, respiratory condition, etc. This includes kidney disease or infection. In another embodiment, the disease, disorder or condition includes haploinsufficiency, autosomal recessive disorders (e.g., with residual function), or paralog activation disorders. In yet another embodiment, the disease, disorder or condition includes autosomal dominant disorders (e.g., with residual function). Such a method includes the step of administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or pharmaceutically acceptable composition thereof to a subject requiring it. In certain embodiments, the method described herein includes administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable composition thereof to a subject.

[0227] In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is livestock such as dogs, cats, cattle, pigs, horses, sheep, or goats. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is livestock such as cattle, pigs, horses, sheep, or goats. In certain embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal such as a rodent, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.

[0228] Proliferative disorders, impairments, or conditions may also be associated with the inhibition of apoptosis of cells in biological specimens or subjects. All types of biological specimens described herein or known in the art are intended to fall within the scope of this disclosure. Compounds of formula (I) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and compositions may induce apoptosis and are therefore useful for treating and / or preventing proliferative disorders, impairments, or conditions.

[0229] In certain embodiments, the proliferative disease treated or prevented using the compound of formula (I) is cancer. As used herein, the term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). All types of cancer disclosed herein or known in the art are intended to be within the scope of this disclosure. Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; tubosarcoma (e.g., lymphangiosarcoma, lymphoendothelial sarcoma, angiosarcoma); appendiceal cancer; benign monoclonal immunoglobulinemia; biliary tract cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., mammary gland cancer, papillary carcinoma, mammary gland cancer, mammary gland cancer); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumors; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); Esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancer (e.g., leukemia such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell ALL, T-cell ALL) CLL, T-cell CLL); Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., diffuse large B-cell lymphoma such as diffuse large B-cell lymphoma (DLCL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue);Lymphomas such as MALT lymphoma, nodular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; as well as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome)). T-cell NHL such as angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma; a mixture of one or more of the above leukemias / lymphomas; as well as multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, muon chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic neoplasm; immunocellular amyloidosis; renal cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma) ); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., Neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinomas (e.g., gastrointestinal and pancreatic neuroendocrine neoplasms (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer); ovarian cancers (e.g., cystadenocarcinoma, ovarian embryonic carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancers (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell neoplasms); penile cancers (e.g., Paget's disease of the penis and scrotum); pineal gland tumors; primitive neuroectodermal neoplasms (PNTs); plasma cell neoplasms; paraneoplastic syndromes; neoplasia in situ; prostate cancers (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancers;This includes, but is not limited to, skin cancers (e.g., squamous cell carcinoma (SCC), keratosinocyanoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancers (e.g., appendiceal cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancers; small intestine cancers; sweat gland cancers; synoviomas; testicular cancers (e.g., seminomas, testicular embryonic carcinoma); thyroid cancers (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancers; vaginal cancers; and vulvar cancers (e.g., Paget's disease of the vulva).

[0230] In some embodiments, proliferative disorders are associated with benign neoplasms. For example, benign neoplasms may include adenomas, fibromas, hemangiomas, tuberous sclerosis, and lipomas. All types of benign neoplasms disclosed herein or known in the art are intended to be within the scope of this disclosure.

[0231] In some embodiments, proliferative disorders are associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are intended to be within the scope of this disclosure.

[0232] In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof, are used to prevent or treat nonproliferative disorders. Exemplary nonproliferative disorders include neurological disorders, autoimmune disorders, immunodeficiency disorders, lysosomal storage disorders, cardiovascular conditions, metabolic disorders, respiratory conditions, inflammatory diseases, renal diseases, or infections.

[0233] In certain embodiments, nonproliferative disorders are neurological disorders. In certain embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof, are used to prevent or treat neurological disorders, disorders, or conditions. Neurological disorders, conditions, or illnesses may include neurodegenerative diseases, psychiatric conditions, or musculoskeletal disorders. Neurological disorders may further include recurrent proliferative disorders, which may be characterized by, for example, expansion of nucleic acid sequences in the genome. For example, recurrent proliferative disorders include myotonic dystrophy, amyotrophic lateral sclerosis, Huntington's disease, trinucleotide recurrent disorders, or polyglutamine disorders (e.g., ataxia, fragile X syndrome). In some embodiments, neurological disorders include recurrent proliferative disorders, such as Huntington's disease. Further neurological disorders, conditions, and conditions include Alzheimer's disease, Huntington's disease, prion diseases (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, kuru disease, or scrapie), intellectual disability (e.g., disorders caused by SETD5 gene mutations, e.g., intellectual disability-facial dysmorphic syndrome, autism spectrum disorder), Lewy body dementia, diffuse Lewy body dementia (DLBD), dementia, and progressive supranuclear palsy (PSP). Progressive bulbar palsy (PBP), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, Parkinson's disease, Down syndrome, multiple system atrophy, spinal muscular atrophy (SMA), progressive spinal and bulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative diseases / motor neuron degenerative diseases, upper motor neuron Neuron disorder, lower motor neuron disorder, Haller-Holden-Spats syndrome, cerebral infarction, traumatic brain injury, chronic traumatic encephalopathy, transient ischemic attack, Ritico-Bodig disease (amyotrophic lateral sclerosis - parkinsonist dementia), Guam-parkinsonist dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Appler disease, Krabbe disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder's disease, Batten disease, Cockayne This includes syndromes, Kaens-Sayer syndrome, Gerstmann-Streusler-Scheinker syndrome and other infectious spongiform encephalopathy, hereditary spastic paraplegia, Leigh syndrome, demyelinating disorders, neuronal ceroid lipofuscinosis, epilepsy, tremor, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injury (e.g., stroke, traumatic brain injury), autism, Machado-Joseph disease, or combinations thereof.In some embodiments, the neurological disorder includes Friedreich's ataxia or Sturge-Weber syndrome. In some embodiments, the neurological disorder includes Huntington's disease. All types of neurological disorders disclosed herein or known in the art are intended to be within the scope of this disclosure.

[0234] In certain embodiments, nonproliferative disorders are autoimmune diseases or immunodeficiency disorders. In certain embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof, are used to prevent or treat autoimmune diseases, disorders or conditions, or immunodeficiency diseases, disorders or conditions. Exemplary autoimmune and immunodeficiency diseases, disorders, and conditions include arthritis (e.g., rheumatoid arthritis, osteoarthritis, gout), Chagas disease, chronic obstructive pulmonary disease (COPD), dermatomyositis, type 1 diabetes, endometriosis, Goodpasture syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, ankylosing spondylitis, IgA nephropathy, idiopathic thrombocytopenic purpura, inflammatory bowel disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, fecal diversion colitis, Behçet's syndrome, infectious colitis, unidentified colitis, interstitial cystitis, and lupus (e.g., systemic lupus erythematosus, discoid lupus, drug-induced lupus, neonatal lupus). This includes lupus dulcis, mixed connective tissue disease, maculoplasty, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonic syndrome, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, scleroderma, Sjögren's syndrome, generalized rigidity syndrome, vasculitis, vitiligo, disorders caused by GATA2 mutations (e.g., GATA2 deficiency; GATA2 haploinsufficiency; Emberger syndrome; monocytopenia and Mycobacterium avium complex / dendritic cell, monocyte, B and NK lymphocyte deficiency; familial myelodysplastic syndrome; acute myeloid leukemia; chronic myelomonocytic leukemia), neutropenia, aplastic anemia, and Wegener's granulomatosis. In some embodiments, autoimmune or immunodeficiency disorders include chronic mucocutaneous candidiasis. All of the above are disclosed herein or known in the art. Types of autoimmune disorders and immunodeficiency disorders are intended to be within the scope of this disclosure.

[0235] In certain embodiments, nonproliferative diseases are cardiovascular diseases. In certain embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof, are used to prevent or treat cardiovascular diseases, disorders, or conditions. Cardiovascular diseases, disorders, or conditions may include conditions relating to the heart or vascular system, such as arteries, veins, or blood. Exemplary cardiovascular diseases, disorders, or conditions include angina pectoris, arrhythmias (atrial, ventricular, or both), heart failure, arteriosclerosis, atherosclerosis, atherosclerosis, cardiac hypertrophy, aneurysms of the heart or blood vessels, myocardial cell dysfunction, carotid artery occlusive disease, endothelial injury after PTCA (percutaneous transluminal coronary angioplasty), hypertension including essential hypertension, pulmonary hypertension and secondary hypertension (renal vascular hypertension, chronic glomerulonephritis), myocardial infarction, myocardial ischemia, peripheral occlusive arteriovenous disease of the limbs, organs or tissues; peripheral artery occlusive disease (PAOD), post-ischemia reperfusion injury of the brain, heart or other organs or tissues, restenosis, stroke, thrombosis, transient ischemic attack (TIA), vascular occlusion, vasculitis and vasoconstriction. All types of cardiovascular diseases, disorders, or conditions disclosed herein or known in the art are intended to be within the scope of this disclosure.

[0236] In certain embodiments, nonproliferative disorders are metabolic disorders. In certain embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof, are used to prevent or treat metabolic diseases, disorders, or conditions. Metabolic diseases, disorders, or conditions may include disorders or conditions characterized by abnormal metabolism, such as disorders related to the consumption of food and water, digestion, nutrient processing, and waste removal. Metabolic diseases, disorders, or conditions may include acid-base imbalances, mitochondrial diseases, wasting syndromes, malabsorption, iron metabolism disorders, calcium metabolism disorders, DNA repair deficiencies, glucose metabolism disorders, hyperlactatemia, and gut microbiota disorders. Exemplary metabolic conditions include obesity, diabetes mellitus (type I or type II), insulin resistance, impaired glucose tolerance, lactose intolerance, eczema, hypertension, Hunter syndrome, Krabbe disease, sickle cell anemia, maple syrup urine disease, Pompe disease, and metachromatic leukodystrophy. All types of metabolic disorders, conditions, or conditions disclosed herein or known in the art are intended to fall within the scope of this disclosure.

[0237] In certain embodiments, nonproliferative diseases are respiratory conditions. In certain embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof, are used to prevent or treat respiratory diseases, disorders, or conditions. Respiratory diseases, disorders, or conditions may include disorders or conditions relating to any part of the respiratory system, such as the lungs, alveoli, trachea, bronchi, nasal cavity, or nose. Exemplary respiratory diseases, disorders, or conditions include asthma, allergies, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), lung cancer, oxygen toxicity, emphysema, chronic bronchitis, and acute respiratory distress syndrome. All types of respiratory diseases, disorders, or conditions disclosed herein or known in the art are intended to be within the scope of this disclosure.

[0238] In certain embodiments, nonproliferative diseases are kidney diseases. In certain embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof, are used to prevent or treat kidney diseases, disorders, or conditions. Kidney diseases, disorders, or conditions may include diseases, disorders, or conditions relating to any part of the waste production, storage, and removal system, including the kidneys, ureters, bladder, urethra, adrenal glands, and pelvis. Examples of kidney diseases include acute renal failure, amyloidosis, Alport syndrome, adenovirus nephritis, acute lobar nephropathy, tubular necrosis, glomerulonephritis, kidney stones, urinary tract infections, chronic kidney disease, polycystic kidney disease, and focal segmental glomerulosclerosis (FSGS). In some embodiments, kidney diseases, disorders, or conditions include HIV-associated nephropathy or hypertensive nephropathy. Alternatively, all types of kidney diseases, disorders, or conditions known in the art are intended to fall within the scope of this disclosure.

[0239] In certain embodiments, nonproliferative diseases are infectious diseases. In certain embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof, or compositions comprising such compounds or pharmaceutically acceptable salts thereof, are used to prevent or treat infectious diseases, disorders, or conditions. Infectious diseases may be caused by pathogens such as viruses or bacteria. Exemplary infectious diseases include human immunodeficiency syndrome (HIV), acquired immunodeficiency syndrome (AIDS), meningitis, African sleeping sickness, actinomycosis, pneumonia, botulism, chlamydia, Chagas disease, Colorado tick fever, cholera, typhus, giardiasis, food poisoning, Ebola hemorrhagic fever, diphtheria, dengue fever, gonorrhea, streptococcal infections (e.g., group A or group B), hepatitis A, and hepatitis B. This includes hepatitis C, herpes simplex, hookworm infection, influenza, Epstein-Barr infection, Kawasaki disease, Kuru, leprosy, leishmaniasis, measles, mumps, norovirus, meningococcal disease, malaria, Lyme disease, listeriosis, rabies, rhinovirus, rubella, tetanus, herpes zoster, scarlet fever, scabies, Zika fever, yellow fever, tuberculosis, toxoplasmosis, or tularemia. In some embodiments, the infection includes cytomegalovirus. All types of infectious diseases, disorders, or conditions disclosed herein or known in the art are intended to be within the scope of this disclosure.

[0240] In certain embodiments, the disease, disorder, or condition is a haploinsufficiency disorder. In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a composition comprising such a compound or a pharmaceutically acceptable salt thereof, is used to prevent or treat a haploinsufficiency disorder, disorder, or condition. A haploinsufficiency disorder, disorder, or condition may refer to a monogenic disorder in which an allele of a gene has a loss-of-function lesion, e.g., a complete loss-of-function lesion. In one embodiment, the loss-of-function lesion exists in an autosomal dominant inheritance pattern or results from sporadic events. In one embodiment, the reduction in the function of a gene product due to a modified allele drives the phenotype of the disease despite the presence of a functional allele (i.e., the disease is haploinsufficient with respect to the gene in question). In one embodiment, a compound of formula (I) increases the expression of a haploinsufficiency locus. In one embodiment, a compound of formula (I) increases one or both alleles at a haploinsufficiency locus.Exemplary haploinsufficiency disorders, conditions, and states include Robinow syndrome, cardiomyopathy, cerebellar ataxia, pheochromocytoma, Charcot-Marie-Tooth disease, neurological disorders, Takenouchi-Kozaki syndrome, Coffin-Siris syndrome, chromosome 1p35 deletion syndrome, spinocerebellar ataxia, hearing loss, seizures, dystonia, GLUT1 deficiency syndrome, GLUT1 deficiency syndrome, stomatin deficiency cold hydrocytosis, basal cell carcinoma, basal cell nevus syndrome, medulloblastoma, somatic cell carcinoma, and brain malformations. Macular degeneration, pyramidal-rod dystrophy, Degerin-Sottas disease, hypomyelinous neuropathy, Lucy-Lewy syndrome, glaucoma, autoimmune lymphoproliferative syndrome, pituitary hormone deficiency, epileptic encephalopathy, premature infancy, popliteal fold syndrome, van der Ude syndrome, Loeys-Dietz syndrome, Scravan-Deardorff syndrome, polycythemia, megacephaly / polymicrogyria / polydactyly / hydrocephalus syndrome, intellectual disability, CINCA syndrome, familial common cold and inflammatory syndrome, transient inheritance Endothelial keratoderma, Mackle-Wells syndrome, Finegold syndrome 1, acute myeloid leukemia, Hein-Sproul-Jackson syndrome, Taton-Brown-Rahman syndrome, Shashi-Pena syndrome, spastic paraplegia, autosomal dominant, macrophthalmia, deficiency, with microcornea, holoprosencephalopathy, schizencephaly, endometrial cancer, ...

Claims

[Claim 1] The invention described in the specification.

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